Small Vessel Disease Subtypes Research Articles

Abstract WP158: Cortical Superficial Siderosis is Associated With Ischemia After Intracerebral Hemorrhage

Background: Ischemia on diffusion weighted imaging (DWI) after intracerebral hemorrhage (ICH) increases the risk of future ischemic stroke. Radiographic markers of small vessel disease, including cerebral microbleeds (CMB), are associated with DWI lesions. Though cortical superficial siderosis (cSS) is also a hemorrhagic small vessel disease subtype, it is unclear if cSS similarly relates to DWI lesions. We hypothesized that cSS would represent a more severe phenotype of small vessel disease and would associate with DWI lesions after ICH independent to other small vessel disease markers. Methods: Using the Intracerebral Hemorrhage Outcomes Project (ICHOP), we included all cases of spontaneous ICH who underwent DWI and susceptibility imaging/gradient echo. DWI hyperintensities were identified if >10mm from the hematoma with decreased ADC signal. cSS were identified as subarachnoid hemosiderin deposition without acute subarachnoid hemorrhage. The relationship of cSS with DWI lesion presence as the outcome was assessed with logistic regression adjusted for ICH score, blood pressure change within 24 hours, and small vessel disease markers (CMB and white matter hyperintensity). Sensitivity analyses were performed to adjust for demographics and ICH location. A secondary analysis using linear regression assessed the association with the number of DWI lesions adjusted for similar covariates. Results: Of 198 patients analyzed, DWI lesions were observed in 31.3% and cSS in 10.6%. The presence of cSS was associated with DWI lesions (adjusted OR 3.72, CI: 1.29-10.72), independent of other small vessel disease markers. Separate sensitivity analyses adjusting for sex, race, and ICH location did not change the association of cSS with DWI lesions. In secondary analyses, cSS was not associated with greater number of DWI lesions counts (b 0.213, CI -0.53-0.63). Discussion: cSS is associated with the presence of DWI lesions, independent to other small vessel disease markers. cSS may represent a severe phenotype of small vessel disease with a risk of ICH recurrence and ischemia. Further work is required to investigate underlying mechanisms and optimal strategies to mitigate competing risks of future hemorrhage and ischemic events in these patients.

Association of Circulating Circular RNAs (hg38_circ_0008980, and CircDLGAP4) in Diagnosis, Diseases Severity, and Prognosis of Ischemic Stroke.

Fast diagnosing ischemic stroke (IS) is a critical issue in clinical studies, as it allows more effective therapy and stops the progression of IS. The blood level of circular RNAs (CircRNAs) after stroke may be a rapid diagnostic marker. In this study, the blood level of circRNAs was evaluated using a real-time polymerase chain reaction (PCR). We used logistic and linear regression analysis to assess the potential of circRNAs levels with the risk of IS. circRNA DLG associated protein 4 (CircDLGAP4) was decreased in patients compared with controls, and logistic regression showed its expression negatively associated with IS risk. The expression level of human genome version 38_Circular_0008980 (hg38_circ_0008980) was reduced significantly in patients with small vessel disease (SVD), and the linear regression analysis showed a negative relationship between hg38_circ_0008980 expressions with SVD subtype. hg38_circ_0008980 expression relative to controls showed a significant association with IS risk. Taken together, we found a significant decrease in the level of hg38_circ_0008980 after IS; it may act as a novel circRNA in IS pathophysiology with a positive correlation with stroke severity.

A typology of cerebral small vessel disease based on imaging markers

BackgroundLacunes, microbleeds, enlarged perivascular spaces (EPVS), and white matter hyperintensities (WMH) are brain imaging features of cerebral small vessel disease (SVD). Based on these imaging markers, we aimed to identify subtypes of SVD and to evaluate the validity of these markers as part of clinical ratings and as biomarkers for stroke outcome.MethodsIn a cross-sectional study, we examined 1207 first-ever anterior circulation ischemic stroke patients (mean age 69.1 ± 15.4 years; mean NIHSS 5.3 ± 6.8). On acute stroke MRI, we assessed the numbers of lacunes and microbleeds and rated EPVS and deep and periventricular WMH. We used unsupervised learning to cluster patients based on these variables.ResultsWe identified five clusters, of which the last three appeared to represent distinct late stages of SVD. The two largest clusters had no to only mild or moderate WMH and EPVS, respectively, and favorable stroke outcome. The third cluster was characterized by the largest number of lacunes and a likewise favorable outcome. The fourth cluster had the highest age, most pronounced WMH, and poor outcome. Showing the worst outcome, the fifth cluster presented pronounced microbleeds and the most severe SVD burden.ConclusionThe study confirmed the existence of different SVD types with different relationships to stroke outcome. EPVS and WMH were identified as imaging features of presumably early progression. The number of microbleeds and WMH severity appear to be promising biomarkers for distinguishing clinical subgroups. Further understanding of SVD progression might require consideration of refined SVD features, e.g., for EPVS and type of lacunes.

