publications

2026

1. ICHOR: A Robust Representation Learning Approach for ASL CBF Maps with Self-Supervised Masked Autoencoders

   Xavier Beltran-Urbano, Yiran Li, Xinglin Zeng, and 10 more authors

   Mar 2026

   Abs arXiv

   

   Arterial spin labeling (ASL) perfusion MRI allows direct quantification of regional cerebral blood flow (CBF) without exogenous contrast, enabling noninvasive measurements that can be repeated without constraints imposed by contrast injection. ASL is increasingly acquired in research studies and clinical MRI protocols. Building on successes in structural imaging, recent efforts have implemented deep learning based methods to improve image quality, enable automated quality control, and derive robust quantitative and predictive biomarkers with ASL derived CBF. However, progress has been limited by variable image quality, substantial inter-site, vendor and protocol differences, and limited availability of labeled datasets needed to train models that generalize across cohorts. To address these challenges, we introduce ICHOR, a self supervised pre-training approach for ASL CBF maps that learns transferable representations using 3D masked autoencoders. ICHOR is pretrained via masked image modeling using a Vision Transformer backbone and can be used as a general-purpose encoder for downstream ASL tasks. For pre-training, we curated one of the largest ASL datasets to date, comprising 11,405 ASL CBF scans from 14 studies spanning multiple sites and acquisition protocols. We evaluated the pre-trained ICHOR encoder on three downstream diagnostic classification tasks and one ASL CBF map quality prediction regression task. Across all evaluations, ICHOR outperformed existing neuroimaging self-supervised pre-training methods adapted to ASL. Pre-trained weights and code will be made publicly available.

2. Temporal Modeling of Amyloid and Tau Trajectories in Alzheimer’s Disease Using PET and Plasma Biomarkers.

   C. A. Brown, K. Cousins, M. Korecka, and 11 more authors

   Annals of neurology, Mar 2026

   Abs DOI

   

   OBJECTIVE This study aimed to compare positron emission tomography (PET) and plasma-based temporal modeling of amyloid and tau biomarkers in Alzheimer’s disease. METHODS Longitudinal amyloid PET (n = 1,097, mean age ± SD = 72.5 ± 7.38 year, 51.4% male), 18F-flortaucipir tau-PET (n = 230, 74.3 ± 7.18 year, 52.2% female), and Fujirebio Lumipulse plasma p-tau217 (n = 752, 72.8 ± 6.93 year, 51.3% male) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and University of Pennsylvania Alzheimer’s Disease Research Center (Penn ADRC) were used to generate biomarker trajectory models using sampled-iterative Local approximation (SILA). SILA models using plasma p-tau217 were compared to amyloid and tau PET-based models to estimate amyloid and tau onset, and factors influencing tau onset and time from tau onset to dementia were evaluated for PET and plasma models. RESULTS Plasma and PET models generated similar results for estimated amyloid and tau onset, with stronger model agreement for tau (r = 0.88[0.86, 0.89], t = 57.4, p < 0.001) than amyloid (r = 0.75[0.72, 0.77], t = 37.4, p < 0.001) onset. Accuracy of estimated onset compared to actual onset was high within modality (mean absolute error [MAE] ≤ 2.03) with slightly greater error (MAE 3.09-3.42) when comparing across modalities (ie, plasma to PET). For both plasma and PET, earlier tau onset was associated with younger amyloid onset, female sex, and ≥1 apolipoprotein (ApoE) ε4 allele. Earlier dementia onset after tau was associated with later tau onset for both plasma and PET, while male sex was associated with shorter tau to dementia gap in plasma models. INTERPRETATION Temporal modeling of plasma biomarkers provides comparable information to PET-based models, particularly for tau onset age, and can serve as a widely accessible tool for clinical assessment of biological disease severity. ANN NEUROL 2026.

3. Discordance of Dopaminergic Dysfunction and Subcortical Atrophy by α-Synuclein Status in Sporadic and Genetic Parkinson’s Disease.

   M. Duong, Sandhitsu R. Das, Pulkit Khandelwal, and 9 more authors

   Movement disorders : official journal of the Movement Disorder Society, Jan 2026

   Cited by 1

   Abs DOI

   

   BACKGROUND Parkinson’s disease (PD) is characterized by predominantly neuronal α-synuclein pathology and dopaminergic dysfunction. Cerebrospinal fluid (CSF) seeding amplification assays (SAA) detect α-synuclein aggregates in vivo, but not all patients with PD have a positive SAA. This pathological heterogeneity among patients may not be entirely captured by binary results from α-synuclein SAA positivity (S+) versus negativity (S-). To further dissect this biological variability, we explored spatial neuroimaging differences in S+ versus S- patients. OBJECTIVE The study aim was to investigate how SAA status influences imaging measures of dopamine denervation and atrophy. METHODS We compare SAA status with CSF proteinopathy markers, 123I-Ioflupane dopamine transporter (DAT), and magnetic resonance imaging (MRI) in participants with sporadic (n = 490), LRRK2-associated (n = 158), and GBA-associated (n = 80) PD from the Parkinson’s Progression Markers Initiative (PPMI). RESULTS Between 64% and 95% of participants in these groups have S+ status. For all groups, S+ participants have decreased putamen DAT neurotransmission compared to S- participants, whereas S- participants have reduced MRI volume in basal ganglia structures relative to S+ participants. With striatal DAT/MRI ratios, S+ participants have disproportionately lower putamen DAT uptake relative to atrophy. In exploratory analyses, participants with cognitive impairment or hyposmia are associated with worse DAT/MRI discordance. By CSF markers, S- participants with sporadic PD have higher CSF pTau181/amyloid-β42 ratio, suggesting Alzheimer’s copathology. CONCLUSIONS S+ patients exhibit more dopaminergic deficit, whereas S- patients have more subcortical atrophy across sporadic and genetic PD. Together, our findings reveal structure/function and DAT/MRI discordance, providing insight into biomarkers and pathophysiology of synucleinopathy and PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

4. Deep learning enhanced ALPS reveals genetic and environmental factors of brain glymphatic function

   Chang-jun Lin, Hao Wu, W. Xian, and 497 more authors

   eBioMedicine, Jan 2026

   Abs DOI

   

   Summary Background The glymphatic system plays a critical role in brain waste clearance and health. Diffusion tensor imaging along the perivascular space (DTI-ALPS) is an emerging approach to assess glymphatic function, but manual analysis is limited by its subjectivity and laboriousness in clinical practice. To address these challenges, we developed a deep learning-enhanced DTI-ALPS (dALPS) method that automates and enhances measurement of DTI-ALPS in large-scale cohorts, enabling us to uncover its genetic and environmental determinants. Methods We proposed an automated workflow combining convolutional neural network (CNN) and You Only Look Once (YOLO) for region-of-interest detection in DTI images. Using this method, we calculated dALPS index for over 65,000 participants from UK Biobank and multiple cohorts, and performed a genome-wide association study (GWAS). Additionally, we conducted transcriptome-wide association study (TWAS) and proteome-wide association study (PWAS) to explore the genetic and molecular underpinnings of glymphatic function. Associations between dALPS and demographic, lifestyle, and clinical traits were comprehensively evaluated. Mediation analysis was conducted to explore the potential mediating role of pharmacological treatments, including antidepressants and sleep medications, in the relationship between disease status and dALPS outcomes. Findings Our automated dALPS index showed excellent reliability and reproducibility compared to conventional manual techniques (intraclass correlation coefficient = 0·95). We observed that the dALPS index was associated with a wide range of body composition measures and brain structures across different age groups and sex. GWAS identified five significant genetic loci associated with dALPS, two of which were replicated in an independent dataset. Subsequent TWAS and PWAS analyses highlighted potential causal genes and proteins linked to brain fluid dynamics. We found that higher healthy lifestyle index (HLI) was positively correlated with improved dALPS, and confirmed the associations between reduced dALPS and various central nervous system (CNS) disorders, including depression, anxiety and neurodegenerative diseases. Notably, mediation analysis indicated that antidepressants were a risk factor for lower brain glymphatic function (P = 0·004) by partly mediating the risk factor of depression. Interpretation The dALPS analysis provides a reliable, precise, and automated biomarker for assessing brain glymphatic function. Our findings illuminate the genetic and environmental determinants of glymphatic activity, underscoring the potential of dALPS in clinical assessment, disease prediction and targeted therapeutic strategies. Funding G.L.’s work is supported by 10.13039/501100001809National Natural Science Foundation of China (No. 32470708, No. 32270701), 10.13039/501100017607Shenzhen Fundamental Research Program (JCYJ20240813151132042), Young Talent Recruitment Project of Guangdong (2019QN01Y139), Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases (ZDSYS20220606100803007) and The Science and Technology Planning Project of Guangdong Province (2023B1212060018). Z.P.’s work is supported by National Natural Science Foundation of China (No. 82271266) and The Shenzhen Medical Research Fund (C2501030).

5. Hippocampal Volume and Brain Tau Pathology in Opioid Use Disorder: Associations with Non-Fatal Opioid Overdose

   Delaney McKinstry, Zhenhao Shi, Astrid P. Ramos-Rolón, and 10 more authors

   Addiction Neuroscience, Jan 2026

   DOI

   

2025

1. Operationalizing postmortem pathology-MRI association studies in Alzheimer’s disease and related disorders with MRI-guided histology sampling

   Chinmayee Athalye, A. Bahena, Pulkit Khandelwal, and 20 more authors

   Acta Neuropathologica Communications, May 2025

   Abs DOI

   

   Postmortem neuropathological examination, while the gold standard for diagnosing neurodegenerative diseases, often relies on limited regional sampling that may miss critical areas affected by Alzheimer’s disease and related disorders. Ultra-high resolution postmortem MRI can help identify regions that fall outside the diagnostic sampling criteria for additional histopathologic evaluation. However, there are no standardized guidelines for integrating histology and MRI in a traditional brain bank. We developed a comprehensive protocol for whole hemisphere postmortem 7T MRI-guided histopathological sampling with whole-slide digital imaging and histopathological analysis, providing a reliable pipeline for high-volume brain banking in heterogeneous brain tissue. Our method uses patient-specific 3D printed molds built from postmortem MRI, allowing standardized tissue processing with a permanent spatial reference frame. To facilitate pathology-MRI association studies, we created a semi-automated MRI to histology registration pipeline and developed a quantitative pathology scoring system using weakly supervised deep learning. We validated this protocol on a cohort of 29 brains with diagnosis on the AD spectrum that revealed correlations between cortical thickness and phosphorylated tau accumulation. This pipeline has broad applicability across neuropathological research and brain banking, facilitating large-scale studies that integrate histology with neuroimaging. The innovations presented here provide a scalable and reproducible approach to studying postmortem brain pathology, with implications for advancing diagnostic and therapeutic strategies for Alzheimer’s disease and related disorders.

2. Epigenetic age acceleration is faster in Black adults and is associated with plasma amyloid

   R. Boyle, Hao Xu, K. Cousins, and 9 more authors

   Alzheimer’s & Dementia, Dec 2025

   Abs DOI

   

   We have previously reported accelerated epigenetic aging in Black individuals relative to White counterparts in a population‐based cohort which further associates with increased cognitive impairment and decline. However, the extent to which this disparity relates to AD in unclear. In a diverse and real‐world clinical dataset, we examined whether there are disparities in accelerated epigenetic aging across self‐identified Black and White adults and the extent to which it associates with AD plasma biomarkers.

3. Alzheimer’s Imaging Consortium.

   Christopher A. Brown, Manuel Taso, Sandhitsu R. Das, and 8 more authors

   Alzheimer’s & dementia : the journal of the Alzheimer’s Association, Dec 2025

   DOI

   
4. Evaluation of Copathology and Clinical Trajectories in Individuals With Tau-Clinical Mismatch

   C. A. Brown, N. S. Mundada, K. Cousins, and 16 more authors

   JAMA Neurology, Dec 2025

   Cited by 1

   Abs DOI

   

   This cohort study investigates if tau-clinical mismatch identifies individuals with copathology and differing clinical trajectories.

5. Fully individualized models for cross-sectional and longitudinal network-based tau spread

   Christopher A. Brown, Sandhitsu R. Das, John A. Detre, and 4 more authors

   Imaging Neuroscience, Dec 2025

   Abs DOI

   

   Abstract Heterogeneity in regional tau burden limits evaluation of disease progression using one-size-fits-all approaches. Prior work using tau positron emission tomography (PET) has highlighted the important role of connectivity to epicenters of tau pathology in explaining this heterogeneity. However, previous studies using population-based epicenters or connectomes fall short of a fully individualized approach to predicting regional tau burden. We use diffusion MRI-derived structural connectomes to assess the prediction of regional tau burden using distance along individual structural connectomes from individualized epicenters of tau pathology both cross-sectionally and longitudinally. Fully individualized models of connectivity and epicenters outperformed models using either population-based connectomes or epicenters in explanation of cross-sectional and longitudinal regional tau burden, improved prediction in validation datasets, and produced stronger single-subject level prediction. Together, these findings demonstrate the power of a fully individualized approach to explain regional tau heterogeneity and provide the strongest in vivo evidence to date for network-based spread of tau pathology.

6. Microstructural and Water Exchange Alterations in ARIA‐E in a Real‐World Cohort Receiving Anti‐Amyloid Therapy

   Christopher A. Brown, Manuel Taso, Sandhitsu R. Das, and 8 more authors

   Alzheimer’s & Dementia, Dec 2025

   Abs DOI

   

   Abstract Background ARIA‐E represents the greatest risk associated with anti‐amyloid therapy (AAT) and is thought to be due to excessive inflammatory response resulting in FLAIR abnormalities on imaging and occasionally symptomatic manifestations. While FLAIR MRI monitoring for ARIA‐E is now routinely performed, additional MRI contrast mechanisms could provide improved detection and mechanistic insights. We investigated perivascular spaces, microstructural alterations, and parenchymal water permeability in a real‐world cohort receiving AAT using novel MRI techniques. Methods Eight participants receiving AAT at the University of Pennsylvania underwent advanced imaging paired with clinical safety MRIs at baseline and during treatment. Advanced imaging sequences included multi‐shell diffusion MRI to assess microstructure, an ultralong TE T2‐weighted sequence to evaluate perivascular spaces structures, and a novel T2‐saturation based water‐exchange sequence. These sequences add <15 minutes to the MRI protocol and can be performed on clinical 3T scanners. We measured microstructure in a composite ROI consisting of cortical regions typically associated with high amyloid deposition as well as in global white matter. Water exchange was calculated specifically in regions that developed ARIA. Results 2 patients developed ARIA‐E after 2 months of treatment that prompted suspension of treatment: (1) mild symptomatic case that went on to develop mild ARIA‐H at 3 months with resolution of ARIA‐E, (2) moderate case that progressed to severe ARIA‐E at 3 months. At baseline these individuals had lower Neurite Density Index (NDI) and Orientation Dispersion Index (ODI) compared to no ARIA (ARIA‐) patients (Figure 1). At 2 months, they had marked increases in NDI and ODI that resolved by 3 months (Figure 2A). In contrast, there was gradual increase in water exchange and white matter free water fraction (FWF) at 2 and 3 months compared to ARIA‐ (Figure 2B). ARIA‐E and ARIA‐H is also readily visualized on water exchange sensitive maps (Figure 3). Quantification of perivascular volume is ongoing. Conclusion Measures of water diffusion and exchange enhance our understanding of ARIA with findings consistent with transient increases in cellularity at ARIA onset and prolonged increases in parenchymal water permeability and edema. Early results suggest microstructure could predict risk for future ARIA. Additional data collection continues.

7. Tau Burden is Best Captured by Magnitude and Extent: Tau-MaX as a Measure of Global Tau

   Christopher A. Brown, Sandhitsu R. Das, K. Cousins, and 9 more authors

   medRxiv, Jan 2025

   Cited by 8

   Abs DOI PDF

   

   Tau exhibits change in both spatial extent and density of pathology along the Alzheimer’s disease (AD) spectrum with each aspect contributing to the overall burden of pathological tau. Nevertheless, studies using Tau PET have measured either magnitude using standardized uptake value ratios (SUVRs) or extent using number of Tau+ regions. We hypothesized that combining these two dimensions into a single measure of Magnitude and eXtent, Tau-MaX, would provide improved quantification of global tau burden as well as allowing for a region-agnostic measure of global tau burden that does not require a pre-specified region of interest (ROI) or meta-ROI. To test this hypothesis, we analyzed 18F-flortaucipir PET scans from local and national consortium data (n=1077 participants total) and used Gaussian-mixture models for data from 64 brain regions, to define both tau positivity and magnitude. We examined cross-sectional and longitudinal change in Tau-MaX across the Alzheimer’s disease (AD) spectrum and compared the association of Tau-MaX, magnitude, and extent with plasma p-tau217 and global cognition. We also compared Tau-MaX using a global, region-agnostic approach to temporal lobe or Braak stage meta-ROIs. Whereas separate assessments of extent and magnitude across the disease spectrum found earlier increases in Tau spatial extent and later increases in magnitude, Tau-MaX was able to dynamically capture this shift demonstrating a stronger association with extent in the preclinical stage and a stronger association with magnitude in clinical stages. Global Tau-MaX differed between disease stages cross-sectionally and changed over time in all stages of disease. Further, Tau-MaX significantly improved associations with plasma p-tau217 and global cognition compared to magnitude or extent alone. Finally, global measures of Tau-MaX performed similarly to meta-ROI measures of Tau-MaX. Together, these findings indicate that combining magnitude and extent provides a robust measure of global tau burden that changes throughout the disease course and is associated with blood-based biomarkers and cognition. This measure may be of particular use for disease staging, as well as serving as an outcome measure to monitor response to therapeutic intervention.

8. Tau Cognitive Mismatch in Alzheimer’s Disease Predicts Presence of Co‐Pathology and Diverging Disease Trajectory

   Christopher A. Brown, Sandhitsu R. Das, K. Cousins, and 13 more authors

   Alzheimer’s & Dementia, Dec 2025

   Abs DOI

   

   Abstract Background The revised Alzheimer’s disease staging criteria use the concept of biological‐clinical mismatch with an expected, canonical progression; identifying individuals who have greater clinical impairment than expected for their biological stage as vulnerable or less impairment than expected as resilient. Here we used T1 (plasma p‐tau217) and T2 (18F‐flortaucipir PET) biomarkers to identify mismatch with global clinical severity measured by the CDR‐SB scale. We then investigated differences in brain structure, alpha synuclein positivity, and longitudinal trajectories of cognition, tau accumulation, and atrophy between canonical, vulnerable and resilient groups. Methods Amyloid positive ADNI participants with available Tau PET (n = 373) or p‐tau217 (n = 392) and CDR‐SB score were included. Mismatch was defined using linear regression between global measures of tau burden, using a composite score of PET binding intensity and extent (Tau‐MaX) or p‐tau217, and CDR‐SB to divide individuals into canonical, vulnerable, and resilient groups. We investigated differences in medial temporal lobe (MTL) structure measured using T1‐ASHS, brain‐wide thickness differences using ANTs, and α‐synuclein status measured with CSF seed amplification assay after controlling for age, sex, education, and global tau burden. We examined longitudinal tau PET, atrophy, and cognitive trajectories between mismatch groups using linear mixed models controlling for age, sex, education, and global tau burden. Finally, we applied the mismatch model generated in ADNI to our local Penn ADRC dataset (n = 160) for replication. Results Both Tau‐MaX and p‐tau217 were moderately associated with CDR‐SB (Figure 1A). Vulnerable individuals had greater neurodegeneration in anterior MTL and temporolimbic regions compared to canonical and resilient groups (Figure 1B‐C), as well as higher prevalence of α‐synuclein co‐pathology (Figure 1D). The vulnerable group showed accelerated cognitive decline even after controlling for rate of tau accumulation, which minimally differed by group (Figure 2A). Vulnerable participants also had accelerated atrophy in MTL and temporolimbic regions (Figure 2B‐C). Results in the Penn ADRC dataset (Figure 3A) were consistent with the ADNI dataset findings (Figure 3B‐D). Conclusions Tau‐cognitive mismatch identifies vulnerable individuals who are more likely to have α‐synuclein co‐pathology and neurodegeneration patterns that overlap with LATE. The plasma‐based models also successfully identified similar vulnerable individuals in an independent dataset.

9. Tau burden is best captured by magnitude and extent: Tau‐MaX as a measure of global tau

   Christopher A. Brown, Sandhitsu R. Das, K. Cousins, and 9 more authors

   Alzheimer’s & Dementia, Jul 2025

   Cited by 2

   Abs DOI

   

   Tau burden consists of both spatial spread and local accumulation, but no study has combined these measures into a single metric to capture overall global tau burden. Here we investigate a new measure combining magnitude and extent—Tau‐MaX—as a marker of Alzheimer’s disease (AD) severity.

10. Tau-Clinical Mismatch Identifies Individuals with Co-Pathology and Predicts Clinical Trajectory

    C. A. Brown, N. S. Mundada, K. Cousins, and 17 more authors

    medRxiv, Jul 2025

    Abs DOI

    

    Importance: The heterogeneous course of Alzheimer’s disease makes it difficult to predict individuals’ cognitive trajectories, which is particularly important in the era of disease modifying therapy. Identifying individuals more likely to have co-pathology and differing disease courses using clinically practical tools remains a critical gap. Objective: To evaluate tau-clinical mismatch for identifying resilient and vulnerable individuals and compare levels of co-pathology and clinical trajectories between groups. Design, Setting, and Participants: Participants were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, inclusion from 2005-2024), Penn Alzheimer’s Disease Research Center Cohort (Penn-ADRC, inclusion from 2002-2025), and Penn Anti-amyloid Therapy Monitoring (Penn-ATM) cohort (inclusion from 2024-2025). All participants were amyloid-beta positive, had clinical assessment, and measures of Tau-PET or plasma p-tau217 available. Exposures: Clinical assessment (CDR-SB) and tau burden (tau-PET or p-tau217) for mismatch group classification. Main Outcomes and Measures: Cross-sectional measures of neurodegeneration (medial temporal lobe volume and thickness, cortical thickness, TAR DNA-binding protein 43 [TDP-43] imaging signature), -synuclein cerebrospinal fluid seed-amplification assay, longitudinal CDR-SB Results: 365 ADNI Tau-PET participants (ages 55-93, 52.6% women) and 524 ADNI p-tau217 participants (ages 56-95, 49.0% women) were used to generate tau-clinical mismatch models with 55.6-57.1% classified as canonical (CDR-SB   Tau), 23.7-24.7% as resilient (CDR-SB < Tau), and 19.3-19.7% as vulnerable (CDR-SB > Tau). Groups showed diverging clinical courses with earlier cognitive impairment seen in vulnerable groups and later impairment in resilient groups. Vulnerable groups showed higher frequencies of co-pathology, with TDP-43 neurodegeneration patterns and -synuclein positivity. Similar findings were seen when applying these models to an independent dataset of 244 individuals (54-92 age, 57.0% women) in Penn-ADRC. Finally, these models were applied to a cohort receiving anti-amyloid therapy to show the utility of this method for predicting individual cognitive trajectories during therapy. Conclusion and Relevance: Tau-clinical mismatch identifies individuals more likely to harbor co-pathology and have diverging clinical trajectories. Plasma-based models produced similar results to Tau-PET models and could be replicated in independent datasets. These models provide an important tool that can be implemented in clinical practice to provide improved individualized prognosis and, potentially, monitoring of response to disease-modifying therapy.

11. Temporal Modeling of Amyloid and Tau Trajectories in Alzheimer’s Disease using PET and Plasma Biomarkers

    Christopher A. Brown, K. Cousins, M. Korecka, and 11 more authors

    medRxiv, Sep 2025

    Abs DOI

    

    Objective: To compare PET and plasma-based temporal modeling of amyloid and tau biomarkers in Alzheimer’s disease Methods: Longitudinal amyloid PET, 18F-flortaucipir tau-PET, and Fujirebio Lumipulse plasma p-tau217 from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and University of Pennsylvania Alzheimer’s Disease Research Center (Penn ADRC) were used to generate biomarker trajectory models using Sampled Iterative Local Approximation (SILA). SILA models using plasma p-tau217 were compared to amyloid and tau PET-based models to estimate tau onset age (ETOA) and estimate amyloid onset age (EAOA), and factors influencing ETOA and time from ETOA to dementia were evaluated for PET and plasma-based models. Results: Plasma-based models generated similar results to PET for EAOA and ETOA, with stronger model agreement for ETOA than EAOA. Accuracy of estimated onset age compared to actual onset age was high within modality with slightly greater error when comparing across modalities (i.e. plasma to PET). For both plasma and PET models, earlier ETOA was associated with younger EAOA, female sex, and [≥]1 ApoE epsilon4 allele. Earlier dementia onset after ETOA was associated with later ETOA for both plasma and PET models, while male sex was associated with shorter tau to dementia gap in plasma models. Interpretation: Temporal modeling of plasma biomarkers provides comparable information to PET-based models, particularly for tau onset age. Plasma-based temporal modeling can serve as a widely accessible tool for clinical assessment of biological disease duration that places the patient on the disease timeline, which may allow for improved discussion of prognosis and treatment decisions.

12. Medial temporal lobe atrophy in Down syndrome along the Alzheimer’s disease continuum.

    B. Buehner, Alejandra O. Morcillo‐Nieto, Sara E. Zsadanyi, and 23 more authors

    Brain : a journal of neurology, Apr 2025

    Cited by 3

    Abs DOI

    

    Medial temporal lobe structures are among the first areas impacted by neurofibrillary tangle pathology, making volumetric changes of these areas promising biomarkers for Alzheimer’s disease. To date, little is known about the integrity of these regions in individuals with Down syndrome, a population which almost invariably develops Alzheimer’s disease and thus offers a unique opportunity to determine the earliest structural changes related to the disease. We aimed to characterize the sequential involvement of medial temporal lobe structures with Alzheimer’s disease progression, explore associations with fluid biomarkers of Alzheimer’s pathology, and assess the utility of regional volumes and cortical thickness in distinguishing Alzheimer’s disease clinical stages in Down syndrome. 138 euploid controls and 259 adults with Down syndrome underwent clinical assessment and MRI scanning, followed by automated segmentation of the medial temporal lobe on T1-weighted images. Parametric statistical tests and local regression models were used to assess the cross-sectional association between regional volumes/cortical thickness and Alzheimer’s disease clinical stage, estimated years of onset, and CSF biomarkers. Additionally, markers were assessed in their ability to distinguish clinical stages using area under the receiver-operating characteristic curves. Results showed a progressive loss of volume and cortical thickness in medial temporal lobe with advancing Alzheimer’s disease stage, showing reduced volume/thickness at the dementia stage in all subregions. The asymptomatic and prodromal groups showed significant differences in the anterior and posterior hippocampus. We identified the entorhinal cortex and posterior hippocampus as the regions showing the earliest loss in Down syndrome, starting 13-15 years before Alzheimer’s disease symptom onset. We observed non-linear structural changes with disease progression, with certain structures (e.g., the parahippocampal cortex) characterized by an initial increase in cortical thickness followed by subsequent thinning. Of all subregions, the hippocampal volumes showed the closest correlation to CSF Aβ42/40, pTau181, and neurofilament light chain levels. Further analyses demonstrated a high predictive value, similar to CSF biomarkers, of the hippocampus in differentiating between individuals with asymptomatic versus prodromal/demented Alzheimer’s disease in Down syndrome. This study provides a novel understanding of the progressive, non-linear volumetric changes of medial temporal lobe structures in relation to Alzheimer’s disease pathology in Down syndrome, which can have important implications for clinical trials monitoring neurodegeneration using MRI. We also show that MRI information can refine the prediction of clinical status in Down syndrome. This is particularly relevant in Down syndrome, where early clinical stages can be challenging to detect due to neurodevelopmental intellectual disability.

13. Electronic Health Records to Test Multimorbidity Influences to Plasma Biomarker Interpretation for Alzheimer’s Disease

    K. Cousins, R. Boyle, Colleen Morse, and 9 more authors

    Annals of Neurology, Dec 2025

    Cited by 1

    Abs DOI

    

    Plasma biomarkers of Alzheimer’s disease (AD) pathology are frequently tested in specialized research settings, which limits the generalizability of findings. Using electronic health records and banked plasma, we evaluated plasma biomarkers—phosphorylated tau 217 (p‐tau217), β‐amyloid 1–42/1–40 (Aβ42/Aβ40) and p‐tau217/Aβ42—in a real‐world, diverse clinical population with multimorbidities.

14. Developing Topics.

    Sandhitsu R. Das, Christopher D. Brown, P. Cook, and 7 more authors

    Alzheimer’s & dementia : the journal of the Alzheimer’s Association, Dec 2025

    DOI

    
15. Brain telomere length associates with hippocampal ptau and is mediated by DNA methylation

    Nadia Dehghani, Qijun Chen, Anil R Wadhwani, and 13 more authors

    Alzheimer’s & Dementia, Dec 2025

    Abs DOI

    

    Telomeres are repetitive DNA sequences at the ends of chromosomes which contribute to maintaining chromosomal stability. Telomere shortening is a hallmark of aging and shorter blood leukocyte telomere length (LTL) has been associated with increased risk for age‐related diseases, however, little is understood about the biology of brain telomeres and how they may be involved in disease. Considering the increased neuropathologic burden of phosphorylated tau (ptau) with age, we investigated how shorter brain telomere length (brain‐TL) may relate to increased ptau burden.

16. Developing Topics.

    Sheina Emrani, Eric Teunissen‐Bermeo, W. Trotman, and 11 more authors

    Alzheimer’s & dementia : the journal of the Alzheimer’s Association, Dec 2025

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17. Exploring the Influence of SSDOH and Self‐Identified Race on Resilience and Vulnerability using Machine Learning for NACC UDS

    E. Fischer, Zahra Khodakarami, Christopher A. Brown, and 4 more authors

    Alzheimer’s & Dementia, Dec 2025

    Abs DOI

    

    Current cognitive analysis methods in neurodegenerative disease rely on the use of individual neuropsychological assessments, which can be subject to variation and bias. A potentially more robust way to represent cognitive status is to use a cognitive age model to predict an individual’s age from their cognitive assessment scores and demographics. This modeling allows for identification of individuals exhibiting resilience or vulnerability to normal aging processes across diverse datasets.

18. Fully automated segmentation of the locus coeruleus: application to assess the effects of age, sex and education

    R. Flores, T. Blanchard, E. Foyard, and 8 more authors

    medRxiv, Jan 2025

    Abs DOI PDF

    

    Background:Locus coeruleus (LC) imaging using neuromelanin-sensitive (NM) MRI sequences is a promising biomarker for detecting early Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). Although semi or fully automatic approaches have been developed to estimate LC integrity by measuring its intensity, these techniques most often rely on a single template built in a standardized space and/or depend on a number of voxels to be accounted that is defined a priori. Thus, these algorithms make it impossible to perform direct volumetric analyses and do not properly account for inter-individual anatomical variability. To fill this gap, our aim was to develop a new multi-atlas fully automated segmentation method using the Automatic Segmentation of Hippocampal Subfields (ASHS) software. A second aim was to investigate the effects of age, sex and education on LC intensity and volume. Method: We used cross-sectional data from 101 cognitively unimpaired older adults (mean age: 73.8+/-6.6 years; mean education: 13.2+/-3.0 years; 58 women, 43 men) from the Age-Well randomized controlled trial for whom high-resolution NM-MRI (T1-w with magnetization transfer; 0.3x0.3x0.75mm3) and standard T1-w MRI (1x1x1mm3) were available. The LC were manually segmented in 30 randomly selected participants on NM-MRI, and the standard T1-w MRI, NM-MRI and bilateral segmentations were fed into the ASHS training pipeline to generate a new atlas (ASHS-LC). ASHS-LC was applied to the 71 remaining subjects to segment the LC and we assessed the effects of age, sex and education on both i) LC intensity (normalized by the intensity of the pons) and ii) LC volume (normalized by the total intracranial volume). Result: Five-fold cross-validation experiments revealed high accuracy of the automatic segmentation relative to manual segmentation (Dice coefficient 0,83+/-0,04). ICCs demonstrated excellent reliability for intensity (ICC = 0.99), whereas reliability for volume was lower (ICC = 0.43). LC intensity was significantly higher in women than in men (Cohen’s d = 0.94, p < 0.001) while no associations with age (beta = -0.0002, p = 0.98) or education (beta = 0.11, p = 0.37) were found. In contrast, LC volume was not different between men and women (Cohen’s d = 0.10, p= 0.55) but was significantly negatively associated with age (beta = -0.25, p = 0.04) and education (beta = -0.27, p = 0.04). Lastly, LC intensity and volume were not statistically correlated, neither using manual segmentation (atlas set: beta = 0.05, p = 0.78) nor ASHS segmentation (atlas set: beta = 0.11, p = 0.57; analysis set: beta = -0.07, p = 0.55). Conclusion: Overall, this new method allows to automatically and accurately segment the LC and offers the opportunity to measure its integrity both in terms of intensity and volume. This is of importance since these two metrics may offer complementary insights into LC integrity, as evidenced by the differing influences of demographic factors on LC intensity and volume.

19. Streamlining 4D Cardiac Image Workflows: Open-Source Tools for Segmentation, Registration, and Visualization

    Jilei Hao, Paul Yushkevich, Ningjun J. Dong, and 5 more authors

    Functional imaging and modeling of the heart : ... International Workshop, FIMH ..., proceedings. FIMH, Jun 2025

    DOI

    
20. Integrating individualized connectome with amyloid pathology improves predictive modeling of future cognitive decline

    Hengda He, Q. Razlighi, Y. Gazes, and 160 more authors

    Communications Medicine, Dec 2025

    Cited by 1

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    The deposition of amyloid-β (Aβ) in the human brain is a hallmark of Alzheimer’s disease and is associated with cognitive decline. Aβ pathology is traditionally assessed at the whole-brain level across neocortical regions using positron emission tomography (PET). However, these measures often show weak associations with future cognitive impairment. A more sensitive pathology metric is needed to quantify early Aβ burden and better predict cognitive decline. Here, we aim to develop a network-based metric of Aβ burden to improve early prediction of cognitive decline in aging populations. We integrated subject-specific brain connectome information with Aβ-PET measures to construct a network-based metric of Aβ burden. Cross-validated predictive modeling was used to evaluate the performance of this metric in predicting longitudinal cognitive decline. Furthermore, we identified a neuropathological signature pattern linked to future cognitive decline, and we validated this pattern in an independent cohort. Our results demonstrate that incorporating individualized structural connectome, but not functional connectome, information into Aβ measures enhances predictive performance for prospective cognitive decline. The identified neuropathological signature pattern is reproducible across cohorts. These findings advance our understanding of the spatial patterns of Aβ pathology and its relationship to brain networks, highlighting the potential of connectome-informed network-based metrics for Aβ-PET imaging in identifying individuals at higher risk of cognitive decline. Amyloid-β peptide is a molecule that is known to accumulate in the brains of people with Alzheimer’s disease. This accumulation starts to occur many years before the symptoms of Alzheimer’s disease, such as memory problems. Current methods to image the brain for amyloid-β peptide usually measure the overall level across the whole brain. In this study, we developed a more sensitive and personalized measure of amyloid-β by also considering how the different parts of a person’s brain are connected. We found that this approach improves the ability to predict future changes in cognition compared to the standard method. Our method might enable earlier identification of people at risk of developing Alzheimer’s disease, which could improve monitoring and treatment. He et al. develop a network-based metric of amyloid-β burden by integrating individualized brain connectomes with amyloid-PET imaging. This approach improves prediction of future cognitive decline in older adults and may support earlier identification of individuals at risk of dementia.

21. BOLD amplitude correlates of preclinical Alzheimer’s disease.

    S. Hrybouski, Sandhitsu R. Das, L. Xie, and 7 more authors

    Neurobiology of aging, Mar 2025

    Cited by 1

    Abs DOI

    

    Alzheimer’s disease (AD) is characterized by a long preclinical stage during which molecular markers of amyloid beta and tau pathology rise, but there is minimal neurodegeneration or cognitive decline. Previous literature suggests that measures of brain function might be more sensitive to neuropathologic burden during the preclinical stage of AD than conventional measures of macrostructure, such as cortical thickness. Among studies that used resting-state functional Magnetic Resonance Imaging (fMRI) acquisitions with Blood Oxygenation Level Dependent (BOLD) contrast, most employed connectivity-based analytic approaches. Consequently, little is known about the effects of amyloid and tau pathology on amplitude of intrinsic BOLD signal fluctuations. To address this knowledge gap, we characterized the effects of preclinical and prodromal AD on the amplitude of low-frequency fluctuations (ALFF) of the BOLD signal both at the whole-brain level and at a more granular level focused on subregions of the medial temporal lobe. We observed reduced ALFF in both preclinical and prodromal AD. In preclinical AD, amyloid positivity was associated with a spatially diffuse ALFF reduction in the frontal, medial parietal, and lateral temporal association cortices. In contrast, tau pathology was negatively associated with ALFF in the entorhinal cortex. These ALFF effects were observed in the absence of observable macrostructural changes in preclinical AD and remained after adjusting for structural atrophy in prodromal AD, indicating that ALFF offers additional sensitivity to early disease processes beyond what is provided by traditional structural imaging biomarkers of neurodegeneration. We conclude that ALFF may be a promising imaging-based biomarker in preclinical AD.

22. Relationships of PGRN with sTREM2 in AD continuum and non-AD pathophysiology and their reciprocal roles in modulating amyloid pathology: two population-based study

    Liang-Yu Huang, Chen-Chen Tan, Wei Xu, and 456 more authors

    Translational Psychiatry, Jul 2025

    Cited by 3

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    Progranulin (PGRN) and soluble triggering receptor expressed on myeloid cells-2 (sTREM2) are emerging biomarkers of Alzheimer’s disease (AD). This study explores the roles of their interplay in modulating amyloid pathology. We analyzed data from 905 participants (mean age = 62.0) in the CABLE cohort and 973 participants (mean age = 73.1) in the ADNI, classified using the A/T/N biomarker framework. One-way ANOVA was used to assess whether cerebrospinal fluid (CSF) PGRN and sTREM2 differed across biomarker profiles and clinical stages. Multiple linear regression models and linear mixed-effects models were used to test the relationships among PGRN, sTREM2, and CSF Aβ1–42 levels. Mediation analysis was used to explore the reciprocal relationships between sTREM2 and PGRN in influencing amyloid pathology. CSF proteomic and bioinformatic analyses were finally used to investigate the underlying biological mechanisms. In both cohorts, PGRN and sTREM2 were higher in individuals within the TN+ profile irrespective of the A status, and followed similar trajectory across different clinical and biomarker stage. CSF PGRN was associated with higher sTREM2 across AD continuum and non-AD pathophysiology. Bidirectional mediation was observed between PGRN (14.6% in CABLE, 15.6% in ADNI) and sTREM2 (29.7% in CABLE, 33.5% in ADNI) in modulating Aβ pathology (p < 0.0001). Proteomic analysis identified 1539 CSF proteins (Bonferroni-corrected p < 7.13 × 10−6) simultaneously associated with PGRN, sTREM2, and Aβ1–42. These proteins are mainly enriched in immune processes and neural plasticity. These findings suggest that the interplay between lysosome function and microglia-related neuroinflammation plays key roles in amyloid metabolism.

23. Challenges and best practices when using ComBAT to harmonize diffusion MRI data

    Pierre-Marc Jodoin, Manon Edde, Gabriel Girard, and 163 more authors

    Scientific Reports, Nov 2025

    Cited by 2

    Abs DOI

    

    Over the years, ComBAT has become the standard method for harmonizing MRI-derived measurements, with its ability to compensate for site-related additive and multiplicative biases while preserving biological variability. However, ComBAT relies on a set of assumptions that, when violated, can result in flawed harmonization. In this paper, we thoroughly review ComBAT’s mathematical foundation, outlining these assumptions, and exploring their implications for the demographic composition necessary for optimal results. Through a series of experiments involving a slightly modified version of ComBAT called Pairwise-ComBAT tailored for normative modeling applications, we assess the impact of various population characteristics, including population size, age distribution, the absence of certain covariates, and the magnitude of additive and multiplicative factors. Based on these experiments, we present five essential recommendations that should be carefully considered to enhance consistency and supporting reproducibility, two essential factors for open science, collaborative research, and real-life clinical deployment.

24. Alzheimer’s Imaging Consortium.

    Pulkit Khandelwal, M. Duong, Lisa Levorse, and 22 more authors

    Alzheimer’s & dementia : the journal of the Alzheimer’s Association, Dec 2025

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25. High‐resolution postmortem 7 tesla MRI yields localized atrophy measures that are more sensitive to tau pathology and neuronal loss in Alzheimer’s disease than corresponding measures on antemortem 3 tesla MRI

    Pulkit Khandelwal, M. Duong, Lisa Levorse, and 22 more authors

    Alzheimer’s & Dementia, Dec 2025

    Abs DOI

    

    Abstract Background Postmortem MRI has opened‐up avenues to study brain structure at ultra high‐resolution revealing details not possible to observe with in vivo MRI. Here, we present a novel package (purple‐mri) which performs tissue segmentation, anatomical parcellation and spatial normalization of postmortem MRI. Additionally, we provide a framework to perform point‐wise surface‐based group‐level studies linking morphometry/histopathology in common coordinate system for postmortem MRI. Method We developed a joint voxel‐ and surface‐based pipeline combining deep learning with classical techniques for topology correction, cortical modeling, inflation, and registration for accurate parcellation of postmortem cerebral hemispheres (Figure 1 Khandelwal et al. 2024). Furthermore, using the GM/WM segmentations derived from postmortem hemisphere and FreeSurfer‐processed antemortem MRI, we performed deformable image registration between the ante‐ and postmortem MRI for each brain specimen. To demonstrate the utility of purple‐mri, point‐wise analysis was performed to correlate thickness (mm) with tau and neuronal loss distribution in corresponding specimens (N = 49) of postmortem (7T at 0.3mm3) and antemortem (3T at 0.8mm3) MRI (Table 1) within the AD continuum diagnosis. An additional 26 postmortem 7T scans without corresponding antemortem scans were included in some analyses. The semi‐quantitative average tau and neuronal loss ratings were derived from histopathological examination across the brain. All analyses include age, sex, and postmortem (or antemortem) interval as covariates. Result Our method parcellates postmortem brain hemisphere using a variety of brain atlases even in areas with low contrast (anterior/posterior regions), profound imaging artifacts and severely atrophied brains (Figure 1). Our registration pipeline provides one‐to‐one correspondence between the two modalities. For thickness/pathology associations (Figure 2), small sparse significant clusters only in superior temporal cortex and precuneus in antemortem MRI (N = 49) were observed. However, postmortem MRI showed much stronger associations across large clusters in temporal, entorhinal cortex, and cingulate for both the matched cases (N = 49) and the full cohort (N = 75), regions implicated in ADRD. Conclusion Purple‐mri paves the way for large‐scale postmortem image analysis. Stronger associations between thickness and average tau burden/neuronal loss than antemortem MRI suggests that our pipeline could inform the development of more precise and sensitive invivo biomarkers by mapping information from postmortem to antemortem MRI in a common reference coordinate system.

26. Segmentation and registration of within‐subject 7 tesla ex vivo and 3 tesla in situ MRI to increase sensitivity of imaging biomarkers

    Pulkit Khandelwal, Sydney A. Lim, W. V. D. Berg, and 3 more authors

    Alzheimer’s & Dementia, Dec 2025

    Abs DOI

    

    Understanding pathological contribution in mixed etiology dementia and atypical Alzheimer’s disease remains challenging. However, in‐vivo MRI and neuropathology studies are hampered by the years of delay between MRI and brain autopsy. Postmortem in‐situ MRI is a good proxy to mitigate this problem (Frigerio et al. 2021) but is logistically challenging. Ex‐vivo MRI offers significant higher anatomical resolution but is influenced by fixation and possible deformation. Therefore, we propose a whole‐hemisphere ex‐vivo to in‐situ/in‐vivo parcellation and registration pipeline “purple‐mri” (Khandelwal et al. 2024) to cater multi‐resolution, translation, and clinical relevance for T2w 7T 0.3 mm3 exvivo and T1w 3T 1x0.5x0.5 mm3 insitu MRI in 21 (age: 57‐88 years; F=9/M=12) control specimens (Table 1).

27. VIOLET: Volumetric Image registration via Optimization and Learning for Efficient image Translation

    Pulkit Khandelwal, M. Duong, Lisa Levorse, and 24 more authors

    In SASHIMI@MICCAI 2025, Dec 2025

    DOI

    
28. Assessing white matter hyperintensities on matched antemortem and postmortem MRI

    Zahra Khodakarami, Pulkit Khandelwal, M. Duong, and 19 more authors

    Alzheimer’s & Dementia, Dec 2025

    Abs DOI

    

    Abstract Background Postmortem MRI offers superior spatial resolution and contrast compared to antemortem MRI, enabling analysis of pathological processes underlying white matter hyperintensities (WMH). However, its correlation with antemortem WMH remains unclear due to postmortem changes, fixation effects, and tissue dehydration. This study compares WMH burden on antemortem and postmortem MRI in the same individuals to assess the suitability of postmortem MRI for structure‐pathology association studies. Method 7T T2‐weighted postmortem and 3T FLAIR antemortem MRIs were acquired from 41 individuals (Table 1). WMH segmentations were generated using Purple‐MRI for postmortem MRI and WMH‐SynthSeg for antemortem MRI (Figure 1). One hemisphere was scanned postmortem, and the corresponding antemortem hemisphere was used for WMH segmentation. Linear regression models examined (I) Antemortem WMH volume as a predictor of postmortem WMH, (II) age at scan as a predictor of antemortem WMH volume, and (III) age at death as a predictor of postmortem WMH volume. Nuisance covariates included antemortem/postmortem intervals (AMI/PMI) and fixation time, as appropriate. Result Table 1 provides a breakdown of demographics and neuropathological diagnoses. A moderate, statistically significant correlation was found between antemortem and postmortem WMH volume (r = 0.47, p = 0.002;Figure 2), remaining significant after adjusting for age and nuisance covariates (Table 1). Both antemortem and postmortem WMH volumes were significantly associated with age (Table 4 [antemortem MRI] and 3 [postmortem MRI]), with a greater antemortem association in absolute terms (t=2.8 vs. t=2.58, n.s.). Other covariates were not significant. Postmortem WMH volume was, on average, 102±121% higher than antemortem, with only a weak association between their relative difference and AMI (r=0.27, p = 0.04), suggesting that WMH increase is due to greater lesion visibility in postmortem MRI rather than WMH growth. This aligns with histological findings showing WMH‐linked pathology in surrounding normal‐appearing white matter. Conclusion This study highlights both a significant association between antemortem and postmortem WMH volume, and a significant bias towards larger WMH in postmortem MRI, above and beyond factors like AMI and fixation time. In subsequent work, we will use matched MRI and histology to study the contribution of vascular and neurodegenerative pathologies to the extent and appearance of WMH on antemortem and postmortem MRI.

29. Achieving detailed medial temporal lobe segmentation with upsampled isotropic training from implicit neural representation

    Yue Li, Pulkit Khandelwal, Rohit Jena, and 8 more authors

    Aug 2025

    Abs arXiv

    

    Imaging biomarkers in magnetic resonance imaging (MRI) are important tools for diagnosing, tracking and treating Alzheimer’s disease (AD). Neurofibrillary tau pathology in AD is closely linked to neurodegeneration and generally follows a pattern of spread in the brain, with early stages involving subregions of the medial temporal lobe (MTL). Accurate segmentation of MTL subregions is needed to extract granular biomarkers of AD progression. MTL subregions are often imaged using T2-weighted (T2w) MRI scans that are highly anisotropic due to constraints of MRI physics and image acquisition, making it difficult to reliably model MTL subregions geometrically and extract morphological measures, such as thickness. In this study, we used an implicit neural representation method to combine isotropic T1-weighted (T1w) and anisotropic T2w MRI to upsample an atlas set of expert-annotated MTL subregions, establishing a multi-modality, high-resolution training set of isotropic data for automatic segmentation with the nnU-Net framework. In an independent test set, the morphological measures extracted using this isotropic model showed stronger effect sizes than models trained on anisotropic in distinguishing participants with mild cognitive impairment (MCI) and cognitively unimpaired individuals. In test-retest analysis, morphological measures extracted using the isotropic model had greater stability. This study demonstrates improved reliability of MRI-derived MTL subregion biomarkers without additional atlas annotation effort, which may more accurately quantify and track the relationship between AD pathology and brain atrophy for monitoring disease progression.

30. Imaging Biomarkers for Neurodegenerative Diseases from Detailed Segmentation of Medial Temporal Lobe Subregions on in vivo Brain MRI Using Upsampling Strategy Guided by High-resolution ex vivo MRI

    Yue Li, Pulkit Khandelwal, L. Xie, and 8 more authors

    Apr 2025

    Abs arXiv

    

    The medial temporal lobe (MTL) is a region impacted extensively and non-uniformly in early stages of Alzheimer’s disease (AD). Regional MTL morphometric measures extracted from magnetic resonance imaging (MRI) are supportive features for the diagnosis of AD and related disorders (ADRD). Different MRI modalities have distinct advantages for MTL morphometry. Anisotropic T2-weighted (T2w) MRI is preferred for hippocampal subfields due to its higher contrast between hippocampal layers. Isotropic T1-weighted (T1w) MRI is beneficial for thickness calculation of extra-hippocampal subregions due to its stable image quality and isotropic resolution. We propose a multi-modality MTL segmentation algorithm that bridges the T1w and T2w modalities by bringing both to a nearly isotropic voxel space. Guided by high-resolution ex vivo 9.4T MRI, an upsampling model was designed for the ground truth segmentations. Combined with non-local means upsampling, this model was used to construct a nearly iso-tropic T1w and T2w MTL subregion segmentation training set, which was used to train a nnUNet model. Morphometric biomarkers extracted by this model were compared to those extracted using conventional models operating in anisotropic spaces on downstream tasks. Biomarkers extracted using the proposed model had greater ability to discriminate between individuals with mild cognitive impairment and cognitively unimpaired; and had great-er longitudinal stability. These findings suggest that the biomarkers derived from T1w and T2w MRI unsampled to nearly isotropic resolution have sig-nificant potential for improving disease diagnosis and monitoring disease progression in ADRD.

