Stroke in the Time of Circadian Medicine.

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 active phase. This review underscores the importance of considering circadian biology for understanding the pathology and treatment choice for stroke and vascular dementia and speculates that considering a patient's chronotype may be an important factor in developing precision treatment following stroke.

Heteroplasmic mitochondrial DNA variants in cardiovascular diseases.

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.

Decision-Making for Preventive Interventions in Asymptomatic Patients.

The decision to treat an incidental finding in an asymptomatic patient results from careful risk-benefit consideration and is often challenging. One of the main aspects is after how many years the group who underwent the intervention and faced the immediate treatment complications will gain a treatment benefit over the conservatively managed group, which maintains a lower but ongoing risk. We identify a common error in decision-making. We illustrate how a risk-based approach using the classical break-even point at the Kaplan-Meier curves can be misleading and advocate for using an outcome-based approach, counting the cumulative number of lost quality-adjusted life years instead. In clinical practice, we often add together the yearly risk of the natural course up to the time point where the number equals the risk of the intervention and assume that the patient will benefit from an intervention beyond this point in time. It corresponds to the crossing of the Kaplan-Meier curves. However, because treatment-related poor outcome occurs at the time of the intervention, while the poor outcome in the conservative group occurs over a given time period, the true benefit of retaining more quality-adjusted life years in the interventional group emerges at a much later time. To avoid overtreatment of patients with asymptomatic diseases, decision-making should be outcome-based with counting the cumulative loss of quality-adjusted life years, rather than risk-based, comparing the interventional risk with the ongoing yearly risk of the natural course.

Long-Term Outcomes in Patients With Spontaneous Cerebellar Hemorrhage: An International Cohort Study.

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 was 67 months (interquartile range, 23-100 months), with a cumulative survival rate of 34% at 10-year follow-up (median follow-up time per center ranged: 15-80 months). In the 347 patients with data on vascular events 92 events occurred in 78 patients, after initial cerebellar ICH: 31 (8.9%) patients had a recurrent ICH (absolute event rate, 1.8 per 100 patient-years [95% CI, 1.2-2.6]), 39 (11%) had an ischemic stroke (absolute event rate, 2.3 [95% CI, 1.6-3.2]), 13 (3.7%) had a myocardial infarction (absolute event rate, 0.8 [95% CI, 0.4-1.3]), and 5 (1.4%) underwent major vascular surgery (absolute event rate, 0.3 [95% CI, 0.1-0.7]). The median time to a first vascular event during follow-up was 27 months (interquartile range, 8.7-50 months), with a cumulative hazard of 47% at 10 years. CONCLUSIONS: The long-term prognosis of patients who survive a first spontaneous cerebellar ICH is poor and comparable to that of patients who survive a first supratentorial ICH. Further identification of patients at high risk of vascular events following the initial cerebellar ICH is needed. Including patients with cerebellar ICH in randomized controlled trials on secondary prevention of patients with ICH is warranted.

Consensus Recommendations for Standardized Data Elements, Scales, and Time Segmentations in Studies of Human Circadian/Diurnal Biology and Stroke.

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 definitions and coding guides for data collection, permitting rapid aggregation of data acquired in different studies, and ensuring a common framework for analysis. To meet this need, the Leducq Consortium International pour la Recherche Circadienne sur l'AVC (CIRCA) convened a Consensus Statement Working Group of leading international researchers in cerebrovascular and circadian/diurnal biology. Using an iterative, mixed-methods process, the working group developed 79 data standards, including 48 common data elements (23 new and 25 modified/unmodified from existing common data elements), 14 intervals for time-anchored analyses of different granularity, and 7 formal, validated scales. This portfolio of standardized data structures is now available to assist researchers in the design, implementation, aggregation, and interpretation of clinical, imaging, and population research related to the influence of human circadian/diurnal biology upon ischemic and hemorrhagic stroke.

C-Reactive Protein, Interleukin-6, and Vascular Recurrence After Stroke: An Individual Participant Data Meta-Analysis.

