Peter Malcolm Rothwell

BACKGROUND: Raised inflammatory biomarkers predict an increased short-term risk of recurrent vascular events after stroke or transient ischemic attack, but it is uncertain whether the hazard is maintained thereafter. In the absence of previous population-based studies, we aimed to determine the predictive value of biomarkers for the long-term risk of recurrent stroke in intensively treated patients following transient ischemic attack or stroke. METHODS: We studied 12 blood biomarkers related to inflammation, neuronal cell damage, and thrombosis soon after transient ischemic attack or stroke in a population-based study (OXVASC [Oxford Vascular Study]; 2002–2011) with follow-up to 2025. We used Cox and negative binomial regressions to assess associations between each log-transformed biomarker (per SD increase) and recurrent stroke (first event and total number), adjusted for age, sex, and baseline vascular risk factors. RESULTS: Of 1292 consecutive patients (mean/SD age, 73.1/13.2 years; 47.8% male), 365 recurrent strokes occurred in 280 patients during 11 336 patient-years. All inflammatory biomarkers were associated with 10-year risk of recurrence, with little impact of adjustment for other risk factors (adjusted incidence rate ratio: IL-6 [interleukin-6], 1.21 [95% CI, 1.04–1.42]; CRP [C-reactive protein], 1.29 [95% CI, 1.11–1.49]; TNFR-1 [tumor necrosis factor receptor-1], 1.24 [95% CI, 1.05–1.46]; and NGAL [neutrophil gelatinase–associated lipocalin], 1.15 [95% CI, 0.99–1.33]). Moreover, number of elevated (top quartile) inflammatory markers was associated with higher burden of recurrence (incidence rate ratio, 1.31 [95% CI, 1.15–1.50]; P <0.001), with no diminution over time (90 days: hazard ratio, 1.24 [95% CI, 0.98–1.57]; 90 days–1 year: 1.24 [95% CI, 0.95–1.62]; 1–5 years: 1.22 [95% CI, 1.01–1.47]; and 5–10 years: 1.34 [95% CI, 1.06–1.68]), and similar associations for transient ischemic attack and minor stroke. Biomarkers related to neuronal cell damage or thrombosis were generally less predictive of recurrent stroke. CONCLUSIONS: Inflammatory biomarkers were more predictive of long-term recurrent stroke than neuronal or thrombotic biomarkers, particularly when several inflammatory markers were raised. Predictive value was independent of other vascular risk factors and did not diminish with duration of follow-up, supporting trials of anti-inflammatory strategies for long-term secondary prevention.

Globally, ischaemic stroke is one of the major causes of death and long-term disability, placing a substantial burden on individuals and healthcare systems (Feigin et al., 2021; Ovbiagele & Nguyen-...

Increased pulsatility of cerebral blood flow is proposed as a potential cause of cerebral small vessel disease (SVD), but the apparent association could be confounded by shared vascular risk factors, especially current and past blood pressure (BP). Most previous studies were small, usually in selected populations, and most did not adjust fully for confounders, particularly heart rate, pulse pressure, and premorbid BP. Therefore, we aimed to determine if cerebral pulsatility is independently associated with SVD on brain imaging. Patients with TIA or minor ischemic stroke (NIH Stroke Scale ≤3) ascertained from 2011 to 2018 in a prospective population-based cohort study in Oxfordshire, the United Kingdom, were included. Cerebral pulsatility was measured with pulsatility index at the middle cerebral artery (MCA-PI) by transcranial Doppler ultrasound, and the burden of SVD was assessed using standard rating scales on MRI. We determined the associations of MCA-PI and SVD (total SVD score) adjusting for age, sex, vascular risk factors, heart rate, baseline BP (systolic, diastolic, and pulse pressure), and multiple premorbid BP readings up to 20 years before the event. We also performed mediation analysis to assess the contribution of MCA-PI on the causal pathway between BP and SVD. Among 1,035 consecutive patients with measurements of both MCA-PI and SVD burden on MRI (mean age 66 years; 52.1% men), higher MCA-PI was associated with the total SVD score on MRI (top vs bottom quartile odds ratio [OR] 9.00, 95% CI 6.32-12.84). The association was attenuated after adjustment, but it remained significant (fully adjusted for systolic and diastolic BP OR 2.67, 1.55-4.60; for PP OR 1.88, 1.12-3.14). The results were consistent for individual markers of SVD (p-het = 0.77). In mediation analysis, 25.0% of the total association between premorbid systolic BP and SVD severity was due to MCA-PI. In this cross-sectional analysis, cerebral pulsatility was positively associated with the increasing burden of cerebral SVD on brain MRI independent of age, sex, vascular risk factors, heart rate, baseline and premorbid BP in patients with TIA or minor ischemic stroke, and also explained a significant proportion of the association between BP and cerebral SVD on brain MRI. Prospective cohort studies and clinical trials targeting cerebral pulsatility are underway, which will help to further establish the role of cerebral pulsatility in SVD.