Obesity paradox and stroke outcomes according to stroke subtype: a propensity score-matched analysis.

Obesity has traditionally been considered a risk factor for ischemic stroke. However, some clinical observations have reported a complex relationship between patients who are overweight or obese with paradoxically better stroke outcomes. Stroke subtypes have differing distributions of risk factors, so this study aimed to explain the relationship between body mass index (BMI) and functional prognosis according to stroke subtype. A prospective institutional database on stroke was accessed between March 2014 and December 2021, and consecutive patients with ischemic stroke were retrospectively selected. BMI was categorized into five groups (underweight, normal weight, overweight, obese, and morbid obesity). The outcome of interest in this study was the modified Rankin Scale (mRS) at 90 d, which was divided into favorable (mRS = 0-2) and unfavorable (mRS ≥ 3) groups. The relationship between functional outcome and BMI was analyzed according to stroke subtype. Among 2779 patients with stroke, 913 (32.9%) had unfavorable outcomes. After a propensity score-matched analysis, obesity was inversely associated with unfavorable outcomes (adjusted odds ratio [aOR] = 0.61, 95% confidence interval [95% CI]: 0.46-0.80) in all patients with stroke. Among the stroke subtypes, overweight (aOR = 0.38, 95% CI: 0.20-0.74) and obese (aOR = 0.40, 95% CI: 0.21-0.76) groups were inversely associated with unfavorable outcomes in the cardioembolism subtype. Obesity (aOR = 0.55, 95% CI: 0.32-0.95) was inversely associated with unfavorable outcomes in the small vessel disease subtype. There was no significant relationship between stroke outcome and BMI classification in the large artery disease subtype. These findings suggest that the obesity paradox in ischemic stroke outcomes might differ according to the stroke subtype.

Monogenic Causes in Familial Stroke Across Intracerebral Hemorrhage and Ischemic Stroke Subtypes Identified by Whole-Exome Sequencing

Whole exome sequencing (WES) has been used to detect rare causative variants in neurological diseases. However, the efficacy of WES in genetic diagnosis of clinically heterogeneous familial stroke remains inconclusive. We prospectively searched for disease-causing variants in unrelated probands with defined familial stroke by candidate gene/hotspot screening and/or WES, depending on stroke subtypes and neuroimaging features at a referral center. The clinical significance of each variant was determined according to the American College of Medical Genetics guidelines. Among 161 probands (mean age at onset 53.2 ± 13.7 years; male 63.4%), 33 participants (20.5%) had been identified with 19 pathogenic/likely pathogenic variants (PVs; WES applied 152/161 = 94.4%). Across subtypes, the highest hit rate (HR) was intracerebral hemorrhage (ICH, 7/18 = 38.9%), particularly with the etiological subtype of structural vasculopathy (4/4 = 100%, PVs in ENG, KRIT1, PKD1, RNF213); followed by ischemic small vessel disease (SVD, 15/48 = 31.3%; PVs in NOTCH3, HTRA1, HBB). In contrast, large artery atherosclerosis (LAA, 4/44 = 9.1%) and cardioembolism (0/11 = 0%) had the lowest HR. NOTCH3 was the most common causative gene (16/161 = 9.9%), presenting with multiple subtypes of SVD (n = 13), ICH (n = 2), or LAA (n = 1). Importantly, we disclosed two previously unreported PVs, KRIT1 p.E379* in a familial cerebral cavernous malformation, and F2 p.F382L in a familial cerebral venous sinus thrombosis. The contribution of monogenic etiologies was particularly high in familial ICH and SVD subtypes in our Taiwanese cohort. Utilizing subtype-guided hotspot screening and/or subsequent WES, we unraveled monogenic causes in 20.5% familial stroke probands, including 1.2% novel PVs. Genetic diagnosis may enable early diagnosis, management and lifestyle modification.Graphical Among 161 familial stroke probands, 33 (20.5%) had been identified pathogenic or likely pathogenic monogenic variants related to stroke. The positive hit rate among all subtypes was high in intracerebral hemorrhage (ICH) and ischemic small vessel disease (SVD). Notably, two previously unreported variants, KRIT1 p.E379* in a familial cerebral cavernous malformation and F2 p.F382L in familial cerebral venous sinus thrombosis, were disclosed. CVT cerebral venous thrombosis; HTN Hypertensive subtype; LAA large artery atherosclerosis; SV structural vasculopathy; U Undetermined.