31. Segmentation of medial temporal lobe subregions in a nearly isotropic space using T2‐weighted MRI with anisotropic resolution

    Yue Li, Pulkit Khandelwal, L. Xie, and 8 more authors

    Alzheimer’s & Dementia, Dec 2025

    Abs DOI

    

    Abstract Background Morphometry of medial temporal lobe (MTL) subregions in brain MRI is sensitive biomarker to Alzheimer’s Disease and other related conditions. While T2‐weighted (T2w) MRI with high in‐plane resolution is widely used to segment hippocampal subfields due to its higher contrast in hippocampus, its lower out‐of‐plane resolution reduces the accuracy of subregion thickness measurements. To address this issue, we developed a nearly isotropic segmentation pipeline that incorporates image and label upsampling and high‐resolution segmentation in T2w MRI. Method First, a high‐resolution atlas was created based on an existing anisotropic atlas derived from 29 individuals. Both T1‐weighted and T2w images in the atlas were upsampled from their original resolution to a nearly isotropic resolution using a non‐local means approach. Manual segmentations within the atlas were also upsampled to match this resolution using a UNet‐based neural network, which was trained on a cohort consisting of both high‐resolution ex vivo and low‐resolution anisotropic in vivo MRI with manual segmentations (Figure 1a). Second, a multi‐modality deep learning‐based segmentation model was trained within this nearly isotropic atlas (Figure 1b). This method was evaluated on independent sets, including cross‐sectional (N = 196) and longitudinal (N = 31) MRI scans, which were used for the group difference analysis (Amyloid+ mild cognitive impairment (A+MCI) vs. Amyloid‐ cognitively normal (A‐CN)) and longitudinal consistency analysis, respectively (Figure 1c). Result Table 1(a) displays the group differences of cross‐sectional median thickness between A+MCI and A‐CN with age as covariate. The T2w segmentation in isotropic space achieved larger effect sizes in the predicted direction (A+MCI < A‐CN) and outperformed T2w anisotropic segmentation over most subregions. Table 1(b) shows the consistency analysis of longitudinal median thickness. When measured as the sum of absolute median thickness differences, the consistency of isotropic T2w segmentation outperformed that of anisotropic T2w segmentation over most subregions. Figure 2 shows the visualization of the segmentation and point‐wise group difference analysis at different resolutions, with isotropic T2w segmentation demonstrating a smoother surface and larger effect sizes than anisotropic T2w segmentation. Conclusion Nearly isotropic subregion segmentation improved the accuracy of cortical thickness as an imaging biomarker for neurodegeneration in T2w MRI.

32. Remembering Ricardo Serrano Insausti 1954-2024.

    Maria Carmen Lorduy, Ana María Navío Serrano, M. M. López, and 3 more authors

    Hippocampus, Mar 2025

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33. Alzheimer’s Imaging Consortium.

    Xueying Lyu, Nidhi S Mundada, Christopher A. Brown, and 11 more authors

    Alzheimer’s & dementia : the journal of the Alzheimer’s Association, Dec 2025

    DOI

    
34. Medial temporal lobe Tau‐Neurodegeneration mismatch from MRI and plasma biomarkers identifies vulnerable and resilient phenotypes with AD

    Xueying Lyu, Nidhi S Mundada, Christopher A. Brown, and 11 more authors

    Alzheimer’s & Dementia, Dec 2025

    Abs DOI

    

    Abstract Background The heterogeneity of Alzheimer’s disease (AD) and lack of well‐validated markers of non‐AD factors (e.g. TDP‐43) present a substantial challenge for therapeutics. Our prior work showed discordance between tau (T) and neurodegeneration (N) identified non‐AD factors in AD through multi‐modality imaging. Here we tried a simplified approach using plasma ptau217 and medial temporal lobe (MTL) morphometry, given this region’s common association with co‐pathologies, particularly LATE‐NC. Method We included 349 ADNI participants (188 cognitively normal, 161 MCI/dementia) with paired T1‐MRI and plasma ptau217. The MTL was segmented into subregions and further parcellated into 100 bilateral super‐points within regional boundaries. T1‐MRI‐derived thickness and amygdala volume represented N, and plasma p‐Tau217 represented T. T‐N residuals, calculated through regression across super‐points and amygdala, were used for weighted clustering. Result P‐Tau217 showed strong association with MTL atrophy (Figure 1A). Three distinct data‐driven T‐N groups were identified based on mismatch patterns (Figure 1B), including a canonical group (N∼T), a vulnerable group (N>T) with negative residuals primarily in anterior hippocampal and extrahippocampal areas, and a resilient group (N<T) with positive residuals. After clustering, group comparisons were restricted to the AD continuum (i.e. A+). While groups differed in regional volumes (e.g., amygdala), tau severity did not vary (Table 1), suggesting these patterns were not driven by AD pathology. The vulnerable group, displayed greater anterior MTL atrophy aligning with their T‐N residual patterns, while the resilient group had less atrophy in anterior extrahippocampal area (Figure 2A). Outside the MTL, the vulnerable group showed greater anterior limbic atrophy whereas the resilient group showed less (Figure 2B). The T‐N groups differed in Clinical Dementia Rating (CDR) with the vulnerable group having the worst ratings and the resilient group the best (Table 1). Notably, the vulnerable group demonstrated greater baseline memory impairment. Longitudinally, the vulnerable group also declined more severely across multiple cognitive domains while resilient group remained most stable (Figure 2C). Conclusion T‐N mismatch within MTL using MRI and plasma biomarkers revealed groups with varying vulnerability/resilience, with the vulnerable group displaying patterns of atrophy and cognition suggestive of LATE‐NC. It offers a less invasive, cost‐effective method for stratifying individuals for therapeutic interventions.

35. Medial temporal lobe Tau-Neurodegeneration mismatch from MRI and plasma biomarkers identifies vulnerable and resilient phenotypes with AD

    X. Lyu, N. S. Mundada, Christopher A. Brown, and 16 more authors

    medRxiv : the preprint server for health sciences, Aug 2025

    Cited by 1

    DOI

    
36. Clinical Manifestations.

    D. Mechanic‐Hamilton, Valerie Humphreys, Danielle Hing, and 3 more authors

    Alzheimer’s & dementia : the journal of the Alzheimer’s Association, Dec 2025

    DOI

    
37. Monitoring Cognition in Patients Undergoing Anti‐Amyloid Therapies with A Remote App‐Based Digital Cognitive Assessment Tool

    D. Mechanic‐Hamilton, Valerie Humphreys, Danielle Hing, and 3 more authors

    Alzheimer’s & Dementia, Dec 2025

    Abs DOI

    

    Mobile, valid and engaging cognitive assessments are essential for detecting and tracking change in cognition. With the approval of anti‐amyloid therapies (AATs), there is a need to monitor for both benefits and risks of these therapies. This pilot study aims to determine the feasibility and usability of an at‐home, app‐based cognitive assessment, the mobile cognitive app performance platform (mCAPP), to remotely collect cognitive performance data in a cohort of patients with Mild Cognitive Impairment (MCI) or mild dementia due to Alzheimer’s disease (AD) undergoing AAT.

38. Predicting the progression of MCI and Alzheimer’s disease on structural brain integrity and other features with machine learning

    Marthe Mieling, Mushfa Yousuf, Nico Bunzeck, and 497 more authors

    GeroScience, Apr 2025

    Cited by 5

    Abs DOI

    

    Machine learning (ML) on structural MRI data shows high potential for classifying Alzheimer’s disease (AD) progression, but the specific contribution of brain regions, demographics, and proteinopathy remains unclear. Using Alzheimer’s Disease Neuroimaging Initiative (ADNI) data, we applied an extreme gradient-boosting algorithm and SHAP (SHapley Additive exPlanations) values to classify cognitively normal (CN) older adults, those with mild cognitive impairment (MCI) and AD dementia patients. Features included structural MRI, CSF status, demographics, and genetic data. Analyses comprised one cross-sectional multi-class classification (CN vs. MCI vs. AD dementia, n = 568) and two longitudinal binary-class classifications (CN-to-MCI converters vs. CN stable, n = 92; MCI-to-AD converters vs. MCI stable, n = 378). All classifications achieved 70–77% accuracy and 61–83% precision. Key features were CSF status, hippocampal volume, entorhinal thickness, and amygdala volume, with a clear dissociation: hippocampal properties contributed to the conversion to MCI, while the entorhinal cortex characterized the conversion to AD dementia. The findings highlight explainable, trajectory-specific insights into AD progression. Supplementary Information The online version contains supplementary material available at 10.1007/s11357-025-01626-5.

39. Enrichment of patients with concomitant limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) on the Alzheimer’s disease continuum using hippocampal volume

    Nidhi S Mundada, X. Lyu, C. A. Brown, and 8 more authors

    Alzheimer’s & Dementia, Dec 2025

    Abs DOI

    

    Clinical overlap between Alzheimer’s disease (AD) and limbic‐predominant age‐related transactive response DNA binding protein 43 (TDP‐43) encephalopathy (LATE), combined with the absence of validated in vivo biomarkers, complicates identification of mixed AD/LATE pathology. We labeled individuals along the AD continuum with suspected concomitant LATE using the lower quartile hippocampal volume (HV) cut‐off and examined associated atrophy and cognitive profiles.

40. Enrichment of patients with concomitant LATE on the Alzheimer’s disease continuum: comparing structural and cognitive trajectories

    N. S. Mundada, X. Lyu, N. Sadeghpour, and 6 more authors

    Alzheimer’s & Dementia, Dec 2025

    Abs DOI

    

    Overlap in clinical presentations, absence of well‐validated in‐vivo biomarkers for Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), and frequent co‐occurrence with AD, complicates identifying mixed AD/LATE cases. Autopsy studies suggest greater hippocampal atrophy in AD patients with concomitant LATE. We aimed to identify patients along the AD continuum enriched for LATE by defining the lower quartile of hippocampal volume (HV) as a biomarker for possible LATE and explore atrophy patterns and cognitive profiles.

41. Enrichment of patients with concomitant LATE on the Alzheimer’s disease continuum using hippocampal volume

    N. S. Mundada, X. Lyu, C. A. Brown, and 8 more authors

    medRxiv, Aug 2025

    DOI

    
42. Developing Topics.

    Briar Nowling, Hamsanandini Radhakrishnan, Christopher A. Olm, and 9 more authors

    Alzheimer’s & dementia : the journal of the Alzheimer’s Association, Dec 2025

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43. White Matter Abnormalities and Cognition in Aging and Alzheimer Disease

    C. Peter, A. Sathe, N. Shashikumar, and 340 more authors

    JAMA Neurology, Jun 2025

    Cited by 13

    Abs DOI

    

    Key Points Question What is the association between white matter microstructure and cognitive performance and decline in aging and Alzheimer disease (AD)? Findings In this large, multicohort prognostic study of 4467 participants and 9208 longitudinal cognitive sessions, white matter free water was associated with cognitive performance and decline, especially memory. Limbic tracts (eg, cingulum, fornix) were most strongly associated across domains, and abnormal AD endophenotypes (eg, SPARE-AD index, APOE ε4 status, amyloid positivity) exacerbated cognitive decline. Meaning White matter microstructural changes were associated with cognitive decline, emphasizing their role in aging and AD assessment; interaction models support a multimodal approach to improve the prediction of cognitive decline.

44. Associations of 18F‐flortaucipir tau PET with quantitative tau histopathology in the medial temporal lobe

    Jeffrey S Phillips, Amanda E Denning, Lisa Levorse, and 15 more authors

    Alzheimer’s & Dementia, Dec 2025

    Abs DOI

    

    18F‐Flortaucipir is widely used for positron emission tomography (PET) imaging of Alzheimer’s disease (AD)‐type tau, but its sensitivity in early Braak stages has been questioned, and hippocampal uptake is at least partially confounded by off‐target binding. We investigated associations between antemortem PET uptake and digitally‐quantified tau and TDP‐43 neuropathology.

45. Associations of 18F‐flortaucipir tau PET with quantitative tau histopathology in the medial temporal lobe

    Jeffrey S Phillips, Amanda E Denning, Lisa Levorse, and 15 more authors

    Alzheimer’s & Dementia, Dec 2025

    Abs DOI

    

    Abstract Background 18F‐Flortaucipir is widely used for positron emission tomography (PET) imaging of Alzheimer’s disease (AD)‐type tau, but its sensitivity in early Braak stages has been questioned, and hippocampal uptake is at least partially confounded by off‐target binding. We investigated associations between antemortem PET uptake and digitally‐quantified tau and TDP‐43 neuropathology. Methods Participants (n = 14, Figure 1) included 5 people with no/low AD neuropathologic change (ADNC) at autopsy, 2 intermediate, and 7 high. Clinical diagnoses included normal cognition (n = 2), AD (n = 5), dementia with Lewy bodies (n = 2), Parkinson’s disease dementia (n = 1), corticobasal syndrome (n = 2), and posterior cortical atrophy (n = 2). We used the Automated Segmentation of Hippocampal Subfields T1 MRI pipeline to segment anterior and posterior hippocampus, Brodmann’s areas (BA) 35 (transentorhinal cortex) & 36, and entorhinal cortex. 18F‐Flortaucipir standardized uptake value ratios (SUVRs) were computed relative to inferior cerebellar grey matter and averaged across hemispheres. Postmortem sampling comprised hippocampal subiculum, CA1, CA2, CA3, and dentate gyrus; BA35 and BA36; and entorhinal cortex. FFPE‐brain tissue was immunostained using PHF1 and phospho‐specific TDP‐43 antibodies and digitally imaged. Two different weakly supervised learning algorithms, Wildcat, were trained to identify tau tangles and threads; or somatic and neuritic phosphorylated TDP‐43 (pTDP‐43) inclusions. Each pathology type was quantified by summary statistics on Wildcat heatmaps, averaged over hippocampal subfields; and over BA35/entorhinal cortex (Denning et al., 2024). We computed non‐parametric correlations between SUVRs and pathology measures at a=0.05 with false discovery rate correction. Results Tangles were associated with SUVRs in BA35/entorhinal cortex (Spearman’s r=0.59, p = 0.029; Figure 2A). The mean hippocampal tangle measure was associated with SUVRs in both anterior (r=0.77, p = 0.002) and posterior (r=0.77, p = 0.002) hippocampus (Figure 2B‐C). Associations between SUVR and tau threads were marginally significant (Figure 2D‐F). In BA35/entorhinal cortex, 9/9 intermediate‐high ADNC cases had SUVRs above an established positivity cutoff of 1.23 (Figure 3). PET SUVRs were not associated with somatic or neuritic pTDP‐43 measures. Conclusion Results suggest 18F‐flortaucipir is sensitive to tau burden in early Braak‐stage regions and primarily reflects neurofibrillary tangles rather than thread‐like tau inclusions.

46. A wireless, 60-channel, AI-enabled neurostimulation platform

    D. Rizzuto, Haydn G. Herrema, Zhe Hu, and 8 more authors

    bioRxiv, Aug 2025

    Abs DOI

    

    Objective Closed-loop neuromodulatory therapies require devices that can both decode ongoing brain states and deliver multi-site stimulation. Methods We describe the Smart Neurostimulation System (SNS), a cranially mounted implant with 60 configurable recording/stimulation channels, inductive power, and onboard spectral-feature classification. In three freely-moving sheep we streamed local-field potentials and conducted two parameter sweep experiments. Results Cross-validated movement classifiers achieved an average AUC > 0.95. Increasing stimulation amplitude and frequency produced post-stimulation elevations in α-band (8-12 Hz) and γ-band (78-82 Hz) power at most target locations. Conclusion The SNS unifies high-density sensing, real-time brain state decoding, and programmable closed-loop stimulation in a single device, demonstrating behavioral-state prediction and parameter-dependent neuromodulation in vivo. Significance These findings establish a preclinical foundation for biomarker-guided stimulation targeting distributed cortical networks underlying memory and cognition. Highlights Wireless 60-channel implant enables simultaneous sensing and stimulation vine study demonstrates reliable classification of movement and stimulation-related modulation of spectral activity The SNS represents a platform for biomarker-guided neuromodulation therapies

47. Effects of APOE Genotypes on Periventricular White Matter Cerebral Blood Flow in Cognitively Intact Adults (P3-3.004)

    S. Sadaghiani, M. Taghvaei, Sudipto Dolui, and 5 more authors

    Neurology, Apr 2025

    DOI

    
48. Developing an anatomically valid segmentation protocol for anterior regions of the medial temporal lobe for neurodegenerative diseases

    Niyousha Sadeghpour, Sydney A. Lim, A. Wuestefeld, and 30 more authors

    bioRxiv, Feb 2025

    Cited by 6

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    Background The anterior portion of the medial temporal lobe (MTL) is one of the first regions targeted by pathology in sporadic Alzheimer’s disease (AD) and Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) indicating a potential for metrics from this region to serve as imaging biomarkers. Leveraging a unique post-mortem dataset of histology and magnetic resonance imaging (MRI) scans we aimed to 1) develop an anatomically valid segmentation protocol for anterior entorhinal cortex (ERC), Brodmann Area (BA) 35, and BA36 for in vivo 3 tesla (T) MRI and 2) incorporate this protocol in an automated approach. Methods We included 20 cases (61-97 years old, 50% females) with and without neurodegenerative diseases (11 vs. 9 cases) to ensure generalizability of the developed protocol. Digitized MTL Nissl-stained coronal histology sections from these cases were annotated and registered to same-subject post-mortem MRI. The protocol was developed by determining the location of histological borders of the MTL cortices in relation to anatomical landmarks. Subsequently the protocol was applied to 15 cases twice, with a 2-week interval, to assess intra-rater reliability with the Dice Similarity Index (DSI). Thereafter it was implemented in our in- house Automatic Segmentation of Hippocampal Subfields (ASHS)-T1 approach and evaluated with DSIs. Results The anterior histological border distances of ERC, BA35 and BA36 were evaluated with respect to various anatomical landmarks and the distance relative to the beginning of the hippocampus was chosen. To formulate segmentation rules, we examined the histological sections for the location of borders in relationship to anatomical landmarks in the coronal sections. The DSI for the anterior MTL cortices for the intra-rater reliability was 0.85-0.88 and for the ASHS-T1 against the manual segmentation was 0.62-0.65. Discussion We developed a reliable segmentation protocol and incorporated it in an automated approach. Given the vulnerability of the anterior MTL cortices to tau deposition in AD and LATE, the updated approach is expected to improve imaging biomarkers for these diseases.

49. Developing an Anatomically Valid Segmentation Protocol for Anterior Regions of the Medial Temporal Lobe for Neurodegenerative Diseases

    Niyousha Sadeghpour, Sydney A. Lim, A. Wuestefeld, and 30 more authors

    Hippocampus, Jul 2025

    Abs DOI

    

    The anterior portion of the medial temporal lobe (MTL) is one of the first regions targeted by pathology in sporadic Alzheimer’s disease (AD) and limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) indicating a potential for metrics from this region to serve as imaging biomarkers. Leveraging a unique post‐mortem dataset of histology and magnetic resonance imaging (MRI) scans, we aimed to (1) develop an anatomically valid segmentation protocol for anterior entorhinal cortex (ERC), Brodmann area (BA) 35, and BA36 for in vivo 3 T MRI and (2) incorporate this protocol in an automated approach. We included 20 cases (61–97 years old, 50% females) with and without neurodegenerative diseases (11 vs. 9 cases) to ensure generalizability of the developed protocol. Digitized MTL Nissl‐stained coronal histology sections from these cases were annotated and registered to same‐subject post‐mortem MRI. The protocol was developed by determining the location of histological borders of the MTL cortices in relation to anatomical landmarks. Subsequently, the protocol was applied to 15 cases twice, with a 2‐week interval, to assess intra‐rater reliability with the Dice Similarity Index (DSI). Thereafter, it was implemented in our in‐house Automatic Segmentation of Hippocampal Subfields (ASHS)‐T1 approach and evaluated with DSIs. The anterior histological border distances of ERC, BA35 and BA36 were evaluated with respect to various anatomical landmarks, and the distance relative to the beginning of the hippocampus was chosen. To formulate segmentation rules, we examined the histological sections for the location of borders in relationship to anatomical landmarks in the coronal sections. The DSI for the anterior MTL cortices for the intra‐rater reliability was 0.85–0.88, and for the ASHS‐T1 against the manual segmentation, it was 0.62–0.65. We developed a reliable segmentation protocol and incorporated it in an automated approach. Given the vulnerability of the anterior MTL cortices to tau deposition in AD and LATE, the updated approach is expected to improve imaging biomarkers for these diseases.

50. Clinical correlates of perfusion and diffusion MRI metrics in cognitively unimpaired older adults.

    Banafsheh Shakibajahromi, Sudipto Dolui, Christopher A. Brown, and 9 more authors

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, Dec 2025

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    Cerebral small vessel disease (CSVD) is associated with vascular risk factors (VRFs) and early executive function (EF) decline. Because periventricular white matter (PVWM) is the most weakly perfused brain region, it may be particularly sensitive to early manifestations of CSVD. Among 101 cognitively unimpaired adults, we assessed the cross-sectional correlations of arterial spin-labeled derived absolute and relative cerebral blood flow (CBF and rCBF, respectively) and diffusion tensor imaging (DTI) metrics in normal-appearing WM (NA-WM) and normal-appearing PVWM (NA-PVWM) with VRFs and EF, and evaluated the mediation and moderation relationships between these variables in amyloid β negative (Aβ-) subjects. CBF, rCBF, and DTI metrics were significantly different in NA-PVWM compared to NA-WM (p < 0.001). In multivariate analysis of the Aβ- group, NA-PVWM rCBF was associated with VRFs (p = 0.012), while NA-PVWM rCBF (p = 0.035) and mean diffusivity (MD) in NA-WM (p = 0.022) and NA-PVWM (p = 0.029) were associated with EF. The association between VRF and EF was not mediated by rCBF and/or MD. However, increased MD was significantly associated with poorer EF for NA-PVWM CBF ⩽16.3 mL/100 g/min and NA-PVWM rCBF ⩽0.35. NA-PVWM rCBF is associated with VRFs and EF and might be an early biomarker for CSVD, especially in the absence of amyloid pathology.

51. Biological age acceleration in Alzheimer’s disease modulates relative cortical to medial temporal lobe neurodegeneration.

    Lasya P. Sreepada, Christopher A. Brown, Sandhitsu R. Das, and 3 more authors

    Neurobiology of aging, Jun 2025

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    Alzheimer’s disease (AD) is highly associated with aging, typically presenting with amnestic, multi-domain cognitive impairment and greater medial temporal lobe (MTL) atrophy relative to cortex. However, approximately 15 % of AD cases present atypically, often at younger ages and with greater cortical involvement relative to MTL. This association between age and AD presentation is imperfect: some younger-onset cases are typical, amnestic presentations while some older-onset cases present less typically. We hypothesize that this discordance may be partially modulated by discordance between chronological age and biological age, defined epigenetically. Participants from the Alzheimer’s Disease Neuroimaging Initiative with MRI and known amyloid status were selected (n = 1011, 44.4 % female, 75.33 ± 7.28 years) and classified as amyloid-negative, cognitively unimpaired (n = 329) or amyloid-positive, symptomatic individuals with mild cognitive impairment or dementia (n = 682). Biological age was estimated in individuals with DNA methylation (n = 448) using established epigenetic clocks. Biological age gap (BAG) was calculated to categorize individuals into "accelerated" (biological age > chronological age) or "decelerated" (biological age < chronological age) groups. We define the Cortico-Medial Temporal index (CoMeT), derived from MRI, to quantify age-adjusted relative differences between cortical and MTL structures. Lower CoMeT scores indicate relatively greater cortical involvement. BAG and CoMeT were significantly correlated (Pearson R=0.13, p = 0.023). Symptomatic individuals with decelerated BAG exhibited significantly lower CoMeT scores than individuals with accelerated BAG, with a large effect size, reflecting greater cortical involvement relative to MTL (Wilcoxon p = 0.023, rank-biserial correlation=-0.98). We conclude that biological aging modulates AD presentation beyond chronological age, providing novel insights into mechanisms underlying AD heterogeneity.

52. Developing Topics.

    Manuel Taso, Christopher A. Brown, Sandhitsu R. Das, and 11 more authors

    Alzheimer’s & dementia : the journal of the Alzheimer’s Association, Dec 2025

    DOI

    
53. Classifying AD and PART: An Epigenetic Signature of Cognitive Resilience

    Anil R Wadhwani, David C. Goldberg, P. D. Jager, and 7 more authors

    Alzheimer’s & Dementia, Dec 2025

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    Whether primary age‐related tauopathy (PART) is a distinct age‐associated disorder or merely a prodrome of Alzheimer’s disease (AD) remains controversial. Both share similar limbic tau but differ in amyloid burden and tau spread. Differential DNA methylation (DNAm) can offers insights into disease biology, biomarkers, and potential therapeutic targets. We therefore used a machine learning classifier trained on DNAm to distinguish PART from AD and then applied the classifier to stratify pathologically‐indeterminate cases.

54. Deposition patterns of proteinopathies in medial temporal lobe subregions: implications for neuroimaging

    L. Wisse, M. Bouwman, Alex Wesseling, and 6 more authors

    Alzheimer’s & Dementia, Dec 2025

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    The medial temporal lobe (MTL) is a hotspot for neurodegenerative pathologies and a key region for neuroimaging studies in dementia. A better understanding of proteinopathy deposition patterns would increase the interpretation of neuroimaging measures. We performed a literature review to quantitatively characterize deposition patterns in MTL subregions for six major proteinopathies targeting the MTL.

55. Tau, atrophy, and domain‐specific cognitive impairment in typical Alzheimer’s disease

    A. Wuestefeld, L. Xie, E. McGrew, and 8 more authors

    Alzheimer’s & Dementia, Jul 2025

    Cited by 3

    Abs DOI

    

    A granular understanding of the mechanisms linking tau pathology to cognitive decline in Alzheimer’s disease is crucial. We investigate mediating effects of medial temporal lobe (MTL) and neocortical neurodegeneration on tau‐induced domain‐specific cognitive impairment in amyloid‐beta (Aβ) positive cognitively normal and impaired adults.

56. A multi‐cohort study of longitudinal and cross‐sectional Alzheimer’s disease biomarkers in cognitively unimpaired older adults

    L. Xie, Sandhitsu R. Das, Yue Li, and 21 more authors

    Alzheimer’s & Dementia, Jan 2025

    Cited by 7

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    The generalizability of neuroimaging and cognitive biomarkers in their sensitivity to detect preclinical Alzheimer’s disease (AD) and power to predict progression in large, multisite cohorts remains unclear.

57. Developing Topics.

    L. Xie, Christopher A. Brown, I. Nasrallah, and 6 more authors

    Alzheimer’s & dementia : the journal of the Alzheimer’s Association, Dec 2025

    DOI

    
58. Associations between Quantitative Neuronal Loss Measures and Postmortem MRI Atrophy Measures in the Human Medial Temporal Lobe in AD and LATE

    Paul Yushkevich, S. Ravikumar, L. Wisse, and 34 more authors

    Alzheimer’s & Dementia, Dec 2025

    Abs DOI

    

    Abstract Background Medial temporal lobe (MTL) atrophy measured on MRI is a sensitive biomarker of AD‐linked neurodegeneration but is not specific to AD. LATE is a common AD co‐pathology that is challenging to distinguish from AD based on available validated biomarkers. LATE and AD are both associated with hippocampus and entorhinal cortex atrophy, but recent studies suggest that there are differences in the severity and spatial patterns of atrophy. We sought to use postmortem MRI and histology to examine how MRI morphometric measures in AD and LATE relate to direct measures of neurodegeneration, including neuron number, size, and density. Method Thionin‐stained 50µm histology sections from 24 brain donors (5 AD‐LATE‐, 14 AD+LATE‐, 5 AD+LATE+) with available 9.4T postmortem MRI were used to delineate subfields CA1, subiculum and entorhinal cortex. Deep learning method StarDist was used to detect star‐shaped objects in thionine slides, combined with weakly‐supervised learning to identify artifact‐free cortical regions and Gaussian mixture modeling to distinguish neurons from glia (Figure 1AB). Validation against stereology measures of neuronal/glial density was performed in 50 separate regions. Neuronal measures were compared to MTL volume and thickness measures extracted from MRI. Result Automated neuronal density estimates (r=0.72, Figure 1C) agreed with stereology, but not glial density. Estimated number and size of neurons in CA1 and ERC were higher in individuals with less CA1/ERC atrophy (Figure 2) consistent with greater neuronal loss in advanced AD and LATE. However, CA1 neuronal and glial density, and ERC glial density, were higher in individuals with greater atrophy, suggesting tighter packing of neurons in remaining tissue and significant contribution of neuropil loss to MRI‐based atrophy measures. Pointwise analysis in Figure 3 shows patterns of association between regional MTL thickness and CA1 neuronal count, size, and density measures. Conclusion These initial feasibility results in two sections in 24 brain donors encourage us to apply this pipeline to a larger dataset of paired postmortem MRI and serial histology sections (Ravikumar et al., 2024) and to study associations between tau pathology, neuronal loss, and MRI‐based measures of atrophy, with the aim of better differentiating atrophy linked to LATE and AD.

2024

1. A harmonized, histology‐based protocol for selection of medial temporal lobe cortical subregion ranges on magnetic resonance imaging

   Jenna N. Adams, H. Baumeister, T. Doan, and 22 more authors

   Alzheimer’s & Dementia, Dec 2024

   Abs DOI

   

   The medial temporal lobe (MTL) has distinct cortical subregions that are differentially vulnerable to pathology and neurodegeneration in diseases such as Alzheimer’s disease. However, previous protocols for segmentation of MTL cortical subregions on magnetic resonance imaging (MRI) vary substantially across research groups, and have been informed by different cytoarchitectonic definitions, precluding consistent interpretations. The Hippocampal Subfields Group aims to create a harmonized, histology‐based protocol for segmentation of MTL cortical subregions that can reliably be applied to T2‐weighted MRI with high in‐plane resolution.

2. Mapping local and distal effects of different neuropathologies on amygdala volume

   Amanda Annettesdotter, Katja Selezneva, Amanda E Denning, and 24 more authors

   Alzheimer’s & Dementia, Dec 2024

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   The amygdala is a hotspot for neuropathologies; however, it is unclear 1) which neuropathologies lead to amygdala neurodegeneration, 2) what specific amygdala subnuclei are affected, and 3) if the neuropathologies related to amygdala volume are local (inside the amygdala), or distal (in other regions). We investigate the relationships between different neuropathologies (tau, amyloid‐β [Aβ], α‐synuclein [α‐syn], and transactive response DNA‐binding protein 43 [TDP‐43]) and amygdala volumes.

3. Mapping local and distal effects of different neuropathologies on amygdala volume

   Amanda Annettesdotter, Katja Selezneva, Amanda E Denning, and 24 more authors

   Alzheimer’s & Dementia, Dec 2024

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   The amygdala is a hotspot for neuropathologies; however, it is unclear 1) which neuropathologies lead to amygdala neurodegeneration, 2) what specific amygdala subnuclei are affected, and 3) if the neuropathologies related to amygdala volume are local (inside the amygdala), or distal (in other regions). We investigate the relationships between different neuropathologies (tau, amyloid‐ß [Aß], a‐synuclein [a‐syn], and transactive response DNA‐binding protein 43 [TDP‐43]) and amygdala volumes.

4. Basic Science and Pathogenesis.

   Sanaz Arezoumandan, Eric Teunissen‐Bermeo, Noah Capp, and 8 more authors

   Alzheimer’s & dementia : the journal of the Alzheimer’s Association, Dec 2024

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   BACKGROUND Alzheimer’s disease (AD) is the most common neurodegenerative disease, and it is characterized by aggregation of misfolded proteins in the brain. Intraneuronal accumulation of tau pathology form neurofibrillary tangles (NFT) in AD. The assessment of the severity of intraneuronal inclusions holds significance in studying the clinicopathological associations in neurodegenerative diseases. Using machine learning methods, we have developed an automated tool to detect NFTs in immunohistochemically stained sections. METHOD We trained a weakly supervised machine learning algorithm called WildCat to classify inclusions in AT8-stained 6µm sections of the hippocampus and locate areas with high probability of NFTs in the tissue. Next, we utilized the WildCat activation outputs and improved the NFT detections by thresholding and applying morphological filters. Finally, in order to validate our methods, we generated a validation dataset using QuPath software by manually annotating NFTs (N = 600) in 175 × 175µm regions of interest (N = 103). We then tested the correlation between manual and automated measurements to validate our method (Fig. 1). RESULT The WildCat classification model showed outstanding performance by accurately distinguishing NFTs from non-tangle inclusions, achieving high accuracy (97.31%), recall (99.37%), and precision (99.3%). In addition, we tested the correlation between final output of our model with manual measurements of tangles in our validation dataset, where we found strong correlations in tangle counts and tangle percent area-occupied between the two methods (R = 0.84-0.88, p<0.001) (Fig. 1). CONCLUSION Automated tools can reliably generate measurements of NFT density in AD tissue sections. Moreover, this method can be applied to other types of pathologies and may offer a helpful tool for the study of other neurodegenerative diseases.

5. Operationalizing postmortem pathology‐MRI association studies in ADRD with MRI‐guided histology sampling: does closer proximity lead to stronger associations?

   Chinmayee Athalye, Pulkit Khandelwal, A. Bahena, and 22 more authors

   Alzheimer’s & Dementia, Dec 2024

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   Histopathological analysis of autopsied brains is the gold standard of diagnosis in neurodegenerative disorders. Co‐registered histology and MRI scans aid in understanding pathology and structural features. Previous studies focused on the medial temporal lobe (MTL) for atrophy patterns in phosphorylated tau (p‐tau) pathology and in whole hemisphere scans with contralateral semi‐quantitative p‐tau measures. Here, we extend this to study ipsilateral quantitative p‐tau and cortical thickness.

6. Medial temporal lobe gray matter microstructure in preclinical Alzheimer’s disease

   Christopher A. Brown, Sandhitsu R. Das, Long Xie, and 7 more authors

   Alzheimer’s & Dementia, May 2024

   Cited by 8

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   Typical MRI measures of neurodegeneration have limited sensitivity in early disease stages. Diffusion MRI (dMRI) microstructural measures may allow for detection in preclinical stages.

7. Support for transmission of tau pathology in humans using individualized epicenters and structural connectomes

   Christopher D. Brown, Sandhitsu R. Das, I. Nasrallah, and 4 more authors

   Alzheimer’s & Dementia, Dec 2024

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   Population‐based functional connectomes help explain heterogeneity in tau spread in Alzheimer’s disease by demonstrating spread among connected neurons from canonical epicenters. However, if the hypothesis of cell‐to‐cell transmission of tau is correct, individual structural connectomes seeded from individual‐specific epicenters of PET‐tau pathology should improve prediction of regional tau patterns.

8. Tau Magnitude and eXent–Tau‐MaX: Capturing tau spread and local accumulation provides a robust metric of tau burden

   Christopher D. Brown, Sandhitsu R. Das, K. Cousins, and 8 more authors

   Alzheimer’s & Dementia, Dec 2024

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   Measures of tau burden have typically relied upon measures of magnitude, such as mean standardized uptake value ratio (SUVR), or extent, such as number of tau positive regions. However, heterogenous patterns of tau spread and accumulation present challenges to using these measures in isolation to quantify tau burden. Therefore, we hypothesized that a combined measure of tau magnitude and extent (Tau‐MaX) would outperform either measure in isolation.

9. Subject‐Level Segmentation Precision Weights for Volumetric Studies Involving Label Fusion

   Christina Chen, Sandhitsu R. Das, M. Tisdall, and 5 more authors

   Human Brain Mapping, Dec 2024

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   In neuroimaging research, volumetric data contribute valuable information for understanding brain changes during both healthy aging and pathological processes. Extracting these measures from images requires segmenting the regions of interest (ROIs), and many popular methods accomplish this by fusing labels from multiple expert‐segmented images called atlases. However, post‐segmentation, current practices typically treat each subject’s measurement equally without incorporating any information about variation in their segmentation precision. This naïve approach hinders comparing ROI volumes between different samples to identify associations between tissue volume and disease or phenotype. We propose a novel method that estimates the variance of the measured ROI volume for each subject due to the multi‐atlas segmentation procedure. We demonstrate in real data that weighting by these estimates markedly improves the power to detect a mean difference in hippocampal volume between controls and subjects with mild cognitive impairment or Alzheimer’s disease.

10. Microstructural changes in the inferior tuberal hypothalamus correlate with daytime sleepiness in Lewy body disease

    Jesse S Cohen, Hamsanandini Radhakrishnan, Christopher A. Olm, and 6 more authors

    medRxiv, Aug 2024

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    Background: Excessive daytime sleepiness (EDS) is a disabling symptom of Lewy body disorders (LBD). The hypothalamus is a key sleep-wake regulator, but its contribution to EDS in LBD remains unclear. Objectives: Use diffusion MRI to evaluate the relationship of hypothalamic microstructure to EDS symptoms in LBD. Methods: We studied 102 patients with clinically-defined LBD (Parkinson’s disease, n=93; Parkinson’s disease dementia, n=4; and dementia with Lewy bodies, n=5) and Epworth Sleepiness Scale (ESS) within 2 years of MRI. Mean diffusivity (MD) was compared between EDS+ (ESS>=10, n=37) and EDS- (ESS<10, n=65) groups in the whole hypothalamus and three subregions, covarying for age and sex. Secondary analyses tested correlations between subregion MD and continuous ESS, global cognition, and motor scores; and between subregion volume and continuous ESS. Results: MD was increased in EDS+ compared to EDS- only in the inferior tuberal subregion (Cohen’s d=0.43, p=0.043, beta=0.117+/-0.057), with trend level differences in the whole hypothalamus (Cohen’s d=0.39, p=0.064, beta=0.070+/-0.037) and superior tuberal subregion (Cohen’s d=0.38, p=0.073, beta=0.063+/-0.035). No difference was seen in the posterior subregion (Cohen’s d=0.1, p=0.628, beta=0.019+/-0.038). Significant correlations with continuous ESS were seen in MD of whole hypothalamus (r2=0.074, p=0.0057), superior tuberal (r2=0.081, p=0.0038), and inferior tuberal (r2=0.073, p=0.0059) subregions. There was no correlation of hypothalamic MD with global cognition or motor scores, and no correlation of whole/subregional hypothalamic volumes with ESS. Conclusions: Daytime sleepiness associates with increased MD in the inferior tuberal hypothalamus in an LBD cohort. This suggests degeneration within this region could contribute to EDS symptoms.

11. Posterior hippocampal sparing in Lewy body disorders with Alzheimer’s copathology: An in vivo MRI study

    Jesse S Cohen, Jeffrey Phillips, Sandhitsu R. Das, and 12 more authors

    NeuroImage : Clinical, Dec 2024

    Cited by 2

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    Highlights • LBD/AD+ shows a subregion-specific pattern of medial temporal lobe atrophy.• Atrophy severity largely follows expectations from Braak tau stages.• However, posterior hippocampus is spared, deviating from Braak.• Radiopathologic correlation is consistent with tau-dependent neurodegeneration.• MRI in LBD/AD+ could help stratify individuals for therapy trials.

12. Combining plasma biomarkers for β‐amyloid diagnosis and cognitive prognosis across the clinical spectrum: normal, amnestic, and non‐amnestic

    K. Cousins, J. Phillips, Sandhitsu R. Das, and 10 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Alzheimer’s disease (AD) is clinically heterogeneous, and can manifest as amnestic or non‐amnestic dementia, or be pre‐manifest in persons with normal cognition (NormCog). Utility of plasma biomarkers to diagnose AD and prognose cognitive decline must be evaluated in a clinically heterogeneous population representative of the AD spectrum. We investigate pathological and cognitive correlates of plasma phosphorylated tau 181 (p‐tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across AD and AD‐related dementias (ADRD). We test 1.) if combing biomarkers improves diagnostic accuracy for β‐amyloid (Aβ) in NormCog and impaired cognition (ImpCog), 2.) if Aβ diagnostic accuracy in ImpCog differs by clinical syndrome (amnestic dementia vs. non‐amnestic dementia vs. mild cognitive impairment [MCI]), and 3.) how biomarkers predict future cognitive decline in Aβ+ and Aβ‐.

13. Pathologic and cognitive correlates of plasma biomarkers in neurodegenerative disease

    K. Cousins, J. Phillips, Sandhitsu R. Das, and 10 more authors

    Alzheimer’s & Dementia, Apr 2024

    Cited by 13

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    We investigate pathological correlates of plasma phosphorylated tau 181 (p‐tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog).

14. Beyond Macrostructure: Is There a Role for Radiomics Analysis in Neuroimaging ?

    Sandhitsu R. Das, Ademola Ilesanmi, D. Wolk, and 1 more author

    Magnetic Resonance in Medical Sciences, Jun 2024

    Cited by 9

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    The most commonly used neuroimaging biomarkers of brain structure, particularly in neurodegenerative diseases, have traditionally been summary measurements from ROIs derived from structural MRI, such as volume and thickness. Advances in MR acquisition techniques, including high-field imaging, and emergence of learning-based methods have opened up opportunities to interrogate brain structure in finer detail, allowing investigators to move beyond macrostructural measurements. On the one hand, superior signal contrast has the potential to make appearance-based metrics that directly analyze intensity patterns, such as texture analysis and radiomics features, more reliable. Quantitative MRI, particularly at high-field, can also provide a richer set of measures with greater interpretability. On the other hand, use of neural networks-based techniques has the potential to exploit subtle patterns in images that can now be mined with advanced imaging. Finally, there are opportunities for integration of multimodal data at different spatial scales that is enabled by developments in many of the above techniques—for example, by combining digital histopathology with high-resolution ex-vivo and in-vivo MRI. Some of these approaches are at early stages of development and present their own set of challenges. Nonetheless, they hold promise to drive the next generation of validation and biomarker studies. This article will survey recent developments in this area, with a particular focus on Alzheimer’s disease and related disorders. However, most of the discussion is equally relevant to imaging of other neurological disorders, and even to other organ systems of interest. It is not meant to be an exhaustive review of the available literature, but rather presented as a summary of recent trends through the discussion of a collection of representative studies with an eye towards what the future may hold.

15. Association of quantitative measurements of postmortem tau tangle and thread pathology with antemortem cortical thickness measurements in neuropathologically confirmed Alzheimer’s Disease continuum patients

    Amanda E Denning, R. Ittyerah, Niyousha Sadeghpour, and 27 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Tau pathology and neurodegeneration in the medial temporal lobe (MTL) are highly associated in Alzheimer’s Disease (AD). However, the spatial pattern of neurodegeneration, contribution of individual tau inclusion types, and influence of MTL co‐pathologies (i.e., TDP‐43) remain poorly understood. Traditional semi‐quantitative ratings or staging schemes of tau pathology capture limited variability in severity and provide no differentiation between inclusion types (i.e., tangles, threads). We correlate semi‐quantitative and quantitative measures of MTL tau pathology from postmortem tissue samples with MTL cortical thickness measures from antemortem MRI.

16. Association of quantitative histopathology measurements with antemortem medial temporal lobe cortical thickness in the Alzheimer’s disease continuum

    Amanda E Denning, R. Ittyerah, Lisa Levorse, and 35 more authors

    Acta Neuropathologica, Sep 2024

    Cited by 13

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    The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer’s disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies.

17. Mapping Anatomical Boundaries from Histology to Antemortem MRI to Inform Automatic Segmentation of Medial Temporal Lobe Subregions

    Amanda E Denning, Sydney A. Lim, Yue Li, and 29 more authors

    Alzheimer’s & Dementia, Dec 2024

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    The medial temporal lobe (MTL) is the epicenter of both primary and concomitant molecular pathologies in Alzheimer’s disease (AD). The intricate anatomy of the MTL has been the subject of extensive study over the past two centuries. However, current PET and MRI AD biomarkers use often crude parcellations of the MTL that have not been sufficiently validated vis‐à‐vis anatomical ground truth. Here we use a unique dataset of finely annotated serial histology, ex vivo MRI and antemortem 3T in vivo MRI of the MTL from 17 brain donors to train and evaluate an automatic MTL subregion segmentation algorithm. To our knowledge, this is the most comprehensive attempt to infuse MRI biomarkers with cytoarchitectural reference annotations.

18. Mapping Anatomical Boundaries from Histology to Antemortem MRI to Inform Automatic Segmentation of Medial Temporal Lobe Subregions

    Amanda E Denning, Sydney A. Lim, Yue Li, and 29 more authors

    Alzheimer’s & Dementia, Dec 2024

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    The medial temporal lobe (MTL) is the epicenter of both primary and concomitant molecular pathologies in Alzheimer’s disease (AD). The intricate anatomy of the MTL has been the subject of extensive study over the past two centuries. However, current PET and MRI AD biomarkers use often crude parcellations of the MTL that have not been sufficiently validated vis‐à‐vis anatomical ground truth. Here we use a unique dataset of finely annotated serial histology, ex vivo MRI and antemortem 3T in vivo MRI of the MTL from 17 brain donors to train and evaluate an automatic MTL subregion segmentation algorithm. To our knowledge, this is the most comprehensive attempt to infuse MRI biomarkers with cytoarchitectural reference annotations.

19. Regional deep atrophy: Using temporal information to automatically identify regions associated with Alzheimer’s disease progression from longitudinal MRI

    M. Dong, L. Xie, Sandhitsu R. Das, and 5 more authors

    Imaging Neuroscience, Sep 2024

    Cited by 1

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    Abstract Longitudinal assessment of brain atrophy, particularly in the hippocampus, is a well-studied biomarker for neurodegenerative diseases, such as Alzheimer’s disease (AD). Estimating brain progression patterns can be applied to understanding the therapeutic effects of amyloid-clearing drugs in research and detecting the earliest sign of accelerated atrophy in clinical settings. However, most state-of-the-art measurements calculate changes directly by segmentation and/or deformable registration of MRI images, and may misreport head motion or MRI artifacts as neurodegeneration, impacting their accuracy. In our previous study, we developed a deep learning method DeepAtrophy that uses a convolutional neural network to quantify differences between longitudinal MRI scan pairs that are associated with time. DeepAtrophy has high accuracy in inferring temporal information from longitudinal MRI scans, such as temporal order or relative interscan interval. DeepAtrophy also provides an overall atrophy score that was shown to perform well as a potential biomarker of disease progression and treatment efficacy. However, DeepAtrophy is not interpretable, and it is unclear what changes in the MRI contribute to progression measurements. In this paper, we propose Regional Deep Atrophy (RDA), which combines the temporal inference approach from DeepAtrophy with a deformable registration neural network and attention mechanism that highlights regions in the MRI image where longitudinal changes are contributing to temporal inference. RDA has similar prediction accuracy as DeepAtrophy, but its additional interpretability makes it more acceptable for use in clinical settings, and may lead to more sensitive biomarkers for disease monitoring and progression understanding in preclinical AD.

20. Regional Deep Atrophy: Using Temporal Information to Automatically Identify Regions Associated with Alzheimer’s Disease Progression from Longitudinal MRI

    M. Dong, L. Xie, L. Wisse, and 4 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Assessment of longitudinal hippocampal atrophy is a well‐studied biomarker for Alzheimer’s disease (AD). However, most state‐of‐the‐art measurements calculate changes directly from MRI images using image registration/segmentation, which may misreport head motion or MRI artifacts as neurodegeneration. We present a deep learning method Regional Deep Atrophy (RDA) that (1) estimates atrophy sensitive to progression by quantifying time‐associated changes in images, especially in preclinical AD stage (as in DeepAtrophy (Dong et al., 2021)), and (2) identifies regions where longitudinal changes significantly influence temporal inference.

21. Hypometabolic mismatch with atrophy and tau pathology in mixed Alzheimer and Lewy body disease.

    M. Duong, Sandhitsu R. Das, Pulkit Khandelwal, and 10 more authors

    Brain : a journal of neurology, Nov 2024

    Cited by 13

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    Polypathology is a major driver of heterogeneity in clinical presentation and extent of neurodegeneration (N) in patients with Alzheimer Disease (AD). Beyond amyloid (A) and tau (T) pathologies, over half of patients with AD have concomitant pathology such as α-synuclein (S) in mixed AD with Lewy Body Disease (LBD). Patients with Mixed Etiology Dementia (MED) such as AD+LBD have faster progression and potentially differential responses to targeted treatments, though the diagnosis of AD+LBD can be challenging given overlapping clinical and imaging features. Development and validation of improved in vivo biomarkers are required to study relationships between N and S and identify imaging patterns reflecting mixed AD+LBD pathologies. We hypothesize that individual proteinopathies, such as T and S, are associated with commensurate levels of N. Thus, we assessed biomarkers of A, T, N and S with positron emission tomography (PET), magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) seeding amplification assay (SAA) data to determine molecular presentations of mixed A+S+ vs. A+S- cognitively impaired patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We found A+S+ patients had parieto-occipital 18F-Fluorodeoxyglucose hypometabolism (a measure of N) disproportionate to the degree of regional atrophy or T burden, highlighting worse hypometabolism associated with S+ SAA. Following up on this hypometabolic mismatch with CSF metabolite and proteome analyses, we found that A+S+ patients exhibited lower CSF levels of dopamine metabolites and synaptic markers like neuronal pentraxin-2 (NPTX2), suggesting that altered neurotransmission and neuron integrity contribute to this dissociation between metabolic PET and MRI. Potential confounders exist when studying relations between N, AD and LBD pathologies, including neuroinflammation and other non-Alzheimer pathologies in MED, though our findings imply posterior hypometabolic mismatch is related more to S than vascular or TDP-43 pathology. A+S+ patients had posterior mismatch with excessive 18F-Fluorodeoxyglucose hypometabolism relative to atrophy or T load, possibly reflecting impaired neuron integrity. Further research must disentangle the impact of multiple proteinopathies and clinicopathologic factors on hypometabolism and atrophy. Cumulatively, patients with mixed AD+LBD etiologies harbor a unique metabolic PET mismatch signature.

22. Basic Science and Pathogenesis.

    Sheina Emrani, Sanaz Arezoumandan, K. Cousins, and 7 more authors

    Alzheimer’s & dementia : the journal of the Alzheimer’s Association, Dec 2024

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    BACKGROUND We recently found region-specific patterns of iron-rich gliosis in frontotemporal lobar degeneration (FTLD) groups with tau (FTLD-Tau; PSP) and TDP-43 (FTLD-TDP) pathology using iron-sensitive MRI of whole-hemispheres. These patterns largely corresponded to regions of early pathology reported in previous traditional histopathologic staging schemes of protein inclusions for FTLD-Tau and FTLD-TDP. Ferritin light chain (FLC) reactivity highlights activated glia but has not been studied extensively in FTLD. We hypothesize neuroinflammation marked by FLC-reactive glia may relate to protein aggregation and contribute to partially distinct regional patterns of Tau vs TDP-43 propagation in FTLD. METHODS We used digital histopathology to measure FLC % area occupied (%AO) in a pilot cohort of 48 FLTD-Tau and 83 FTLD-TDP patients in three frontal cortical regions implicated early in FTLD-Tau (i.e., motor cortex [MOT]) and FTLD-TDP (orbitofrontal cortex [OFC]) staging and an intermediate region for both staging schemes (medial frontal cortex [MFC]). We used linear mixed effect (LME) models to test the effect of region*group on FLC %AO while adjusting for age, sex, disease duration, and hemisphere sampled; individual was included as random-intercept. Similarly, within-group LME models tested for the association of %AO of Tau/TDP inclusions on FLC %AO. Between- and within-group t-tests were used to further examine FLC %AO levels. RESULTS In the total cohort, we found lower FLC%AO in MFC (Beta = -.008, SE = .002, p = <.001) and OFC (Beta = -.008 SE = .002, p = <.001) than MOT of FTLD-Tau compared to FTLD-TDP (Figure 1). T-tests showed OFC FLC%AO was higher in FTLD-TDP than FTLD-Tau (p = <.001; Figure 1) and MOT FLC%AO was higher than OFC FLC%AO in FTLD-Tau (p = 0.01). Separate LME models for Tau and TDP %AO was positively associated with FLC%AO across regions (Tau; Beta = 0.1 SE = .06, p = .03; TDP; Beta = 0.5 SE = .2, p = .02). CONCLUSION In our preliminary sampling, iron-rich gliosis is associated with protein aggregation in partially-dissociated regional patterns in FLTD-Tau vs FTLD-TDP, recapitulating previous histopathological staging schemes. Future work will more comprehensively model the association of iron-rich gliosis and protein aggregation across the brain.