BACKGROUND: Anti-inflammatory therapies reduce recurrent vascular events in coronary disease. Existing studies have reported highly conflicting findings for the association of blood inflammatory markers with vascular recurrence after stroke leading to uncertainty about the potential of anti-inflammatory therapies after stroke and no consensus about the utility of measurement of inflammatory markers in current guidelines. METHODS: We investigated the association between hsCRP (high-sensitivity C-reactive protein), IL-6 (interluekin-6), and recurrent major adverse cardiovascular events (MACE), and stroke from individual participant data from 8420 patients with ischemic stroke/transient ischemic attack from 10 prospective studies. We did within-study multivariable regression analyses and then combined adjusted risk ratio (RR) by random-effects meta-analysis. RESULTS: During 18 920 person-years of follow-up, 1407 (16.7% [95% CI, 15.9-17.5]) patients had MACE and 1191 (14.1% [95% CI, 13.4-14.9]) patients had recurrent stroke. On bivariate analysis, baseline IL-6 was associated with MACE (RR, 1.26 [95% CI, 1.10-1.43]) and recurrent stroke (RR, 1.18 [95% CI, 1.05-1.32]), per unit increase logeIL-6. Similar associations were observed for hsCRP (MACE RR, 1.19 [95% CI, 1.09-1.29]; recurrent stroke RR, 1.12 [95% CI, 1.04-1.21], per unit increase logehsCRP). After adjustment for vascular risk factors and treatment, independent associations remained with MACE (IL-6, RR, 1.12 [95% CI, 1.04-1.21]; hsCRP, RR, 1.09 [95% CI, 1.04-1.15]) and recurrent stroke (IL-6, RR, 1.09 [95% CI, 1.00-1.19]; hsCRP, RR, 1.05 [95% CI, 1.00-1.11]). Comparing the top with the bottom quarters (Q4 versus Q1), IL-6 (RR, 1.35 [95% CI, 1.09-1.67]) and hsCRP (RR, 1.31 [95% CI, 1.07-1.61]) were associated with MACE after adjustment. Similar results were observed for recurrent stroke for IL-6 (RR, 1.33 [95% CI, 1.08-1.65]) but not hsCRP (RR, 1.16 [95% CI, 0.93-1.43]). CONCLUSIONS: Blood markers of inflammation were independently associated with vascular recurrence after stroke, strengthening the rationale for randomized trials of anti-inflammatory therapies for secondary prevention after ischemic stroke/TIA.

Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial.

BACKGROUND: Studies 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. METHODS: The 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-fatal myocardial infarction or non-fatal stroke. Endpoints were identified by participant report or record linkage to National Health Service datasets and were adjudicated by a committee masked to treatment allocation. The primary endpoint was assessed as the time to first occurrence of an event in the intention-to-treat population (ie, all participants randomly assigned to a treatment group). Safety was assessed in all participants who submitted at least one follow-up questionnaire. The study is registered with EudraCT (2011-001968-21) and ISRCTN (18157641), and is now complete. FINDINGS: Between Dec 17, 2011, and June 5, 2018, 24 610 individuals were screened and 21 104 were randomly assigned to evening (n=10 503) or morning (n=10 601) dosing groups. Mean age at study entry was 65·1 years (SD 9·3); 12 136 (57·5%) participants were men; 8968 (42·5%) were women; 19 101 (90·5%) were White; 98 (0·5%) were Black, African, Caribbean, or Black British (ethnicity was not reported by 1637 [7·8%] participants); and 2725 (13·0%) had a previous cardiovascular disease. By the end of study follow-up (March 31, 2021), median follow-up was 5·2 years (IQR 4·9-5·7), and 529 (5·0%) of 10 503 participants assigned to evening treatment and 318 (3·0%) of 10 601 assigned to morning treatment had withdrawn from all follow-up. A primary endpoint event occurred in 362 (3·4%) participants assigned to evening treatment (0·69 events [95% CI 0·62-0·76] per 100 patient-years) and 390 (3·7%) assigned to morning treatment (0·72 events [95% CI 0·65-0·79] per 100 patient-years; unadjusted hazard ratio 0·95 [95% CI 0·83-1·10]; p=0·53). No safety concerns were identified. INTERPRETATION: Evening dosing of usual antihypertensive medication was not different from morning dosing in terms of major cardiovascular outcomes. Patients can be advised that they can take their regular antihypertensive medications at a convenient time that minimises any undesirable effects. FUNDING: British Heart Foundation.

