RAAS/HPA Axis Abnormalities and Hypothalamic Connectivity in Hypertension: A Multimodal MRI Study

Hypertension is associated with brain remodeling and an increased risk of cognitive impairment. Although endocrine hormones play a central role in blood pressure regulation, how endocrine abnormalities are associated with brain network reorganization and cognitive function in hypertensive populations remains unclear. This study aimed to investigate whether renin-angiotensin-aldosterone system (RAAS) and hypothalamic-pituitary-adrenal (HPA) axis abnormalities are associated with distinct multimodal brain alterations and cognitive profiles in hypertension.

In this cross-sectional study, 47 hypertensive adults underwent endocrine profiling, neuropsychological assessment, and resting-state functional MRI (rs-fMRI) and T1-weighted structural MRI on a 3.0T scanner. Image analyses included amplitude of Low-Frequency Fluctuations (ALFF), Voxel-based Morphometry (VBM), and hypothalamic seed-based Functional Connectivity (FC). Based on plasma levels of angiotensin II (Ang II), adrenocorticotropic hormone (ACTH), and aldosterone (ALD), patients were classified as endocrine-abnormal hypertension (EH; n = 20) or non-endocrine hypertension (NEH; n = 27). Group differences and endocrine-imaging associations were examined.

Compared with the NEH group, the EH group showed poorer performance on memory and language measures. The EH group also showed reduced ALFF in frontal regions and increased ALFF in the cerebellum, together with reduced gray matter volume in posterior cortical regions. Hypothalamic seed-to-voxel FC was reduced in the EH group with frontal, temporal, and occipital cortical regions and increased with cerebellar regions. In whole-sample analyses, hypothalamic-vermal connectivity was negatively associated with global cognition and language performance, cerebellar ALFF was negatively associated with episodic memory performance, and right superior frontal gyrus ALFF was negatively associated with circulating ALD levels.

Endocrine abnormalities in hypertension are associated with a distinct pattern of brain alterations characterized by prefrontal hypofunction, posterior cortical gray matter reductions, and altered hypothalamic-cortical and hypothalamic-cerebellar connectivity, accompanied by poorer performance on memory and language measures. These findings suggest that hypertensive patients with endocrine abnormalities may represent a subgroup with greater brain and cognitive vulnerability.