Background and ObjectivesChronic kidney disease is a recognized risk factor for adverse neurocognitive outcomes, but the effect of acute kidney injury (AKI) on brain health remains less well define...

Introduction: Coronary arterial calcification on computed tomography (CT), or CT-coronary artery calcification (CAC), is a widely studied risk factor for acute coronary events, but although intracranial arterial calcification on CT brain imaging (CT-IAC) is also a frequent finding in older individuals, there is no consensus on its prognostic significance, particularly whether its presence, severity, or site predict cognitive impairment or dementia. Given the clinical and mechanistic importance of any associations, we did a systematic review and meta-analysis. Methods: Studies published before 30 January 2026 were identified from bibliographic databases, reference lists, and forward or backward screening. Inclusion criteria were: (1) studies of adults linking CT-IAC/CAC with later cognitive impairment or dementia; (2) reporting adjusted effect measures with 95% confidence interval or p values (or calculable); (3) calcification assessed by CT/CT angiography and cognition by recognised tests or expert evaluation. Studies were summarised qualitatively and pooled quantitatively depending on heterogeneity. Results: Six cross-sectional studies and three longitudinal studies reported data on CT-IAC and cognitive status. Among five studies that reported associations for presence vs. absence of CT-IAC, presence of calcification was weakly associated with cognitive impairment or dementia (three cross-sectional studies – pooled adjusted odds ratio [aOR] = 1.42, 0.88–2.28, p = 0.15; two longitudinal studies – aOR = 1.51, 1.03–2.22, p = 0.033; all studies – aOR = 1.48, 1.10–1.99, p = 0.01). Among five studies that reported associations for more severe vs. milder CT-IAC, severe calcification was more strongly associated with the cognitive outcome (two cross-sectional studies – pooled aOR = 2.29, 0.50–10.57, p = 0.29; three longitudinal studies – aOR = 1.84, 1.28–2.65, p = 0.001; all studies – aOR = 1.74, 1.28–2.36, p = 0.0004), including in two longitudinal cohorts in patients with stroke/transient ischaemic attack (pooled aOR = 1.73, 1.22–2.46, p = 0.002). In two longitudinal studies, severity of vertebrobasilar CT-IAC also predicted dementia (pooled aOR = 2.12, 1.06–4.21, p = 0.033), and severity of medial/internal elastic lamina (IEL) CT-IAC was a stronger predictor of dementia (pooled aOR = 2.35, 1.29–4.28, p = 0.005) than severity of intimal CT-IAC (pooled aOR = 1.29, 0.75–2.23, p = 0.36). For coronary CT-CAC, three longitudinal cohorts revealed weak associations with dementia (per standard deviation increase in calcification measures – pooled adjusted hazards ratio = 1.15, 1.02–1.30, p = 0.025). Conclusion: In longitudinal studies, presence and severity of CT-IAC are both independently associated with dementia, driven mainly by medial/IEL calcification, with weaker associations for intimal and coronary calcification. In cross-sectional studies, the associations for both CT-IAC measures were of a similar magnitude to the longitudinal analyses but were not statistically significant. Future studies should determine age- and dementia-subtype specific associations.

