Vascular Disease and Multiple Sclerosis: A Post-mortem Study Exploring Their Relationships

Ruth Geraldes; Margaret M. Esiri; Rafael Perera; Sydney A. Yee; Damian Jenkins; Jacqueline Palace; Gabriele C. DeLuca


Brain. 2020;143(10):2998-3012. 

In This Article

Abstract and Introduction


Vascular comorbidities have a deleterious impact on multiple sclerosis clinical outcomes but it is unclear whether this is mediated by an excess of extracranial vascular disease (i.e. atherosclerosis) and/or of cerebral small vessel disease or worse multiple sclerosis pathology. To address these questions, a study using a unique post-mortem cohort wherein whole body autopsy reports and brain tissue were available for interrogation was established. Whole body autopsy reports were used to develop a global score of systemic vascular disease that included aorta and coronary artery atheroma, cardiac hypertensive disease, myocardial infarction and ischaemic stroke. The score was applied to 85 multiple sclerosis cases (46 females, age range 39 to 84 years, median 62.0 years) and 68 control cases. Post-mortem brain material from a subset of the multiple sclerosis (n = 42; age range 39–84 years, median 61.5 years) and control (n = 39) cases was selected for detailed neuropathological study. For each case, formalin-fixed paraffin-embedded tissue from the frontal and occipital white matter, basal ganglia and pons was used to obtain a global cerebral small vessel disease score that captured the presence and/or severity of arteriolosclerosis, periarteriolar space dilatation, haemosiderin leakage, microinfarcts, and microbleeds. The extent of multiple sclerosis-related pathology (focal demyelination and inflammation) was characterized in the multiple sclerosis cases. Regression models were used to investigate the influence of disease status on systemic vascular disease and cerebral small vessel disease scores and, in the multiple sclerosis group, the relationship between multiple sclerosis-related pathology and both vascular scores. We show that: (i) systemic cardiovascular burden, and specifically atherosclerosis, is lower and cerebral small vessel disease is higher in multiple sclerosis cases that die at younger ages compared with control subjects; (ii) the association between systemic vascular disease and cerebral small vessel disease is stronger in patients with multiple sclerosis compared with control subjects; and (iii) periarteriolar changes, including periarteriolar space dilatation, haemosiderin deposition and inflammation, are key features of multiple sclerosis pathology outside the classic demyelinating lesion. Our data argue against a common primary trigger for atherosclerosis and multiple sclerosis but suggest that an excess burden of cerebral small vessel disease in multiple sclerosis may explain the link between vascular comorbidity and accelerated irreversibility disability.


Multiple sclerosis is a chronic CNS demyelinating disease in which inflammation, blood–brain barrier disruption, and neurodegeneration are cardinal features. There is marked heterogeneity in multiple sclerosis clinical severity (Thompson et al., 2018), with some patients reaching clinical disability milestones much sooner than others (Vukusic and Confavreux, 2007; Tutuncu et al., 2013; Confavreux and Vukusic, 2014; McKay et al., 2017). Patients with multiple sclerosis who have vascular comorbidities, such as diabetes, hypertension, hypercholesterolaemia and heart disease, have accelerated disability accumulation, requiring a walking aid sooner (Marrie et al., 2010) and have lower brain volumes than their counterparts without comorbidities (Pichler et al., 2019). The mechanism by which vascular risk factors impact disability in multiple sclerosis is not known.

It is well established that vascular risk factors influence the burden of systemic vascular disease, most commonly atherosclerosis, through a complex interplay of genes and environmental factors (Webber et al., 2012; Qiu and Fratiglioni, 2015; Head et al., 2017). However, whether individuals with multiple sclerosis have a higher burden of systemic vascular disease compared to those without multiple sclerosis, has been difficult to ascertain. Epidemiological studies use broad case definitions (Marrie et al., 2014) and only a few small studies, showing inconsistent results, have performed arterial imaging in patients with multiple sclerosis (Jakimovski et al., 2019). Further, attempts to link vascular risk factors or systemic vascular disease to cerebral small vessel disease (cSVD) have relied on surrogate in vivo imaging markers, such as white matter signal change, perivascular space dilatation, and ischaemic change (Pantoni, 2010; Gouw et al., 2011, Wardlaw et al., 2013a, b; Cuadrado-Godia et al., 2018), which are difficult to distinguish from imaging signatures related to the pathological processes associated with multiple sclerosis. These limitations have precluded a meaningful assessment of the relationship between systemic vascular disease and cSVD in the multiple sclerosis brain during life.

Post-mortem studies provide an opportunity to dissect the relative contributions of cSVD and multiple sclerosis-related pathology. A recently developed standardized post-mortem scoring system of cSVD has allowed reliable and reproducible assessment of signatures (Skrobot et al., 2016), including myelin rarefaction, small arteriolar changes [i.e. arteriolosclerosis, periarteriolar haemosiderin deposition (PHL)], and presence of ischaemia and microhaemorrhages. Surprisingly, despite the relevance of vascular comorbidity on clinical outcome and of the blood–brain barrier on the evolution of the multiple sclerosis lesions (Spencer et al., 2018), the extent of cSVD has not been evaluated in multiple sclerosis (Geraldes et al., 2017). Further, how cSVD relates to objective measures of systemic vascular disease in multiple sclerosis remains elusive. Of course, objective measures of systemic vascular disease would be best derived from whole-body autopsy data, which are typically neglected in patients with multiple sclerosis who donate their brains for research.

We hypothesized that multiple sclerosis associates with more severe systemic and cerebral vascular disease. To evaluate this, we had access to an internationally unique post-mortem cohort wherein whole-body autopsy reports and brain tissue were available for assessment of systemic vascular disease and cSVD, respectively, so that their severity and relationships could be explored in multiple sclerosis and controls. First, we show that multiple sclerosis has vascular changes that extend beyond the venule, affecting the arteriole, even in the absence of vascular comorbidity. Second, we provide evidence of a complex, age-dependent relationship between systemic vascular disease and cSVD that differs in multiple sclerosis cases compared to controls. Finally, we demonstrate that an excess burden of cSVD in multiple sclerosis may explain the link between vascular comorbidity and accelerated irreversible disability.