23. Multi‐atlas fully automated segmentation of the locus coeruleus in in vivo neuromelanin‐sensitive MRI

    R. Flores, T. Blanchard, E. Foyard, and 5 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Locus coeruleus (LC) imaging using neuromelanin‐sensitive (NM) MRI sequences is a promising biomarker for detecting early Alzheimer’s Disease (AD). Although automatic approaches have been developed to estimate LC integrity by measuring its intensity, these techniques most often rely on a single template built in a standardized space and/or depend on a number of voxels to be accounted that is defined a priori. Thus, these algorithms make it impossible to perform direct volumetric analyses and do not properly account for inter‐individual anatomical variability. To fill this gap, our aim was to develop a new multi‐atlas fully automated segmentation method using the Automatic Segmentation of Hippocampal Subfields (ASHS) software.

24. Multi‐atlas fully automated segmentation of the locus coeruleus in in vivo neuromelanin‐sensitive MRI

    R. Flores, T. Blanchard, E. Foyard, and 5 more authors

    Alzheimer’s & Dementia, Dec 2024

    Cited by 1

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    Locus coeruleus (LC) imaging using neuromelanin‐sensitive (NM) MRI sequences is a promising biomarker for detecting early Alzheimer’s Disease (AD). Although automatic approaches have been developed to estimate LC integrity by measuring its intensity, these techniques most often rely on a single template built in a standardized space and/or depend on a number of voxels to be accounted that is defined a priori. Thus, these algorithms make it impossible to perform direct volumetric analyses and do not properly account for inter‐individual anatomical variability. To fill this gap, our aim was to develop a new multi‐atlas fully automated segmentation method using the Automatic Segmentation of Hippocampal Subfields (ASHS) software.

25. Feasibility, validity, and normative data for the remote Uniform Data Set neuropsychological battery at the University of Pennsylvania Alzheimer’s Disease Research Center

    Katherine Hackett, Yidan Shi, Laura Schankel, and 8 more authors

    Alzheimer’s & Dementia : Diagnosis, Assessment & Disease Monitoring, Oct 2024

    Cited by 1

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    We investigated the feasibility and validity of the remotely‐administered neuropsychological battery from the National Alzheimer’s Coordinating Center Uniform Data Set (UDS T‐Cog).

26. Open-source graphical user interface for the creation of synthetic skeletons for medical image analysis

    Christian Herz, Nicolas Vergnet, Sijie Tian, and 9 more authors

    Journal of Medical Imaging, May 2024

    Cited by 3

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    Abstract. Purpose Deformable medial modeling is an inverse skeletonization approach to representing anatomy in medical images, which can be used for statistical shape analysis and assessment of patient-specific anatomical features such as locally varying thickness. It involves deforming a pre-defined synthetic skeleton, or template, to anatomical structures of the same class. The lack of software for creating such skeletons has been a limitation to more widespread use of deformable medial modeling. Therefore, the objective of this work is to present an open-source user interface (UI) for the creation of synthetic skeletons for a range of medial modeling applications in medical imaging. Approach A UI for interactive design of synthetic skeletons was implemented in 3D Slicer, an open-source medical image analysis application. The steps in synthetic skeleton design include importation and skeletonization of a 3D segmentation, followed by interactive 3D point placement and triangulation of the medial surface such that the desired branching configuration of the anatomical structure’s medial axis is achieved. Synthetic skeleton design was evaluated in five clinical applications. Compatibility of the synthetic skeletons with open-source software for deformable medial modeling was tested, and representational accuracy of the deformed medial models was evaluated. Results Three users designed synthetic skeletons of anatomies with various topologies: the placenta, aortic root wall, mitral valve, cardiac ventricles, and the uterus. The skeletons were compatible with skeleton-first and boundary-first software for deformable medial modeling. The fitted medial models achieved good representational accuracy with respect to the 3D segmentations from which the synthetic skeletons were generated. Conclusions Synthetic skeleton design has been a practical challenge in leveraging deformable medial modeling for new clinical applications. This work demonstrates an open-source UI for user-friendly design of synthetic skeletons for anatomies with a wide range of topologies.

27. BOLD fMRI signal changes in preclinical Alzheimer’s disease

    S. Hrybouski, Sandhitsu R. Das, L. Xie, and 10 more authors

    Alzheimer’s & Dementia, Dec 2024

    Cited by 1

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    Previous work suggests functional abnormalities in the human brain in preclinical Alzheimer’s disease. However, little has been explored about the relationship between BOLD fMRI signal amplitude/energy over time and AD pathology. In this work we analyzed the effects of AD progression on amplitude of low‐frequency fluctuations (ALFF) during resting‐state fMRI scans both at the whole‐brain level and at a more granular level, focused on regions of the medial temporal lobe (MTL) that are most vulnerable to AD pathology.

28. BOLD Amplitude Correlates of Preclinical Alzheimer’s Disease

    S. Hrybouski, Sandhitsu R. Das, L. Xie, and 7 more authors

    medRxiv : the preprint server for health sciences, Oct 2024

    Cited by 1

    DOI

    
29. MTL networks are differentially affected by tau pathology

    S. Hrybouski, Sandhitsu R. Das, L. Xie, and 9 more authors

    Alzheimer’s & Dementia, Dec 2024

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    The extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional alterations in the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. Here, we examined the relationship between tau accumulation in the (trans)entorhinal cortex and functional connectivity (FC) in two MTL‐affiliated brain networks — the Anterior‐Temporal (AT) and Posterior‐Medial (PM) — in normal agers, individuals with preclinical AD, and patients with symptomatic AD.

30. MTL networks are differentially affected by tau pathology

    S. Hrybouski, Sandhitsu R. Das, L. Xie, and 9 more authors

    Alzheimer’s & Dementia, Dec 2024

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    The extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional alterations in the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. Here, we examined the relationship between tau accumulation in the (trans)entorhinal cortex and functional connectivity (FC) in two MTL‐affiliated brain networks — the Anterior‐Temporal (AT) and Posterior‐Medial (PM) — in normal agers, individuals with preclinical AD, and patients with symptomatic AD.

31. Diffuse juxtacortical white matter texture changes in pre‐clinical Alzheimer’s disease

    Ademola Ilesanmi, Xueying Lyu, E. McGrew, and 3 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Detection of neurodegeneration during preclinical stages of Alzheimer’s disease (AD) is critical for disease prediction and monitoring. Macrostructural brain changes (volume/thickness) during preclinical AD are often not detectable in cross‐sectional studies. Microstructural changes manifested as alterations in texture features may capture subtle neurodegeneration at this stage. Here we investigated the discriminative ability of texture‐based radiomics features in both gray and juxtacortical white matter in preclinical AD.

32. Overview of ADNI MRI

    Clifford Jack, A. Arani, Bret J. Borowski, and 23 more authors

    Alzheimer’s & Dementia, Sep 2024

    Cited by 38

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    The magnetic resonance imaging (MRI) Core has been operating since Alzheimer’s Disease Neuroimaging Initiative’s (ADNI) inception, providing 20 years of data including reliable, multi‐platform standardized protocols, carefully curated image data, and quantitative measures provided by expert investigators. The overarching purposes of the MRI Core include: (1) optimizing and standardizing MRI acquisition methods, which have been adopted by many multicenter studies and trials worldwide and (2) providing curated images and numeric summary values from relevant MRI sequences/contrasts to the scientific community. Over time, ADNI MRI has become increasingly complex. To remain technically current, the ADNI MRI protocol has changed substantially over the past two decades. The ADNI 4 protocol contains nine different imaging types (e.g., three dimensional [3D] T1‐weighted and fluid‐attenuated inversion recovery [FLAIR]). Our view is that the ADNI MRI data are a greatly underutilized resource. The purpose of this paper is to educate the scientific community on ADNI MRI methods and content to promote greater awareness, accessibility, and use.

33. Genetic associations with dementia‐related proteinopathy: Application of item response theory

    Y. Katsumata, D. Fardo, Lincoln M P Shade, and 146 more authors

    Alzheimer’s & Dementia, Mar 2024

    Cited by 5

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    Although dementia‐related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete.

34. Automated deep learning segmentation of high-resolution 7 Tesla postmortem MRI for quantitative analysis of structure-pathology correlations in neurodegenerative diseases

    Pulkit Khandelwal, M. Duong, S. Sadaghiani, and 34 more authors

    Imaging Neuroscience, May 2024

    Cited by 7

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    Abstract Postmortem MRI allows brain anatomy to be examined at high resolution and to link pathology measures with morphometric measurements. However, automated segmentation methods for brain mapping in postmortem MRI are not well developed, primarily due to limited availability of labeled datasets, and heterogeneity in scanner hardware and acquisition protocols. In this work, we present a high-resolution dataset of 135 postmortem human brain tissue specimens imaged at 0.3 mm3 isotropic using a T2w sequence on a 7T whole-body MRI scanner. We developed a deep learning pipeline to segment the cortical mantle by benchmarking the performance of nine deep neural architectures, followed by post-hoc topological correction. We evaluate the reliability of this pipeline via overlap metrics with manual segmentation in 6 specimens, and intra-class correlation between cortical thickness measures extracted from the automatic segmentation and expert-generated reference measures in 36 specimens. We also segment four subcortical structures (caudate, putamen, globus pallidus, and thalamus), white matter hyperintensities, and the normal appearing white matter, providing a limited evaluation of accuracy. We show generalizing capabilities across whole-brain hemispheres in different specimens, and also on unseen images acquired at 0.28 mm3 and 0.16 mm3 isotropic T2*w fast low angle shot (FLASH) sequence at 7T. We report associations between localized cortical thickness and volumetric measurements across key regions, and semi-quantitative neuropathological ratings in a subset of 82 individuals with Alzheimer’s disease (AD) continuum diagnoses. Our code, Jupyter notebooks, and the containerized executables are publicly available at the project webpage (https://pulkit-khandelwal.github.io/exvivo-brain-upenn/).

35. High‐resolution 7 tesla postmortem MRI for quantitative analysis of structure‐pathology correlations in neurodegenerative diseases

    Pulkit Khandelwal, M. Duong, S. Sadaghiani, and 34 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Postmortem MRI allows brain anatomy to be examined at high‐resolution linking pathology with morphometric measurements. However, automated methods for analyzing postmortem MRI are not well developed. We present a deep learning‐based framework for automated segmentation of cortical mantle, subcortical structures (caudate, putamen, globus pallidus, and thalamus), white matter hyperintensities (WMH), and normal appearing white matter in (n = 135) postmortem human brain tissue specimens (Table 1) imaged at 0.3 mm3 T2w 7T spanning Alzheimer’s disease and related dementias. We show generalizing capabilities across unseen images acquired at 0.28 mm3 and 0.16 mm3 T2*w 7T FLASH sequence. We report associations between localized cortical thickness and volumetric measurements across key regions and semi‐quantitative neuropathological ratings.

36. High‐resolution 7 tesla postmortem MRI for quantitative analysis of structure‐pathology correlations in neurodegenerative diseases

    Pulkit Khandelwal, M. Duong, S. Sadaghiani, and 34 more authors

    Alzheimer’s & Dementia, Dec 2024

    Abs DOI

    

    Postmortem MRI allows brain anatomy to be examined at high‐resolution linking pathology with morphometric measurements. However, automated methods for analyzing postmortem MRI are not well developed. We present a deep learning‐based framework for automated segmentation of cortical mantle, subcortical structures (caudate, putamen, globus pallidus, and thalamus), white matter hyperintensities (WMH), and normal appearing white matter in (n=135) postmortem human brain tissue specimens (Table 1) imaged at 0.3 mm3 T2w 7T spanning Alzheimer’s disease and related dementias. We show generalizing capabilities across unseen images acquired at 0.28 mm3 and 0.16 mm3 T2*w 7T FLASH sequence. We report associations between localized cortical thickness and volumetric measurements across key regions and semi‐quantitative neuropathological ratings.

37. Surface-Based Parcellation and Vertex-wise Analysis of Ultra High-resolution ex vivo 7 tesla MRI in Alzheimer’s disease and related dementias

    Pulkit Khandelwal, M. Duong, Lisa Levorse, and 20 more authors

    In MLCN@MICCAI, Mar 2024

    Abs DOI arXiv

    

    Magnetic resonance imaging (MRI) is the standard modality to understand human brain structure and function in vivo (antemortem). Decades of research in human neuroimaging has led to the widespread development of methods and tools to provide automated volume-based segmentations and surface-based parcellations which help localize brain functions to specialized anatomical regions. Recently ex vivo (postmortem) imaging of the brain has opened-up avenues to study brain structure at sub-millimeter ultra high-resolution revealing details not possible to observe with in vivo MRI. Unfortunately, there has been limited methodological development in ex vivo MRI primarily due to lack of datasets and limited centers with such imaging resources. Therefore, in this work, we present one-of-its-kind dataset of 82 ex vivo T2w whole brain hemispheres MRI at 0.3 mm isotropic resolution spanning Alzheimer’s disease and related dementias. We adapted and developed a fast and easy-to-use automated surface-based pipeline to parcellate, for the first time, ultra high-resolution ex vivo brain tissue at the native subject space resolution using the Desikan-Killiany-Tourville (DKT) brain atlas. This allows us to perform vertex-wise analysis in the template space and thereby link morphometry measures with pathology measurements derived from histology. We will open-source our dataset docker container, Jupyter notebooks for ready-to-use out-of-the-box set of tools and command line options to advance ex vivo MRI clinical brain imaging research on the project webpage.

38. Surface-based parcellation and vertex-wise analysis of ultra high-resolution ex vivo 7 tesla MRI in neurodegenerative diseases

    Pulkit Khandelwal, M. Duong, Constanza Fuentes, and 19 more authors

    ArXiv, Mar 2024

    DOI

    
39. Automatic Segmentation of Medial Temporal Lobe Subregions in Multi‐Scanner, Multi‐Modality Magnetic Resonance Imaging of Variable Quality

    Yue Li, L. Xie, Pulkit Khandelwal, and 9 more authors

    Hippocampus, May 2024

    Cited by 1

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    Objectives Volumetry of subregions in the medial temporal lobe (MTL) computed from automatic segmentation in MRI can track neurodegeneration in Alzheimer’s disease. However, poor quality MR images can lead to unreliable segmentation of MTL subregions. Considering that different MRI contrast mechanisms and field strengths (jointly referred to as “modalities” here) offer distinct advantages in imaging different parts of the MTL, we developed a muti-modality segmentation model using both 7 tesla (7T) and 3 tesla (3T) structural MRI to obtain robust segmentation in poor-quality images. Method MRI modalities including 3T T1-weighted, 3T T2-weighted, 7T T1-weighted and 7T T2-weighted (7T-T2w) of 197 participants were collected from a longitudinal aging study at the Penn Alzheimer’s Disease Research Center. Among them, 7T-T2w was used as the primary modality, and all other modalities were rigidly registered to the 7T-T2w. A model derived from nnU-Net took these registered modalities as input and outputted subregion segmentation in 7T-T2w space. 7T-T2w images most of which had high quality from 25 selected training participants were manually segmented to train the multi-modality model. Modality augmentation, which randomly replaced certain modalities with Gaussian noise, was applied during training to guide the model to extract information from all modalities. Results The multi-modality model delivered good performance regardless of 7T-T2w quality, while the single-modality model under-segmented subregions in poor-quality images. The multi-modality model generally demonstrated stronger discrimination of A+MCI versus A-CU. Intra-class correlation and Bland-Altman plots demonstrate that the multi-modality model had higher longitudinal segmentation consistency in all subregions while the single-modality model had low consistency in poor-quality images. Conclusion The multi-modality MRI segmentation model provides an improved biomarker for neurodegeneration in the MTL that is robust to image quality. It also provides a framework for other studies which may benefit from multimodal imaging.

40. Robust multi‐modality segmentation of medial temporal lobe subregions using both 3‐tesla and 7‐tesla magnetic resonance imaging

    Yue Li, Pulkit Khandelwal, L. Xie, and 7 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Volumetry of subregions in the medial temporal lobe (MTL) computed from automatic segmentation in MRI can track neurodegeneration in Alzheimer’s disease. However, dropout artifacts are present in some modalities, leading to poor image quality and unreliable segmentation of MTL subregions. Considering that MRI modalities with different field strength offer distinct advantages in imaging different parts of the MTL, we developed a muti‐modality segmentation model using both 7‐tesla (7T) and 3‐tesla (3T) structural MRI to obtain robust segmentation in poor‐quality images.

41. Robust multi‐modality segmentation of medial temporal lobe subregions using both 3‐tesla and 7‐tesla magnetic resonance imaging

    Yue Li, Pulkit Khandelwal, L. Xie, and 7 more authors

    Alzheimer’s & Dementia, Dec 2024

    Abs DOI

    

    Volumetry of subregions in the medial temporal lobe (MTL) computed from automatic segmentation in MRI can track neurodegeneration in Alzheimer’s disease. However, dropout artifacts are present in some modalities, leading to poor image quality and unreliable segmentation of MTL subregions. Considering that MRI modalities with different field strength offer distinct advantages in imaging different parts of the MTL, we developed a muti‐modality segmentation model using both 7‐tesla (7T) and 3‐tesla (3T) structural MRI to obtain robust segmentation in poor‐quality images.

42. Event‐based modeling of T‐N mismatch reveals distinct spatio‐temporal trajectories of subtypes with likely co‐pathology in Alzheimer’s disease

    Xueying Lyu, Paul Yushkevich, S. Hrybouski, and 10 more authors

    Alzheimer’s & Dementia, Dec 2024

    Abs DOI

    

    The heterogeneity of Alzheimer’s disease (AD) and lack of well‐validated markers of co‐pathologies present a substantial challenge for therapeutics. We previously found phenotypes defined by Tau (T) ‐ Neurodegeneration (N) discordance linked to non‐Alzheimer’s pathologies (e.g. TDP‐43, vascular disease). In this work, we aim to leverage T‐N mismatch for identifying distinct spatial‐temporal progression patterns of non‐AD pathologies.

43. Clinical Manifestations.

    Dawn J. Mechanic-Hamilton, Valerie Humphreys, Alex Prusky, and 2 more authors

    Alzheimer’s & dementia : the journal of the Alzheimer’s Association, Dec 2024

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    BACKGROUND Mobile, valid and engaging cognitive assessments are essential for detecting and tracking change in research participants and patients at risk for Alzheimer’s Disease and Related Dementias (ADRDs). This pilot study aims to determine the feasibility and generalizability of an at-home, app-based cognitive assessment, the mobile cognitive app performance platform (mCAPP), to detect cognitive changes associated with aging and preclinical AD. METHOD mCAPP includes three gamified tasks (Figure 1): (1) a "concentration" memory task that includes learning and matching hidden card pairs with increasing memory load, pattern separation features (lure vs. non-lure), and spatial memory (2) a stroop-like task ("brick drop") with speeded word and color identification and response inhibition components and (3) a digit-symbol coding-like task ("space imposters") with increasing pairs. Participants used mCAPP at home for two weeks and completed the NACC UDS3 and additional paper and pencil tests. Participants included ninety-three adults (72% female; age = 72.5±5.5, education = 16.4±2.6; 49.5% White, 49.5% Black/African American, 1% Multiracial) without cognitive impairment enrolled in the Penn ADRC cohort. A subgroup also completed longitudinal mCAPP testing and amyloid PET imaging. RESULT Participants played 11±4 sessions over two weeks, with 61% playing more than the assigned sessions. Most participants (97%) used a smartphone. Usability rating was 6.3±0.8 (1-7 scale). Most participants rated the difficulty of the tasks as "just right" for Concentration (93%), Brick Drop (84%), and Space Imposters (87%) after playing the games for the first time. 70% reported preferring mobile device cognitive assessment to standard in-person cognitive batteries. All tasks showed lower performance with increasing cognitive load (p’s<.05). mCAPP measures correlated with paper and pencil tests from analogous domains on paper and pencil measures (p’s<.01). Participants with a positive amyloid PET scan showed a trend toward slower and less accurate performance on some mCAPP measures. CONCLUSION This pilot study shows mCAPP usability for at-home use in a diverse cohort of older adults. Performance across measures indicate initial reliability and validity of mCAPP. Future work will include the evaluation of mCAPP performance relationships with biomarkers and longitudinal data analysis. Remote, accessible, and reliable cognitive assessment has the potential to reduce barriers to research participation and clinical care.

44. Remote App‐Based Cognitive Assessment in Aging and Pre‐Clinical Alzheimer’s Disease in a Diverse Sample of Older Adults

    Dawn J. Mechanic-Hamilton, Valerie Humphreys, Alex Prusky, and 2 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Mobile, valid and engaging cognitive assessments are essential for detecting and tracking change in research participants and patients at risk for Alzheimer’s Disease and Related Dementias (ADRDs). This pilot study aims to determine the feasibility and generalizability of an at‐home, app‐based cognitive assessment, the mobile cognitive app performance platform (mCAPP), to detect cognitive changes associated with aging and preclinical AD.

45. Percentile‐based hippocampal volume MRI biomarker for distinguishing concomitant LATE and AD from pure LATE and pure AD

    Nidhi S Mundada, Xueying Lyu, E. McGrew, and 4 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Due to the lack of in vivo molecular biomarkers for Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), which commonly co‐occurs with Alzheimer’s disease (AD), it is challenging to identify patients with mixed AD/LATE pathology. Autopsy studies have suggested that AD patients with greater hippocampal atrophy are disproportionately enriched in having concomitant LATE. Here we define the lower quartile of hippocampal volume as a biomarker of possible LATE with AD.

46. Postmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer’s disease

    S. Ravikumar, Amanda E Denning, Sydney A. Lim, and 24 more authors

    Nature Communications, Jun 2024

    Cited by 27

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    Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer’s Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers. Using high-resolution ex vivo MRI and serial histology, Ravikumar et al. characterise 3D tau spread across histologically defined medial temporal lobe subregions thus providing a postmortem reference for in vivo studies on early Alzheimer’s disease.

47. Postmortem MRI signature of Hippocampal Sclerosis of Aging

    G. Rådman, Amanda E Denning, S. Ravikumar, and 22 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Hippocampal Sclerosis of aging (HS) refers to age‐related selective neuronal loss and gliosis in hippocampal cornu ammonis 1 (CA1) and subiculum that is out of proportion to tau pathology in Alzheimer’s Disease (AD). HS is related to cognitive decline and memory impairments separately from other neurodegenerative pathologies. To date, in vivo imaging biomarkers of HS of aging are non‐existent, and their development would greatly improve diagnosis and prognosis in memory clinics. We therefore aimed to characterize the magnetic resonance imaging (MRI) signature of HS among autopsy confirmed cases of HS.

48. Clinical Manifestations.

    Rachel Rovere, Erin Liebenberg, Kimberly Halberstadter, and 2 more authors

    Alzheimer’s & dementia : the journal of the Alzheimer’s Association, Dec 2024

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    BACKGROUND This study assesses the sensitivity of the mobile cognitive app performance platform (mCAPP), a mobile and engaging cognitive assessment tool, to participant sleep duration. METHOD The mCAPP includes three gamified tasks: a memory task ("Concentration"), a stroop-like task ("Brick Drop"), and a digit-symbol coding-like task ("Space Imposters"). For all games, shorter reaction times and fewer guesses indicates better performance. The cohort included 50 participants (72% female; age = 71.9±4.5; education = 16.8±2.3; 51% white; 49% Black/African American) without cognitive impairment who are enrolled in the Penn ADRC cohort. Sleep data was collected via actigraphy (Fitbit). Game performance and overnight sleep prior to gameplay were analyzed as a whole and grouped by fewer (quartile 1; Q1) and higher (quartile 4; Q4) minutes of sleep. RESULT The average number of minutes of sleep was 378.0±96.5. Overall, minutes of sleep showed a significant negative correlation with reaction time on Space Imposters (ρ = 0.001). Participants with the fewest minutes of nighttime sleep performed slower than those with the most sleep on Space Imposters (Q1 M = 2.73; Q4 M = 2.40; p<.001), Brick Drop (Q1 M = 1.58; Q4 M = 1.31; p = .004), and Concentration (Q1 M = 5.25; Q4 M = 5.02; p = .006). There was not a significant difference in number of errors on Space Imposters (p = 0.53) or Brick Drop (p = 0.45) when comparing performance of participants with lower and higher quartiles of sleep, but there was a significant difference in the number of guesses on Concentration (Q1 M = 14.91; Q4 M = 12.80; p = 0.01). CONCLUSION The mCAPP can remotely detect differences in cognitive performance related to nighttime sleep prior to gameplay. Future studies will examine differences in performance related to the time-of-day gameplay occurs (how long after overnight sleep) and whether performance is affected by daytime napping. A larger data set will also be used to fully determine the sensitivity of mCAPP to participant sleep duration and examine within-participant effects.

49. Developing an anatomically valid segmentation protocol for anterior regions of the medial temporal lobe

    Niyousha Sadeghpour, Sydney A. Lim, A. Wuestefeld, and 28 more authors

    Alzheimer’s & Dementia, Dec 2024

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    The anterior portion of the MTL is one of the first regions targeted by pathology in sporadic Alzheimer’s disease (AD) indicating the potential for imaging metrics from this region to serve as valuable imaging biomarkers. However, most existing automated approaches for MTL segmentation do not incorporate anterior MTL subregions, and the few that do fail to account for its complex anatomical variability. Leveraging a unique postmortem dataset consisting of histology and structural MRI scans we aimed to develop an anatomically valid segmentation protocol for anterior entorhinal cortex (ERC), Brodmann Area (BA) 35, and BA36 and apply it for automated MTL segmentation of in vivo 3 tesla (T) MRI.

50. Implementation and validation of face de‐identification (de‐facing) in ADNI4

    C. Schwarz, M. Choe, Stephanie Rossi, and 21 more authors

    Alzheimer’s & Dementia, Oct 2024

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    Recent technological advances have increased the risk that de‐identified brain images could be re‐identified from face imagery. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a leading source of publicly available de‐identified brain imaging, who quickly acted to protect participants’ privacy.

51. Implementation and Validation of Face De‐Identification (de‐facing) in ADNI‐4

    C. Schwarz, D. Tosun, Paul Yushkevich, and 17 more authors

    Alzheimer’s & Dementia, Dec 2024

    Cited by 1

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    Recent advances in automatic face recognition have increased the risk that de‐identified research imaging data could be re‐identified from face imagery in brain scans.

52. Does Neurodegeneration Lag Behind Tau Deposition in Alzheimer Dementia?

    Ujashi Shah, L. Xie, E. McGrew, and 2 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Alzheimer’s disease (AD) is defined by the presence of ß‐amyloid (Aß) plaques and tau‐based neurofibrillary tangles (NFTs). Understanding the temporal relationship of NFTs with atrophy in early AD regions, specifically the medial temporal lobe (MTL), is critical for monitoring disease progression. Accumulation of NFTs has been suggested to precede atrophy because cross‐sectional measures of atrophy are more weakly associated with baseline tracer uptake than prospective longitudinal ones. However, longitudinal measures may be more sensitive to disease‐related atrophy at early AD stages. To address this, we examine cross‐sectional versus longitudinal measures before or after the time of tau PET.

53. MRI Correlates of Executive Function in Cognitively Normal Older Subjects

    Banafsheh Shakibajahromi, Sudipto Dolui, Christopher D. Brown, and 7 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Cerebral small vessel disease (CSVD) is the most prevalent cause of vascular cognitive impairment. Executive function impairment and white matter (WM) lesions occur early in CSVD, the latter typically in periventricular WM (PVWM) ‐ the least perfused brain region. Accounting for vascular risk factors (VRF) and amyloid status in cognitively normal older subjects, we assessed the relationship between Trail‐making test (TMT) performance and MRI measures preceding WM lesions: arterial spin labeling (ASL)‐derived cerebral blood flow (CBF) and diffusion tensor imaging (DTI) indices in normal‐appearing WM (NAWM) and normal‐appearing PVWM (NAPVWM).

54. MRI Correlates of Executive Function in Cognitively Normal Older Subjects

    Banafsheh Shakibajahromi, Sudipto Dolui, Christopher D. Brown, and 7 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Cerebral small vessel disease (CSVD) is the most prevalent cause of vascular cognitive impairment. Executive function impairment and white matter (WM) lesions occur early in CSVD, the latter typically in periventricular WM (PVWM) ‐ the least perfused brain region. Accounting for vascular risk factors (VRF) and amyloid status in cognitively normal older subjects, we assessed the relationship between Trail‐making test (TMT) performance and MRI measures preceding WM lesions: arterial spin labeling (ASL)‐derived cerebral blood flow (CBF) and diffusion tensor imaging (DTI) indices in normal‐appearing WM (NAWM) and normal‐appearing PVWM (NAPVWM).

55. Biological aging is associated with atypical neurodegenerative patterns in Alzheimer’s disease

    Lasya P. Sreepada, Christopher D. Brown, Sandhitsu R. Das, and 3 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Atypical presentations of Alzheimer’s disease (AD), which demonstrate more cortical involvement relative to medial temporal lobe (MTL), are generally associated with younger age of onset. Age, defined chronologically, is a primary driver of AD pathology and neurodegeneration. However, some young onset cases are typical, amnestic presentations and some older onset cases present more cortical atrophy. We hypothesize that a biological definition of age, defined using epigenetic clock measures, may be even more tightly linked to atypicality than chronological age.

56. Biological aging is associated with atypical neurodegenerative patterns in Alzheimer’s disease

    Lasya P. Sreepada, Christopher D. Brown, Sandhitsu R. Das, and 3 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Atypical presentations of Alzheimer’s disease (AD), which demonstrate more cortical involvement relative to medial temporal lobe (MTL), are generally associated with younger age of onset. Age, defined chronologically, is a primary driver of AD pathology and neurodegeneration. However, some young onset cases are typical, amnestic presentations and some older onset cases present more cortical atrophy. We hypothesize that a biological definition of age, defined using epigenetic clock measures, may be even more tightly linked to atypicality than chronological age.

57. Effects of Amyloid Pathology and Vascular Risk Factors on Regional Cerebral Blood Flow Patterns

    M. Taghvaei, S. Sadaghiani, Banafsheh Shakibajahromi, and 7 more authors

    Alzheimer’s & Dementia, Dec 2024

    Abs DOI

    

    Regional cerebral blood flow (CBF) can be noninvasively quantified using arterial spin labeled (ASL) perfusion MRI. In Alzheimer’s disease (AD) and mild cognitive impairment (MCI), hypoperfusion typically occurs in precuneus, posterior cingulate cortex (PCC), and hippocampus. Small vessel disease (SVD), a systemic disorder that commonly underlies vascular cognitive impairment, also causes brain hypoperfusion. Many dementia patients demonstrate both neurodegenerative and vascular pathologies, which may interact to accelerate cognitive decline. Here we used advanced background‐suppressed 3D ASL to assess CBF variations across the AD spectrum and in relation to risk factors for AD and SVD.

58. Regional cerebral blood flow reflects both neurodegeneration and microvascular integrity across the Alzheimer’s continuum

    M. Taghvaei, Sudipto Dolui, S. Sadaghiani, and 8 more authors

    Alzheimer’s & Dementia, Dec 2024

    Cited by 9

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    Alzheimer’s disease (AD) typically involves both neurodegenerative and vascular pathologies, each associated with reductions in cerebral blood flow (CBF). However, it remains unclear whether vascular and neural contributions to regional CBF can be differentiated.

59. Clinical Manifestations.

    A. Wuestefeld, Salena Cui, Sandhitsu R. Das, and 5 more authors

    Alzheimer’s & dementia : the journal of the Alzheimer’s Association, Dec 2024

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    BACKGROUND Tau pathology is closely related to cognitive decline in Alzheimer’s disease (AD). Neurodegeneration is the putative mechanism by which tau leads to cognitive deficits. However, there is limited work on the associations between tau, neurodegeneration, and specific cognitive domains. We investigate potential mediating effects of medial temporal lobe (MTL) and neocortical neurodegeneration for different cognitive domains in amyloid-β-positive (Aβ+) adults. METHOD We included 325 positron emission tomography (PET) Aβ+ individuals across the AD spectrum from the Alzheimer’s Disease Neuroimaging Initiative (age: 72±8 [55-90]; 51.1% female, education: 16±2 years). Hippocampal volume and cortical thickness were measured from T1-weighted structural magnetic resonance imaging in typical AD regions (Fig. 1). Using flortaucipir-PET, tau was quantified for two composite regions (MTL, neocortical). Included cognitive measures are shown in Fig. 1. Mediation analyses between tau-PET, thickness/volume, and cognition were performed. Cognitive measures were adjusted to isolate the function of interest (Fig. 1). RESULT Higher tau-PET uptake and lower thickness were associated with lower performance on all cognitive measures. In simple mediations, tau-immediate recall associations were mediated by MTL, parietal, and temporal regions (Fig. 2A). Tau-delayed recall associations were mediated by MTL regions. Tau-late recall and tau-recognition associations were mediated by MTL and parietal regions. Tau-fluency and tau-executive functioning associations were mediated by MTL and parietal regions, as well as temporal regions for fluency. Complex mediations investigated significant mediators simultaneously (Fig. 2B+3). Depending if MTL/neocortical tau remained significant when covarying for the other tau measure in a regression, the complex mediation models focused on MTL and/or neocortical regions (Fig. 2B description). Hippocampus mediated the tau-late recall and tau-recognition associations. Brodmann area 35 mediated the tau-delayed recall association. Tau-fluency was, at a trend level, mediated by inferior temporal thickness. Tau-executive functioning did not demonstrate a mediation effect, potentially due to limited frontal atrophy. All mediators were partial mediators explaining up to 23% of variance. CONCLUSION The results suggest that MTL tau pathology, partially mediated by macrostructural changes, lead to impairments in specific memory domains in early AD. Impairments in fluency and executive functioning, however, seem more likely to follow from tau-induced effects in neocortical regions.

60. Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories

    A. Wuestefeld, H. Baumeister , Jenna N. Adams, and 32 more authors

    Hippocampus, Feb 2024

    Cited by 8

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    The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer’s disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the entorhinal and parahippocampal cortices as well as Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl‐stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 μm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized slices spaced 5 mm apart (pixel size 0.4 μm at 20× magnification). Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while the definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists’ agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed less saliently. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically‐informed neuroimaging research on the human MTL cortex.

61. Medial temporal lobe atrophy patterns in early-versus late-onset amnestic Alzheimer’s disease

    A. Wuestefeld, A. Pichet Binette, D. Westen, and 12 more authors

    Alzheimer’s Research & Therapy, Sep 2024

    Cited by 3

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    The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer’s disease (EOAD). Yet, detailed examination of MTL subfields and drivers of atrophy in amnestic EOAD is lacking. BioFINDER-2 participants with memory impairment, abnormal amyloid-β and tau-PET were included. Forty-one amnestic EOAD individuals ≤65 years and, as comparison, late-onset AD (aLOAD, ≥70 years, n = 154) and amyloid-β-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups: aLOAD showed thinner entorhinal cortices than aEOAD; aEOAD showed thinner parietal regions than aLOAD. aEOAD showed lower white matter hyperintensities than aLOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity were found. We found evidence for MTL atrophy in amnestic EOAD and overall similar levels to aLOAD of MTL tau pathology and co-pathologies.

62. Medial temporal lobe atrophy patterns in early- versus late-onset amnestic Alzheimer’s disease

    A. Wuestefeld, A. Pichet Binette, D. Westen, and 12 more authors

    bioRxiv, May 2024

    Cited by 7

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    Background The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer’s disease (EOAD). Yet, detailed examination of MTL subfield volumes and drivers of atrophy in amnestic EOAD is lacking. Methods BioFINDER-2 participants with memory impairment, abnormal amyloid-β status and tau-PET were included. Forty-one EOAD individuals aged ≥65 years and, as comparison, late-onset AD (LOAD, ≤70 years, n=154) and Aβ-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. Results AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups, although LOAD showed thinner entorhinal cortices compared to EOAD. EOAD showed lower WMH compared to LOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity was found. Conclusions We found in vivo evidence for MTL atrophy in amnestic EOAD and overall similar levels to LOAD of MTL tau pathology and co-pathologies.

63. The association between tau pathology and later stages of memory processing is mediated by medial temporal lobe atrophy in typical Alzheimer’s Disease

    A. Wuestefeld, Salena Cui, Sandhitsu R. Das, and 5 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Tau pathology is closely related to cognitive decline in Alzheimer’s disease (AD). Neurodegeneration is the putative mechanism by which tau leads to cognitive deficits. However, there is limited work on the associations between tau, neurodegeneration, and specific cognitive domains. We investigate potential mediating effects of medial temporal lobe (MTL) and neocortical neurodegeneration for different cognitive domains in amyloid‐ß‐positive (Aß+) adults.

64. Correction: Baseline structural MRI and plasma biomarkers predict longitudinal structural atrophy and cognitive decline in early Alzheimer’s disease

    L. Xie, Sandhitsu R. Das, L. Wisse, and 6 more authors

    Alzheimer’s Research & Therapy, Jan 2024

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65. Spatial Pattern of Medial Temporal Lobe Cross‐Sectional and Longitudinal Structural Change in Cognitively Normal Individuals

    L. Xie, Sandhitsu R. Das, Yue Li, and 21 more authors

    Alzheimer’s & Dementia, Dec 2024

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    The medial temporal lobe’s (MTL) early involvement in tau pathology makes it a key focus in the development of preclinical Alzheimer’s disease (AD) biomarkers. ROI analyses in prior studies reported significant MTL structural differences in cognitively normal individuals with and without β‐amyloid (A+/‐CN). Pointwise analysis, offering spatial information of early neurodegeneration, has potential to pinpoint “signature regions” of pathological change, but has been underexplored in the MTL. This study employs a specialized pointwise analysis pipeline to examine the spatial pattern of MTL structural change in subgroups dichotomized by both β‐amyloid and tau status in a large cohort of CN individuals.

66. Spatial Pattern of Medial Temporal Lobe Cross‐Sectional and Longitudinal Structural Change in Cognitively Normal Individuals

    L. Xie, Sandhitsu R. Das, Yue Li, and 21 more authors

    Alzheimer’s & Dementia, Dec 2024

    Abs DOI PDF

    

    The medial temporal lobe’s (MTL) early involvement in tau pathology makes it a key focus in the development of preclinical Alzheimer’s disease (AD) biomarkers. ROI analyses in prior studies reported significant MTL structural differences in cognitively normal individuals with and without ß‐amyloid (A+/‐CN). Pointwise analysis, offering spatial information of early neurodegeneration, has potential to pinpoint “signature regions” of pathological change, but has been underexplored in the MTL. This study employs a specialized pointwise analysis pipeline to examine the spatial pattern of MTL structural change in subgroups dichotomized by both ß‐amyloid and tau status in a large cohort of CN individuals.

67. Utilizing Advanced Artificial Intelligence for Automated Detection and Segmentation of Amyloid‐Related Imaging Abnormality (ARIA)

    L. Xie, Paul Yushkevich, Sandhitsu R. Das, and 2 more authors

    Alzheimer’s & Dementia, Dec 2024

    Cited by 1

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    The recent breakthrough in monoclonal antibody treatment for Alzheimer’s disease (AD) has ushered in a new phase in AD healthcare. However, associated amyloid‐related imaging abnormalities (ARIA) present a significant risk to patients, necessitating careful monitoring. Detection by radiologists can be challenging and may suffer from inconsistency. This study investigates the potential of advanced artificial intelligence (AI) for automated detection of micro‐hemorrhage (mH) in GRE MRI and ARIA‐like abnormal hyper‐intensity in FLAIR MRI, the two primary manifestations of ARIA.

68. Utilizing Advanced Artificial Intelligence for Automated Detection and Segmentation of Amyloid‐Related Imaging Abnormality (ARIA)

    L. Xie, Paul Yushkevich, Sandhitsu R. Das, and 2 more authors

    Alzheimer’s & Dementia, Dec 2024

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    The recent breakthrough in monoclonal antibody treatment for Alzheimer’s disease (AD) has ushered in a new phase in AD healthcare. However, associated amyloid‐related imaging abnormalities (ARIA) present a significant risk to patients, necessitating careful monitoring. Detection by radiologists can be challenging and may suffer from inconsistency. This study investigates the potential of advanced artificial intelligence (AI) for automated detection of micro‐hemorrhage (mH) in GRE MRI and ARIA‐like abnormal hyper‐intensity in FLAIR MRI, the two primary manifestations of ARIA.

69. Insights into LATE from postmortem imaging

    Paul Yushkevich, Amanda E Denning, Lisa Levorse, and 18 more authors

    Alzheimer’s & Dementia, Dec 2024

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    Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE) is a neurodegenerative disease that is often comorbid with Alzheimer’s disease (AD) and for which there are no reliable specific chemical or PET biomarkers available. Recent progress in disease‐modifying treatments for AD elevates the need for reliable in vivo detection of LATE and other comorbid neurodegenerative diseases. The promise of postmortem and antemortem MRI studies in LATE is that they will lead to the discovery of patterns of neurodegeneration associated with TDP‐43 pathology that could be reliably detected in vivo and used as a biomarker of LATE.

70. Morphometry of medial temporal lobe subregions using high‐resolution T2‐weighted MRI in ADNI3: Why, how, and what’s next?

    Paul Yushkevich, R. Ittyerah, Yue Li, and 10 more authors

    Alzheimer’s & Dementia, Sep 2024

    Cited by 5

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    This paper for the 20th anniversary of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) provides an overview of magnetic resonance imaging (MRI) of medial temporal lobe (MTL) subregions in ADNI using a dedicated high‐resolution T2‐weighted sequence. A review of the work that supported the inclusion of this imaging modality into ADNI Phase 3 is followed by a brief description of the ADNI MTL imaging and analysis protocols and a summary of studies that have used these data. This review is supplemented by a new study that uses novel surface‐based tools to characterize MTL neurodegeneration across biomarker‐defined AD stages. This analysis reveals a pattern of spreading cortical thinning associated with increasing levels of tau pathology in the presence of elevated amyloid beta, with apparent epicenters in the transentorhinal region and inferior hippocampal subfields. The paper concludes with an outlook for high‐resolution imaging of the MTL in ADNI Phase 4.

2023

1. Stress-related reduction of hippocampal subfield volumes in major depressive disorder: A 7-Tesla study

   Judy Alper, Rui Feng, G. Verma, and 14 more authors

   Frontiers in Psychiatry, Feb 2023

   Cited by 9

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   Background Major depressive disorder (MDD) is a prevalent health problem with complex pathophysiology that is not clearly understood. Prior work has implicated the hippocampus in MDD, but how hippocampal subfields influence or are affected by MDD requires further characterization with high-resolution data. This will help ascertain the accuracy and reproducibility of previous subfield findings in depression as well as correlate subfield volumes with MDD symptom scores. The objective of this study was to assess volumetric differences in hippocampal subfields between MDD patients globally and healthy controls (HC) as well as between a subset of treatment-resistant depression (TRD) patients and HC using automatic segmentation of hippocampal subfields (ASHS) software and ultra-high field MRI. Methods Thirty-five MDD patients and 28 HC underwent imaging using 7-Tesla MRI. ASHS software was applied to the imaging data to perform automated hippocampal segmentation and provide volumetrics for analysis. An exploratory analysis was also performed on associations between symptom scores for diagnostic testing and hippocampal subfield volumes. Results Compared to HC, MDD and TRD patients showed reduced right-hemisphere CA2/3 subfield volume (p = 0.01, η2 = 0.31 and p = 0.3, η2 = 0.44, respectively). Additionally, negative associations were found between subfield volumes and life-stressor checklist scores, including left CA1 (p = 0.041, f2 = 0.419), left CA4/DG (p = 0.010, f2 = 0.584), right subiculum total (p = 0.038, f2 = 0.354), left hippocampus total (p = 0.015, f2 = 0.134), and right hippocampus total (p = 0.034, f2 = 0.110). Caution should be exercised in interpreting these results due to the small sample size and low power. Conclusion Determining biomarkers for MDD and TRD pathophysiology through segmentation on high-resolution MRI data and understanding the effects of stress on these regions can enable better assessment of biological response to treatment selection and may elucidate the underlying mechanisms of depression.

2. Association of Sleep-Disordered Breathing and Medial Temporal Lobe Atrophy in Cognitively Unimpaired Amyloid-Positive Older Adults

   Claire André, E. Kuhn, S. Réhel, and 12 more authors

   Neurology, May 2023

   Cited by 19

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   Background and Objectives Sleep disordered breathing (SDB) has been related to amyloid deposition and an increased dementia risk. However, how SDB relates to medial temporal lobe neurodegeneration and subsequent episodic memory impairment is unclear. Our objective was to investigate the impact of amyloid positivity on the associations between SDB severity, medial temporal lobe subregions, and episodic memory performance in cognitively unimpaired older adults. Methods Data were acquired between 2016 and 2020 in the context of the Age-Well randomized controlled trial of the Medit-Aging European project. Participants older than 65 years who were free of neurologic, psychiatric, or chronic medical diseases were recruited from the community. They completed a neuropsychological evaluation, in-home polysomnography, a Florbetapir PET, and an MRI, including a specific high-resolution assessment of the medial temporal lobe and hippocampal subfields. Multiple linear regressions were conducted to test interactions between amyloid status and SDB severity on the volume of MTL subregions, controlling for age, sex, education, and the ApoE4 status. Secondary analyses aimed at investigating the links between SDB, MTL subregional atrophy, and episodic memory performance at baseline and at a mean follow-up of 20.66 months in the whole cohort and in subgroups stratified according to amyloid status. Results We included 122 cognitively intact community-dwelling older adults (mean age ± SD: 69.40 ± 3.85 years, 77 women, 26 Aβ+ individuals) in baseline analyses and 111 at follow-up. The apnea-hypopnea index interacted with entorhinal (β = −0.81, p < 0.001, pη2 = 0.19), whole hippocampal (β = −0.61, p < 0.001, pη2 = 0.10), subiculum (β = −0.56, p = 0.002, pη2 = 0.08), CA1 (β = −0.55, p = 0.002, pη2 = 0.08), and DG (β = −0.53, p = 0.003, pη2 = 0.08) volumes such that a higher sleep apnea severity was related to lower MTL subregion volumes in amyloid-positive individuals, but not in those who were amyloid negative. In the whole cohort, lower whole hippocampal (r = 0.27, p = 0.005) and CA1 (r = 0.28, p = 0.003) volumes at baseline were associated with worse episodic memory performance at follow-up. Discussion Overall, we showed that SDB was associated with MTL atrophy in cognitively asymptomatic older adults engaged in the Alzheimer continuum, which may increase the risk of developing memory impairment over time. Trial Registration Information ClinicalTrials.gov Identifier: NCT02977819.

3. Comparison of histological delineation of the entorhinal, perirhinal, ectorhinal, and parahippocampal cortices by different neuroanatomy laboratories

   H. Baumeister, A. Wuestefeld , Jenna N. Adams, and 19 more authors

   Alzheimer’s & Dementia, Dec 2023

   Cited by 1

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   The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and a hotspot of neurodegenerative processes (e.g., accumulation of tau tangles or TDP‐43). Importantly, the MTL cortex comprises several subregions with distinct functional, cytoarchitectonic, and macro‐anatomical features (Fig. 1). In vivo imaging studies measuring atrophy or aggregates of pathologies in these subregions rely on various segmentation protocols. Comparability of these imaging studies is limited as segmentation protocols differ, which results from different macro‐anatomical parcellations and cytoarchitectonic definitions of MTL subregions. Thus, it must be clarified to which extent definitions of MTL subregions overlap between neuroanatomists, to establish a harmonized MTL magnetic resonance imaging (MRI) segmentation protocol. We give an overview of cytoarchitectonic definitions of MTL cortex subregions provided by four neuroanatomists from independent laboratories.

4. Medial temporal lobe gray matter microstructure alterations provide improved sensitivity to detect neurodegeneration associated with Alzheimer’s disease biomarkers

   Christopher A. Brown, Sandhitsu R. Das, L. Xie, and 5 more authors

   Alzheimer’s & Dementia, Dec 2023

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   Despite the strengths conventional structural imaging measures to detect atrophy, cross‐sectional relationships between neurodegeneration and Alzheimer’s disease (AD) biomarkers in early stages is limited. Neurite orientation dispersion and density imaging (NODDI) measures microstructural alterations that are unique from conventional structural metrics. Alterations in microstructure have been detected in individuals with AD compared to cognitively normal individuals, but there is sparse data regarding the relationship between these metrics and AD biomarkers. Here we sought to characterize how NODDI metrics in the medial temporal lobe (MTL) are associated with plasma AD biomarkers.

5. Prediction of Regional Tau Spread Using Individualized Tau Epicenters and Structural Connectomes (S39.002)

   Christopher Brown, Sandhitsu R. Das, Ilya Nasrallah, and 4 more authors

   Wednesday, April 26, Apr 2023

   DOI

   
6. A (Sub)field Guide to Quality Control in Hippocampal Subfield Segmentation on Highresolution T2-weighted MRI

   K. Canada, N. Mazloum-Farzaghi, G. Rådman, and 22 more authors

   bioRxiv, Dec 2023

   Cited by 1

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   Inquiries into properties of brain structure and function have progressed due to developments in magnetic resonance imaging (MRI). To sustain progress in investigating and quantifying neuroanatomical details in vivo, the reliability and validity of brain measurements are paramount. Quality control (QC) is a set of procedures for mitigating errors and ensuring the validity and reliability of brain measurements. Despite its importance, there is little guidance on best QC practices and reporting procedures. The study of hippocampal subfields in vivo is a critical case for QC because of their small size, inter-dependent boundary definitions, and common artifacts in the MRI data used for subfield measurements. We addressed this gap by surveying the broader scientific community studying hippocampal subfields on their views and approaches to QC. We received responses from 37 investigators spanning 10 countries, covering different career stages, and studying both healthy and pathological development and aging. In this sample, 81% of researchers considered QC to be very important or important, and 19% viewed it as fairly important. Despite this, only 46% of researchers reported on their QC processes in prior publications. In many instances, lack of reporting appeared due to ambiguous guidance on relevant details and guidance for reporting, rather than absence of QC. Here, we provide recommendations for correcting errors to maximize reliability and minimize bias. We also summarize threats to segmentation accuracy, review common QC methods, and make recommendations for best practices and reporting in publications. Implementing the recommended QC practices will collectively improve inferences to the larger population, as well as have implications for clinical practice and public health.

7. T1 MRI reveals differential hippocampal atrophy in Lewy Body Disorders with and without Alzheimer’s copathology

   Jesse S Cohen, J. Phillips, Sandhitsu R. Das, and 7 more authors

   Alzheimer’s & Dementia, Dec 2023

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   Lewy body disorders (LBD) include Parkinson disease (PD), Parkinson disease dementia (PDD), and dementia with Lewy bodies (DLB). LBD are the second leading cause of neurodegenerative dementia after Alzheimer’s disease (AD). An estimated 50% of LBD patients have coexisting AD pathology (LBD+AD), which correlates with shorter time to dementia and death. Autopsy evidence suggests that verbal memory impairment correlates with the severity of hippocampal tau pathology in LBD. However, it is unknown whether greater hippocampal tau burden in LBD+AD causes neurodegeneration detectable by in vivo structural MRI, and whether hippocampal atrophy explains verbal memory impairment.