Low Heart Rate Is Associated with Cerebral Pulsatility after TIA or Minor Stroke.

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 bpm/mmHg: -0.02, -0.04, 0.03, all p < 0.001), with HR particularly associated with low end-diastolic cerebral velocity (0.86, p = 0.014). Beat-to-beat HR was strongly associated with concurrent low DBP and high SBP, potentially mediating the association with greater beat-to-beat cerebral pulsatility (average ∆MCA-PI vs HR/DBP/SBP unadjusted: -0.062, -0.052, 0.0092; adjusted for concurrent BP: -0.039, -0.11, 0.041). The beat-to-beat association between HR and MCA-PI increased with age, beta-blockers, arterial stiffness, low HR (age > 70 + HR < 65 vs age < 70 + HR > 65: -0.081 vs -0.024, interaction p < 0.001), and severe SVD on MRI (age > 70 + severe vs age < 70 + none: -0.087 vs -0.047, interaction p = 0.03), with interactions between age, severe SVD, and low HR synergistically increasing MCA-PI. INTERPRETATION: Low HR is associated with greater cerebral pulsatility in patients with SVD, potentially mediated by lower diastolic blood flow and representing a novel potential treatment target. ANN NEUROL 2022;92:909-920.

Consistencies and Differences in Intermediate Physiological Phenotypes of Vascular Ageing between Ischaemic Stroke Aetiologies.

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 (SVD), cardioembolic (CE), or undetermined events were derived, including adjustment for cardiovascular risk factors. Relationships were characterized by mixed linear models. RESULTS: In 909 eligible patients, MCA-PI, PWV, and SBPV were all positively skewed. Mean values were greatest in LAS than CE and lowest in SVD (p < 0.001). However, after adjustment for age, sex, and risk factors, PI was greatest in LAS and lowest in CE stroke, whilst PWV was greatest in SVD and undetermined stroke (p < 0.001). In multivariate linear models, age was more strongly associated with PWV and PI in patients with small vessel stroke than other aetiologies, particularly under the age of 65, but SBPV was only weakly associated with demographic indices in all stroke subtypes. CONCLUSIONS: Intermediate cardiovascular phenotypes of vascular ageing had similar demographic associations between stroke aetiologies, but these were particularly strong in patients with small vessel stroke under the age of 65, implying a potential role of these phenotypes in increasing stroke risk in this patient group.

Rural versus metropolitan comparison of processes of care in the community-based management of TIA and minor stroke in Australia (an analysis from the INSIST study).

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 years (SD, 10.7) and 127 (43%) were women. Rural participants were more likely to be managed solely by a general practitioner (GP) than metropolitan participants (34% v 20%) and less likely to be referred to a JHHANC specialist (13% v 38%) or have brain magnetic resonance imaging (MRI) [24% v 51%]. Those rural participants who were referred, also waited longer (both p < 0.001). Recurrent stroke, myocardial infarction and death at 12 months were not significantly different between rural and metropolitan participants. CONCLUSIONS: Although TIAMS prognosis in rural settings where solely GP care is common is very good, the processes of care in such areas are inferior to metropolitan. This suggests there is further scope to support rural GPs to optimise care of TIAMS patients.

Long-Term Secondary Prevention: Management of Blood Pressure After a Transient Ischemic Attack or Stroke.

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 promise to improve management of BP in current practice.

Aortic Stiffness, Pulse Pressure, and Cerebral Pulsatility Progress Despite Best Medical Management: The OXVASC Cohort.

