Peter Rothwell

BACKGROUND Spontaneous intracerebral hemorrhage (ICH) in the cerebellum has a poor short-term prognosis, whereas data on the long-term case fatality and recurrent vascular events are sparse. Herewith, we aimed to assess the long-term case fatality and recurrence rate of vascular events after a first cerebellar ICH. METHODS In this international cohort study, we included patients from 10 hospitals (the United States and Europe from 1997 to 2017) aged ≥18 years with a first spontaneous cerebellar ICH who were discharged alive. Data on long-term case fatality and recurrence of vascular events (recurrent ICH [supratentoria or infratentorial], ischemic stroke, myocardial infarction, or major vascular surgery) were collected for survival analysis and absolute event rate calculation. RESULTS We included 405 patients with cerebellar ICH (mean age [SD], 72 [13] years, 49% female). The median survival time …

Background: Socioeconomic deprivation is associated with an increased risk of stroke. However, there is scant evidence on its impact on long-term stroke outcomes. We investigate its long-term impact on stroke incidence, mortality, functional outcome, quality-of-life and life-expectancy. Methods: In a prospective population-based cohort, deprivation (based on residential postcode and stratified into quartiles using the national cut-points for England) was related to incident stroke, 10-year mortality, disability (modified Rankin Scale>2), institutionalisation in long-term care facilities, quality of life (Euroqol-5Dimensions), and life expectancy (including disability-free and quality-adjusted) after first-ever stroke. Cox, logistic and ordinary least squares regression were used to adjust for age, sex, urban-rural mix, previous comorbidity/disability, risk factors, stroke severity and type. Findings: Out of a population of 94,567 people …

Background: The increased risk of dementia after delirium and infection might be influenced by cerebral small vessel disease-SVD. We determined associations between hospitalisations with delirium, and with infection on follow-up after TIA/minor stroke and 5-year dementia risk, stratified by moderate/severe SVD on baseline brain imaging. Methods: In a population-based study (n=94 567) of TIA/minor stroke (NIHSS<3) ascertained 2002-2012 (Oxford Vascular Study-OXVASC), hospitalisations on follow-up were identified from the Oxford Cognitive Comorbidity, Frailty and Ageing Research Database-ORCHARD. Delirium and infection were defined by ICD-10 coding supplemented by hand-searching of hospital records. Dementia was diagnosed using clinical/cognitive assessment, medical records and death certificates. Dementia risk was determined using time-varying Cox analysis with multivariable adjustment …

Time-of-day significantly influences the severity and incidence of stroke. Evidence has emerged not only for circadian governance over stroke risk factors, but also for important determinants of clinical outcome. In this review, we provide a comprehensive overview of the interplay between chronobiology and cerebrovascular disease. We discuss circadian regulation of pathophysiological mechanisms underlying stroke onset or tolerance as well as in vascular dementia. This includes cell death mechanisms, metabolism, mitochondrial function, and inflammation/immunity. Furthermore, we present clinical evidence supporting the link between disrupted circadian rhythms and increased susceptibility to stroke and dementia. We propose that circadian regulation of biochemical and physiological pathways in the brain increase susceptibility to damage after stroke in sleep and attenuate treatment effectiveness during the …

BackgroundThe increased risk of dementia after delirium and infection might be influenced by cerebral white matter disease (WMD). In patients with transient ischaemic attack (TIA) and minor stroke, we assessed associations between hospital admissions with delirium and 5-year dementia risk and between admissions with infection and dementia risk, stratified by WMD severity (moderate or severe vs absent or mild) on baseline brain imaging.MethodsWe included patients with TIA and minor stroke (National Institutes of Health Stroke Score <3) from the Oxford Vascular Study (OXVASC), a longitudinal population-based study of the incidence and outcomes of acute vascular events in a population of 94 567 individuals, with no age restrictions, attending eight general practices in Oxfordshire, UK. Hospitalisation data were obtained through linkage to the Oxford Cognitive Comorbidity, Frailty, and Ageing Research …

BackgroundStroke is a leading cause of morbidity and mortality. Retinal imaging allows non-invasive assessment of the microvasculature. Consequently, retinal imaging is a technology which is garnering increasing attention as a means of assessing cardiovascular health and stroke risk.MethodsA biomedical literature search was performed to identify prospective studies that assess the role of retinal imaging derived biomarkers as indicators of stroke risk.ResultsTwenty-four studies were included in this systematic review. The available evidence suggests that wider retinal venules, lower fractal dimension, increased arteriolar tortuosity, presence of retinopathy, and presence of retinal emboli are associated with increased likelihood of stroke. There is weaker evidence to suggest that narrower arterioles and the presence of individual retinopathy traits such as microaneurysms and arteriovenous nicking indicate …

Background and ObjectivesAnti-inflammatory therapies reduce major adverse cardiovascular events (MACE) in coronary artery disease but remain unproven after stroke. Establishing the subtype-specific association between inflammatory markers and recurrence risk is essential for optimal selection of patients in randomized trials (RCTs) of anti-inflammatory therapies for secondary stroke prevention.MethodsUsing individual participant data (IPD) identified from a systematic review, we analyzed the association between high-sensitivity C-reactive protein, interleukin-6 (IL-6), and vascular recurrence after ischemic stroke or transient ischemic attack. The prespecified coprimary end points were (1) any recurrent MACE (first major coronary event, recurrent stroke, or vascular death) and (2) any recurrent stroke (ischemic, hemorrhagic, or unspecified) after sample measurement. Analyses were performed stratified by …

BackgroundMultimorbidity is common in patients with stroke and is associated with increased medium- to long-term mortality, but its value for clinical decision-making and case-mix adjustment will depend on other factors, such as age, stroke severity, etiological subtype, prior disability, and vascular risk factors.AimsIn the absence of previous studies, we related multimorbidity to long-term post-stroke mortality with stratification by these factors.MethodsIn patients ascertained in a population-based stroke incidence study (Oxford Vascular Study; 2002–2017), we related pre-stroke multimorbidity (weighted/unweighted Charlson comorbidity index (CCI)) to all-cause/vascular/non-vascular mortality (1/5/10 years) using regression models adjusted/stratified by age, sex, predicted early outcome (THRIVE score), stroke severity (NIH stroke scale (NIHSS)), etiology (Trial of Org 10172 in Acute Stroke Treatment (TOAST …

IntroductionCerebral blood flow (CBF) declines with age and abnormalities in CBF are associated with age-related cerebrovascular disease and neurodegeneration. Women have higher CBF than men, although this sex-difference diminishes to some extent with age in healthy subjects. The physiological drivers of these age/sex differences are uncertain, but might be secondary to age and sex-differences in haemoglobin (Hb) level. Hb levels are inversely correlated with CBF, are lower in women, and decline with age in men, but the interrelations between these factors have not been explored systematically either in healthy subjects or across the full age-range in patients with vascular risk factors. We aimed to determine the age-specific interrelations between sex, Hb, and CBF velocity in a large cohort of patients with cerebrovascular disease.Patients and methodsIn patients with a recent transient ischaemic attack or …

IntroductionInflammation is an emerging target for secondary prevention after stroke and randomised trials of anti-inflammatory therapies are ongoing. Fibrinogen, a putative pro-inflammatory marker, is associated with first stroke, but its association with major adverse cardiovascular events (MACE) after stroke is unclear.Materials and MethodsWe did a systematic review investigating the association between fibrinogen and post-stroke vascular recurrence. Authors were invited to provide individual-participant data (IPD) and where available we did within-study multivariable analyses with adjustment for cardiovascular risk factors and medications. Adjusted summary-level data was extracted from published reports from studies that did not provide IPD. We pooled risk ratios (RR) by random-effects meta-analysis by comparing supra-median with sub-median fibrinogen levels and performed pre-specified subgroup …

