Cerebral microbleeds as a marker of small vessel disease : new insights from neuro-imaging and clinical studies in stroke patients

Introduction: A portfolio of studies is presented aimed at understanding the clinical and pathophysiological significance of cerebral microbleeds (CMBs) in stroke patients. CMBs are the radiological marker of microscopic haemosiderin deposits on iron-sensitiveMRI sequences (mainly gradient-recalled echo [GRE] T2* MRI). They are common in patients with cerebrovascular disease and are hypothesised to be a biomarker for brain small vessel diseases, including hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). Important questions relating to CMBs include their use as a prognostic marker for antithrombotic-related intracerebral haemorrhage (ICH) and cognitive impairment. Our aims were to address the pathophysiological and clinical relevance of CMBs using longitudinal, case-control and cross-sectional studies. Methods: Patients were ascertained from prospective databases of admissions to the stroke service at the National Hospital for Neurology and Neurosurgery and at University College London Hospital’s (UCLH) NHS Trust. Magnetic resonance imaging data was collected and analysed for markers of small vessel disease including CMBs. Clinical and radiological associations of CMBs were determined using appropriate statistical tests. Objectives: First, ways of improving microbleed detection and reporting were explored through the development of a visual rating scale (theMicrobleed Anatomical Rating Scale, MARS) aimed at reliably rating CMBs. Second, the prognostic relevance of CMBs was investigated for antiplatelet-related ICH in a case-comparison study. Third, the detection of new CMBs over time and the factors that influence this were explored. Fourth, the impact of CMBs on cognitive impairment was studied in a cross-sectional study. Finally, the association between CMBs and acute silent ischaemia on diffusion-weighted MRI was investigated via a multi-centre cross-sectional MRI study of patients with ICH. Main findings: 1. MARS is a reliable scale with good intra- and inter-rater agreement for rating CMBs presence and number in any brain location. 2. Lobar CMBs, especially if numerous, are a risk factor for antiplatelet-related ICH independent of the extent of white matter changes. 3. CMBs accumulate over time in stroke patients, and the risk is related to baseline systolic blood pressure. 4. Lobar CMBs are an independent predictor of frontal executive impairment; this suggests that CAA is a potential underlying contributor to cognitive impairment. 5. Silent acute infarcts are frequent in patients within 3 months of ICH, especially in those with probable CAA, and are associated with markers of small vessel disease severity, including CMBs. Conclusion: These studies provide new information on detection, clinical impact and associations of CMBs in stroke patients. They suggest that CMBs have useful roles in understanding pathophysiology, diagnosis and prognosis in patients with small vessel diseases. Further studies are required to determine the direct therapeutic consequences of CMBs, but the present work suggests several promising areas for future research.