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 determined by intraclass correlation coefficients. Rates of progression and their determinants, stratified by age and sex, were determined by mixed-effects linear models, adjusted for age, sex, and cardiovascular risk factors. RESULTS: In 188 surviving, eligible patients with repeat assessments after a median of 5.8 years. PWV, aoPP, and MCA-PI were highly reproducible (intraclass correlation coefficients, 0.71, 0.59, and 0.65, respectively), with progression of PWV (2.4%; P<0.0001) and aoPP (3.5%; P<0.0001) but not significantly for MCA-PI overall (0.93; P=0.22). However, PWV increased at a faster rate with increasing age (0.009 m/s per y/y; P<0.0001), while aoPP and MCA-PI increased significantly above the age of 55 years (aoPP, P<0.0001; MCA-PI, P=0.009). Higher aortic systolic blood pressure and diastolic blood pressure predicted a greater rate of progression of PWV and aoPP, but not MCA-PI, although current MCA-PI was particularly strongly associated with concurrent aoPP (P<0.001). CONCLUSIONS: Arterial pulsatility and aortic stiffness progressed significantly after 55 years of age despite the best medical treatment. Progression of stiffness and aoPP was determined by high blood pressure, but MCA-PI predominantly reflected current aoPP. Treatments targetting cerebral pulsatility may need to principally target aortic stiffness and pulse pressure to have the potential to prevent cerebral small vessel disease.

Long-Term Impact of Urgent Secondary Prevention After Transient Ischemic Attack and Minor Stroke: Ten-Year Follow-Up of the EXPRESS Study.

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 on 10-year recurrent stroke risk, functional outcomes, quality-of-life, and costs. RESULTS: A reduction in stroke risk in phase 2 was still evident at 10 years (55/23.3% versus 82/31.6%; hazard ratio=0.68 [95% CI, 0.48-0.95]; P=0.024), as was the impact on risk of disabling or fatal stroke (17/7.7% versus 32/13.1%; hazard ratio=0.54 [0.30-0.97]; P=0.036). These effects were due to maintenance of the early reduction in stroke risk, with neither additional benefit nor rebound catch-up after 90 days (post-90 days hazard ratio=0.88 [0.65-1.44], P=0.88; and hazard ratio=0.83 [0.42-1.65], P=0.59, respectively). Disability-free life expectancy was 0.59 (0.03-1.15; P=0.043) years higher in patients in phase 2, as was quality-adjusted life expectancy (0.49 [0.03-0.95]; P=0.036). Overall, 10-year costs were nonsignificantly higher in patients attending the phase 2 clinic ($1022 [-3865-5907]; P=0.66). The additional cost per quality-adjusted life year gained in phase 2 versus phase 1 was $2103, well below current cost-effectiveness thresholds. CONCLUSIONS: Urgent assessment and treatment of patients with transient ischemic attack or minor stroke resulted in a long-term reduction in recurrent strokes and improved outcomes, with little atrophy of the early benefit over time, representing good value for money even with a 10-year time horizon. Our results suggest that other effective acute treatments in transient ischemic attack/minor stroke in the short-term will also have the potential to have long-term benefit.

Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes: Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6.