Background and aim Rapid outpatient evaluation and treatment of TIA in structured clinics have been shown to reduce stroke recurrence. It is unclear whether short-term downtrends in TIA incidence and admissions have had enduring impact on TIA clinic activity. This study aims to measure the impact of the pandemic on hospitals with rapid TIA clinics. Methods Relevant services were identified by literature search and contacted. Three years of monthly data were requested – a baseline pre-COVID period (April 2018 to March 2020) and an intra-COVID period (April 2020 to March 2021). TIA presentations, ischemic stroke presentations, and reperfusion trends inclusive of IV thrombolysis (IVT) and endovascular thrombectomy (EVT) were recorded. Pandemic impact was measured with interrupted time series analysis, a segmented regression approach to test an effect of an intervention on a time-dependent outcome using a defined impact model. Results Six centers provided data for a total of 6,231 TIA and 13,191 ischemic stroke presentations from Australia (52.1%), Canada (35.0%), Italy (7.6%), and England (5.4%). TIA clinic volumes remained constant during the pandemic (2.9, 95% CI –1.8 to 7.6, p = 0.24), as did ischemic stroke (2.9, 95% CI –7.8 to 1.9, p = 0.25), IVT (−14.3, 95% CI −36.7, 6.1, p < 0.01), and EVT (0, 95% CI –16.9 to 16.9, p = 0.98) counts. Proportion of ischemic strokes requiring IVT decreased from 13.2 to 11.4% (p < 0.05), but those requiring EVT did not change (16.0 to 16.7%, p = 0.33). Conclusion This suggests that the pandemic has not had an enduring effect on TIA clinic or stroke service activity for these centers …

MethodsIn our method, the first step consists of an initial candidate detection step that detects CMBs with high sensitivity. In the second step, candidate discrimination step is performed using a knowledge distillation framework, with a multi-tasking teacher network that guides the student network to classify CMB and non-CMB instances in an offline manner. Finally, a morphological clean-up step further reduces false positives using anatomical constraints. We used four datasets consisting of different modalities specified above, acquired using various protocols and with a variety of pathological and demographic characteristics.ResultsOn cross-validation within datasets, our method achieved a cluster-wise true positive rate (TPR) of over 90% with an average of< 2 false positives per subject. The knowledge distillation framework improves the cluster-wise TPR of the student model by 15%. Our method is flexible in terms …

BackgroundPatients who had a cryptogenic stroke (CS) suspected to be causally related to a patent foramen ovale (PFO) are candidates for percutaneous PFO closure. In such patients, it is important to screen for atrial fibrillation (AF). Limited guidance is available regarding AF monitoring strategies in CS patients with PFO addressing optimal monitoring technology and duration.AimTo provide a narrative review of cardiac rhythm monitoring in CS patients considered for PFO closure, including current practices, stroke recurrences after CS, findings from monitoring studies in CS patients, and predictors for AF detection published in the literature. To propose a personalized strategy for cardiac monitoring in CS patients, accounting for aspects predicting AF detection.Summary of reviewAF detection in CS patients is predicted by age, left atrial enlargement, prolonged PR interval, frequent premature atrial contractions …

We thank Dr. DiNicolantonio for his comments, which highlight the pathophysiological differences between cardiac and cerebrovascular disease as we demonstrated with the relative odds of stroke versus myocardial infarction.[1] However, we feel that it is inappropriate to extrapolate from a population of patients with heart failure (as in COMET),[2] or coronary artery disease, to the management of primary hypertension in patients at increased stroke risk.Our previous larger meta-analysis showed the detrimental effects of all beta-blockers on blood pressure variability and specifically stroke risk,[3, 4] while this paper identified heterogeneity amongst beta-blockers subtypes, and did demonstrate a deleterious clinical effect of non-selective beta-blockade compared to selective agents. In addition, although atenolol is associated with a greater risk of stroke compared to other classes of antihypertensive agents, it does not" …

BackgroundAspirin is an inexpensive, readily available treatment globally with the potential to be an effective adjuvant therapy to prevent recurrence of colorectal cancer (CRC) after completing standard primary treatment. This landmark study conducted entirely in the Asia-Pacific region, where incidence of CRC is increasing, is the first international Phase III double-blind placebo-controlled trial to report the activity of aspirin in the secondary prevention of CRC (NCT 00565708).MethodsPatients with Dukes’ C and high-risk Dukes’ B CRC were randomised to Aspirin 200mg daily or placebo for 3 years after surgery and completion of standard adjuvant therapy (including 3+ months of chemotherapy) and followed for 5+ years. The primary endpoint was Disease-Free Survival (DFS). The primary analysis used a stratified Cox model, with those commencing study treatment (modified intention to treat (mITT) and with all …

We thank the respondent for his comments, but his statement that changes in blood pressure variability do not affect the risk of stroke is incorrect. In 4 papers in the Lancet [2-5] we demonstrated the strong relationship between blood pressure variability and stroke risk, and how medications which affect BP variability have parallel effects on stroke risk. As stated, the primary purpose of this paper was to deal specifically with the heterogeneity amongst beta-blockers, and should only be understood in the light of this previous research. In particular,'atenolol reduces blood pressure variability'is a significant misinterpretation. We showed that atenolol relatively increases blood pressure variability and is worse at preventing stroke than other classes of antihypertensive drugs.[3, 4] This paper shows simply that non-selective beta-blockers have a more detrimental effect. Finally, the respondent has mentioned specific trials …

Objective: Arterial stiffness, cerebral pulsatility, and beat-to-beat blood pressure variability partly mediate the relationship between hypertension and stroke, but it is unknown if these intermediate phenotypes of vascular ageing differ between stroke aetiologies. We therefore aimed to characterize differences in these intermediate cardiovascular phenotypes between patients presenting with strokes of different aetiologies. Methods: In consecutive patients on best medical management 1 month after TIA or nondisabling stroke (Oxford Vascular Study), arterial stiffness (PWV) was measured by applanation tonometry (Sphygmocor), middle cerebral blood flow velocity, and pulsatility index (MCA-PI) were measured by transcranial ultrasound (TCD, DWL Doppler Box), and beat-to-beat BP variability was measured with a Finometer. Differences between patients with large artery (LAS), small vessel …

BackgroundIntravenous thrombolysis is recommended before endovascular treatment, but its value has been questioned in patients who are admitted directly to centres capable of endovascular treatment. Existing randomised controlled trials have indicated non-inferiority of endovascular treatment alone or have been statistically inconclusive. We formed the Improving Reperfusion Strategies in Acute Ischaemic Stroke collaboration to assess non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment.MethodsWe conducted a systematic review and individual participant data meta-analysis to establish non-inferiority of endovascular treatment alone versus intravenous thrombolysis plus endovascular treatment. We searched PubMed and MEDLINE with the terms "stroke", "endovascular treatment", "intravenous thrombolysis", and synonyms for articles published from …

We thank Dr. Bruno for the comment on our article. 1 Although our focus was on how the ordinal and dichotomous forms of the 3-month modified Rankin Scale (mRS) relate to long-term outcomes and costs, we did exclude patients with pre-stroke mRS> 1 and> 2 to verify our findings in additional analyses. We agree that there is a need to establish more uniform methods for ascertainment of pre-stroke disability, which currently relies on measures like the mRS that were not originally designed for this purpose and may be vulnerable to confounding factors, such as sex differences in pre-morbid mRS ratings. 2 The single-question approach suggested by Dr. Bruno is likely to be useful in time-pressured clinical situations to establish whether a patient has significant pre-morbid disability. However, it does not quantify pre-stroke disability which is important for evaluating treatment outcome (ie, to what extent did the patient …

BackgroundGuidelines recommend routine frailty screening for all hospitalised older adults to inform care decisions, based mainly on studies in elective or speciality-specific settings. However, most hospital bed days are accounted for by acute non-elective admissions, in which the prevalence and prognostic value of frailty might differ, and uptake of screening is limited. We therefore did a systematic review and meta-analysis of frailty prevalence and outcomes in unplanned hospital admissions.MethodsWe searched MEDLINE, EMBASE and CINAHL up to 31/01/2023 and included observational studies using validated frailty measures in adult hospital-wide or general medicine admissions. Summary data on the prevalence of frailty and associated outcomes, measurement tools, study setting (hospital-wide vs general medicine), and design (prospective vs retrospective) were extracted and risk of bias assessed …

