Strategic white matter hyperintensity locations associated with post-stroke cognitive impairment: A multicenter study in 1568 stroke patients.

BACKGROUND: Post-stroke cognitive impairment (PSCI) occurs in up to 50% of stroke survivors. Presence of pre-existing vascular brain injury, in particular the extent of white matter hyperintensities (WMH), is associated with worse cognitive outcome after stroke, but the role of WMH location in this association is unclear. AIMS: We determined if WMH in strategic white matter tracts explain cognitive performance after stroke. METHODS: Individual patient data from nine ischemic stroke cohorts with magnetic resonance imaging (MRI) were harmonized through the Meta VCI Map consortium. The association between WMH volumes in strategic tracts and domain-specific cognitive functioning (attention and executive functioning, information processing speed, language and verbal memory) was assessed using linear mixed models and lasso regression. We used a hypothesis-driven design, primarily addressing four white matter tracts known to be strategic in memory clinic patients: the left and right anterior thalamic radiation, forceps major, and left inferior fronto-occipital fasciculus. RESULTS: The total study sample consisted of 1568 patients (39.9% female, mean age = 67.3 years). Total WMH volume was strongly related to cognitive performance on all four cognitive domains. WMH volume in the left anterior thalamic radiation was significantly associated with cognitive performance on attention and executive functioning and information processing speed and WMH volume in the forceps major with information processing speed. The multivariable lasso regression showed that these associations were independent of age, sex, education, and total infarct volume and had larger coefficients than total WMH volume. CONCLUSION: These results show tract-specific relations between WMH volume and cognitive performance after ischemic stroke, independent of total WMH volume. This implies that the concept of strategic lesions in PSCI extends beyond acute infarcts and also involves pre-existing WMH. DATA ACCESS STATEMENT: The Meta VCI Map consortium is dedicated to data sharing, following our guidelines.

Burden of intracranial artery calcification in white patients with ischemic stroke.

INTRODUCTION: The diagnostic workup of stroke doesn't identify an underlying cause in two-fifths of ischemic strokes. Intracranial arteriosclerosis is acknowledged as a cause of stroke in Asian and Black populations, but is underappreciated as such in whites. We explored the burden of Intracranial Artery Calcification (IAC), a marker of intracranial arteriosclerosis, as a potential cause of stroke among white patients with recent ischemic stroke or TIA. PATIENTS AND METHODS: Between December 2005 and October 2010, 943 patients (mean age 63.8 (SD ± 14.0) years, 47.9% female) were recruited, of whom 561 had ischemic stroke and 382 a TIA. CT-angiography was conducted according to stroke analysis protocols. The burden of IAC was quantified on these images, whereafter we assessed the presence of IAC per TOAST etiology underlying the stroke and assessed associations between IAC burden, symptom severity, and short-term functional outcome. RESULTS: IAC was present in 62.4% of patients. Furthermore, IAC was seen in 84.8% of atherosclerotic strokes, and also in the majority of strokes with an undetermined etiology (58.5%). Additionally, patients with larger IAC burden presented with heavier symptoms (adjusted OR 1.56 (95% CI [1.06-2.29]), but there was no difference in short-term functional outcome (1.14 [0.80-1.61]). CONCLUSION: IAC is seen in the majority of white ischemic stroke patients, aligning with findings from patient studies in other ethnicities. Furthermore, over half of patients with a stroke of undetermined etiology presented with IAC. Assessing IAC burden may help identify the cause in ischemic stroke of undetermined etiology, and could offer important prognostic information.

Cerebellar-Induced Aphasia After Stroke: Evidence for the "Linguistic Cerebellum".

The cerebellum is traditionally known to subserve motor functions. However, for several decades, the concept of the "cerebellar cognitive affective syndrome" has evolved. Studies in healthy participants and patients have confirmed the cerebellar role in language. The exact involvement of the cerebellum regarding cerebellar aphasia remains uncertain. We included 43 cerebellar stroke patients who were tested at 3 months post-onset with the Boston Naming Test (BNT), the Token Test (TT), and the Diagnostic Instrument for Mild Aphasia (DIMA). Lesion side (left/right) and volume (cm3) were investigated. Patients significantly deviated on the following: BNT (p<0.001), TT (p<0.05), DIMA subtests: sentences repetition (p=0.001), semantic odd-picture-out (p<0.05), sentence completion (p<0.05) without an effect of lesion location (left/right) or volume (cm3) (p>0.05). Our clinical study confirms a non-lateralized cerebellar aphasia post-stroke, characterized by impairments in word retrieval, phonology, semantics, and syntax resembling cerebral-induced aphasia. The integral cerebellum appears to interact with eloquent cortico-subcortical language areas.