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 blood pressure, estimated glomerular filtration rate, and prior atrial fibrillation on treatment effects was assessed using interaction P values. Risk of major adverse cardiovascular event was analyzed according to prior stroke. RESULTS: A total of 106/6480 participants had a stroke (1.0 event/100 patient-years of observation [PYO]). Semaglutide reduced incidence of any stroke versus placebo (0.8 versus 1.1 events/100 PYO; hazard ratio, 0.68 [95% CI, 0.46-1.00]; P=0.048), driven by significant reductions in risk of small-vessel occlusion (0.3 versus 0.7 events/100 PYO; hazard ratio, 0.51 [95% CI, 0.29-0.89]; P=0.017). Hazard ratios for risk of any stroke with semaglutide versus placebo were 0.60 (95% CI, 0.37-0.99; 0.5 versus 0.9 events/100 PYO) and 0.89 (95% CI, 0.47-1.69; 2.7 versus 3.0 events/100 PYO) in those without and with prior stroke, respectively. Except for prior atrial fibrillation (Pinteraction=0.025), no significant interactions were observed between treatment effects on risk of any stroke and subgroups investigated, or between treatment effects on risk of major adverse cardiovascular event and prior stroke (Pinteraction >0.05 for all). CONCLUSIONS: Semaglutide reduced incidence of any first stroke during the trials versus placebo in people with type 2 diabetes at high cardiovascular risk, primarily driven by small-vessel occlusion prevention. Semaglutide treatment, versus placebo, lowered the risk of stroke irrespective of prior stroke at baseline. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01720446 and NCT02692716.

Diagnosis of non-consensus transient ischaemic attacks with focal, negative, and non-progressive symptoms: population-based validation by investigation and prognosis.

BACKGROUND: Diagnosis 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. METHODS: We 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 treated according to secondary prevention guidelines. Risks of stroke (7-day, 90-day, and 10-year risks) and risks of all major vascular events (from the time of first event, and from the time of seeking medical attention) were established by face-to-face follow-up visits and were compared with the risk expected from age and sex-specific stroke incidence in the underlying study population. FINDINGS: Between April 1, 2002, and March 31, 2018, 2878 patients were identified with minor ischaemic stroke (n=1287), classic TIA (n=1021), or non-consensus TIA (n=570). Follow-up was to Oct 1, 2018 (median 5·2 [IQR 2·6-9·2] years). 577 first recurrent strokes after the index event occurred during 17 009 person-years of follow-up. 90-day stroke risk from time of the index event after a non-consensus TIA was similar to that after classic TIA (10·6% [95% CI 7·8-12·9] vs 11·6% [95% CI 9·6-13·6]; hazard ratio 0·87, 95% CI 0·64-1·19; p=0·43), and higher than after amaurosis fugax (4·3% [95% CI 0·6-8·0]; p=0·042). However, patients with non-consensus TIA were less likely to seek medical attention on the day of the event than were those with classic TIA (336 of 570 [59%] vs 768 of 1021 [75%]; odds ratio [OR] 0·47, 95% CI 0·38-0·59; p<0·0001) and were more likely to have recurrent strokes before seeking attention (45 of 570 [8%] vs 47 of 1021 [5%]; OR 1·77, 95% CI 1·16-2·71; p=0·007). After excluding such recurrent strokes, 7-day stroke risk after seeking attention for non-consensus TIA (2·9% [95% CI 1·5-4·3]) was still considerably higher than the expected background risk (relative risk [RR] 203, 95% CI 113-334), particularly if the patient sought attention on the day of the index event (5·0% [2·1-7·9]; RR 300, 137-569). 10-year risk of all major vascular events was similar for non-consensus and classic TIAs (27·1% [95% CI 22·8-31·4] vs 30·9% [27·2-33·7]; p=0·12). Baseline prevalence of atrial fibrillation, patent foramen ovale, and arterial stenoses were also similar for non-consensus TIA and classic TIA, although stenoses in the posterior circulation were more frequent with non-consensus TIA (OR 2·21, 95% CI 1·59-3·08; p<0·0001). INTERPRETATION: Patients with non-consensus TIA are at high early and long-term risk of stroke and have cardiovascular pathological findings on investigation similar to those of classic TIA. Designation of non-consensus TIAs as definite cerebrovascular events will increase overall TIA diagnoses by about 50%. FUNDING: Wellcome Trust, National Institute for Health Research Oxford Biomedical Research Centre, Wolfson Foundation, Masonic Charitable Foundation, and British Heart Foundation.

Cognitive Predictors of Delirium on Long-Term Follow-Up after TIA and Stroke: Population-Based Cohort Study.

