Postmortem brain MRI reveals differential associations of subcortical and limbic volumes with cortical thinning and neuropathology patterns

Sep 30, 2026

Postmortem brain MRI and neuropathological assessment are used to clarify how distinct neuropathologies shape deep brain structure across neurodegenerative diseases. The study separates subcortical and limbic volumetry in Alzheimer’s disease, Lewy body disease, FTLD-TDP, and FTLD-Tau by relating regional volumes to cortical thinning and pathology signatures. Results show disease-specific structure–structure and structure–pathology relationships, including differential morphometric links and distinct hippocampal and thalamic associations.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages21

Reading Time53 min

AccessFree to download

Abstract

Introduction

Methods

Results

Discussion

Highlights

1. Introduction

bioRxiv preprint doi: [https://doi.org/10.64898/2025.12.30.697140](https://doi.org/10.64898/2025.12.30.697140); this version posted December 31, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Postmortem brain MRI reveals differential associations of subcortical and limbic volumes with cortical thinning and neuropathology patterns Pulkit Khandelwal1,2*, Michael Tran Duong1*, Lisa M. Levorse1 , Winifred Trotman1 , Alejandra Bahena1 , Sydney A. Lim1 , Amanda E. Denning1 , Eunice Chung1 , Christopher A. Olm1 , Hamsanandini Radhakrishnan1 , Ranjit Ittyerah1 , Karthik Prabhakaran1 , Gabor Mizsei1 , Theresa Schuck1 , Sheina Emrani1 , Joaquin A. Vizcarra1 , John Robinson1 , Daniel T. Ohm1 , Jeffrey S. Phillips1 , Jesse Cohen3 , Laura E. M. Wisse4 , John A. Detre1 , Ilya M. Nasrallah1 , Christopher A. Brown1 , Sandhitsu R. Das1 , Edward B. Lee1 , M. Dylan Tisdall1 , David J. Irwin1 , Corey T. McMillan1 , David A. Wolk1 and Paul A. Yushkevich1 1 University of Pennsylvania, Philadelphia, PA, USA 2 Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA 3 University of Florida, Jacksonville, Florida, USA 4 Lund University, Lund, Sweden * Authors contributed equally, [pkhandelwal1@mgh.harvard.edu](pkhandelwal1@mgh.harvard.edu) [and](and mduong@sas.upenn.edu)[ ](and mduong@sas.upenn.edu)[mduong@sas.upenn.edu](and mduong@sas.upenn.edu) Abstract Introduction: The impact of different neuropathologies on deep brain structures remains to be understood. Here, we distinguish subcortical and limbic volumetry in neurodegenerative diseases involving p-tau, α -synuclein and TDP-43 . Methods: We acquired neuropathological measures and brain segmentations from postmortem analysis of 132 donors with Alzheimer’s disease (AD; n=60), Lewy body disease (LBD; n=26), Frontotemporal Lobar Degeneration with TDP-43 (FTLD-TDP; n=21) and FTLD-Tau (n=25) . Results: In FTLD-TDP and FTLD-Tau, thalamus and striatum volumes were lower than in AD or LBD. While AD had diffuse cortico-subcortical and cortico-limbic morphometric associations, LBD had more limited parieto-occipital cortico-limbic associations. FTLD-TDP had cortico-subcortical associations while FTLD-Tau had cortico-limbic associations. In AD and FTLD-Tau, hippocampal volumes correlated with ptau burden, neuron loss and gliosis. In LBD, thalamic α-synuclein severity was associated with subcortical and limbic volumes. In FTLD-TDP, TDP-43 load had no such significant associations. Discussion: Postmortem neuroimaging reveals unique structure-structure and structure-pathology relationships across regions and diseases. Highlights ● FTLD-Tau and FTLD-TDP show lower thalamic and striatal volumes than AD or LBD groups. ● Subcortical and limbic volume loss significantly correlates with global brain shrinkage in AD. ● LBD exhibits less postmortem subcortical and limbic atrophy compared to other groups. Parietooccipital atrophy corresponds to limbic but not subcortical volume loss in LBD. ● FTLD-Tau has cortico-limbic morphometric associations while FTLD-TDP has cortico-subcortical associations. ● In AD and FTLD-Tau, hippocampal volume correlates with p-tau load, neuronal loss and gliosis semiquantitative measures. ● In LBD, thalamic α-synuclein burden is associated with subcortical and limbic volumes. ● In FTLD-TDP, TDP-43 pathology burden shows no significant volume associations. bioRxiv preprint doi: [https://doi.org/10.64898/2025.12.30.697140](https://doi.org/10.64898/2025.12.30.697140); this version posted December 31, 2025. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. I

FAQs

How does the study distinguish subcortical and limbic volumetry across diseases?

It uses postmortem analysis to acquire neuropathological measures and brain segmentations, then analyzes how regional subcortical/limbic volumes relate to cortical thinning and pathology patterns across Alzheimer’s disease, Lewy body disease, FTLD-TDP, and FTLD-Tau.

Which brain regions show lower volumes in FTLD compared with AD or LBD?

In FTLD-TDP and FTLD-Tau, thalamus and striatum volumes are lower than in Alzheimer’s disease or Lewy body disease groups.

What hippocampal and thalamic pathology associations are reported?

In AD and FTLD-Tau, hippocampal volumes correlate with p-tau burden, neuron loss, and gliosis measures. In LBD, thalamic α-synuclein severity is associated with subcortical and limbic volumes, while FTLD-TDP shows no significant volume associations for TDP-43 load.

Sep 30, 2026

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