Search Results for: Stroke

Stroke, Ahead of Print. BACKGROUND:Acute respiratory infection transiently increases risk for childhood arterial ischemic stroke (AIS). We hypothesize that this paradox of a common exposure linked to a rare outcome could be explained by either (1) the infection hypothesis: unusual or multiple pathogens or (2) the host response hypothesis: heterogeneity in the inflammatory response to infection. We leverage metagenomic next-generation sequencing (mNGS), a comprehensive microbial detection tool, to test the first hypothesis.METHODS:The VIPS II study (Vascular Effects of Infection in Pediatric Stroke II) prospectively enrolled children with AIS at 22 international sites over 5 years (December 2016 to January 2022). Sites measured prestroke clinical infection via standardized parental interviews and chart abstraction. To assess more broadly the background spectrum of pathogens, a central research laboratory performed mNGS on plasma and oropharyngeal swabs collected within 72 hours of stroke. mNGS was also performed on biological samples from stroke-free children (June 2017 to January 2022), both without (well) and with (ill) documentation of clinical infection.RESULTS:VIPS II enrolled 205 patients with AIS, 95 stroke-free well children, and 47 stroke-free ill children. Clinical infection, most commonly upper respiratory tract infection, was detected in 81 of 205 (40%) of patients. Both plasma and oropharyngeal swab mNGS data were available for 190 of 205 patients with AIS, 91 of 95 stroke-free well children, and 27 of 47 stroke-free ill children. mNGS detected viruses in 27 of 190 (14%) patients with AIS, 9 of 91 stroke-free well children (10%), and 9 of 27 (33%) stroke-free ill children. Most were common upper respiratory viruses. Coinfections were rare. Similar viruses were found in patients with AIS and stroke-free children.CONCLUSIONS:mNGS detected a variety of common childhood viruses in both patients with AIS and stroke-free children, suggesting that the type of infection does not explain AIS susceptibility. Rather, the alternative hypothesis regarding an unusual host immune response to common infections in the pathogenicity of AIS should be further explored.

Approximately 500 000 individuals have survived childhood cancer in the US, and this number is growing each year. Unfortunately, these survivors carry a substantial burden of morbidity. The most prevalent severe or life-threatening chronic health conditions include endocrine disorders, subsequent neoplasms, and cardiovascular disease. These conditions are directly related to chemotherapy and/or radiation therapy used to treat the childhood cancer; examples include anthracycline-related cardiomyopathy, radiation-related breast and central nervous system subsequent neoplasms, and radiation-related coronary-artery disease and stroke. Radiation-related conditions are age- and dose-related, but generally develop within the radiation field. Chemotherapy-related conditions are also dose- and age-related but may affect multiple organs due to the systemic nature of the exposures. The conditions develop at varying intervals after the therapeutic exposures. Whereas chemotherapy-related complications can be seen as early as within 5 years of the exposure, radiation-associated complications are usually delayed and are typically diagnosed after 10 or more years from exposure. These conditions can cause premature death, resulting in a significant gap in life expectancy compared with the general population. The past decade has seen an increasing interest in a phenomenon called accelerated aging primarily from investigators leveraging the resources offered by the Childhood Cancer Survivor Study (CCSS) and the St Jude Lifetime (SJLIFE) Cohorts.

