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Background and purpose: \ud \ud The aim of this study was to determine whether early and late death are associated with different baseline factors in intracerebral haemorrhage (ICH) survivors.\ud \ud Methods: \ud \ud This was a secondary analysis of the multicentre prospective observational CROMIS‐2 ICH study. Death was defined as ‘early’ if occurring within 6 months of study entry and ‘late’ if occurring after this time point.\ud \ud Results: \ud \ud In our cohort (n = 1094), there were 306 deaths (per 100 patient‐years: absolute event rate, 11.7; 95% confidence intervals, 10.5–13.1); 156 were ‘early’ and 150 ‘late’. In multivariable analyses, early death was independently associated with age [per year increase; hazard ratio (HR), 1.05, P = 0.003], history of hypertension (HR, 1.89, P = 0.038), pre‐event modified Rankin scale score (per point increase; HR, 1.41, P < 0.0001), admission National Institutes of Health Stroke Scale score (per point increase; HR, 1.11, P < 0.0001) and haemorrhage volume >60 mL (HR, 4.08, P < 0.0001). Late death showed independent associations with age (per year increase; HR, 1.04, P = 0.003), pre‐event modified Rankin scale score (per point increase; HR, 1.42, P = 0.001), prior anticoagulant use (HR, 2.13, P = 0.028) and the presence of intraventricular extension (HR, 1.73, P = 0.033) in multivariable analyses. In further analyses where time was treated as continuous (rather than dichotomized), the HR of previous cerebral ischaemic events increased with time, whereas HRs for Glasgow Coma Scale score, National Institutes of Health Stroke Scale score and ICH volume decreased over time.\ud \ud Conclusions: \ud \ud We provide new evidence that not all baseline factors associated with early mortality after ICH are associated with mortality after 6 months and that the effects of baseline variables change over time. Our findings could help design better prognostic scores for later death after ICH.

Background: Stroke commonly affects cognition and, by definition, much vascular dementia follows stroke. However, there are fundamental limitations in our understanding of vascular cognitive impairment, restricting understanding of prevalence, trajectories, mechanisms, prevention, treatment, and patient service needs. Aims: Rates, Risks and Routes to Reduce Vascular Dementia (R4VaD) is an observational cohort study of post-stroke cognition. We aim to recruit a wide range of patients with stroke, presenting to geographically diverse UK hospitals, into a longitudinal study to determine rates of, and risk factors for, cognitive and related impairments after stroke, to assess potential mechanisms and improve prediction models. Methods: We will recruit at least 2000 patients within six weeks of stroke with or without capacity to consent, and collect baseline demographic, clinical, socioeconomic, lifestyle, cognitive, neuropsychiatric and informant data using streamlined patient centred methods appropriate to the stage after stroke. We will obtain more detailed assessments at 4-8 weeks after the baseline assessment and follow-up by phone and post yearly to at least 2 years. We will assess diagnostic neuroimaging in all, and high-sensitivity inflammatory markers, genetics, blood pressure (BP) and diffusion tensor imaging in mechanistic sub-studies. Planned Outputs: R4VaD will provide reliable data on long-term cognitive function after stroke, stratified by prior cognition, stroke- and patient-related variables, and improved risk prediction. It will create a platform enabling sharing of data, imaging and samples. Participants will be consented for re-contact, facilitating future clinical trials, and providing a resource for the stroke and dementia research communities.

