Longitudinal analysis of hippocampal subfield atrophy and network centrality associated with cognitive decline in Alzheimer's disease progression.

backgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by structural degeneration of the hippocampus. Previous studies have demonstrated that specific hippocampal subfields, such as the cornu ammonis (CA)1 and the subiculum, are susceptible to AD-related atrophy. However, most previous studies have focused on cross-sectional volumetric changes without investigating the interrelationships between subfields or their network-level functions throughout the disease progression. PURPOSE: To examine the longitudinal volumetric changes in the hippocampal subfields over 2 years in individuals who progressed from mild cognitive impairment (MCI) to AD. In addition, we aimed to investigate the associations between cognitive decline, inter-region structural correlation, and network-based centrality profiles of subfields based on atrophy covariance and changes in subfield volume.

methodsT1-weighted magnetic resonance images of 258 participants who progressed from MCI to AD were obtained from the Alzheimer's Disease Neuroimaging Initiative. Hippocampal subfield volumes were extracted at baseline and during follow-up using FreeSurfer's longitudinal pipeline (v7.4.1). The subfield volume changes were examined using the paired-t tests. Cognitive decline was measured as the percentage change in the Mini-Mental State Examination (MMSE) scores. The partial Pearson's correlations between subfield volume changes and MMSE change were calculated after adjusting for baseline age, sex, education level, and apolipoprotein ε4 status. A structural covariance network was constructed using inter-subfield partial correlations. Four graph-theoretical centrality measurements (degree, betweenness, closeness, and eigenvector) were computed from the network to identify structurally central subfields.

resultsMost hippocampal subfields demonstrated important volume decreases over 2 years, with the left fimbria, subiculum head, and dentate gyrus head showing the most atrophy. The left hippocampus showed significantly greater volume decreases than the right hippocampus. Volume changes in the left presubiculum body, the CA3 head, and the dentate gyrus head were strongly correlated with MMSE decline. Notably, structured covariance patterns between anatomically and functionally relevant subfields within the CA1-CA3-CA4-dentate gyrus axis and subiculum complex were found by inter-regional analysis. Network-based analysis identified the left CA1 head and left dentate gyrus head as central hubs across all four-centrality metrics. Other subfields, including the left subiculum head and left molecular layer head, also showed high centrality in several respects, indicating their possible coordinating functions in hippocampal degeneration.

conclusionsThis study provides a comprehensive longitudinal analysis of hippocampal subfield atrophy, inter-regional co-atrophy patterns, and network centrality during MCI-to-AD progression. Our findings demonstrate that several subfields, including the left CA1 and dentate gyrus, are structurally and functionally central in the hippocampal atrophy network. The integration of volumetric, correlation-based, and graph theory-based approaches offers new insights into the coordinated degeneration of the hippocampus in AD, emphasizing the importance of subfield-level network dynamics in understanding the disease progression.