Stroke, Ahead of Print. BACKGROUND:Analyses of genomic and proteomics data in prospective biobank studies in diverse populations may discover novel or repurposing drug targets for stroke.METHODS:We extracted individualcis-protein quantitative trait locus for 2923 proteins measured using Olink Explore panel from a genome-wide association study in prospective China Kadoorie Biobank and UK Biobank, both established ≈20 years ago. Thesecis-protein quantitative trait loci were used in ancestry-specific 2-sample Mendelian randomization analyses of ischemic stroke (IS) in East Asians (n=22 664 cases) and Europeans (n=62 100 cases). We further undertook colocalization analyses to examine the shared causal variants ofcis-protein quantitative trait locus with stroke, along with various downstream analyses (eg, phenome-wide association study, drug development lookups) to clarify mechanisms of action and druggability.RESULTS:In Mendelian randomization analyses, the genetically predicted plasma levels of 10 proteins were significantly associated with IS in East Asians (n=2) and Europeans (n=9), with 6 proteins (FGF5 [fibroblast growth factor 5], TMPRSS5 [transmembrane protease serine 5], FURIN, F11 [coagulation factor XI], ALDH2 [aldehyde dehydrogenase 2], and ABO) showing positive and 4 (GRK5 [G protein-coupled receptor kinase 5], KIAA0319 [dyslexia-associated protein KIAA0319], PROCR [endothelial protein C receptor], and MMP12 [macrophage metalloelastase 12]) showing inverse associations, all directionally consistent between East Asians and Europeans. Colocalization analyses provided strong evidence (posterior probabilities for the H4 hypothesis ≥0.7) of shared genetic variants with IS for 9 out of 10 proteins (except ABO). Moreover, 8 proteins were also causally associated, in the expected directions, with systolic blood pressure (positive/inverse: 4/2), low-density lipoprotein cholesterol (1 positive), body mass index (1 inverse), type 2 diabetes (2/1), or atrial fibrillation (3/1). Phenome-wide association study analyses and lookups in knock-out mouse models confirmed their importance for IS or stroke-related traits (eg, hematologic phenotypes). Of these 10 proteins, 1 was not druggable (ABO), 3 had known primary (F11) or potentially repurposed (ALDH2, MMP12) drug targets for stroke, and 6 (PROCR, GRK5, FGF5, FURIN, KIAA0319, and TMPRSS5) had no evidence of any drug targets.CONCLUSIONS:Proteogenomic investigation in diverse ancestry populations identified the causal relevance of 10 proteins for IS, with several being potentially novel or repurposed targets that could be prioritized for further investigation.

Stroke, Ahead of Print. BACKGROUND:Bone marrow mononuclear cell (BM-MNC) intraarterial transplantation has emerged as a potential stroke therapy. We aimed to determine whether BM-MNC therapy induces changes in diffusion tensor imaging metrics of major white matter tracts.METHODS:The IBIS trial was an investigator-initiated multicenter, phase IIb, randomized, controlled, assessor-blinded, clinical trial. Seventy-seven patients (aged 18–80 years) with a nonlacunar middle cerebral artery ischemic stroke within 1 to 7 days from stroke onset and a National Institutes of Health Stroke Scale score of 6 to 20 were included. The primary outcome was the modified Rankin Scale score at 6 months. Among these participants, 38 patients (20 BM-MNCs-treated and 18 controls) had diffusion tensor imaging data available at both baseline and 6-month follow-up. Fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity for white matter tracts were obtained. We determined the average changes in diffusion tensor imaging-metric values over the follow-up period and correlated corticospinal tract integrity with clinical outcomes using Spearman´s correlation coefficient.RESULTS:The mean (SD) age was 60.7 (14.01) years; 22 (57.9%) were men, and 31 (81.6%) underwent thrombectomy. The median (IQR) National Institutes of Health Stroke Scale score before randomization was 12 (9–15). Baseline diffusion tensor imaging metrics were comparable between groups. Fractional anisotropy values of patients treated with BM-MNC decreased significantly less throughout corticospinal tract ipsilateral to stroke lesion (−0.05 [95% CI, −0.07 to −0.03] versus −0.06 [95% CI, −0.09 to −0.04];P

Stroke, Ahead of Print. BACKGROUND:There is debate on the link between dietary fiber intake and stroke risk. The purpose of this study was to look at how it impacts dietary fiber intake and stroke risk, as well as mortality among stroke survivors. Two-sample Mendelian randomization was also used to investigate the causal relationship.METHODS:This research examined information from 1453 patients with stroke participating in the National Health and Nutrition Examination Survey from 1999 to 2018. To assess the incidence of stroke, we conducted a survey-weighted multivariate logistic regression analysis and subgroup analysis. To evaluate the mortality associated with stroke, we used Kaplan-Meier survival analysis combined with survey-weighted Cox regression models. Using 2-sample Mendelian randomization and inverse-variance weighted method, we established a causal relationship between dietary fiber intake and stroke. The article was organized according to Strengthening the Reporting of Observational Studies in Epidemiology and Strengthening the Reporting of Observational Studies in Epidemiology Using Mendelian Randomization guidelines.RESULTS:In the fully adjusted model, dietary fiber intake was negatively associated with stroke (odds ratio, 0.98 [95% CI, 0.97–0.99];P