Modifiable and non-modifiable risk factors of dementia on midlife cerebral small vessel disease in cognitively healthy middle-aged adults: the PREVENT-Dementia study

BackgroundConsiderable overlap exists between the risk factors of dementia and cerebral small vessel disease (SVD). However, studies remain limited to older cohorts wherein pathologies of both dementia (e.g. amyloid) and SVD (e.g. white matter hyperintensities) already co-exist. In younger asymptomatic adults, we investigated differential associations and interactions of modifiable and non-modifiable inherited risk factors of (future) late-life dementia to (present-day) mid-life SVD.MethodsCognitively healthy middle-aged adults (aged 40–59; mean 51.2 years) underwent 3T MRI (n = 630) as part of the PREVENT-Dementia study. To assess SVD, we quantified white matter hyperintensities, enlarged perivascular spaces, microbleeds, lacunes, and computed composite scores of SVD burden and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). Non-modifiable (inherited) risk factors were APOE4 status and parental family history of dementia. Modifiable risk factors were derived from the 2020 Lancet Commission on dementia prevention (early/midlife: education, hypertension, obesity, alcohol, hearing impairment, head injuries). Confirmatory factor analysis (CFA) was used to evaluate the latent variables of SVD and risk factors. Structural equation modelling (SEM) of the full structural assessed associations of SVD with risk factors and APOE4*risk interaction.ResultsIn SEM, the latent variable of global SVD related to the latent variable of modifiable midlife risk SVD (β = 0.80, p = .009) but not non-modifiable inherited risk factors of APOE4 or family history of dementia. Interaction analysis demonstrated that the effect of modifiable risk on SVD was amplified in APOE4 non-carriers (β = − 0.31, p = .009), rather than carriers. These associations and interaction effects were observed in relation to the SVD subtype of hypertensive arteriopathy, rather than CAA. Sensitivity analyses using separate general linear models validated SEM results.ConclusionsEstablished modifiable risk factors of future (late-life) dementia related to present-day (mid-life) SVD, suggesting that early lifestyle modifications could potentially reduce rates of vascular cognitive impairment attributed to SVD, a major ‘silent’ contributor to global dementia cases. This association was amplified in APOE4 non-carriers, suggesting that lifestyle modifications could be effective even in those with genetic predisposition to dementia.

A-3 Small-Vessel Childhood Primary Angiitis of the CNS: A Longitudinal Case Study

Abstract Childhood primary angiitis of the central nervous system (cPACNS) is a rare autoimmune and cerebrovascular inflammatory disease associated with cognitive, behavioral, psychiatric, motor, sensory and/or visual symptoms. This longitudinal case study describes deficits associated with a rare course of refractory small vessel cPACNS (sv-cPACNS) with presentation uncharacteristically confined to the right hemisphere. Improved understanding of sv-cPACNS may promote diagnostic clarity and subsequent intervention for a rare and often refractory presentation that is scientifically underserved. Records indicate onset of acute events (paralysis, migraines, stroke-like symptoms) with diagnosis of sv-cPACNS based on brain biopsy. MRI revealed abnormalities restricted to the right cerebral hemisphere. Treatments included high-dose steroids, chemotherapy, IVIg, and other immunomodulatory agents. Treatment course was refractory with many failed therapies until remission on current monoclonal antibody regimen (Natalizumab). Patient was referred due to poor academic and social progression. Neuropsychological results indicated a profile congruent with nonverbal learning disorder, including dysfunction in visuospatial reasoning, fine motor, mathematics, and social judgement. Compared to prior evaluation (age 11), reduced overall intellectual functioning, working memory, and processing speed were observed. This case study examines an 18-year-old patient with sv-cPACNS and cognitive difficulties. Results were consistent with limited research demonstrating low average intellectual functioning with longitudinal declines in working memory and processing speed. Results enhance the current understanding of sv-cPACNS by illustrating a nonverbal learning disorder profile, coinciding with right hemispheric involvement. Unfortunately, the long-term impact on cognitive functioning, especially in small-vessel disease subtype, is still not well understood. Findings add to phenotypic variability and developmental course of previously refractory sv-cPACNS.