Background and ObjectivesPatients with multimorbidity are underrepresented in clinical trials. Inclusion in stroke trials is often limited by exclusion based on premorbid disability, concerns about worse poststroke outcomes in acute treatment trials, and a possibly increased proportion of hemorrhagic vs ischemic stroke in prevention trials. Multimorbidity is associated with an increased mortality after stroke, but it is unclear whether this is driven by an increased stroke severity or is confounded by particular stroke subtypes or premorbid disability. We aimed to determine the independent association of multimorbidity with stroke severity taking account of these main potential confounders.MethodsIn a population-based incidence study (Oxford Vascular Study; 2002–2017), prestroke multimorbidity (Charlson Comorbidity Index [CCI]; unweighted/weighted) in all first-in-study strokes was related to postacute severity (≈24 …

BackgroundHypertension is the leading modifiable risk factor for cerebral small vessel diseases (SVDs). Yet, it is unknown whether antihypertensive drug classes differentially affect microvascular function in SVDs.AimsTo test whether amlodipine has a beneficial effect on microvascular function when compared to either losartan or atenolol, and whether losartan has a beneficial effect when compared to atenolol in patients with symptomatic SVDs.DesignTREAT-SVDs is an investigator-led, prospective, open-label, randomised crossover trial with blinded endpoint assessment (PROBE design) conducted at five study sites across Europe. Patients aged 18 years or older with symptomatic SVD who have an indication for antihypertensive treatment and are suffering from either sporadic SVD and a history of lacunar stroke or vascular cognitive impairment (group A) or CADASIL (group B) are randomly allocated 1:1:1 to …

BackgroundThe prevalence of atherosclerosis and the long-term risk of major vascular events in people who have had a transient ischaemic attack or minor ischaemic stroke, regardless of the causal relationship between the index event and atherosclerosis, are not well known. In this analysis, we applied the ASCOD (atherosclerosis, small vessel disease, cardiac pathology, other causes, and dissection) grading system to estimate the 5-year risk of major vascular events according to whether there was a causal relationship between atherosclerosis and the index event (ASCOD grade A1 and A2), no causal relationship (A3), and with or without a causal relationship (A1, A2, and A3). We also aimed to estimate the prevalence of different grades of atherosclerosis and identify associated risk factors.MethodsWe analysed patient data from TIAregistry.org, which is an international, prospective, observational registry of …

We thank Dr. Gocan et al. for their interest in our study 1. The aim of our study was to quantify the predictive value of DWI positivity in a setting that is generalizable to routine clinical practice; therefore, diagnosis was based on the clinical judgement of an experienced vascular neurologist within the paradigm of internationally recognized WHO diagnostic criteria.We acknowledge the complexities surrounding the use of DWI in the diagnosis of TIA; indeed, we have been publishing in this area for the past two decades. 2, 3 Up to 60% of patients referred to a TIA clinic are ultimately diagnosed as mimics and many—for example, migraine—have non-trivial rates of DWI positivity. This emphasizes the importance of the 2010 AAN guideline cautioning on using MRI as a diagnostic stroke/TIA gold standard. 4

BackgroundHypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease.MethodsWe did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine …

Background:Studies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension.Methods:The TIME study is a prospective, pragmatic, decentralised, parallel group study in the UK, that recruited adults with hypertension and taking at least one antihypertensive medication. Eligible participants were randomly assigned 1 to 1, without restriction, stratification, or minimisation, to take all of their usual antihypertensive medications in either the morning, 0600 to 1000 h, or in the evening, 2000 to 0000 h.. Participants were followed up for the composite primary endpoint of vascular death or hospitalisation for non fatal myocardial …

Objectives To compare processes of care and clinical outcomes of community‐based management of TIAs and minor strokes (TIAMS) between rural and metropolitan Australia. Design Inception cohort study between 2012 and 2016 with 12‐month follow‐up after index event (sub‐study of INSIST). Setting Hunter and Manning valley regions of New South Wales, within the referral territory of the John Hunter Hospital Acute Neurovascular Clinic (JHHANC). Participants Consecutive patients of 16 participating general practices, presenting with possible TIAMS to either primary or secondary care. Main Outcome Measures Processes of care (referrals, key management processes, time‐based metrics) and clinical outcomes. Results Of 613 participants with possible TIAMS who completed the baseline interview, 298 were adjudicated as having TIAMS (119 from rural, 179 from metropolitan). Mean age was 72.3 …

Increasing evidence indicates that circadian and diurnal rhythms robustly influence stroke onset, mechanism, progression, recovery, and response to therapy in human patients. Pioneering initial investigations yielded important insights but were often single-center series, used basic imaging approaches, and used conflicting definitions of key data elements, including what constitutes daytime versus nighttime. Contemporary methodologic advances in human neurovascular investigation have the potential to substantially increase understanding, including the use of large multicenter and national data registries, detailed clinical trial data sets, analysis guided by individual patient chronotype, and multimodal computed tomographic and magnetic resonance imaging. To fully harness the power of these approaches to enhance pathophysiologic knowledge, an important foundational step is to develop standardized …

ImportanceThe coexistence of underlying causes in patients with transient ischemic attack (TIA) or minor ischemic stroke as well as their associated 5-year risks are not well known.ObjectiveTo apply the ASCOD (atherosclerosis, small vessel disease, cardiac pathology, other cause, or dissection) grading system to assess coexistence of underlying causes of TIA and minor ischemic stroke and the 5-year risk for major vascular events.Design, Setting, and ParticipantsThis international registry cohort (TIAregistry.org) study enrolled 4789 patients from June 1, 2009, to December 31, 2011, with 1- to 5-year follow-up at 61 sites in 21 countries. Eligible patients had a TIA or minor stroke (with modified Rankin Scale score of 0 or 1) within the last 7 days. Among these, 3847 patients completed the 5-year follow-up by December 31, 2016. Data were analyzed from October 1, 2022, to June 15, 2023.ExposureFive-year follow …

Reducing blood pressure (BP) is a highly effective strategy for long-term stroke prevention. Despite overwhelmingly clear evidence from randomized trials that antihypertensive therapy substantially reduces the risk of stroke in primary prevention, uncertainty still surrounds the issue of BP lowering after cerebrovascular events, and the risk of recurrent stroke, coronary events, and vascular death remains significant. Important questions in a secondary prevention setting include should everyone be treated regardless of their poststroke BP, how soon after a stroke should BP-lowering treatment be commenced, how intensively should BP be lowered, what drugs are best, and how should long-term BP control be optimized and monitored. We review the evidence on BP control after a transient ischemic attack or stroke to address these unanswered questions and draw attention to some recent developments that hold …

BackgroundMulti‐phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes.ObjectivesTo discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events.MethodsSummary statistics from genome wide‐association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI‐1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi …

Introduction: Multimorbidity is highly prevalent in patients with transient ischaemic attack (TIA) or stroke, and is associated with increased short- and long-term mortality thereafter. Underlying mechanisms behind this relationship are unclear, and it is unknown whether increased inflammatory or prothrombotic factors might explain increased mortality. Methods: Using the population-based Oxford Vascular Study (OXVASC), we used a panel of 16 blood biomarkers relating to inflammation (IL-6, CRP, NGAL, sTNF-R1), thrombosis/atherogenesis (TM, fibrinogen, vWF, P-Selectin, PZ, D-Dimer, Anti-PC, ADAMTS-13), and cardiac or neuronal cell damage (NT-proBNP, hFABP, NSE, BDNF). Samples were obtained at stroke/TIA onset, and patients were followed up to 10 years. Biomarker levels were log-transformed to facilitate analysis. Multimorbidity immediately prior to TIA/stroke onset was assessed using the Charlson …

Background and ObjectivesCurrent genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke.MethodsWe performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18–59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS.ResultsWe observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both …

BackgroundControversy exists as to whether the threshold for blood pressure-lowering treatment should differ between people with and without type 2 diabetes. We aimed to investigate the effects of blood pressure-lowering treatment on the risk of major cardiovascular events by type 2 diabetes status, as well as by baseline levels of systolic blood pressure.MethodsWe conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using the Blood Pressure Lowering Treatment Trialists' Collaboration dataset. Trials with information on type 2 diabetes status at baseline were eligible if they compared blood pressure-lowering medications versus placebo or other classes of blood pressure-lowering medications, or an intensive versus a standard blood pressure-lowering strategy, and reported at least 1000 persons-years of follow-up in each group. Trials exclusively on …

