Small Vessel Stroke Research Articles

Causality between cognitive performance and cardiovascular disease: A bidirectional Mendelian randomization study

BackgroundGrowing evidence points to a connection between cardiovascular disease and cognitive impairment. These observational study findings, however, were not all uniform, and some did not discover a link like this. Investigating the causal link between cognitive impairment and cardiovascular disease is vital. MethodUsing publicly available genome-wide association study (GWAS) summary datasets and stringent screening instrumental variables, we carried out a bidirectional Mendelian randomization study. To investigate the causality between cardiovascular disease and cognitive impairment, three different MR techniques—inverse variance weighted (IVW), MR-Egger, and weighted median—as well as various sensitivity analyses—Cochran's Q, ivw_radial, leave-one-out (LOO), MR-Egger intercept, and MR-PRESSO—were used. ResultsThe causal impact of genetically predicted cognitive performance on hypertension, atrial fibrillation, heart failure, coronary atherosclerosis, coronary artery disease, and myocardial infarction was detected in the forward MR analysis, but not stroke or any subtypes. We only discover the causal effects of hypertension, any stroke, and its subtypes (ischemic and small vessel stroke) on cognitive performance in the reverse MR analysis. ConclusionThis MR analysis offers proof of a causal link between cognitive impairment and elevated cardiovascular disease risk. Our research emphasizes the value of cognitively impaired patients being screened for cardiovascular disease, which may offer fresh perspectives on cardiovascular disease prevention.

Circulating sex hormone-binding globulin levels and ischemic stroke risk: a Mendelian randomization study.

Previous studies have presented conflicting findings regarding the protective effects of circulating sex hormone-binding globulin (SHBG) on ischemic stroke (IS). This study aimed to assess the causal effect of SHBG on IS using Mendelian randomization (MR) analysis and to identify potential mediators. First, the causal effect of SHBG on any IS (AIS), cardioembolic stroke (CES), large artery stroke (LAS), and small vessel stroke (SVS) was assessed by inverse variance weighed (IVW) method. Two additional MR methods (weighted median and MR-Egger) were used to supplement the IVW results. Subsequently, a two-step MR was further performed to assess whether three glycemic profiles [fasting glucose, fasting insulin, and glycated hemoglobin (HbA1c)] and five lipid profiles (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, non-HDL cholesterol, total cholesterol, and triglycerides) mediated the causal effect. Furthermore, Cochrane's Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis were performed for sensitivity analyses. The IVW results showed that SHBG significantly reduced SVS risk (odds ratio= 0.60, 95% confidence interval: 0.47-0.77, P = 4.60E-05). The weighted median and MR-Egger results were parallel to IVW. However, no significant associations were found between SHBG and AIS, CES, and LAS. Mediation analysis indicated that HbA1c may be involved in SHBG reducing SVS risk. Sensitivity tests demonstrated the reliability of causal estimates. Circulating SHBG levels may decrease SVS risk by lowering HbA1c levels. Therefore, individuals with low circulating SHBG levels should focus on glycemic control to reduce future SVS risk.

Cerebral Small Vessel Disease: Early-Life Antecedents and Long-Term Implications for the Brain, Aging, Stroke, and Dementia.

Cerebral small vessel disease is common in older adults and increases the risk of stroke, cognitive impairment, and dementia. While often attributed to midlife vascular risk factors such as hypertension, factors from earlier in life may contribute to later small vessel disease risk. In this review, we summarize current evidence for early-life effects on small vessel disease, stroke and dementia focusing on prenatal nutrition, and cognitive ability, education, and socioeconomic status in childhood. We discuss possible reasons for these associations, including differences in brain resilience and reserve, access to cognitive, social, and economic resources, and health behaviors, and we consider the extent to which these associations are independent of vascular risk factors. Although early-life factors, particularly education, are major risk factors for Alzheimer disease, they are less established in small vessel disease or vascular cognitive impairment. We discuss current knowledge, gaps in knowledge, targets for future research, clinical practice, and policy change.

