Hippocampal sclerosis of aging at post‐mortem is evident on MRI more than a decade prior

Abstract

IntroductionHippocampal sclerosis of aging (HS) is an important component of combined dementia neuropathology. However, the temporal evolution of its histologically‐defined features is unknown. We investigated pre‐mortem longitudinal hippocampal atrophy associated with HS, as well as with other dementia‐associated pathologies.MethodsWe analyzed hippocampal volumes from magnetic resonance imaging (MRI) segmentations in 64 dementia patients with longitudinal MRI follow‐up and post‐mortem neuropathological evaluation, including HS assessment in the hippocampal head and body.ResultsSignificant HS‐associated hippocampal volume changes were observed throughout the evaluated timespan, up to 11.75 years before death. These changes were independent of age and Alzheimer's disease (AD) neuropathology and were driven specifically by CA1 and subiculum atrophy. AD pathology, but not HS, was associated significantly with the rate of hippocampal atrophy.DiscussionHS‐associated volume changes are detectable on MRI earlier than 10 years before death. Based on these findings, volumetric cutoffs could be derived for in vivo differentiation between HS and AD.HIGHLIGHTS Hippocampal atrophy was found in HS+ patients earlier than 10 years before death. These early pre‐mortem changes were driven by reduced CA1 and subiculum volumes. Rates of hippocampus and subfield volume decline were independent of HS. In contrast, steeper atrophy rates were associated with AD pathology burden. Differentiation between AD and HS could be facilitated based on these MRI findings.

Longitudinal Hippocampal Atrophy in Hippocampal Sclerosis of Aging

“…There are limited studies examining longitudinal atrophy in HS-A, and as such this study represents a valuable contribution to the field. While other studies examining HS-A have generally found faster rates of hippocampal atrophy in those with HS-A and LATE-NC with concurrent ADNC, we found that the HS-A group had visually slower rates of atrophy compared to the other pathology groups, though the results did not always reach statistical significance [14,18,19]. A potential explanation for the slower atrophy in HS-A individuals is that those with HS-A (and LATE-NC) had higher rates of hippocampal decline earlier in the disease stage and the rate decreased after the bulk of atrophy had already occurred, while those with ADNC and no LATE-NC or HS-A, who tended to be younger, were at an earlier disease stage and therefore, had increased rates of hippocampal atrophy.…”

“…We found this using both initial and final available hippocampal volumes, and when using the smallest of the right or left hippocampal volumes. Our results are in line with the findings of a recent similar study, which found that individuals with hippocampal atrophy had significantly lower hippocampal volumes up to a decade before death [14]. This other study was performed in a group where all participants had dementia, and there was a very high rate (over 50%) of HS-A; however, in our study we compared participants with HS-A to other pathologically defined groups, not just ADNC but also LATE-NC without HS-A and those without ADNC or LATE-NC, in a sample that spanned normal cognition to dementia.…”

“…One potential explanation for this observation is that the hippocampal atrophy in HS-A starts early in the course of cognitive impairment. The findings of the current study support the notion that profound hippocampal atrophy is an early event in those with HS-A pathology, a finding supported by the recent study from Ortega et al [14]. While concomitant ADNC was common in those with HS-A, not all participants with HS-A had ADNC, and those with ADNC but no HS-A did not have as low hippocampal volumes but did seem to have a slightly greater rate of loss.…”

Sex differences in the relationship between depression and Alzheimer’s disease—mechanisms, genetics, and therapeutic opportunities

“…The hippocampus, a crucial structure for memory and cognition, holds a key role in depression and AD development ( Idunkova et al, 2023 ; Ortega-Cruz et al, 2023 ). Sex differences in hippocampal volume (HV) may contribute to depression and AD pathogenesis, such as women may experience faster hippocampal atrophy, resulting in a greater decrease in hippocampal volume than men ( DuMont et al, 2023 ), and thus, women could be more susceptible to experiencing greater cognitive decline in the context of depression in AD compared with men.…”