Vascular disease in multiple sclerosis: impact on pathology and radiologic outcomes

Shared risk factors, immobility, and inflammation may predispose to systemic- and cerebro-vascular disease in Multiple Sclerosis (MS). On the other hand, vascular risk factors (VRF) and comorbidities may have a direct impact on MS pathology. A post mortem and an in vivo magnetic resonance imaging (MRI) study were set up as complementary approaches to test these hypotheses. In the first, objective measures of systemic and cerebro-vascular disease were obtained from a unique cohort of MS and non-MS cases in whom whole body autopsy reports and brain tissue were available for study. This work revealed that cardiovascular disease is less common, but has a stronger impact on cerebral small vessel disease (cSVD) in MS compared with non-MS, and associates with a lower burden of active plaques. Histological analysis showed an increased cSVD burden in those who die young with highly active MS and that periarteriolar hemosiderin deposition, enlarged spaces and inflammation are key features of MS pathology. In the in vivo brain MRI study imaging markers were compared between MS cases with and without VRF and non-MS cases with VRF. By doing so, imaging discriminators between MS and cSVD were identified. While MS does not seem to influence cSVD imaging markers, the different VRF have distinct effects on MS imaging markers: smoking and dyslipidaemia associating with a higher burden of these markers and diabetes having the opposite effect. Using this combined approach, this thesis advanced the knowledge of the contribution of vascular disease/VRF into MS radiological and pathological heterogeneity, identified markers that can be useful on MS differential diagnosis, and has evidenced that the cerebral microvasculature is structurally abnormal in MS and may be an important therapeutic target.