The role of leptin in ischemic stroke and its subtypes: A Mendelian randomization study

Background and aimsObservational studies have suggested a relationship between leptin and risk of stroke. However, evidence for the association remains inconsistent, and whether the association reflects a causal relationship remains to be established. To clarify this relationship, we adopted a two-sample Mendelian randomization (MR) analysis to investigate whether leptin plays a causal role in the risk of stroke and its subtypes. Methods and resultsFive independent single-nucleotide polymorphisms (SNPs) associated with the leptin level from genome-wide association studies (GWASs) of European individuals were selected. We performed an MR analysis using the inverse-variance-weighted (IVW) as primary method to examine the causal effects of leptin on ischemic stroke (IS). Moreover, MR-Egger intercept and Cochran's Q statistic were also performed to detect the pleiotropy or heterogeneity of our MR results. Genetically predicted circulating leptin level was not associated with ischemic stroke [odds ratio (OR): 1.48, 95% confidence interval (CI): 0.78–2.8, P = 0.22], large artery stroke (OR: 1.44, 95% CI: 0.39–5.25, P = 0.57), cardioembolic stroke (OR:1.33, 95% CI: 0.55–3.22, P = 0.52), and small vessel stroke (OR: 1.48, 95% CI: 0.39–5.63, P = 0.56) using the IVW method. Likewise, there is no convincing evidence for the associations between leptin levels and cardiovascular diseases (CVD) risk factors. ConclusionsThis study did not provide evidence that leptin levels are associated with increased risk of stroke and its subtypes.

Causal Effects of YKL-40 on Ischemic Stroke and Its Subtypes: A 2-Sample Mendelian Randomization Study.

Background Chitinase-3 like protein 1 (CHI3L1, YKL-40)was reported to be implicated in the development of ischemic stroke, but whether the association between them was causal remained unclear. We conducted a 2-sample Mendelian randomization study to explore the associations of genetically determined plasma YKL-40 with ischemic stroke and its subtypes (large artery stroke, small vessel stroke, and cardioembolic stroke). Methods and Results Based on genome-wide association study dataof 3394 European-descent individuals, we selected 13 single-nucleotide polymorphisms associated with plasma YKL-40 as genetic instruments. Summary data about ischemic stroke and its subtypes were obtained from the Multiancestry Genome-wide Association Study of Stroke Consortium, involving 34 217 ischemic stroke cases and 406 111 controls of European ancestry. We used the inverse-variance weighted method followed by a series of sensitivity analyses to assess the causal associations of plasma YKL-40 with ischemic stroke and its subtypes. The primary analysis showed that genetically determined high YKL-40 levels were associated with increased risks of large artery stroke (odds ratio [OR], 1.08 [95% CI, 1.04-1.12]; P=1.73×10-4) and small vessel stroke (OR, 1.05 [95% CI, 1.01-1.09]; P=7.96×10-3) but not with ischemic stroke or cardioembolic stroke. Sensitivity analyses further confirmed these associations, and Mendelian randomization-Egger indicated no evidence of genetic pleiotropy. In addition, supplementary analysis based on the summary data from the Olink proximity extension assay cardiovascular I (Olink CVD-I) panel showed that high YKL-40 levels were positively associated with the risks of large artery stroke (OR, 1.15 [95% CI, 1.08-1.22]; P=4.16×10-6) but not with small vessel stroke. Conclusions Genetically determined high plasma YKL-40 levels were causal associated with increased risks of large artery stroke.

Neurological phenotype of adenosine deaminase 2 deficient patients: a cohort study.

Patients with adenosine deaminase 2 (ADA2) deficiency can present with various neurological manifestations due to vasculopathies and autoinflammation. These include ischaemic and hemorrhagic stroke, but less clearly defined neurological symptoms have also been reported. In this cohort study, patients with confirmed ADA2 deficiency from seven university hospitals in the Netherlands were included. The frequency and recurrence rates of neurological manifestations before and after initiation of tumor necrosis factor α (TNF-α) inhibiting therapy were analyzed. Twenty-nine patients were included with a median age at presentation of 5 years (interquartile range 1-17). Neurological manifestations occurred in 19/29 (66%) patients and were the presenting symptom in 9/29 (31%) patients. Transient ischaemic attack (TIA)/ischaemic stroke occurred in 12/29 (41%) patients and was the presenting symptom in 8/29 (28%) patients. In total, 25 TIAs/ischaemic strokes occurred in 12 patients, one after initiation of TNF-α inhibiting therapy and one whilst switching between TNF-α inhibitors. None was large-vessel occlusion stroke. Two hemorrhagic strokes occurred: one aneurysmatic subarachnoid hemorrhage and one spontaneous intracerebral hemorrhage. Most neurological symptoms, including cranial nerve deficits, vertigo, ataxia and seizures, were caused by TIAs/ischaemic strokes and seldom recurred after initiation of TNF-α inhibiting therapy. Neurological manifestations, especially TIA/ischaemic stroke, are common in patients with ADA2 deficiency and frequently are the presenting symptom. Because it is a treatable cause of young stroke, for which antiplatelet and anticoagulant therapy are considered contraindicated, awareness amongst neurologists and pediatricians is important. Screening for ADA2 deficiency in young patients with small-vessel ischaemic stroke without an identified cause should be considered.