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 depression, baseline stroke severity, and admission illness severity. RESULTS: Among 1,565 TIA/stroke survivors, 158 patients (mean/SD age = 79.2/11.5 years) had ≥1 admission and 59 (37%) had ≥1 delirium episode. Mean/SD time between baseline TIA/stroke and admission was 4.7/3.6 years and between most recent OXVASC cognitive testing and admission was 1.7/1.8 years. MMSE and MoCA scores were associated with delirium: odds ratio (OR) = 1.16 (95% CI 1.07-1.27, p < 0.0001 per point decrease in MMSE) and OR = 1.20 (1.11-1.30, p < 0.0001 MoCA) and associations were robust to adjustment for all covariates, including stroke severity: OR = 1.11 (1.01-1.22, p = 0.03, MMSE) and OR = 1.15 (1.05-1.25, p = 0.003, MoCA). All 10 subtests on the MoCA and 4/11 on the MMSE were significantly associated with delirium with highest predictive value for frontal/executive and recall domains. CONCLUSIONS: Cognitive impairment of increasing severity after TIA/stroke predisposed to delirium particularly deficits in frontal/executive domains and recall. Long-term risk of delirium should be considered as part of the overall cerebrovascular disease burden.

Apathy in small vessel cerebrovascular disease is associated with deficits in effort-based decision making.

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 decision boundary with a particular drift rate. Tract-based spatial statistics were used to assess the relationship between white matter tract integrity and apathy, while accounting for depression. Overall, patients with apathy accepted significantly fewer offers on this decision-making task. Notably, while apathetic patients were less responsive to low rewards, they were also significantly averse to investing in high effort. Significant reductions in white matter integrity were observed to be specifically related to apathy, but not to depression. These included pathways connecting brain regions previously implicated in effort-based decision making in healthy people. The drift rate to decision parameter was significantly associated with both apathy and altered white matter tracts, suggesting that both brain and behavioural changes in apathy are associated with this single parameter. On the other hand, depression was associated with an increase in the decision boundary, consistent with an increase in the amount of evidence required prior to making a decision. These findings demonstrate altered effort-based decision making for reward in apathy, and also highlight dissociable mechanisms underlying apathy and depression in small vessel disease. They provide clear potential brain and behavioural targets for future therapeutic interventions, as well as modelling parameters that can be used to measure the effects of treatment at the behavioural level.

Utility of white matter disease and atrophy on routinely acquired brain imaging for prediction of long-term delirium risk: population-based cohort study.

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 pre-admission cognition. RESULTS: among 1,565 TIA/stroke survivors with 194 hospital admissions (158 patients, mean/standard deviation age at admission = 79.2/11.5 years), delirium occurred in 59 (37%). WMC and atrophy on baseline imaging were associated with delirium [odds ratio (OR) = 3.41, 1.21-5.85, P = 0.001 and OR = 2.50, 1.23-5.08, P = 0.01 (unadjusted) and OR = 2.67, 1.21-5.85, P = 0.02 and OR = 2.18, 1.00-4.73, P = 0.05 (adjusted age and sex)]. Associations were strengthened when analyses were restricted to patients hospitalised within 5 years of baseline brain imaging [OR = 6.04, 2.39-15.24, P < 0.0001 and OR = 4.64, 1.46-14.82, P = 0.009 (unadjusted)] but only WMC remained significant after adjustment for all covariates including pre-admission cognition (OR = 4.83, 1.29-18.13, P = 0.02 for Mini-Mental State Examination and OR = 5.15, 1.26-21.09, P = 0.02 for Montreal Cognitive Assessment). CONCLUSIONS: WMC and atrophy on brain imaging done up to 5 years earlier predicted delirium and may have clinical utility in risk stratification. Associations with WMC but not atrophy were independent of pre-admission cognitive impairment.

Association of Younger vs Older Ages With Changes in Incidence of Stroke and Other Vascular Events, 2002-2018.