The CODECS study: COgnitive DEficits in Cerebellar Stroke.

Part of the extra-pyramidal system, the cerebellum is more and more recognized by its non-motor functions known as the cerebellar cognitive affective syndrome. Several studies have identified disturbances specifically in executive and attentional functions after focal cerebellar lesions. However, most studies were performed in small and heterogeneous patient groups. Furthermore, there is a substantial variation in the methodology of assessment. Here, we present the results of a large and homogeneous cohort of patients with isolated uniform cerebellar lesions. After three months post-stroke all patients underwent structural neuroimaging to confirm an isolated lesion and were given neuropsychological testing. The results show that cerebellar lesions relate to mild but long-term cognitive impairment in a broad spectrum of neurocognitive functions compared to normative values. These findings confirm involvement of the cerebellum in cognitive processing and supports the theory of 'dysmetria of thought' based upon uniform cerebellar processing in multiple cognitive domains. This study highlights the following results: 1-Cognitive impairments after isolated cerebellar stroke is confirmed in several cognitive domains. 2-Semantic and phonemic fluency are most affected in cerebellar stroke patients. 3-Verbal deficits show an age-independent long term effect post-stroke and should be studied further in depth. 4-Cognitive disorders after cerebellar stroke are more prominent in women than men.

White Matter Hyperintensity Volume and Poststroke Cognition: An Individual Patient Data Pooled Analysis of 9 Ischemic Stroke Cohort Studies.

BACKGROUND: White matter hyperintensities (WMH) are associated with cognitive dysfunction after ischemic stroke. Yet, uncertainty remains about affected domains, the role of other preexisting brain injury, and infarct types in the relation between WMH burden and poststroke cognition. We aimed to disentangle these factors in a large sample of patients with ischemic stroke from different cohorts. METHODS: We pooled and harmonized individual patient data (n=1568) from 9 cohorts, through the Meta VCI Map consortium (www.metavcimap.org). Included cohorts comprised patients with available magnetic resonance imaging and multidomain cognitive assessment <15 months poststroke. In this individual patient data meta-analysis, linear mixed models were used to determine the association between WMH volume and domain-specific cognitive functioning (Z scores; attention and executive functioning, processing speed, language and verbal memory) for the total sample and stratified by infarct type. Preexisting brain injury was accounted for in the multivariable models and all analyses were corrected for the study site as a random effect. RESULTS: In the total sample (67 years [SD, 11.5], 40% female), we found a dose-dependent inverse relationship between WMH volume and poststroke cognitive functioning across all 4 cognitive domains (coefficients ranging from -0.09 [SE, 0.04, P=0.01] for verbal memory to -0.19 [SE, 0.03, P<0.001] for attention and executive functioning). This relation was independent of acute infarct volume and the presence of lacunes and old infarcts. In stratified analyses, the relation between WMH volume and domain-specific functioning was also largely independent of infarct type. CONCLUSIONS: In patients with ischemic stroke, increasing WMH volume is independently associated with worse cognitive functioning across all major domains, regardless of old ischemic lesions and infarct type.

Sex Differences in Poststroke Cognitive Impairment: A Multicenter Study in 2343 Patients With Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment (PSCI) occurs in about half of stroke survivors. Cumulative evidence indicates that functional outcomes of stroke are worse in women than men. Yet it is unknown whether the occurrence and characteristics of PSCI differ between men and women. METHODS: Individual patient data from 9 cohorts of patients with ischemic stroke were harmonized and pooled through the Meta-VCI-Map consortium (n=2343, 38% women). We included patients with visible symptomatic infarcts on computed tomography/magnetic resonance imaging and cognitive assessment within 15 months after stroke. PSCI was defined as impairment in ≥1 cognitive domains on neuropsychological assessment. Logistic regression analyses were performed to compare men to women, adjusted for study cohort, to obtain odds ratios for PSCI and individual cognitive domains. We also explored sensitivity and specificity of cognitive screening tools for detecting PSCI, according to sex (Mini-Mental State Examination, 4 cohorts, n=1814; Montreal Cognitive Assessment, 3 cohorts, n=278). RESULTS: PSCI was found in 51% of both women and men. Men had a lower risk of impairment of attention and executive functioning (men: odds ratio, 0.76 [95% CI, 0.61-0.96]), and language (men: odds ratio, 0.67 [95% CI, 0.45-0.85]), but a higher risk of verbal memory impairment (men: odds ratio, 1.43 [95% CI, 1.17-1.75]). The sensitivity of Mini-Mental State Examination (<25) for PSCI was higher for women (0.53) than for men (0.27; P=0.02), with a lower specificity for women (0.80) than men (0.96; P=0.01). Sensitivity and specificity of Montreal Cognitive Assessment (<26.) for PSCI was comparable between women and men (0.91 versus 0.86; P=0.62 and 0.29 versus 0.28; P=0.86, respectively). CONCLUSIONS: Sex was not associated with PSCI occurrence but affected domains differed between men and women. The latter may explain why sensitivity of the Mini-Mental State Examination for detecting PSCI was higher in women with a lower specificity compared with men. These sex differences need to be considered when screening for and diagnosing PSCI in clinical practice.