Stroke, Ahead of Print. BACKGROUND:The pathological basis underlying motor impairment in older adults is partially accounted for by Alzheimer disease and related dementias pathologies. We tested the hypothesis that arteriolosclerosis, a pathological correlate of small vessel disease, outside the cerebrum is related to motor impairment in older adults above and beyond Alzheimer disease and related dementias pathologies.METHODS:The data were from decedents of a community-based clinical-autopsy study. Arteriolosclerosis was assessed in the cerebrum (as 1 of 10 Alzheimer disease and related dementias pathologies), midbrain, cerebellum, pons, and 4 levels of the spinal cord. Parkinsonism was assessed using the Unified Parkinson Disease Rating Scale. Other motor performances included timed-peg placement and finger tapping, grip and pinch strength, walking 8 ft and turning 360° twice, and sensor-derived metrics assessing tandem walk. Multivariate linear regression models were used to examine the association of arteriolosclerosis across varied motor performances.RESULTS:The participants (n=403) were on average 91.4 (6.1) years old at death, and 73.2% (n=295) were women. The frequency of moderate/severe arteriolosclerosis varied outside the cerebrum, ranging from 15.5% (40/258) in the pons to 49.6% (200/403) in the spinal cord. The correlation of the severity of arteriolosclerosis between these regions ranged from unrelated to modestly related. Spinal arteriolosclerosis was associated with impaired motor function (P=0.006), in particular more severe parkinsonism (estimate, 0.170; SE, 0.071;P=0.018) and less hand dexterity (estimate, −0.022; SE, 0.009;P=0.014). Arteriolosclerosis of the cerebellum was associated with impaired tandem walk (P=0.012), in particular more variability in the acceleration signal in the mediolateral direction (estimate, 0.023; SE, 0.011;P=0.040). Arteriolosclerosis in the pons or midbrain was not associated with motor performances.CONCLUSIONS:Arteriolosclerosis severity varies in the central nervous system tissues outside of the cerebrum and is differentially associated with varied motor performances, suggesting that the adverse motor consequences of small vessel disease in older adults may be underestimated by studies focusing only on the brain.

Circulation, Ahead of Print. BACKGROUND:Elevated plasma levels of Lp(a) [lipoprotein(a)] are a causal risk factor for coronary heart disease and stroke in European individuals, but the causal relevance of Lp(a) for different stroke types and in East Asian individuals with different Lp(a) genetic architecture is uncertain.METHODS:We measured plasma levels of Lp(a) in a nested case–control study of 18 174 adults (mean [SD] age, 57 [10] years; 49% female) in the China Kadoorie Biobank (CKB) and performed a genome-wide association analysis to identify genetic variants affecting Lp(a) levels, with replication in ancestry-specific subsets in UK Biobank. We further performed 2-sample Mendelian randomization analyses, associating ancestry-specific Lp(a)-associated instrumental variants derived from CKB or from published data in European individuals with risk of myocardial infarction (n=17 091), ischemic stroke (IS [n=29 233]) and its subtypes, or intracerebral hemorrhage (n=5845) in East Asian and European individuals using available data from CKB and genome-wide association analysis consortia.RESULTS:In CKB observational analyses, plasma levels of Lp(a) were log-linearly and positively associated with higher risks of myocardial infarction and IS, but not with ICH. In genome-wide association analysis, we identified 29 single nucleotide polymorphisms independently associated with Lp(a) that together explained 33% of variance in Lp(a) in Chinese individuals. In UK Biobank, the lead Chinese variants identified in CKB were replicated in 1260 Chinese individuals, but explained only 10% of variance in Lp(a) in European individuals. In Mendelian randomization analyses, however, there were highly concordant effects of Lp(a) across both ancestries for all cardiovascular disease outcomes examined. In combined analyses of both ancestries, the proportional reductions in risk per 100 nmol/L lower genetically predicted Lp(a) levels for myocardial infarction were 3-fold greater than for total IS (rate ratio, 0.78 [95% CI, 0.76–0.81] versus 0.94 [0.92–0.96]), but were similar to those for large-artery IS (0.80 [0.73–0.87]; n=8134). There were weaker associations with cardioembolic IS (0.92 [95% CI, 0.86–0.98]; n=11 730), and no association with small-vessel IS (0.99 [0.91–1.07]; n=12 343) or with intracerebral hemorrhage (1.08 [0.96–1.21]; n=5845).CONCLUSIONS:The effects of Lp(a) on risk of myocardial infarction and large-artery IS were comparable in East Asian and European individuals, suggesting that people with either ancestry could expect comparable proportional benefits for equivalent reductions in Lp(a), but there was little effect on other stroke types.