Objective: To examine the impact of prior comorbidity and multimorbidity on the long-term risks and costs of institutionalisation following stroke. Background: Institutionalisation is common following stroke. However, the risks of institutionalisation vary between studies, and the influence of prior comorbidity or multimorbidity in predicting institutionalisation and its costs following stroke are unknown. Design/Methods: Patients from the population-based Oxford Vascular Study were ascertained from 2002–2018 and followed until 2020. Clinical information, including past medical history and prior comorbidities, was obtained as soon as possible following the index event through patient interviews and medical records. Comorbidity was defined as one Charlson Comorbidity Index (CCI) comorbidity, and multimorbidity was defined as two or more. Patients who were previously institutionalised were excluded. The 10-year risks of institutionalisation were determined using crude and adjusted …

Background Increased cerebral arterial pulsatility is associated with cerebral small vessel disease, recurrent stroke, and dementia despite the best medical treatment. However, no study has identified the rates and determinants of progression of arterial stiffness and pulsatility. Methods In consecutive patients within 6 weeks of transient ischemic attack or nondisabling stroke (OXVASC [Oxford Vascular Study]), arterial stiffness (pulse wave velocity [PWV]) and aortic systolic, aortic diastolic, and aortic pulse pressures (aoPP) were measured by applanation tonometry (Sphygmocor), while middle cerebral artery (MCA) peak (MCA-PSV) and trough (MCA-EDV) flow velocity and Gosling pulsatility index (PI; MCA-PI) were measured by transcranial ultrasound (transcranial Doppler, DWL Doppler Box). Repeat assessments were performed at the 5-year follow-up visit after intensive medical treatment and agreement …

Background GLP-1 RA (glucagon-like peptide-1 receptor agonists), including semaglutide, may reduce stroke risk in people with type 2 diabetes. This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk. Methods SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and PIONEER 6 (Peptide Innovation for Early Diabetes Treatment) were randomized cardiovascular outcome trials of subcutaneous and oral semaglutide in people with type 2 diabetes at high cardiovascular risk, respectively. Time to first stroke and stroke subtypes were analyzed using a Cox proportional hazards model stratified by trial with pooled treatment as a factor. The impact of prior stroke, prior myocardial infarction or stroke, age, sex, systolic …

Background Beat‐to‐beat blood pressure variability (BPV) is associated with an increased risk of stroke but can be driven by both healthy physiological processes and failure of compensatory mechanisms. Blood pressure (BP) complexity measures structured, organized variations in BP, as opposed to random fluctuations, and its reduction may therefore identify pathological beat‐to‐beat BPV. Methods and Results In the prospective, population‐based OXVASC (Oxford Vascular Study) Phenotyped Cohort with transient ischemic attack or minor stroke, patients underwent at least 5 minutes of noninvasive beat‐to‐beat monitoring of BP (Finometer) and ECG to derive the following: BPV (coefficient of variation) and complexity (modified multiscale entropy) of systolic BP and diastolic BP, heart rate variability (SD of R‐R intervals), and baroreflex sensitivity (BRS; Welch's method), in low‐ (0.04–0.15 Hz) and high …

BackgroundPatients who have had a transient ischaemic attack or minor stroke have an increased risk of cardiovascular events for the following 5 years. We aimed to assess 5-year functional outcomes in patients with transient ischaemic attack or minor ischaemic stroke and to determine the factors associated with long-term disability.MethodsWe analysed data from patients in TIAregistry.org, an international, prospective, observational registry of patients with transient ischaemic attack or minor ischaemic stroke from 61 specialised centres in 21 countries. Patients aged 18 years or older who had a transient ischaemic attack or minor stroke within the previous 7 days between May 30, 2009, and Dec 30, 2011, with a baseline modified Rankin scale (mRS) score of 0–1, and who had been followed up for 5 years, were eligible for inclusion in this study. We evaluated whether existing comorbidities and stroke recurrence …

Background and ObjectivesIn the past decade, there have been major improvements in the control of risk factors, acute stroke therapies, and rehabilitation after the availability of high-quality evidence and guidelines on best practices in the acute phase. In this changing landscape, we aimed to investigate the stroke admission rates, time trends, risk factors, and outcomes during the period of 2014–2019 using German nationwide data.MethodsWe obtained data of all acute stroke hospitalizations by the Federal Statistical Office. All hospitalized cases of adults (age 18 years or older) with acute stroke from the years 2014–2019 were analyzed regarding time trends, risk factors, treatments, morbidity, and in-hospital mortality according to stroke subtype (all-cause/ischemic/hemorrhagic).ResultsBetween 2014 and 2019, overall stroke hospitalizations in adults (median age = 76 years, [IQR: 65–83 years]) initially increased …

Introduction TIA and stroke cause cognitive impairment with a typical “vascular” pattern, including prominent frontal/executive deficits. Cognitive impairment is associated with increased delirium risk and the few available data suggest that executive dysfunction is important. We therefore determined the predictive value of both severity and pattern of cognitive deficits for delirium on long-term follow-up after TIA/stroke. Methods Surviving TIA/stroke participants on October 1, 2013, in the Oxford Vascular Study (OXVASC) were assessed prospectively for delirium during all hospitalizations over the subsequent 6 months. Associations between OXVASC pre-admission mini-mental state examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores, and delirium during hospitalizations on follow-up were determined using logistic regression adjusted for covariates, including demographic factors, history of …

Chronic kidney disease (CKD) is a rapidly rising global health burden that affects nearly 40% of older adults. Epidemiologic data suggest that individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing cognitive disorders and dementia, and thus represent a vulnerable population. It is currently unknown to what extent this risk may be attributable to a clustering of traditional risk factors such as hypertension and diabetes mellitus leading to a high prevalence of both symptomatic and subclinical ischaemic cerebrovascular lesions, or whether other potential mechanisms, including direct neuronal injury by uraemic toxins or dialysis-specific factors could also be involved. These knowledge gaps may lead to suboptimal prevention and treatment strategies being implemented in this group. In this review, we explore the mechanisms of susceptibility and risk in the relationship between CKD and cognitive disorders.

ImportanceSome studies have reported increasing stroke incidence at younger ages (<55 years) but have often relied only on administrative data, and more population-based studies of adjudicated stroke are required. An understanding of the drivers of any increase in incidence of young stroke also requires comparisons with stroke trends at older ages and with trends in incidence of other vascular events at younger ages.ObjectiveTo determine temporal changes in incidence of stroke and other major vascular events at younger vs older ages.Design, Setting, and ParticipantsProspective population-based incidence study conducted from April 2002 to March 2018 with a mean catchment population of 94 567 in Oxfordshire, England.ExposuresCalendar time, premorbid vascular risk factors, and occupation.Main Outcomes and MeasuresChanges in incidence of stroke, transient ischemic attack (TIA), and other major …

Background and Purpose Urgent assessment aimed at reducing stroke risk after transient ischemic attack or minor stroke is cost-effective over the short-term. However, it is unclear if the short-term impact is lost on long-term follow-up, with recurrent events being delayed rather than prevented. By 10-year follow-up of the EXPRESS study (Early Use of Existing Preventive Strategies for Stroke), previously showing urgent assessment reduced 90-day stroke risk by 80%, we determined whether that early benefit was still evident long-term for stroke risk, disability, and costs. Methods EXPRESS was a prospective population-based before (phase 1: April 2002–September 2004; n= 310) versus after (phase 2: October 2004–March 2007; n= 281) study of the effect of early assessment and treatment of transient ischemic attack/minor stroke on early recurrent stroke risk, with an external control. This report assesses the effect …

BackgroundContemporary data on stroke epidemiology and the availability of national stroke clinical registries are important for providing evidence to improve practice and support policy decisions.AimsTo update the most current incidence, case-fatality, and mortality rates on stroke and identify national stroke clinical registries worldwide.MethodsWe searched multiple databases (based on our existing search strategy) to identify new original papers, published between 1 November 2018 and 15 December 2021, that met ideal criteria for data on stroke incidence and case-fatality, and added these to the studies reported in our last review. To identify national stroke clinical registries, we updated our last search, using PubMed, from 6 February 2015 until 6 January 2022. We also screened reference lists of review papers, citation history of papers, and the gray literature. Mortality codes for International Classification of …