Risk of recurrent stroke in Rotterdam between 1990 and 2020: a population-based cohort study.

Background: After an initial stroke, current clinical practice is aimed at preventing recurrent stroke. Thus far, population-based estimates on the risk of recurrent stroke remain scarce. Here we describe the risk of recurrent stroke in a population-based cohort study. Methods: We included Rotterdam Study participants who developed a first-ever incident stroke during follow-up between 1990 until 2020. During further follow-up, these participants were monitored for the occurrence of a recurrent stroke. We determined stroke subtypes based on clinical and imaging information. We calculated ten-year overall and sex-specific cumulative incidences of first recurrent stroke. To reflect changing secondary preventive strategies employed in recent decades, we then calculated the risk of recurrent stroke within ten-year epochs based on first-ever stroke date (1990-2000, 2000-2010 and 2010-2020). Findings: In total, 1701 participants (mean age 80.3 years, 59.8% women) from 14,163 community-living individuals suffered a first stroke between 1990 and 2020. Of these strokes, 1111 (65.3%) were ischaemic, 141 (8.3%) haemorrhagic, and 449 (26.4%) unspecified. During 6585.3 person-years of follow-up, 331 (19.5%) suffered a recurrent stroke, of which 178 (53.8%) were ischaemic, 34 (10.3%) haemorrhagic and 119 (36.0%) unspecified. Median time between first and recurrent stroke was 1.8 (interquartile range 0.5-4.6) years. Overall ten-year recurrence risk following first-ever stroke was 18.0% (95% CI 16.2%-19.8%), 19.3% (16.3%-22.3%) in men and 17.1% (14.8%-19.4%) in women. Recurrent stroke risk declined over time, with a ten-year risk of 21.4% (17.9%-24.9%) between 1990 and 2000 and 11.0% (8.3%-13.8%) between 2010 and 2020. Interpretation: In this population-based study, almost one in five people with first-ever stroke suffered a recurrence within ten years of the initial stroke. Furthermore, recurrence risk declined between 2010 and 2020. Funding: Netherlands Organization for Health Research and Development, EU's Horizon 2020 research programme and the Erasmus Medical Centre MRACE grant.

Migraine and the risk of stroke in a middle-aged and elderly population: A prospective cohort study.

BACKGROUND: It has been suggested that patients with migraine have a higher risk of stroke. Despite considerable research on this topic in younger populations, a clear answer is still lacking for older individuals. We studied the association between migraine and the risk of stroke in a middle-aged and elderly population. METHODS: Within the ongoing prospective population-based Rotterdam Study, the presence of migraine was assessed using a validated questionnaire in a structured interview between 2006 and 2011, which formed the baseline. The association between migraine and the risk of stroke was analyzed using Cox proportional-hazards models with adjustments for age, sex, and cardiometabolic risk factors. RESULTS: A total of 6925 (mean age 65.7 ± 11.3 years, 57.8% females) stroke-free participants were included. At baseline, 1030 (14.9%) participants had lifetime history of migraine. During a median follow-up of 6.2 years, 195 participants developed a stroke (163 ischemic stroke). Analyzing the association between migraine and stroke, we found a hazard ratio of 1.44 with a 95% confidence interval of 0.96-2.15. The results were similar for the ischemic stroke (HR 1.50, CI: 0.97-2.32). CONCLUSION: Our data suggested an association between migraine and the risk of stroke in a middle-aged and elderly population, but this was not statistically significant.

Sex Differences in Carotid Atherosclerosis: A Systematic Review and Meta-Analysis.

