Selective Hippocampal Subfield Atrophy Mediates Cognitive Decline in Cushing's Disease

Abstract

Background: Cushing's disease (CD) provides insight into how prolonged high cortisol exposure affects brain structure. While CD patients show cognitive and emotional symptoms linked to hippocampal function and detailed analysis of hippocampal subfield changes remains limited. Methods: The study included 91 patients with active CD and 53 matched healthy controls who underwent T1-weighted magnetic resonance imaging and comprehensive neuropsychological assessment. We employed voxel-based morphometry, automated segmentation, and shape analysis to evaluate gray matter volume, subfield volumes, and hippocampal morphology. Clinical correlations of hippocampal subfield volumes were also explored. Results: Compared to controls, CD patients showed decreased hippocampal gray matter volume, particularly in the body and tail regions. Specific subfields, including presubiculum-body, subiculum-body, CA4-body, and granule cell layer, showed significant volume reductions. Shape analysis revealed corresponding surface alterations. Notably, left CA4-body and left GC-ML-DG-body volumes mediated the relationship between cortisol levels and cognitive performance. Conclusions: CD patients exhibit distinct patterns of hippocampal atrophy affecting specific subfields, with changes correlating to hormone levels and cognitive symptoms. These structural alterations may serve as potential biomarkers for CD and provide insight into the mechanisms underlying cognitive dysfunction in hypercortisolism.