Objective Beta‐blockers are beneficial in coronary artery disease but less so in stroke prevention and dementia, potentially due to reduced heart rate (HR). Cerebral pulsatility is strongly associated with cerebral small vessel disease (SVD) and may be increased by lower diastolic pressures resulting from longer cardiac cycles. Methods Patients 4–6 weeks after TIA or non‐disabling stroke (Oxford Vascular Study) underwent 5 minutes continuous monitoring of blood pressure (BP), electrocardiogram (ECG), and middle cerebral artery flow velocity (transcranial ultrasound). Beat‐to‐beat relationships between HR, blood pressure and Gosling's pulsatility index (MCA‐PI) are reported as beta‐coefficients from general linear models for each individual. Results Across 759 patients, average MCA‐PI during monitoring was associated with lower HR and diastolic BP (DBP) and greater systolic BP (SBP) (∆MCA‐PI per 10 …

Substantial improvements have taken place in the outcomes of patients with cerebrovascular disease since the beginning of the 21st century. These improvements are mainly due to the rapid translation of clinical research findings into service provision, including the roll-out of urgent assessment and treatment of patients with suspected transient ischaemic attack or minor stroke, and the swift provision of thrombectomy for those with major ischaemic stroke. There is much to celebrate, but also much to lose over the next 20 years if progress is not maintained. Overall stroke incidence is falling in almost all high-income countries, but increases in life expectancy mean that the number of patients with stroke has not fallen. Moreover, the age-specific incidence of stroke is projected to rise in many low-income countries, and the consequences of the high prevalence of smoking in India and China are mostly still to be …

MethodsWe searched 3 databases (including CENTRAL, MEDLINE, and Embase) and 2 trials registers and reviewed reference lists to February 2021. We included only randomized controlled trials comparing clinical outcomes of carotid endarterectomy using local anesthesia and that done under general anesthesia. Data extraction, risk of bias assessment, and quality of evidence were measured by 3 independent reviewers. We analyzed a pooled Peto odds ratio and corresponding 95% CI for stroke and death occurring within 30 days of surgery. We performed meta-analysis using RevMan 5.4.

Background and ObjectivesIndividuals with chronic kidney disease (CKD) appear to be at increased risk of cognitive impairment, with both vascular and neurodegenerative mechanisms postulated. To explore the vascular hypothesis, we studied the association between CKD and dementia before and after TIA and stroke.MethodsIn a prospective, population-based cohort study of TIA and stroke (Oxford Vascular Study; 2002–2012), pre-event and new postevent dementia were ascertained through direct patient assessment and follow-up for 5 years, supplemented by review of hospital/primary care records. Associations between pre-event dementia and CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) were examined using logistic regression and between postevent dementia and CKD using Cox and competing risk regression models, adjusted for age, sex, education, stroke …

Cerebral microbleeds (CMBs) appear as small, circular, well defined hypointense lesions of a few mm in size on T2*-weighted gradient recalled echo (T2*-GRE) images and appear enhanced on susceptibility weighted images (SWI). Due to their small size, contrast variations and other mimics (e.g. blood vessels), CMBs are highly challenging to detect automatically. In large datasets (e.g. the UK Biobank dataset), exhaustively labelling CMBs manually is difficult and time consuming. Hence it would be useful to preselect candidate CMB subjects in order to focus on those for manual labelling, which is essential for training and testing automated CMB detection tools on these datasets. In this work, we aim to detect CMB candidate subjects from a larger dataset, UK Biobank, using a machine learning-based, computationally light pipeline. For our evaluation, we used 3 different datasets, with different intensity characteristics, acquired with different scanners. They include the UK Biobank dataset and two clinical datasets with different pathological conditions. We developed and evaluated our pipelines on different types of images, consisting of SWI or GRE images. We also used the UK Biobank dataset to compare our approach with alternative CMB preselection methods using non-imaging factors and/or imaging data. Finally, we evaluated the pipeline's generalisability across datasets. Our method provided subject-level detection accuracy >80% on all the datasets (within-dataset results), and showed good generalisability across datasets, providing a consistent accuracy of over 80%, even when evaluated across different modalities.

BackgroundEffects of early blood pressure (BP) lowering on cerebral perfusion in patients with moderate/severe occlusive carotid disease after transient ischemic attack (TIA) and non-disabling stroke are uncertain.AimsWe aimed to evaluate the changes in transcranial Doppler (TCD) indices in patients undergoing blood pressure lowering soon after TIA/non-disabling stroke.MethodsConsecutive eligible patients (1 November 2011 to 30 October 2018) attending a rapid-access clinic with TIA/non-disabling stroke underwent telemetric home blood pressure monitoring (HBPM) for 1 month and middle cerebral artery velocities measurements ipsilateral to carotid stenosis on TCD ultrasound in the acute setting and at 1 month. Hypertensive patients (HBPM ⩾ 135/85) underwent intensive BP-lowering guided by HBPM unless they had bilateral severe occlusive disease (⩾ 70%). Changes in BP and TCD parameters …

ImportanceOverall stroke incidence is falling in high-income countries, but data on time trends in incidence of young stroke (ie, stroke in individuals younger than 55 years) are conflicting. An age-specific divergence in incidence, with less favorable trends at younger vs older ages, might be a more consistent underlying finding across studies.ObjectiveTo compare temporal trends in incidence of stroke at younger vs older ages in high-income countries.Data SourcesPubMed and EMBASE were searched from inception to February 2022. One additional population-based study (Oxford Vascular Study) was also included.Study SelectionStudies reporting age-specific stroke incidence in high-income countries at more than 1 time point.Data Extraction and SynthesisFor all retrieved studies, 2 authors independently reviewed the full text against the inclusion criteria to establish their eligibility. Meta-analysis was performed …

Mitochondria are implicated in the pathogenesis of cardiovascular diseases (CVDs) but the reasons for this are not well understood. Maternally-inherited population variants of mitochondrial DNA (mtDNA) which affect all mtDNA molecules (homoplasmic) are associated with cardiometabolic traits and the risk of developing cardiovascular disease. However, it is not known whether mtDNA mutations only affecting a proportion of mtDNA molecules (heteroplasmic) also play a role. To address this question, we performed a high-depth (~1000-fold) mtDNA sequencing of blood DNA in 1,399 individuals with hypertension (HTN), 1,946 with ischemic heart disease (IHD), 2,146 with ischemic stroke (IS), and 723 healthy controls. We show that the per individual burden of heteroplasmic single nucleotide variants (mtSNVs) increases with age. The age-effect was stronger for low-level heteroplasmies (heteroplasmic fraction, HF, 5–10%), likely reflecting acquired somatic events based on trinucleotide mutational signatures. After correcting for age and other confounders, intermediate heteroplasmies (HF 10–95%) were more common in hypertension, particularly involving non-synonymous variants altering the amino acid sequence of essential respiratory chain proteins. These findings raise the possibility that heteroplasmic mtSNVs play a role in the pathophysiology of hypertension.