Association Between Prekallikrein and Stroke: A Mendelian Randomization Study.

Background High plasma prekallikrein was reported to be associated with increased risks of stroke, but the causality for these associations remains unclear. We aimed to investigate the associations of genetically predicted plasma prekallikrein concentrations with all-cause stroke, ischemic stroke, 3 ischemic stroke subtypes, and intracerebral hemorrhage (ICH) using a 2-sample Mendelian randomization approach. Methods and Results Seven independent prekallikrein-related single-nucleotide polymorphisms were identified as genetic instruments for prekallikrein based on a genome-wide association study with 1000 European individuals. The summary statistics for all-cause stroke, ischemic stroke, and ischemic stroke subtypes were obtained from the Multiancestry Genome-wide Association Study of Stroke Consortium with 40 585 cases and 406 111 controls of European ancestry. The summary statistics for ICH were obtained from the ISGC (International Stroke Genetics Consortium) with 1545 ICH cases and 1481 controls of European ancestry. In the main analysis, the inverse-variance weighted method was applied to estimate the associations of plasma prekallikrein concentrations with all-cause stroke, ischemic stroke, ischemic stroke subtypes, and ICH. Genetically predicted high plasma prekallikrein levels were significantly associated with elevated risks of all-cause stroke (odds ratio [OR] per SD increase, 1.04 [95% CI, 1.02-1.06]; P=5.44×10-5), ischemic stroke (OR per SD increase, 1.05 [95% CI, 1.03-1.07]; P=1.42×10-5), cardioembolic stroke (OR per SD increase, 1.08 [95% CI, 1.03-1.12]; P=3.75×10-4), and small vessel stroke (OR per SD increase, 1.11 [95% CI, 1.06-1.17]; P=3.02×10-5). However, no significant associations were observed for genetically predicted prekallikrein concentrations with large artery stroke and ICH. Conclusions This Mendelian randomization study found that genetically predicted high plasma prekallikrein concentrations were associated with increased risks of all-cause stroke, ischemic stroke, cardioembolic stroke, and small vessel stroke, indicating that prekallikrein might have a critical role in the development of stroke.

Inflammation biomarkers in acute ischemic stroke according to different etiologies.

High throughput technologies provide new opportunities to further investigate the pathophysiology of ischemic strokes. The present cross-sectional study aimed to evaluate potential associations between the etiologic subtypes of ischemic stroke and blood-based proteins. We investigated the associations between ischemic stroke subtypes and a panel of circulating inflammation biomarkers in 364 patients included in the Stroke Cohort Augsburg (SCHANA). Stroke etiologies were categorized according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification. Serum concentrations of 52 biomarkers were measured using the Bio-Plex Pro™ Human Cytokine Screening Panel, ICAM-1 set and VCAM-1 set, plus the Pro™ Human TH17 cytokine sCD40L set and IL31 set (all Bio-Rad, USA). Multivariable linear regression models were used to examine associations. Point estimates were calculated as the mean difference in -standardized cytokine levels on the log2 -scale. Stromal-cell-derived-factor 1 alpha (SDF-1a) showed significantly higher serum levels in cardioembolic compared with large vessel atherosclerotic stroke (β = 0.48; 95% CI 0.22; 0.75; Padj = 0.036). Significantly lower levels of interleukin-6 (IL-6) (β = -0.53; 95% CI -0.84; -0.23; Padj = 0.036) and macrophage migration inhibitory factor (MIF) (β = -0.52; 95% CI -0.84; -0.21; Padj = 0.043) were found in the small vessel versus large vessel stroke subtype. Immune dysregulations observed in different stroke subtypes might help uncover pathophysiological mechanisms of the disease. Further studies are needed to validate identified biomarkers in diverse study populations before they can potentially be used in clinical practice to further improve stroke management and patient outcomes.