Relationship between Methylenetetrahydrofolate Reductase C677T Homozygous Mutation and Cerebral Small Vessel Disease Subtypes

Background: Neuroimaging detects cerebral small vessel disease (CSVD) subtypes, including infarction, asymptomatic lacunes, cerebral microbleeds, white matter hyperintensities (WMHs), and enlarged perivascular space. Methylenetetrahydrofolate reductase (MTHFR) plays an essential role in the metabolism of folic acid and homocysteine. The purpose of this study was to investigate the relationship between the MTHFR C677T mutation and CSVD subtypes.Methods: A total of 144 patients with acute ischemic stroke who visited the Korea University Guro Hospital between April 2020 and August 2020 were retrospectively reviewed. After excluding 24 patients, due to missing laboratory, clinical, or imaging information, a total of 120 patients were analyzed.Results: Among the 120 participants, 25% were included in the MTHFR C677T homozygous mutation group, which had significantly lower folic acid levels (6.24±4.21 ng/mL vs. 8.24±4.21 ng/mL, p=0.03) and higher total homocysteine levels (17.09±14.07 μmol/L vs. 9.65±3.19 μmol/L, p<0.01). Using multiple logistic regression analysis, the homozygous mutation (adjusted odds ratio [aOR]=4.29; 95% confidence interval [CI]=1.16–15.90) and age (aOR=1.06; 95% CI=1.01–1.11) were independently associated with moderate to severe WMHs. Additionally, moderate to severe WMHs were more frequent in the homozygous mutation group (86.7% vs. 66.7%, p=0.01). In a detailed analysis, the homozygous mutation group showed a significantly higher rate of moderate to severe periventricular WMH (PWMH) (86.7% vs. 65.6%, p<0.01).Conclusion: The MTHFR C677T homozygous mutation was positively correlated with moderate to severe PWMH subtypes of CSVD.

The Contribution of White Matter Diffusion and Cortical Perfusion Pathology to Vascular Cognitive Impairment: A Multimode Imaging-Based Machine Learning Study.

Widespread impairments in white matter and cerebrovascular integrity have been consistently implicated in the pathophysiology of patients with small vessel disease (SVD). However, the neural circuit mechanisms that underlie the developing progress of clinical cognitive symptoms remain largely elusive. Here, we conducted cross-modal MRI scanning including diffusion tensor imaging and arterial spin labeling in a cohort of 113 patients with SVD, which included 74 patients with vascular mild cognitive impairment (vMCI) and 39 patients without vMCI symptoms, and hence developed multimode imaging-based machine learning models to identify markers that discriminated SVD subtypes. Diffusion and perfusion features, respectively, extracted from individual white matter and gray matter regions were used to train three sets of classifiers in a nested 10-fold fashion: diffusion-based, perfusion-based, and combined diffusion-perfusion-based classifiers. We found that the diffusion-perfusion combined classifier achieved the highest accuracy of 72.57% with leave-one-out cross-validation, with the diffusion features largely spanning the capsular lateral pathway of the cholinergic tracts, and the perfusion features mainly distributed in the frontal-subcortical-limbic areas. Furthermore, diffusion-based features within vMCI group were associated with performance on executive function tests. We demonstrated the superior accuracy of using diffusion-perfusion combined multimode imaging features for classifying vMCI subtype out of a cohort of patients with SVD. Disruption of white matter integrity might play a critical role in the progression of cognitive impairment in patients with SVD, while malregulation of coritcal perfusion needs further study.