The size of the human head is determined by growth in the first years of life, while the rest of the body typically grows until early adulthood1. Such complex developmental processes are regulated by various genes and growth pathways2. Rare genetic syndromes have revealed genes that affect head size3, but the genetic drivers of variation in head size within the general population remain largely unknown. To elucidate biological pathways underlying the growth of the human head, we performed the largest genome-wide association study on human head size to date (N = 79,107). We identified 67 genetic loci, 50 of which are novel, and found that these loci are preferentially associated with head size and mostly independent from height. In subsequent neuroimaging analyses, the majority of genetic variants demonstrated widespread effects on the brain, whereas the effects of 17 variants could be localized to one or two specific brain regions. Through hypothesis-free approaches, we find a strong overlap of head size variants with both cancer pathways and cancer genes. Gene set analyses showed enrichment for different types of cancer and the p53, Wnt and ErbB signalling pathway. Genes overlapping or close to lead variants – such as TP53, PTEN and APC – were enriched for genes involved in macrocephaly syndromes (up to 37-fold) and high-fidelity cancer genes (up to 9-fold), whereas this enrichment was not seen for human height variants. This indicates that genes regulating early brain and cranial growth are associated with a propensity to neoplasia later in life, irrespective of height. Our results warrant further investigations of the link between head size and cancer, as well as its clinical implications in the general population.

Background The prevalence of ex vivo 'high on-treatment platelet reactivity (HTPR)' and its relationship with recurrent vascular events/outcomes in patients with ischaemic cerebrovascular disease (CVD) is unclear. Methods A systematic review and meta-analysis was performed in accordance with the PRISMA statement. MEDLINE, EMBASE and Cochrane Library were searched for completed manuscripts until May 2019 on TIA/ischaemic stroke patients, >= 18 years, treated with commonly-prescribed antiplatelet therapy, who had platelet function/reactivity testing and prospective follow-up data on recurrent stroke/TIA, myocardial infarction, vascular death or other cerebrovascular outcomes. Data were pooled using random-effects meta-analysis. Primary outcome was the composite risk of recurrent stroke/TIA, myocardial infarction or vascular death. Secondary outcomes were recurrent stroke/TIA, severe stroke (NIHSS > 16) or disability/impairment (modified Rankin scale >= 3) during follow-up. Results Antiplatelet-HTPR prevalence was 3-65% with aspirin, 8-56% with clopidogrel and 1.8-35% with aspirin-clopidogrel therapy. Twenty studies (4989 patients) were included in our meta-analysis. There was a higher risk of the composite primary outcome (OR 2.93, 95% CI 1.90-4.51) and recurrent ischaemic stroke/TIA (OR 2.43, 95% CI 1.51-3.91) in patients with vs. those without 'antiplatelet-HTPR' on any antiplatelet regimen. These risks were also more than twofold higher in patients with vs. those without 'aspirin-HTPR' and 'dual antiplatelet-HTPR', respectively. Clopidogrel-HTPR status did not significantly predict outcomes, but the number of eligible studies was small. The risk of severe stroke was higher in those with vs. without antiplatelet-HTPR (OR 2.65, 95% CI 1.00-7.01). Discussion Antiplatelet-HTPR may predict risks of recurrent vascular events/outcomes in CVD patients. Given the heterogeneity between studies, further prospective, multi-centre studies are warranted.

Diffusion tensor imaging (DTI) metrics such as fractional anisotropy (FA) and mean diffusivity (MD) have been proposed as clinical trial markers of cerebral small vessel disease (SVD) due to their associations with outcomes such as cognition. However, studies investigating this have been predominantly single-centre. As clinical trials are likely to be multisite, further studies are required to determine whether associations with cognition of similar strengths can be detected in a multicentre setting. One hundred and nine patients (mean age =68 years) with symptomatic lacunar infarction and confluent white matter hyperintensities (WMH) on MRI was recruited across six sites as part of the PRESERVE DTI substudy. After handling missing data, 3T-MRI scanning was available from five sites on five scanner models (Siemens and Philips), alongside neuropsychological and quality of life (QoL) assessments. FA median and MD peak height were extracted from DTI histogram analysis. Multiple linear regressions were performed, including normalized brain volume, WMH lesion load, and n° lacunes as covariates, to investigate the association of FA and MD with cognition and QoL. DTI metrics from all white matter were significantly associated with global cognition (standardized β =0.268), mental flexibility (β =0.306), verbal fluency (β =0.376), and Montreal Cognitive Assessment (MoCA) (β =0.273). The magnitudes of these associations were comparable with those previously reported from single-centre studies found in a systematic literature review. In this multicentre study, we confirmed associations between DTI parameters and cognition, which were similar in strength to those found in previous single-centre studies. The present study supports the use of DTI metrics as biomarkers of disease progression in multicentre studies.