8. 97 Looking in the Webcam Reflection: A Scoping Review of Videoconferencing-Based Teleneuropsychological Assessment Since the Start of the COVID-19 Pandemic

   Stan Colcombe, L. Crivelli, J. Fox-Fuller, and 9 more authors

   Journal of the International Neuropsychological Society, Nov 2023

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   Objective: Following the start of the SARS-COV-2 (COVID-19) pandemic there was a rapid uptake in teleneuropsychology (TeleNP). Many clinicians and researchers used videoconferencing technologies (e.g., Zoom®) to conduct remote neuropsychological assessments. Prior reviews (e.g., Marra et al., 2020) have indicated promise for the use of videoconference-based approaches to cognitive assessment under certain circumstances, though arguably nobody foresaw the widespread use of teleNP during the pandemic. Given the rapid expansion in the teleNP literature in the past couple of years, in this scoping review we specifically discuss research updates made during the COVID-19 pandemic pertaining to teleNP assessment of adults conducted via videoconferencing and their potential clinical applications. Participants and Methods: GoogleScholar and PubMed were used to search for peer-reviewed original research articles published between January 1, 2020 (i.e., the approximate beginning of the COVID-19 pandemic) and August 1, 2022. Broad search terms were used pertaining to teleNP, remote cognitive assessment, videoconferencing, and neuropsychological assessment, resulting in 16 articles. Results: Though most of the included studies were based in the United States (n=5), there was international representation across studies (Chile=1; United Kingdom=1; Australia=2; New Zealand=1; France=2; Greece=1; Japan=2, Singapore=1). All of the identified articles examined TeleNP-related research questions using cognitive tests administered via videoconferencing that have been previously studied in-person to varying degrees. Several of the studies focused on psychometric characterization (i.e., reliability and validity) of the examined tests when delivered via videoconferencing, whereas others focused on demonstrating the relative equivalence of neuropsychological scores obtained via videoconferencing versus in-person evaluations. Conclusions: Formal psychometric studies of traditional in-person neuropsychological tests delivered via videoconferencing since the start of the COVID-19 pandemic suggest that this remote modality of assessment is generally reliable and valid. Moreover, multiple recent studies have demonstrated relative equivalence of neuropsychological scores obtained via videoconferencing versus neuropsychological test scores obtained in-person. When considered alongside teleNP research conducted prior to the COVID-19 pandemic (e.g. Cullum et al., 2014), recent studies on videoconference-based neuropsychological assessment indicate that videoconferencing may not necessarily be a complete substitute for an in-person comprehensive evaluation given the inherent limitations of the procedure. However, teleNP via videoconferencing may be a promising tool in the neuropsychologist’s toolbox because it can help reduce common barriers to in-person neuropsychological assessment (e.g., travel time to clinics). Additional research on videoconferencing-based cognitive assessment is needed, especially in low-and-middle income countries (LMIC) and diverse populations where there may be more economic barriers to remote neuropsychological assessment relative to more economically-developed countries. Notably it is possible that research from LMIC may have been missed through the screening processes used in this review (e.g., inclusion of articles written in English).

9. Evaluation of quantitative measurements of tau pathology with semi‐quantitative ratings and age

   Amanda E Denning, R. Ittyerah, Niyousha Sadeghpour, and 17 more authors

   Alzheimer’s & Dementia, Dec 2023

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   It is assumed quantitative digital neuropathology methods will provide more information than semi‐quantitative ratings, but this presumption lacks formal assessment. Here, we compare quantitative, whole‐slide measurements of phosphorylated tau tangles and threads with semi‐quantitative tau pathology ratings. We evaluate whether quantitative measurements provide additional prediction beyond Braak stage for variables associated with tau pathology, examining the association of quantitative tau measurements in high Braak stages with age at death and measures of severity of TDP‐43 and alpha‐synuclein co‐pathologies. We hypothesized that even within the same high Braak stage, quantitative tau measurements would decrease with age at death, as younger patients often require more tau pathology for disease severity comparable to older patients, and increase with higher co‐pathology ratings, since prior work suggests co‐pathologies increase with disease severity.

10. 42 Cognitive and Neuroanatomic Correlates of Olfactory Function in Cognitively Unimpaired and Impaired Older Adults

    M. Dicalogero, Vidyulata Kamath, David A. Wolk, and 5 more authors

    Journal of the International Neuropsychological Society, Nov 2023

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    Objective: Olfactory function declines during normal aging; however, accelerated olfactory decline is observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). Moreover, olfactory deficits in pre-clinical AD are associated with future cognitive decline. Odor identification and memory deficits have been consistently reported in early stage AD indicating its potential sensitivity to AD pathophysiology in olfactory and limbic structures, yet few studies of olfaction have incorporated structural measures in a well-characterized cohort of older adults. In the current study we examined the association between odor identification impairment, cognition, and medial temporal lobe (MTL) sub-regions in cognitively unimpaired and impaired older adults. Participants and Methods: We enrolled 140 participants (age=72.25±6.54, 56% female, years of education=16.30±2.63, 82% Caucasian, 15% Black/AA, 3% Multiracial) from the Penn Alzheimer’s Disease Research Center Clinical Cohort. Participants completed the Sniffin’ Sticks Odor Identification Test (SS-OIT), cognitive testing (NACC UDS2 or UDS3 and additional cognitive tests), and MRI scans (3T Siemens MAGNETOM Prisma MRI scanner). For the SS-OIT, participants were presented with 16 odorants using felt-tipped pen dispensers and asked to identify each odor from four multiple-choice options. Scores range from 0 to 16. Additionally, cognitive domains were created by averaging z-scores from tests within each domain: attention, memory, language, executive function, and visuospatial. This cohort was divided into participants with unimpaired cognition (n=96) and impaired cognition (MCI, dementia; n=44) using established normative data and consensus diagnosis. Linear regressions were performed to examine the association between SS-OIT score, each cognitive domain, and MTL measurements for unimpaired and impaired groups. For all analyses, we controlled for age, race, sex, education, smoking status, and hypertension and additionally for MOCA score and intracranial volume with MTL measurements. Results: In the unimpaired group, SS-OIT significantly associated with language (p<.05). In the impaired group, SS-OIT significantly associated with language and memory (p<.05). In the unimpaired group, SS-OIT significantly associated with right anterior hippocampal volume (p<.05). In the impaired group, significant associations were found between SS-OIT and right anterior hippocampal volume (p<.05) and left hippocampal mean thickness (p<.05). Additionally, SS-OIT significantly associated with left and right entorhinal cortex volume (p<.05) and mean thickness (p<.05). Conclusions: This study reveals that lower odor identification performance is related to lower performance on measures of cognition and atrophy in MTL sub-regions in unimpaired and impaired older adults. Our findings support prior results demonstrating relationships between olfactory function, cognition, and MTL sub-regions. Specifically, olfactory function and episodic memory have been shown to follow similar patterns of decline in the course of AD, potentially reflecting AD pathology in shared regions of the MTL subserving episodic memory and olfactory function. Our findings demonstrate that reductions in both cortical thickness and grey matter volume of MTL regions are linked to olfactory deficits in individuals at risk for Alzheimer’s dementia. Future steps will include the analysis of longitudinal cognitive and imaging indices and the incorporation of fluid biomarker data.

11. Comparison of Focal Hippocampal T2‐Weighted MRI and Whole‐Brain T1‐Weighted MRI for Detection of Longitudinal Atrophy Using Deep Learning‐Based and Conventional Approaches

    M. Dong, L. Xie, L. Wisse, and 5 more authors

    Alzheimer’s & Dementia, Dec 2023

    Cited by 1

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    Longitudinal measurement of medial temporal lobe (MTL) atrophy is shown to be effective in measuring Alzheimer’s disease (AD) progression and has been extensively studied on T1‐weighted MRI. However, there has been little work analyzing atrophy on high‐resolution T2‐weighted MRI of the hippocampal region, and it is unknown which MRI modality would yield a more effective biomarker of disease progression. We compare atrophy measurements derived from T1 and T2‐weighted MRI using a deep learning framework DeepAtrophy and a deformation‐based morphometry method ALOHA.

12. Regional Deep Atrophy: a Self-Supervised Learning Method to Automatically Identify Regions Associated With Alzheimer’s Disease Progression From Longitudinal MRI

    M. Dong, L. Xie, Sandhitsu R. Das, and 5 more authors

    ArXiv, Apr 2023

    Cited by 2

    Abs DOI arXiv

    

    Longitudinal assessment of brain atrophy, particularly in the hippocampus, is a well-studied biomarker for neurodegenerative diseases, such as Alzheimer’s disease (AD). In clinical trials, estimation of brain progressive rates can be applied to track therapeutic efficacy of disease modifying treatments. However, most state-of-the-art measurements calculate changes directly by segmentation and/or deformable registration of MRI images, and may misreport head motion or MRI artifacts as neurodegeneration, impacting their accuracy. In our previous study, we developed a deep learning method DeepAtrophy that uses a convolutional neural network to quantify differences between longitudinal MRI scan pairs that are associated with time. DeepAtrophy has high accuracy in inferring temporal information from longitudinal MRI scans, such as temporal order or relative inter-scan interval. DeepAtrophy also provides an overall atrophy score that was shown to perform well as a potential biomarker of disease progression and treatment efficacy. However, DeepAtrophy is not interpretable, and it is unclear what changes in the MRI contribute to progression measurements. In this paper, we propose Regional Deep Atrophy (RDA), which combines the temporal inference approach from DeepAtrophy with a deformable registration neural network and attention mechanism that highlights regions in the MRI image where longitudinal changes are contributing to temporal inference. RDA has similar prediction accuracy as DeepAtrophy, but its additional interpretability makes it more acceptable for use in clinical settings, and may lead to more sensitive biomarkers for disease monitoring in clinical trials of early AD.

13. Image-to-Image Translation Between Tau Pathology and Neuronal Metabolism PET in Alzheimer Disease with Multi-domain Contrastive Learning

    M. Duong, Sandhitsu R. Das, Pulkit Khandelwal, and 5 more authors

    In MLCN@MICCAI, Apr 2023

    Cited by 1

    DOI

    
14. 89 Performance and Usability of a Remote App-Based Assessment of Cognition Among Older Adult Mobile Game Players and Non-Players

    Kimberly Halberstadter, La’cendria Pulley, Rachel Rovere, and 3 more authors

    Journal of the International Neuropsychological Society, Nov 2023

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    Objective: Mobile, valid, and engaging cognitive assessments are essential for detecting and tracking change in research participants and patients at risk for Alzheimer’s Disease and Related Dementias (ADRDs). The mobile cognitive app performance platform (mCAPP) includes memory and executive functioning tasks to remotely detect cognitive changes associated with aging and preclinical Alzheimer’s disease. This study assesses participants’ comfort and subjective experiences with mCAPP as the potential utility and advantage of mobile app-based assessments for remote monitoring among older adults will depend upon usability and adoptability of such technology. Participants and Methods: The mCAPP includes three gamified tasks: (1) a memory task involving learning and matching hidden card pairs (“Concentration”) (2) a stroop-like task (“Brick Drop”), and (3) a digit-symbol coding-like task (“Space Imposters”). Participants included 37 older adults (60% female; age=72±4.4; years of education=17±2.5; 67% White) with normal cognition enrolled in the Penn ADRC cohort. Participants completed one baseline session of mCAPP in-person, followed by two weeks of at-home use with eight scheduled sessions. Information on prior experience with mobile technology and games was collected, and usability of mCAPP was measured at baseline and after 2-weeks of use with the IBM Computer Usability Satisfaction Questionnaire and the mHeath App Usability Questionnaire (MAUQ) respectively. Feedback on perceived difficulty, enjoyment, and likelihood to play mCAPP games again on their own was collected. Results: Participants completed on average 11±4.9 sessions over 2 weeks, with each session lasting 11.5±2.5 minutes. 59% of participants reported using their mobile device to play games (“mobile game players”). Performance on mCAPP tasks was slower at baseline for non-players, with trend-level differences on higher-load blocks of Space Imposters (p=.057 and .059). No differences in game performance were seen between groups after playing 8 sessions at-home. There were no differences in usability of mCAPP between groups, with average usability 8.2±1.5 (IBM, 0-9 scale) at T1 and 6.2±0.8 (MAUQ, 1-7 scale) after completion of two weeks of at-home use (TLast). Reported enjoyment was moderate to high for both groups at baseline and increased over time. Likelihood to play Concentration and Brick Drop again trended lower among nonplayers at T1 (p=.061 and .054), but not at TLast. Further, change in likelihood to play mCAPP from T1 to TLast was positive among non-players, with change for Concentration significantly higher for non-players than for players (p=.037). Conclusions: Participants were willing and able to complete at-home cognitive testing and most completed more than the assigned sessions. While participants who do not play games on their own mobile device were slower on some tasks at baseline, these differences dissipated with further play at-home. Usability and enjoyment of mCAPP games were high regardless of mobile game-playing status, and non-players demonstrated increased willingness to play mCAPP games again at the end of participation compared to baseline. This pilot study shows preliminary feasibility and adoptability of mobile app-based assessment regardless of prior experience with mobile games.

15. A - 02 Performance and Usage of a Remote App-Based Cognitive Assessment among Older Adults with a Range of Technology Experience.

    Kimberly Halberstadter, Rachel Rovere, Erin Liebenberg, and 2 more authors

    Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists, Oct 2023

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    OBJECTIVE The mobile cognitive app performance platform (mCAPP), an app-based cognitive assessment, includes memory and executive functioning tasks to remotely detect cognitive changes associated with aging and preclinical Alzheimer’s disease. This study examines the relationship between prior experience and comfort with mobile technology and subjective experiences with mCAPP. METHOD 60 older adults (73% female; age = 74 ± 4.8; education = 17 ± 2.4 years; 48% Black/African American) with normal cognition enrolled in the Penn Alzheimer’s Disease Research Center cohort completed one baseline session and two weeks of at-home mCAPP use. This study included measures of prior experience with mobile technology and games, at-home mCAPP performance and usage levels, and feedback on mCAPP usability. RESULTS 62% of participants reported using mobile devices to play games ("game-players"), and they did not differ from non-users in age or global cognitive status. Game-players self-reported significantly higher proficiency with specific mobile technology features (p = 0.028), but not perceived independence or confidence with technology. mCAPP performance differences were present at baseline but not by the 8th at-home session. Usability and enjoyment of mCAPP were high and increased for both groups. Non-players reported lower likelihood to play mCAPP games at baseline (p < 0.05), but in practice increased play frequency throughout at-home use and reported higher likelihood to play mCAPP games afterwards (p ≤ 0.001). CONCLUSION (S) Participants with varying mobile game experience-levels were willing and able to use mCAPP at-home. Both groups found mCAPP easy and enjoyable to use, and non-players particularly showed increased adoption of mCAPP. This pilot study shows preliminary feasibility of mobile app-based assessment regardless of prior experience with mobile games.

16. Aging and Alzheimer’s disease have dissociable effects on local and regional medial temporal lobe connectivity

    S. Hrybouski, Sandhitsu R. Das, L. Xie, and 9 more authors

    Brain Communications, Sep 2023

    Cited by 21

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    The extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional disruption of the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity (FC) alterations between anterior and posterior regions of the MTL and in MTL‐associated functional communities – the Anterior‐Temporal (AT) and Posterior‐Medial (PM) networks – in normal agers, individuals with preclinical AD, and patients with Mild Cognitive Impairment or mild dementia due to AD.

17. Aging and Alzheimer’s Disease Have Dissociable Effects on Local and Regional Medial Temporal Lobe Connectivity

    S. Hrybouski, Sandhitsu R. Das, L. Xie, and 9 more authors

    Alzheimer’s & Dementia, Dec 2023

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    The extent to which pathological processes in aging and Alzheimer’s disease (AD) relate to functional disruption of the medial temporal lobe (MTL)‐dependent brain networks is poorly understood. To address this knowledge gap, we examined functional connectivity (FC) alterations between anterior and posterior regions of the MTL and in MTL‐associated functional communities – the Anterior‐Temporal (AT) and Posterior‐Medial (PM) networks – in normal agers, individuals with preclinical AD, and patients with Mild Cognitive Impairment or mild dementia due to AD.

18. Aging and Alzheimer’s Disease Have Dissociable Effects on Medial Temporal Lobe Connectivity

    S. Hrybouski, S. Das, L. Xie, and 9 more authors

    medRxiv : the preprint server for health sciences, Jan 2023

    Cited by 8

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19. Ex vivo, in situ perfusion protocol for human brain fixation compatible with microscopy, MRI techniques, and anatomical studies

    R. Insausti, A. Insausti, M. Muñoz López, and 18 more authors

    Frontiers in Neuroanatomy, Mar 2023

    Cited by 22

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    We present a method for human brain fixation based on simultaneous perfusion of 4% paraformaldehyde through carotids after a flush with saline. The left carotid cannula is used to perfuse the body with 10% formalin, to allow further use of the body for anatomical research or teaching. The aim of our method is to develop a vascular fixation protocol for the human brain, by adapting protocols that are commonly used in experimental animal studies. We show that a variety of histological procedures can be carried out (cyto- and myeloarchitectonics, histochemistry, immunohistochemistry, intracellular cell injection, and electron microscopy). In addition, ex vivo, ex situ high-resolution MRI (9.4T) can be obtained in the same specimens. This procedure resulted in similar morphological features to those obtained by intravascular perfusion in experimental animals, provided that the postmortem interval was under 10 h for several of the techniques used and under 4 h in the case of intracellular injections and electron microscopy. The use of intravascular fixation of the brain inside the skull provides a fixed whole human brain, perfectly fitted to the skull, with negligible deformation compared to conventional techniques. Given this characteristic of ex vivo, in situ fixation, this procedure can probably be considered the most suitable one available for ex vivo MRI scans of the brain. We describe the compatibility of the method proposed for intravascular fixation of the human brain and fixation of the donor’s body for anatomical purposes. Thus, body donor programs can provide human brain tissue, while the remainder of the body can also be fixed for anatomical studies. Therefore, this method of human brain fixation through the carotid system optimizes the procurement of human brain tissue, allowing a greater understanding of human neurological diseases, while benefiting anatomy departments by making the remainder of the body available for teaching purposes.

20. Circular-SWAT for deep learning based diagnostic classification of Alzheimer’s disease: application to metabolome data

    T. Jo, Junpyo Kim, Paula Bice, and 493 more authors

    eBioMedicine, Oct 2023

    Cited by 12

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    Summary Background Deep learning has shown potential in various scientific domains but faces challenges when applied to complex, high-dimensional multi-omics data. Alzheimer’s Disease (AD) is a neurodegenerative disorder that lacks targeted therapeutic options. This study introduces the Circular-Sliding Window Association Test (c-SWAT) to improve the classification accuracy in predicting AD using serum-based metabolomics data, specifically lipidomics. Methods The c-SWAT methodology builds upon the existing Sliding Window Association Test (SWAT) and utilizes a three-step approach: feature correlation analysis, feature selection, and classification. Data from 997 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) served as the basis for model training and validation. Feature correlations were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA), and Convolutional Neural Networks (CNN) were employed for feature selection. Random Forest was used for the final classification. Findings The application of c-SWAT resulted in a classification accuracy of up to 80.8% and an AUC of 0.808 for distinguishing AD from cognitively normal older adults. This marks a 9.4% improvement in accuracy and a 0.169 increase in AUC compared to methods without c-SWAT. These results were statistically significant, with a p-value of 1.04 × 10ˆ-4. The approach also identified key lipids associated with AD, such as Cer(d16:1/22:0) and PI(37:6). Interpretation Our results indicate that c-SWAT is effective in improving classification accuracy and in identifying potential lipid biomarkers for AD. These identified lipids offer new avenues for understanding AD and warrant further investigation. Funding The specific funding of this article is provided in the acknowledgements section.

21. Automated deep learning segmentation of high-resolution 7 T postmortem MRI for quantitative analysis of structure-pathology correlations in neurodegenerative diseases

    Pulkit Khandelwal, M. Duong, S. Sadaghiani, and 34 more authors

    Mar 2023

    Abs arXiv

    

    Postmortem MRI allows brain anatomy to be examined at high resolution and to link pathology measures with morphometric measurements. However, automated segmentation methods for brain mapping in postmortem MRI are not well developed, primarily due to limited availability of labeled datasets, and heterogeneity in scanner hardware and acquisition protocols. In this work, we present a high resolution of 135 postmortem human brain tissue specimens imaged at 0.3 mm^3 isotropic using a T2w sequence on a 7T whole-body MRI scanner. We developed a deep learning pipeline to segment the cortical mantle by benchmarking the performance of nine deep neural architectures, followed by post-hoc topological correction. We then segment four subcortical structures (caudate, putamen, globus pallidus, and thalamus), white matter hyperintensities, and the normal appearing white matter. We show generalizing capabilities across whole brain hemispheres in different specimens, and also on unseen images acquired at 0.28 mm^3 and 0.16 mm^3 isotropic T2*w FLASH sequence at 7T. We then compute localized cortical thickness and volumetric measurements across key regions, and link them with semi-quantitative neuropathological ratings. Our code, Jupyter notebooks, and the containerized executables are publicly available at: https://pulkit-khandelwal.github.io/exvivo-brain-upenn

22. Automated deep learning segmentation of high-resolution 7 T ex vivo MRI for quantitative analysis of structure-pathology correlations in neurodegenerative diseases

    Pulkit Khandelwal, M. Duong, S. Sadaghiani, and 33 more authors

    ArXiv, Mar 2023

    Cited by 4

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23. A - 06 Sensitivity of Remote App-Based Assessment of Cognition among Older Adults to Fatigue-Mediated Differences in Cognitive Functioning.

    Erin Liebenberg, Rachel Rovere, Kimberly Halberstadter, and 2 more authors

    Archives of clinical neuropsychology : the official journal of the National Academy of Neuropsychologists, Oct 2023

    Cited by 1

    Abs DOI

    

    OBJECTIVE This study assesses the sensitivity of the mobile cognitive app performance platform (mCAPP), a mobile and engaging cognitive assessment tool, to participant reported fatigue. METHOD The mCAPP includes three gamified tasks: a memory task ("Concentration"), a stroop-like task ("Brick Drop"), and a digit-symbol coding-like task ("Space Imposters"). For all games, shorter reaction times and fewer guesses indicate better performance. The cohort included 55 participants (72.73% female; age = 71.60 ± 4.48; education = 16.71 ± 2.30; 49.1% white; 49.1% Black/African American, 1.8% Multiracial) without cognitive impairment who are enrolled in the Penn ADRC cohort. Performance was analyzed as a whole and grouped into days of high (7+) and low (0-3) fatigue (range 0-10). RESULTS The average fatigue rating was 2.61 ± 2.51. Overall, higher reported fatigue was weakly correlated with more time spent (ρ = 0.22) and a higher number of guesses on Concentration (ρ = 0.12; p-values<0.01). There was a significant difference in speed for those with high fatigue (M = 2.825) and low fatigue (M = 2.592; p = 0.018) on Space Imposters, but not on Brick Drop (p = 0.15). On Concentration, those with high fatigue needed a higher number of guesses (M = 5.356) compared to low fatigue (M = 5.095; p = 0.003) and more time was spent on individual guesses for those with high fatigue (M = 17.587) compared to low fatigue (M = 13.357; p < 0.001). CONCLUSION The mCAPP can remotely detect differences in cognitive performance in self-reported high and low fatigue states. Future studies will include looking at sleep data to determine objective measures of fatigue-related behavior and in-depth analysis of performance within-subject.

24. iEEG-recon: A Fast and Scalable Pipeline for Accurate Reconstruction of Intracranial Electrodes and Implantable Devices

    Alfredo Lucas, B. Scheid, A. Pattnaik, and 11 more authors

    medRxiv, Jun 2023

    Cited by 12

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    Background: Collaboration between epilepsy centers is essential to integrate multimodal data for epilepsy research. Scalable tools for rapid and reproducible data analysis facilitate multicenter data integration and harmonization. Clinicians use intracranial EEG (iEEG) in conjunction with non-invasive brain imaging to identify epileptic networks and target therapy for drug-resistant epilepsy cases. Our goal was to promote ongoing and future collaboration by automating the process of electrode reconstruction, which involves the labeling, registration, and assignment of iEEG electrode coordinates on neuroimaging. These tasks are still performed manually in many epilepsy centers. We developed a standalone, modular pipeline that performs electrode reconstruction. We demonstrate our tool’s compatibility with clinical and research workflows and its scalability on cloud platforms. Methods: We created iEEG-recon, a scalable electrode reconstruction pipeline for semi-automatic iEEG annotation, rapid image registration, and electrode assignment on brain MRIs. Its modular architecture includes three modules: a clinical module for electrode labeling and localization, and a research module for automated data processing and electrode contact assignment. To ensure accessibility for users with limited programming and imaging expertise, we packaged iEEG-recon in a containerized format that allows integration into clinical workflows. We propose a cloud-based implementation of iEEG-recon, and test our pipeline on data from 132 patients at two epilepsy centers using retrospective and prospective cohorts. Results: We used iEEG-recon to accurately reconstruct electrodes in both electrocorticography (ECoG) and stereoelectroencephalography (SEEG) cases with a 10 minute running time per case, and  20 min for semi-automatic electrode labeling. iEEG-recon generates quality assurance reports and visualizations to support epilepsy surgery discussions. Reconstruction outputs from the clinical module were radiologically validated through pre- and post-implant T1-MRI visual inspections. Our use of ANTsPyNet deep learning approach for brain segmentation and electrode classification was consistent with the widely-used Freesurfer segmentation. Discussion: iEEG-recon is a valuable tool for automating reconstruction of iEEG electrodes and implantable devices on brain MRI, promoting efficient data analysis, and integration into clinical workflows. The tool’s accuracy, speed, and compatibility with cloud platforms make it a useful resource for epilepsy centers worldwide. Comprehensive documentation is available at https://ieeg-recon.readthedocs.io/en/latest/

25. Improved Seizure Onset-Zone Lateralization in Temporal Lobe Epilepsy using 7T Resting-State fMRI: A Direct Comparison with 3T

    Alfredo Lucas, E. Cornblath, N. Sinha, and 6 more authors

    medRxiv, Jun 2023

    Cited by 5

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    Objective: Resting-state functional magnetic resonance imaging (rs-fMRI) at ultra high- field strengths ([≥]7T) is known to provide superior signal-to-noise and statistical power than comparable acquisitions at lower field strengths. In this study, we aim to provide a direct comparison of the seizure onset-zone (SOZ) lateralizing ability of 7T rs-fMRI and 3T rs-fMRI. Methods: We investigated a cohort of 70 temporal lobe epilepsy (TLE) patients. A paired cohort of 19 patients had 3T and 7T rs-fMRI acquisitions for direct comparison between the two field strengths. Forty-three patients had only 3T, and 8 patients had only 7T rs- fMRI acquisitions. We quantified the functional connectivity between the hippocampus and other nodes within the default mode network (DMN) using seed-to-voxel connectivity, and measured how hippocampo-DMN connectivity could inform SOZ lateralization at 7T and 3T field strengths. Results: Differences between hippocampo-DMN connectivity ipsilateral and contralateral to the SOZ were significantly higher at 7T (pFDR=0.008) than at 3T (pFDR=0.80) when measured in the same subjects. We found that our ability to lateralize the SOZ, by distinguishing subjects with left TLE from subjects with right TLE, was superior at 7T (AUC = 0.97) than 3T (AUC = 0.68). Our findings were reproduced in extended cohorts of subjects scanned at either 3T or 7T. Our rs-fMRI findings at 7T, but not 3T, are consistent and highly correlated (Spearman Rho=0.65) with clinical FDG-PET lateralizing hypometabolism. Significance: We show superior SOZ lateralization in TLE patients when using 7T relative to 3T rs-fMRI, supporting the adoption of high-field strength functional imaging in the epilepsy presurgical evaluation.

26. Subcortical functional connectivity gradients in temporal lobe epilepsy

    Alfredo Lucas, Sofia Mouchtaris, E. Cornblath, and 7 more authors

    NeuroImage : Clinical, May 2023

    Cited by 7

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    Highlights • First principal subcortical gradient follows lower to higher computational hierarchy.• Patients with temporal lobe epilepsy (TLE) have an expanded first principal gradient.• The ipsilateral hippocampus drives expanded principal gradient in right vs. left TLE.

27. Subcortical Functional Connectivity Gradients in Temporal Lobe Epilepsy

    Alfredo Lucas, Sofia Mouchtaris, E. Cornblath, and 7 more authors

    medRxiv, Jan 2023

    Cited by 8

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    Background and Motivation: Functional gradients have been used to study differences in connectivity between healthy and diseased brain states, however this work has largely focused on the cortex. Because the subcortex plays a key role in seizure initiation in temporal lobe epilepsy (TLE), subcortical functional-connectivity gradients may help further elucidate differences between healthy brains and TLE, as well as differences between left (L)-TLE and right (R)-TLE. Methods: In this work, we calculated subcortical functional-connectivity gradients (SFGs) from resting-state functional MRI (rs-fMRI) by measuring the similarity in connectivity profiles of subcortical voxels to cortical gray matter voxels. We performed this analysis in 23 R-TLE patients and 32 L-TLE patients (who were otherwise matched for age, gender, disease specific characteristics, and other clinical variables), and 16 controls. To measure differences in SFGs between L-TLE and R-TLE, we quantified deviations in the average functional gradient distributions, as well as their variance, across subcortical structures. Results: We found an expansion, measured by increased variance, in the principal SFG of TLE relative to controls. When comparing the gradient across subcortical structures between L-TLE and R-TLE, we found that abnormalities in the ipsilateral hippocampal gradient distributions were significantly different between L-TLE and R-TLE. Conclusion: Our results suggest that expansion of the SFG is characteristic of TLE. Subcortical functional gradient differences exist between left and right TLE and are driven by connectivity changes in the hippocampus ipsilateral to the seizure onset zone.

28. Tau‐neurodegeneration mismatch reveals vulnerability and resilience to comorbidities in Alzheimer’s continuum

    Xueying Lyu, M. Duong, L. Xie, and 16 more authors

    Alzheimer’s & Dementia, Dec 2023

    Cited by 13

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    Variability in relationship of tau‐based neurofibrillary tangles (T) and neurodegeneration (N) in Alzheimer’s disease (AD) arises from non‐specific nature of N, modulated by non‐AD co‐pathologies, age‐related changes, and resilience factors.

29. tau‐neurodegeneration mismatch from inter‐modality image translation using deep learning

    Xueying Lyu, Pulkit Khandelwal, M. Duong, and 6 more authors

    Alzheimer’s & Dementia, Dec 2023

    Cited by 1

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    The relationship between tau neurofibrillary tangles (T) and neurodegeneration (N) may offer clues to potential presence of comorbidities, as well as relative resilience and vulnerability to Alzheimer’s disease (AD) pathology. We have previously developed measures of tau PET (T) and cortical thickness (N) mismatch based on linear model residuals. However, the underlying relationships between T and N are likely complex and non‐linear. Moreover, predicting cortical thickness based on local tau level may miss non‐local contributions of tauopathy. Here we investigate T‐N mismatch using a deep‐learning 3D image translation neural network to estimate synthetic maps of cortical thickness based on tau PET images. Deviation between the synthetic and actual cortical thickness serves as a metric of T‐N mismatch.

30. Tau-Neurodegeneration mismatch reveals vulnerability and resilience to comorbidities in Alzheimer’s continuum

    X. Lyu, M. Duong, L. Xie, and 17 more authors

    medRxiv : the preprint server for health sciences, Feb 2023

    Cited by 9

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31. 98 Remote App-Based Assessment of Memory and Executive Functioning in Aging and Pre-Clinical Alzheimer’s Disease

    Dawn J. Mechanic-Hamilton, Kimberly Halberstadter, M. Dicalogero, and 3 more authors

    Journal of the International Neuropsychological Society, Nov 2023

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    Objective: Mobile, valid, and engaging cognitive assessments are essential for detecting and tracking change in research participants and patients at risk for Alzheimer’s Disease and Related Dementias (ADRDs). This pilot study aims to determine the feasibility and performance of app-based memory and executive functioning tasks included in the mobile cognitive app performance platform (mCAPP), to remotely detect cognitive changes associated with aging and preclinical Alzheimer’s Disease (AD). Participants and Methods: The mCAPP includes three gamified tasks: (1) a memory task that includes learning and matching hidden card pairs and incorporates increasing memory load, pattern separation features (lure vs. non-lure), and spatial memory (2) a stroop-like task (“brick drop”) with speeded word and color identification and response inhibition components and (3) a digit-symbol coding-like task (“space imposters”) with increasing pairs and incidental learning components. The cohort completed the NACC UDS3 neuropsychological battery, selected NIH Toolbox tasks, and additional cognitive testing sensitive to pre-clinical AD, within six months of the mCAPP testing. Participants included thirty-seven older adults (60% female; age=72±4.4, years of education=17±2.5; 67% Caucasian, 30% Black/AA, 3% Multiracial) with normal cognition who are enrolled in the Penn Alzheimer’s Disease Research Center (ADRC) cohort. Participants completed one in-person session and two weeks of at-home testing, with eight scheduled sessions, four in the morning and four in the afternoon. Participants also completed questionnaires and an interview about technology use and wore activity trackers to collect daily step and sleep data and answered questions about mood, anxiety, and fatigue throughout the two weeks of at-home data collection. Results: The participants completed an average of 11 at-home sessions, with the majority choosing to play extra sessions. Participants reported high usability ratings for all tasks and the majority rated the task difficulty as acceptable. On all mCAPP tasks, participant performance declined in accuracy and speed with increasing memory load and task complexity. mCAPP tasks correlated significantly with paper and pencil measures and several NIH Toolbox tasks (p<0.05). Examination of performance trends over multiple sessions indicates stabilization of performance within 4-6 sessions on memory mCAPP measures and 5-7 sessions on executive functioning mCAPP measures. Preliminary analyses indicate differences in mCAPP measures and imaging biomarkers. Conclusions: Participants were willing and able to complete at-home cognitive testing and most chose to complete more than the assigned sessions. Remote data collection is feasible and well-tolerated. We show preliminary construct validity with the UDS3 and NIH Toolbox and test-retest reliability following a period of task learning and performance improvement and stabilization. This work will help to advance remote detection and monitoring of early cognitive changes associated with preclinical AD. Future directions will include further evaluation of the relationships between mCAPP performance, behavioral states, and neuroimaging biomarkers as well as the utility of detection of practice effects in identifying longitudinal change and risk for ADRD-related cognitive decline.

32. Remote App‐Based Assessment of Memory and Executive Functioning in Aging and Pre‐Clinical Alzheimer’s Disease in a Diverse Sample of Older Adults

    Dawn J. Mechanic-Hamilton, Kimberly Halberstadter, Rachel Rovere, and 2 more authors

    Alzheimer’s & Dementia, Dec 2023

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    Mobile, valid and engaging cognitive assessments are essential for detecting and tracking change in research participants and patients at risk for Alzheimer’s Disease and Related Dementias (ADRDs). This pilot study aims to determine the feasibility and generalizability of at‐home, app‐based cognitive assessments included in the mobile cognitive app performance platform (mCAPP), to detect cognitive changes associated with aging and preclinical AD.

33. Hippocampal Enlargement and White Matter Hyperintensities in Obstructive Sleep Apnea Patients

    Manasa Mula, Alex Mathew, Sandhitsu R. Das, and 14 more authors

    Alzheimer’s & Dementia, Dec 2023

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    Obstructive sleep apnea (OSA), which results from recurrent collapses of the upper airway system, affects around 27% of the geriatric population with mild cognitive impairment (MCI) and causes intermittent hypoxia and sleep fragmentation (Mubashir et al., 2019). Prior research suggests that OSA results in brain ischemic preconditioning, causing hippocampal enlargement due to adaptive hippocampal neurogenesis (Rosenzweig et al., 2013). OSA has also been linked to increased white matter hyperintensities (WMHs) through hypoxic‐ ischemic injury, which contribute to cognitive decline in dementias such as Alzheimer’s disease (Zacharias et al., 2021). Previous research necessitates studying the effects of apnea in an elderly population with MCI.

34. Neuroanatomical and cellular degeneration associated with a social disorder characterized by new ritualistic belief systems in a TDP-C patient vs. a Pick patient

    Daniel T. Ohm, Emma Rhodes, A. Bahena, and 16 more authors

    Frontiers in Neurology, Oct 2023

    Cited by 1

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    Frontotemporal dementia (FTD) is a spectrum of clinically and pathologically heterogenous neurodegenerative dementias. Clinical and anatomical variants of FTD have been described and associated with underlying frontotemporal lobar degeneration (FTLD) pathology, including tauopathies (FTLD-tau) or TDP-43 proteinopathies (FTLD-TDP). FTD patients with predominant degeneration of anterior temporal cortices often develop a language disorder of semantic knowledge loss and/or a social disorder often characterized by compulsive rituals and belief systems corresponding to predominant left or right hemisphere involvement, respectively. The neural substrates of these complex social disorders remain unclear. Here, we present a comparative imaging and postmortem study of two patients, one with FTLD-TDP (subtype C) and one with FTLD-tau (subtype Pick disease), who both developed new rigid belief systems. The FTLD-TDP patient developed a complex set of values centered on positivity and associated with specific physical and behavioral features of pigs, while the FTLD-tau patient developed compulsive, goal-directed behaviors related to general themes of positivity and spirituality. Neuroimaging showed left-predominant temporal atrophy in the FTLD-TDP patient and right-predominant frontotemporal atrophy in the FTLD-tau patient. Consistent with antemortem cortical atrophy, histopathologic examinations revealed severe loss of neurons and myelin predominantly in the anterior temporal lobes of both patients, but the FTLD-tau patient showed more bilateral, dorsolateral involvement featuring greater pathology and loss of projection neurons and deep white matter. These findings highlight that the regions within and connected to anterior temporal lobes may have differential vulnerability to distinct FTLD proteinopathies and serve important roles in human belief systems.

35. A multivariate MRI model of Alzheimer’s disease risk is associated with clinical diagnosis, PET imaging, and plasma biomarkers in a mixed dementia sample

    J. Phillips, S. T. Govindarajan, Gyujoon Hwang, and 8 more authors

    Alzheimer’s & Dementia, Dec 2023

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    We sought to validate two structural MRI‐based brain health models: Spatial Pattern of Atrophy for REcognition of Alzheimer’s disease (SPARE‐AD) and SPARE‐Brain Age Gap (SPARE‐BAG), which estimates the discrepancy between biological brain age and chronological age. These models’ generalization to non‐amnestic AD (naAD) syndromes and associations with positron emission tomography (PET) and plasma biomarkers remain underinvestigated. We hypothesized that SPARE‐AD scores in naAD would be lower (less abnormal) than in amnestic AD (aAD) but elevated (more abnormal) relative to controls; and that SPARE‐AD but not SPARE‐BAG scores would be associated with PET and plasma biomarkers of AD.

36. Quantifying associations of four major proteinopathies with grey matter atrophy: an imaging‐pathology study

    J. Phillips, J. Robinson, K. Cousins, and 8 more authors

    Alzheimer’s & Dementia, Dec 2023

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    Gross atrophy observed on MRI provides a clinically useful marker of possible neurodegenerative disease. However, autopsy studies of polypathology suggest atrophy is likely driven not by a single proteinopathy but also co‐pathologies. We hypothesized that in a clinically heterogeneous autopsy sample, amyloid‐ß, tau, a‐synuclein, and TDP‐43, would co‐occur within regions, and that co‐pathologies would have independent associations with grey matter atrophy.

37. Quantifying associations of four major proteinopathies with grey matter atrophy: an imaging‐pathology study

    J. Phillips, J. Robinson, K. Cousins, and 8 more authors

    Alzheimer’s & Dementia, Dec 2023

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    Gross atrophy observed on MRI provides a clinically useful marker of possible neurodegenerative disease. However, autopsy studies of polypathology suggest atrophy is likely driven not by a single proteinopathy but also co‐pathologies. We hypothesized that in a clinically heterogeneous autopsy sample, amyloid‐β, tau, α‐synuclein, and TDP‐43, would co‐occur within regions, and that co‐pathologies would have independent associations with grey matter atrophy.

38. Antiamyloid Monoclonal Antibody Therapy for Alzheimer Disease

    Vijay K. Ramanan, M. Armstrong, Parichita Choudhury, and 6 more authors

    Neurology, Jul 2023

    Cited by 49

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    With recent data demonstrating that lecanemab treatment can slow cognitive and functional decline in early symptomatic Alzheimer disease (AD), it is widely anticipated that this drug and potentially other monoclonal antibody infusions targeting β-amyloid protein will imminently be realistic options for some patients with AD. Given that these new antiamyloid monoclonal antibodies (mAbs) are associated with nontrivial risks and burdens of treatment that are radically different from current mainstays of AD management, effectively and equitably translating their use to real-world clinical care will require systematic and practice-specific modifications to existing workflows and infrastructure. In this Emerging Issues in Neurology article, we provide practical guidance for a wide audience of neurology clinicians on logistic adaptations and decision making around emerging antiamyloid mAbs. Specifically, we briefly summarize the rationale and available evidence supporting antiamyloid mAb use in AD to facilitate appropriate communication with patients and care partners on potential benefits. We also discuss pragmatic approaches to optimizing patient selection and treatment monitoring, with a particular focus on the value of incorporating shared decision making and multidisciplinary collaboration. In addition, we review some of the recognized limitations of current knowledge and highlight areas of future evolution to guide the development of sustainable and flexible models for treatment and follow-up. As the field enters a new era with disease-modifying treatment options for AD, it will be critical for neurology practices to prepare and continually innovate to ensure optimal outcomes for patients.

39. Improved Segmentation of Deep Sulci in Cortical Gray Matter Using a Deep Learning Framework Incorporating Laplace’s Equation

    S. Ravikumar, Ranjit Itttyerah, Sydney A. Lim, and 29 more authors

    ArXiv, Mar 2023

    Cited by 1

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    When developing tools for automated cortical segmentation, the ability to produce topologically correct segmentations is important in order to compute geometrically valid morphometry measures. In practice, accurate cortical segmentation is challenged by image artifacts and the highly convoluted anatomy of the cortex itself. To address this, we propose a novel deep learning-based cortical segmentation method in which prior knowledge about the geometry of the cortex is incorporated into the network during the training process. We design a loss function which uses the theory of Laplace’s equation applied to the cortex to locally penalize unresolved boundaries between tightly folded sulci. Using an ex vivo MRI dataset of human medial temporal lobe specimens, we demonstrate that our approach outperforms baseline segmentation networks, both quantitatively and qualitatively.

40. Using an ex vivo MRI atlas of the human medial temporal lobe to characterize the 3D distribution of neurofibrillary tangle burden across histologically defined subregions

    S. Ravikumar, Amanda E Denning, Sydney A. Lim, and 28 more authors

    Alzheimer’s & Dementia, Dec 2023

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    Accumulation of tau neurofibrillary tangles (NFT) in the medial temporal lobe (MTL) is an early pathological change associated with neurodegeneration in Alzheimer’s Disease (AD). Current understanding of the spread of NFTs within the MTL is based on 2‐D histological sections sampled at sparse locations. Here, using human MTL specimens from donors with diagnoses spanning the AD continuum, we examine 3‐D quantitative maps of NFT burden derived from serial histology leveraging a high‐resolution, ex vivo MRI atlas, thus enabling more granular analyses.

41. Integrating color deconvolution thresholding and weakly supervised learning for automated segmentation of neurofibrillary tangle and neuropil threads

    H. Roh, D. Irwin, M. Muñoz López, and 22 more authors

    Medical Imaging, Apr 2023

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    Abnormally phosphorylated tau proteins are known to be a major indicator of Alzheimer’s Disease (AD) with strong association with memory loss and cognitive decline. Automated generation of pixel-wise accurate neurofibrillary tangles (NFTs) and neuropil threads (NTs) segmentation is a challenging task, due to lack of ground truth segmentation data of these abnormal tau pathology. This problem is most prominent in the case of segmenting NTs, where the small threadlike morphology makes pixel-wise labeling a laborious task and unrealistic for large-scale studies. Lack of ground truth data poses a significant limitation for many learning-based methods to generate accurate segmentations of NFTs and NTs. This work presents an automated pipeline for pixel level segmentation of NFTs and NTs that does not rely on ground truth segmentation data. The pipeline is composed of four main steps: (1) color deconvolution is used to separate histopathology images into staining channels (DAB, Hematoxylin, and Eosin), (2) Otsu’s thresholding is used on the DAB stain channel to generate pixel level segmentation of abnormal tau proteins staining, (3) a weakly-supervised learning paradigm (WildCat), using only global descriptors of images, is used to generate density maps of potential regions of NFTs and NTs, and (4) density maps and segmentations are then integrated using connected component analysis to localize NFTs and NTs in the detected tau segmentations. Our results show high global classification accuracy for NFTs (Acc:0.96) and NTs (Acc:0.91), and statistically significant distinctions when evaluating the percent area occupied of the detected NTs relative to expert ratings of NTs severity. Qualitative assessment of the NFTs and NTs results showed accurate pixel-level segmentations of the NFTs, while modest performance for NTs.

42. Developing an anatomically valid segmentation protocol for early tau regions: the anterior medial temporal lobe cortices

    Niyousha Sadeghpour, R. Ittyerah, Amanda E Denning, and 30 more authors

    Alzheimer’s & Dementia, Dec 2023

    Cited by 1

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    The anterior portion of the medial temporal lobe (MTL) is one of the earliest regions showing tau deposition in Alzheimer’s disease (AD) and hence a key focus area for AD imaging biomarkers. However, the anatomical variability of the anterior MTL presents a challenge for segmentation protocols. Leveraging a novel postmortem dataset with histology and MRI, we aimed to develop a histologically‐informed segmentation protocol for the anterior entorhinal cortex (ERC), Brodmann Area (BA) 35 (approximates transentorhinal cortex), and BA36 for in vivo 3 tesla (T) MRI.

43. Periventricular White Matter Fractional Anisotropy as a Biomarker of Cerebral Small Vessel Disease (P11-6.007)

    Banafsheh Shakibajahromi, Sudipto Dolui, Christopher Brown, and 7 more authors

    Wednesday, April 26, Apr 2023

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44. Impact of white matter hyperintensities on structural connectivity and cognition in cognitively intact ADNI participants.

    M. Taghvaei, D. Mechanic-Hamilton, S. Sadaghiani, and 12 more authors

    Neurobiology of aging, Dec 2023

    Cited by 4

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    We used indirect brain mapping with virtual lesion tractography to test the hypothesis that the extent of white matter tract disconnection due to white matter hyperintensities (WMH) is associated with corresponding tract-specific cognitive performance decrements. To estimate tract disconnection, WMH masks were extracted from FLAIR MRI data of 481 cognitively intact participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and used as regions of avoidance for fiber tracking in diffusion MRI data from 50 healthy young participants from the Human Connectome Project. Estimated tract disconnection in the right inferior fronto-occipital fasciculus, right frontal aslant tract, and right superior longitudinal fasciculus mediated the effects of WMH volume on executive function. Estimated tract disconnection in the left uncinate fasciculus mediated the effects of WMH volume on memory and in the right frontal aslant tract on language. In a subset of ADNI control participants with amyloid data, positive status increased the probability of periventricular WMH and moderated the relationship between WMH burden and tract disconnection in executive function performance.

45. Young versus older subject diffusion magnetic resonance imaging data for virtual white matter lesion tractography

    M. Taghvaei, P. Cook, S. Sadaghiani, and 10 more authors

    Human Brain Mapping, May 2023

    Cited by 7

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    White matter hyperintensity (WMH) lesions on T2 fluid‐attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) and changes in adjacent normal‐appearing white matter can disrupt computerized tract reconstruction and result in inaccurate measures of structural brain connectivity. The virtual lesion approach provides an alternative strategy for estimating structural connectivity changes due to WMH. To assess the impact of using young versus older subject diffusion MRI data for virtual lesion tractography, we leveraged recently available diffusion MRI data from the Human Connectome Project (HCP) Lifespan database. Neuroimaging data from 50 healthy young (39.2 ± 1.6 years) and 46 healthy older (74.2 ± 2.5 years) subjects were obtained from the publicly available HCP‐Aging database. Three WMH masks with low, moderate, and high lesion burdens were extracted from the WMH lesion frequency map of locally acquired FLAIR MRI data. Deterministic tractography was conducted to extract streamlines in 21 WM bundles with and without the WMH masks as regions of avoidance in both young and older cohorts. For intact tractography without virtual lesion masks, 7 out of 21 WM pathways showed a significantly lower number of streamlines in older subjects compared to young subjects. A decrease in streamline count with higher native lesion burden was found in corpus callosum, corticostriatal tract, and fornix pathways. Comparable percentages of affected streamlines were obtained in young and older groups with virtual lesion tractography using the three WMH lesion masks of increasing severity. We conclude that using normative diffusion MRI data from young subjects for virtual lesion tractography of WMH is, in most cases, preferable to using age‐matched normative data.

46. Hippocampal volume loss in individuals with a history of non‐fatal opioid overdose

    Dustin R Todaro, Xinyi Li, Lais S. Pereira-Rufino, and 9 more authors

    Addiction Biology, Sep 2023

    Cited by 7

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    Incidence of opioid‐related overdoses in the United States has increased dramatically over the past two decades. Despite public emphasis on overdose fatalities, most overdose cases are not fatal. Although there are case reports of amnestic syndromes and acute injury to the hippocampus following non‐fatal opioid overdose, the effects of such overdoses on brain structure are poorly understood. Here, we investigated the neuroanatomical correlates of non‐fatal opioid overdoses by comparing hippocampal volume in opioid use disorder (OUD) patients who had experienced an opioid overdose (OD; N = 17) with those who had not (NOD; N = 32). Voxel‐based morphometry showed lower hippocampal volume in the OD group than in the NOD group, which on post hoc analysis was evident in the left but not the right hippocampus. These findings strengthen the evidence that hippocampal injury is associated with non‐fatal opioid overdose, which is hypothesized to underlie overdose‐related amnestic syndrome.

47. Craniofacial Soft-Tissue Anthropomorphic Database with Magnetic Resonance Imaging and Unbiased Diffeomorphic Registration

    D. Villavisanis, Pulkit Khandelwal, Zachary D. Zapatero, and 7 more authors

    Plastic and Reconstructive Surgery, Apr 2023

    Cited by 7

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    Background: Objective assessment of craniofacial surgery outcomes in a pediatric population is challenging because of the complexity of patient presentations, diversity of procedures performed, and rapid craniofacial growth. There is a paucity of robust methods to quantify anatomical measurements by age and objectively compare craniofacial dysmorphology and postoperative outcomes. Here, the authors present data in developing a racially and ethnically sensitive anthropomorphic database, providing plastic and craniofacial surgeons with “normal” three-dimensional anatomical parameters with which to appraise and optimize aesthetic and reconstructive outcomes. Methods: Patients with normal craniofacial anatomy undergoing head magnetic resonance imaging (MRI) scans from 2008 to 2021 were included in this retrospective study. Images were used to construct composite (template) images with diffeomorphic image registration method using the Advanced Normalization Tools package. Composites were thresholded to generate binary three-dimensional segmentations used for anatomical measurements in Materalise Mimics. Results: High-resolution MRI scans from 130 patients generated 12 composites from an average of 10 MRI sequences each: four 3-year-olds, four 4-year-olds, and four 5-year-olds (two male, two female, two Black, and two White). The average head circumference of 3-, 4-, and 5-year-old composites was 50.3, 51.5, and 51.7 cm, respectively, comparable to normative data published by the World Health Organization. Conclusions: Application of diffeomorphic registration-based image template algorithm to MRI is effective in creating composite templates to represent “normal” three-dimensional craniofacial and soft-tissue anatomy. Future research will focus on development of automated computational tools to characterize anatomical normality, generation of indices to grade preoperative severity, and quantification of postoperative results to reduce subjectivity bias.

48. Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories

    A. Wuestefeld, H. Baumeister , J.N. Adams, and 37 more authors

    bioRxiv, May 2023

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    The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer’s disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the cortices that make up the parahippocampal gyrus (entorhinal and parahippocampal cortices) and the adjacent Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized (20X resolution) slices with 5 mm spacing. Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists’ agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed more gradually. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed human neuroimaging research on the MTL cortex.

49. A multi‐site study of Alzheimer’s disease neuroimaging and cognitive biomarkers in 2819 cognitively normal individuals

    L. Xie, Sandhitsu R. Das, L. Wisse, and 6 more authors

    Alzheimer’s & Dementia, Dec 2023

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    Developing effective Alzheimer’s disease (AD) biomarkers in cognitively normal (CN) individuals is crucial. Prior studies have identified neuroimaging and cognitive measures that are sensitive to preclinical AD. However, the generalizability of these biomarkers in large, multi‐site cohorts and their power to predict disease progression remain unclear. Structural MRI, tau PET and standardized cognitive tests of 2819 CN adults were pooled from three studies to investigate the power of these measures in discriminating ß‐amyloid positivity (A+/‐) and predicting disease progression.

50. Baseline structural MRI and plasma biomarkers predict longitudinal structural atrophy and cognitive decline in early Alzheimer’s disease

    L. Xie, Sandhitsu R. Das, L. Wisse, and 5 more authors

    Alzheimer’s Research & Therapy, Apr 2023

    Cited by 31

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    Background Crucial to the success of clinical trials targeting early Alzheimer’s disease (AD) is recruiting participants who are more likely to progress over the course of the trials. We hypothesize that a combination of plasma and structural MRI biomarkers, which are less costly and non-invasive, is predictive of longitudinal progression measured by atrophy and cognitive decline in early AD, providing a practical alternative to PET or cerebrospinal fluid biomarkers. Methods Longitudinal T1-weighted MRI, cognitive (memory-related test scores and clinical dementia rating scale), and plasma measurements of 245 cognitively normal (CN) and 361 mild cognitive impairment (MCI) patients from ADNI were included. Subjects were further divided into β-amyloid positive/negative (Aβ+/Aβ−)] subgroups. Baseline plasma (p-tau_181 and neurofilament light chain) and MRI-based structural medial temporal lobe subregional measurements and their association with longitudinal measures of atrophy and cognitive decline were tested using stepwise linear mixed effect modeling in CN and MCI, as well as separately in the Aβ+/Aβ− subgroups. Receiver operating characteristic (ROC) analyses were performed to investigate the discriminative power of each model in separating fast and slow progressors (first and last terciles) of each longitudinal measurement. Results A total of 245 CN (35.0% Aβ+) and 361 MCI (53.2% Aβ+) participants were included. In the CN and MCI groups, both baseline plasma and structural MRI biomarkers were included in most models. These relationships were maintained when limited to the Aβ+ and Aβ− subgroups, including Aβ− CN (normal aging). ROC analyses demonstrated reliable discriminative power in identifying fast from slow progressors in MCI [area under the curve (AUC): 0.78–0.93] and more modestly in CN (0.65–0.73). Conclusions The present data support the notion that plasma and MRI biomarkers, which are relatively easy to obtain, provide a prediction for the rate of future cognitive and neurodegenerative progression that may be particularly useful in clinical trial stratification and prognosis. Additionally, the effect in Aβ− CN indicates the potential use of these biomarkers in predicting a normal age-related decline.

51. Tau burden is associated with cross‐sectional and longitudinal neurodegeneration in the medial temporal lobe in cognitively normal individuals

    L. Xie, L. Wisse, Sandhitsu R. Das, and 4 more authors

    Alzheimer’s & Dementia, Jun 2023

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    Neurofibrillary tangle pathology is thought to drive neurodegeneration in beta‐amyloid positive (A+) cognitively normal (CN) individuals, i.e., preclinical Alzheimer’s disease (AD). However, in beta‐amyloid negative (A‐) CN, the contribution of tau pathology [primary age‐related tauopathy (PART)] to neurodegeneration remains uncertain. We investigate the correlation between tau burden measured by PET in the medial temporal lobe (MTL) and MRI‐derived cross‐sectional and longitudinal structural atrophy in these cohorts.

52. Mapping Medial Temporal Lobe Longitudinal Change in Preclinical Alzheimer’s Disease

    Paul Yushkevich, L. Xie, L. Wisse, and 6 more authors

    Alzheimer’s & Dementia, Dec 2023

    Cited by 3

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    The medial temporal lobe (MTL) is a site of early tau pathology and neurodegeneration in AD. In recent work [1], we reported that rates of change in MTL subregion volumes on longitudinal structural T1‐MRI differ significantly between cognitively unimpaired individuals with and without amyloid pathology (A+CU vs A‐CU), suggesting that these measures are effective biomarkers for tracking disease progression in preclinical AD. Here, we develop a specialized pipeline that quantifies pointwise longitudinal change across the MTL, revealing more informative spatial patterns of early neurodegeneration than summary volumetric longitudinal measures.

2022

1. Fully Automated 3D Segmentation and Diffeomorphic Medial Modeling of the Left Ventricle Mitral Valve Complex in Ischemic Mitral Regurgitation

   A. H. Aly, Pulkit Khandelwal, A. H. Aly, and 8 more authors

   Medical image analysis, Jun 2022

   Cited by 15

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   There is an urgent unmet need to develop a fully-automated image-based left ventricle mitral valve analysis tool to support surgical decision making for ischemic mitral regurgitation patients. This requires an automated tool for segmentation and modeling of the left ventricle and mitral valve from immediate pre-operative 3D transesophageal echocardiography. Previous works have presented methods for semi-automatically segmenting and modeling the mitral valve, but do not include the left ventricle and do not avoid self-intersection of the mitral valve leaflets during shape modeling. In this study, we develop and validate a fully automated algorithm for segmentation and shape modeling of the left ventricular mitral valve complex from pre-operative 3D transesophageal echocardiography. We performed a 3-fold nested cross validation study on two datasets from separate institutions to evaluate automated segmentations generated by nnU-net with the expert manual segmentation which yielded average overall Dice scores of 0.82±0.03 (set A), 0.87±0.08 (set B) respectively. A deformable medial template was subsequently fitted to the segmentation to generate shape models. Comparison of shape models to the manual and automatically generated segmentations resulted in an average Dice score of 0.93-0.94 and 0.75-0.81 for the left ventricle and mitral valve, respectively. This is a substantial step towards automatically analyzing the left ventricle mitral valve complex in the operating room.

2. Regional distribution and maturation of tau pathology among phenotypic variants of Alzheimer’s disease

   Sanaz Arezoumandan, S. Xie, K. Cousins, and 13 more authors

   Acta Neuropathologica, Jul 2022

   Cited by 19

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3. Deep learning-based automated segmentation of resection cavities on postsurgical epilepsy MRI

   T. Arnold, Ramya Muthukrishnan, A. Pattnaik, and 9 more authors

   NeuroImage : Clinical, Aug 2022

   Cited by 13

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   Highlights • We developed an open-source algorithm for resection cavity segmentation.• Algorithm performance (0.76–0.84 DSC) approached interrater reliability (0.84 DSC).• This tool can be used to estimate postoperative remnant volumes (e.g. hippocampus).• All code and model weights are available: https://github.com/penn-cnt/DeepResection.

4. Implanting intracranial electrodes does not affect spikes or network connectivity in nearby or connected brain regions

   E. Conrad, R. Shinohara, James J Gugger, and 6 more authors

   Network Neuroscience, Apr 2022

   Cited by 4

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   Abstract To determine the effect of implanting electrodes on electrographic features of nearby and connected brain regions in patients with drug-resistant epilepsy, we analyzed intracranial EEG recordings from 10 patients with drug-resistant epilepsy who underwent implant revision (placement of additional electrodes) during their hospitalization. We performed automated spike detection and measured EEG functional networks. We analyzed the original electrodes that remained in place throughout the full EEG recording, and we measured the change in spike rates and network connectivity in these original electrodes in response to implanting new electrodes. There was no change in overall spike rate pre- to post-implant revision (t(9) = 0.1, p = 0.95). The peri-revision change in the distribution of spike rate and connectivity across electrodes was no greater than chance (Monte Carlo method, spikes: p = 0.40, connectivity: p = 0.42). Electrodes closer to or more functionally connected to the revision site had no greater change in spike rate or connectivity than more distant or less connected electrodes. Changes in electrographic features surrounding electrode implantation are no greater than baseline fluctuations occurring throughout the intracranial recording. These findings argue against an implant effect on spikes or network connectivity in nearby or connected brain regions.

5. Deep Learning Registration with Scan‐temporal Consistency May Improve Detection of Alzheimer’s Disease Progression

   M. Dong, L. Xie, Jiancong Wang, and 3 more authors

   Alzheimer’s & Dementia, Dec 2022

   Abs DOI

   

   Structural changes in Alzheimer’s disease (AD) can be detected as atrophy in the medial temporal lobe (MTL), which is normally studied by applying volumetric or deformation‐based morphometry (DBM) to longitudinal scans. However, conventional DMB methods are computationally intensive and may not estimate the atrophy accurately due to the noise in the longitudinal images, e.g., head motion or MRI artifacts. We hypothesize that deep learning models can be trained to estimate atrophy from longitudinal MRI scans and are more sensitive to biological changes rather than artifactual.

6. Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease

   M. Duong, Sandhitsu R. Das, Xueying Lyu, and 289 more authors

   Nature Communications, Mar 2022

   Cited by 38

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   Alzheimer’s disease (AD) is defined by amyloid (A) and tau (T) pathologies, with T better correlated to neurodegeneration (N). However, T and N have complex regional relationships in part related to non-AD factors that influence N. With machine learning, we assessed heterogeneity in 18F-flortaucipir vs. 18F-fluorodeoxyglucose positron emission tomography as markers of T and neuronal hypometabolism (NM) in 289 symptomatic patients from the Alzheimer’s Disease Neuroimaging Initiative. We identified six T/NM clusters with differing limbic and cortical patterns. The canonical group was defined as the T/NM pattern with lowest regression residuals. Groups resilient to T had less hypometabolism than expected relative to T and displayed better cognition than the canonical group. Groups susceptible to T had more hypometabolism than expected given T and exhibited worse cognitive decline, with imaging and clinical measures concordant with non-AD copathologies. Together, T/NM mismatch reveals distinct imaging signatures with pathobiological and prognostic implications for AD. In Alzheimer’s disease (AD) tau and neurodegeneration have complex regional relationships. Here, the authors show neuronal hypometabolism discordant with tau burden defines functional resilience or susceptibility to Alzheimer’s pathology via limbic/cortical axes. Susceptible groups have faster cognitive decline and evidence of non-Alzheimer’s pathologies.

7. Medial Temporal Lobe Networks in Alzheimer’s Disease: Structural and Molecular Vulnerabilities

   R. Flores, Sandhitsu R. Das, L. Xie, and 5 more authors

   The Journal of Neuroscience, Jan 2022

   Cited by 50

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   The medial temporal lobe (MTL) is connected to the rest of the brain through two main networks: the anterior-temporal (AT) and the posterior-medial (PM) systems. Given the crucial role of the MTL and networks in the physiopathology of Alzheimer’s disease (AD), the present study aimed at (1) investigating whether MTL atrophy propagates specifically within the AT and PM networks, and (2) evaluating the vulnerability of these networks to AD proteinopathies. To do that, we used neuroimaging data acquired in human male and female in three distinct cohorts: (1) resting-state functional MRI (rs-fMRI) from the aging brain cohort (ABC) to define the AT and PM networks (n = 68); (2) longitudinal structural MRI from Alzheimer’s disease neuroimaging initiative (ADNI)GO/2 to highlight structural covariance patterns (n = 349); and (3) positron emission tomography (PET) data from ADNI3 to evaluate the networks’ vulnerability to amyloid and tau (n = 186). Our results suggest that the atrophy of distinct MTL subregions propagates within the AT and PM networks in a dissociable manner. Brodmann area (BA)35 structurally covaried within the AT network while the parahippocampal cortex (PHC) covaried within the PM network. In addition, these networks are differentially associated with relative tau and amyloid burden, with higher tau levels in AT than in PM and higher amyloid levels in PM than in AT. Our results also suggest differences in the relative burden of tau species. The current results provide further support for the notion that two distinct MTL networks display differential alterations in the context of AD. These findings have important implications for disease spread and the cognitive manifestations of AD. SIGNIFICANCE STATEMENT The current study provides further support for the notion that two distinct medial temporal lobe (MTL) networks, i.e., anterior-temporal (AT) and the posterior-medial (PM), display differential alterations in the context of Alzheimer’s disease (AD). Importantly, neurodegeneration appears to occur within these networks in a dissociable manner marked by their covariance patterns. In addition, the AT and PM networks are also differentially associated with relative tau and amyloid burden, and perhaps differences in the relative burden of tau species [e.g., neurofibriliary tangles (NFTs) vs tau in neuritic plaques]. These findings, in the context of a growing literature consistent with the present results, have important implications for disease spread and the cognitive manifestations of AD in light of the differential cognitive processes ascribed to them.

8. Repeatability of B1+ inhomogeneity correction of volumetric (3D) glutamate CEST via High‐permittivity dielectric padding at 7T

   Paul S Jacobs, Blake Benyard, Abigail T. J. Cember, and 9 more authors

   Magnetic Resonance in Medicine, Aug 2022

   Cited by 11

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   Ultra‐high field MR imaging lacks B1+ inhomogeneity due to shorter RF wavelengths used at higher field strengths compared to human anatomy. CEST techniques tend to be highly susceptible to B1+ inhomogeneities due to a high and uniform B1+ field being necessary to create the endogenous contrast. High‐permittivity dielectric pads have seen increasing usage in MR imaging due to their ability to tailor the spatial distribution of the B1+ field produced. The purpose of this work is to demonstrate that dielectric materials can be used to improve glutamate weighted CEST (gluCEST) at 7T.

9. Deep Learning for Ultra High Resolution T2‐weighted 7 Tesla Ex vivo Magnetic Resonance Imaging Reveals Differential Subcortical Atrophy across Neurodegenerative Diseases

   Pulkit Khandelwal, M. Duong, E. Chung, and 31 more authors

   Alzheimer’s & Dementia, Dec 2022

   Cited by 2

   Abs DOI

   

   Ex vivo magnetic resonance imaging (MRI) of the brain provides remarkable advantages over in vivo MRI for linking neuroanatomy and morphometry to underlying pathology (Yushkevich et al. 2021, Ravikumar et al. 2021). Subcortical structures show atrophy in certain neurodegenerative diseases, especially Frontotemporal Lobar Degeneration with TDP‐43 (FTLD‐TDP) and four‐repeat (4R) tauopathies (i.e., Corticobasal Degeneration, Progressive Supranuclear Palsy) (Miletić et al. 2022), yet few methods exist to measure subcortical atrophy in ex vivo MRI. We present a framework to quantify subcortical morphometry using 7 Tesla ex vivo MRI and distinguish atrophy patterns across neurodegenerative spectrums.

10. Deep learning pipeline for cortical gray matter segmentation and thickness analysis in Ultra High Resolution T2w 7 Tesla Ex vivo MRI across neurodegenerative diseases reveals associations with underlying neuropathology

    Pulkit Khandelwal, S. Sadaghiani, E. Chung, and 30 more authors

    Alzheimer’s & Dementia, Dec 2022

    Cited by 3

    Abs DOI

    

    Ex vivo magnetic resonance imaging (MRI) enables detailed characterization of neuroanatomy (Augustinack et al. 2013), such as hippocampal subfields in the medial temporal lobe (MTL) (Yushkevich et al. 2021, Ravikumar et al. 2021). However, automated cortical segmentation methods in ex vivo MRI are not well developed due to limited data availability and heterogeneity in scanners and acquisition. Here, we investigate a deep learning framework to parcellate the cortical mantle, compute thickness and link them with neuropathology ratings across 16 cortical regions in 7 Tesla MRIs of 38 ex vivo brain specimens spanning Alzheimer Disease and Related Dementias.

11. Mapping hippocampal glutamate in mesial temporal lobe epilepsy with glutamate weighted CEST (GluCEST) imaging

    Alfredo Lucas, R. Nanga, P. Hadar, and 9 more authors

    Human Brain Mapping, Sep 2022

    Cited by 20

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    Temporal lobe epilepsy (TLE) is one of the most common subtypes of focal epilepsy, with mesial temporal sclerosis (MTS) being a common radiological and histopathological finding. Accurate identification of MTS during presurgical evaluation confers an increased chance of good surgical outcome. Here we propose the use of glutamate‐weighted chemical exchange saturation transfer (GluCEST) magnetic resonance imaging (MRI) at 7 Tesla for mapping hippocampal glutamate distribution in epilepsy, allowing to differentiate lesional from non‐lesional mesial TLE. We demonstrate that a directional asymmetry index, which quantifies the relative difference between GluCEST contrast in hippocampi ipsilateral and contralateral to the seizure onset zone, can differentiate between sclerotic and non‐sclerotic hippocampi, even in instances where traditional presurgical MRI assessments did not provide evidence of sclerosis. Overall, our results suggest that hippocampal glutamate mapping through GluCEST imaging is a valuable addition to the presurgical epilepsy evaluation toolbox.

12. Resting state functional connectivity demonstrates increased segregation in bilateral temporal lobe epilepsy

    Alfredo Lucas, E. Cornblath, N. Sinha, and 9 more authors

    Epilepsia, Aug 2022

    Cited by 21

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    Temporal lobe epilepsy (TLE) is the most common type of focal epilepsy. An increasingly identified subset of patients with TLE consists of those who show bilaterally independent temporal lobe seizures. The purpose of this study was to leverage network neuroscience to better understand the interictal whole brain network of bilateral TLE (BiTLE).

13. Tau‐Neurodegeneration mismatch reveals vulnerability and resilience in Alzheimer’s continuum and Non‐Alzheimer’s pathophysiology

    Xueying Lyu, M. Duong, L. Xie, and 15 more authors

    Alzheimer’s & Dementia, Dec 2022

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    In previous work (Das et al., 2021), we exploited the non‐specific nature of neurodegeneration by investigating the amount and spatial pattern of deviation from the level of neurodegeneration (N) expected for a given level of tau (T). Using a data‐driven clustering approach based on T‐N mismatch, we found phenotypes that had greater N than expected for T (“vulnerable”) and phenotypes with less N than expected for T (“resilient”) in specific patterns. Here we extend this work to include amyloid positive (A+) and negative (A‐) participants. The logic of inclusion of A‐ individuals is that areas of mismatch in A+ individuals is likely driven by factors outside of AD pathology, which can be present in the absence of AD pathology.

14. At‐Home Data Collection with an App‐Based Cognitive Assessment for Detecting Memory and Executive Functioning Changes in Aging and Pre‐Clinical AD

    Dawn J. Mechanic-Hamilton, Kimberly Halberstadter, Sean Lydon, and 2 more authors

    Alzheimer’s & Dementia, Dec 2022

    Abs DOI

    

    Mobile, valid and engaging cognitive assessments are essential for detecting and tracking change in research participants and patients at risk for Alzheimer’s Disease and Related Dementias (ADRDs). This pilot study aims to determine the feasibility of at‐home, app‐based memory and executive functioning tasks included in the mobile cognitive app performance platform (mCAPP), to detect cognitive changes associated with aging and preclinical AD.

15. The Polygenic Risk Score Knowledge Base offers a centralized online repository for calculating and contextualizing polygenic risk scores

    Madeline L. Page, Elizabeth L Vance, Matthew E Cloward, and 475 more authors

    Communications Biology, Sep 2022

    Cited by 8

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    The process of identifying suitable genome-wide association (GWA) studies and formatting the data to calculate multiple polygenic risk scores on a single genome can be laborious. Here, we present a centralized polygenic risk score calculator currently containing over 250,000 genetic variant associations from the NHGRI-EBI GWAS Catalog for users to easily calculate sample-specific polygenic risk scores with comparable results to other available tools. Polygenic risk scores are calculated either online through the Polygenic Risk Score Knowledge Base (PRSKB; https://prs.byu.edu) or via a command-line interface. We report study-specific polygenic risk scores across the UK Biobank, 1000 Genomes, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), contextualize computed scores, and identify potentially confounding genetic risk factors in ADNI. We introduce a streamlined analysis tool and web interface to calculate and contextualize polygenic risk scores across various studies, which we anticipate will facilitate a wider adaptation of polygenic risk scores in future disease research. The Polygenic Risk Score Knowledge Base (PRSKB) is a web-based interface that stores data from >2,300 distinct genome-wide association studies, and can estimate polygenic risk scores for general use.

16. Neuropsychological and Neuroanatomical Features of Patients with Behavioral/Dysexecutive Variant Alzheimer’s Disease (AD): A Comparison to Behavioral Variant Frontotemporal Dementia and Amnestic AD Groups

    Sophia Dominguez Perez, J. Phillips, Catherine Norise, and 12 more authors

    Journal of Alzheimer’s Disease, Aug 2022

    Cited by 13

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    Background: An understudied variant of Alzheimer’s disease (AD), the behavioral/dysexecutive variant of AD (bvAD), is associated with progressive personality, behavior, and/or executive dysfunction and frontal atrophy. Objective: This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to behavioral variant frontotemporal dementia (bvFTD), amnestic AD (aAD), and subjects with normal cognition. Methods: Subjects included 16 bvAD, 67 bvFTD, 18 aAD patients, and 26 healthy controls. Neuropsychological assessment and MRI data were compared between these groups. Results: Compared to bvFTD, bvAD showed more significant visuospatial impairments (Rey Figure copy and recall), more irritability (Neuropsychological Inventory), and equivalent verbal memory (Philadelphia Verbal Learning Test). Compared to aAD, bvAD indicated more executive dysfunction (F-letter fluency) and better visuospatial performance. Neuroimaging analysis found that bvAD showed cortical thinning relative to bvFTD posteriorly in left temporal-occipital regions; bvFTD had cortical thinning relative to bvAD in left inferior frontal cortex. bvAD had cortical thinning relative to aAD in prefrontal and anterior temporal regions. All patient groups had lower volumes than controls in both anterior and posterior hippocampus. However, bvAD patients had higher average volume than aAD patients in posterior hippocampus and higher volume than bvFTD patients in anterior hippocampus after adjustment for age and intracranial volume. Conclusion: Findings demonstrated that underlying pathology mediates disease presentation in bvAD and bvFTD.

17. Neuropsychological and neuroanatomical features of patients with behavioral variant Alzheimer’s disease (AD): a comparison to behavioral variant frontotemporal dementia and amnestic AD groups

    Sophia Dominguez Perez, J. Phillips, Catherine Norise, and 12 more authors

    medRxiv, Jan 2022

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    An understudied non-amnestic variant of Alzheimer’s disease (AD), behavioral variant AD (bvAD) is associated with progressive personality, behavior, or executive dysfunction and frontal atrophy. This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to behavioral variant frontotemporal dementia (bvFTD), amnestic AD (aAD), and subjects with normal cognition. Subjects included 16 bvAD, 67 bvFTD, and 18 aAD patients, and 26 healthy controls. Compared to bvFTD, bvAD showed more significant visuospatial impairments (Rey Figure copy and recall), more irritability (Neuropsychological Inventory), and equivalent verbal memory (Philadelphia Verbal Learning Test). Compared to aAD, bvAD indicated more executive dysfunction (F-letter fluency) and better visuospatial performance. Neuroimaging analysis found that bvAD showed cortical thinning relative to bvFTD posteriorly in left temporal-occipital regions; bvFTD had cortical thinning relative to bvAD in left inferior frontal cortex. bvAD had cortical thinning relative to aAD in prefrontal and anterior temporal regions. All patient groups had lower volumes than controls in both anterior and posterior hippocampus. However, bvAD patients had higher average volume than aAD patients in posterior hippocampus and higher volume than bvFTD patients in anterior hippocampus after adjustment for age and intracranial volume. Findings demonstrated that underlying pathology mediates disease presentation in bvAD and bvFTD.

18. Combining high‐resolution ex vivo MRI and histopathology to identify medial temporal lobe atrophy patterns specific to tau pathology in Alzheimer’s Disease

    S. Ravikumar, Amanda E Denning, Sydney A. Lim, and 26 more authors

    Alzheimer’s & Dementia, Dec 2022

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    Tau pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is an early pathological change associated with Alzheimer’s disease (AD). MRI measures of MTL neurodegeneration have proven to be sensitive to change during preclinical AD. Current measures are confounded by the presence of non‐AD pathologies (e.g., TDP‐43, ageing). Here, we combine ex vivo imaging with histopathological ratings of tau and TDP‐43 to identify fine‐grained MTL atrophy patterns specific to tau. Such an analysis could be used to define MTL “hotspots” where in vivo measures of neurodegeneration are expected to be strongly associated with tau, potentially enabling the development of biomarkers that are more effective during early AD clinical trials.

19. A Taxonomy of Seizure Spread Patterns, Speed of Spread, and Associations With Structural Connectivity

    A. Revell, A. Pattnaik, E. Conrad, and 9 more authors

    bioRxiv, Oct 2022

    Cited by 4

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    Although seizure detection algorithms are widely used to localize seizure onset on intracranial EEG in epilepsy patients, relatively few studies focus on seizure activity beyond the seizure onset zone to direct treatment of surgical patients with epilepsy. To address this gap, we develop and compare fully automated deep learning algorithms to detect seizure activity on single channels, effectively quantifying spread when deployed across multiple channels. Across 275 seizures in 71 patients, we discover that the extent of seizure spread across the brain and the timing of seizure spread between temporal lobe regions is associated with both surgical outcomes and the brain’s structural connectivity between temporal lobes. Finally, we uncover a hierarchical structure of seizure spread patterns highlighting the relationship between clusters of seizures. Collectively, these findings underscore the broad utility in quantifying seizure activity past seizure onset to identify novel mechanisms of seizure evolution and its relationship to potential seizure freedom.

20. Associations of phosphorylated tau pathology with whole‐hemisphere ex vivo morphometry in 7 tesla MRI

    S. Sadaghiani, W. Trotman, Sydney A. Lim, and 32 more authors

    Alzheimer’s & Dementia, Dec 2022

    Cited by 11

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    Neurodegenerative disorders are associated with different pathologies that often co‐occur but cannot be measured specifically with in vivo methods.

21. Associations between cortical microinfarcts, hippocampal atrophy, and cerebral small vessel disease

    S. Sadaghiani, Sudipto Dolui, Pulkit Khandelwal, and 6 more authors

    Alzheimer’s & Dementia, Dec 2022

    Abs DOI

    

    Brain cortical microinfarcts (CMI) are negatively correlated with cognitive function in both normal aging and Alzheimer’s disease (AD). High‐field structural magnetic resonance imaging (MRI) has facilitated in vivo detection of CMIs but their significance and underlying pathological mechanism remain uncertain. Here we assessed correlations between CMIs and medial temporal lobe (MTL) cortical thickness, white matter hyperintensity (WMH) volume, and relative periventricular white matter cerebral blood flow (PVWM CBF) in healthy individuals. PVWM CBF is thought to provide a measure of cerebral small vessel function.

22. Linking histology to post‐mortem 7T MRI measures of neurodegeneration

    S. Sadaghiani, S. Ravikumar, R. Ittyerah, and 17 more authors

    Alzheimer’s & Dementia, Dec 2022

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    Neurodegenerative disorders are associated with different pathologies that often co‐occur and have differential contribution to the pattern of cognitive impairment. The majority of these pathologies cannot be detected or measured by in‐vivo methods; therefore, recognition of the topographic patterns of them and association with MRI findings may provide probabilistic non‐invasive biomarkers. We investigated the association of cortical and medial temporal lobe subregional thickness measured from postmortem MRI and semi‐quantitative pathologic measures in order to provide a methodological approach for linking pathological and radiological measures.

23. Mechanisms of Cognitive Decline due to White Matter Lesions in Cognitively Intact Older Adults

    M. Taghvaei, P. Cook, Pulkit Khandelwal, and 9 more authors

    Alzheimer’s & Dementia, Dec 2022

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    White matter hyperintensities (WMH) on FLAIR MRI are highly prevalent in older adults and are linked to cognitive deficits as well as dementia. Likely mechanisms underlying associations between WMH and cognitive deficits include widespread partial disconnection due to the diffuse nature of progressive WMH and/or tract‐specific disconnection syndromes. We used a virtual lesion approach to evaluate cognitive deficits in domains associated with three tracts: left arcuate fasciculus (LAF; verbal working memory), inferior longitudinal fasciculus (ILF; visual processing), and fornix (memory).

24. P67. DEVELOPMENT OF A CRANIOFACIAL SOFT TISSUE ANTHROPOMORPHIC DATABASE: APPLICATION OF DIFFEOMORPHIC ALGORITHMS TO MRI

    D. Villavisanis, Pulkit Khandelwal, Zachary D. Zapatero, and 8 more authors

    Plastic and Reconstructive Surgery - Global Open, Apr 2022

    Cited by 4

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25. PART is part of SNAP‐MCI

    L. Wisse, L. Xie, Xueying Lyu, and 6 more authors

    Alzheimer’s & Dementia, Dec 2022

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    Mild Cognitive Impairment with Suspected non‐Alzheimer’s Pathophysiology (SNAP‐MCI) represents a group of patients with Alzheimer’s disease (AD) like neurodegeneration without beta‐amyloid pathology. While this group likely has a heterogeneous etiology, tau pathology, as in Primary Age‐Related Tauopathy (PART), has been hypothesized to play a major role. We investigate tau positron emission tomography (PET) uptake in the medial temporal lobe (MTL) in SNAP‐MCI and the association of MTL Tau‐PET uptake with structural measures and delayed recall in beta‐amyloid negative (A‐) MCI patients.

26. Deep label fusion: A generalizable hybrid multi-atlas and deep convolutional neural network for medical image segmentation

    L. Xie, L. Wisse, Jiancong Wang, and 7 more authors

    Medical image analysis, Nov 2022

    Cited by 58

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    Deep convolutional neural networks (DCNN) achieve very high accuracy in segmenting various anatomical structures in medical images but often suffer from relatively poor generalizability. Multi-atlas segmentation (MAS), while less accurate than DCNN in many applications, tends to generalize well to unseen datasets with different characteristics from the training dataset. Several groups have attempted to integrate the power of DCNN to learn complex data representations and the robustness of MAS to changes in image characteristics. However, these studies primarily focused on replacing individual components of MAS with DCNN models and reported marginal improvements in accuracy. In this study we describe and evaluate a 3D end-to-end hybrid MAS and DCNN segmentation pipeline, called Deep Label Fusion (DLF). The DLF pipeline consists of two main components with learnable weights, including a weighted voting subnet that mimics the MAS algorithm and a fine-tuning subnet that corrects residual segmentation errors to improve final segmentation accuracy. We evaluate DLF on five datasets that represent a diversity of anatomical structures (medial temporal lobe subregions and lumbar vertebrae) and imaging modalities (multi-modality, multi-field-strength MRI and Computational Tomography). These experiments show that DLF achieves comparable segmentation accuracy to nnU-Net (Isensee et al., 2020), the state-of-the-art DCNN pipeline, when evaluated on a dataset with similar characteristics to the training datasets, while outperforming nnU-Net on tasks that involve generalization to datasets with different characteristics (different MRI field strength or different patient population). DLF is also shown to consistently improve upon conventional MAS methods. In addition, a modality augmentation strategy tailored for multimodal imaging is proposed and demonstrated to be beneficial in improving the segmentation accuracy of learning-based methods, including DLF and DCNN, in missing data scenarios in test time as well as increasing the interpretability of the contribution of each individual modality.

27. Tau burden is associated with cross‐sectional and longitudinal neurodegeneration in the medial temporal lobe in cognitively normal individuals

    L. Xie, L. Wisse, Sandhitsu R. Das, and 4 more authors

    Alzheimer’s & Dementia, Dec 2022

    Cited by 3

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    Neurofibrillary tangle pathology is thought to drive neurodegeneration in beta‐amyloid positive (A+) cognitively normal (CN) individuals, i.e., preclinical Alzheimer’s disease (AD).However, in beta‐amyloid negative (A‐) CN, the contribution of tau pathology [primary age‐related tauopathy (PART)] to neurodegeneration remains uncertain. We investigate the correlation between tau burden measured by PET in the medial temporal lobe (MTL) and MRI‐derived cross‐sectional and longitudinal structural atrophy in these cohorts.

28. Self- and Partner-Reported Subjective Memory Complaints: Association with Objective Cognitive Impairment and Risk of Decline

    Leah Zuroff, L. Wisse, T. Glenn, and 15 more authors

    Journal of Alzheimer’s Disease Reports, Jul 2022

    Cited by 12

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    Background: Episodic memory decline is a hallmark of Alzheimer’s disease (AD). Subjective memory complaints (SMCs) may represent one of the earliest signs of impending cognitive decline. The degree to which self- or partner-reported SMCs predict cognitive change remains unclear. Objective: We aimed to evaluate the relationship between self- and partner-reported SMCs, objective cognitive performance, AD biomarkers, and risk of future decline in a well-characterized longitudinal memory center cohort. We also evaluated whether study partner characteristics influence reports of SMCs. Methods: 758 participants and 690 study partners were recruited from the Penn Alzheimer’s Disease Research Center Clinical Core. Participants included those with Normal Cognition, Mild Cognitive Impairment, and AD. SMCs were measured using the Prospective and Retrospective Memory Questionnaire (PRMQ), and were evaluated for their association with cognition, genetic, plasma, and neuroimaging biomarkers of AD, cognitive and functional decline, and diagnostic progression over an average of four years. Results: We found that partner-reported SMCs were more consistent with cognitive test performance and increasing symptom severity than self-reported SMCs. Partner-reported SMCs showed stronger correlations with AD-associated brain atrophy, plasma biomarkers of neurodegeneration, and longitudinal cognitive and functional decline. A 10-point increase on baseline PRMQ increased the annual risk of diagnostic progression by approximately 70%. Study partner demographics and relationship to participants influenced reports of SMCs in AD participants only. Conclusion: Partner-reported SMCs, using the PRMQ, have a stronger relationship with the neuroanatomic and cognitive changes associated with AD than patient-reported SMCs. Further work is needed to evaluate whether SMCs could be used to screen for future decline.

2021

1. Regional distribution of tau pathology in subfields of hippocampus among phenotypic variants of AD and FTLD‐tau

   Sanaz Arezoumandan, K. Cousins, J. Phillips, and 10 more authors

   Alzheimer’s & Dementia, Dec 2021

   DOI

   
2. Early stages of tau pathology and its associations with functional connectivity, atrophy and memory

   D. Berron, J. Vogel, P. Insel, and 10 more authors

   Brain, Mar 2021

   Cited by 164

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   In Alzheimer’s disease, postmortem studies have shown that the first cortical site where neurofibrillary tangles appear is the transentorhinal region, a subregion within the medial temporal lobe that largely overlaps with area 35, and the entorhinal cortex. Here we used tau‐PET imaging to investigate the sequence of tau pathology progression within the human medial temporal lobe and across regions in the posterior‐medial system. Our objective was to study how medial temporal tau is related to functional connectivity, regional atrophy, and memory performance.

3. Staging tau pathology with tau PET in Alzheimer’s disease: a longitudinal study

   Shi‐Dong Chen, Jiaying Lu, Hong-Qi Li, and 471 more authors

   Translational Psychiatry, Sep 2021

   Cited by 60

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   A biological research framework to define Alzheimer’ disease with dichotomized biomarker measurement was proposed by National Institute on Aging–Alzheimer’s Association (NIA–AA). However, it cannot characterize the hierarchy spreading pattern of tau pathology. To reflect in vivo tau progression using biomarker, we constructed a refined topographic 18 F-AV-1451 tau PET staging scheme with longitudinal clinical validation. Seven hundred and thirty-four participants with baseline 18 F-AV-1451 tau PET (baseline age 73.9 ± 7.7 years, 375 female) were stratified into five stages by a topographic PET staging scheme. Cognitive trajectories and clinical progression were compared across stages with or without further dichotomy of amyloid status, using linear mixed-effect models and Cox proportional hazard models. Significant cognitive decline was first observed in stage 1 when tau levels only increased in transentorhinal regions. Rates of cognitive decline and clinical progression accelerated from stage 2 to stage 3 and stage 4. Higher stages were also associated with greater CSF phosphorylated tau and total tau concentrations from stage 1. Abnormal tau accumulation did not appear with normal β-amyloid in neocortical regions but prompt cognitive decline by interacting with β-amyloid in temporal regions. Highly accumulated tau in temporal regions independently led to cognitive deterioration. Topographic PET staging scheme have potentials in early diagnosis, predicting disease progression, and studying disease mechanism. Characteristic tau spreading pattern in Alzheimer’s disease could be illustrated with biomarker measurement under NIA–AA framework. Clinical–neuroimaging–neuropathological studies in other cohorts are needed to validate these findings.

4. Application of histopathologically derived 3D tau burden map as in‐vivo region of interest for biomarker analysis

   Sandhitsu R. Das, L. Xie, R. Flores, and 41 more authors

   Alzheimer’s & Dementia, Dec 2021

   Cited by 1

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   Quantitative three‐dimensional maps of tau neurofibrillary tangles (NFT) burden derived from dense serial histology have potential application for in‐vivo biomarker studies. We constructed a group‐level NFT burden map from 15 medial temporal lobe (MTL) specimens, majority with Primary Age‐Related Tauopathy (PART) or low‐level Alzheimer’s disease neuropathologic change, and showed relatively greater NFT burden in the anterior vs. posterior MTL. We investigated whether in‐vivo MRI and PET measures in ROIs derived from this map show meaningful biological relationships.

5. Tau‐Atrophy Variability Reveals Phenotypic Heterogeneity in Alzheimer’s Disease

   Sandhitsu R. Das, Xueying Lyu, M. Duong, and 9 more authors

   Annals of Neurology, Oct 2021

   Cited by 40

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   Tau neurofibrillary tangles (T) are the primary driver of downstream neurodegeneration (N) and subsequent cognitive impairment in Alzheimer’s disease (AD). However, there is substantial variability in the T‐N relationship – manifested in higher or lower atrophy than expected for level of tau in a given brain region. The goal of this study was to determine if region‐based quantitation of this variability allows for identification of underlying modulatory factors, including polypathology.

6. Diagnosing Mild Cognitive Impairment Among Racially Diverse Older Adults: Comparison of Consensus, Actuarial, and Statistical Methods

   Kathryn Devlin, L. Brennan, Laura Saad, and 5 more authors

   Journal of Alzheimer’s Disease, Nov 2021

   Cited by 12

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   Background: Actuarial and statistical methods have been proposed as alternatives to conventional methods of diagnosing mild cognitive impairment (MCI), with the aim of enhancing diagnostic and prognostic validity, but have not been compared in racially diverse samples. Objective: We compared the agreement of consensus, actuarial, and statistical MCI diagnostic methods, and their relationship to race and prognostic indicators, among diverse older adults. Methods: Participants (N = 354; M age = 71; 68% White, 29% Black) were diagnosed with MCI or normal cognition (NC) according to clinical consensus, actuarial neuropsychological criteria (Jak/Bondi), and latent class analysis (LCA). We examined associations with race/ethnicity, longitudinal cognitive and functional change, and incident dementia. Results: MCI rates by consensus, actuarial criteria, and LCA were 44%, 53%, and 41%, respectively. LCA identified three MCI subtypes (memory; memory/language; memory/executive) and two NC classes (low normal; high normal). Diagnostic agreement was substantial, but agreement of the actuarial method with consensus and LCA was weaker than the agreement between consensus and LCA. Among cases classified as MCI by actuarial criteria only, Black participants were over-represented, and outcomes were generally similar to those of NC participants. Consensus diagnoses best predicted longitudinal outcomes overall, whereas actuarial diagnoses best predicted longitudinal functional change among Black participants. Conclusion: Consensus diagnoses optimize specificity in predicting dementia, but among Black older adults, actuarial diagnoses may be more sensitive to early signs of decline. Results highlight the need for cross-cultural validity in MCI diagnosis and should be explored in community- and population-based samples.

7. DeepAtrophy: Teaching a neural network to detect progressive changes in longitudinal MRI of the hippocampal region in Alzheimer’s disease

   M. Dong, L. Xie, Sandhitsu R. Das, and 5 more authors

   NeuroImage, Aug 2021

   Cited by 20

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   Measures of change in hippocampal volume derived from longitudinal MRI are a well-studied biomarker of disease progression in Alzheimer’s disease (AD) and are used in clinical trials to track therapeutic efficacy of disease-modifying treatments. However, longitudinal MRI change measures based on deformable registration can be confounded by MRI artifacts, resulting in over-estimation or underestimation of hippocampal atrophy. For example, the deformation-based-morphometry method ALOHA (Das et al., 2012) finds an increase in hippocampal volume in a substantial proportion of longitudinal scan pairs from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study, unexpected, given that the hippocampal gray matter is lost with age and disease progression. We propose an alternative approach to quantify disease progression in the hippocampal region: to train a deep learning network (called DeepAtrophy) to infer temporal information from longitudinal scan pairs. The underlying assumption is that by learning to derive time-related information from scan pairs, the network implicitly learns to detect progressive changes that are related to aging and disease progression. Our network is trained using two categorical loss functions: one that measures the network’s ability to correctly order two scans from the same subject, input in arbitrary order; and another that measures the ability to correctly infer the ratio of inter-scan intervals between two pairs of same-subject input scans. When applied to longitudinal MRI scan pairs from subjects unseen during training, DeepAtrophy achieves greater accuracy in scan temporal ordering and interscan interval inference tasks than ALOHA (88.5% vs. 75.5% and 81.1% vs. 75.0%, respectively). A scalar measure of time-related change in a subject level derived from DeepAtrophy is then examined as a biomarker of disease progression in the context of AD clinical trials. We find that this measure performs on par with ALOHA in discriminating groups of individuals at different stages of the AD continuum. Overall, our results suggest that using deep learning to infer temporal information from longitudinal MRI of the hippocampal region has good potential as a biomarker of disease progression, and hints that combining this approach with conventional deformation-based morphometry algorithms may lead to improved biomarkers in the future.

8. Remote neuropsychological assessment using the UDS v3.0 T‐Cog: Preliminary data among participants at the Penn ADRC

   K. Hackett, M. Ferrara, S. Newman, and 9 more authors

   Alzheimer’s & Dementia, Dec 2021

   Cited by 2

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   Due to the COVID‐19 pandemic, collection of the Uniform Data Set (UDS) at Alzheimer’s Disease Research Centers (ADRCs) transitioned to remote administration via the T‐Cog. Feasibility of data collection and dissemination of normative data in individuals across the cognitive spectrum will be necessary for accurate utilization of remotely‐captured neurocognitive performance and classification of cognitive function.

9. Gray Matter Segmentation in Ultra High Resolution 7 Tesla ex vivo T2w MRI of Human Brain Hemispheres

   Pulkit Khandelwal, S. Sadaghiani, S. Ravikumar, and 29 more authors

   ArXiv, Oct 2021

   Cited by 4

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   Ex vivo MRI of the brain provides remarkable advantages over in vivo MRI for visualizing and characterizing detailed neuroanatomy. However, automated cortical segmentation methods in ex vivo MRI are not well developed, primarily due to limited availability of labeled datasets, and heterogeneity in scanner hardware and acquisition protocols. In this work, we present a high resolution 7 Tesla dataset of 32 ex vivo human brain specimens. We benchmark the cortical mantle segmentation performance of nine neural network architectures, trained and evaluated using manually-segmented 3D patches sampled from specific cortical regions, and show excellent generalizing capabilities across whole brain hemispheres in different specimens, and also on unseen images acquired at different magnetic field strength and imaging sequences. Finally, we provide cortical thickness measurements across key regions in 3D ex vivo human brain images. Our code and processed datasets are publicly available at https://github.com/Pulkit-Khandelwal/picsl-ex-vivo-segmentation.

10. Oh brother, where art tau? Amyloid, neurodegeneration, and cognitive decline without elevated tau

    Lauren McCollum, Sandhitsu R. Das, L. Xie, and 6 more authors

    NeuroImage : Clinical, Jun 2021

    Cited by 15

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    Highlights • Amyloid, tau and neurodegeneration are Alzheimer’s disease (AD) biomarkers.• Mild cognitive impairment (MCI) cases were grouped using the “A/T/(N)” model.• A+T-N+ MCI had less episodic memory loss and slower decline than A+T+N+ MCI.• A+T-N+ MCI was more like A-T-N+ than A+T+N+ MCI on whole brain cortical thickness.• A+T-N+ MCI’s less “AD-like” profile suggests that non-AD pathologies drive symptoms.

11. Development and pilot data for an app‐based cognitive assessment for detecting memory and executive functioning changes in aging and pre‐clinical AD

    Dawn J. Mechanic-Hamilton, Sean Lydon, Alexander Miller, and 3 more authors

    Alzheimer’s & Dementia, Dec 2021

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    Mobile, valid and engaging cognitive assessments are essential for detecting and tracking change in research participants and patients at risk for Alzheimer’s Disease and Related Dementias (ADRDs). This pilot study aims to determine the feasibility and psychometric properties of app‐based memory and executive functioning tasks included in the mobile cognitive app performance platform (mCAPP), to detect cognitive changes associated with aging and preclinical Alzheimer’s Disease (AD).

12. Ex vivo MRI atlas of the human medial temporal lobe: characterizing neurodegeneration due to tau pathology

    S. Ravikumar, L. Wisse, Sydney A. Lim, and 28 more authors

    Acta Neuropathologica Communications, Oct 2021

    Cited by 42

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    Tau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human postmortem MTL specimens with histology-based pathological assessments of the MTL. MTL specimens were obtained from twenty-nine brain donors, including patients with AD, other dementias, and individuals with no known history of neurological disease. Ex vivo MRI scans were combined using a customized groupwise diffeomorphic registration approach to construct a 3D probabilistic atlas that captures the anatomical variability of the MTL. Using serial histology imaging in eleven specimens, we labelled the MTL subregions in the atlas based on cytoarchitecture. Leveraging the atlas and neuropathological ratings of tau and TAR DNA-binding protein 43 (TDP-43) pathology severity, morphometric analysis was performed to correlate regional MTL thickness with the severity of tau pathology, after correcting for age and TDP-43 pathology. We found significant correlations between tau pathology and thickness in the entorhinal cortex (ERC) and stratum radiatum lacunosum moleculare (SRLM). When focusing on cases with low levels of TDP-43 pathology, we found strong associations between tau pathology and thickness in the ERC, SRLM and the subiculum/cornu ammonis 1 (CA1) subfields of the hippocampus, consistent with early Braak stages.

13. Unfolding the medial temporal lobe to characterize neurodegeneration due to Alzheimer’s disease pathology

    S. Ravikumar, L. Wisse, Sydney A. Lim, and 27 more authors

    Alzheimer’s & Dementia, Dec 2021

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    Measurements of medial temporal lobe (MTL) neurodegeneration derived using MRI have been shown to be sensitive to changes during the early stages of AD. The specificity of these measurements to tau neurofibrillary tangle (NFT) pathology is limited by other frequently comorbid non‐AD factors which also cause structural changes in the MTL. Here, we directly link changes in MTL structure to underlying NFT pathology by combining ex vivo MRI with ratings of NFT severity derived from serial histology using a dataset of 18 human MTL specimens. We hypothesize that such an analysis can be used to define MTL “hotspots” where in vivo measures will be more sensitive to disease progression in preclinical AD than current state of the art biomarkers.

14. Unfolding the Medial Temporal Lobe Cortex to Characterize Neurodegeneration Due to Alzheimer’s Disease Pathology Using Ex vivo Imaging

    S. Ravikumar, L. Wisse, Sydney A. Lim, and 26 more authors

    In MLCN@MICCAI, Dec 2021

    Cited by 3

    DOI

    
15. A framework For brain atlases: Lessons from seizure dynamics

    A. Revell, Alexander B. Silva, T. Arnold, and 6 more authors

    NeuroImage, Jun 2021

    Cited by 42

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    Brain maps, or atlases, are essential tools for studying brain function and organization. The abundance of available atlases used across the neuroscience literature, however, creates an implicit challenge that may alter the hypotheses and predictions we make about neurological function and pathophysiology. Here, we demonstrate how parcellation scale, shape, anatomical coverage, and other atlas features may impact our prediction of the brain’s function from its underlying structure. We show how network topology, structure-function correlation (SFC), and the power to test specific hypotheses about epilepsy pathophysiology may change as a result of atlas choice and atlas features. Through the lens of our disease system, we propose a general framework and algorithm for atlas selection. This framework aims to maximize the descriptive, explanatory, and predictive validity of an atlas. Broadly, our framework strives to provide empirical guidance to neuroscience research utilizing the various atlases published over the last century.

16. White matter signals reflect information transmission between brain regions during seizures

    A. Revell, Marc Jaskir, Alfredo Lucas, and 14 more authors

    Brain, Sep 2021

    Cited by 11

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    White matter supports critical brain functions such as learning and memory, modulates the distribution of action potentials, and transmits neural information between brain regions. Notably, neuronal cell bodies exist in deeper white matter tissue, neurotransmitter vesicles are released directly in white matter, and white matter blood-oxygenation level dependent (BOLD) signals are detectable across a range of different tasks—all appearing to reflect a dynamic, active tissue from which recorded signals can reveal meaningful information about the brain. Yet, the signals within white matter have largely been ignored. Here, we elucidate the properties of white matter signals using intracranial EEG in a bipolar montage. We show that such signals capture the communication between brain regions and differentiate pathophysiologies of epilepsy. In direct contradiction to past assumptions that white matter functional signals provide little value, we show that white matter recordings can elucidate brain function and pathophysiology. Broadly, white matter functional recordings acquired through implantable devices may provide a wealth of currently untapped knowledge about the neurobiology of disease.

17. Fully Automated Placental Volume Quantification From 3D Ultrasound for Prediction of Small‐for‐Gestational‐Age Infants

    N. Schwartz, I. Oguz, Jiancong Wang, and 6 more authors

    Journal of Ultrasound in Medicine, Sep 2021

    Cited by 11

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    Early placental volume (PV) has been associated with small‐for‐gestational‐age infants born under the 10th/5th centiles (SGA10/SGA5). Manual or semiautomated PV quantification from 3D ultrasound (3DUS) is time intensive, limiting its incorporation into clinical care. We devised a novel convolutional neural network (CNN) pipeline for fully automated placenta segmentation from 3DUS images, exploring the association between the calculated PV and SGA.