Contribution of Racial and Ethnic Differences in Cerebral Small Vessel Disease Subtype and Burden to Risk of Cerebral Hemorrhage Recurrence.

Black and Hispanic survivors of intracerebral hemorrhage (ICH) are at higher risk of recurrent intracranial bleeding. MRI-based markers of chronic cerebral small vessel disease (CSVD) are consistently associated with recurrent ICH. We therefore sought to investigate whether racial/ethnic differences in MRI-defined CSVD subtype and severity contribute to disparities in ICH recurrence risk. We analyzed data from the Massachusetts General Hospital ICH study (n = 593) and the Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study (n = 329). Using CSVD markers derived from MRIs obtained within 90 days of index ICH, we classified ICH cases as cerebral amyloid angiopathy (CAA)-related, hypertensive arteriopathy (HTNA)-related, and mixed etiology. We quantified CSVD burden using validated global, CAA-specific, and HTNA-specific scores. We compared CSVD subtype and severity among White, Black, and Hispanic ICH survivors and investigated its association with ICH recurrence risk. We analyzed data for 922 ICH survivors (655 White, 130 Black, 137 Hispanic). Minority ICH survivors had greater global CSVD (p = 0.011) and HTNA burden (p = 0.021) on MRI. Furthermore, minority survivors of HTNA-related and mixed-etiology ICH demonstrated higher HTNA burden, resulting in increased ICH recurrence risk (all p < 0.05). We uncovered significant differences in CSVD subtypes and severity among White and minority survivors of primary ICH, with direct implication for known disparities in ICH recurrence risk. Future studies of racial/ethnic disparities in ICH outcomes will benefit from including detailed MRI-based assessment of CSVD subtypes and severity and investigating social determinants of health.

Classification differentiates clinical and neuroanatomic features of cerebral small vessel disease.

Age-related cerebral small vessel disease involves heterogeneous pathogenesis, such as arteriosclerosis/lipohyalinosis and cerebral amyloid angiopathy. MRI can visualize the brain lesions attributable to small vessel disease pathologies, including white-matter hyperintensities, lacune and cerebral microbleeds. However, these MRI markers usually coexist in small vessel disease of different aetiologies. Currently, there is no available classification integrating these neuroimaging markers for differentiating clinical and neuroanatomic features of small vessel disease yet. In this study, we tested whether our proposed stratification scheme could characterize specific clinical, neuroanatomic and potentially pathogenesis/aetiologies in classified small vessel disease subtypes. Cross-sectional analyses from a community-based non-demented non-stroke cohort consisting of ≥50 years old individuals were conducted. All participants were scanned 3T brain MRI for small vessel disease detection and neuroanatomic measurements and underwent physical and cognitive assessments. Study population were classified into robust and four small vessel disease groups based on imaging markers indicating (i) bleeding or non-bleeding; (ii) specific location of cerebral microbleeds; and (iii) the severity and combination of white-matter hyperintensities and lacune. We used whole-brain voxel-based morphometry analyses and tract-based spatial statistics to evaluate the regional grey-matter volume and white-matter microstructure integrity for comparisons among groups. Among the 735 participants with eligible brain MRI images, quality screening qualified 670 for grey-matter volume analyses and 617 for white-matter microstructural analyses. Common and distinct patterns of the clinical and neuroimaging manifestations were found in the stratified four small vessel disease subgroups. Hierarchical clustering analysis revealed that small vessel disease type 4 had features distinct from the small vessel disease types 1, 2 and 3. Abnormal white-matter microstructures and cognitive function but preserved physical function and grey-matter volume were found in small vessel disease type 4. Among small vessel disease types 1, 2 and 3, there were similar characteristics but different severity; the clinical features showed both physical frail and cognitive impairment and the neuroanatomic features revealed frontal–subcortical white-matter microstructures and remote, diffuse cortical abnormalities. This novel stratification scheme highlights the distinct clinical and neuroanatomic features of small vessel disease and the possible underlying pathogenesis. It could have potential application in research and clinical settings.

In vivo neuroinflammation and cerebral small vessel disease in mild cognitive impairment and Alzheimer’s disease

IntroductionAssociations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the...

CIMT as a risk factor for stroke subtype: A systematic review.