Background:\ud Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events.\ud \ud Methods:\ud The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627).\ud \ud Findings:\ud Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92).\ud \ud Interpretation:\ud These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention.

Background and Purpose— Cerebral microbleeds (MB) are potential risk factors for intracerebral hemorrhage (ICH), but it is unclear if they are a contraindication to using antithrombotic drugs. Insights could be gained by pooling data on MB frequency stratified by antithrombotic use in cohorts with ICH and ischemic stroke (IS)/transient ischemic attack (TIA). Methods— We performed a systematic review of published and unpublished data from cohorts with stroke or TIA to compare the presence of MB in: (1) antithrombotic users vs nonantithrombotic users with ICH; (2) antithrombotic users vs nonusers with IS/TIA; and (3) ICH vs ischemic events stratified by antithrombotic use. We also analyzed published and unpublished follow-up data to determine the risk of ICH in antithrombotic users with MB. Results— In a pooled analysis of 1460 ICH and 3817 IS/TIA, MB were more frequent in ICH vs IS/TIA in all treatment groups, but the excess increased from 2.8 (odds ratio; range, 2.3–3.5) in nonantithrombotic users to 5.7 (range, 3.4–9.7) in antiplatelet users and 8.0 (range, 3.5–17.8) in warfarin users ( P difference=0.01). There was also an excess of MB in warfarin users vs nonusers with ICH (OR, 2.7; 95% CI, 1.6–4.4; P P =0.33; P difference=0.01). There was a smaller excess of MB in antiplatelet users vs nonusers with ICH (OR, 1.7; 95% CI, 1.3–2.3; P P P difference=0.25). In pooled follow-up data for 768 antithrombotic users, presence of MB at baseline was associated with a substantially increased risk of subsequent ICH (OR, 12.1; 95% CI, 3.4–42.5; P Conclusions— The excess of MB in warfarin users with ICH compared to other groups suggests that MB increase the risk of warfarin-associated ICH. Limited prospective data corroborate these findings, but larger prospective studies are urgently required.

OBJECTIVE To perform a systematic review and pooled meta-analysis of published studies to assess whether the presence of leukoaraiosis on neuroimaging before treatment with thrombolysis (IV or intra-arterial) is associated with an increased risk of symptomatic intracerebral hemorrhage (sICH) or poor functional outcome. METHODS We included studies of patients with acute ischemic stroke, treated with IV or intra-arterial thrombolysis, which assessed functional outcome (3-month modified Rankin Scale [mRS]) or sICH in relation to leukoaraiosis on pretreatment neuroimaging (CT or MRI). We used random-effects models to calculate pooled relative risks (RR) of sICH and poor functional outcome (mRS ≥ 2) for any vs no leukoaraiosis (using any rating scale) and for no to mild vs moderate to severe leukoaraiosis (using the Van Swieten or Fazekas Schmidt scale). RESULTS We identified 15 studies (total n = 6,967). For sICH outcome, the RR was 1.65 (n = 5,551; 95% confidence interval [CI] 1.26-2.16, p = 0.001) with an absolute risk (AR) increase of 2.5% for any leukoaraiosis vs none. The RR was 2.4 (n = 4,192; 95% CI 1.83-3.14, p = 0.001) with an AR increase of 6.2% for moderate to severe vs no to mild leukoaraiosis. For poor functional outcome; the RR was 1.30 (n = 3,401; 95% CI 1.19-1.42, p = 0.001) with an AR increase of 15.4% for any leukoaraiosis vs none. The RR was 1.31 (n = 3,659; 95% CI 1.22-1.42, p = 0.001) with an AR increase of 17.5% for moderate to severe vs no to mild leukoaraiosis. No statistical heterogeneity was noted for any of the analyses. CONCLUSIONS Leukoaraiosis presence and severity are consistently associated with an increased risk of sICH and poor functional outcome after IV or intra-arterial thrombolysis for acute ischemic stroke.

