Abstract

Numerous research groups worldwide have focused on postmortem imaging to bridge the resolution gap between clinical neuroimaging and neuropathology data. We developed a standardized protocol for brain embedding, imaging, and processing, facilitating alignment between antemortem MRI, postmortem MRI, and pathology to observe brain atrophy and structural damage progression over time. Using 7T postmortem ex vivo MRI, we explore the potential correlation of amygdala and hippocampal atrophy with neuropathological burden in both Down syndrome (DS) and Alzheimer’s disease (AD) cohorts. Using 7T postmortem ex vivo MRI scans from 66 cases (12 DS and 54 AD) alongside a subset of antemortem scans (n=17), we correlated manually segmented hippocampal and amygdala volumes, adjusted for age, sex, and ApoE4 status, with pathological indicators such as Thal phase, Braak stage, limbic-predominant age-related TDP-43 encephalopathy (LATE) stage, hippocampal sclerosis (HS), and Lewy body (LB) stage. A significant correlation was observed between postmortem and antemortem volumes for the hippocampus, but a similar trend observed for the amygdala did not reach statistical significance. DS individuals exhibited notably smaller hippocampal and amygdala volumes compared to AD subjects. In DS, lower hippocampal and amygdala volumes correlated with more severe Braak stage, without significant associations with Thal phase. LATE and HS pathologies were uncommon in DS cases but trended toward smaller hippocampal volumes. In AD, lower hippocampal volume associated with dementia duration, advanced Thal phase, Braak stage, LATE stage, and HS presence, whereas reduced amygdala volume correlated mainly with severe LATE stage and HS, but not with Thal or Braak stages. No significant LB correlation was detected in either DS or AD cohorts. Hippocampal volume in AD appears influenced by both AD and LATE pathologies, while amygdala volume seems primarily influenced by LATE. In DS, smaller hippocampal volume, relative to AD, appears primarily influenced by tau pathology.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study was funded by the National Institutes of Health R01 AG063525, R01 MH111265, P30 AG066468, R01 AG069912, U19 AG068054, P30 AG066519 and the Alzheimer Biomarkers Consortium Down Syndrome and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U01 AG051406 and U01 AG051412), as well as the Bioengineering in Psychiatry Training Program (T32 MH119168).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Committee for Oversight and Research and Clinical Training Involving Decedents of the University of Pittsburgh gave ethical approval for this work.

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Footnotes

↵# Data used in preparation of this article were obtained from the Neurodegeneration in Aging Down syndrome (NiAD) database (niad.loni.usc.edu) and Alzheimer’s Disease in Down syndrome (ADDS) database. As such, the investigators within the ABC-DS study contributed to the design and implementation of ABC-DS and/or provided data but did not participate in analysis or writing of this report. A complete listing of ABC-DS investigators can be found at: https://www.nia.nih.gov/research/abc-ds#data

Data Availability

All data produced in the present work are contained in the manuscript

Abbreviations3Dthree-dimensionalADAlzheimer’s diseaseApoE4apolipoprotein E allele 4DSDown syndromeDSMSEDown syndrome mental status examinationGREGRadient EchoHShippocampal sclerosisLATElimbic-predominant age-relatedTDP-43encephalopathyLBLewy bodyMMSEmini mental state examinationMP2RAGEMagnetization Prepared – RApid Gradient EchoMRImagnetic resonance imagingNFTneurofibrillary tangleSPACESampling Perfection with Application optimized Contrast using different flip angle EvolutionTDP-43TAR DNA-binding protein 43PMIpostmortem interval