An increase in the common carotid artery intima-media thickness (CCA-IMT) is generally considered an early marker of atherosclerosis and is a well-established predictor of cardiovascular disease (CVD). An association between changes in CCA-IMT and risk of stroke has been reported but has conflicting findings. The present meta-analysis was aimed to clarify the association between CCA-IMT with the risk of stroke and its subtype by estimating pooled analysis of published literature. Comprehensive search for all published articles was performed in electronic databases including PubMed, Embase, Cochrane Library, Trip Databases, Worldwide Science, CINAHL and Google Scholar from 01 January 1950 to 30 April 2020. In our meta-analysis, a total of 19 studies, of which sixteen studies involving 3475 ischaemic stroke (IS) cases and 11826 controls; six studies with 902 large vessel disease (LVD) and 548 small vessel disease (SVD) of IS subtypes; five studies with 228 intracerebral haemorrhage (ICH) and 1032 IS cases, were included. Our findings suggest a strong association between increased CCA-IMT with risk of IS as compared to control subjects [SMD=1.46, 95% CI=0.90-2.02]. However, there is an increased risk of LVD as compared to the SVD subtype of IS [SMD=0.36, 95% CI=0.19-0.52] and more chance of occurrence of IS rather than ICH [SMD=0.71, 95% CI=0.28-1.41]. Carotid intima thickness measurements are found to be associated with the risk of stroke along with its subtypes and may be used as a diagnostic marker for predicting the risk of stroke events.

Rs1234313 and rs45454293 are risk factors of cerebral arterial thrombosis, large artery atherosclerosis, and carotid plaque in the Han Chinese population: a case-control study

BackgroundIschemic stroke is a leading cause of mortality and morbidity worldwide. Stenosis or blockage of an artery from atherosclerosis can cause insufficient cerebral blood supply, which leads to ischemic stroke. It has been reported that the polymorphisms of TNFSF4 (tumor necrosis factor super family member 4) are associated with multiple autoimmune diseases. However, it is still unclear whether TNFSF4 gene polymorphisms are associated with ischemic stroke in the Han Chinese population. Here we analyzed the association between TNFSF4 single nucleotide polymorphisms (SNPs) and cerebral arterial thrombosis in the Han Chinese population.MethodWe consecutively recruited 481 patients with cerebral arterial thrombosis and 538 healthy controls. Neck ultrasonography and magnetic resonance imaging (MRI) were used to evaluate large artery atherosclerosis (LAA) and small vessel disease (SVD), as well as the thickness and calcification of carotid artery. DNA was purified from the peripheral blood samples. TNFSF4 SNPs, rs1234313 and rs45454293, were genotyped using PCR.Resultsrs1234313 SNP had a significant correlation with the LAA and SVD subtypes in allelic (G vs A), dominate (GG/GA vs AA) and genotypic (GA vs AA; GG vs AA) models, as well as with the calcification of carotid plaque in dominant (GG/GA vs AA, p = 0.022) and genotypic (GA vs AA, p = 0.01) models. rs45454293 SNP had a significant correlation with the LAA and SVD subtypes in allelic (G vs A) and genotypic models, as well as with the thick carotid plaque in allelic (G vs A, p = 0.01) model.ConclusionTNFSF4 SNPs, rs1234313 and rs45454293, are associated with the risk of specific subtypes of cerebral arterial thrombosis in the Han Chinese population.

Abstract 49: White Matter Hyperintensity Spatial Pattern Variations reflect distinct Cerebral Small Vessel Disease Pathologies

