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OBJECTIVE: To determine the prevalence and risk factors for cerebral microbleeds (CMB) at different locations in a large healthy community population. METHODS: 8159 subjects from UK Biobank with MRI scans suitable for CMB analysis were included. Brain susceptibility weighted imaging (SWI) data was acquired on two identical 3.0 T scanners. The Microbleed Anatomical Rating Scale (MARS) was used to identify definite CMB. Generalized linear models were used to determine independent associations with all CMB and lobar, deep and infratentorial CMB. RESULTS: The mean age at scan was 62.1±7.4 years. One of more definite CMB were detected in 572 (7.0%) of subjects. Of those with CMB 439 (76.7%) had lobar CMB, 103 (18.0%) had deep CMB, and 83 (14.5%) had infratentorial CMB. Age was an independent risk factor for CMB in all locations. ApoE4 and male sex were positively, and higher BMI were negatively associated, with lobar CMB. In contrast, hypertension, smoking and alcohol consumption were associated with deep CMB, but not with lobar CMB. Only age was associated with infratentorial CMB. The associations were unchanged after controlling for WMH lesion volume as a marker of small vessel disease severity. CONCLUSIONS: In this large population based study, the CMB prevalence detected using a low sensitivity and high specificity system was 7%. There were distinct risk factor profiles for CMB in lobar and deep locations consistent with different underlying pathophysiological processes.

Objective: To identify haematological traits with a causal role in the development of stroke and stroke subtypes. Background: Blood cells and coagulation factors have many important roles including oxygen transport, immune response, iron homeostasis, clearance of apoptotic cells and toxins, vascular and endothelial cell function, response to systemic stress, and haemostasis. A recent analysis found evidence of a causal effect of several blood cell traits on coronary heart disease and Type 2 diabetes, but the causal relevance of haematological traits for stroke and its subtypes has not been established. This information is critical to inform the development of novel treatments for stroke patients. Design/Methods: We conducted a literature review of genome-wide association studies of haematological traits and downloaded publicly available summary statistics from these studies and the MEGASTROKE consortium. Mendelian randomization analyses were used to examine whether haematological traits have a causal effect on the development of stroke and its subtypes in both European-only and trans-ethnic populations. A gene score constructed from independent genetic variants associated with each trait was used as an instrumental variable to obtain an estimate of the causal effect using the ratio, inverse-variance weighted, weighted median, and MR-Egger approaches. Results: The literature review identified 36 blood cell traits (platelets, mature/immature red cells, and myeloid/lymphoid/compound white cells), 43 coagulation factors, and 3 markers of platelet function from 28 published GWAS, which included data from UK Biobank, INTERVAL, CHARGE Consortium, CARe Consortium, BioBank Japan Project, ARIC, Rotterdam Study, Framingham Heart Study, and other cohorts, involving over 350,000 individuals. Genetic associations with stroke and stroke subtypes were available in 67,162 cases and 454,450 controls. Preliminary analyses on a subset of traits showed that plateletcrit had a significant causal effect (p < 8.4746 × 10−4) on all stroke (AS), any ischaemic stroke (AIS), and cardioembolic stroke (CES) in both European-only and trans-ethnic populations; Factor VIII activity had a significant causal effect on AS, AIS, large-artery stroke (LAS), and CES in both populations; and von Willebrand Factor had a significant causal effect on AS and AIS in both populations and a marginally significant effect (p < 1 × 10−3) on CES in a trans-ethnic population. There were also suggestive causal associations of 27 of the blood cell traits on stroke and various subtypes; of activated partial thromboplastin time and Factor VII clotting activity with AS, AIS, and small vessel stroke (SVS); and of prothrombin time and collagen lag time with CES. Conclusions: Our preliminary analyses have so far identified one blood cell trait, 2 coagulation factors, and one marker of platelet function that exhibit evidence of a significant causal association with stroke and various subtypes of stroke, as well as numerous haematological traits that are marginally significant or suggestive of a causal effect. Further investigation of these traits could lead to the development of novel drug targets for the treatment and prevention of stroke.

Glioblastomas (GBM) are the commonest and most aggressive primary tumour of the brain. They are associated with an appalling prognosis with only survivals of a matter of weeks in untreated patients, improving to 14 - 16 months with radiotherapy with concomitant and adjuvant chemotherapy. In this era of molecular biology diagnosis still relies on the WHO Classification system that only requires a tumour to have features of an astrocytic tumour with either necrosis or microvascular proliferation on light microscopy. Yet it is clear that GBMs form a very heterogenous group of tumours. Although there are recognized histological variants (e.g. giant cell GBM, GBM with oligodendroglial differentiation) it is doubtful how useful these are for predicting outcome. It is clear we need to be able to better subtype GBMs to consider individualizing treatment. We have known for some time that glioblastomas can arise from two pathways – either as a primary ‘de novo’ GBM or a ‘secondary’ GBM from a pre-existing low grade glioma. These two subtypes have different mutations and activate different pathways within the cells. The discovery of mutations of the isocitrate dehydrogenase (IDH) gene, an early marker of astrocytic tumor development, has lead to the realization that some GBMs have this mutation. This cohort of patients have a far better prognosis with a median survival of 31 months compared to the 15 months in IDH-wild type.