Methods83 patients with MRI evidence of SVD were recruited from the Oxford Vascular Study (OXVASC) and Oxford neurology clinics. They were investigated using a novel effort-based decision making task and the Apathy Evaluation Scale (AES). Structural and diffusion weighted MRI was conducted to measure white matter lesion load (WMLL) and tract integrity, indexed by Fractional anisotropy (FA).ResultsPatients with apathy demonstrated a significant reduction in motivated behaviour and were sig-nificantly less incentivised by low levels of reward. Diffusion weighted imaging demonstrated that apathy was characterised by focal changes to limbic association tracts, including the uncinate fasciculus and cingulum bundle, as well as fronto-striatal white matter tracts. Importantly, global measures of disease severity did not independently associate with apathy.DiscussionReduced incentivisation by low reward …

Introduction: Genetic studies of early-onset disease have been an effective strategy to identify novel pathways and drug targets generalizable also to later-onset disease. Few studies have investigated the sex-specific genetic associations with early-onset ischemic stroke even though several features of ischemic stroke differ between males and females. We hypothesized that stratifying the GWAS by sex would reveal novel stroke loci. Methods: We performed a transethnic ischemic stroke GWAS of 3,056 female cases and 4,462 male cases < 60 years-old and 16,192 and 16,048 sex-matched controls, respectively, from the Early Onset Stroke Genetics Consortium. Results: We identified a significant association in women with a locus in close proximity to TMX1, a transmembrane platelet protein that inhibits platelet function. Additionally, we identified 2 other suggestive (P < 5 x 10-6) loci in females (see Table), i.e., at …

BackgroundStudies have suggested that evening dosing with antihypertensive therapy might have better outcomes than morning dosing. The Treatment in Morning versus Evening (TIME) study aimed to investigate whether evening dosing of usual antihypertensive medication improves major cardiovascular outcomes compared with morning dosing in patients with hypertension.MethodsThe TIME study is a prospective, pragmatic, decentralised, parallel-group study in the UK, that recruited adults (aged ≥18 years) with hypertension and taking at least one antihypertensive medication. Eligible participants were randomly assigned (1:1), without restriction, stratification, or minimisation, to take all of their usual antihypertensive medications in either the morning (0600–1000 h) or in the evening (2000–0000 h). Participants were followed up for the composite primary endpoint of vascular death or hospitalisation for non …

Background brain imaging done as part of standard care may have clinical utility beyond its immediate indication. Using delirium as an exemplar, we determined the predictive value of baseline brain imaging variables [white matter changes (WMC) and atrophy] for delirium risk on long-term follow-up after transient ischemic attack (TIA)/stroke in a population-based cohort study. Methods surviving TIA/stroke participants in the Oxford Vascular Study (OXVASC) were assessed prospectively for delirium during all hospitalisations over 6 months (2013–14). Using logistic regression, independent associations were determined between baseline OXVASC computed tomography or magnetic resonance brain imaging measures of WMC and cerebral atrophy (none/mild versus moderate/severe) and delirium adjusted for age, sex, baseline stroke severity, depression, illness severity and …

Patients who have ischaemic stroke or a transient ischaemic attack have a high risk of recurrent ischaemic stroke. This risk is highest in the first few days after the primary ischaemic event and then slowly decreases over time. Therefore, it is important to start secondary prevention as soon as possible, ideally oriented to the pathophysiology of cerebral ischaemia in the individual patient. Early antithrombotic therapy is particularly important. Several large randomised trials have found that aspirin significantly reduces the risk of recurrent ischaemic stroke in patients without overt atrial fibrillation, with the greatest benefit in the first few weeks after transient ischaemic attack or stroke. 1 Subsequent trials found that the combinations of aspirin plus clopidogrel or aspirin plus ticagrelor were more effective than aspirin monotherapy during this early high-risk period, albeit with an increased bleeding risk. 2 However, in longer …

White matter hyperintensities (WMHs) have been associated with various cerebrovascular and neurodegenerative diseases. Reliable quantification of WMHs is essential for understanding their clinical impact in normal and pathological populations. Automated segmentation of WMHs is highly challenging due to heterogeneity in WMH characteristics between deep and periventricular white matter, presence of artefacts and differences in the pathology and demographics of populations. In this work, we propose an ensemble triplanar network that combines the predictions from three different planes of brain MR images to provide an accurate WMH segmentation. In the loss functions the network uses anatomical information regarding WMH spatial distribution in loss functions, to improve the efficiency of segmentation and to overcome the contrast variations between deep and periventricular WMHs. We evaluated our …

Background: One-year risk of stroke in transient ischemic attack and minor stroke (TIAMS) managed in secondary care settings has been reported as 5–8%. However, evidence for the outcomes of TIAMS in community care settings is limited. Methods: The INternational comparison of Systems of care and patient outcomes In minor Stroke and TIA (INSIST) study was a prospective inception cohort community-based study of patients of 16 general practices in the Hunter–Manning region (New South Wales, Australia). Possible-TIAMS patients were recruited from 2012 to 2016 and followed-up for 12 months post-index event. Adjudication as TIAMS or TIAMS-mimics was by an expert panel. We established 7-days, 90-days, and 1-year risk of stroke, TIA, myocardial infarction (MI), coronary or carotid revascularization procedure and death; and medications use at 24 h post-index event. Results: Of 613 participants (mean age; 70 ± 12 years), 298 (49%) were adjudicated as TIAMS. TIAMS-group participants had ischemic strokes at 7-days, 90-days, and 1-year, at Kaplan-Meier (KM) rates of 1% (95% confidence interval; 0.3, 3.1), 2.1% (0.9, 4.6), and 3.2% (1.7, 6.1), respectively, compared to 0.3, 0.3, and 0.6% of TIAMS-mimic-group participants. At one year, TIAMS-group-participants had twenty-five TIA events (KM rate: 8.8%), two MI events (0.6%), four coronary revascularizations (1.5%), eleven carotid revascularizations (3.9%), and three deaths (1.1%), compared to 1.6, 0.6, 1.0, 0.3, and 0.6% of TIAMS-mimic-group participants. Of 167 TIAMS-group participants who commenced or received enhanced therapies, 95 (57%) were treated within 24 h post-index …

Background and Purpose: No systematic review of the literature has dedicated itself to looking at the management of symptomatic carotid stenosis in women. In this scoping review, we aimed to identify all randomized controlled trials (RCTs) that reported sex-specific outcomes for patients who underwent carotid revascularization, and determine whether sufficient information is reported within these studies to assess women’s short and long-term outcomes. Methods: We systematically searched Medline, Embase, Pubmed, and Cochrane libraries for RCTs published between 1991 and 2020 that included women and compared either endarterectomy with stenting, or any revascularization (endarterectomy or stenting) with medical therapy in patients with symptomatic high grade (greater than 50%) carotid stenosis. Results: From 1,537 references examined, 27 eligible studies were identified. Sex-specific outcomes were …

Patients with small vessel cerebrovascular disease frequently suffer from apathy, a debilitating neuropsychiatric syndrome, the underlying mechanisms of which remain to be established. Here we investigated the hypothesis that apathy is associated with disrupted decision making in effort-based decision making, and that these alterations are associated with abnormalities in the white matter network connecting brain regions that underpin such decisions. Eighty-two patients with MRI evidence of small vessel disease were assessed using a behavioural paradigm as well as diffusion weighted MRI. The decision-making task involved accepting or rejecting monetary rewards in return for performing different levels of physical effort (hand grip force). Choice data and reaction times were integrated into a drift diffusion model that framed decisions to accept or reject offers as stochastic processes approaching a …

BackgroundThe genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease.MethodsWe did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic …

BackgroundPatients with stroke due to spontaneous (non-traumatic) intracerebral haemorrhage (ICH) are at risk of recurrent ICH, ischaemic stroke, and other serious vascular events. We aimed to analyse these risks in population-based studies and compare them with the risks in RESTART, which assessed antiplatelet therapy after ICH.MethodsWe pooled individual patient data from two prospective, population-based inception cohort studies of all patients with an incident firs-in-a-lifetime ICH in Oxfordshire, England (Oxford Vascular Study; April 1, 2002, to Sept 28, 2018) and Lothian, Scotland, UK (Lothian Audit of the Treatment of Cerebral Haemorrhage; June 1, 2010, to May 31, 2013). We quantified the absolute and relative risks of recurrent ICH, ischaemic stroke, or any serious vascular event (non-fatal stroke, non-fatal myocardial infarction, or vascular death), stratified by ICH location (lobar vs non-lobar) and …

Current guidelines for primary and secondary prevention of stroke in patients with carotid atherosclerosis are based on the quantification of the degree of stenosis and symptom status. Recent publications have demonstrated that plaque morphology and composition, independent of the degree of stenosis, are important in the risk stratification of carotid atherosclerotic disease. This finding raises the question as to whether current guidelines are adequate or if they should be updated with new evidence, including imaging for plaque phenotyping, risk stratification, and clinical decision-making in addition to the degree of stenosis. To further this discussion, this roadmap consensus article defines the limits of luminal imaging and highlights the current evidence supporting the role of plaque imaging. Furthermore, we identify gaps in current knowledge and suggest steps to generate high-quality evidence, to add relevant …