The residual recurrence risk after atrial fibrillation (AF)-related stroke is high despite anticoagulation, thereby necessitating new therapies. The importance of inflammation in AF is increasingly recognized. However, patients with AF-related stroke were excluded from recent trials of anti-inflammatory therapies. It is uncertain whether associations between IL-6/high-sensitivity C-reactive protein (hsCRP) and poststroke recurrence are modified by AF status. In this study, we aimed to analyze the association between IL-6/hsCRP and recurrence according to AF history. We leveraged individual participant data from studies identified by systematic review. We analyzed associations between IL-6/hsCRP and recurrent stroke/major adverse cardiovascular events (MACEs) (defined as fatal or nonfatal recurrent stroke or major coronary events) using multivariable Cox regression analyses (conditional logistic regression for 1 study) adjusted for age, sex, index event, cardiovascular risk factors, and medication use, stratified by AF status. Data from 11 prospective studies with 10,080 patients (2,134 with AF, mean age 70 years, 59.3% male) were included. During 21,080 person-years of follow-up, 1,677 patients had MACEs and 1,342 had recurrent stroke. Inflammatory markers were higher in patients with AF, irrespective of stroke severity and timing of measurement, with elevated levels persisting well beyond the acute phase. hsCRP was associated with recurrent MACEs in patients with AF (adjusted risk ratio [aRR] 1.14, 95% CI 1.04-1.25, per log_e-unit increase) and without AF (aRR 1.08, 1.03-1.13) (P_interaction 0.30). There were similar associations on per-quarter analysis in patients with AF (aRR 1.51, 1.04-2.18) and without AF (aRR 1.32, 1.10-1.59) (Q4 vs Q1). No association was observed between hsCRP and recurrent stroke in either group. For IL-6, there was no evidence of interaction according to AF status for MACEs (P_interaction 0.57) or recurrent stroke (P_interaction 0.82). The aRR per log_e unit for MACE was 1.17 (1.07-1.27) in patients without AF and 1.10 (0.91-1.34) in those with AF. The corresponding aRR for recurrent stroke was 1.15 (1.05-1.25) and 1.12 (0.91-1.37) in patients without and with AF, respectively. These data highlight the importance of inflammatory mechanisms in vascular recurrence irrespective of AF, provide rationale for the inclusion of patients with AF in trials of anti-inflammatory therapy, and support a selection approach in future trials based on elevated inflammatory marker levels, rather than stroke etiology alone.

IIntroduction: Worse stroke outcome in women than men is partly explained by differences in age, aetiology and pre-morbid disability, but lower haemoglobin (Hb) could also contribute, particularly at younger ages. We therefore aimed to explore whether lower Hb levels might correlate with stroke outcome in younger women. Methods: In a population-based cohort (Oxford Vascular study) we studied all patients aged ≤55 years with a stroke between 1st April 2002 and 31st March 2023 and face-to-face follow up at one-month. We used ordinal multi-regression models to assess one-month post-stroke modified Rankin Scale score (mRS), and the change from pre-morbid status (ΔmRS), in relation to Hb levels (continuous and by WHO definition of anaemia) and sex, with adjustment for age, vascular comorbidities, pre-morbid mRS and medications. Results: Among 348 patients (mean/SD age = 45.4/8.01; 149 female, 42.8%) anaemia was associated with a higher post-stroke mRS (adjusted OR=3.18, 95%CI =1.66-6.06, p<0.001) and greater ΔmRS (adjusted OR=2.72, 1.39-5.30, p=0.003). These trends were consistent in both women and men analysed separately and in those with ischaemic stroke only. Women had higher one-month mRS compared with men (adjusted OR=1.58,1.05-2.38, p=0.03), but further adjustment for the sex difference in Hb (mean/SD Hb: 13.12/1.64 g/dl in women vs 15.13/1.36 in men, p<0.001) removed the effect of sex (fully adjusted OR=1.07, 0.65-1.74, p=0.80). The higher ΔmRS in women (adjusted OR=1.57, 1.04-2.38, p=0.03) also diminished after adjustment for Hb (fully adjusted OR=1.04; 0.64-1.70, p=0.87). Conclusion: Low Hb levels are associated with a poor outcome after stroke and could be a clinically important determinant of the sex-difference in stroke outcome at younger ages. If confirmed, these findings further justify correction of iron-deficient anaemia at the population level and in situations where stroke risk is increased.

Background: Coronary arterial calcification predicts coronary events, but although intracranial arterial calcification on CT (CT‐IAC) is a frequent finding in older individuals, few longitudinal studies have assessed whether its severity or site predict dementia. We did a population‐based study in patients with transient ischemic attack (TIA) or stroke to assess these associations. Methods: In a matched case–control study of patients with minor stroke/transient ischemic attack nested in the population‐based OXVASC (Oxford Vascular Study), severity (qualitatively and semiautomated volume) and location (intimal or internal elastic lamina) of CT‐IAC in cases who developed dementia on follow‐up was compared with that in age‐/sex‐matched controls who did not (logistic regression adjusted for other risk factors). Results: In OXVASC (cases/controls=200/200; mean age=78.0±9.3 years), dementia was independently associated with severity of internal carotid artery CT‐IAC on visual assessment (bilateral severe—adjusted OR [aOR], 2.02 [95% CI, 1.26–3.23], P =0.004) and quantitative volume (top versus bottom tertile—aOR, 2.35 [95% CI, 1.33–4.16], P =0.003), driven mainly by individuals with very high calcification volumes (≥600 mm ³ versus 0–299 mm ³ —aOR, 6.23 [95% CI, 1.24–31.24], P =0.026). Similar trends were observed for CT‐IAC in the internal carotid artery and vertebrobasilar artery combined (top versus bottom tertile—aOR, 2.59[95% CI, 1.43–4.68], P =0.002), including after exclusion of recurrent stroke (aOR, 2.60 [95% CI, 1.33–5.08], P =0.005) and patients with moderate/severe white matter disease (aOR, 3.19 [95% CI, 1.54–6.62], P =0.002). Internal carotid artery CT‐IAC of the internal elastic lamina independently predicted dementia after adjusting for qualitative (aOR, 1.84 [95% CI, 1.11–3.05, P =0.019) or quantitative (aOR, 1.78 [95% CI, 1.06–2.99], P =0.029) CT‐IAC severity. Conclusions: Severity of CT‐IAC independently predicts future dementia after stroke/ transient ischemic attack. The extent of any nonlinearity and calcification‐ or dementia‐subtype differences should be determined in larger studies.