Exploring the Causality of Type 1 Diabetes and Stroke Risk: A Mendelian Randomization Study and Meta-analysis.

Type II diabetes was causally related to stroke, which is a risk factor for stroke. However, the causal relationship between type I diabetes(T1D) and stroke, especially its subtypes, remains unclear. To determine whether T1D has a genetic causal link to stroke and its subtypes, we undertook this mendelian randomization (MR) study. The genome-wide association studies (GWAS) of T1D was the source of exposure. The outcomes were strokes and their subtypes, including ischemic stroke (IS), small vessel stroke (SVS), cardioembolic stroke (CES), large artery atherosclerosis stroke (LAS), intracerebral hemorrhage (ICH), lobar intracerebral hemorrhage (LICH), and non-lobar intracerebral hemorrhage (NLICH). We used outcome GWAS conducted by ISGC consortium for the initial phase and GWAS from MEGASTROKE consortium as the data for the replication phase to confirm the causal association. Besides, we conducted a meta-analysis of the causal association from ISGC and MEGASTROKE databases to confirm robust causality. Inverse-variance weighting (IVW) was utilized as the primary method to estimate the causality between T1D and stroke. The Cochran's Q test and the MR-PRESSO global test were used to examine the sensitivity. We discovered the causal relationship between T1D and SVS (OR = 1.17, 95% CI: 1.07-1.28, p = 6.0 × 10- 4), CES (OR = 1.11, 95%CI: 1.03-1.21, p = 0.0080) in initial stage. The replication phase validated T1D has a causal relationship with SVS (OR = 1.12, 95% CI: 1.06-1.18, p = 4.0 × 10- 5), but not with stroke and other subtypes. The meta-analysis of initial and replication stage again supported the causal link between T1D and SVS (OR = 1.13, 95% CI: 1.08-1.18, p < 0.05). However, no causal relationship was found between T1D and other stroke subtypes. The sensitivity analysis also supported the robust of these results. In conclusion, T1D was causally associated with SVS, but not with other subtypes of stroke. More investigation is needed to understand the underlying biology mechanism.

Assessment of bidirectional relationships between brain imaging-derived phenotypes and stroke: a Mendelian randomization study

BackgroundStroke is a major cause of mortality and long-term disability worldwide. Whether the associations between brain imaging-derived phenotypes (IDPs) and stroke are causal is uncertain.MethodsWe performed two-sample bidirectional Mendelian randomization (MR) analyses to explore the causal associations between IDPs and stroke. Summary data of 587 brain IDPs (up to 33,224 individuals) from the UK Biobank and five stroke types (sample size range from 301,663 to 446,696, case number range from 5,386 to 40,585) from the MEGASTROKE consortium were used.ResultsForward MR indicated 14 IDPs belong to projection fibers or association fibers were associated with stroke. For example, higher genetically determined mean diffusivity (MD) in the right external capsule was causally associated with an increased risk of small vessel stroke (IVW OR = 2.76, 95% CI 2.07 to 3.68, P = 5.87 × 10−12). Reverse MR indicated that genetically determined higher risk of any ischemic stroke was associated with increased isotropic or free water volume fraction (ISOVF) in body of corpus callosum (IVW β = 0.23, 95% CI 0.14 to 0.33, P = 3.22 × 10−7). This IDP is a commissural fiber and it is not included in the IDPs identified by forward MR.ConclusionsWe identified 14 IDPs with statistically significant evidence of causal effects on stroke or stroke subtypes. We also identified potential causal effects of stroke on one IDP of commissural fiber. These findings might guide further work toward identifying preventative strategies at the brain imaging levels.

Associations of lipids and lipid-lowering drugs with risk of stroke: a Mendelian randomization study.