BACKGROUND: Over the last decades, several individual studies on sex differences in carotid atherosclerosis have been performed covering a wide range of plaque characteristics and including different populations. This systematic review and meta-analysis aims to summarize previously reported results on sex differences in carotid atherosclerosis and present a roadmap explaining next steps needed for implementing this knowledge in clinical practice. METHODS: We systematically searched PubMed, Embase, Web of Science, Cochrane Central, and Google Scholar for eligible studies including both male and female participants reporting prevalence of imaging characteristics of carotid atherosclerosis and meta-analyzed these studies. Studies had to report at least the following: (1) calcifications; (2) lipid-rich necrotic core; (3) intraplaque hemorrhage; (4) thin-or-ruptured fibrous cap; (5) plaque ulceration; (6) degree of stenosis; (7) plaque size; or (8) plaque inflammation. We prespecified which imaging modalities had to be used per plaque characteristic and excluded ultrasonography. RESULTS: We included 42 articles in our meta-analyses (ranging from 2 through 23 articles per plaque characteristic). Men had more frequently a larger plaque compared to women and, moreover, had more often plaques with calcifications (odds ratio=1.57 [95% CI, 1.23-2.02]), lipid-rich necrotic core (odds ratio=1.87 [95% CI, 1.36-2.57]), and intraplaque hemorrhage (odds ratio=2.52 [95% CI, 1.74-3.66]), or an ulcerated plaque (1.81 [95% CI, 1.30-2.51]). Furthermore, we found more pronounced sex differences for lipid-rich necrotic core in symptomatic opposed to asymptomatic participants. CONCLUSIONS: In this systematic review and meta-analysis, we demonstrate convincing evidence for sex differences in carotid atherosclerosis. All kinds of plaque features-plaque size, composition, and morphology-were more common or larger in men compared to women. Our results highlight that sex is an important variable to include in both study design and clinical-decision making. Further investigation of sex-specific stroke risks with regard to plaque composition is warranted.

Carotid Plaque Characteristics Predict Recurrent Ischemic Stroke and TIA: The PARISK (Plaque At RISK) Study.

BACKGROUND: Patients with symptomatic carotid stenosis are at high risk for recurrent stroke. The decision for carotid endarterectomy currently mainly relies on degree of stenosis (cutoff value >50% or 70%). Nevertheless, also, patients with mild-to-moderate stenosis still have a considerable recurrent stroke risk. Increasing evidence suggests that carotid plaque composition rather than degree of stenosis determines plaque vulnerability; however, it remains unclear whether this also provides additional information to improve clinical decision making. OBJECTIVES: The PARISK (Plaque At RISK) study aimed to improve the identification of patients at increased risk of recurrent ischemic stroke using multimodality carotid imaging. METHODS: The authors included 244 patients (71% men; mean age, 68 years) with a recent symptomatic mild-to-moderate carotid stenosis in a prospective multicenter cohort study. Magnetic resonance imaging (carotid and brain) and computed tomography angiography (carotid) were performed at baseline and after 2 years. The clinical endpoint was a recurrent ipsilateral ischemic stroke or transient ischemic attack (TIA). Cox proportional hazards models were used to assess whether intraplaque hemorrhage (IPH), ulceration, proportion of calcifications, and total plaque volume in ipsilateral carotid plaques were associated with the endpoint. Next, the authors investigated the predictive performance of these imaging biomarkers by adding these markers (separately and simultaneously) to the ECST (European Carotid Surgery Trial) risk score. RESULTS: During 5.1 years follow-up, 37 patients reached the clinical endpoint. IPH presence and total plaque volume were associated with recurrent ipsilateral ischemic stroke or TIA (HR: 2.12 [95% CI: 1.02-4.44] for IPH; HR: 1.07 [95% CI: 1.00-1.15] for total plaque volume per 100 µL increase). Ulcerations and proportion of calcifications were not statistically significant determinants. Addition of IPH and total plaque volume to the ECST risk score improved the model performance (C-statistics increased from 0.67 to 0.75-0.78). CONCLUSIONS: IPH and total plaque volume are independent risk factors for recurrent ipsilateral ischemic stroke or TIA in patients with mild-to-moderate carotid stenosis. These plaque characteristics improve current decision making. Validation studies to implement plaque characteristics in clinical scoring tools are needed. (PARISK: Validation of Imaging Techniques [PARISK]; NCT01208025).

