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Background: Cognitive slowing occurs in ~70% of multiple sclerosis (MS) patients. The pathophysiology of this slowing is unknown. Neurovascular coupling, acute localized blood flow increases following neural activity, is essential for efficient cognition. Loss of vascular compliance along the cerebrovascular tree would result in suboptimal vasodilation, neurovascular uncoupling, and cognitive slowing. Objective: To assess vascular compliance along the cerebrovascular tree and its relationship to MS-related cognition. Methods: We tested vascular compliance along the cerebrovascular tree by dividing cerebral cortex into nested layers. MS patients and healthy controls were scanned using a dual-echo functional magnetic resonance imaging (fMRI) sequence while they periodically inhaled room air and hypercapnic gas mixture. Cerebrovascular reactivity was calculated from both cerebral blood flow (arterial) and blood-oxygen-level-dependent signal (venous) increases per unit increase in end-tidal CO2. Results: Arterial cerebrovascular reactivity changes along the cerebrovascular tree were reduced in cognitively slow MS compared to cognitively normal MS and healthy controls. These changes were fit to exponential functions, the decay constant (arterial compliance index; ACI) of which was associated with individual subjects' reaction time and predicted reaction time after controlling for disease processes. Conclusion: Such associations suggest prospects for utility of ACI in predicting future cognitive disturbances, monitoring cognitive deficiencies and therapeutic responses, and implicates neurovascular uncoupling as a mechanism of cognitive slowing in MS. [ABSTRACT FROM AUTHOR]