18. Ex vivo MRI and histopathology detect novel iron-rich cortical inflammation in frontotemporal lobar degeneration with tau versus TDP-43 pathology

    M. Tisdall, Daniel T. Ohm, Rebecca Lobrovich, and 14 more authors

    NeuroImage : Clinical, Dec 2021

    Cited by 32

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    Graphical abstract

19. Joint ex vivo MRI and histology detect iron-rich cortical gliosis in Tau and TDP-43 proteinopathies

    M. Tisdall, Daniel T. Ohm, Rebecca Lobrovich, and 14 more authors

    bioRxiv, Apr 2021

    Cited by 3

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    Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging therapeutic trials tailored to disease-specific mechanisms. Moreover, MRI-derived measures have had limited success to date discriminating between FTLD-Tau or FTLD-TDP. T2*-weighted (T2*w) ex vivo MRI has previously been shown to be sensitive to non-heme iron in healthy intracortical lamination and myelin, and to pathological iron deposits in amyloid-beta plaques and activated microglia in Alzheimer’s disease (AD). However, an integrated, ex vivo MRI and histopathology approach is understudied in FTLD. We apply joint, whole-hemisphere ex vivo MRI at 7T and histopathology to the study autopsy-confirmed FTLD-Tau (n=3) and FTLD-TDP (n=2), relative to an AD disease-control brain with antemortem clinical symptoms of frontotemporal dementia and an age-matched healthy control. We detect distinct laminar patterns of novel iron-laden glial pathology in both FTLD-Tau and FTLD-TDP brains. We find iron-positive ameboid and hypertrophic microglia and astrocytes largely in deeper GM and adjacent WM in FTLD-Tau. In contrast, FTLD-TDP presents prominent superficial cortical layer iron reactivity in astrocytic processes enveloping small blood vessels with limited involvement of adjacent WM, as well as more diffuse distribution of punctate iron-rich dystrophic microglial processes across all GM lamina. This integrated MRI/histopathology approach reveals ex vivo MRI features that are consistent with these pathological observations distinguishing FTLD-Tau and FTLD-TDP, including prominent irregular hypointense signal in deeper cortex in FTLD-Tau whereas FTLD-TDP showed upper cortical layer hypointense bands and diffuse cortical speckling. Moreover, differences in adjacent WM degeneration and iron-rich gliosis on histology between FTLD-Tau and FTLD-TDP were also readily apparent on MRI as hyperintense signal and irregular areas of hypointensity, respectively that were more prominent in FTLD-Tau compared to FTLD-TDP. These unique histopathological and radiographic features were distinct from HC and AD brains, suggesting that iron-sensitive T2*w MRI, adapted to in vivo application at sufficient resolution, may offer an opportunity to improve antemortem diagnosis of FTLD proteinopathies using tissue-validated methods.

20. The ANTsX ecosystem for quantitative biological and medical imaging

    N. Tustison, P. Cook, A. Holbrook, and 11 more authors

    Scientific Reports, Apr 2021

    Cited by 335

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    The Advanced Normalizations Tools ecosystem, known as ANTsX, consists of multiple open-source software libraries which house top-performing algorithms used worldwide by scientific and research communities for processing and analyzing biological and medical imaging data. The base software library, ANTs, is built upon, and contributes to, the NIH-sponsored Insight Toolkit. Founded in 2008 with the highly regarded Symmetric Normalization image registration framework, the ANTs library has since grown to include additional functionality. Recent enhancements include statistical, visualization, and deep learning capabilities through interfacing with both the R statistical project (ANTsR) and Python (ANTsPy). Additionally, the corresponding deep learning extensions ANTsRNet and ANTsPyNet (built on the popular TensorFlow/Keras libraries) contain several popular network architectures and trained models for specific applications. One such comprehensive application is a deep learning analog for generating cortical thickness data from structural T1-weighted brain MRI, both cross-sectionally and longitudinally. These pipelines significantly improve computational efficiency and provide comparable-to-superior accuracy over multiple criteria relative to the existing ANTs workflows and simultaneously illustrate the importance of the comprehensive ANTsX approach as a framework for medical image analysis.

21. Accurate and Robust Alignment of Differently Stained Histologic Images Based on Greedy Diffeomorphic Registration

    Ludovic Venet, Sarthak Pati, Michal Feldman, and 3 more authors

    Applied sciences (Basel, Switzerland), Feb 2021

    Cited by 24

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    Histopathologic assessment routinely provides rich microscopic information about tissue structure and disease process. However, the sections used are very thin, and essentially capture only 2D representations of a certain tissue sample. Accurate and robust alignment of sequentially cut 2D slices should contribute to more comprehensive assessment accounting for surrounding 3D information. Towards this end, we here propose a two-step diffeomorphic registration approach that aligns differently stained histology slides to each other, starting with an initial affine step followed by estimating a deformation field. It was quantitatively evaluated on ample (n = 481) and diverse data from the automatic non-rigid histological image registration challenge, where it was awarded the second rank. The obtained results demonstrate the ability of the proposed approach to robustly (average robustness = 0.9898) and accurately (average relative target registration error = 0.2%) align differently stained histology slices of various anatomical sites while maintaining reasonable computational efficiency (<1 min per registration). The method was developed by adapting a general-purpose registration algorithm designed for 3D radiographic scans and achieved consistently accurate results for aligning high-resolution 2D histologic images. Accurate alignment of histologic images can contribute to a better understanding of the spatial arrangement and growth patterns of cells, vessels, matrix, nerves, and immune cell interactions.

22. Accuracy of high-frequency oscillations recorded intraoperatively for classification of epileptogenic regions

    S. Weiss, R. Staba, A. Sharan, and 8 more authors

    Scientific Reports, Nov 2021

    Cited by 24

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    To see whether acute intraoperative recordings using stereo EEG (SEEG) electrodes can replace prolonged interictal intracranial EEG (iEEG) recording, making the process more efficient and safer, 10 min of iEEG were recorded following electrode implantation in 16 anesthetized patients, and 1–2 days later during non-rapid eye movement (REM) sleep. Ripples on oscillations (RonO, 80–250 Hz), ripples on spikes (RonS), sharp-spikes, fast RonO (fRonO, 250–600 Hz), and fast RonS (fRonS) were semi-automatically detected. HFO power and frequency were compared between the conditions using a generalized linear mixed-effects model. HFO rates were compared using a two-way repeated measures ANOVA with anesthesia type and SOZ as factors. A receiver-operating characteristic (ROC) curve analysis quantified seizure onset zone (SOZ) classification accuracy, and the scalar product was used to assess spatial reliability. Resection of contacts with the highest rate of events was compared with outcome. During sleep, all HFOs, except fRonO, were larger in amplitude compared to intraoperatively (p < 0.01). HFO frequency was also affected (p < 0.01). Anesthesia selection affected HFO and sharp-spike rates. In both conditions combined, sharp-spikes and all HFO subtypes were increased in the SOZ (p < 0.01). However, the increases were larger during the sleep recordings (p < 0.05). The area under the ROC curves for SOZ classification were significantly smaller for intraoperative sharp-spikes, fRonO, and fRonS rates (p < 0.05). HFOs and spikes were only significantly spatially reliable for a subset of the patients (p < 0.05). A failure to resect fRonO areas in the sleep recordings trended the most sensitive and accurate for predicting failure. In summary, HFO morphology is altered by anesthesia. Intraoperative SEEG recordings exhibit increased rates of HFOs in the SOZ, but their spatial distribution can differ from sleep recordings. Recording these biomarkers during non-REM sleep offers a more accurate delineation of the SOZ and possibly the epileptogenic zone.

23. Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions

    L. Wisse, S. Ravikumar, R. Ittyerah, and 27 more authors

    Acta Neuropathologica Communications, Jul 2021

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    The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-β and α-synuclein pathology were rated on a scale of 0 (absent)—3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm3 post-mortem MRI scans of excised MTL specimens from the contralateral hemisphere using a semi-automated approach. Spearman’s rank correlations were performed between neurodegenerative pathologies and thickness, correcting for age, sex and hemisphere, including all four proteinopathies in the model. We found significant associations of (1) TDP-43 with thickness in all subregions (r =  − 0.27 to r =  − 0.46), and (2) tau with BA35 (r =  − 0.31) and SRLM thickness (r =  − 0.33). In amyloid-β and TDP-43 negative cases, we found strong significant associations of tau with ERC (r =  − 0.40), BA35 (r =  − 0.55), subiculum (r =  − 0.42) and CA1 thickness (r =  − 0.47). This unique dataset shows widespread MTL atrophy in relation to TDP-43 pathology and atrophy in regions affected early in Braak stageing and tau pathology. Moreover, the strong association of tau with thickness in early Braak regions in the absence of amyloid-β suggests a role of Primary Age-Related Tauopathy in neurodegeneration.

24. Pathological drivers of neurodegeneration in suspected non-Alzheimer’s disease pathophysiology

    L. Wisse, R. Flores, L. Xie, and 8 more authors

    Alzheimer’s Research & Therapy, May 2021

    Cited by 28

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    Little is known about the heterogeneous etiology of suspected non-Alzheimer’s pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of β-amyloid. Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal lobe (MTL) measures in β-amyloid-negative subjects. Subjects with antemortem MRI and autopsy data were selected from ADNI (n=63) and the University of Pennsylvania (n=156). Pathological diagnoses and semi-quantitative scores of MTL tau, neuritic plaques, α-synuclein, and TDP-43 pathology and MTL structural MRI measures from antemortem T1-weighted MRI scans were obtained. β-amyloid status (A+/A−) was determined by CERAD score and neurodegeneration status (N+/N−) by hippocampal volume. SNAP reflects a heterogeneous group of pathological diagnoses. In ADNI, SNAP (A−N+) had significantly more neuropathological diagnoses than A+N+. In the A− group, tau pathology was associated with hippocampal, entorhinal cortex, and Brodmann area 35 volume/thickness and TDP-43 pathology with hippocampal volume. SNAP had a heterogeneous profile with more mixed pathologies than A+N+. Moreover, a role for TDP-43 and tau pathology in driving MTL neurodegeneration in the absence of β-amyloid was supported.

25. Tau pathology mediates age effects on medial temporal lobe structure.

    L. Wisse, L. Xie, S.R. Das, and 8 more authors

    Neurobiology of aging, Sep 2021

    Cited by 19

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    Hippocampal atrophy is endemic in ’normal aging’ but it is unclear what factors drive age-related changes in medial temporal lobe (MTL) structural measures. We investigated cross-sectional (n = 191) and longitudinal (n = 164) MTL atrophy patterns in cognitively normal older adults from ADNI-GO/2 with no to low cerebral β-amyloid and assessed whether white matter hyperintensities (WMHs) and cerebrospinal fluid (CSF) phospho tau (p-tau) levels can explain age-related changes in the MTL. Age was significantly associated with hippocampal volumes and Brodmann Area (BA) 35 thickness, regions affected early by neurofibrillary tangle pathology, in the cross-sectional analysis and with anterior and/or posterior hippocampus, entorhinal cortex and BA35 in the longitudinal analysis. CSF p-tau was significantly associated with hippocampal volumes and atrophy rates. Mediation analyses showed that CSF p-tau levels partially mediated age effects on hippocampal atrophy rates. No significant associations were observed for WMHs. These findings point toward a role of tau pathology, potentially reflecting Primary Age-Related Tauopathy, in age-related MTL structural changes and suggests a potential role for tau-targeted interventions in age-associated neurodegeneration and memory decline.

26. Deformable Image Registration using Neural ODEs

    Yifan Wu, Tom Z. Jiahao, Jiancong Wang, and 3 more authors

    ArXiv, Sep 2021

    Cited by 1

    
27. NODEO: A Neural Ordinary Differential Equation Based Optimization Framework for Deformable Image Registration

    Yifan Wu, Tom Z. Jiahao, Jiancong Wang, and 3 more authors

    In Computer Vision and Pattern Recognition, Aug 2021

    Cited by 41

    Abs DOI arXiv PDF

    

    Deformable image registration (DIR), aiming to find spatial correspondence between images, is one of the most critical problems in the domain of medical image analysis. In this paper, we present a novel, generic, and accurate diffeomorphic image registration framework that utilizes neural ordinary differential equations (NODEs). We model each voxel as a moving particle and consider the set of all voxels in a 3D image as a high-dimensional dynamical system whose trajectory determines the targeted deformation field. Our method leverages deep neural networks for their expressive power in modeling dynamical systems, and simultaneously optimizes for a dynamical system between the image pairs and the corresponding transformation. Our formulation allows various constraints to be imposed along the transformation to maintain desired regularities. Our experiment results show that our method outperforms the benchmarks under various metrics. Additionally, we demonstrate the feasibility to expand our framework to register multiple image sets using a unified form of transformation, which could possibly serve a wider range of applications.

28. Baseline structural MRI and plasma biomarkers predict longitudinal structural atrophy and cognitive decline in early AD

    L. Xie, Sandhitsu R. Das, L. Wisse, and 4 more authors

    Alzheimer’s & Dementia, Dec 2021

    Cited by 1

    Abs DOI

    

    In clinical trials targeting early Alzheimer’s disease (AD), recruiting participants that are more likely to progress over the course of the trials is crucial to success. Molecular and neurodegenerative markers obtained through PET or in cerebrospinal fluid have significant prognostic value, but they are costly or invasive. In this study, we hypothesize that a combination of plasma and structural MRI biomarkers, which overcome these limitations, are predictive of longitudinal progression measured by atrophy and cognitive decline in early AD, providing a more feasible solution.

29. Deep Label Fusion: A 3D End-to-End Hybrid Multi-Atlas Segmentation and Deep Learning Pipeline

    L. Xie, L. Wisse, Jiancong Wang, and 6 more authors

    ArXiv, Mar 2021

    Cited by 2

    Abs DOI arXiv

    

    Deep learning (DL) is the state-of-the-art methodology in various medical image segmentation tasks. However, it requires relatively large amounts of manually labeled training data, which may be infeasible to generate in some applications. In addition, DL methods have relatively poor generalizability to out-of-sample data. Multi-atlas segmentation (MAS), on the other hand, has promising performance using limited amounts of training data and good generalizability. A hybrid method that integrates the high accuracy of DL and good generalizability of MAS is highly desired and could play an important role in segmentation problems where manually labeled data is hard to generate. Most of the prior work focuses on improving single components of MAS using DL rather than directly optimizing the final segmentation accuracy via an end-to-end pipeline. Only one study explored this idea in binary segmentation of 2D images, but it remains unknown whether it generalizes well to multi-class 3D segmentation problems. In this study, we propose a 3D end-to-end hybrid pipeline, named deep label fusion (DLF), that takes advantage of the strengths of MAS and DL. Experimental results demonstrate that DLF yields significant improvements over conventional label fusion methods and U-Net, a direct DL approach, in the context of segmenting medial temporal lobe subregions using 3T T1-weighted and T2-weighted MRI. Further, when applied to an unseen similar dataset acquired in 7T, DLF maintains its superior performance, which demonstrates its good generalizability.

30. The what and when of olfactory working memory in humans.

    Andrew I Yang, G. N. Dikecligil, Heidi Jiang, and 7 more authors

    Current biology : CB, Aug 2021

    Cited by 22

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31. 3D Mapping of Neurofibrillary Tangle Burden in the Human Medial Temporal Lobe

    Paul Yushkevich, M. M. López, Maria Mercedes Iñiguez Onzoño Martin, and 37 more authors

    bioRxiv, Jan 2021

    Cited by 6

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    Tau protein neurofibrillary tangles (NFT) are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer’s disease (AD) and related dementias. Our knowledge of the pattern of NFT progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in AD, is based on conventional 2D histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe (MTL) specimens were used to construct 3D quantitative maps of NFT burden in the MTL at individual and group levels. These maps reveal significant variation in NFT burden along the anterior-posterior axis. While early NFT pathology is thought to be confined to the transentorhinal region, we find similar levels of NFT burden in this region and other MTL subregions, including amygdala, temporopolar cortex, and subiculum/CA1.

32. Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe.

    Paul Yushkevich, M. Muñoz López, María Mercedes Iñiguez Onzoño Martin, and 37 more authors

    Brain : a journal of neurology, Jul 2021

    Cited by 66

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    Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer’s disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer’s disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangle was measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden reveal significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we find similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu Ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer’s disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.

33. Automatic Segmentation of Bone Selective MR Images for Visualization and Craniometry of the Cranial Vault.

    C. Zimmerman, Pulkit Khandelwal, L. Xie, and 6 more authors

    Academic radiology, Apr 2021

    Cited by 6

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    RATIONALE AND OBJECTIVES Solid-state MRI has been shown to provide a radiation-free alternative imaging strategy to CT. However, manual image segmentation to produce bone-selective MR-based 3D renderings is time and labor intensive, thereby acting as a bottleneck in clinical practice. The objective of this study was to evaluate an automatic multi-atlas segmentation pipeline for use on cranial vault images entirely circumventing prior manual intervention, and to assess concordance of craniometric measurements between pipeline produced MRI and CT-based 3D skull renderings. MATERIALS AND METHODS Dual-RF, dual-echo, 3D UTE pulse sequence MR data were obtained at 3T on 30 healthy subjects along with low-dose CT images between December 2018 to January 2020 for this prospective study. The four-point MRI datasets (two RF pulse widths and two echo times) were combined to produce bone-specific images. CT images were thresholded and manually corrected to segment the cranial vault. CT images were then rigidly registered to MRI using mutual information. The corresponding cranial vault segmentations were then transformed to MRI. The "ground truth" segmentations served as reference for the MR images. Subsequently, an automated multi-atlas pipeline was used to segment the bone-selective images. To compare manually and automatically segmented MR images, the Dice similarity coefficient (DSC) and Hausdorff distance (HD) were computed, and craniometric measurements between CT and automated-pipeline MRI-based segmentations were examined via Lin’s concordance coefficient (LCC). RESULTS Automated segmentation reduced the need for an expert to obtain segmentation. Average DSC was 90.86 ± 1.94%, and average 95th percentile HD was 1.65 ± 0.44 mm between ground truth and automated segmentations. MR-based measurements differed from CT-based measurements by 0.73-1.2 mm on key craniometric measurements. LCC for distances between CT and MR-based landmarks were vertex-basion: 0.906, left-right frontozygomatic suture: 0.780, and glabella-opisthocranium: 0.956 for the three measurements. CONCLUSION Good agreement between CT and automated MR-based 3D cranial vault renderings has been achieved, thereby eliminating the laborious manual segmentation process. Target applications comprise craniofacial surgery as well as imaging of traumatic injuries and masses involving both bone and soft tissue.

2020

1. In Vivo Image-Based 4D Modeling of Competent and Regurgitant Mitral Valve Dynamics

   A. H. Aly, E. Lai, N. Yushkevich, and 6 more authors

   Experimental Mechanics, Aug 2020

   Cited by 7

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2. Multimodal image analysis and subvalvular dynamics in ischemic mitral regurgitation

   A. H. Aly, Yoshiaki Saito, W. Bouma, and 6 more authors

   JTCVS Open, Oct 2020

   Cited by 2

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   Background The exact geometric pathogenesis of leaflet tethering in ischemic mitral regurgitation (IMR) and the relative contribution of each component of the mitral valve complex (MVC) remain largely unknown. In this study, we sought to further elucidate mitral valve (MV) leaflet remodeling and papillary muscle dynamics in an ovine model of IMR with magnetic resonance imaging (MRI) and 3-dimensional echocardiography (3DE). Methods Multimodal imaging combining 3DE and MRI was used to analyze the MVC at baseline, 30 minutes post–myocardial infarction (MI), and 12 weeks post-MI in ovine IMR models. Advanced 3D imaging software was used to trace the MVC from each modality, and the tracings were verified against resected specimens. Results 3DE MV remodeling was regionally heterogenous and observed primarily in the anterior leaflet, with significant increases in surface area, especially in A2 and A3. The posterior leaflet was significantly shortened in P2 and P3. Mean posteromedial papillary muscle (PMPM) volume was decreased from 1.9 ± 0.2 cm3 at baseline to 0.9 ± 0.3 cm3 at 12 weeks post-MI (P < .05). At 12 weeks post-MI, the PMPM was predominately displaced horizontally and outward along the intercommissural axis with minor apical displacement. The subvalvular contribution to tethering is a combination of unilateral movement, outward displacement, and degeneration of the PMPM. These findings have led to a proposed new framework for characterizing PMPM dynamics in IMR. Conclusions This study provides new insights into the complex interrelated and regionally heterogenous valvular and subvalvular mechanisms involved in the geometric pathogenesis of IMR tethering.

3. Remote effects of temporal lobe epilepsy surgery: Long‐term morphological changes after surgical resection

   T. Arnold, Lohith G. Kini, J. Bernabei, and 8 more authors

   Epilepsia Open, Nov 2020

   Cited by 7

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   Epilepsy surgery is an effective treatment for drug‐resistant patients. However, how different surgical approaches affect long‐term brain structure remains poorly characterized. Here, we present a semiautomated method for quantifying structural changes after epilepsy surgery and compare the remote structural effects of two approaches, anterior temporal lobectomy (ATL), and selective amygdalohippocampectomy (SAH).

4. Hippocampal subfield pathologic burden in Lewy body diseases vs. Alzheimer’s disease

   D. Coughlin, R. Ittyerah, Claire S. Peterson, and 14 more authors

   Neuropathology and Applied Neurobiology, Sep 2020

   Cited by 31

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   Lewy body diseases (LBD) are characterized by alpha‐synuclein (SYN) pathology, but comorbid Alzheimer’s disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid‐beta (Aβ) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing.

5. Variability in tau‐atrophy relationships reveals underlying phenotypes in individuals on the Alzheimer’s disease continuum

   Sandhitsu R. Das, L. Xie, Lauren McCollum, and 6 more authors

   Alzheimer’s & Dementia, Dec 2020

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   Tau neurofibrillary tangles (T) are thought to be the primary driver of downstream neurodegeneration (N) and subsequent cognitive impairment in AD. However, there is substantial variability in the T‐N relationship – manifested in higher or lower atrophy than expected for the level of tau in a given brain region. We quantitatively describe and categorize source(s) of variability using region‐based measures of T and N to gain insight into underlying modulatory factors, including polypathology.

6. DeepAtrophy: Teaching a Neural Network to Differentiate Progressive Changes from Noise on Longitudinal MRI in Alzheimer’s Disease

   M. Dong, L. Xie, Sandhitsu R. Das, and 5 more authors

   ArXiv, Oct 2020

   Cited by 1

   Abs arXiv

   

   Volume change measures derived from longitudinal MRI (e.g. hippocampal atrophy) are a well-studied biomarker of disease progression in Alzheimer’s Disease (AD) and are used in clinical trials to track the therapeutic efficacy of disease-modifying treatments. However, longitudinal MRI change measures can be confounded by non-biological factors, such as different degrees of head motion and susceptibility artifact between pairs of MRI scans. We hypothesize that deep learning methods applied directly to pairs of longitudinal MRI scans can be trained to differentiate between biological changes and non-biological factors better than conventional approaches based on deformable image registration. To achieve this, we make a simplifying assumption that biological factors are associated with time (i.e. the hippocampus shrinks overtime in the aging population) whereas non-biological factors are independent of time. We then formulate deep learning networks to infer the temporal order of same-subject MRI scans input to the network in arbitrary order; as well as to infer ratios between interscan intervals for two pairs of same-subject MRI scans. In the test dataset, these networks perform better in tasks of temporal ordering (89.3%) and interscan interval inference (86.1%) than a state-of-the-art deformation-based morphometry method ALOHA (76.6% and 76.1% respectively) (Das et al., 2012). Furthermore, we derive a disease progression score from the network that is able to detect a group difference between 58 preclinical AD and 75 beta-amyloid-negative cognitively normal individuals within one year, compared to two years for ALOHA. This suggests that deep learning can be trained to differentiate MRI changes due to biological factors (tissue loss) from changes due to non-biological factors, leading to novel biomarkers that are more sensitive to longitudinal changes at the earliest stages of AD.

7. Detecting biological changes in longitudinal MRI scans of Alzheimer’s disease patients in the hippocampus region with deep learning

   M. Dong, L. Xie, Sandhitsu R. Das, and 2 more authors

   Alzheimer’s & Dementia, Dec 2020

   Cited by 1

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   Alzheimer’s Disease (AD) is characterized by gradual loss of gray matter, particularly in the medial temporal lobe (MTL) and hippocampus. Longitudinal change in hippocampal volume on MRI is an effective biomarker to monitor disease progression in AD. However, neurodegenerative changes in the hippocampus on longitudinal MRI can be obscured by differences in MRI signal that are unrelated to disease progression, such as different amounts of head motion, noise, or MRI artifact. We hypothesize that a deep learning model can be trained to distinguish true biological changes from nonsystematic factors, leading to a more sensitive biomarker of disease progression.

8. Sensitive biomarkers to Alzheimer’s disease progression in longitudinal MRI from deep learning

   M. Dong, L. Xie, Jiancong Wang, and 3 more authors

   Alzheimer’s & Dementia, Dec 2020

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   In clinical trials of disease‐modifying treatments of Alzheimer’s disease (AD), the measure of hippocampus volume change from longitudinal MRI is a well‐studied biomarker of disease progression. However, even the most sensitive longitudinal MRI measures can be confounded by the presence of motion and susceptibility artifacts. We hypothesize that deep learning can be used to differentiate MRI changes due to biological factors (tissue loss) from changes due to artifact and other non‐biological factors, leading to novel biomarkers that are more sensitive to longitudinal change that can accurately evaluate disease progression.

9. Characterization of hippocampal subfields using ex vivo MRI and histology data: Lessons for in vivo segmentation

   R. Flores, D. Berron, S. Ding, and 14 more authors

   Hippocampus, Jun 2020

   Cited by 41

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   Hippocampal subfield segmentation on in vivo MRI is of great interest for cognition, aging, and disease research. Extant subfield segmentation protocols have been based on neuroanatomical references, but these references often give limited information on anatomical variability. Moreover, there is generally a mismatch between the orientation of the histological sections and the often anisotropic coronal sections on in vivo MRI. To address these issues, we provide a detailed description of hippocampal anatomy using a postmortem dataset containing nine specimens of subjects with and without dementia, which underwent a 9.4 T MRI and histological processing. Postmortem MRI matched the typical orientation of in vivo images and segmentations were generated in MRI space, based on the registered annotated histological sections. We focus on the following topics: the order of appearance of subfields, the location of subfields relative to macroanatomical features, the location of subfields in the uncus and tail and the composition of the dark band, a hypointense layer visible in T2‐weighted MRI. Our main findings are that: (a) there is a consistent order of appearance of subfields in the hippocampal head, (b) the composition of subfields is not consistent in the anterior uncus, but more consistent in the posterior uncus, (c) the dark band consists only of the CA‐stratum lacunosum moleculare, not the strata moleculare of the dentate gyrus, (d) the subiculum/CA1 border is located at the middle of the width of the hippocampus in the body in coronal plane, but moves in a medial direction from anterior to posterior, and (e) the variable location and composition of subfields in the hippocampal tail can be brought back to a body‐like appearance when reslicing the MRI scan following the curvature of the tail. Our findings and this publicly available dataset will hopefully improve anatomical accuracy of future hippocampal subfield segmentation protocols.

10. Contribution of mixed pathology to medial temporal lobe atrophy in Alzheimer’s disease

    R. Flores, L. Wisse, Sandhitsu R. Das, and 9 more authors

    Alzheimer’s & Dementia, Apr 2020

    Cited by 90

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    It is unclear how different proteinopathies (tau, transactive response DNA‐binding protein 43 [TDP‐43], amyloid β [Aβ], and α‐synuclein) contribute to atrophy within medial temporal lobe (MTL) subregions in Alzheimer’s disease (AD).

11. Neurodegeneration in medial temporal lobe subregions propagates within distinct functional networks in the AD continuum

    R. Flores, Sandhitsu R. Das, L. Xie, and 4 more authors

    Alzheimer’s & Dementia, Dec 2020

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    The medial temporal lobe (MTL) is extensively connected to the rest of the brain through two specific networks: the anterior‐temporal (AT) and the posterior‐medial (PM) systems. As neurodegeneration is thought to occur along specific networks, our aim was to evaluate whether atrophy in perirhinal (PRC) vs parahippocampal cortices (PHC) ‐ two MTL nodes of the AT vs PM systems, respectively ‐ covary over time with distinct brain regions reflecting the AT vs PM networks.

12. Volumetric glutamate imaging (GluCEST) using 7T MRI can lateralize nonlesional temporal lobe epilepsy: A preliminary study

    P. Hadar, Lohith G. Kini, R. Nanga, and 11 more authors

    Brain and Behavior, Sep 2020

    Cited by 15

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    Drug‐resistant epilepsy patients show worse outcomes after resection when standard neuroimaging is nonlesional, which occurs in one‐third of patients. In prior work, we employed 2‐D glutamate imaging, Glutamate Chemical Exchange Saturation Transfer (GluCEST), to lateralize seizure onset in nonlesional temporal lobe epilepsy (TLE) based on increased ipsilateral GluCEST signal in the total hippocampus and hippocampal head. We present a significant advancement to single‐slice GluCEST imaging, allowing for three‐dimensional analysis of brain glutamate networks.

13. The development of a valid, reliable, harmonized segmentation protocol for hippocampal subfields and medial temporal lobe cortices: A progress update

    R. La Joie, R. Olsen, D. Berron, and 24 more authors

    Alzheimer’s & Dementia, Dec 2020

    Cited by 1

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    The medial temporal lobe (MTL, i.e. hippocampus and adjacent cortices) is particularly vulnerable to age‐related diseases: Alzheimer’s disease, other age‐related proteinothies (TDP‐43, AGD, etc) and vascular injury. Yet, the subregional pattern of vulnerability is thought to differ across etiologies; characterizing these differences using high‐resolution MRI may provide more insight in disease processes and better biomarkers. However, substantial differences in subfield definition has hindered the ability to compare results across laboratories or draw robust conclusions (Figure 1). The Hippocampal Subfields Group (HSG) is an international group seeking to remedy this problem by developing a histologically‐valid, reliable, and freely available segmentation protocol for high‐resolution T2‐weighted 3T MRI (http://www.hippocampalsubfields.com)

14. Domain Generalizer: A Few-shot Meta Learning Framework for Domain Generalization in Medical Imaging

    Pulkit Khandelwal, and Paul Yushkevich

    In DART/DCL@MICCAI, Aug 2020

    Cited by 47

    Abs DOI arXiv

    

    Deep learning models perform best when tested on target (test) data domains whose distribution is similar to the set of source (train) domains. However, model generalization can be hindered when there is significant difference in the underlying statistics between the target and source domains. In this work, we adapt a domain generalization method based on a model-agnostic meta-learning framework [1] to biomedical imaging. The method learns a domain-agnostic feature representation to improve generalization of models to the unseen test distribution. The method can be used for any imaging task, as it does not depend on the underlying model architecture. We validate the approach through a computed tomography (CT) vertebrae segmentation task across healthy and pathological cases on three datasets. Next, we employ few-shot learning, i.e. training the generalized model using very few examples from the unseen domain, to quickly adapt the model to new unseen data distribution. Our results suggest that the method could help generalize models across different medical centers, image acquisition protocols, anatomies, different regions in a given scan, healthy and diseased populations across varied imaging modalities.

15. Longitudinal network connectivity measurements in medial temporal lobe subregions discriminate preclinical Alzheimer’s from amyloid‐β negative controls

    Pulkit Khandelwal, L. Xie, D. Bassett, and 4 more authors

    Alzheimer’s & Dementia, Dec 2020

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    Finding sensitive outcome measures for disease progression in clinical trials of preclinical Alzheimer’s disease (AD) remains challenging. We hypothesize that longitudinal network connectivity measurements of the medial temporal lobe (MTL) subregions, sites of earliest tau pathology, are more sensitive to progression at early stages than annualized subregional atrophy rates, thus, increasing power to detect a significant effect in a shorter timeframe.

16. Sensitive Measures of Cognition in Mild Cognitive Impairment

    Nathaniel Klooster, S. Humphries, E. Cardillo, and 8 more authors

    Journal of Alzheimer’s Disease, Jul 2020

    Cited by 6

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    Background: Sensitive measures of cognition are needed in preclinical and prodromal Alzheimer’s disease (AD) to track cognitive change and evaluate potential interventions. Neurofibrillary tangle pathology in AD is first observed in Brodmann Area 35 (BA35), the medial portion of the perirhinal cortex. The importance of the perirhinal cortex for semantic memory may explain early impairments of semantics in preclinical AD. Additionally, our research has tied figurative language impairment to neurodegenerative disease. Objective: We aim to identify tasks that are sensitive to cognitive impairment in individuals with mild cognitive impairment (MCI), and that are sensitive to atrophy in BA35. Methods: Individuals with MCI and cognitively normal participants (CN) were tested on productive and receptive experimental measures of semantic memory and experimental tests of figurative language comprehension (including metaphor and verbal analogy). Performance was related to structural imaging and standard neuropsychological assessment. Results: On the experimental tests of semantics and figurative language, people with MCI performed worse than CN participants. The experimental semantic memory tasks are sensitive and specific; performance on the experimental semantic memory tasks related to medial temporal lobe structural integrity, including BA35, while standard neuropsychological assessments of semantic memory did not, demonstrating the sensitivity of these experimental measures. A visuo-spatial analogy task did not differentiate groups, confirming the specificity of semantic and figurative language tasks. Conclusion: These experimental measures appear sensitive to cognitive change and neurodegeneration early in the AD trajectory and may prove useful in tracking cognitive change in clinical trials aimed at early intervention.

17. Optimized extraction of the medial temporal lobe for postmortem MRI based on custom 3D printed molds

    Jade Lasserve, Sydney A. Lim, L. Wisse, and 21 more authors

    Alzheimer’s & Dementia, Dec 2020

    Cited by 3

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    Structural magnetic resonance imaging (MRI) biomarkers are important for early detection of Alzheimer’s Disease (AD). However, atrophy measures can be confounded by changes due to aging and comorbid non‐AD neurodegenerative pathologies. Linking postmortem MRI of the medial temporal lobe (MTL) to histopathology may identify focal patterns of change associated specifically with early AD. We implemented a pipeline of high‐resolution MRI of MTL specimens and serial histopathology imaging [REF]. However, the task of extracting the intact MTL specimen such that it fits into the MRI coil requires anatomical expertise and has proven error prone. Here we present an algorithm to automatically create 3D printed molds guiding MTL extraction.

18. Neural and behavioral correlates of episodic memory are associated with temporal discounting in older adults.

    Karolina M. Lempert, D. Mechanic-Hamilton, L. Xie, and 7 more authors

    Neuropsychologia, Jul 2020

    Cited by 26

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    When facing decisions involving trade-offs between smaller, sooner and larger, delayed rewards, people tend to discount the value of future rewards. There are substantial individual differences in this tendency toward temporal discounting, however. One neurocognitive system that may underlie these individual differences is episodic memory, given the overlap in the neural circuitry involved in imagining the future and remembering the past. Here we tested this hypothesis in older adults, including both those that were cognitively normal and those with amnestic mild cognitive impairment (MCI). We found that performance on neuropsychological measures of episodic memory retrieval was associated with temporal discounting, such that people with better memory discounted delayed rewards less. This relationship was specific to episodic memory and temporal discounting, since executive function (another cognitive ability) was unrelated to temporal discounting, and episodic memory was unrelated to risk tolerance (another decision-making preference). We also examined cortical thickness and volume in medial temporal lobe regions critical for episodic memory. Entorhinal cortical thickness was associated with reduced temporal discounting, with episodic memory performance partially mediating this association. The inclusion of MCI participants was critical to revealing these associations between episodic memory and entorhinal cortical thickness and temporal discounting. These effects were larger in the MCI group, reduced after controlling for MCI status, and statistically significant only when including MCI participants in analyses. Overall, these findings suggest that individual differences in temporal discounting are driven by episodic memory function, and that a decline in medial temporal lobe structural integrity may impact temporal discounting.

19. Feed-forward, feed-back, and distributed feature representation during visual word recognition revealed by human intracranial neurophysiology

    L. Long, Minda Yang, N. Kriegeskorte, and 18 more authors

    Oct 2020

    Cited by 2

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    Scientists debate where, when, and how different visual, orthographic, lexical, and semantic features are involved in visual word recognition. In this study, we investigate intracranial neurophysiology data from 151 patients engaged in reading single words. Using representational similarity analysis, we characterize the neural representation of a hierarchy of word features across the entire cerebral cortex. We find evidence of both feed-forward and feedback processing, with early representation of visual and lexical information in lingual gyrus followed by lexical representation in fusiform gyrus and semantic sensitivity in inferior frontal gyrus, with letter representation emerging later in fusiform gyrus. Furthermore, we observed a variety of anatomically heterogeneous temporal response shapes, and these functional populations had significant feature sensitivity. Taken together, our results demonstrate the early influence of lexical, phonological, and semantic features in visual word recognition and reveal feed-forward, feed-back, and anatomically distributed processing mechanisms that contribute to visual word recognition.

20. Epigenetic measurement of biological age associates with tau load in normal brain aging

    Marissa J. Maroni, D. Wolk, Sandhitsu R. Das, and 6 more authors

    Alzheimer’s & Dementia, Dec 2020

    Cited by 4

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    Aging is the most established risk factor for sporadic Alzheimer’s Disease (AD). However, relative risk of AD varies greatly across individuals. One potential explanation for this heterogeneity is that chronological age may not reflect differences in biological aging. One measure of biological age is the “epigenetic clock” which utilizes a weighted statistical model from >350 CpG sites that captures the cumulative work of an individual’s epigenetic maintenance system and has been demonstrated to relate to age, mortality, and survival. In this study, we test the hypothesis that the epigenetic clock will be related to two regional brain aging signatures associated with AD, including neurofibrillary tau tangle (NFTs) load and reduced cortical thickness.

21. Cognitive and neurodegenerative profile differences between “mismatch MCI” (A+T‐N+ MCI) And “prodromal AD” (A+T+N+ MCI) increase with time

    Lauren McCollum, Sandhitsu R. Das, Jieqiong Wang, and 6 more authors

    Alzheimer’s & Dementia, Dec 2020

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    Per the Amyloid/Tau/Neurodegeneration (A/T/N) framework, beta‐amyloid accumulates during preclinical Alzheimer’s Disease (AD), followed by tau, then neurodegeneration. As AD symptoms are most linked to tau and neurodegeneration, both are expected by the MCI stage of disease. Thus, A+T‐N+ MCI (“mismatch MCI”) is thought to have both AD pathophysiology and non‐AD pathology, with the latter (given absence of tau) driving neurodegeneration and symptoms. We investigate the cognitive and neurodegenerative profile of mismatch MCI compared to “standard” A+T+N+ MCI (“prodromal AD”).

22. Tau Status Portends Different Baseline and Longitudinal Cognitive Performance in Amyloid- and Neurodegeneration-positive Mild Cognitive Impairment (MCI) (4723)

    Lauren McCollum, L. Wisse, Salena Cui, and 5 more authors

    Neurology, Apr 2020

    DOI

    
23. Detection of Alzheimer’s Disease-Related Cognitive Change With the Mobile Cognitive App Performance Platform

    Dawn J. Mechanic-Hamilton, Sean Lydon, Alexander Miller, and 4 more authors

    Innovation in Aging, Dec 2020

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    Abstract This study investigates the psychometric properties of the mobile cognitive app performance platform (mCAPP), designed to detect memory changes associated with preclinical Alzheimer’s Disease (AD). The mCAPP memory task includes learning and matching hidden card pairs and incorporates increasing memory load, pattern separation features, and spatial memory. Participants included 30 older adults with normal cognition. They completed the mCAPP, paper and pencil neuropsychological tests and a subset completed a high-resolution structural MRI. The majority of participants found the difficulty level of the mCAPP game to be “just right”. Accuracy on the mCAPP correlated with performance on memory and executive measures, while speed of performance on the mCAPP correlated with performance on attention and executive function measures. Longer trial duration correlated with measures of the parahippocampal cortex. The relationship of mCAPP variables with molecular biomarkers, at-home and burst testing, and development of additional cognitive measures will also be discussed.

24. Development of the mobile cognitive app performance platform for detection of AD‐related cognitive change

    Dawn J. Mechanic-Hamilton, Sean Lydon, Kimberly Halberstadter, and 3 more authors

    Alzheimer’s & Dementia, Dec 2020

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    This pilot study investigates the psychometric properties of a mobile app‐based memory task, the mobile cognitive app performance platform (mCAPP), to detect memory changes associated with preclinical Alzheimer’s Disease (AD). A mobile, reliable, valid, short, and engaging cognitive assessment is necessary for early detection and tracking change in individuals at risk for AD.

25. Issue Information Page

    A. Mehdiani, Alexander Albert, H. Dalyanoĝlu, and 11 more authors

    Journal of Cardiac Surgery, Jan 2020

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26. Intraoperative post-annuloplasty three-dimensional valve analysis does not predict recurrent ischemic mitral regurgitation

    F. Meijerink, Inez J Wijdh-Den Hamer, W. Bouma, and 13 more authors

    Journal of Cardiothoracic Surgery, Jul 2020

    Cited by 3

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    Background High ischemic mitral regurgitation (IMR) recurrence rates continue to plague IMR repair with undersized ring annuloplasty. We have previously shown that pre-repair three-dimensional echocardiography (3DE) analysis is highly predictive of IMR recurrence. The objective of this study was to determine the quantitative change in 3DE annular and leaflet tethering parameters immediately after repair and to determine if intraoperative post-repair 3DE parameters would be able to predict IMR recurrence 6 months after repair. Methods Intraoperative pre- and post-repair transesophageal real-time 3DE was performed in 35 patients undergoing undersized ring annuloplasty for IMR. An advanced modeling algorhythm was used to assess 3D annular geometry and regional leaflet tethering. IMR recurrence (≥ grade 2) was assessed with transthoracic echocardiography 6 months after repair. Results Annuloplasty significantly reduced septolateral diameter, commissural width, annular area, and tethering volume and significantly increased all segmental tethering angles (except A2). Intraoperative post-repair annular geometry and leaflet tethering did not differ significantly between patients with recurrent IMR ( n  = 9) and patients with non-recurrent IMR ( n  = 26). No intraoperative post-repair predictors of IMR recurrence could be identified. Conclusions Undersized ring annuloplasty changes mitral geometry acutely, exacerbates leaflet tethering, and generally fixes IMR acutely, but it does not always fix the delicate underlying chronic problem of continued left ventricular dilatation and remodeling. This may explain why pre-repair 3D valve geometry (which reflects chronic left ventricular remodeling) is highly predictive of recurrent IMR, whereas immediate post-repair 3D valve geometry (which does not completely reflect chronic left ventricular remodeling anymore) is not.

27. Minimally interactive placenta segmentation from three-dimensional ultrasound images

    I. Oguz, N. Yushkevich, A. Pouch, and 6 more authors

    Journal of Medical Imaging, Jan 2020

    Cited by 15

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    Abstract. Purpose: Placental size in early pregnancy has been associated with important clinical outcomes, including fetal growth. However, extraction of placental size from three-dimensional ultrasound (3DUS) requires time-consuming interactive segmentation methods and is prone to user variability. We propose a semiautomated segmentation technique that requires minimal user input to robustly measure placental volume from 3DUS images. Approach: For semiautomated segmentation, a single, central 2D slice was manually annotated to initialize an automated multi-atlas label fusion (MALF) algorithm. The dataset consisted of 47 3DUS volumes obtained at 11 to 14 weeks in singleton pregnancies (28 anterior and 19 posterior). Twenty-six of these subjects were imaged twice within the same session. Dice overlap and surface distance were used to quantify the automated segmentation accuracy compared to expert manual segmentations. The mean placental volume measurements obtained by our method and VOCAL (virtual organ computer-aided analysis), a leading commercial semiautomated method, were compared to the manual reference set. The test–retest reliability was also assessed. Results: The overlap between our automated segmentation and manual (mean Dice: 0.824  ±  0.061, median: 0.831) was within the range reported by other methods requiring extensive manual input. The average surface distance was 1.66  ±  0.96  mm. The correlation coefficient between test–retest volumes was r  =  0.88, and the intraclass correlation was ICC  (  1  )    =  0.86. Conclusions: MALF is a promising method that can allow accurate and reliable segmentation of the placenta with minimal user interaction. Further refinement of this technique may allow for placental biometry to be incorporated into clinical pregnancy surveillance.

28. 7T Epilepsy Task Force Consensus Recommendations on the use of 7T in Clinical Practice.

    Giske Opheim, A. G. Kolk, K. M. Bloch, and 41 more authors

    Neurology, Dec 2020

    Cited by 59

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    Identifying a structural brain lesion on MRI has important implications in epilepsy and is the most important correlate to seizure freedom after surgery in patients with drug-resistant focal onset epilepsy. However, at conventional magnetic field strengths (1.5 and 3T) only around 60-85% of MRI examinations reveal such lesions. Over the last decade, studies have demonstrated the added value of 7T MRI in patients with and without known epileptogenic lesions from 1.5 and/or 3T. However, translation of 7T MRI to clinical practice is still challenging, particularly in centers new to 7T, and there is a need for practical recommendations on targeted use of 7T MRI in the clinical management of patients with epilepsy. The 7T Epilepsy Task Force - an international group representing 21 7T MRI centers with experience from scanning over 2000 patients with epilepsy - would hereby like to share its experience with the neurology community regarding the appropriate clinical indications, patient selection and preparation, acquisition protocols and setup, technical challenges, and radiological guidelines for 7T MRI in epilepsy patients. This article mainly addresses structural imaging, but also presents multiple non-structural MRI techniques that benefit from 7T and hold promise as future directions in epilepsy. Answering to the increased availability of 7T MRI as an approved tool for diagnostic purposes, this article aims to give guidance on clinical 7T MRI epilepsy management by giving recommendations on referral, suitable 7T MRI protocols and image interpretation.

29. Automated Meshing of Anatomical Shapes for Deformable Medial Modeling: Application to the Placenta in 3D Ultrasound

    A. Pouch, Paul Yushkevich, A. H. Aly, and 10 more authors

    In IEEE International Symposium on Biomedical Imaging, Apr 2020

    Cited by 5

    Abs DOI

    

    Deformable medial modeling is an approach to extracting clinically useful features of the morphological skeleton of anatomical structures in medical images. Similar to any deformable modeling technique, it requires a pre-defined model, or synthetic skeleton, of a class of shapes before modeling new instances of that class. The creation of synthetic skeletons often requires manual interaction, and the deformation of the synthetic skeleton to new target geometries is prone to registration errors if not well initialized. This work presents a fully automated method for creating synthetic skeletons (i.e., 3D boundary meshes with medial links) for flat, oblong shapes that are homeomorphic to a sphere. The method rotationally cross-sections the 3D shape, approximates a 2D medial model in each cross-section, and then defines edges between nodes of neighboring slices to create a regularly sampled 3D boundary mesh. In this study, we demonstrate the method on 62 segmentations of placentas in first-trimester 3D ultrasound images and evaluate its compatibility and representational accuracy with an existing deformable modeling method. The method may lead to extraction of new clinically meaningful features of placenta geometry, as well as facilitate other applications of deformable medial modeling in medical image analysis.

30. Multi-institutional noninvasive in vivo characterization of IDH, 1p/19q, and EGFRvIII in glioma using neuro-Cancer Imaging Phenomics Toolkit (neuro-CaPTk)

    Saima Rathore, S. Mohan, S. Bakas, and 18 more authors

    Neuro-oncology Advances, Dec 2020

    Cited by 27

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    Abstract Background Gliomas represent a biologically heterogeneous group of primary brain tumors with uncontrolled cellular proliferation and diffuse infiltration that renders them almost incurable, thereby leading to a grim prognosis. Recent comprehensive genomic profiling has greatly elucidated the molecular hallmarks of gliomas, including the mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), loss of chromosomes 1p and 19q (1p/19q), and epidermal growth factor receptor variant III (EGFRvIII). Detection of these molecular alterations is based on ex vivo analysis of surgically resected tissue specimen that sometimes is not adequate for testing and/or does not capture the spatial tumor heterogeneity of the neoplasm. Methods We developed a method for noninvasive detection of radiogenomic markers of IDH both in lower-grade gliomas (WHO grade II and III tumors) and glioblastoma (WHO grade IV), 1p/19q in IDH-mutant lower-grade gliomas, and EGFRvIII in glioblastoma. Preoperative MRIs of 473 glioma patients from 3 of the studies participating in the ReSPOND consortium (collection I: Hospital of the University of Pennsylvania [HUP: n = 248], collection II: The Cancer Imaging Archive [TCIA; n = 192], and collection III: Ohio Brain Tumor Study [OBTS, n = 33]) were collected. Neuro-Cancer Imaging Phenomics Toolkit (neuro-CaPTk), a modular platform available for cancer imaging analytics and machine learning, was leveraged to extract histogram, shape, anatomical, and texture features from delineated tumor subregions and to integrate these features using support vector machine to generate models predictive of IDH, 1p/19q, and EGFRvIII. The models were validated using 3 configurations: (1) 70–30% training–testing splits or 10-fold cross-validation within individual collections, (2) 70–30% training–testing splits within merged collections, and (3) training on one collection and testing on another. Results These models achieved a classification accuracy of 86.74% (HUP), 85.45% (TCIA), and 75.15% (TCIA) in identifying EGFRvIII, IDH, and 1p/19q, respectively, in configuration I. The model, when applied on combined data in configuration II, yielded a classification success rate of 82.50% in predicting IDH mutation (HUP + TCIA + OBTS). The model when trained on TCIA dataset yielded classification accuracy of 84.88% in predicting IDH in HUP dataset. Conclusions Using machine learning algorithms, high accuracy was achieved in the prediction of IDH, 1p/19q, and EGFRvIII mutation. Neuro-CaPTk encompasses all the pipelines required to replicate these analyses in multi-institutional settings and could also be used for other radio(geno)mic analyses.

31. Building an Ex Vivo Atlas of the Earliest Brain Regions Affected by Alzheimer’s Disease Pathology

    S. Ravikumar, L. Wisse, R. Ittyerah, and 23 more authors

    In IEEE International Symposium on Biomedical Imaging, Apr 2020

    Cited by 7

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    Earliest neuropathological changes in Alzheimer’s Disease (AD) emerge in the medial temporal lobe (MTL). In order for MRI biomarkers to detect changes linked specifically to AD pathology (as opposed to aging or other pathological factors) macroscopic patterns of structural change in the MTL must be linked to the underlying neuropathology. To provide such a linkage, we are conducting an autopsy imaging study combining ex vivo MRI and serial histopathology. Information from multiple subjects can be studied by creating a “population average” atlas of the MTL. We present a groupwise registration approach for constructing the atlas that is able to successfully capture the complex structure of the MTL, and anatomical variability across subjects. This atlas allows us to generate maps of cortical thickness measurements and identify regions in the MTL where structural changes correlate most strongly with AD progression. We show that using this atlas, we are able to find a significant correlation between atrophy and AD pathology in the MTL sub-regions associated with the earliest stages of AD pathology as described by Braak and Braak [1].

32. Novel ex vivo MRI atlas of the medial temporal lobe can be used to characterize structural changes due to Alzheimer’s disease pathology

    S. Ravikumar, L. Wisse, L. Xie, and 27 more authors

    Alzheimer’s & Dementia, Dec 2020

    Cited by 1

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    Finding effective biomarkers that can support early‐stage clinical trials is a major challenge in Alzheimer’s Disease (AD). MRI measures of structural change in the medial temporal lobe (MTL) have proven to be sensitive to change in the early stages of AD. However, other frequently comorbid non‐AD factors (e.g. cerebrovascular disease, TDP‐43 pathology) also cause changes in the MTL. For MRI biomarkers to detect changes specifically linked to AD pathology, patterns of structural change must be linked to the underlying neuropathology. To provide this linkage, we use ex vivo imaging with pathologically derived ratings of AD and non‐AD pathology to study the localized effects of the disease on MTL structure. We hypothesize that such an analysis can be used to define MTL “hotspots” where in vivo measures will be more sensitive to disease progression in preclinical AD than current state of the art biomarkers.