BackgroundAmong asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence.MethodsACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly …

Robust automated segmentation of white matter hyperintensities (WMHs) in different datasets (domains) is highly challenging due to differences in acquisition (scanner, sequence), population (WMH amount and location) and limited availability of manual segmentations to train supervised algorithms. In this work we explore various domain adaptation techniques such as transfer learning and domain adversarial learning methods, including domain adversarial neural networks and domain unlearning, to improve the generalisability of our recently proposed triplanar ensemble network, which is our baseline model. We used datasets with variations in intensity profile, lesion characteristics and acquired using different scanners. For the source domain, we considered a dataset consisting of data acquired from 3 different scanners, while the target domain consisted of 2 datasets. We evaluated the domain adaptation …

IntroductionUnruptured intracranial aneurysms (UIAs) are common incidental imaging findings, but there are few data in patients with transient ischaemic attack (TIA)/stroke. The frequency of UIA might be higher due to shared risk factors, but rupture risk might be reduced by intensive secondary prevention. We determined the prevalence and prognosis of UIA in patients with suspected TIA/minor stroke.MethodsAll patients referred to the population-based Oxford Vascular Study (2011–2020) with suspected TIA/minor stroke and non-invasive angiography were included. We determined the prevalence of incidental asymptomatic UIA and the risk of subsequent subarachnoid haemorrhage (SAH) by follow-up on intensive medical treatment, with guideline-based monitoring/management. We also did a systematic review of UIA prevalence/prognosis in cohorts with TIA/stroke.FindingsAmong 2013 eligible patients, 95 (4.7 …

Background and Purpose Prestroke dementia prevalence is high and impacts outcome. Although the IQCODE (Informant Questionnaire on Cognitive Decline in the Elderly) is being used to assess prestroke cognition, data on its validity for prestroke dementia are lacking. We studied the accuracy of the short-form (16-item) IQCODE for pre-event dementia in a population-based study of all transient ischemic attack (TIA)/stroke. Methods All patients with TIA/stroke in a defined population of ≈92 720 (Oxford Vascular Study, 2002–2017) with IQCODE were included. IQCODE questionnaires were given to participants at baseline interview with instructions to pass to an informant for completion and return by post. Diagnosis of pre-event dementia was defined as prior diagnosis of dementia, or dementia by the Diagnostic and Statistical Manual of Mental Disorders-IV criteria on study interview and hand-searching of the …

ObjectiveCurrent guidelines recommending rapid revascularisation of symptomatic carotid stenosis are largely based on data from clinical trials performed at a time when best medical therapy was potentially less effective than today. The risk of stroke and its predictors among patients with symptomatic carotid stenosis awaiting revascularisation in recent randomised controlled trials (RCTs) and in medical arms of earlier RCTs was assessed.MethodsThe pooled data of individual patients with symptomatic carotid stenosis randomised to stenting (CAS) or endarterectomy (CEA) in four recent RCTs, and of patients randomised to medical therapy in three earlier RCTs comparing CEA vs. medical therapy, were compared. The primary outcome event was any stroke occurring between randomisation and treatment by CAS or CEA, or within 120 days after randomisation.ResultsA total of 4 754 patients from recent trials and …

ObjectiveNo systematic review of the literature has dedicated itself to looking at the management of symptomatic carotid stenosis in female patients. In this scoping review, we aimed to identify all randomised controlled trials (RCTs) that reported sex-specific outcomes for patients who underwent carotid revascularisation, and determine whether sufficient information is reported within these studies to assess short-term and long-term outcomes in female patients.Design, setting and participantsWe systematically searched Medline, Embase, Pubmed and Cochrane libraries for RCTs published between 1991 and 2020 that included female patients and compared either endarterectomy with stenting, or any revascularisation (endarterectomy or stenting) with medical therapy in patients with symptomatic high-grade (>50%) carotid stenosis.ResultsFrom 1537 references examined, 27 eligible studies were identified. Sex …

BackgroundThe effects of pharmacological blood-pressure-lowering on cardiovascular outcomes in individuals aged 70 years and older, particularly when blood pressure is not substantially increased, is uncertain. We compared the effects of blood-pressure-lowering treatment on the risk of major cardiovascular events in groups of patients stratified by age and blood pressure at baseline.MethodsWe did a meta-analysis using individual participant-level data from randomised controlled trials of pharmacological blood-pressure-lowering versus placebo or other classes of blood-pressure-lowering medications, or between more versus less intensive treatment strategies, which had at least 1000 persons-years of follow-up in each treatment group. Participants with previous history of heart failure were excluded. Data were obtained from the Blood Pressure Lowering Treatment Triallists' Collaboration. We pooled the data …

ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.

Background and purposePre-stroke dementia prevalence is high and impacts outcome. Although the Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE) is being used to assess pre-stroke cognition, data on its validity for pre-stroke dementia are lacking. We studied the accuracy of the short-form (16-item) IQCODE for pre-event dementia in a population-based study of all TIA/stroke.MethodsAll patients with TIA/stroke in a defined population of 92 728 (Oxford Vascular Study, 2002-2017) with IQCODE were included. IQCODE questionnaires were given to participants at baseline interview with instructions to pass to an informant for completion and return by post. Diagnosis of pre-event dementia was defined as prior diagnosis of dementia, or dementia by the DSM-IV criteria on study interview and hand-searching of the entire medical record blinded to IQCODE. Reliability of the IQCODE for dementia …

Background and Purpose Blood pressure variability (BPV) from beat to beat is associated with an increased risk of cardiovascular events and enables rapid assessment of BPV, but the underlying causes of elevated BPV are unclear. Methods In consecutive patients within 4 to 6 weeks of transient ischemic attack or nondisabling stroke (OXVASC [Oxford Vascular Study]), continuous noninvasive blood pressure was measured beat to beat over 5 minutes (Finometer). Arterial stiffness was measured by carotid-femoral pulse wave velocity (Sphygmocor). After automated and manual data cleaning, associations between BPV (residual coefficient of variation), demographic factors, and arterial stiffness were determined for both systolic and diastolic blood pressure, by ANOVA and linear models. Relationships between demographic factors and arterial stiffness were determined by interaction terms and mediation …

BackgroundIntracranial arterial stenosis (ICAS) is an important cause of stroke worldwide. Separate reports in Caucasians and Asians with stroke/transient ischaemic attack (TIA) have suggested lower ICAS prevalence in Caucasians, but there has been no direct comparisons of the two ethnic groups with the same criteria to define ICAS.MethodsAcute minor stroke or TIA patients in two cohorts respectively recruiting patients in Oxford (2011–2018, predominantly Caucasians) and Hong Kong (2011–2015, predominantly Chinese) were compared. ICAS was defined as ≥50% stenosis/occlusion in any major intracranial artery in MR/CT angiography. Prevalence, distribution and risk factors of ICAS were compared between the two cohorts. We also systematically reviewed literature on ICAS prevalence in stroke/TIA patients in different populations.ResultsAmong 1287 patients from Oxford and 691 from Hong Kong …

BackgroundBeat-to-beat blood pressure variability is associated with increased stroke risk but its importance at different ages is unclear.AimsTo determine the age-sex distribution of blood pressure variability in patients with transient ischemic stroke or minor stroke.MethodsIn consecutive patients within six weeks of transient ischemic stroke or non-disabling stroke (Oxford Vascular Study), non-invasive blood pressure was measured beat-to-beat over five minutes (Finometer). The age-sex distribution of blood pressure variability (residual coefficient of variation) was determined for systolic blood pressure and diastolic blood pressure. The risk of top-decile blood pressure variability was estimated (logistic regression), unadjusted, and adjusted for age, sex, and cardiovascular risk factors.ResultsIn 908 of 1013 patients, excluding 54 in atrial fibrillation and 51 with low quality recordings, residual coefficient of variation …