Stroke is a leading cause of death worldwide, but it is unclear whether circulating lipids and lipid-lowering drugs are causally associated with stroke and its subtypes. We used two-sample Mendelian randomization (MR) to examine the effects of blood lipids and lipid-lowering drugs on stroke and its subtypes. The inverse variance weighted Mendelian randomization (IVW-MR) revealed the low-density lipoprotein cholesterol (LDL-C) (OR, 1.46; 95% CI, 1.17-1.83; p = 0.0008) and apolipoprotein B (apoB) (OR, 1.46; 95% CI, 1.21-1.77; p = 0.0001) was positively correlated with large artery stroke (LAS). However, no causal effect was found in LDL-C and apoB on LAS risk when we conducted mvMR. The IVW-MR also found a suggestive evidence that decreased LDL-C levels mediated by the PCSK9 (proprotein convertase subtilisin-kexin type 9) gene were associated with a reduced risk of any stroke (AS) (OR, 1.31; 95% CI, 1.13-1.52; p = 0.0003), any ischemic stroke (AIS) (OR, 1.29; 95% CI, 1.10-1.51; p = 0.001), and LAS (OR, 1.73; 95% CI, 1.15-2.59; p = 0.008), while NPC1L1 (Niemann-Pick C1-like protein)-mediated LDL-C levels were associated with a higher risk of small vessel stroke (SVS) (OR, 6.10; 95% CI, 2.13-17.43; p = 0.0008). The SMR revealed that expression of PCSK9 was associated with risk of AS (OR, 1.15; 95% CI, 1.03-1.28; p = 0.01), AIS (OR, 1.02; 95% CI, 1.14-1.29; p = 0.03), cardioembolic stroke (CES) (OR, 1.28; 95% CI, 1.01-1.61; p = 0.04). And, a significant association was found between the expression of NPC1L1 and the risk of SVS (OR, 1.15; 95% CI, 1.00-1.32; p = 0.04). We cautiously find that LDL-C and apoB was positively correlated with LAS. These findings suggest that the reducing LDL-C levels could be an effective prevention strategy for reducing the risk of stroke.

Essential nutrients and cerebral small vessel diseases: a two-sample Mendelian randomization study.

Previous studies have suggested a potential association between nutrients and cerebral small vessel disease (CSVD), but this association has not been fully addressed. We intended to clarify the causal associations between four categories of essential nutrients (amino acids, polyunsaturated fatty acids, minerals and vitamins) and two acute manifestations of CSVD (intracerebral hemorrhage and small vessel stroke) using two-sample Mendelian randomization (MR) analysis. We obtained European-based large-scale genome-wide association studies (GWASs) related to CSVD (6,255 cases and 233,058 controls) and nutrient concentrations. Causality evaluation mainly included the results of the inverse variance-weighted (IVW) method. The simple median method, the weighted median method and the MR-Egger method were adopted for sensitivity analyses. For ICH or SVS, increased levels of phenylalanine (OR = 1.188, p < 0.001) and dihomo-gamma-linolenic acid (DGLA) (OR = 1.153, p = 0.001) showed risk effects, while docosapentaenoic acid (DPA) (OR = 0.501, p < 0.001), zinc (OR = 0.919, p < 0.001), and arachidonic acid (OR = 0.966, p = 0.007) showed protective effects. For lobar hemorrhage or SVS, AA (OR = 0.978, p < 0.001), zinc (OR = 0.918, p < 0.001), and retinol (OR = 0.753, p < 0.001) showed risk effects; DPA (OR = 0.682, p = 0.022), gamma-linolenic acid (OR = 0.120, p = 0.033) and 25(OH)D (OR = 0.874, p = 0.040) showed protective effects. For nonlobar hemorrhage or SVS, DGLA (OR = 1.088, p < 0.001) and phenylalanine (OR = 1.175, p = 0.001) showed risk effects. Our study analyzed the effect of nutrients on CSVD risk from a genetic perspective, with implications for CSVD prevention through nutrient supplementation.

Ischemic Stroke and Cerebral Microbleeds: A Two-Sample Bidirectional Mendelian Randomization Study.

