Cerebral small vessel disease: mechanistic insights, ethnic differences and prognostic value

Small vessel disease (SVD) accounts for approximately 25% of all strokes and 45% of all dementias. Although the small vessels cannot be visualised with conventional neuroimaging, the pathological changes in the cerebral white and deep grey matter secondary to SVD has been adopted as markers of SVD. These are best appreciated with magnetic resonance imaging (MRI) and includes recent small subcortical infarcts, white matter hyperintensity (WMH), lacunes, cerebral microbleeds and enlarged perivascular spaces (PVSs). There are however a number of outstanding questions regarding these surrogate neuroimaging markers of SVD and how these markers may influence clinical management. First, although a high burden of microbleeds have been associated with an increased risk of intracerebral haemorrhage (ICH) and possibly recurrent ischaemic stroke in patients with TIA or ischaemic stroke, how microbleeds should influence antithrombotic treatment use after TIA or ischaemic stroke remains uncertain. Second, the long-term prognostic implications of enlarged PVSs in patients with TIA or ischaemic stroke have not been studied. Third, although previous studies have shown possible ethnic differences in prevalence of microbleeds, whether there are any ethnic differences in prevalence of other neuroimaging markers of SVD remains unclear. Fourth, although a Total SVD Score was recently proposed to measure the global SVD burden, the prognostic value of this score in patients with TIA or ischaemic stroke has yet to be studied. Fifth, the relationships of long-term premorbid blood pressure with global SVD burden is unknown. Finally, the age and sex specific associations between renal impairment, carotid and cerebral pulsatility with burden of SVD has yet to be studied. The aim of my thesis was therefore to determine the clinical correlates, ethnic differences and long-term prognostic implications of a range of neuroimaging markers and global burden of SVD. I also aimed to determine the relationships of global SVD burden with long-term mean premorbid blood pressure, renal impairment and carotid pulsatiltiy. I have collected, collated and analysed clinical and neuroimaging data from two independent cohorts - the Oxford Vascular Study (OXVASC) and The University of Hong Kong (HKU). In particular I worked as one of the Clinical Research Fellows at OXVASC and was involved in regular recruitment, assessment and follow up of study patients. In OXVASC, 1080 predominantly Caucasians with TIA or ischaemic stroke who had a cerebral MRI performed at baseline was recruited during 2004 to 2014. I interpreted all these MRIs, specifically coding the burden of microbleeds, enlarged perivascular spaces and lacunes. I was involved in obtaining funding and developing the HKU cohort, which includes 1003 predominantly Chinese with ischaemic stroke recruited during 2008-2014 who had a cerebral MRI performed at baseline. I saw about 25% of the patients in the cohort and was involved in interpreting all of the MRIs of the cohort. All patients from both cohorts were followed-up regularly and adverse events including recurrent ischaemic stroke and ICH was determined. Presence and burden of periventricular and subcortical WMH, lacunes, microbleeds, basal ganglia and centrum semiovale PVSs was determined for all patients and the global burden of SVD estimated according to the Total SVD Score. There are several clinically relevant findings in this thesis. First, I have shown that in Caucasians and Chinese with â¥5 microbleeds, withholding antiplatelet drugs during the first year after TIA or ischaemic stroke may be inappropriate, especially early after TIA. However, the risk of ICH is likely to outweigh any benefit thereafter. Second, I have shown that TIA or ischaemic stroke patients with microbleeds on warfarin had an increased risk of subsequent ICH. However, this risk was not different from that of antiplatelet users with microbleeds. Third, I have shown that a high burden of MRI-visible basal ganglia PVSs is independently associated with an increased risk of recurrent ischaemic stroke, but not ICH. However, the prognostic value of MRI-visible centrum semiovale PVSs in the TIA or ischaemic stroke population is limited. Fourth, I demonstrated significant ethnic differences in underlying prevalence and burden of neuroimaging markers of SVD - Chinese had a greater prevalence of microbleeds, lacunes and subcortical WMH, whilst Caucasians had a greater prevalence of periventricular WMH and PVSs. Fifth, I validated the Total SVD Score and showed that the SVD Score is able to predict risk of recurrent ischaemic stroke and ICH in Caucasians and Chinese, but is unable to identify patients at high risk of ICH from those at high risk of recurrent ischaemic stroke. Sixth, I showed that mean premorbid blood pressure, especially diastolic blood pressure measurements taken 10-20 years prior to TIA or ischaemic stroke was most strongly associated with global SVD burden suggesting a latency effect of hypertension on the pathogenesis of SVD. Finally, I demonstrated age-specific associations between renal impairment, internal carotid artery pulsatility index and SVD burden.