Age‐related small vessel disease: a potential contributor to neurodegeneration in multiple sclerosis

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Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system wherein, after an initial phase of transient neurological defects, slow neurological deterioration due to progressive neuronal loss ensues. Age is a major determinant of MS progression onset and disability. Over the past years, several mechanisms have been proposed to explain the key drivers of neurodegeneration and disability accumulation in MS. However, the effect of commonly encountered age‐related cerebral vessel disease, namely small vessel disease (SVD), has been largely neglected and constitutes the aim of this review. SVD shares some features with MS, that is, white matter demyelination and brain atrophy, and has been shown to contribute to the neuronal damage seen in vascular cognitive impairment. Several lines of evidence suggest that an interaction between MS and SVD may influence MS‐related neurodegeneration. SVD may contribute to hypoperfusion, reduced vascular reactivity and tissue hypoxia, features seen in MS. Venule and endothelium abnormalities have been documented in MS but the role of arterioles and of other neurovascular unit structures, such as the pericyte, has not been explored. Vascular risk factors (VRF) have recently been associated with faster progression in MS, though the mechanisms are unclear since very few studies have addressed the impact of VRF and SVD on MS imaging and pathology outcomes. Therapeutic agents targeting the microvasculature and the neurovascular unit may impact both SVD and MS and may benefit patients with dual pathology.

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