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

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.

Distinct influence of different vascular risk factors on white matter brain lesions in multiple sclerosis

“…The documented effect of smoking and hyperlipidaemia on ‘MS-specific’ lesions supports a direct influence on MS pathology, possibly through promotion of acute inflammation 2 8–11. In line with our results, HT12 and DM13 and total VRF5 have failed to show an impact on T2 lesion volume in MS, although MS-specific lesion locations were not studied, and individual VRFs, including smoking, were not adjusted for.…”

“…Our results need to be interpreted with caution since the number of patients included in each individual VRF group was low (from 10 in diabetes group to 80 in the smoking group) and no information regarding VRF treatment that may have an impact on MS WML2 15 was available. Additionally, VRFs may be present for different lengths of time and be managed more or less effectively, for example smoking usually starts in adolescence before the onset of MS and it is not treatable by medication, whereas HT, DM and dyslipidaemia tend to develop later and are treated; thus, smoking may be a higher VRF in our cohort of patients.…”

“…Vascular risk factors (VRF) and comorbidities are associated with worse clinical outcomes in multiple sclerosis (MS) 1. Higher T2 white matter brain lesions (WML) volumes have been seen in patients with MS with concomitant arterial hypertension (HT) and smoking 2 3. It is not clear whether or not this increase of lesion load is due to a higher burden of MS or vascular WML nor whether the effects of individual VRF on MS WML differ.…”

Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier

“…The effects of smoking in more global vascular disease are well established, but research into a direct influence of tobacco smoke on the BBB remains sparse 43. There is an increased rate of small vessel brain disease in smokers, and a link has been demonstrated between small vessel disease and MS 44. The nicotine, free radicals and nitric oxide associated with smoking have all been shown to have a disruptive effect on tight junctions and endothelial cell function in the brain 43.…”

Investigation of ischemic and demyelinating lesions by cerebral vasoreactivity based on transcranial Doppler sonography: a comparative study

“…The other factor that might affect the vasoreactivity measurement in patients with MS is the volume and number of the lesions. 35 As we have not undertaken MS lesion volumetry, we cannot comment on the issue.…”