Recent observational studies have reported the association between ischemic stroke (IS) and cerebral microbleeds (CMBs). Whether this reflects a causal association remains to be established. Herein, we adopted a two-sample bidirectional Mendelian randomization (MR) analysis to comprehensively evaluate the causal association of IS and CMBs. The summary-level genome-wide association studies (GWASs) data of IS were obtained from the GIGASTROKE consortium (62,100 European ancestry cases and 1,234,808 European ancestry controls). All IS cases could be further divided into large-vessel atherosclerosis stroke (LVS, n = 6399), cardio-embolic stroke (CES, n = 10,804) and small-vessel occlusion stroke (SVS, n = 6811). Meanwhile, we used publicly available summary statistics from published GWASs of CMBs (3556 of the 25,862 European participants across 2 large initiatives). A bidirectional MR analysis was conducted using inverse-variance weighting (IVW) as the major outcome, whereas MR-Egger and weighted median (WM) were used to complement the IVW estimates as they can provide more robust estimates in a broader set of scenarios but are less efficient (wider CIs). A Bonferroni-corrected threshold of p < 0.0125 was considered significant, and p values between 0.0125 and 0.05 were considered suggestive of evidence for a potential association. We detected that higher risk of IS [IVW odds ratio (OR) 1.47, 95% confidence interval (CI) 1.04-2.07, p = 0.03] and SVS (IVW OR 1.62, 95% CI 1.07-2.47, p = 0.02) were significantly associated with CMBs. Reverse MR analyses found no significant evidence for a causal effect of CMBs on IS and its subtypes. Our study provides potential evidence that IS and SVS are causally linked to increased risk of CMBs. Further research is needed to determine the mechanisms of association between IS and CMBs.

Prevalence of Iron Deficiency Anaemia in Ischaemic Stroke

Background: Iron Deficiency Anaemia has been proposed as a risk factor for developing ischemic stroke. In long-term follow-up studies, and it is also known to increase the risk of death. Very little is known about the prevalence of Iron Deficiency Anaemia (IDA) in Bangladeshi stroke patients. We aimed to determine the prevalence of IDA among admitted patients of acute ischemic stroke in a tertiary care hospital in Bangladesh. Materials and methods: In this cross-sectional study, 75 patients with acute ischemic stroke were selected purposively from the Neurology &amp; Medicine Department of Comilla medical college hospital from February 2021 to May 2021. Traditional risk factors for stroke, stroke type and severity at admission were recorded for each patient. Anaemia is defined as haemoglobin &lt;12gm/dl in women &amp; &lt;13gm/dl in men. IDA was defined as serum ferritin level &lt;20 μgm/L in males and &lt;40 μgm/L in females. Results: Mean age was 65.8 (±11.4) years. Sixty percent of patients were male. Hypertension was the most prevalent risk factor present in 73.3% of the cases, followed by diabetes mellitus (49.3%), smoking (28.0%), ischaemic heart disease (25.3%), and dyslipidemia (21.3%). Small vessel strokes were the most common, accounting for 48% of all the patients, followed by large vessels getting affected in 38.7% of the cases. Prevalence IDA was 24%. (95% confidence interval: 14.9%-35.3%). However, the proportion of IDA among patients with severe stroke was 84.6% compared to 11.3% in non-severe strokes (p=0.001). Conclusion: Prevalence of IDA in acute ischemic stroke is significant and it is associated with severe stroke in our hospital. Central Medical College Journal Vol 6 No 1 January 2022 Page: 7-13

Global distributions of age- and sex-related arterial stiffness: systematic review and meta-analysis of 167 studies with 509,743 participants.

Arterial stiffening is central to the vascular ageing process and a powerful predictor and cause of diverse vascular pathologies and mortality. We investigated age and sex trajectories, regional differences, and global reference values of arterial stiffness as assessed by pulse wave velocity (PWV). Measurements of brachial-ankle or carotid-femoral PWV (baPWV or cfPWV) in generally healthy participants published in three electronic databases between database inception and August 24th, 2020 were included, either as individual participant-level or summary data received from collaborators (n=248,196) or by extraction from published reports (n=274,629). Quality was appraised using the Joanna Briggs Instrument. Variation in PWV was estimated using mixed-effects meta-regression and Generalized Additive Models for Location, Scale, and Shape. The search yielded 8920 studies, and 167 studies with 509,743 participants from 34 countries were included. PWV depended on age, sex, and country. Global age-standardised means were 12.5m/s (95% confidence interval: 12.1-12.8m/s) for baPWV and 7.45m/s (95% CI: 7.11-7.79m/s) for cfPWV. Males had higher global levels than females of 0.77m/s for baPWV (95% CI: 0.75-0.78m/s) and 0.35m/s for cfPWV (95% CI: 0.33-0.37m/s), but sex differences in baPWV diminished with advancing age. Compared to Europe, baPWV was substantially higher in the Asian region (+1.83m/s, P=0.0014), whereas cfPWV was higher in the African region (+0.41m/s, P<0.0001) and differed more by country (highest in Poland, Russia, Iceland, France, and China; lowest in Spain, Belgium, Canada, Finland, and Argentina). High vs. other country income was associated with lower baPWV (-0.55m/s, P=0.048) and cfPWV (-0.41m/s, P<0.0001). China and other Asian countries featured high PWV, which by known associations with central blood pressure and pulse pressure may partly explain higher Asian risk for intracerebral haemorrhage and small vessel stroke. Reference values provided may facilitate use of PWV as a marker of vascular ageing, for prediction of vascular risk and death, and for designing future therapeutic interventions. This study was supported by the excellence initiative VASCage funded by the Austrian Research Promotion Agency, by the National Science Foundation of China, and the Science and Technology Planning Project of Hunan Province. Detailed funding information is provided as part of the Acknowledgments after the main text.