33. Measurements of production cross sections of WZ and same-sign WW boson pairs in association with two jets in proton-proton collisions at s=13TeV

    A. Sirunyan, A. Tumasyan, W. Adam, and 497 more authors

    Physics Letters B, Oct 2020

    Cited by 50

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    Abstract Measurements of production cross sections of W Z and same-sign W W boson pairs in association with two jets in proton-proton collisions at s = 13 TeV at the LHC are reported. The data sample corresponds to an integrated luminosity of 137 fb − 1 , collected with the CMS detector during 2016–2018. The measurements are performed in the leptonic decay modes and , where l , l ′ = e , . Differential fiducial cross sections as functions of the invariant masses of the jet and charged lepton pairs, as well as of the leading-lepton transverse momentum, are measured for W ± W ± production and are consistent with the standard model predictions. The dependence of differential cross sections on the invariant mass of the jet pair is also measured for W Z production. An observation of electroweak production of W Z boson pairs is reported with an observed (expected) significance of 6.8 (5.3) standard deviations. Constraints are obtained on the structure of quartic vector boson interactions in the framework of effective field theory.

34. Automated Analysis of Low-Field Brain MRI in Cerebral Malaria

    Danni Tu, M. Goyal, Jordan D Dworkin, and 18 more authors

    bioRxiv, Dec 2020

    Cited by 7

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    A central challenge of medical imaging studies is to extract biomarkers that characterize pathology or predict disease outcomes. State-of-the-art automated approaches to identify these biomarkers in high-resolution, high-quality magnetic resonance images have performed well. However, such methods may not translate to low resolution, lower quality images acquired on MRI scanners with lower magnetic field strength. In low-resource settings where low-field scanners are more common and there is a shortage of available radiologists to manually interpret MRI scans, it is therefore essential to develop automated methods that can augment or replace manual interpretation while accommodating reduced image quality. Motivated by a project in which a cohort of children with cerebral malaria were imaged using 0.35 Tesla MRI to evaluate the degree of diffuse brain swelling, we introduce a fully automated framework to translate radiological diagnostic criteria into image-based biomarkers. We integrate multi-atlas label fusion, which leverages high-resolution images from another sample as prior spatial information, with parametric Gaussian hidden Markov models based on image intensities, to create a robust method for determining ventricular cerebrospinal fluid volume. We further propose normalized image intensity and texture measurements to determine the loss of gray-to-white matter tissue differentiation and sulcal effacement. These integrated biomarkers are found to have excellent classification performance for determining severe cerebral edema due to cerebral malaria.

35. ANTsX: A dynamic ecosystem for quantitative biological and medical imaging

    N. Tustison, P. Cook, A. Holbrook, and 11 more authors

    medRxiv, Oct 2020

    Cited by 13

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    The Advanced Normalizations Tools ecosystem, known as ANTsX, consists of multiple open- source software libraries which house top-performing algorithms used worldwide by scientific and research communities for processing and analyzing biological and medical imaging data. The base software library, ANTs, is built upon, and contributes to, the NIH-sponsored Insight Toolkit. Founded in 2008 with the highly regarded Symmetric Normalization image registration framework, the ANTs library has since grown to include additional functionality. Recent enhancements include statistical, visualization, and deep learning capabilities through interfacing with both the R statistical project (ANTsR) and Python (ANTsPy). Additionally, the corresponding deep learning extensions ANTsRNet and ANTsPyNet (built on the popular TensorFlow/Keras libraries) contain several popular network architectures and trained models for specific applications. One such comprehensive application is a deep learning analog for generating cortical thickness data from structural T1-weighted brain MRI. Not only does this significantly improve computational efficiency and provide comparable-to-superior accuracy over the existing ANTs pipeline but it also illustrates the importance of the comprehensive ANTsX approach as a framework for medical image analysis.

36. Cross-sectional and longitudinal medial temporal lobe subregional atrophy patterns in semantic variant primary progressive aphasia.

    L. Wisse, Molly B. Ungrady, R. Ittyerah, and 6 more authors

    Neurobiology of aging, Nov 2020

    Cited by 8

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    T1-magnetic resonance imaging (MRI) studies report early atrophy in the left anterior temporal lobe, especially the perirhinal cortex, in semantic variant primary progressive aphasia (svPPA). Improved segmentation protocols using high-resolution T2-MRI have enabled fine-grained medial temporal lobe (MTL) subregional measurements, which may provide novel information on the atrophy pattern and disease progression in svPPA. We aimed to investigate the MTL subregional atrophy pattern cross-sectionally and longitudinally in patients with svPPA as compared with controls and patients with Alzheimer’s disease (AD). MTL subregional volumes were obtained using the Automated Segmentation for Hippocampal Subfields software from high-resolution T2-MRIs in 15 svPPA, 37 AD, and 23 healthy controls. All MTL volumes were corrected for intracranial volume and parahippocampal cortices for slice number. Longitudinal atrophy rates of all subregions were obtained using an unbiased deformation-based morphometry pipeline in 6 svPPA patients, 9 controls, and 12 AD patients. Cross-sectionally, significant volume loss was observed in svPPA compared with controls in the left MTL, right cornu ammonis 1 (CA1), Brodmann area (BA)35, and BA36 (subdivisions of the perirhinal cortex). Compared with AD patients, svPPA patients had significantly smaller left CA1, BA35, and left and right BA36 volumes. Longitudinally, svPPA patients had significantly greater atrophy rates of left and right BA36 than controls but not relative to AD patients. Fine-grained analysis of MTL atrophy patterns provides information about the evolution of atrophy in svPPA. These results indicate that MTL subregional measures might be useful markers to track disease progression or for clinical trials in svPPA.

37. High‐resolution postmortem MRI reveals TDP‐43 association with medial temporal lobe subregional atrophy

    L. Wisse, S. Ravikumar, R. Ittyerah, and 28 more authors

    Alzheimer’s & Dementia, Dec 2020

    Cited by 3

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    The medial temporal lobe (MTL) is a hotspot of different neurodegenerative pathologies, and recent studies have shown associations of severity of pathology with atrophy measured on antemortem MRI. However, these studies are limited by the interval between time of scan and death and the relatively low resolution of the commonly acquired in vivo MRI scans, limiting the granularity of the regions being measured. We investigate the association of different neurodegenerative pathologies, particularly TDP‐43, and the thickness of different MTL subregions measured on high‐resolution postmortem MRI. As prior work suggests an anterior‐to‐posterior gradient of atrophy for TDP‐43 in frontotemporal dementia spectrum disorders and Limbic‐predominant Age‐related TDP‐43 Encephalopathy (LATE), we also examined differences along the long axis of the MTL.

38. Hippocampal subfield volumetry from structural isotropic 1 mm3 MRI scans: A note of caution

    L. Wisse, G. Chételat, A. Daugherty, and 11 more authors

    Human Brain Mapping, Oct 2020

    Cited by 124

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    Spurred by availability of automatic segmentation software, in vivo MRI investigations of human hippocampal subfield volumes have proliferated in the recent years. However, a majority of these studies apply automatic segmentation to MRI scans with approximately 1 × 1 × 1 mm3 resolution, a resolution at which the internal structure of the hippocampus can rarely be visualized. Many of these studies have reported contradictory and often neurobiologically surprising results pertaining to the involvement of hippocampal subfields in normal brain function, aging, and disease. In this commentary, we first outline our concerns regarding the utility and validity of subfield segmentation on 1 × 1 × 1 mm3 MRI for volumetric studies, regardless of how images are segmented (i.e., manually or automatically). This image resolution is generally insufficient for visualizing the internal structure of the hippocampus, particularly the stratum radiatum lacunosum moleculare, which is crucial for valid and reliable subfield segmentation. Second, we discuss the fact that automatic methods that are employed most frequently to obtain hippocampal subfield volumes from 1 × 1 × 1 mm3 MRI have not been validated against manual segmentation on such images. For these reasons, we caution against using volumetric measurements of hippocampal subfields obtained from 1 × 1 × 1 mm3 images.

39. Tau pathology mediates age effects on medial temporal lobe atrophy

    L. Wisse, L. Xie, Sandhitsu R. Das, and 3 more authors

    Alzheimer’s & Dementia, Dec 2020

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    Age effects on the hippocampus are well established, but age‐effects on adjacent cortical regions less so. Moreover, aging has often been investigated using cross‐sectional designs, seldomly separating aging effects from the effects of β‐amyloid. We investigate the effect of aging on medial temporal lobe (MTL) subregions cross‐sectionally and longitudinally in β‐amyloid‐negative (A‐) cognitively normal (CN) older adults and the role of tau pathology, a potential mediator.

40. Longitudinal atrophy in early Braak regions in preclinical Alzheimer’s disease

    L. Xie, L. Wisse, Sandhitsu R. Das, and 6 more authors

    Human Brain Mapping, Aug 2020

    Cited by 53

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    A major focus of Alzheimer’s disease (AD) research has been finding sensitive outcome measures to disease progression in preclinical AD, as intervention studies begin to target this population. We hypothesize that tailored measures of longitudinal change of the medial temporal lobe (MTL) subregions (the sites of earliest cortical tangle pathology) are more sensitive to disease progression in preclinical AD compared to standard cognitive and plasma NfL measures. Longitudinal T1‐weighted MRI of 337 participants were included, divided into amyloid‐β negative (Aβ−) controls, cerebral spinal fluid p‐tau positive (T+) and negative (T−) preclinical AD (Aβ+ controls), and early prodromal AD. Anterior/posterior hippocampus, entorhinal cortex, Brodmann areas (BA) 35 and 36, and parahippocampal cortex were segmented in baseline MRI using a novel pipeline. Unbiased change rates of subregions were estimated using MRI scans within a 2‐year‐follow‐up period. Experimental results showed that longitudinal atrophy rates of all MTL subregions were significantly higher for T+ preclinical AD and early prodromal AD than controls, but not for T− preclinical AD. Posterior hippocampus and BA35 demonstrated the largest group differences among hippocampus and MTL cortex respectively. None of the cross‐sectional MTL measures, longitudinal cognitive measures (PACC, ADAS‐Cog) and cross‐sectional or longitudinal plasma NfL reached significance in preclinical AD. In conclusion, longitudinal atrophy measurements reflect active neurodegeneration and thus are more directly linked to active disease progression than cross‐sectional measurements. Moreover, accelerated atrophy in preclinical AD seems to occur only in the presence of concomitant tau pathology. The proposed longitudinal measurements may serve as efficient outcome measures in clinical trials.

41. Subtle differences in the appearance of hippocampal layers differentiate preclinical AD from healthy aging

    L. Xie, Sandhitsu R. Das, L. Wisse, and 5 more authors

    Alzheimer’s & Dementia, Dec 2020

    Cited by 1

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    Degeneration of the stratum radiatum lacunosum moleculare (SRLM), located between the cornu ammonis (CA)/subiculum and dentate gyrus (DG) subfields of the hippocampus (Figure 1) and containing apical dendrites of CA pyramidal cells, may be an early feature of AD and can be observed in postmortem studies (Adler et al, 2018). The pathological change in SRLM may produce subtle alteration of image signal on high‐resolution in vivo MRI. We hypothesize that convolutional neural networks (CNNs) can detect such alterations in preclinical AD, yielding a more sensitive biomarker than conventional morphological measurements.

42. 3D Mapping of TAU Neurofibrillary Tangle Pathology in the Human Medial Temporal Lobe

    Paul Yushkevich, Maria Mercedes Iniguez Onzono Martin, R. Ittyerah, and 30 more authors

    In IEEE International Symposium on Biomedical Imaging, Apr 2020

    Cited by 5

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    Tau protein neurofibrillary tangles (NFT) are linked to neuronal and synaptic loss and cognitive decline in Alzheimer’s disease (AD) and related dementias. In AD, NFT pathology is known to spread through the cortex in a characteristic pattern, starting in the medial temporal lobe. However, the exact 3D pattern of NFT progression has not been described, and capturing this pattern quantitatively can help inform in vivo AD imaging biomarkers. We present a computational framework for generating 3D maps of NFT load from ex vivo MRI and serial histology. Weakly supervised deep learning is used to detect NFTs on histology slides prepared with an anti-tau immunohistochemistry stain, and a multi-stage registration pipeline that leverages 3D printing is used for histology-MRI alignment. Derived maps of NFT density are strongly concordant with manual NFT counting, as well as categorical NFT severity ratings used for clinical diagnosis.

43. NEW RELIGIOUS MOVEMENTS AND METHODS OF PROTECTION AGAINST THEIR CRIMINAL ACTIVITIES

    Paul Yushkevich

    Apr 2020

    DOI

    
44. Bone-Selective Magnetic Resonance Imaging as a Nonradiative Alternative to Computed Tomography for Cranial Vault Imaging: Concordance and Implementation of an Automated Segmentation Pipeline for Timely Image Processing

    C. Zimmerman, Pulkit Khandelwal, Rosaline S. Zhang, and 7 more authors

    Plastic and Reconstructive Surgery Global Open, Sep 2020

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    METHODS: Eight Yucatan miniature pigs, 4 donors and 4 recipients, were used. Right forelimbs of donor animals were amputated at mid-humeral level, to maintain integrity of forearm fascial compartments, and preserved with EVNLP until replantation. The right forelimb of the recipient animal was amputated, and a central venous line was placed in the contralateral neck. Perfusate electrolytes, gases, O 2 saturation, muscle contractility, surface temperature (infrared thermography), and peripheral perfusion (indocyanine green agiography) were assessed during EVNLP. The humerus was fixed with a single 3.5 mm LC-DCP plate; microsurgical anastomosis of the brachial artery, cephalic vein, and repair of radial, ulnar, and median nerves were performed under an operative microscope. Tendons of the biceps and triceps were repaired with pulvertaft weave technique. The first animal did not receive systemic immunosuppression. Systemic immunosuppression for the remaining 3 pigs included induction with antithymoglobulin, followed by daily cyclosporine (CSA), mycophenolate mofetil, and methylprednisolone. CSA trough levels were measured daily. Limbs were monitored clinically and histologically for signs of rejection. Bone healing was confirmed with CT scan at euthanasia. The endpoint of the study was 90 days.

2019

1. Cerebrospinal Fluid AD Biomarkers and Regional [18F]-Flortaucipir Uptake in Lewy Body Disorders (S10.009)

   David Coughlin, Jeffrey Phillips, Emily Roll, and 11 more authors

   Neurology, Apr 2019

   Cited by 1

   DOI

   
2. 18F-AV-1451 Tau Tracer Uptake Correlates with Medial Temporal Lobe Subregional Atrophy in Amyloid Negative Individuals (P5.1-012)

   Sandhitsu R. Das, Long Xie, L. Wisse, and 3 more authors

   Neurology, Apr 2019

   DOI

   
3. In vivo measures of tau burden are associated with atrophy in early Braak stage medial temporal lobe regions in amyloid‐negative individuals

   Sandhitsu R. Das, L. Xie, L. Wisse, and 5 more authors

   Alzheimer’s & Dementia, Sep 2019

   Cited by 40

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   It is unclear the degree to which tau pathology in the medial temporal lobe (MTL) measured by 18F‐flortaucipir positron emission tomography relates to MTL subregional atrophy and whether this relationship differs between amyloid‐β–positive and amyloid‐β–negative individuals.

4. IC‐P‐043: CONTRIBUTION OF TAU, TDP‐43, β‐AMYLOID AND α‐SYNUCLEIN TO MEDIAL TEMPORAL LOBE ATROPHY

   R. Flores, L. Wisse, Sandhitsu R. Das, and 8 more authors

   Alzheimer’s & Dementia, Jul 2019

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   Background: The Risk Reduction for Alzheimer’s Disease (rrAD) trial is designed to assess the effects of aerobic exercise and intensive vascular risk reduction on cognitive performance in older adults who are at high risk for AD. About 640 normal adults age 60 to 85 years with family history of dementia or subjective memory complaints, hypertension, and a sedentary life style are being enrolled at four clinical sites. BrainMRI scans are obtained at baseline and 24 months, and are being processed centrally at the trial imaging coordinating center (ICC). We aims to share our experience from our neuroimaging core. Methods: Data Acquisition: 3T MRI scanners (GE, Siemens and Philips) are used. The sequences used include: 3D T1-weighted high-resolution MPRAGE to quantify brain morphometry; T2 FLAIR tomeasurewhite matter lesions; DTI to assess brain white matter microstructural integrity and structural connectivity; resting-state fMRI to assess neural functional connectivity; 3D pCASL to assess regional brain perfusion; T2*weighted imaging to detect hemorrhage; and phase-contrast imaging to measure blood flow into the brain. Quality Control: All images are transferred via the web-based Globus software (https://www.globus.org/) in DICOM format to the ICC within 24 hours after acquisition. The ICC team completes quality control (QC) within three business days. The QC ensures subject anonymity, accuracy and image quality (imaging distortion, artifacts and signal-to-noise ratio) for all scans. The data collection sites are notified immediately if any severe image artifacts and clinically significant lesions are found. Recommendations are provided if a participant should be rescanned and/or if phantom QC scans should be performed (Fig. 1). Data Analysis: All imaging results are aligned to 3D MPRAGE images. MPRAGE images are segmented and standardized to MNI305 space using FreeSurfer. To reduce the impact of atrophy and distortion in older brains for group analyses, imaging results are standardized to MNI space via the FreeSurfer pipeline (Fig. 2). Results: With vigorous subject recruitment, data acquisition, QC and data analysis procedures, we have acquired over 350 high-qualityMRI datasets by January 2019. Scanner hardware issues have been timely detected and resolved to reduce scan delay. Conclusions: Successful procedures of a multicenter neuroimaging trial are demonstrated. IC-P-042 DIFFERENTIATING TAUOPATHIES WITH A NOVEL DIFFUSION TENSOR IMAGING METHOD TO INVESTIGATE CORTICAL ARCHITECTURE

5. P1‐441: CONTRIBUTION OF TAU, TDP‐43, β‐AMYLOID AND α‐SYNUCLEIN TO MEDIAL TEMPORAL LOBE ATROPHY

   R. Flores, L. Wisse, Sandhitsu R. Das, and 8 more authors

   Alzheimer’s & Dementia, Jul 2019

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   Robin de Flores, Laura Wisse, Sandhitsu R. Das, Long Xie, Corey T. McMillan, John Q. Trojanowski, Murray Grossman, Eddie B. Lee, David Irwin, Paul A. Yushkevich, David A. Wolk, Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA; Penn Image Computing and Science Laboratory (PICSL), University of Pennsylvania, Philadelphia, PA, USA; Penn FTD Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, PA, USA; Penn Memory Center, University of Pennsylvania, Philadelphia, PA, USA. Contact e-mail: robindeflores@gmail.com

6. LONG-TERM NSAID THERAPY IN OLDER ADULTS: EFFECTS ON AT(N)V IMAGING BIOMARKERS

   R. Grunstein, S. Duffy, J. Shine, and 7 more authors

   Jul 2019

   
7. Hippocampal tau pathology burden in Lewy body disorders (P1.1-014)

   R. Ittyerah, David Coughlin, Jeffrey Phillips, and 11 more authors

   Neurology, Apr 2019

   DOI

   
8. Convergent Evidence for a Longevity Genetic Locus Associated with Tau Load in PART (S34.007)

   Kyra S Jefferson-George, David Wolk, Edward B. Lee, and 6 more authors

   Neurology, Apr 2019

   DOI

   
9. Functional control of electrophysiological network architecture using direct neurostimulation in humans

   A. Khambhati, Ari E. Kahn, J. Costantini, and 20 more authors

   Network Neuroscience, Jan 2019

   Cited by 59

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   Chronically implantable neurostimulation devices are becoming a clinically viable option for treating patients with neurological disease and psychiatric disorders. Neurostimulation offers the ability to probe and manipulate distributed networks of interacting brain areas in dysfunctional circuits. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. By integrating multimodal intracranial recordings and diffusion-weighted imaging from patients with drug-resistant epilepsy, we test hypothesized structural and functional rules that predict altered patterns of synchronized local field potentials. We demonstrate the ability to predictably reconfigure functional interactions depending on stimulation strength and location. Stimulation of areas with structurally weak connections largely modulates the functional hubness of downstream areas and concurrently propels the brain towards more difficult-to-reach dynamical states. By using focal perturbations to bridge large-scale structure, function, and markers of behavior, our findings suggest that stimulation may be tuned to influence different scales of network interactions driving cognition.Author SummaryBrain stimulation devices capable of perturbing the physiological state of neural systems are rapidly gaining popularity for their potential to treat neurological and psychiatric disease. A root problem is that underlying dysfunction spans a large-scale network of brain regions, requiring the ability to control the complex interactions between multiple brain areas. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. We demonstrate the ability to predictably reconfigure patterns of interactions between functional brain areas by modulating the strength and location of stimulation. Our findings have high significance for designing stimulation protocols capable of modulating distributed neural circuits in the human brain.

10. Virtual resection predicts surgical outcome for drug-resistant epilepsy.

    Lohith G. Kini, J. Bernabei, Fadi Mikhail, and 15 more authors

    Brain : a journal of neurology, Oct 2019

    Cited by 113

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    Patients with drug-resistant epilepsy often require surgery to become seizure-free. While laser ablation and implantable stimulation devices have lowered the morbidity of these procedures, seizure-free rates have not dramatically improved, particularly for patients without focal lesions. This is in part because it is often unclear where to intervene in these cases. To address this clinical need, several research groups have published methods to map epileptic networks but applying them to improve patient care remains a challenge. In this study we advance clinical translation of these methods by: (i) presenting and sharing a robust pipeline to rigorously quantify the boundaries of the resection zone and determining which intracranial EEG electrodes lie within it; (ii) validating a brain network model on a retrospective cohort of 28 patients with drug-resistant epilepsy implanted with intracranial electrodes prior to surgical resection; and (iii) sharing all neuroimaging, annotated electrophysiology, and clinical metadata to facilitate future collaboration. Our network methods accurately forecast whether patients are likely to benefit from surgical intervention based on synchronizability of intracranial EEG (area under the receiver operating characteristic curve of 0.89) and provide novel information that traditional electrographic features do not. We further report that removing synchronizing brain regions is associated with improved clinical outcome, and postulate that sparing desynchronizing regions may further be beneficial. Our findings suggest that data-driven network-based methods can identify patients likely to benefit from resective or ablative therapy, and perhaps prevent invasive interventions in those unlikely to do so.

11. P2‐462: SEMANTIC RICHNESS IN PEOPLE WITH PRECLINICAL ALZHEIMER’S DISEASE

    Nathaniel Klooster, Arun Pilania, L. Wisse, and 4 more authors

    Alzheimer’s & Dementia, Jul 2019

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    Although there have not been published norms for older adults of this test so far, it has been found that this test is more sensitive than visual naming tests in mixed etiology dementia. The aim of this study was to analyze the performance in the ANT of older adults and generate normative data. Methods: Cross-sectional descriptive-observational study. We evaluated 73 adults (57 women, age range: 55-93, mean age: 68.41 SD: 9.09), without concomitant pathologies that potentially affect cognition. Spanish ANT adaptation was administered. SPSS program was used and Pearson correlations, ANOVA, means and standard deviations were calculated to generate normative data. Results: There were no differences in performance according to gender. A moderate negative significant correlation with age was found (r -.511, p< .001). The sample was divided into five age groups 50-59 years (M 43.94 SD 3.57), 60-69 years (M 43.94 SD 3.56), 70-79 years (M 39.87 SD 4.49), 80-89 years (M 39.25 SD 2.55) and 90-99 years (M 39.00 SD 2.83). A low positive significant correlation was found with education (r .397, p1⁄4 .001). A later analysis revealed that this correlation only occurs in the group of 50-59 years and 70-79 years. Conclusions: In the present study, the performance in the ANT of older adults was analyzed and normative data were generated. It was observed that age and education influence the performance of this test. Future studies should examine these results by expanding the sample.

12. Neural and behavioral correlates of declarative memory are associated with temporal discounting in older adults

    Karolina M. Lempert, D. Mechanic-Hamilton, L. Xie, and 7 more authors

    bioRxiv, Jul 2019

    Cited by 5

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    When facing intertemporal choices, or decisions involving trade-offs between smaller, sooner and larger, delayed rewards, people tend to discount the value of future rewards. There are substantial individual differences in this tendency toward temporal discounting, however. The neurocognitive mechanisms underlying these individual differences remain unclear. One possibility is that individual differences in declarative memory ability underlie individual differences in temporal discounting. Here we tested this hypothesis in older adults (both cognitively normal and with mild cognitive impairment), given that declarative memory declines with age, at rates that vary across individuals. We related temporal discounting to performance on neuropsychological measures of declarative memory, as well as to structural measures of medial temporal lobe regions that are critical for memory. Performance on episodic and semantic memory retrieval tasks was associated with temporal discounting, such that people with better declarative memory discounted delayed rewards less. This relationship held even when controlling for executive function abilities that might influence memory retrieval. Underlining the specificity of this association, performance on measures of executive function (Trail Making Test, Digit Span Backwards, lexical fluency) was unrelated to temporal discounting, and declarative memory ability was unrelated to risk preferences. Finally, cortical thickness in the entorhinal cortex was associated with reduced temporal discounting, with declarative memory ability partially mediating this association. These findings suggest that individual differences in temporal discounting are primarily driven by memory ability, and not executive function, and that a decline in medial temporal lobe structural integrity with aging may impact time preferences. Significance statement Despite the large body of literature supporting the role of both declarative memory and executive function in choices between immediate and delayed rewards (intertemporal choices), no study has examined which of these neurocognitive mechanisms underlies individual differences in the tendency to discount future rewards (temporal discounting). This has been challenging given the limited variability in, and high correlation between, these abilities in young adults. Here we show that older adults with better declarative memory discount delayed rewards less, even when controlling for executive function. Moreover, cortical thickness in entorhinal cortex, a region integral to memory processes, is also associated with temporal discounting. This knowledge will aid in the development of interventions to increase patience, especially as memory declines with aging.

13. Quantitative three‐dimensional echocardiographic analysis of the bicuspid aortic valve and aortic root: A single modality approach

    M. Levack, G. Mecozzi, Jayant S Jainandunsing, and 8 more authors

    Journal of Cardiac Surgery, Dec 2019

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    Patients with bicuspid aortic valves (BAV) are heterogeneous with regard to patterns of root remodeling and valvular dysfunction. Two‐dimensional echocardiography is the standard surveillance modality for patients with aortic valve dysfunction. However, ancillary computed tomography or magnetic resonance imaging is often necessary to characterize associated patterns of aortic root pathology. Conversely, the pairing of three‐dimensional (3D) echocardiography with novel quantitative modeling techniques allows for a single modality description of the entire root complex. We sought to determine 3D aortic valve and root geometry with this quantitative approach.

14. Erratum: Li et al., “The DNA Repair-Associated Protein Gadd45γ Regulates the Temporal Coding of Immediate Early Gene Expression within the Prelimbic Prefrontal Cortex and Is Required for the Consolidation of Associative Fear Memory”

    Xiang Li, P. Marshall, L. Leighton, and 21 more authors

    The Journal of Neuroscience, Mar 2019

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    In the article “The DNA Repair-Associated Protein Gadd45 Regulates the Temporal Coding of Immediate Early Gene Expression within the Prelimbic Prefrontal Cortex and Is Required for the Consolidation of Associative Fear Memory” by Xiang Li, Paul R. Marshall, Laura J. Leighton, Esmi L. Zajaczkowski, Ziqi Wang, Sachithrani U. Madugalle, Jiayu Yin, Timothy W. Bredy, and Wei Wei, which appeared on pages 970 –983 of the February 6, 2019 issue, some of the references on page 971, first full paragraph, appeared incorrectly. Beginning with the third sentence, the references “Baker-Andresen et al., 2013”, “Li et al., 2014”, and “Miller et al., 2010; Baker-Andresen et al., 2013; Li et al., 2014” should appear as “Savell et al., 2016”, “Rudenko et al., 2013”, and “Massart et al., 2015; Wright et al., 2015”, respectively. In addition, the following references should be added to the reference list:

15. AMYLOID-POSITIVE COGNITIVE IMPAIRMENT IS LESS “ALZHEIMER’S-LIKE” IN THE ABSENCE OF TAU NEUROINFLAMMATION IN AT-CELLTGF- b RECEPTOR DISRUPTED P301S MOUSE

    Lauren McCollum, Sandhitsu R. Das, L. Xie, and 5 more authors

    Mar 2019

    
16. Cognitive Profiles in Amyloid-Positive Mild Cognitive Impairment and Alzheimer’s Disease with and without Tau (P2.1-030)

    Lauren McCollum, L. Wisse, Sandhitsu R. Das, and 3 more authors

    Neurology, Apr 2019

    Abs DOI

    

    Objective: To determine differences in cognitive profiles of amyloid-positive individuals (A+) with mild cognitive impairment (MCI) and Alzheimer’s Disease (AD) with and without concomitant pathologic tau (T+/T−). Background: A major source of heterogeneity in AD is mixed pathology (e.g. vascular with AD pathology), posing challenges for research and clinical care. The recently developed ATN framework for AD pathology classifies individuals based on amyloid (A), tau (T), and neurodegeneration (N) status. Tau pathology is directly linked to neurodegeneration and cognitive decline in AD. Thus, cognitive impairment in setting of amyloid without tau suggests an alternate driver of neuronal injury. Design/Methods: Data from ADNI was utilized. Inclusion criteria were amyloid positivity (based on composite SUVR of 1.11 with florbetapir PET) and diagnosis of MCI or AD. A tau cut-off of 1.22 SUVR in bilateral extrahippocampal medial temporal lobe using the novel tau PET tracer AV-1451 was derived from amyloid-negative controls. A+T− and A+T+ groups were compared. Results: 43 amyloid-positive individuals with MCI or AD met inclusion criteria: 13 A+T− and 30 A+T+. The A+T− group was older (75.8 vs 69.9 years, p=0.026), had higher MMSE (27.2 vs. 24.2, p=0.044), and better scores on verbal memory recall (AVTOT6 5.31 vs 2.70, p=0.024). However, the A+T− group performed worse on Trails B, a measure of executive function/sequencing, but this did not reach significance (145.5 vs 131.1, p=0.628). Conclusions: Amongst a cohort of amyloid-positive MCI and AD, tau-negative individuals displayed clinical differences from counterparts with concomitant tau pathology, including somewhat better memory, but, if anything, relatively more affected executive function. The less AD-like pattern of the A+T− group may support the notion that symptomatic patients who are A+T− may have non-AD pathologies driving their clinical symptoms. Further investigation will examine the burden of white matter hyperintensities, a marker of vascular disease, and patterns of cortical thickness in these groups. Disclosure: Dr. McCollum has nothing to disclose. Dr. Wisse has nothing to disclose. Dr. Das has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Rancho Biosciences. Dr. de Flores has nothing to disclose. Dr. Yushkevich has nothing to disclose. Dr. Wolk has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Merck, Jannsen, Eli Lilly and GE.

17. P4-068: AMYLOID-POSITIVE COGNITIVE IMPAIRMENT IS LESS “ALZHEIMER’S-LIKE” IN THE ABSENCE OF TAU

    Lauren McCollum, Sandhitsu R. Das, L. Xie, and 5 more authors

    Alzheimer’s & Dementia, Jul 2019

    DOI PDF

    
18. Distribution of Hippocampal Tau Pathology in Amnestic and Non-Amnestic Forms of Alzheimer’s Disease (S34.009)

    Simon Miller, Jeffrey Phillips, R. Ittyerah, and 7 more authors

    Neurology, Apr 2019

    DOI

    
19. Abstract #117: Changes in high frequency activity depend on frequency of electrical stimulation in the human cortex

    Uma R. Mohan, M. Sperling, A. Sharan, and 9 more authors

    Brain Stimulation, Mar 2019

    DOI

    
20. The effects of direct brain stimulation in humans depend on frequency, amplitude, and white-matter proximity

    Uma R. Mohan, A. J. Watrous, Jonathan F. Miller, and 15 more authors

    bioRxiv, Aug 2019

    Cited by 96

    Abs DOI PDF

    

    Researchers have used direct electrical brain stimulation to treat a range of neurological and psychiatric disorders. However, for brain stimulation to be maximally effective, clinicians and researchers should optimize stimulation parameters according to desired outcomes. To examine how different kinds of stimulation affect human brain activity, we compared the changes in neuronal activity that resulted from stimulation at a range of frequencies, amplitudes, and locations with direct human brain recordings. We recorded human brain activity directly with electrodes that were implanted in widespread regions across 106 neurosurgical epilepsy patients while systematically stimulating across a range of parameters and locations. Overall, stimulation most often had an inhibitory effect on neuronal activity, consistent with earlier work. When stimulation excited neuronal activity, it most often occurred from high-frequency stimulation. These effects were modulated by the location of the stimulating electrode, with stimulation sites near white matter more likely to cause excitation and sites near gray matter more likely to inhibit neuronal activity. By characterizing how different stimulation parameters produced specific neuronal activity patterns on a large scale, our results help guide clinicians and researchers when designing stimulation protocols to cause precisely targeted changes in human brain activity.

21. Progress update from the hippocampal subfields group

    R. Olsen, Valerie A. Carr, A. Daugherty, and 43 more authors

    Alzheimer’s & Dementia : Diagnosis, Assessment & Disease Monitoring, Jun 2019

    Cited by 64

    Abs DOI PDF

    

    Heterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on in vivo magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence.

22. Longitudinal Changes in Hippocampal Subfield Volume Associated with Collegiate Football

    S. Parivash, Maged Goubran, Brian D. Mills, and 22 more authors

    Journal of Neurotrauma, Sep 2019

    Cited by 23

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    Collegiate football athletes are subject to repeated traumatic brain injuriesthat may cause brain injury. The hippocampus is composed of several distinct subfields with possible differential susceptibility to injury. The aim of this study is to determine whether there are longitudinal changes in hippocampal subfield volume in collegiate football. A prospective cohort study was conducted over a 5-year period tracking 63 football and 34 volleyball male collegiate athletes. Athletes underwent high-resolution structural magnetic resonance imaging, and automated segmentation provided hippocampal subfield volumes. At baseline, football (n = 59) athletes demonstrated a smaller subiculum volume than volleyball (n = 32) athletes (−67.77 mm3; p = 0.012). A regression analysis performed within football athletes similarly demonstrated a smaller subiculum volume among those at increased concussion risk based on athlete position (p = 0.001). For the longitudinal analysis, a linear mixed-effects model assessed the interaction between sport and time, revealing a significant decrease in cornu ammonis area 1 (CA1) volume in football (n = 36) athletes without an in-study concussion compared to volleyball (n = 23) athletes (volume difference per year = −35.22 mm3; p = 0.005). This decrease in CA1 volume over time was significant when football athletes were examined in isolation from volleyball athletes (p = 0.011). Thus, this prospective, longitudinal study showed a decrease in CA1 volume over time in football athletes, in addition to baseline differences that were identified in the downstream subiculum. Hippocampal changes may be important to study in high-contact sports.

23. The Cancer Imaging Phenomics Toolkit (CaPTk): Technical Overview.

    Sarthak Pati, Ashish Singh, Saima Rathore, and 22 more authors

    Brainlesion : glioma, multiple sclerosis, stroke and traumatic brain injuries. BrainLes, Oct 2019

    Cited by 97

    DOI PDF

    
24. The Cancer Imaging Phenomics Toolkit (CaPTk): Technical Overview

    Sarthak Pati, Ashish Singh, Saima Rathore, and 22 more authors

    In BrainLes@MICCAI, Oct 2019

    
25. Medial temporal lobe subfield volumes are spared in non-amnestic Alzheimer’s disease (P5.7-001)

    Jeffrey Phillips, L. Wisse, Paul Yushkevich, and 3 more authors

    Neurology, Apr 2019

    DOI

    
26. Facilitating Manual Segmentation of 3D Datasets Using Contour And Intensity Guided Interpolation

    S. Ravikumar, L. Wisse, Yang Gao, and 2 more authors

    In IEEE International Symposium on Biomedical Imaging, Apr 2019

    Cited by 5

    Abs DOI

    

    Manual segmentation of anatomical structures in 3D imaging datasets is a highly time-consuming process. This process can be sped up using interslice interpolation techniques, which require only a small subset of slices to be manually segmented. In this paper, we propose a two-step interpolation approach that utilizes a “binary weighted averaging” algorithm to interpolate contour information, and the random forest framework to perform intensity-based label classification. We present the results of experiments performed in the context of hippocampal segmentations in ex vivo MRI scans. Compared to the random walker algorithm and morphology-based interpolation, the proposed method produces more accurate segmentations and smoother 3D reconstructions.

27. Fully automated placental volume quantification from 3DUS for prediction of small‐for‐gestational age infants: 1049

    N. Schwartz, I. Oguz, Jiancong Wang, and 6 more authors

    American Journal of Obstetrics and Gynecology, Jan 2019

    Cited by 3

    DOI

    
28. Characterizing the role of the structural connectome in seizure dynamics.

    Preya Shah, Arian Ashourvan, Fadi Mikhail, and 9 more authors

    Brain : a journal of neurology, Jul 2019

    Cited by 71

    Abs DOI PDF

    

    How does the human brain’s structural scaffold give rise to its intricate functional dynamics? This is a central question in translational neuroscience that is particularly relevant to epilepsy, a disorder affecting over 50 million subjects worldwide. Treatment for medication-resistant focal epilepsy is often structural-through surgery or laser ablation-but structural targets, particularly in patients without clear lesions, are largely based on functional mapping via intracranial EEG. Unfortunately, the relationship between structural and functional connectivity in the seizing brain is poorly understood. In this study, we quantify structure-function coupling, specifically between white matter connections and intracranial EEG, across pre-ictal and ictal periods in 45 seizures from nine patients with unilateral drug-resistant focal epilepsy. We use high angular resolution diffusion imaging (HARDI) tractography to construct structural connectivity networks and correlate these networks with time-varying broadband and frequency-specific functional networks derived from coregistered intracranial EEG. Across all frequency bands, we find significant increases in structure-function coupling from pre-ictal to ictal periods. We demonstrate that short-range structural connections are primarily responsible for this increase in coupling. Finally, we find that spatiotemporal patterns of structure-function coupling are highly stereotyped for each patient. These results suggest that seizures harness the underlying structural connectome as they propagate. Mapping the relationship between structural and functional connectivity in epilepsy may inform new therapies to halt seizure spread, and pave the way for targeted patient-specific interventions.

29. Structural and functional asymmetry of medial temporal subregions in unilateral temporal lobe epilepsy: A 7T MRI study

    Preya Shah, D. Bassett, L. Wisse, and 7 more authors

    Human Brain Mapping, Jun 2019

    Cited by 49

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    Mesial temporal lobe epilepsy (TLE) is a common neurological disorder affecting the hippocampus and surrounding medial temporal lobe (MTL). Although prior studies have analyzed whole‐brain network distortions in TLE patients, the functional network architecture of the MTL at the subregion level has not been examined. In this study, we utilized high‐resolution 7T T2‐weighted magnetic resonance imaging (MRI) and resting‐state BOLD‐fMRI to characterize volumetric asymmetry and functional network asymmetry of MTL subregions in unilateral medically refractory TLE patients and healthy controls. We subdivided the TLE group into mesial temporal sclerosis patients (TLE‐MTS) and MRI‐negative nonlesional patients (TLE‐NL). Using an automated multi‐atlas segmentation pipeline, we delineated 10 MTL subregions per hemisphere for each subject. We found significantly different patterns of volumetric asymmetry between the two groups, with TLE‐MTS exhibiting volumetric asymmetry corresponding to decreased volumes ipsilaterally in all hippocampal subfields, and TLE‐NL exhibiting no significant volumetric asymmetries other than a mild decrease in whole‐hippocampal volume ipsilaterally. We also found significantly different patterns of functional network asymmetry in the CA1 subfield and whole hippocampus, with TLE‐NL patients exhibiting asymmetry corresponding to increased connectivity ipsilaterally and TLE‐MTS patients exhibiting asymmetry corresponding to decreased connectivity ipsilaterally. Our findings provide initial evidence that functional neuroimaging‐based network properties within the MTL can distinguish between TLE subtypes. High‐resolution MRI has potential to improve localization of underlying brain network disruptions in TLE patients who are candidates for surgical resection.

30. Dynamic Theta Networks in the Human Medial Temporal Lobe Support Episodic Memory.

    E. Solomon, J. Stein, Sandhitsu R. Das, and 8 more authors

    Current biology : CB, Apr 2019

    Cited by 94

    Abs DOI PDF

    

    The medial temporal lobe (MTL) is a locus of episodic memory in the human brain. It is comprised of cytologically distinct subregions that, in concert, give rise to successful encoding and retrieval of context-dependent memories. However, the functional connections between these subregions are poorly understood. To determine functional connectivity among MTL subregions, we had 131 subjects fitted with indwelling electrodes perform a verbal memory task and asked how encoding or retrieval correlated with inter-regional synchronization. Using phase-based measures of connectivity, we found that synchronous theta (4-8 Hz) activity underlies successful episodic memory. During encoding, we observed a dynamic pattern of connections converging on the left entorhinal cortex, beginning with the perirhinal cortex and shifting through hippocampal subfields. Retrieval-associated networks demonstrated enhanced involvement of the subiculum and CA1, reflecting a substantial reorganization of the encoding network. We posit that coherent theta activity within the MTL marks periods of successful memory, but distinct patterns of connectivity dissociate key stages of memory processing.

31. Spike and-Slab Group LASSOs for Grouped Regression and Sparse Generalized Additive Models

    A. Valcarcel, J. Muschelli, D. Pham, and 5 more authors

    Apr 2019

    Cited by 28

    
32. TAPAS: A Thresholding Approach for Probability Map Automatic Segmentation in Multiple Sclerosis

    A. Valcarcel, J. Muschelli, D. Pham, and 5 more authors

    NeuroImage : Clinical, Apr 2019

    Cited by 7

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    Total brain white matter lesion (WML) volume is the most widely established magnetic resonance imaging (MRI) outcome measure in studies of multiple sclerosis (MS). To estimate WML volume, there are a number of automatic segmentation methods, yet, manual delineation remains the gold standard approach. These approaches often yield a probability map to which a threshold is applied to create lesion segmentation masks. Unfortunately, few approaches systematically determine the threshold employed; many methods use a manually selected threshold, thus introducing human error and bias into the automated procedure. In this study, we propose and validate an automatic thresholding algorithm, Thresholding Approach for Probability Map Automatic Segmentation in Multiple Sclerosis (TAPAS), to obtain subject-specific threshold estimates for probability map automatic segmentation of T2-weighted (T2) hyperintense WMLs. Using multimodal MRI, the proposed method applies an automatic segmentation algorithm to obtain probability maps. We obtain the true subject-specific threshold that maximizes Sørensen-Dice Similarity Coefficient (DSC). Then the subject-specific thresholds are modeled on a naive estimate of volume using a general additive model. Applying this model, we predict a subject-specific threshold in data not used for training. We ran a Monte Carlo-resampled split-sample cross-validation (100 validation sets) using two data sets: the first obtained from the Johns Hopkins Hospital (JHH) on a Philips 3 Tesla (3T) scanner (n = 94) and a second collected at the Brigham and Women’s Hospital (BWH) using a Siemens 3T scanner (n = 40). By means of the proposed automated technique, in the JHH data, we found an average reduction in subject-level absolute error of 0.1 mL per one mL increase in manual volume. Using Bland-Altman analysis, we found that volumetric bias associated with group-level thresholding is mitigated when applying TAPAS. The BWH data showed similar absolute error estimates using group-level thresholding or TAPAS likely since Bland-Altman analyses indicate no systematic biases associated with group or TAPAS volume estimates. The current study presents the first validated fully automated method for subject-specific threshold prediction to segment brain lesions.

33. Accurate and Robust Alignment of Variable-stained Histologic Images Using a General-purpose Greedy Diffeomorphic Registration Tool

    Ludovic Venet, Sarthak Pati, Paul Yushkevich, and 1 more author

    ArXiv, Apr 2019

    Cited by 11

    Abs arXiv

    

    Variously stained histology slices are routinely used by pathologists to assess extracted tissue samples from various anatomical sites and determine the presence or extent of a disease. Evaluation of sequential slides is expected to enable a better understanding of the spatial arrangement and growth patterns of cells and vessels. In this paper we present a practical two-step approach based on diffeomorphic registration to align digitized sequential histopathology stained slides to each other, starting with an initial affine step followed by the estimation of a detailed deformation field.

34. Older Adult Normative Data for the Sniffin’ Sticks Odor Identification Test

    K. Vickers, Kathleen A. Breslin, D. Roalf, and 5 more authors

    Archives of Clinical Neuropsychology, Mar 2019

    Cited by 5

    DOI PDF

    
35. PC234. Automated Image Analysis to Determine Local Wall Strain of Abdominal Aortic Aneurysms

    A. Vrudhula, A. H. Aly, Paul Yushkevich, and 5 more authors

    Journal of Vascular Surgery, Jun 2019

    DOI PDF

    
36. Barnes-Hut Approximation for Point SetGeodesic Shooting

    Jiancong Wang, L. Xie, Paul Yushkevich, and 1 more author

    ArXiv, Jul 2019

    Abs arXiv

    

    Geodesic shooting has been successfully applied to diffeo-morphic registration of point sets. Exact computation of the geodesicshooting between point sets, however, requiresO(N2) calculations each time step on the number of points in the point set. We proposean approximation approach based on the Barnes-Hut algorithm to speedup point set geodesic shooting. This approximation can reduce the al-gorithm complexity toO(N b+N logN). The evaluation of the proposedmethod in both simulated images and the medial temporal lobe thick-ness analysis demonstrates a comparable accuracy to the exact point set geodesic shooting while offering up to 3-fold speed up. This improvementopens up a range of clinical research studies and practical problems towhich the method can be effectively applied.

37. IC‐04‐05: CROSS‐SECTIONAL AND LONGITUDINAL MEDIAL TEMPORAL LOBE SUBREGIONAL ATROPHY IN SUSPECTED NON‐ALZHEIMER’S PATHOPHYSIOLOGY

    L. Wisse, L. Xie, Sandhitsu R. Das, and 3 more authors

    Alzheimer’s & Dementia, Jul 2019

    Abs DOI PDF

    

    not available.

38. O2-08-05: PATHOLOGICAL DRIVERS OF NEURODEGENERATION IN SUSPECTED NON-ALZHEIMER’S PATHOPHYSIOLOGY

    L. Wisse,  Flores Robin, Sandhitsu R. Das, and 7 more authors

    Alzheimer’s & Dementia, Jul 2019

    DOI PDF

    
39. P2‐354: MEDIAL TEMPORAL LOBE CORRELATES OF ANOSAGNOSIA IN PRODROMAL AD

    L. Wisse, T. Glenn, Sandhitsu R. Das, and 4 more authors

    Alzheimer’s & Dementia, Jul 2019

    Abs DOI PDF

    

    subregional Background: Animal studies have provided strong evidence for the propagation of neurofibrillary tau tangles through connected neurons. Here, we test the theory of tau spreading through communi-cating neurons in humans by placing a seed in the entorhinal cortex and allowing it to diffuse naturally through the human connectome, and comparing the predicted pattern of tau to observed regional tau load in living humans. Methods: AV1451-PET scans from 175 cognitively intact individuals (69 amyloid-positive), 57 amyloid-positive individuals with

40. P4‐591: THE DEVELOPMENT OF A HARMONIZED SEGMENTATION PROTOCOL FOR HIPPOCAMPAL SUBFIELDS: AN UPDATE

    L. Wisse, D. Berron, R. Olsen, and 24 more authors

    Alzheimer’s & Dementia, Jul 2019

    Abs DOI

    

    [Sudre 2015], and further normalized to global or regional brain volumes, respectively. Global and regional WMH loads were log-transformed due to right-skewed distributions, and then z-transformed. WMH loads were compared between groups using analysis of covariance (ANCOVA), correcting for age and scanners. Linear regression was performed to examine associations between global or regional WMH loads, age and vascular risk factors, assessed with the simple Framingham Risk Score (FRS-CVD). Results: Global (p1⁄40.012), parietal DWMH (p1⁄40.015), parietal PWMH (p1⁄40.019), occipital DWMH (p1⁄40.004) and occipital PWMH (p1⁄40.001) loads were increased in SCD-Ab+ compared to asymptomatic cognitively normal Abcontrols (NC-Ab-). Only occipital DWMH load was significantly higher in MCI-Ab+ compared to MCI-Ab(p1⁄40.004). Only frontal PWMH and DWMH loads were positively associated with FRSCVD without the age component (FRS-CVDwoa), after controlling for age. Conclusions: Global, occipital and parietal WMH loads are increased in SCD-Ab+, suggesting that WMH may be an early biomarker in AD. Occipital DWMH seem to be more specific to AD, with significantly higher load also in MCI-Ab+ compared to MCI-Ab-, while only frontal WMH were associated with vascular risk factors, after correcting for age. esday, July 17, 2019 S1549

41. Tau and neurodegeneration mismatch is a signature of polypathology in AD continuum (P1.1-011)

    David Wolk, John Q. Trojanowski, David J. Irwin, and 6 more authors

    Neurology, Apr 2019

    DOI

    
42. Automated segmentation of medial temporal lobe subregions on in vivo T1‐weighted MRI in early stages of Alzheimer’s disease

    L. Xie, L. Wisse, J. Pluta, and 8 more authors

    Human Brain Mapping, Apr 2019

    Cited by 105

    Abs DOI PDF

    

    Medial temporal lobe (MTL) substructures are the earliest regions affected by neurofibrillary tangle pathology—and thus are promising biomarkers for Alzheimer’s disease (AD). However, automatic segmentation of the MTL using only T1‐weighted (T1w) magnetic resonance imaging (MRI) is challenging due to the large anatomical variability of the MTL cortex and the confound of the dura mater, which is commonly segmented as gray matter by state‐of‐the‐art algorithms because they have similar intensity in T1w MRI. To address these challenges, we developed a novel atlas set, consisting of 15 cognitively normal older adults and 14 patients with mild cognitive impairment with a label explicitly assigned to the dura, that can be used by the multiatlas automated pipeline (Automatic Segmentation of Hippocampal Subfields [ASHS‐T1]) for the segmentation of MTL subregions, including anterior/posterior hippocampus, entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36, and parahippocampal cortex on T1w MRI. Cross‐validation experiments indicated good segmentation accuracy of ASHS‐T1 and that the dura can be reliably separated from the cortex (6.5% mislabeled as gray matter). Conversely, FreeSurfer segmented majority of the dura mater (62.4%) as gray matter and the degree of dura mislabeling decreased with increasing disease severity. To evaluate its clinical utility, we applied the pipeline to T1w images of 663 ADNI subjects and significant volume/thickness loss is observed in BA35, ERC, and posterior hippocampus in early prodromal AD and all subregions at later stages. As such, the publicly available new atlas and ASHS‐T1 could have important utility in the early diagnosis and monitoring of AD and enhancing brain‐behavior studies of these regions.