Network impact score is an independent predictor of post-stroke cognitive impairment: A multicenter cohort study in 2341 patients with acute ischemic stroke.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is a common consequence of stroke. Accurate prediction of PSCI risk is challenging. The recently developed network impact score, which integrates information on infarct location and size with brain network topology, may improve PSCI risk prediction. AIMS: To determine if the network impact score is an independent predictor of PSCI, and of cognitive recovery or decline. METHODS: We pooled data from patients with acute ischemic stroke from 12 cohorts through the Meta VCI Map consortium. PSCI was defined as impairment in ≥ 1 cognitive domain on neuropsychological examination, or abnormal Montreal Cognitive Assessment. Cognitive recovery was defined as conversion from PSCI < 3 months post-stroke to no PSCI at follow-up, and cognitive decline as conversion from no PSCI to PSCI. The network impact score was related to serial measures of PSCI using Generalized Estimating Equations (GEE) models, and to PSCI stratified according to post-stroke interval (<3, 3-12, 12-24, >24 months) and cognitive recovery or decline using logistic regression. Models were adjusted for age, sex, education, prior stroke, infarct volume, and study site. RESULTS: We included 2341 patients with 4657 cognitive assessments. PSCI was present in 398/844 patients (47%) <3 months, 709/1640 (43%) at 3-12 months, 243/853 (28%) at 12-24 months, and 208/522 (40%) >24 months. Cognitive recovery occurred in 64/181 (35%) patients and cognitive decline in 26/287 (9%). The network impact score predicted PSCI in the univariable (OR 1.50, 95%CI 1.34-1.68) and multivariable (OR 1.27, 95%CI 1.10-1.46) GEE model, with similar ORs in the logistic regression models for specified post-stroke intervals. The network impact score was not associated with cognitive recovery or decline. CONCLUSIONS: The network impact score is an independent predictor of PSCI. As such, the network impact score may contribute to a more precise and individualized cognitive prognostication in patients with ischemic stroke. Future studies should address if multimodal prediction models, combining the network impact score with demographics, clinical characteristics and other advanced brain imaging biomarkers, will provide accurate individualized prediction of PSCI. A tool for calculating the network impact score is freely available at https://metavcimap.org/features/software-tools/lsm-viewer/.

Plasma amyloid-ß40 in relation to subclinical atherosclerosis and cardiovascular disease: A population-based study.

BACKGROUND AND AIMS: We aimed to determine associations of plasma amyloid-ß40 (Aß40) with subclinical atherosclerosis and risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. METHODS: Between 2002 and 2005, plasma Aß40 was measured by single molecule array (SiMoA®) in 3879 participants of the population-based Rotterdam Study (mean age: 71 years, 61% female). Subclinical atherosclerosis was quantified as computed tomography-assessed calcification volumes. We determined the association of Aß40 with calcification volumes and clinical ASCVD event risk, and repeated the analyses for ASCVD in a replication cohort of 1467 individuals. RESULTS: Higher levels of Aß40 were associated with increased volumes of calcification in the coronary arteries and to a lesser extent extracranial carotid arteries, independent of traditional cardiovascular risk factors. Of all 3879 participants, 748 developed ASCVD during a median 9.7 years of follow-up. In age- and sex-adjusted models, higher Aß40 predisposed to a minor increase in ASCVD risk (HR [95%CI]: 1.11[1.02-1.21] per 1-SD increase in Aß40), driven by coronary heart disease (HR: 1.17[1.05-1.29]) rather than stroke (HR: 1.04[0.93-1.16]). However, excess risk of clinical outcomes was largely explained by baseline differences in cardiovascular risk factors and attenuated after further adjustment (for ASCVD- HR: 1.05[0.96-1.15] and for CHD- HR: 1.08[0.96-1.20]). Results were similar in the replication cohort, with highest risk estimates for CHD (HR: 1.24[1.04-1.48]) in age- and sex-adjusted models, attenuated after adjustment for cardiovascular risk factors (HR: 1.15[0.96-1.39]). CONCLUSIONS: In this population-based study, higher plasma amyloid-ß40 is associated with subclinical atherosclerosis, but not risk of first-ever ASCVD after accounting for traditional cardiovascular risk factors.

Plasma ß-Amyloid, Total-Tau, and Neurofilament Light Chain Levels and the Risk of Stroke: A Prospective Population-Based Study.

BACKGROUND AND OBJECTIVES: To unravel whether Alzheimer disease-related pathology or neurodegeneration plays a role in stroke etiology, we determined the effect of plasma levels ß-amyloid (Aß), total-tau, and neurofilament light chain (NfL) on risk of stroke and its subtypes. METHODS: Between 2002 and 2005, we measured plasma Aß40, Aß42, total-tau, and NfL in 4,661 stroke-free participants from the population-based Rotterdam Study. We used Cox proportional-hazards models to determine the association between these markers with incident stroke for the entire cohort, per stroke subtype, and by median age, sex, APOE ε4 carriership, and education. RESULTS: After a mean follow-up of 10.8 ± 3.3 years, 379 participants had a first-ever stroke. Log2 total-tau at baseline showed a nonlinear association with risk of any stroke and ischemic stroke: compared to the first (lowest) quartile, the adjusted hazard ratio (HR) for the highest quartile total-tau was 1.68 (95% CI 1.18-2.40) for any stroke. Log2 NfL was associated with an increased risk of any stroke (HR per 1-SD increase 1.27, 95% CI 1.12-1.44), ischemic stroke, and hemorrhagic stroke (HR 1.56, 95% CI 1.14-2.12). Log2 Aß40, Aß42, and Aß42/40 ratio levels were not associated with stroke risk. DISCUSSION: Participants with higher total-tau and NfL at baseline had a higher risk of stroke and several stroke subtypes. These findings support the role of markers of neurodegeneration in the etiology of stroke. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that higher plasma levels of total-tau and NfL are associated with an increased risk of subsequent stroke.

