MRI-Driven Longitudinal Studies of Hippocampal Alterations During the Initial Cognitive Decline

Objective: Based on available magnetic resonance imaging (MRI) studies, hippocampal alteration is one of the hallmarks during cognitive decline. However, the longitudinal hippocampal morphometric changes during the initial cognitive decline are unclear. Exploring a validated biomarker with high clinical relevance is urgent. Methods and procedures: This work proposed an automated MRI-driven longitudinal hippocampal alteration analysis system (LHAAS), which consists of hippocampal segmentation, reconstruction, registration, multivariate morphometric feature extraction, and longitudinal analysis of hippocampal morphometric and volumetric differences between groups. LHAAS was applied on two groups: cognitive unimpaired (CU) participants who maintained cognitive unimpaired (non-Progressors), and participants who converted to MCI during the following four years (Progressors). Results: LHAAS can detect and visualize subtle deformations in the bilateral hippocampus of CU progressors four years before they show initial cognitive decline. For CU progressors, hippocampal atrophy initially occurs at the CA1 subregion and then along with disease progression, spreading to the CA2-3 and Subiculum subregion, exhibiting a left-greater-than-right trend. The volumetric analyses showed similar results. Besides, hippocampal subregions highly correlated with clinical measurement were identified by correlation analysis. Conclusion: LHAAS can accurately reflect the small hippocampal subregional atrophy at preclinical AD. This proposed system can track the longitudinal hippocampal alterations in the early stages of AD and provide insights for early intervention. Clinical and Translational Impact Statement: LHAAS offers early detection of subtle hippocampal alterations at preclinical AD. This advance enables pathological research and timely interventions to potentially improve patient outcomes in clinical implementation.