Background and purpose The Montreal Cognitive Assessment (MoCA) is an increasingly popular clinical screening tool for detecting cognitive impairment in stroke, but few studies have directly compared performance on the MoCA with neuropsychological assessment. Our retrospective study examined the extent to which intact performance on the MoCA reflects intact cognition as determined by neuropsychological assessment. Methods In this retrospective study, cognitive profiles for 136 acute stroke patients admitted to the Acute Stroke Unit who had available MoCA and neuropsychological assessment data were examined. Results 22% of our patients were deemed cognitively intact on the MoCA. Of these, 78% were found to be impaired (≤ 5%ile) on neuropsychological assessment in one or more cognitive domains. The most common impairments were in general intelligence, information processing speed and visual memory; three areas not assessed by the MoCA. In addition, a high proportion (up to 59%) of patients who scored the maximum points in one of the MoCA-specified domains were impaired on comparable neuropsychological assessment. Conclusions Our findings suggest that although the MoCA may be a useful screening tool post-stroke in detecting gross impairments, neuropsychological assessment is still necessary for a comprehensive and reliable detection of domain-specific cognitive deficits, which can more reliably inform us for realistic goal setting and vocational advice vital for effective rehabilitation.

Background: Vascular cognitive impairment causes significant disability in the elderly and is common following ischaemic stroke. Although the underlying mechanisms and prognostic factors remain unclear, small vessel diseases are known to contribute. Cerebral microbleeds (CMBs) are a magnetic resonance imaging (MRI) manifestation of small vessel diseases and may contribute to vascular cognitive impairment, particularly frontal-executive functions. We hypothesized that baseline CMBs would predict long-term cognitive outcome, specifically frontal-executive function. Methods: A cohort of consecutive patients found to have CMBs when first referred to a stroke clinic, together with a CMB-free control group matched for age, gender and clinicoradiological characteristics, were invited for follow-up cognitive assessment a median of 5.7 years later. MRI and detailed cognitive assessment (including current intellectual function, verbal memory, visual memory, naming skills, perceptual functions, frontal-executive functions; and speed and attention) were performed at baseline and follow-up. Patients were classified (blinded to MRI and clinical data) as impaired or unimpaired in each domain using predefined criteria. We compared the prevalence of cognitive impairments in each domain at baseline and follow-up and investigated clinical and radiological predictors [including baseline CMBs and white matter changes (WMCs)] of frontal-executive cognitive impairment. Results: Of the original cohort of 55 patients, 13 died without follow-up. Twenty-six of the surviving patients (9 with, 17 without baseline CMBs) agreed to follow-up neuropsychological assessment; 21 of these patients had a repeat MRI scan. The median number of cognitive domains impaired increased, regardless of the presence of baseline CMBs (with baseline CMBs: median 3, range 0–5 at follow-up vs. median 2, range 0–2 at baseline, p = 0.016; without CMBs: median 1.0, range 0–5 at follow-up vs. median 0, range 0–5 at baseline, p = 0.035). Frontal-executive impairment at follow-up was more prevalent in patients with baseline CMBs than in those without (78 vs. 29%, p = 0.038). The presence of baseline CMBs predicted frontal-executive impairment at follow-up (OR 8.40, 95% CI 1.27–55.39, p = 0.027). Fifty percent of patients with CMBs versus 8% of patients without baseline CMBs developed new CMBs (p = 0.047). The severity of WMCs increased; the difference was statistically significant only in patients without baseline CMBs (p = 0.027). There were no new cortical infarcts. Conclusion: In stroke clinic patients, CMBs are consistently associated with frontal-executive impairment; baseline CMBs are associated with frontal-executive impairment at follow-up after 5.7 years. The presence of CMBs has prognostic relevance for long-term cognitive outcome in stroke clinic patients, and may help to optimally target preventive strategies in individuals at highest risk of cognitive decline.