Safety and efficacy of aspirin, unfractionated heparin, both, or neither during endovascular stroke treatment (MR CLEAN-MED): an open-label, multicentre, randomised controlled trial.

BACKGROUND: Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke. METHODS: We did an open-label, multicentre, randomised controlled trial with a 2 × 3 factorial design in 15 centres in the Netherlands. We enrolled adult patients (ie, ≥18 years) with ischaemic stroke due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 h of symptom onset. Eligible patients had a score of 2 or more on the National Institutes of Health Stroke Scale, and a CT or MRI ruling out intracranial haemorrhage. Randomisation was done using a web-based procedure with permuted blocks and stratified by centre. Patients were randomly assigned (1:1) to receive either periprocedural intravenous aspirin (300 mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (5000 IU bolus followed by 1250 IU/h for 6 h), low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days. Symptomatic intracranial haemorrhage was the main safety outcome. Analyses were based on intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. This trial is registered with the International Standard Randomised Controlled Trial Number, ISRCTN76741621. FINDINGS: Between Jan 22, 2018, and Jan 27, 2021, we randomly assigned 663 patients; of whom, 628 (95%) provided deferred consent or died before consent could be asked and were included in the modified intention-to-treat population. On Feb 4, 2021, after unblinding and analysis of the data, the trial steering committee permanently stopped patient recruitment and the trial was stopped for safety concerns. The risk of symptomatic intracranial haemorrhage was higher in patients allocated to receive aspirin than in those not receiving aspirin (43 [14%] of 310 vs 23 [7%] of 318; adjusted OR 1·95 [95% CI 1·13-3·35]) as well as in patients allocated to receive unfractionated heparin than in those not receiving unfractionated heparin (44 [13%] of 332 vs 22 [7%] of 296; 1·98 [1·14-3·46]). Both aspirin (adjusted common OR 0·91 [95% CI 0·69-1·21]) and unfractionated heparin (0·81 [0·61-1·08]) led to a non-significant shift towards worse modified Rankin Scale scores. INTERPRETATION: Periprocedural intravenous aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of symptomatic intracranial haemorrhage without evidence for a beneficial effect on functional outcome. FUNDING: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation.

Visit-to-visit blood pressure variability and the risk of stroke in the Netherlands: A population-based cohort study.

BACKGROUND: Apart from blood pressure level itself, variation in blood pressure has been implicated in the development of stroke in subgroups at high cardiovascular risk. We determined the association between visit-to-visit blood pressure variability and stroke risk in the general population, taking into account the size and direction of variation and several time intervals prior to stroke diagnosis. METHODS AND FINDINGS: From 1990 to 2016, we included 9,958 stroke-free participants of the population-based Rotterdam Study in the Netherlands. This is a prospective cohort study including participants aged 45 years and older. Systolic blood pressure (SBP) variability was calculated as absolute SBP difference divided by mean SBP over 2 sequential visits (median 4.6 years apart). Directional SBP variability was defined as SBP difference over 2 visits divided by mean SBP. Using time-varying Cox proportional hazards models adjusted for age, sex, mean SBP, and cardiovascular risk factors, hazard ratios (HRs) for stroke up to January 2016 were estimated per SD increase and in tertiles of variability. We also conducted analyses with 3-, 6-, and 9-year intervals between variability measurement and stroke assessment. These analyses were repeated for diastolic blood pressure (DBP). The mean age of the study population was 67.4 ± 8.2 years and 5,776 (58.0%) were women. During a median follow-up of 10.1 years, 971 (9.8%) participants had a stroke, including 641 ischemic, 89 hemorrhagic, and 241 unspecified strokes. SBP variability was associated with an increased risk of hemorrhagic stroke (HR per SD 1.27, 95% CI 1.05-1.54, p = 0.02) and unspecified stroke (HR per SD 1.21, 95% CI 1.09-1.34, p < 0.001). The associations were stronger for all stroke subtypes with longer time intervals; the HR for any stroke was 1.29 (95% CI 1.21-1.36, p < 0.001) at 3 years, 1.47 (95% CI 1.35-1.59, p < 0.001) at 6 years, and 1.38 (95%CI 1.24-1.51, p < 0.001) at 9 years. For DBP variability, we found an association with unspecified stroke risk. Both the rise and fall of SBP and the fall of DBP were associated with an increased risk for unspecified stroke. Limitations of the study include that, due to an average interval of 4 years between visits, our findings may not be generalizable to blood pressure variability over shorter periods. CONCLUSIONS: In this population-based study, we found that visit-to-visit blood pressure variation was associated with an increased risk of unspecified and hemorrhagic stroke, independent of direction of variation or mean blood pressure.

