Prefrontal Neurovascular Coupling Abnormalities Associated With Cognitive Performance in Multiple Sclerosis

Abstract

ABSTRACT Background Cognitive impairment is a prevalent and debilitating feature in multiple sclerosis (MS), yet its pathophysiology remains incompletely understood. Dysfunction of the neurovascular unit (NVU) and impaired neurovascular coupling (NVC) may be related to cognitive performance in MS, but this pathway remains insufficiently studied. This study investigated whether NVC abnormalities are associated with cognitive performance in MS. Methods Ninety‐seven MS patients and 83 healthy controls (HCs) underwent resting‐state functional magnetic resonance imaging (rs‐fMRI) and arterial spin labeling (ASL) perfusion MRI acquisition. The amplitude of low‐frequency fluctuations (ALFF) was used as an index of regional spontaneous neuronal activity, and cerebral blood flow (CBF) was quantified. NVC was quantified globally (CBF‐ALFF correlation) and regionally (CBF/ALFF ratio). We analyzed the correlations between regional NVC metrics and cognitive performance and Expanded Disability Status Scale (EDSS) scores. Sensitivity analyses tested robustness across alternative functional metrics, gray matter volume (GMV), T2 lesion volume, disability severity, treatment status, and the relapsing‐remitting multiple sclerosis (RRMS) subgroup. Results Compared with HCs, MS patients demonstrated (1) reduced CBF‐ALFF coupling in the ALFF‐based analysis, and (2) increased CBF/ALFF ratios in the bilateral medial prefrontal cortex (mPFC). The regional mPFC finding, particularly on the left, remained robust across sensitivity analyses and was associated with worse cognitive performance and higher EDSS scores. Conclusion These findings suggest altered NVC in MS, with regional prefrontal abnormalities representing the most robust and clinically relevant finding. Regional prefrontal NVC abnormalities may provide a potential imaging correlate of cognitive performance in MS.