Causal Associations between Functional/Structural Connectivity and Stroke: A Bidirectional Mendelian Randomization Study

Disruption of brain resting-state networks (RSNs) is known to be related to stroke exposure, but determining causality can be difficult in epidemiological studies. We used data on genetic variants associated with the levels of functional (FC) and structural connectivity (SC) within 7 RSNs identified from a genome-wide association study (GWAS) meta-analysis among 24,336 European ancestries. The data for stroke and its subtypes were obtained from the MEGASTROKE consortium, including up to 520,000 participants. We conducted a two-sample bidirectional Mendelian randomization (MR) study to investigate the causality relationship between FC and SC within 7 RSNs and stroke and its subtypes. The results showed that lower global mean FC and limbic network FC were associated with a higher risk of any ischemic stroke and small vessel stroke separately. Moreover, ventral attention network FC and default mode network SC have a positive causal relationship with the risk of small vessel stroke and large artery stroke, respectively. In the inverse MR analysis, any stroke and large artery stroke were causally related to dorsal attention network FC and somatomotor FC, respectively. The present study provides genetic support that levels of FC or SC within different RSNs have contrasting causal effects on stroke and its subtypes. Moreover, there is a combination of injury and compensatory physiological processes in brain RSNs following a stroke. Further studies are necessary to validate our results and explain the physiological mechanisms.

Genetic insights into the risk of metabolic syndrome and its components on stroke and its subtypes: Bidirectional Mendelian randomization.

The role of metabolic syndrome (MetS) on stroke has been explored only in many observational studies. We conducted Mendelian randomization (MR) to clarify whether or not the genetically predicted MetS and its components are causally associated with stroke and its subtypes. Genetic instruments of MetS and its components and outcome data sets for stroke and its subtypes came from the gene-wide association study in the UK Biobank and MEGASTROKE consortium, respectively. Inverse variance weighting was utilized as the main method. Genetically predicted MetS, waist circumference (WC), and hypertension increase the risk of stroke. WC and hypertension are related to increased risk of ischemic stroke. MetS, WC, hypertension, and triglycerides (TG) are causally associated with the increasing of large artery stroke. Hypertension increased the risk of cardioembolic stroke. Hypertension and TG lead to 77.43- and 1.19-fold increases, respectively, in small vessel stroke (SVS) risk. The protective role of high-density lipoprotein cholesterol on SVS is identified. Results of the reverse MR analyses show that stroke is related to hypertension risk. From the genetical variants perspective, our study provides novel evidence that early management of MetS and its components are effective strategies to decrease the risk of stroke and its subtypes.

Genetic considerations in cerebral small vessel diseases.

Cerebral small vessel disease (CSVD) encompasses a broad clinical spectrum united by pathology of the small vessels of the brain. CSVD is commonly identified using brain magnetic resonance imaging with well characterized markers including covert infarcts, white matter hyperintensities, enlarged perivascular spaces, and cerebral microbleeds. The pathophysiology of CSVD is complex involving genetic determinants, environmental factors, and their interactions. While the role of vascular risk factors in CSVD is well known and its management is pivotal in mitigating the clinical effects, recent research has identified novel genetic factors involved in CSVD. Delineating genetic determinants can promote the understanding of the disease and suggest effective treatments and preventive measures of CSVD at the individual level. Here we review CSVD focusing on recent advances in the genetics of CSVD. The knowledge gained has advanced understanding of the pathophysiology of CSVD, offered promising early results that may improve subtype identification of small vessel strokes, has led to additional identification of mendelian forms of small vessel strokes, and is getting closer to influencing clinical care through pharmacogenetic studies.