Importance: Some 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. Objective: To determine temporal changes in incidence of stroke and other major vascular events at younger vs older ages. Design, Setting, and Participants: Prospective population-based incidence study conducted from April 2002 to March 2018 with a mean catchment population of 94 567 in Oxfordshire, England. Exposures: Calendar time, premorbid vascular risk factors, and occupation. Main Outcomes and Measures: Changes in incidence of stroke, transient ischemic attack (TIA), and other major vascular events (myocardial infarction, sudden cardiac death, and peripheral vascular events) stratified by age, sex, diagnostic workup, etiology, and severity. Results: A total of 2429 incident strokes were ascertained (mean age, 73.6 [SD, 14.4] years; 51.3% female). From 2002-2010 to 2010-2018, stroke incidence increased significantly among participants younger than 55 years (incidence rate ratio [IRR], 1.67; 95% CI, 1.31-2.14) but fell significantly among participants aged 55 years or older (IRR, 0.85; 95% CI, 0.78-0.92; P < .001 for difference). The significant increase in incidence at younger than 55 years was independent of sex, stroke severity, pathological subtype, and changes in investigation and was also seen for TIA (IRR, 1.87; 95% CI, 1.36-2.57) but not for myocardial infarction and other major vascular events (IRR, 0.73; 95% CI, 0.58-0.93). Although TIA and stroke at younger than 55 years were significantly associated with diabetes (risk ratio [RR], 3.47; 95% CI, 2.54-4.74), hypertension (RR, 2.52; 95% CI, 2.04-3.12), current smoking (RR, 2.38; 95% CI, 1.92-2.94), and obesity (RR, 1.36; 95% CI, 1.07-1.72), the significant increase in incidence from 2002-2010 to 2010-2018 was still seen in individuals without these risk factors. The increase was greatest in professional/managerial occupations (IRR, 2.52; 95% CI, 1.75-3.62) and least in partially skilled/unskilled occupations (IRR, 1.17; 95% CI, 0.79-1.74). The proportion of TIAs and strokes among those younger than 55 years without known vascular risk factors increased significantly over time (45 [30.4%] vs 115 [42.4%]; absolute difference, 12.0%; 95% CI, 2.6-21.5), especially in patients with cryptogenic events (10 [18.5%] vs 63 [49.2%]; absolute difference, 30.7%; 95% CI, 17.2-44.2; P < .001; P = .002 for heterogeneity). Conclusions and Relevance: Comparing persons living in Oxfordshire, England, in 2002-2010 vs 2010-2018, there was a significant increase in stroke incidence in those younger than 55 years, but a decrease in those aged 55 years or older. Given the absence of this divergence for other vascular events, further research is needed to understand the causes of this difference.

Blood Pressure Control and Recurrent Stroke After Intracerebral Hemorrhage in 2002 to 2018 Versus 1981 to 1986: Population-Based Study.

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 (1995­2001) in Oxfordshire: Oxfordshire Community Stroke Project (OCSP; 1981­1986) and OXVASC (Oxford Vascular Study; 2002­2018). Results: Two hundred seventy-seven patients (753 patient-years of follow-up) with first-ever primary ICH were ascertained in OXVASC and OCSP. Baseline systolic BP was comparable between the 2 studies (mean/SD=183.8/36.5 in OXVASC versus 178.1/38.2 in OCSP, P=0.30) but among one hundred thirty-seven 90-day survivors, mean BP during follow-up was substantially lower in OXVASC versus OCSP (135.2/16.4 versus 157.3/17.8, P<0.0001). Risks of recurrent stroke (per 100 patient-years) decreased from 10.3 (95% CI, 4.7­19.5) in OCSP to 3.1 (1.8­4.8) in OXVASC (P=0.006), predominantly driven by a reduction at younger ages (5-year risk at age <75 years: 35.4% versus 6.9%, P=0.001; hazard ratio, 0.14 [0.04­0.54]). Conclusions: Risks of recurrent stroke after primary ICH have fallen significantly in Oxfordshire over the past 4 decades, coinciding with substantial improvements in BP control during follow-up.