Introduction: Cerebral small vessel disease (SVD) comprise of heterogeneous pathologies affecting small cerebral vessels. A novel phenotyping approach using etiology-based SVD imaging markers may improve discovery of SVD-related mechanisms. Topographical patterns seen in common SVD subtypes (hypertension-related (HTN) and cerebral amyloid angiopathy (CAA)) suggest that spatial location may reflect regionally different SVD pathology. We propose a machine-learning method leveraging spatial location information to partition WMH (a representative SVD imaging marker) into patterns that can discriminate underlying SVD pathology. Method: We selected subjects with WMH on FLAIR MRI from the Alzheimer’s Disease Neuroimaging Initiative database and created WMH segmentation maps using a custom deep learning algorithm. We performed voxel-based spectral clustering analysis on aligned WMH maps to group image voxels into clusters, maximizing within-group and minimizing between-group similarities. HTN-SVD risk was scored using serial blood pressure measurements and medication history. We quantified CAA risk using the Boston criteria. We used multivariable regression to evaluate extent to which different WMH clusters influenced CAA and HTN-SVD risks. Demographics and total WMH volume were included as covariates. Results: We analyzed 878 subjects; 39% were hypertensive, 4.4% had probable CAA. We observed partitioning of WMH into five distinct clusters, which demonstrate recognizable spatial distributions that suggest biological relevance (deep, periventricular, subcortical, anterior horns of lateral ventricles, posterior predominant). Multivariable regression models revealed independent associations of WMH clusters with CAA (posterior predominant WM; p=0.02; ß=0.63), and HTN-SVD (deep WM; p=0.01; ß=0.20). Conclusion: WMH occur in unique spatial patterns that reflect different underlying SVD pathology. WMH spatial pattern variations may serve as etiology-based SVD imaging markers, providing a critical new tool in efforts to resolve homogeneous disease mechanisms among heterogeneous disease presentations. Such strategy enhances genomic studies, allowing more comprehensive modelling of genetic effects on SVD pathogenesis.

Dolichoectasia and Small Vessel Disease in Young Patients With Transient Ischemic Attack and Stroke.

We evaluated whether basilar dolichoectasia is associated with markers of cerebral small vessel disease in younger transient ischemic attack and ischemic stroke patients. We used data from the SIFAP1 study (Stroke in Young Fabry Patients), a large prospective, hospital-based, screening study for Fabry disease in young (<55 years) transient ischemic attack/stroke patients in whom detailed clinical data and brain MRI were obtained, and stroke subtyping with TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment) was performed. Dolichoectasia was found in 508 of 3850 (13.2%) of patients. Dolichoectasia was associated with older age (odds ratio per decade, 1.26; 95% confidence interval, 1.09-1.44), male sex (odds ratio, 1.96; 95% confidence interval, 1.59-2.42), and hypertension (odds ratio, 1.39; 95% confidence interval, 1.13-1.70). Dolichoectasia was more common in patients with small infarctions (33.9% versus 29.8% for acute lesions, P=0.065; 29.1% versus 16.5% for old lesions, P<0.001), infarct location in the brain stem (12.4% versus 6.9%, P<0.001), and in white matter (27.8% versus 21.1%, P=0.001). Microbleeds (16.3% versus 4.7%, P=0.001), higher grades of white matter hyperintensities (P<0.001), and small vessel disease subtype (18.1% versus 12.4%, overall P for differences in TOAST (P=0.018) were more often present in patients with dolichoectasia. Dolichoectasia is associated with imaging markers of small vessel disease and brain stem localization of acute and old infarcts in younger patients with transient ischemic attack and ischemic stroke. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583.

Clinical role of von Willebrand factor in acute ischemic stroke.

An elevated level of von Willebrand factor (VWF) is associated with an increased risk for coronary heart disease and ischemic stroke. The objective of the study was to determine whether the level of VWF is associated with the cardioembolic subtype of ischemic stroke, stroke severity, and clinical outcome. In this study 108 patients suffering from acute ischemic stroke (AIS) were included. According to the etiology of the stroke, patients were classified into the subtype of cardioembolic (CE) stroke and the group with non-CE stroke. Patients with non-CE stroke were further classified into subtype of large vessel disease, subtype of small vessel disease and subtype of cryptogenic stroke. Laboratory tests were performed in the acute phase and VWF was determined for all patients. The National Institutes of Health Stroke Scale (NIHSS) was applied on admission and the modified Rankin scale (MRS) at discharge. The only significant factor which predicted CE stroke was age (B= 0.077; standard error, SE= 0.026; P= 0.003). The level of VWF was not significantly higher in the group with the cardioembolic stroke compared to the group with non-CE stroke. Patients assessed by NIHSS on admission as the most disabled had significantly higher levels of VWF (B= 0.006; SE= 0.003; P= 0.045). Those with higher scores of MRS at discharge also had significantly increased levels of VWF (B= 0.006; SE= 0.003; P= 0.028). Among the patients with ischemic stroke, levels of VWF were not increased in those with CE stroke. High levels of VWF were associated with greater severity of stroke as well as with poor clinical outcome.