Background: Incidence of stroke and certain cancers is increasing at younger ages in many high-income countries, prompting healthcare systems to consider how best to improve prevention, such as earlier primary care health checks. We assessed potential barriers to the success of the current proposal in England to reduce the starting age of the 5-yearly NHS health check from 40 to 30 years. Methods: In a prospective population-based study (Oxford Vascular Study; 1/4/2002–31/3/23) of 94 567 people in a subpopulation of Oxfordshire, UK, we assessed all participants with incident acute vascular events occurring at age 30–44 years and determined the proportion of those who would have qualified for active risk management were they to have had the proposed new health check prior to their event (i.e. premorbid QRISK3-10-year absolute CV-risk ≥ 10%). We also assessed CV-risk relative to age-specific ‘ideal’ risk (QRISK3-Relative Risk (RR) score, predicted “healthy-heart-age”) and number of risk factors above recommended target. Results: During 433,797 person-years of ascertainment, 217 individuals aged 30–44 years had an incident vascular event (crude incidence rate 50/100 000 person years). Of these, 155 would have been eligible for an earlier health check. The median 10-year predicted CV risk in this group was only 2.5% (IQR = 1.1–4.8%), with 148 (95%) falling below the 10% threshold for active risk management. The median 10-year risk among the 49 women was 1.1% (IQR 0.5–2.2%), with none having a predicted risk above the 10% threshold. Yet, the mean predicted “healthy heart age” gap was 9 years(SD = 7), and 137(88%) had at least one treatable risk factor above target level. Conclusions: The majority of vascular events at age 30–44 years occur in individuals with treatable risk factors above target level, yet the vast majority had falsely reassuring premorbid 10-year CV risks that were well below the 10% threshold for treatment, potentially undermining the effectiveness of earlier primary care health checks.

BACKGROUND: Depression is common after stroke and is associated with increased mortality. However, there are few data on the prevalence, predictors, or prognosis of depression after transient ischemic attack (TIA). Although poststroke depression is often assumed to be due to the brain lesion or disability, patients with TIA may also be susceptible due to shared risk factors, lifestyle/medication changes, or worries about stroke. METHODS: The prevalence of depression 1 and 12 months after TIA was assessed in a population-based cohort (OXVASC [Oxford Vascular Study]) from 2014 to 2020. Depression was related to risk factors (including infarction on brain imaging) in a multivariable logistic regression model and outcome (disability, quality of life, institutionalization, recurrent events, and mortality) in a Cox proportional hazard regression model during 5-year follow-up after adjustment for covariates that were found to be significant ( P P =0.022). Depression was independently associated with younger age (adjusted odds ratio/decade, 0.74 [95% CI, 0.60–0.90]), low baseline mood (4.06 [95% CI, 2.31–7.15]), past depression (1.81 [95% CI, 1.09–3.03]), multimorbidity (1.19 [95% CI, 1.02–1.39]), living alone (1.94 [95% CI, 1.14–3.32]), disability (3.53 [95% CI, 1.89–6.59]), and deprivation (1.28 [95% CI, 1.03–1.59]). After adjustment for confounders, depression did not predict risk of recurrent vascular events (adjusted hazard ratio [aHR], 1.42 [95% CI, 0.76–2.64]; P =0.27) but did predict increased 5-year all-cause mortality (aHR, 2.27 [95% CI, 1.21–4.27]; P =0.011), independently of acute lesions on brain imaging (aHR, 2.18 [95% CI, 1.09–4.34]; P =0.027), and particularly when persistent (present at 1- and 12-month follow-up; aHR, 4.58 [95% CI, 2.07–10.13]; P P P =0.003) within 5 years and with reduced quality of life (coefficient, −0.245; P <0.001). CONCLUSIONS: Depression is common early after TIA, independent of acute ischemia on brain imaging, and persistent depression is also strongly associated with adverse outcomes.