43. IC‐02‐04: NOVEL MEASURES OF LONGITUDINAL CHANGE IN MEDIAL TEMPORAL LOBE SUBREGIONS DISCRIMINATE PRECLINICAL ALZHEIMER’S DISEASE PATIENTS FROM AMYLOID‐β NEGATIVE CONTROLS

    L. Xie, L. Wisse, Sandhitsu R. Das, and 4 more authors

    Alzheimer’s & Dementia, Jul 2019

    Abs DOI PDF

    

    not available. SATURDAY, JULY 13, 2019 ALZHEIMER’S IMAGING CONSORTIUM PODIUM PRESENTATIONS IC-04 IMAGING NON-ALZHEIMER’S PATHOLOGIES IC-04-01 THE SEARCH FOR PATHOLOGICALLY VALID IMAGING BIOMARKERS: AD PATHOLOGY COMES NOTALONE Stefan J. Teipel, Michel J. Grothe, Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany; German Center for Neurodegenerative Diseases (DZNE) – Rostock/Greifswald, Rostock, Germany. Contact e-mail: stefan.teipel@med.uni-rostock.de

44. IC‐P‐134: NOVEL MEASURES OF LONGITUDINAL CHANGE IN MEDIAL TEMPORAL LOBE SUBREGIONS DISCRIMINATE PRECLINICAL ALZHEIMER’S DISEASE PATIENTS FROM AMYLOID‐β NEGATIVE CONTROLS

    L. Xie, L. Wisse, Sandhitsu R. Das, and 4 more authors

    Alzheimer’s & Dementia, Jul 2019

    Abs DOI PDF

    

    IC-P-134 NOVEL MEASURES OF LONGITUDINAL CHANGE IN MEDIALTEMPORAL LOBE SUBREGIONS DISCRIMINATE PRECLINICAL ALZHEIMER’S DISEASE PATIENTS FROM AMYLOID-b NEGATIVE CONTROLS Long Xie, Laura Wisse, Sandhitsu R. Das, Ranjit Ittyerah, de Flores Robin, Paul A. Yushkevich, David A. Wolk, and Alzheimer’s Disease Neuroimaging Initiative, Penn Image Computing and Science Laboratory (PICSL), University of Pennsylvania, Philadelphia, PA, USA; University of Pennsylvania, Philadelphia, PA, USA. Contact e-mail: darren.xie0625@ gmail.com

45. Improving Multi-atlas Segmentation by Convolutional Neural Network Based Patch Error Estimation

    L. Xie, Jiancong Wang, M. Dong, and 2 more authors

    In International Conference on Medical Image Computing and Computer-Assisted Intervention, Oct 2019

    Cited by 10

    DOI

    
46. P1‐374: NOVEL MEASURES OF LONGITUDINAL CHANGE IN MEDIAL TEMPORAL LOBE SUBREGIONS DISCRIMINATE PRECLINICAL ALZHEIMER’S DISEASE PATIENTS FROM AMYLOID‐β NEGATIVE CONTROLS

    L. Xie, L. Wisse, Sandhitsu R. Das, and 4 more authors

    Alzheimer’s & Dementia, Jul 2019

    Cited by 1

    Abs DOI PDF

    

    cortices (P<0.001). The significant cortical thinning on the right hemisphere of SD group was found in inferior-parietal cortex and the banks of superior temporal sulcus (P<0.01). Conclusions: We demonstrated a diffused cortical thinning pattern in SD group compared to age-matchedAAMI group. The significant cortical thinning in SD group were profound on the left hemisphere especially in the temporal lobe and less profound on the left hemisphere.

47. Diffeomorphic Medial Modeling

    Paul Yushkevich, A. H. Aly, Jiancong Wang, and 4 more authors

    Information processing in medical imaging : proceedings of the ... conference, Feb 2019

    Cited by 6

    Abs DOI arXiv PDF

    

    Deformable shape modeling approaches that describe objects in terms of their medial axis geometry (e.g., m-reps [10]) yield rich geometrical features that can be useful for analyzing the shape of sheet-like biological structures, such as the myocardium. We present a novel shape analysis approach that combines the benefits of medial shape modeling and diffeomorphometry. Our algorithm is formulated as a problem of matching shapes using diffeomorphic flows under constraints that approximately preserve medial axis geometry during deformation. As the result, correspondence between the medial axes of similar shapes is maintained. The approach is evaluated in the context of modeling the shape of the left ventricular wall from 3D echocardiography images.

48. NUMERICAL SIMULATION OF REACTION-DIFFUSION PROCESSES IN THE PROBLEM OF STUDYING THE COLLECTIVE BEHAVIOR OF MICROORGANISMS

    Paul Yushkevich, D. A. Korshik, and A. G. Maslovskaya

    Messenger AmSU, Feb 2019

    DOI PDF

    
49. P1‐372: THE DIFFERENCE OF CORTICAL THICKNESS BETWEEN SEMANTIC DEMENTIA PATIENTS AND AGE ASSOCIATED MILD COGNITIVE IMPAIRMENT SUBJECTS

    Paul Yushkevich

    Alzheimer’s & Dementia, Jul 2019

    Abs DOI PDF

    

    degree of accuracy combining structural images with SVM model which may be of potential use in the clinical diagnosis. Our study may also provide information to reveal underlying mechanisms of cognitive impairment in WMLs. References: 1. Yu, D., et al., Soluble Epoxide Hydrolase-Derived Linoleic Acid Oxylipins in Serum Are Associated with Periventricular White Matter Hyperintensities and VascularCognitive Impairment. TranslStrokeRes, 2018. 2.Brickman, A.M., et al., Reconsidering harbingers of dementia: progression of parietal lobe white matter hyperintensities predicts Alzheimer’s disease incidence. Neurobiol Aging, 2015. 36(1): p. 27-32.

50. [ 11 C]MK-6884 PET TRACER FOR M4 MUSCARINIC CHOLINERGIC RECEPTORS IN ALZHEIMER’S DISEASE: COMPARISON WITH [ 18 F]FDG PET RELATIVE SPARING OF MEDIAL TEMPORAL SUBREGION VOLUMES IN NON-AMNESTIC ALZHEIMER’S DISEASE

    Paolo Zanotti-Fregonara, Meixiang Yu, Quentin Funk, and 10 more authors

    Jul 2019

    
51. IC‐P‐143: RELATIVE SPARING OF MEDIAL TEMPORAL SUBREGION VOLUMES IN NON‐AMNESTIC ALZHEIMER’S DISEASE

    P. Zanotti-Fregonara, Meixiang Yu, Quentin Funk, and 10 more authors

    Alzheimer’s & Dementia, Jul 2019

    Cited by 2

    Abs DOI PDF

    

    IC-P-142 [C]MK-6884 PET TRACER FOR M4 MUSCARINIC CHOLINERGIC RECEPTORS IN ALZHEIMER’S DISEASE: COMPARISON WITH [F]FDG PET Belen Pascual, Paolo Zanotti-Fregonara, Meixiang Yu, Quentin Funk, Arbones Victoria, Yuchuan Wang, Wenping Li, Amy Cheng, Matt Anderson, Eric D. Hostetler, Anthony S. Basile, Joseph C.Masdeu, Houston Methodist Neurological Institute, Houston, TX, USA; Merck & Co., Inc., Kenilworth, NJ, USA. Contact e-mail: bpascual@ houstonmethodist.org

52. Self- and Informant-Reported Subjective Memory Complaints: Association with Depression, Cognitive Impairment, and Decline (S13.006)

    Leah Zuroff, Jessica Bove, David A. Wolk, and 1 more author

    Neurology, Apr 2019

    DOI

    

2018

1. Characterizing the human hippocampus in aging and Alzheimer’s disease using a computational atlas derived from ex vivo MRI and histology

   D. Adler, L. Wisse, R. Ittyerah, and 18 more authors

   In Proceedings of the National Academy of Sciences of the United States of America, Mar 2018

   Cited by 166

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2. Abstract 11933: Extracting Clinical Pearls From Heart Sound Waves: A Deep Learning Approach

   A. H. Aly, Yumeng Guo, Jiancong Wang, and 5 more authors

   Circulation, Nov 2018

   
3. Semi-automated Image Segmentation of the Midsystolic Left Ventricular Mitral Valve Complex in Ischemic Mitral Regurgitation

   A. H. Aly, A. H. Aly, Mahmoud Elrakhawy, and 9 more authors

   In STACOM@MICCAI, Sep 2018

   Cited by 2

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4. Determining a Short Form Montreal Cognitive Assessment (s-MoCA) Czech Version: Validity in Mild Cognitive Impairment Parkinson’s Disease and Cross-Cultural Comparison

   O. Bezdicek, M. Červenková, T. Moore, and 8 more authors

   Assessment, Jun 2018

   Cited by 23

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   The Montreal Cognitive Assessment (MoCA) is one of the most common screening instruments for mild cognitive impairment. However, the standard MoCA is approximately two times longer to administer than the Mini-Mental State Examination. A total of 699 Czech and 175 American participants received the standard MoCA Czech and English versions and in the clinical part, a sample of 102 nondemented patients with Parkinson’s disease (PD). We created a validated Czech short version (s-MoCA-CZ) from the original using item response theory. As expected, s-MoCA-CZ scores were highly correlated with the standard version (Pearson r = .94, p < .001). s-MoCA-CZ also had 80% classification accuracy in the differentiation of PD mild cognitive impairment from PD without impairment. The s-MoCA-CZ, a brief screening tool, is shorter to administer than the standard MoCA. It provides high-classification accuracy for PD mild cognitive impairment and is equivalent to that of the standard MoCA-CZ.

5. IC‐P‐202: AV1451 TAU TRACER UPTAKE CORRELATES WITH HIPPOCAMPAL CA1 SUBFIELD ATROPHY IN AMYLOID‐NEGATIVE INDIVIDUALS

   Sandhitsu R. Das, R. Ittyerah, L. Wisse, and 3 more authors

   Alzheimer’s & Dementia, Jul 2018

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6. Longitudinal and cross-sectional structural MRI correlates of AV-1451 uptake

   Sandhitsu R. Das, L. Xie, L. Wisse, and 6 more authors

   Jul 2018

   
7. Longitudinal and cross-sectional structural magnetic resonance imaging correlates of AV-1451 uptake.

   Sandhitsu R. Das, L. Xie, L. Wisse, and 5 more authors

   Neurobiology of aging, Jun 2018

   Cited by 68

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   We examined the relationship between in vivo estimates of tau deposition as measured by 18F-AV-1451 tau positron emission tomography imaging and cross-sectional cortical thickness, as well as rates of antecedent cortical thinning measured from magnetic resonance imaging in individuals with and without evidence of cerebral amyloid in 63 participants from the Alzheimer’s Disease Neuroimaging Initiative study, including 32 cognitively normal individuals (mean age 74 years), 27 patients with mild cognitive impairment (mean age 76.8 years), and 4 patients diagnosed with Alzheimer’s disease (mean age 80 years). We hypothesized that structural measures would correlate with 18F-AV-1451 in a spatially local manner and that this correlation would be stronger for longitudinal compared to cross-sectional measures of cortical thickness and in those with cerebral amyloid versus those without. Cross-sectional and longitudinal estimates of voxelwise atrophy were made from whole brain maps of cortical thickness and rates of thickness change. In amyloid-β-positive individuals, the correlation of voxelwise atrophy across the whole brain with a summary measure of medial temporal lobe (MTL) 18F-AV-1451 uptake demonstrated strong local correlations in the MTL with longitudinal atrophy that was weaker in cross-sectional analysis. Similar effects were seen in correlations between 31 bilateral cortical regions of interest. In addition, several nonlocal correlations between atrophy and 18F-AV-1451 uptake were observed, including association between MTL atrophy and 18F-AV-1451 uptake in parietal lobe regions of interest such as the precuneus. Amyloid-β-negative individuals only showed weaker correlations in data uncorrected for multiple comparisons. While these data replicate previous reports of associations between 18F-AV-1451 uptake and cross-sectional structural measures, the current results demonstrate a strong relationship with longitudinal measures of atrophy. These data support the notion that in vivo measures of tau pathology are tightly linked to the rate of neurodegenerative change.

8. P3‐390: IDENTIFYING ALTERED BRAIN NETWORKS USING DIFFUSION TENSOR IMAGING IN ELDERLY SUBJECTS WITH SUBJECTIVE COGNITIVE IMPAIRMENT

   Sandhitsu R. Das, R. Ittyerah, L. Wisse, and 3 more authors

   Alzheimer’s & Dementia, Jul 2018

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9. P4‐314: A HARMONIZED PROTOCOL FOR IN VIVO HUMAN HIPPOCAMPAL SUBFIELD SEGMENTATION: INITIAL RESULTS OF THE 3 TESLA PROTOCOL

   A. Daugherty,  LauraWisse, R. Amaral, and 46 more authors

   Alzheimer’s & Dementia, Jul 2018

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10. Cancer imaging phenomics toolkit: quantitative imaging analytics for precision diagnostics and predictive modeling of clinical outcome

    C. Davatzikos, Saima Rathore, S. Bakas, and 22 more authors

    Journal of Medical Imaging, Jul 2018

    Cited by 190

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11. Associative memory for conceptually unitized word pairs in mild cognitive impairment is related to the volume of the perirhinal cortex

    Emma Delhaye, D. Mechanic-Hamilton, Laura Saad, and 5 more authors

    Hippocampus, Dec 2018

    Cited by 19

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    Unitization, that is, the encoding of an association as one integrated entity, has been shown to improve associative memory in populations presenting with associative memory deficit due to hippocampal dysfunction, such as amnesic patients with focal hippocampal lesions and healthy older adults. One reason for this benefit is that encoding of unitized associations would rely on the perirhinal cortex (PrC) and thus minimize the need for hippocampal recruitment. Mild cognitive impairment (MCI) is accompanied by a deficit in associative memory. However, unitization has never been studied to explore the potential benefit in associative memory in MCI, maybe because MCI is characterized by PrC pathology. However, the PrC may potentially still function sufficiently to allow for the successful adoption of unitization. In this study, we aimed at assessing whether unitization could attenuate MCI patients’ associative memory deficit, and whether the ability to remember unitized associations would be modulated by the integrity of the PrC in MCI patients. Unitization was manipulated at a conceptual level, by encouraging participants to encode unrelated word pairs as new compound words. Participants also underwent a structural MRI exam, and measures of PrC were extracted (Brodmann Areas [BA] 35 and 36). Results showed that, contrary to healthy controls, MCI patients did not benefit from unitization. Moreover, their memory performance for unitized associations was related to the measure of PrC integrity (BA35), while it was not the case in controls. This finding thus suggests that unitization does not help to attenuate the associative deficit in MCI patients, and brings support to the literature linking unitization to the PrC function.

12. Closed-loop stimulation of temporal cortex rescues functional networks and improves memory

    Youssef Ezzyat, P. Wanda, Deborah F. Levy, and 19 more authors

    Nature Communications, Feb 2018

    Cited by 288

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    Memory failures are frustrating and often the result of ineffective encoding. One approach to improving memory outcomes is through direct modulation of brain activity with electrical stimulation. Previous efforts, however, have reported inconsistent effects when using open-loop stimulation and often target the hippocampus and medial temporal lobes. Here we use a closed-loop system to monitor and decode neural activity from direct brain recordings in humans. We apply targeted stimulation to lateral temporal cortex and report that this stimulation rescues periods of poor memory encoding. This system also improves later recall, revealing that the lateral temporal cortex is a reliable target for memory enhancement. Taken together, our results suggest that such systems may provide a therapeutic approach for treating memory dysfunction. Memory lapses can occur due to ineffective encoding, but it is unclear if targeted brain stimulation can improve memory performance. Here, authors use a closed-loop system to decode and stimulate periods of ineffective encoding, showing that stimulation of lateral temporal cortex can enhance memory.

13. Electrical Stimulation in Hippocampus and Entorhinal Cortex Impairs Spatial and Temporal Memory

    Abhinav Goyal, Jonathan F. Miller, A. J. Watrous, and 17 more authors

    The Journal of Neuroscience, May 2018

    Cited by 71

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    The medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients of both sexes who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects’ abilities to remember items located far away from boundaries. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred. SIGNIFICANCE STATEMENT Numerous studies have implicated the medial temporal lobe (MTL) in encoding spatial and temporal memories, but they have not been able to causally demonstrate the nature of the cognitive processes by which this occurs in real-time. Electrical brain stimulation is able to demonstrate causal links between a brain region and a given function with high temporal precision. By examining behavior in a memory task as subjects received MTL stimulation, we provide the first causal evidence demonstrating the role of the MTL in organizing the spatial and temporal aspects of episodic memory.

14. Clinical validation of automated hippocampal segmentation in temporal lobe epilepsy

    P. Hadar, Lohith G. Kini, C. Coto, and 7 more authors

    NeuroImage : Clinical, Oct 2018

    Cited by 16

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    Objective To provide a multi-atlas framework for automated hippocampus segmentation in temporal lobe epilepsy (TLE) and clinically validate the results with respect to surgical lateralization and post-surgical outcome. Methods We retrospectively identified 47 TLE patients who underwent surgical resection and 12 healthy controls. T1-weighted 3 T MRI scans were acquired for all subjects, and patients were identified by a neuroradiologist with regards to lateralization and degree of hippocampal sclerosis (HS). Automated segmentation was implemented through the Joint Label Fusion/Corrective Learning (JLF/CL) method. Gold standard lateralization was determined from the surgically resected side in Engel I (seizure-free) patients at the two-year timepoint. ROC curves were used to identify appropriate thresholds for hippocampal asymmetry ratios, which were then used to analyze JLF/CL lateralization. Results The optimal template atlas based on subject images with varying appearances, from normal-appearing to severe HS, was demonstrated to be composed entirely of normal-appearing subjects, with good agreement between automated and manual segmentations. In applying this atlas to 26 surgically resected seizure-free patients at a two-year timepoint, JLF/CL lateralized seizure onset 92% of the time. In comparison, neuroradiology reads lateralized 65% of patients, but correctly lateralized seizure onset in these patients 100% of the time. When compared to lateralized neuroradiology reads, JLF/CL was in agreement and correctly lateralized all 17 patients. When compared to nonlateralized radiology reads, JLF/CL correctly lateralized 78% of the nine patients. Significance While a neuroradiologist’s interpretation of MR imaging is a key, albeit imperfect, diagnostic tool for seizure localization in medically-refractory TLE patients, automated hippocampal segmentation may provide more efficient and accurate epileptic foci localization. These promising findings demonstrate the clinical utility of automated segmentation in the TLE MR imaging pipeline prior to surgical resection, and suggest that further investigation into JLF/CL-assisted MRI reading could improve clinical outcomes. Our JLF/CL software is publicly available at https://www.nitrc.org/projects/ashs/.

15. Predictive control of electrophysiological network architecture using direct, single-node neurostimulation in humans

    A. Khambhati, Ari E. Kahn, J. Costantini, and 20 more authors

    bioRxiv, Mar 2018

    Cited by 8

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    Chronically implantable neurostimulation devices are becoming a clinically viable option for treating patients with neurological disease and psychiatric disorders. Neurostimulation offers the ability to probe and manipulate distributed networks of interacting brain areas in dysfunctional circuits. Here, we use tools from network control theory to examine the dynamic reconfiguration of functionally interacting neuronal ensembles during targeted neurostimulation of cortical and subcortical brain structures. By integrating multi-modal intracranial recordings and diffusion tensor imaging from patients with drug-resistant epilepsy, we test hypothesized structural and functional rules that predict altered patterns of synchronized local field potentials. We demonstrate the ability to predictably reconfigure functional interactions depending on stimulation strength and location. Stimulation of areas with structurally weak connections largely modulates the functional hubness of downstream areas and concurrently propels the brain towards more difficult-to-reach dynamical states. By using focal perturbations to bridge large-scale structure, function, and markers of behavior, our findings suggest that stimulation may be tuned to influence different scales of network interactions driving cognition.

16. Lateralized hippocampal oscillations underlie distinct aspects of human spatial memory and navigation

    Jonathan F. Miller, A. J. Watrous, Melina Tsitsiklis, and 17 more authors

    Nature Communications, Jun 2018

    Cited by 147

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    The hippocampus plays a vital role in various aspects of cognition including both memory and spatial navigation. To understand electrophysiologically how the hippocampus supports these processes, we recorded intracranial electroencephalographic activity from 46 neurosurgical patients as they performed a spatial memory task. We measure signals from multiple brain regions, including both left and right hippocampi, and we use spectral analysis to identify oscillatory patterns related to memory encoding and navigation. We show that in the left but not right hippocampus, the amplitude of oscillations in the 1–3-Hz “low theta” band increases when viewing subsequently remembered object–location pairs. In contrast, in the right but not left hippocampus, low-theta activity increases during periods of navigation. The frequencies of these hippocampal signals are slower than task-related signals in the neocortex. These results suggest that the human brain includes multiple lateralized oscillatory networks that support different aspects of cognition.Theta oscillations are implicated in memory formation. Here, the authors show that low-theta oscillations in the hippocampus are differentially modulated between each hemisphere, with oscillations in the left increasing when successfully learning object–location pairs and in the right during spatial navigation.

17. Quantitative MRI of Perivascular Spaces at 3T for Early Diagnosis of Mild Cognitive Impairment

    M. Niazi, M. Karaman, S. Das, and 3 more authors

    American Journal of Neuroradiology, Aug 2018

    Cited by 32

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    The authors automated the identification of enlarged perivascular spaces in brain MR images using a custom quantitative program designed with Matlab. They quantified the densities of enlarged perivascular spaces for patients with mild cognitive impairment (n=14) and age-matched cognitively healthy controls (n=15) and compared them to determine whether the density of enlarged perivascular spaces can serve as an imaging surrogate for mild cognitive impairment diagnosis. The density of enlarged perivascular spaces was found to be significantly higher in those with mild cognitive impairment compared with age-matched healthy control subjects. BACKGROUND AND PURPOSE: The limitations inherent in the current methods of diagnosing mild cognitive impairment have constrained the use of early therapeutic interventions to delay the progression of mild cognitive impairment to dementia. This study evaluated whether quantifying enlarged perivascular spaces observed on MR imaging can help differentiate those with mild cognitive impairment from cognitively healthy controls and, thus, have an application in the diagnosis of mild cognitive impairment. MATERIALS AND METHODS: We automated the identification of enlarged perivascular spaces in brain MR Images using a custom quantitative program designed with Matlab. We then quantified the densities of enlarged perivascular spaces for patients with mild cognitive impairment (n = 14) and age-matched cognitively healthy controls (n = 15) and compared them to determine whether the density of enlarged perivascular spaces can serve as an imaging surrogate for mild cognitive impairment diagnosis. RESULTS: Quantified as a percentage of volume fraction (v/v%), densities of enlarged perivascular spaces were calculated to be 2.82 ± 0.40 v/v% for controls and 4.17 ± 0.57 v/v% for the mild cognitive impairment group in the subcortical brain (P < .001), and 2.74 ± 0.57 v/v% for the controls and 3.90 ± 0.62 v/v% for the mild cognitive impairment cohort in the basal ganglia (P < .001). Maximum intensity projections exhibited a visually conspicuous difference in the distributions of enlarged perivascular spaces for a patient with mild cognitive impairment and a control patient. By means of receiver operating characteristic curve analysis, we determined the sensitivity and specificity of using enlarged perivascular spaces as a differentiating biomarker between mild cognitive impairment and controls to be 92.86% and 93.33%, respectively. CONCLUSIONS: The density of enlarged perivascular spaces was found to be significantly higher in those with mild cognitive impairment compared with age-matched healthy control subjects. The density of enlarged perivascular spaces, therefore, may be a useful imaging biomarker for the diagnosis of mild cognitive impairment.

18. Combining Deep Learning and Multi-atlas Label Fusion for Automated Placenta Segmentation from 3DUS

    Baris U. Oguz, Jiancong Wang, N. Yushkevich, and 5 more authors

    In DATRA/PIPPI@MICCAI, Sep 2018

    Cited by 20

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19. Tau PET imaging predicts cognition in atypical variants of Alzheimer’s disease

    J. Phillips, Sandhitsu R. Das, C. Mcmillan, and 6 more authors

    Human Brain Mapping, Feb 2018

    Cited by 61

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20. Quantitative assessment of finger tapping characteristics in mild cognitive impairment, Alzheimer’s disease, and Parkinson’s disease

    D. Roalf, Petra E. Rupert, Dawn J. Mechanic-Hamilton, and 6 more authors

    Journal of Neurology, Apr 2018

    Cited by 104

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21. High interictal connectivity within the resection zone is associated with favorable post-surgical outcomes in focal epilepsy patients

    Preya Shah, J. Bernabei, Lohith G. Kini, and 10 more authors

    NeuroImage : Clinical, Nov 2018

    Cited by 56

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    Objective Patients with drug-resistant focal epilepsy are often candidates for invasive surgical therapies. In these patients, it is necessary to accurately localize seizure-generators to ensure seizure freedom following intervention. While intracranial electroencephalography (iEEG) is the gold standard for mapping networks for surgery, this approach requires inducing and recording seizures, which may cause patient morbidity. The goal of this study is to evaluate the utility of mapping interictal (non-seizure) iEEG networks to identify targets for surgical treatment. Methods We analyze interictal iEEG recordings and neuroimaging from 27 focal epilepsy patients treated via surgical resection. We generate interictal functional networks by calculating pairwise correlation of iEEG signals across different frequency bands. We identify electrodes falling within surgically resected tissue (i.e. the resection zone), and compute node-level and edge-level synchrony in relation to the resection zone. We associate these metrics with post-surgical outcomes. Results Greater overlap between resected electrodes and highly synchronous electrodes is associated with favorable post-surgical outcomes. Additionally, good outcome patients have significantly higher connectivity localized within the resection zone compared to those with poorer postoperative seizure control. This finding persists following normalization by a spatially-constrained null model. Conclusions This study suggests that spatially-informed interictal network synchrony measures can distinguish between good and poor post-surgical outcomes. By capturing clinically relevant information during interictal periods, our method may ultimately reduce the need for prolonged invasive implants and provide insights into the pathophysiology of an epileptic brain. We discuss next steps for translating these findings into a prospectively useful clinical tool.

22. Mapping the structural and functional network architecture of the medial temporal lobe using 7T MRI

    Preya Shah, D. Bassett, L. Wisse, and 12 more authors

    Human Brain Mapping, Feb 2018

    Cited by 62

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23. P1‐669: AWARENESS OF MILD COGNITIVE IMPAIRMENT AND MILD ALZHEIMER’S DISEASE DEMENTIA DIAGNOSES IS ASSOCIATED WITH DECREASED SELF‐RATINGS OF QUALITY OF LIFE IN OLDER ADULTS

    S. Stites, Jonathan D. Rubright, K. Harkins, and 2 more authors

    Alzheimer’s & Dementia, Jul 2018

    Cited by 1

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24. Defining SNAP by cross-sectional and longitudinal definitions of neurodegeneration

    L. Wisse, S.R. Das, C. Davatzikos, and 4 more authors

    NeuroImage : Clinical, Feb 2018

    Cited by 16

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    Introduction Suspected non-Alzheimer’s pathophysiology (SNAP) is a biomarker driven designation that represents a heterogeneous group in terms of etiology and prognosis. SNAP has only been identified by cross-sectional neurodegeneration measures, whereas longitudinal measures might better reflect “active” neurodegeneration and might be more tightly linked to prognosis. We compare neurodegeneration defined by cross-sectional ‘hippocampal volume’ only (SNAP/L−) versus both cross-sectional and longitudinal ‘hippocampal atrophy rate’ (SNAP/L+) and investigate how these definitions impact prevalence and the clinical and biomarker profile of SNAP in Mild Cognitive Impairment (MCI). Methods 276 MCI patients from ADNI-GO/2 were designated amyloid “positive” (A+) or “negative” (A−) based on their florbetapir scan and neurodegeneration ‘positive’ or ‘negative’ based on cross-sectional hippocampal volume and longitudinal hippocampal atrophy rate. Results 74.1% of all SNAP participants defined by the cross-sectional definition of neurodegeneration also met the longitudinal definition of neurodegeneration, whereas 25.9% did not. SNAP/L+ displayed larger white matter hyperintensity volume, a higher conversion rate to dementia over 5 years and a steeper decline on cognitive tasks compared to SNAP/L− and the A- CN group. SNAP/L− had more abnormal values on neuroimaging markers and worse performance on cognitive tasks than the A- CN group, but did not show a difference in dementia conversion rate or longitudinal cognition. Discussion Using a longitudinal definition of neurodegeneration in addition to a cross-sectional one identifies SNAP participants with significant cognitive decline and a worse clinical prognosis for which cerebrovascular disease may be an important driver.

25. IC‐P‐132: AGE AND VASCULAR DISEASE EFFECTS ON MEDIAL TEMPORAL LOBE SUBREGIONS IN COGNITIVELY NORMAL OLDER ADULTS

    L. Wisse, Mohamad Habes, Sandhitsu R. Das, and 2 more authors

    Alzheimer’s & Dementia, Jul 2018

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26. P2‐405: AGE AND VASCULAR DISEASE EFFECTS ON MEDIAL TEMPORAL LOBE SUBREGIONS IN COGNITIVELY NORMAL OLDER ADULTS

    L. Wisse, Mohamad Habes, Sandhitsu R. Das, and 2 more authors

    Alzheimer’s & Dementia, Jul 2018

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27. P4‐298: MEDIAL TEMPORAL LOBE SUBREGIONAL ATROPHY PATTERN IN SEMANTIC VARIANT PRIMARY PROGRESSIVE APHASIA AND ASSOCIATIONS WITH COGNITIVE IMPAIRMENTS

    L. Wisse, Molly B. Ungrady, D. Wolk, and 5 more authors

    Alzheimer’s & Dementia, Jul 2018

    Cited by 1

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28. Quantifying effects of Alzheimer ’ s disease on the human hippocampus using an ex vivo atlas combining MRI and histology

    L. Wisse, D. Adler, R. Ittyerah, and 20 more authors

    Jul 2018

    
29. Automated Multi-Atlas Segmentation of Hippocampal and Extrahippocampal Subregions in Alzheimer’s Disease at 3T and 7T: What Atlas Composition Works Best?

    L. Xie, R. Shinohara, R. Ittyerah, and 15 more authors

    Journal of Alzheimer’s Disease, Mar 2018

    Cited by 11

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30. Characterizing Anatomical Variability and Alzheimer’s Disease Related Cortical Thinning in the Medial Temporal Lobe Using Graph-Based Groupwise Registration and Point Set Geodesic Shooting

    L. Xie, L. Wisse, Sandhitsu R. Das, and 4 more authors

    In ShapeMI@MICCAI, Sep 2018

    Cited by 5

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31. Early Tau Burden Correlates with Higher Rate of Atrophy in Transentorhinal Cortex

    L. Xie, Sandhitsu R. Das, L. Wisse, and 3 more authors

    Journal of Alzheimer’s Disease, Feb 2018

    Cited by 34

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32. IC-P-173 PATTERN OF CORTICALTHINNING AND SHAPE VARIABILITY RELATED TO ALZHEIMER’S DISEASE IN REGIONS AFFECTED BY EARLIEST NEUROFIBRILLARY TANGLE PATHOLOGY

    L. Xie, L. Wisse, Sandhitsu R. Das, and 3 more authors

    Feb 2018

    
33. P3‐407: PATTERN OF CORTICAL THINNING AND SHAPE VARIABILITY RELATED TO ALZHEIMER’S DISEASE IN REGIONS AFFECTED BY EARLIEST NEUROFIBRILLARY TANGLE PATHOLOGY

    L. Xie, L. Wisse, Sandhitsu R. Das, and 3 more authors

    Alzheimer’s & Dementia, Jul 2018

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34. P4‐320: DURA MATTERS: FAILURE TO ACCOUNT FOR THE DURA MATER CONFOUNDS MEASURES OF ATROPHY IN CORTICAL REGIONS LINKED TO THE EARLIEST NEUROFIBRILLARY TANGLE PATHOLOGY

    L. Xie, L. Wisse, Sandhitsu R. Das, and 3 more authors

    Alzheimer’s & Dementia, Jul 2018

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35. Task‐enhanced arterial spin labeled perfusion MRI predicts longitudinal neurodegeneration in mild cognitive impairment

    L. Xie, Sandhitsu R. Das, Arun Pilania, and 6 more authors

    Hippocampus, Nov 2018

    Cited by 10

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    Mild cognitive impairment (MCI) is considered a prodromal stage of Alzheimer’s disease (AD), but is also recognized to be a heterogeneous condition. Biomarkers that predict AD progression in MCI are of clinical significance because they can be used to better identify appropriate candidates for therapeutic intervention studies. It has been hypothesized that comparing to structural measurements, functional ones may be more sensitive to early disease abnormalities and the sensitivity could be further enhanced when combined with cognitive task, a “brain stress test.” In this study, we investigated the value of regional cerebral blood flow (CBF), measured by arterial spin labeled perfusion MRI (ASL MRI) during a memory‐encoding task, in predicting the estimated rate of hippocampal atrophy, an established marker of AD progression. Thirty‐one amnestic MCI patients (20 male and 11 female; age: 70.9 ± 6.5 years, range from 56 to 83 years; mini mental status examination: 27.8 ± 1.8) and 42 normal control subjects (13 male and 29 female; age: 70.6 ± 8.8 years, range from 55 to 88 years; mini mental status examination: 29.1 ± 1.2) were included in this study. We compared the predictive value of CBF during task to CBF during rest and structural volumetry. Both region‐of‐interest and voxelwise analyses showed that baseline CBF measurements during task (strongest effect in fusiform gyrus, region‐of‐interest analysis statistics: r = 0.56, p = .003), but not resting ASL MRI or structural volumetry, were correlated with the estimated rate of hippocampal atrophy in amnestic MCI patients. Further, stepwise linear regression demonstrated that resting ASL MRI and volumetry did not provide complementary information in prediction. These results support the notion that physiologic measures during a cognitive challenge may increase the ability to detect subtle functional changes that predict progression. As such, ASL MRI could have important utility in stratifying candidates for AD treatment trials.

36. S2‐01‐03: LINKING POSTMORTEM MRI AND DENSE HISTOLOGY

    Paul Yushkevich

    Alzheimer’s & Dementia, Jul 2018

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37. User-Guided Segmentation of Multi-modality Medical Imaging Datasets with ITK-SNAP

    Paul Yushkevich, Artem Pashchinskiy, I. Oguz, and 10 more authors

    Neuroinformatics, Jun 2018

    Cited by 160

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2017

1. [P3–294]: CROSS‐SECTIONAL AND LONGITUDINAL BRAIN NETWORK ATROPHY IN DIFFERENT STAGES OF ALZHEIMER’s DISEASE AND IN RELATION TO COGNITIVE MEASURES

   J. Arendonk, L. Wisse, Sandhitsu R. Das, and 2 more authors

   Alzheimer’s & Dementia, Jul 2017

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2. A protocol for manual segmentation of medial temporal lobe subregions in 7 Tesla MRI

   D. Berron, P. Vieweg, A. Hochkeppler, and 11 more authors

   NeuroImage : Clinical, May 2017

   Cited by 131

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   Recent advances in MRI and increasing knowledge on the characterization and anatomical variability of medial temporal lobe (MTL) anatomy have paved the way for more specific subdivisions of the MTL in humans. In addition, recent studies suggest that early changes in many neurodegenerative and neuropsychiatric diseases are better detected in smaller subregions of the MTL rather than with whole structure analyses. Here, we developed a new protocol using 7 Tesla (T) MRI incorporating novel anatomical findings for the manual segmentation of entorhinal cortex (ErC), perirhinal cortex (PrC; divided into area 35 and 36), parahippocampal cortex (PhC), and hippocampus; which includes the subfields subiculum (Sub), CA1, CA2, as well as CA3 and dentate gyrus (DG) which are separated by the endfolial pathway covering most of the long axis of the hippocampus. We provide detailed instructions alongside slice-by-slice segmentations to ease learning for the untrained but also more experienced raters. Twenty-two subjects were scanned (19–32 yrs, mean age = 26 years, 12 females) with a turbo spin echo (TSE) T2-weighted MRI sequence with high-resolution oblique coronal slices oriented orthogonal to the long axis of the hippocampus (in-plane resolution 0.44 × 0.44 mm2) and 1.0 mm slice thickness. The scans were manually delineated by two experienced raters, to assess intra- and inter-rater reliability. The Dice Similarity Index (DSI) was above 0.78 for all regions and the Intraclass Correlation Coefficients (ICC) were between 0.76 to 0.99 both for intra- and inter-rater reliability. In conclusion, this study presents a fine-grained and comprehensive segmentation protocol for MTL structures at 7 T MRI that closely follows recent knowledge from anatomical studies. More specific subdivisions (e.g. area 35 and 36 in PrC, and the separation of DG and CA3) may pave the way for more precise delineations thereby enabling the detection of early volumetric changes in dementia and neuropsychiatric diseases.

3. Self‐gated MRI of multiple beat morphologies in the presence of arrhythmias

   F. Contijoch, Srikanth K. Iyer, J. Pilla, and 6 more authors

   Magnetic Resonance in Medicine, Aug 2017

   Cited by 32

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4. [O1–12–06]: RELATIONSHIP BETWEEN LONGITUDINAL STRUCTURAL ATROPHY AND AV1451 TAU UPTAKE IN AMYLOID‐POSITIVE INDIVIDUALS

   Sandhitsu R. Das, L. Xie, L. Wisse, and 4 more authors

   Alzheimer’s & Dementia, Jul 2017

   DOI

   
5. Multiple Sclerosis Lesion Segmentation Using Joint Label Fusion

   M. Dong, I. Oguz, Nagesh Subbana, and 3 more authors

   In Patch-MI@MICCAI, Sep 2017

   Cited by 4

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6. Direct Brain Stimulation Modulates Encoding States and Memory Performance in Humans.

   Youssef Ezzyat, J. Kragel, John F. Burke, and 23 more authors

   Current biology : CB, May 2017

   Cited by 220

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7. Joint Intensity Fusion Image Synthesis Applied to Multiple Sclerosis Lesion Segmentation

   G. Fleishman, A. Valcarcel, D. Pham, and 5 more authors

   In BrainLes@MICCAI, Sep 2017

   Cited by 9

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8. The medial temporal lobe organizes memory across time and space: Causal evidence from brain stimulation

   Abhinav Goyal, Jonathan F. Miller, A. J. Watrous, and 18 more authors

   bioRxiv, Nov 2017

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   The medial temporal lobe (MTL) is widely implicated in supporting episodic memory and navigation, but its precise functional role in organizing memory across time and space remains elusive. Here we examine the specific cognitive processes implemented by MTL structures (hippocampus and entorhinal cortex) to organize memory by using electrical brain stimulation, leveraging its ability to establish causal links between brain regions and features of behavior. We studied neurosurgical patients who performed spatial-navigation and verbal-episodic memory tasks while brain stimulation was applied in various regions during learning. During the verbal memory task, stimulation in the MTL disrupted the temporal organization of encoded memories such that items learned with stimulation tended to be recalled in a more randomized order. During the spatial task, MTL stimulation impaired subjects’ abilities to remember items using view-independent (allocentric) navigation strategies. These stimulation effects were specific to the MTL. Our findings thus provide the first causal demonstration in humans of the specific memory processes that are performed by the MTL to encode when and where events occurred. Significance Statement Numerous studies have implicated the medial temporal lobe (MTL) in encoding spatial and temporal memories, but they have not been able to causally demonstrate the nature of the cognitive processes by which this occurs in real-time. Electrical brain stimulation is able to demonstrate causal links between a brain region and a given function with high temporal precision. By examining behavior in a memory task as subjects received MTL stimulation, we provide the first causal evidence demonstrating the role of the MTL in organizing the spatial and temporal aspects of episodic memory.

9. Interictal epileptiform discharges impair word recall in multiple brain areas

   P. Horak, S. Meisenhelter, Yinchen Song, and 20 more authors

   Epilepsia, Mar 2017

   Cited by 94

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10. Effects of the Insulin Sensitizer Metformin in Alzheimer Disease: Pilot Data From a Randomized Placebo-controlled Crossover Study

    A. Koenig, Dawn J. Mechanic-Hamilton, S. Xie, and 6 more authors

    Alzheimer Disease & Associated Disorders, Apr 2017

    Cited by 286

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11. Similar patterns of neural activity predict memory function during encoding and retrieval

    J. Kragel, Youssef Ezzyat, M. Sperling, and 13 more authors

    Neuroimage, Jul 2017

    Cited by 69

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12. Electrophysiological Signatures of Spatial Boundaries in the Human Subiculum

    Sang Ah Lee, Jonathan F. Miller, A. J. Watrous, and 14 more authors

    The Journal of Neuroscience, Nov 2017

    Cited by 60

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    Environmental boundaries play a crucial role in spatial navigation and memory across a wide range of distantly related species. In rodents, boundary representations have been identified at the single-cell level in the subiculum and entorhinal cortex of the hippocampal formation. Although studies of hippocampal function and spatial behavior suggest that similar representations might exist in humans, boundary-related neural activity has not been identified electrophysiologically in humans until now. To address this gap in the literature, we analyzed intracranial recordings from the hippocampal formation of surgical epilepsy patients (of both sexes) while they performed a virtual spatial navigation task and compared the power in three frequency bands (1–4, 4–10, and 30–90 Hz) for target locations near and far from the environmental boundaries. Our results suggest that encoding locations near boundaries elicited stronger theta oscillations than for target locations near the center of the environment and that this difference cannot be explained by variables such as trial length, speed, movement, or performance. These findings provide direct evidence of boundary-dependent neural activity localized in humans to the subiculum, the homolog of the hippocampal subregion in which most boundary cells are found in rodents, and indicate that this system can represent attended locations that rather than the position of one’s own body. SIGNIFICANCE STATEMENT Spatial computations using environmental boundaries are an integral part of the brain’s spatial mapping system. In rodents, border/boundary cells in the subiculum and entorhinal cortex reveal boundary coding at the single-neuron level. Although there is good reason to believe that such representations also exist in humans, the evidence has thus far been limited to functional neuroimaging studies that broadly implicate the hippocampus in boundary-based navigation. By combining intracranial recordings with high-resolution imaging of hippocampal subregions, we identified a neural marker of boundary representation in the human subiculum.

13. Theta band power increases in the posterior hippocampus predict successful episodic memory encoding in humans

    Jui-Jui Lin, M. Rugg, Sandhitsu R. Das, and 4 more authors

    Hippocampus, Oct 2017

    Cited by 100

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14. Dice Overlap Measures for Objects of Unknown Number: Application to Lesion Segmentation

    I. Oguz, A. Carass, D. Pham, and 6 more authors

    In BrainLes@MICCAI, Sep 2017

    Cited by 11

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15. Gradient Boosted Trees for Corrective Learning

    Baris U. Oguz, R. Shinohara, Paul Yushkevich, and 1 more author

    In MLMI@MICCAI, Sep 2017

    Cited by 9

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16. A tract-specific approach to assessing white matter in preterm infants

    D. Pecheva, Paul Yushkevich, D. Batalle, and 8 more authors

    Neuroimage, Aug 2017

    Cited by 34

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    &NA; Diffusion‐weighted imaging (DWI) is becoming an increasingly important tool for studying brain development. DWI analyses relying on manually‐drawn regions of interest and tractography using manually‐placed waypoints are considered to provide the most accurate characterisation of the underlying brain structure. However, these methods are labour‐intensive and become impractical for studies with large cohorts and numerous white matter (WM) tracts. Tract‐specific analysis (TSA) is an alternative WM analysis method applicable to large‐scale studies that offers potential benefits. TSA produces a skeleton representation of WM tracts and projects the group’s diffusion data onto the skeleton for statistical analysis. In this work we evaluate the performance of TSA in analysing preterm infant data against results obtained from native space tractography and tract‐based spatial statistics. We evaluate TSA’s registration accuracy of WM tracts and assess the agreement between native space data and template space data projected onto WM skeletons, in 12 tracts across 48 preterm neonates. We show that TSA registration provides better WM tract alignment than a previous protocol optimised for neonatal spatial normalisation, and that TSA projects FA values that match well with values derived from native space tractography. We apply TSA for the first time to a preterm neonatal population to study the effects of age at scan on WM tracts around term equivalent age. We demonstrate the effects of age at scan on DTI metrics in commissural, projection and association fibres. We demonstrate the potential of TSA for WM analysis and its suitability for infant studies involving multiple tracts. Graphical abstract Figure. No caption available. HighlightsEvaluation of tract‐specific analysis (TSA) for white matter studies in infants.TSA improves white matter tract alignment over scalar‐based registration.TSA closely approximates native space tractography DTI values.The first application of TSA to a neonatal population.

17. Tau PET Imaging Predicts Cognition in Atypical Variants of Alzheimer’s Disease (P6.077)

    Jeffrey Phillips, Sandhitsu R. Das, C. Mcmillan, and 4 more authors

    Neurology, Apr 2017

    Cited by 1

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18. 213: Novel 3D morphologic analysis of the early placenta using deformable medial modeling

    A. Pouch, I. Oguz, N. Yushkevich, and 3 more authors

    American Journal of Obstetrics and Gynecology, Apr 2017

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19. Image Segmentation and Modeling of the Pediatric Tricuspid Valve in Hypoplastic Left Heart Syndrome

    A. Pouch, A. H. Aly, A. Lasso, and 8 more authors

    Functional imaging and modeling of the heart : ... International Workshop, FIMH ..., proceedings. FIMH, Jun 2017

    Cited by 16

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20. Spatiotemporal Segmentation and Modeling of the Mitral Valve in Real-Time 3D Echocardiographic Images

    A. Pouch, A. H. Aly, E. Lai, and 7 more authors

    In International Conference on Medical Image Computing and Computer-Assisted Intervention, Sep 2017

    Cited by 8

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21. Hippocampal gamma‐slow oscillation coupling in macaques during sedation and sleep

    A. Richardson, Xilin Liu, Pauline K. Weigand, and 8 more authors

    Hippocampus, Nov 2017

    Cited by 9

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22. Mapping of pain circuitry in early post-natal development using manganese-enhanced MRI in rats.

    M. Sperry, Benjamin M. Kandel, S. Wehrli, and 5 more authors

    Neuroscience, Jun 2017

    Cited by 14

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23. A patch-based framework for new ITK functionality: Joint fusion, denoising, and non-local super-resolution

    N. Tustison, B. Avants, Hongzhi Wang, and 4 more authors

    The Insight Journal, Mar 2017

    Cited by 2

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    In an earlier Insight Journal article, we introduced an ITK implementation of the adaptive patch-based image denoising algorithm described in [3]. We follow-up up that offering with a generalized non-local, patch-based ITK class framework and a refactored denoising class. In addition, we provide two ITK implementations of related, well-known algorithms. The first is a non-local super resolution method described in [1, 2]. The second is the multivariate joint label fusion algorithm of [4, 5] with additional extensions, denoted as “joint intensity fusion”, which will be described in a forthcoming manuscript. Accompanying these ITK classes are documented programming interfaces which use our previously introduced unique command line interface routines. Several 2-D examples on brain imaging data are provided to qualitatively demonstrate performance.

24. Neural Correlates of Verbal Episodic Memory and Lexical Retrieval in Logopenic Variant Primary Progressive Aphasia

    Khaing T. Win, J. Pluta, Paul Yushkevich, and 5 more authors

    Frontiers in Neuroscience, Jun 2017

    Cited by 48

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    Objective: Logopenic variant primary progressive aphasia (lvPPA) is commonly associated with Alzheimer’s disease (AD) pathology. But lvPPA patients display different cognitive and anatomical profile from the common clinical AD patients, whose verbal episodic memory is primarily affected. Reports of verbal episodic memory difficulty in lvPPA are inconsistent, and we hypothesized that their lexical retrieval impairment contributes to verbal episodic memory performance and is associated with left middle temporal gyrus atrophy. Methods: We evaluated patients with lvPPA (n = 12) displaying prominent word-finding and repetition difficulties, and a demographically-matched cohort of clinical Alzheimer’s disease (AD, n = 26), and healthy seniors (n = 16). We assessed lexical retrieval with confrontation naming and verbal episodic memory with delayed free recall. Whole-brain regressions related naming and delayed free recall to gray matter atrophy. Medial temporal lobe (MTL) subfields were examined using high in-plane resolution imaging. Results: lvPPA patients had naming and delayed free recall impairments, but intact recognition memory. In lvPPA, delayed free recall was related to naming; both were associated with left middle temporal gyrus atrophy but not MTL atrophy. Despite cerebrospinal fluid evidence consistent with AD pathology, examination of MTL subfields revealed no atrophy in lvPPA. While AD patients displayed impaired delayed free recall, this deficit did not correlate with naming. Regression analyses related delayed free recall deficits in clinical AD patients to MTL subfield atrophy, and naming to left middle temporal gyrus atrophy. Conclusion: Unlike amnestic AD patients, MTL subfields were not affected in lvPPA patients. Verbal episodic memory deficit observed in lvPPA was unlikely to be due to a hippocampal-mediated mechanism but appeared to be due to poor lexical retrieval. Relative sparing of MTL volume and intact recognition memory are consistent with previous reports of hippocampal-sparing variant cases of AD pathology, where neurofibrillary tangles are disproportionately distributed in cortical areas with relative sparing of the hippocampus. This suggests that AD neuropathology in lvPPA may originate in neuronal networks outside of the MTL, which deviates from the typical Braak staging pattern of spreading pathology in clinical AD.

25. A harmonized segmentation protocol for hippocampal and parahippocampal subregions: Why do we need one and what are the key goals?

    L. Wisse, A. Daugherty, R. Olsen, and 41 more authors

    Hippocampus, Jan 2017

    Cited by 148

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26. [IC‐P‐109]: REGIONAL AV1451 UPTAKE AND CORTICAL THICKNESS IN RELATION TO MEMORY, LANGUAGE AND EXECUTIVE FUNCTIONING IN AMYLOID‐POSITIVE SUBJECTS

    L. Wisse, Sandhitsu R. Das, L. Xie, and 3 more authors

    Alzheimer’s & Dementia, Jul 2017

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27. [O1–06–01]: REGIONAL AV1451 UPTAKE AND CORTICAL THICKNESS IN RELATION TO MEMORY, LANGUAGE AND EXECUTIVE FUNCTIONING IN AMYLOID‐POSITIVE SUBJECTS

    L. Wisse, Sandhitsu R. Das, L. Xie, and 3 more authors

    Alzheimer’s & Dementia, Jul 2017

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28. [P4–507]: ALZHEIMER’s DISEASE AND THE HIPPOCAMPUS: NOVEL INSIGHTS FROM AN EX VIVO COMPUTATIONAL ATLAS COMBINING MRI AND HISTOLOGY

    L. Wisse, D. Adler, R. Ittyerah, and 17 more authors

    Alzheimer’s & Dementia, Jul 2017

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29. Medial temporal lobe subregional morphometry using high resolution MRI in Alzheimer’s disease.

    D. Wolk, Sandhitsu R. Das, S. Mueller, and 2 more authors

    Neurobiology of aging, Jul 2017

    Cited by 87

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30. [IC‐P‐153]: TAU BURDEN CORRELATES WITH LONGITUDINAL STRUCTURAL CHANGE IN REGIONS AFFECTED BY EARLIEST NEUROFIBRILLARY TANGLE PATHOLOGY IN AMYLOID‐β POSITIVE ADNI SUBJECTS

    L. Xie, Sandhitsu R. Das, L. Wisse, and 3 more authors

    Alzheimer’s & Dementia, Jul 2017

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31. Multi‐template analysis of human perirhinal cortex in brain MRI: Explicitly accounting for anatomical variability

    L. Xie, J. Pluta, Sandhitsu R. Das, and 9 more authors

    Neuroimage, Jul 2017

    Cited by 40

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32. [P4–249]: TAU BURDEN CORRELATES WITH LONGITUDINAL STRUCTURAL CHANGE IN REGIONS AFFECTED BY EARLIEST NEUROFIBRILLARY TANGLE PATHOLOGY IN AMYLOID‐β‐POSITIVE ADNI SUBJECTS

    L. Xie, Sandhitsu R. Das, L. Wisse, and 3 more authors

    Alzheimer’s & Dementia, Jul 2017

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33. ITK-SNAP: An Intractive Medical Image Segmentation Tool to Meet the Need for Expert-Guided Segmentation of Complex Medical Images

    Paul Yushkevich, and G. Gerig

    IEEE Pulse, Jul 2017

    Cited by 125

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