New insights into mechanisms of small vessel disease stroke from genetics.

Cerebral small vessel disease (SVD) is a common cause of lacunar strokes, vascular cognitive impairment (VCI) and vascular dementia. SVD is thought to result in reduced cerebral blood flow, impaired cerebral autoregulation and increased blood-brain barrier (BBB) permeability. However, the molecular mechanisms underlying SVD are incompletely understood. Recent studies in monogenic forms of SVD, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 'sporadic' SVD have shed light on possible disease mechanisms in SVD. Proteomic and biochemical studies in post-mortem monogenic SVD patients, as well as in animal models of monogenic disease have suggested that disease pathways are shared between different types of monogenic disease, often involving the impairment of extracellular matrix (ECM) function. In addition, genetic studies in 'sporadic' SVD have also shown that the disease is highly heritable, particularly among young-onset stroke patients, and that common variants in monogenic disease genes may contribute to disease processes in some SVD subtypes. Genetic studies in sporadic lacunar stroke patients have also suggested distinct genetic mechanisms between subtypes of SVD. Genome-wide association studies (GWAS) have also shed light on other potential disease mechanisms that may be shared with other diseases involving the white matter, or with pathways implicated in monogenic disease. This review brings together recent data from studies in monogenic SVD and genetic studies in 'sporadic' SVD. It aims to show how these provide new insights into the pathogenesis of SVD, and highlights the possible convergence of disease mechanisms in monogenic and sporadic SVD.

The homocysteine associated variant rs548987 of SLC17A3 confers susceptibility to ischemic stroke in Chinese population

Ischemic stroke is a common cause of death due to obstructed blood supply of the brain. Despite growing numbers of research, etiology underlying ischemic stroke remains complex and elusive. Elevated plasma homocysteine has been known as a risk factor for ischemic stroke. Recently, a genome-wide association study reported association between rs548987 of SLC17A3 and homocysteine. Given existing relation between homocysteine and ischemic stroke, SLC17A3 was believed to be a promising candidate gene of ischemic stroke. Indeed, its association with ischemic stroke was previously reported in a western population. Herein, we used rs548987 as a candidate genetic variant of ischemic stroke and performed association analysis in a Chinese population with 918 ischemic stroke cases and 979 controls. Although rs548987 failed to show significant association with total ischemic stroke and large vessel disease subtype, the C allele of rs548987 showed significant association with small vessel disease subtype of ischemic stroke (OR=0.68, p=0.004). Our preliminary results suggested different genetic etiology underlying the two most common subtypes of ischemic stroke and provided additional evidence to understand contribution of homocysteine to the disease.

Association study of C-reactive protein associated gene HNF1A with ischemic stroke in Chinese population.

BackgroundIschemic stroke is a life-threatening condition due to obstructed blood supply of the brain. Elevation of plasma C-reactive protein, an important inflammatory marker, was known to associate with increased risk of ischemic stroke. Previous studies reported association between genetic variants of HNF1A and plasma level of C-reactive protein. The HNF1A gene encodes a hepatocyte transcription factor which might have regulatory effects on C-reactive protein synthesis in liver. Therefore, the C-reactive protein associated gene HNF1A seems to be a promising candidate gene for ischemic stroke.ResultsWe used HNF1A as a candidate gene of ischemic stroke and evaluated seven common variants of HNF1A for their contribution to ischemic stroke. The association analysis of HNF1A variants with ischemic stroke was performed in a Chinese population with 918 cases and 979 controls. For total ischemic stroke and large vessel disease subtype, none of variants exceeded significant threshold. For small vessel disease subtype of ischemic stroke, the G allele of rs7953249 showed nominal association (OR = 0.82, p = 0.04) after data adjustment for conventional risk factors. However, our preliminary results did not survived bonferroni correction for multiple comparisons.ConclusionsCommon genetic variants of HNF1A showed nominal association with small vessel disease subtype of ischemic stroke though not survived bonferroni correction for multiple comparisons. The association between HNF1A and ischemic stroke is limited by small effects of individual SNPs. Our study provided additional genetic evidences to understand the role of HNF1A gene and C-reactive protein underlying ischemic stroke.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-016-0313-3) contains supplementary material, which is available to authorized users.