Selective hippocampal subfield atrophy mediates cognitive decline in Cushing’s Disease.

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, detailed analysis of hippocampal subfield changes and their correlations with peripheral blood gene expression profiles 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. Additionally, RNA sequencing was performed to characterize peripheral blood leukocyte transcriptome profiles in a subgroup of 25 CD patients and 30 matched HCs. Results Compared to controls, CD patients showed decreased hippocampal gray matter volume, particularly in 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 GC-ML-DG-body volumes mediated the relationship between cortisol levels and cognitive performance, and left CA4-body volume demonstrated a positive correlation with peripheral blood LINC02193 expression. Conclusions . CD patients exhibit distinct patterns of hippocampal atrophy affecting specific subfields, with changes correlating to hormone levels and cognitive symptoms, and discrete hippocampal subfield volumes associated with gene expression profiles. These structural and transcriptomic alterations may serve as potential biomarkers for CD and provide insight into the mechanisms underlying cognitive dysfunction in hypercortisolism.