Short-term Trajectories of Poststroke Cognitive Function: A STROKOG Collaboration Study.

Past studies on poststroke cognitive function have focused on the average performance or change over time, but few have investigated patterns of cognitive trajectories after stroke. This project used latent class growth analysis (LCGA) to identify clusters of patients with similar patterns of cognition scores over the first-year poststroke and the extent to which long-term cognitive outcome is predicted by the clusters ("trajectory groups"). Data were sought from the Stroke and Cognition consortium. LCGA was used to identify clusters of trajectories based on standardized global cognition scores at baseline (T1) and at the 1-year follow-up (T2). One-step individual participant data meta-analysis was used to examine risk factors for trajectory groups and association of trajectory groups with cognition at the long-term follow-up (T3). Nine hospital-based stroke cohorts with 1,149 patients (63% male; mean age 66.4 years [SD 11.0]) were included. The median time assessed at T1 was 3.6 months poststroke, 1.0 year at T2, and 3.2 years at T3. LCGA identified 3 trajectory groups, which were characterized by different mean levels of cognition scores at T1 (low-performance, -3.27 SD [0.94], 17%; medium-performance, -1.23 SD [0.68], 48%; and high-performance, 0.71 SD [0.77], 35%). There was significant improvement in cognition for the high-performance group (0.22 SD per year, 95% CI 0.07-0.36), but changes for the low-performance and medium-performance groups were not significant (-0.10 SD per year, 95% CI -0.33 to 0.13; 0.11 SD per year, 95% CI -0.08 to 0.24, respectively). Factors associated with the low- (vs high-) performance group include age (relative risk ratio [RRR] 1.18, 95% CI 1.14-1.23), years of education (RRR 0.61, 95% CI 0.56-0.67), diabetes (RRR 3.78, 95% CI 2.08-6.88), large artery vs small vessel strokes (RRR 2.77, 95% CI 1.32-5.83), and moderate/severe strokes (RRR 3.17, 95% CI 1.42-7.08). Trajectory groups were predictive of global cognition at T3, but its predictive power was comparable with scores at T1. The trajectory of cognitive function over the first-year poststroke is heterogenous. Baseline cognitive function ∼3.6 months poststroke is a good predictor of long-term cognitive outcome. Older age, lower levels of education, diabetes, large artery strokes, and greater stroke severity are risk factors for lower cognitive performance over the first year.

Intercellular adhesion molecule 4 and ischemic stroke: a two-sample Mendelian randomization study

BackgroundExperimental studies suggested that intercellular adhesion molecule 4 (ICAM-4) might be implicated in ischemic stroke, but the population-based evidence on the relationship between ICAM-4 and ischemic stroke were limited. Herein, we performed a two-sample Mendelian randomization (MR) analysis to investigate the associations of genetically determined plasma ICAM-4 with the risks of ischemic stroke and its subtypes.MethodsA total of 11 single-nucleotide polymorphisms associated with ICAM-4 were selected as instrumental variables based on the genome-wide association studies (GWAS) with 3,301 European individuals. Summary-level data about ischemic stroke and its subtypes were obtained from the Multi-ancestry GWAS launched by the International Stroke Genetics Consortium. We used the inverse-variance weighted method followed by a series of sensitivity analyses to evaluate the associations of genetically determined ICAM-4 with the risks of ischemic stroke and its subtypes.ResultsGenetically determined higher ICAM-4 levels were significantly associated with increased risks of ischemic stroke (in the IVW method fitted to multiplicative random effects model: odds ratio [OR] per standard deviation [SD] increase, 1.04; 95% confidence interval [CI], 1.01–1.07; P = 0.006; in the IVW analysis with fixed effects model: OR per SD increase, 1.04; 95% CI, 1.01–1.07; P = 0.003) and cardioembolic stroke (in multiplicative random effects model: OR per SD increase, 1.08; 95% CI, 1.02–1.14; P = 0.004; in fixed effects model: OR per SD increase, 1.08; 95% CI, 1.03–1.13; P = 0.003). There was no association of ICAM-4 with the risks of large artery stroke and small vessel stroke. MR-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses with different MR methods further confirmed these findings.ConclusionsWe found positive associations of genetically determined plasma ICAM-4 with the risks of ischemic stroke and cardioembolic stroke. Future studies are needed to explore the detailed mechanism and investigate the targeting effect of ICAM-4 on ischemic stroke.