Stroke, Ahead of Print. BACKGROUND:Few neuropathologic studies focus on the associations of cerebrovascular pathologies with cognition in older Black adults.METHODS:We conducted a nested substudy of participants who were enrolled in 1 of 4 harmonized longitudinal cohort studies—the Minority Aging Research Study, African American Clinical Core, Rush Memory and Aging Project, and Religious Order Study before coming to autopsy. Neuropathologic evaluation included assessment of cerebrovascular and neurodegenerative pathologies. We first documented single and mixed cerebrovascular profiles and neurodegenerative pathologies in 112 Black decedents and examined the pathological burden with cognitive function proximate to death. In secondary analyses, we matched 2:1 the 112 Black decedents to 214 White decedents from the same cohorts using Mahalanobis distance matching and conducted linear regression models to examine racial differences in the burden of each vascular pathology and their associations with cognition.RESULTS:In older Black decedents, macroscopic infarcts were present in 37%, microinfarcts in 30%, basal ganglia arteriolosclerosis in 20%, cerebral amyloid angiopathy in 32%, and atherosclerosis in 14%. Single cerebrovascular profiles were present in 29% and mixed cerebrovascular profiles in 40%. Microinfarcts (estimate=−0.51, SE=0.23,P=0.03) and arteriolosclerosis in the basal ganglia (estimate =−0.29, SE=0.13,P=0.03) were associated with lower global cognition independent of neurodegenerative pathologies. Further, microinfarcts were associated with lower episodic and semantic memory, and perceptual speed, whereas arteriolosclerosis was associated with only semantic memory. Mixed vascular profiles were also associated with lower episodic memory and perceptual speed. In secondary analyses, the burden of cerebrovascular pathologies and cognitive associations were similar across races.CONCLUSIONS:Cerebrovascular pathologies are common in older Black decedents, most often as a mixed cerebrovascular pathology profile. Arteriosclerosis and microinfarcts were associated with lower cognition above and beyond the presence of neurodegenerative pathologies. Burden and cognitive associations with cerebrovascular pathologies were similar across races.

Stroke, Ahead of Print. BACKGROUND:ANNEXA-I (Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of FXA Inhibitors) was a randomized trial that demonstrated that andexanet compared with usual care in patients with intracranial hemorrhage associated with FXa (factor Xa) inhibitor treatment reduces the risk of hematoma expansion and increases the risk of arterial thromboembolic events.METHODS:In a secondary analysis of the ANNEXA-I trial, we compared the effects of andexanet with usual care on change in anti-FXa activity and endogenous thrombin potential (ETP) using Wilcoxon rank-sum test. We examined the associations between 1-hour reduction in anti-FXa and 1-hour increase in ETP and hematoma expansion at 12 hours (≥12.5 mL or percentage volume change ≥35%) using logistic regression, both unadjusted and adjusted for time from symptom onset to baseline scan, baseline diastolic blood pressure, hematoma volume, baseline biomarker level and time from baseline scan to treatment, and association with arterial thromboembolic events (ischemic stroke, myocardial infarction, and systemic embolism) during 30 days of follow-up using Cox regression, both unadjusted and adjusted for age, baseline biomarker level, prior MI, and eligibility for treatment with high-dose andexanet.RESULTS:ANNEXA-I enrolled 530 patients. Among 438 patients with baseline anti-FXa results, andexanet compared with usual care reduced anti-FXa activity at 1 hour (median, 8.6 versus 97.5 ng/mL; median reduction from baseline, 98.3 versus 10.9 ng/mL;P

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Stroke, Volume 56, Issue 5, Page 1343-1348, May 1, 2025. Consecutive enrollment of eligible patients is fundamental to the internal and external validities of randomized controlled trials. The generalizability of trial results is greatly undermined when enrolled patients are not representative of the broader target population, which is especially likely if a large proportion of otherwise-eligible individuals receive treatment outside the trial. In this article, we discuss the problem that such selective recruitment or cherry-picking of patients poses to clinical trials. We explore factors contributing to such cherry-picking, such as the What’s In It For Us problem for subinvestigators, and discuss strategies to identify when cherry-picking is going on in a trial. We also critically examine various strategies to mitigate cherry-picking. Moreover, we propose a method to quantify cherry-picking within an acute stroke trial while distinguishing it from simple underrecruitment. It is only when we seek to consistently quantify the problem of cherry-picking, that we will make meaningful strides toward resolving this issue and further strengthening the validity of our randomized controlled trials.

Stroke, Volume 56, Issue 5, Page 1295-1297, May 1, 2025.

Stroke, Volume 56, Issue 5, Page 1349-1350, May 1, 2025. According to Global Stroke Fact Sheet 2022, stroke is the second leading cause of death and a major cause of disability. Stroke treatment and care need immediate attention and fill the large existing gaps. This article focuses on the gaps in stroke prevention, management, and care. The author has highlighted 2 main facts, time window and watch-and-wait, which play a critical role in the management of patients upon stroke onset.