Comparison of automated office blood pressure measurement with 24-hour ambulatory blood pressure measurement.

PURPOSE: Although 24-hour ambulatory blood pressure measurement (24-h ABPM) is the most important method to establish true hypertension, in clinical practice often repeated automated office blood pressure (AOBP) measurements are used because of convenience and lower costs. We aimed to assess the agreement rate between a 30 and 60 min AOBP and 24-h ABPM. MATERIALS AND METHODS: Patients with known hypertension (cohort 1) and patients visiting the neurology outpatient clinic after minor stroke or transient ischaemic attack (cohort 2) were selected. We performed AOBP for 30-60 min at 5-min intervals followed by 24-h ABPM and calculated average values of both measurements. Agreement between the two methods was studied with McNemar and Bland-Altman plots with a clinically relevant limit of agreement of ≤10 mm Hg difference in systolic BP. RESULTS: Our final cohort consisted of 135 patients from cohort 1 and 72 patients from cohort 2. We found relatively low agreement based on the clinical relevant cut-off value; 64.7% of the measurements were within the limits of agreement for 24-h systolic and 50.2% for 24-h diastolic. This was 61.4% for daytime systolic and 56.6% for daytime diastolic. In 73.5% of the patients, both methods led to the same diagnosis of either being hypertensive or non-hypertensive. This resulted in a significant difference between the methods to determine the diagnosis of hypertension (p < 0.0001). CONCLUSION: We conclude that 30-60 min AOBP measurements cannot replace a 24-h ABPM and propose to perform 24-h ABPM at least on a yearly basis to confirm AOBP measurements.

Sex Differences in Plaque Composition and Morphology Among Symptomatic Patients With Mild-to-Moderate Carotid Artery Stenosis.

BACKGROUND AND PURPOSE: Incidence of ischemic stroke differs between men and women, with substantially higher rates in men. The underlying mechanism of this difference remains poorly understood but may be because of differences in carotid atherosclerosis. Using an in-depth imaging-based approach, we investigated differences between carotid plaque composition and morphology in male and female patients with stroke, taking into account differences in total plaque burden. Additionally, we investigated all possible within-artery combinations of plaque characteristics to explore differences between various plaque phenotypes. METHODS: We included 156 men and 68 women from the PARISK (Plaque At Risk) study, a prospective cohort study of patients with recent ischemic cerebrovascular symptoms and <70% ipsilateral carotid stenosis. Plaque characteristics (intraplaque hemorrhage [IPH], lipid-rich necrotic core [LRNC], calcifications, thin-or-ruptured fibrous cap, ulcerations, total plaque volume) were assessed with magnetic resonance imaging and multidetector-row computed tomography angiography. We used multivariable logistic and linear regression analyses to assess sex differences in plaque characteristics. RESULTS: We found significant difference in total plaque volume between men and women (ß=22.9 mm3 [95% CI, 15.4-30.5]; mean volume in men 1399±425 mm3, in women 1011±242 mm3). Additionally, men were more likely to have IPH (odds ratio [OR]=2.8 [95% CI, 1.3-6.3]; IPH proportion in men 49%, in women 16%) and LRNC (OR=2.4 [95% CI, 1.2-4.7]; LRNC proportion in men 73%, in women 41%) even after adjustment for total plaque volume. We found no sex-specific differences in plaque volume-corrected volumes of IPH, LRNC, and calcifications. In terms of coexistence of plaque characteristics, we found that men had more often a plaque with coexistence of calcifications, LRNC, and IPH (OR=2.7 [95% CI, 1.2-7.0]), with coexistence of thin-or-ruptured fibrous cap/ulcerations, LRNC, and IPH (OR=2.4 [95% CI, 1.1-5.9]), and with coexistence of all plaque characteristics (OR=3.0 [95% CI, 1.2-8.6]). CONCLUSIONS: In symptomatic patients with mild-to-moderate carotid stenosis, men are more likely to have a high-risk carotid plaque with IPH and LRNC than women, regardless of total plaque burden. Men also have more often a plaque with multiple vulnerable plaque components, which could comprise an even higher stroke risk. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01208025.

Motivational interviewing in a nurse-led outpatient clinic to support lifestyle behaviour change after admission to a stroke unit: a randomized controlled trial.