IntroductionThere is limited knowledge of the effects of blood pressure (BP) lowering on cerebral haemodynamics after transient ischaemic attack (TIA) and non-disabling stroke, particularly at older ages. We aimed to evaluate changes in transcranial Doppler (TCD) haemodynamic indices in patients undergoing early blood pressure lowering after TIA/non-disabling stroke, irrespective of age.Patients and methodsAmong consecutive eligible patients attending a rapid-access clinic with suspected TIA/non-disabling stroke and no evidence of extra/intracranial stenosis, hypertensive ones underwent intensive BP-lowering guided by daily home telemetric blood pressure monitoring (HBPM). Clinic-based BP, HBPM, End-tidal CO2 and bilateral middle cerebral artery (MCA) velocity on TCD were compared in the acute setting versus one-month follow-up; changes were stratified by baseline hypertension (clinic-BP≥140 …

Background and Purpose The PROGRESS trial (Perindopril Protection Against Recurrent Stroke Study) conducted in the early 1990s showed that blood pressure (BP) lowering therapy reduced the risks of recurrent stroke by about 50% after spontaneous intracerebral hemorrhage (ICH). However, the ICH subgroup was a minority, and trial cohorts are invariably selective. Therefore, it is unclear whether the impact of BP control on risk of recurrent stroke in ICH observed in PROGRESS would be as great in real-world practice. Methods We compared BP control (mean BP during study follow-up) and risks of recurrent stroke after first-ever primary ICH in 2 colocated population-based studies before and after the PROGRESS trial (1995–2001) in Oxfordshire: Oxfordshire Community Stroke Project (OCSP; 1981–1986) and OXVASC (Oxford Vascular Study; 2002–2018). Results Two hundred seventy-seven patients …

BackgroundSome studies have suggested a link between antihypertensive medication and cancer, but the evidence is so far inconclusive. Thus, we aimed to investigate this association in a large individual patient data meta-analysis of randomised clinical trials.MethodsWe searched PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from Jan 1, 1966, to Sept 1, 2019, to identify potentially eligible randomised controlled trials. Eligible studies were randomised controlled trials comparing one blood pressure lowering drug class with a placebo, inactive control, or other blood pressure lowering drug. We also required that trials had at least 1000 participant years of follow-up in each treatment group. Trials without cancer event information were excluded. We requested individual participant data from the authors of eligible trials. We pooled individual participant-level data from …

BackgroundIntracranial atherosclerotic stenosis is a highly prevalent cause of stroke worldwide with important ethnic disparities. Widely considered to be a common cause of stroke in Asian and Afro-Caribbean populations, relatively less is known about the burden and significance of intracranial atherosclerotic stenosis in Caucasians.AimsWe aim to highlight recent insights and advances into the prevalence, prognosis, and treatment of symptomatic and asymptomatic atherosclerotic intracranial atherosclerotic stenosis in Caucasian patients.Summary of reviewWe identified 48 articles studying intracranial atherosclerotic stenosis in Caucasian patients with ischemic stroke or transient ischemic attack. Most studies were on hospital-based cohorts of consecutive patients and half were graded as “fair” quality. There was significant variation between studies in the definition of intracranial atherosclerotic stenosis and in …

Cerebral arterial pulsatility is strongly associated with cerebral small vessel disease and lacunar stroke yet its dependence on central versus local haemodynamic processes is unclear. In a population-based study of patients on best medical managment, 4–6 weeks after a TIA or non-disabling stroke, arterial stiffness and aortic systolic, diastolic and pulse pressures were measured (Sphygmocor). Middle cerebral artery peak and trough flow velocities and Gosling’s pulsatility index were measured by transcranial ultrasound. In 981 participants, aortic and cerebral pulsatility rose strongly with age in both sexes, but aortic diastolic pressure fell more with age in men whilst cerebral trough velocity fell more in women. There was no significant association between aortic systolic or diastolic blood pressure with cerebral peak or trough flow velocity but aortic pulse pressure explained 37% of the variance in cerebral arterial …

Background Long-term antiplatelet treatment is associated with major bleeding. Aims To determine the costs associated with major bleeding in patients treated with aspirin-based antiplatelet treatment for secondary prevention of vascular events without routine prescription of proton-pump inhibitors and to estimate the likely long-term savings from routine co-prescription. Methods In a prospective population-based cohort study of TIA, ischemic stroke, and MI treated with antiplatelet drugs, we evaluated hospital care costs associated with bleed management during 10-year follow-up. Bleeding-associated costs were averaged across all patients. For upper GI-bleeds, mean costs were compared with the cost of routine co-prescription of proton-pump inhibitor. Results Among 3166 patients on antiplatelet therapy with 405 first bleeding events, the average cost of major bleeding was 13,093(SD20,501 …

Mitochondrial DNA (mtDNA) variants influence the risk of late-onset human diseases, but the reasons for this are poorly understood. Undertaking a hypothesis-free analysis of 5,689 blood-derived biomarkers with mtDNA variants in 16,220 healthy donors, here we show that variants defining mtDNA haplogroups Uk and H4 modulate the level of circulating N-formylmethionine (fMet), which initiates mitochondrial protein translation. In human cytoplasmic hybrid (cybrid) lines, fMet modulated both mitochondrial and cytosolic proteins on multiple levels, through transcription, post-translational modification and proteolysis by an N-degron pathway, abolishing known differences between mtDNA haplogroups. In a further 11,966 individuals, fMet levels contributed to all-cause mortality and the disease risk of several common cardiovascular disorders. Together, these findings indicate that fMet plays a key role in common age …

With both an aging population and greater post-stroke survival, multimorbidity is a growing healthcare challenge, affecting over 40% of stroke patients, and rising rapidly and predictably with increasing age. Commonly defined as the co-occurrence of two or more chronic conditions, multimorbidity burden is a strong adverse prognostic factor, associated with greater short- and long-term stroke mortality, worse rehabilitation outcomes, and reduced use of secondary prevention. Chronic kidney disease can be considered as the archetypal comorbidity, being age-dependent and also affecting about 40% of stroke patients. Chronic kidney disease and stroke share very similar traditional cardiovascular risk factor profiles such as hypertension and diabetes, though novel chronic kidney disease-specific risk factors such as inflammation and oxidative stress have also been proposed. Using chronic kidney disease as an …

BackgroundBalancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk.MethodsWe did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke …

BackgroundDiagnosis of transient ischaemic attacks (TIAs) can be difficult. There is consensus on classic symptoms (eg, motor weakness, dysphasia, hemianopia, monocular visual loss) but no consensus on several monosymptomatic events with sudden-onset, non-progressive, focal negative symptoms (eg, isolated diplopia, dysarthria, vertigo, ataxia, sensory loss, and bilateral visual disturbance), with much variation in investigation and treatment.MethodsWe prospectively ascertained and investigated all strokes and sudden onset transient neurological symptoms in a population of 92 728 people (no age restrictions) from Oxfordshire, UK, who sought medical attention at nine primary care practices or at the John Radcliffe Hospital, Oxford, UK (Oxford Vascular Study). Patients classified at baseline with minor ischaemic stroke (National Institutes of Health Stroke Score <5), classic TIA, or non-consensus TIA were …

BackgroundThe effects of pharmacological blood pressure lowering at normal or high-normal blood pressure ranges in people with or without pre-existing cardiovascular disease remains uncertain. We analysed individual participant data from randomised trials to investigate the effects of blood pressure lowering treatment on the risk of major cardiovascular events by baseline levels of systolic blood pressure.MethodsWe did a meta-analysis of individual participant-level data from 48 randomised trials of pharmacological blood pressure lowering medications versus placebo or other classes of blood pressure-lowering medications, or between more versus less intensive treatment regimens, which had at least 1000 persons-years of follow-up in each group. Trials exclusively done with participants with heart failure or short-term interventions in participants with acute myocardial infarction or other acute settings were …

Study designProspective, population-based study (Oxford Vascular Study) between April 1, 2002, and April 1, 2017, and a systematic review using MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials between January 1, 1980, and October 1, 2020.

1 Howard DPJ, Gaziano L, Rothwell PM. Risk of stroke in relation to degree of asymptomatic carotid stenosis: a population-based cohort study, systematic review, and meta-analysis. Lancet Neurol 2021; 20: 193–202. 2 Nicolaides AN, Kakkos SK, Kyriacou E, et al. Asymptomatic internal carotid artery stenosis and cerebrovascular risk stratification.