Background MRI-visible perivascular spaces (PVS) are potential neuroimaging markers of cerebral small vessel disease, but their functional significance and mechanisms remain uncertain. We investigated the association between PVS and cognitive impairment, and other MRI markers of small vessel disease, in a patient cohort of ischaemic stroke/transient ischaemic attack (TIA) referrals. Methods Data were collected from a prospective observational database. Standardised detailed neuropsychological testing was performed. A validated visual rating scale on T-2-weighted MRI was used to categorise PVS severity; validated scales were used to assess white matter hyperintensities (WMH), cerebral microbleeds (CMB) and lacunes. Results We included 246 patients (45.1% female, mean age 62 years). No significant association between PVS severity grade in any brain region and impairment in any cognitive domain was identified. In multivariable analysis, WMH and hypertension (but not age) were independently associated with basal ganglia PVS severity (OR: 1.27; p< 0.0001 and OR: 4.89; p= 0.013, respectively). Increasing PVS severity in the basal ganglia was associated with lacunar stroke subtype (p< 0.0001). Age and hypertension (but not WMH or lacunar stroke subtype) were independently associated with centrum semiovale PVS severity (OR: 1.19; p= 0.013 and OR: 3.71; p= 0.007, respectively). Conclusions PVS do not have an independent association with cognitive impairment in patients with ischaemic stroke or TIA. The associations with clinical-radiological factors are consistent with the hypothesis that PVS reflect cerebral small vessel disease; the different associations for basal ganglia and centrum semiovale PVS might indicate different underlying small vessel arteriopathies according to PVS anatomical distribution, but this requires further study.

Background Fabry disease, an X-linked lysosomal storage disorder, leads to multi-organ dysfunction, including cerebrovascular disease and psychological disorders. However, the prevalence and pattern of associated cognitive dysfunction is not well understood. Objectives To investigate whether there is reliable evidence for neuropsychological impairment in patients with Fabry disease and which cognitive domains are affected. To estimate the prevalence of and factors associated with depression in patients with Fabry disease. Method Qualitative systematic review of the literature of studies conducting neuropsychological assessment or measuring the prevalence of depression in adults with Fabry disease using the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines where appropriate. Results There is some evidence for neuropsychological impairment in Fabry disease in executive functioning, information processing speed and attention, with preservation of: general intellectual functioning, memory, naming, perceptual functioning and global cognitive functioning. Prevalence rates of depression in Fabry disease ranged from 15%to 62%,with the largest study to date reporting a prevalence rate of 46 %. The most common factor associated with depression was neuropathic pain, both directly and indirectly by affecting social and adaptive functioning. Conclusion Our review suggests that Fabry disease may be associated with a characteristic pattern of cognitive deficits and a high prevalence of psychological disorders such as depression but highlights the limited available data. Exploring the nature of cognitive impairment in Fabry disease using standardised neuropsychological assessment, brain imaging and measures of depression is an important task for future research.

Little is known about the pattern of subacute cognitive domain impairments after ischaemic stroke, nor the temporal evolution of such impairments. Our objective was to investigate the pattern of cognitive impairment in different neuropsychological domains up to a year after ischaemic stroke. We included prospectively collected data from an observational database of stroke patients at the National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. Patients were categorised into temporal groups according to the time between the index stroke and neuropsychological profiling. The prevalence of impairment in different cognitive domains was then compared between these categories. The final cohort consisted of 209 patients. Frontal executive function, perceptual and nominal skills all showed a strong trend, with levels of impairment of approximately 30 % at\1 month and less than half this at[3 months (p\0.05). Speed and attention was the most impaired domain, but had the greatest trend for decreasing impairment, from 72.4 % acutely to 37.9 % after 3 months (p\0.01). By contrast, we found that impairment in visual and verbal memory showed no statistically significant change over time. Our results suggest a domain-specific improvement in cognition after ischaemic stroke. Early assessments may overestimate longer term cognitive deficits, particularly in speed and attention and perceptual functions. The domain-specific improvement patterns may help to inform long-term rehabilitation plans, which should not be based solely on cognitive assessments undertaken within the first month after stroke.