AIMS: Modification of health behaviour is an important part of stroke risk management. However, the majority of people with cardiovascular disease fail to sustain lifestyle modification in the long term. We aimed to evaluate the effectiveness of motivational interviewing to encourage lifestyle behaviour changes after transient ischaemic attack (TIA) or minor ischaemic stroke. METHODS AND RESULTS: We performed a randomized controlled open-label phase II trial with blinded endpoint assessment. The intervention consisted of three 15-minute visits in 3 months by a motivational interviewing trained nurse practitioner. Patients in the control group received standard consultation after 1 and 3 months by a nurse practitioner. Primary outcome was lifestyle behaviour change, defined as smoking cessation and/or increased physical activity (30 min/day) and/or healthy diet improvement (5 points at the Food Frequency Questionnaire) at 6 months. We adjusted for age and sex with multivariable logistic regression. Between January 2014 and February 2016, we included 136 patients (of whom 68 were assigned to the intervention group). Twenty-five of 55 patients in the intervention group (45%) and 27 of 61 patients in the control group (44%) had changed their lifestyle at 6 months. We found no effect of motivational interviewing on lifestyle behaviour change after 6 months (aOR 0.99; 95% confidence interval: 0.44-2.26). CONCLUSION: Our results do not support the effectiveness of motivational interviewing in supporting lifestyle behaviour change after TIA or ischaemic stroke. However, the overall lifestyle behaviour change was high and might be explained by the role of specialized nurses in both groups.

Life expectancy with and without dementia in persons with mild cognitive impairment in the community.

BACKGROUND: Various clinical studies have provided estimates of life expectancy of patients with mild cognitive impairment (MCI) from outpatient clinics, but whether these apply to community-dwelling individuals at home or in primary care is uncertain. METHODS: Within the population-based Rotterdam Study, we studied life expectancy with and without dementia in 648 community-dwelling persons with MCI and 6410 without MCI. Participants aged 60 years and older were assessed for MCI at baseline (2002-2014) and subsequently followed for the onset of dementia and death. We used multistate life tables to determine age-specific life expectancy with and without dementia by sex, educational attainment, and MCI subtype. RESULTS: Total life expectancy for MCI ranged from 21.4 years (95% CI: 19.0-23.6) at age 60 to 2.6 years (1.6-3.6) at age 95. With advancing age, an increasing proportion of these years was lived with dementia (2.9 years [1.8-4.0] at age 60; 1.2 [0.2-2.2] at age 95). Women and higher educated individuals lived longer and lived more years with dementia. No differences in total life expectancy were observed by MCI subtype, although individuals with amnestic MCI lived a larger proportion of those years with dementia. CONCLUSIONS: Prognosis of MCI, in terms of life years lived with and without dementia, is more favorable in the general population than described in prior clinical observations, due likely to a substantial proportion of individuals with MCI in the clinic not seeking medical attention in an earlier stage.

Effect of routine preoperative screening for aortic calcifications using noncontrast computed tomography on stroke rate in cardiac surgery: the randomized controlled CRICKET study.

OBJECTIVES: To evaluate if routine screening for aortic calcification using unenhanced CT lowers the risk of stroke and alters the surgical approach in patients undergoing general cardiac surgery compared with standard of care (SoC). METHODS: In this prospective, multicenter, randomized controlled trial, adult patients scheduled for cardiac surgery from September 2014 to October 2019 were randomized 1:1 into two groups: SoC alone, including chest radiography, vs. SoC plus preoperative noncontrast CT. The primary endpoint was in-hospital perioperative stroke. Secondary endpoints were preoperative change of the surgical approach, in-hospital mortality, and postoperative delirium. The trial was halted halfway for expected futility, as the conditional power analysis showed a chance < 1% of finding the hypothesized effect. RESULTS: A total of 862 patients were evaluated (SoC-group: 433 patients (66 ± 11 years; 74.1% male) vs. SoC + CT-group: 429 patients (66 ± 10 years; 69.9% male)). The perioperative stroke rate (SoC + CT: 2.1%, 9/429 vs. SoC: 1.2%, 5/433, p = 0.27) and rate of changed surgical approach (SoC + CT: 4.0% (17/429) vs. SoC: 2.8% (12/433, p = 0.35) did not differ between groups. In-hospital mortality and postoperative delirium were comparable between groups. In the SoC + CT group, aortic calcification was observed on CT in the ascending aorta in 28% (108/380) and in the aortic arch in 70% (265/379). CONCLUSIONS: Preoperative noncontrast CT in cardiac surgery candidates did not influence the surgical approach nor the incidence of perioperative stroke compared with standard of care. Aortic calcification is a frequent finding on the CT scan in these patients but results in major surgical alterations to prevent stroke in only few patients. KEY POINTS: • Aortic calcification is a frequent finding on noncontrast computed tomography prior to cardiac surgery. • Routine use of noncontrast computed tomography does not often lead to a change of the surgical approach, when compared to standard of care. • No effect was observed on perioperative stroke after cardiac surgery when using routine noncontrast computed tomography screening on top of standard of care.