Validation of external and internal exposome of the findings associated to cerebral small vessel disease: A Mendelian randomization study

The exposome characterizes all environmental exposures and their impact on a disease. To determine the causally-associated components of the exposome for cerebral small vessel disease (CSVD), we performed mendelian randomization analysis of 5365 exposures on six clinical and subclinical CSVD measures. We found statistically significant evidence (FDR-corrected P < 0.05) that hypertension, high cholesterol, longer television-watching time, lower educational qualifications, younger age of first sexual intercourse, smoking, reduced pulmonary function, higher subjective overall health rating, and frequent tiredness were associated with increased risk of intracerebral hemorrhage or small vessel stroke. Adiposity, diabetes, frequent alcoholic drinks, higher white blood cell count and neutrophil count were significantly associated with higher risk of non-lobar hemorrhage or small vessel stroke, but not lobar hemorrhage. Hypertension, higher arm or leg fat-free mass and higher sitting height were significantly associated with higher white matter hyperintensities. The results were robust to sensitivity analyses and showed no evidence of horizontal pleiotropy. We also identified 41 exposures suggestively associated (uncorrected P < 0.05) with multiple CSVD measures as the “the CSVD exposome”. This exposome-wide association study provides insight into CSVD development and prevention.

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Cerebral small vessel disease or intracranial large vessel atherosclerosis may carry different risk for future strokes

Stroke and Vascular Neurology ◽

10.1136/svn-2019-000305 ◽

2020 ◽

Vol 5 (2) ◽

pp. 128-137

Author(s):

Huimin Chen ◽

Yuesong Pan ◽

Lixia Zong ◽

Jing Jing ◽

Xia Meng ◽

...

Keyword(s):

Regression Models ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Arterial Stenosis ◽

Small Vessel ◽

Minor Stroke ◽

Bleeding Events ◽

Stroke Outcomes ◽

Vessel Disease ◽

Increased Risk

BackgroundThe effect of cerebral small vessel disease (CSVD) and intracranial arterial stenosis (ICAS) on stroke outcomes remains unclear.MethodsData of 1045 patients with minor stroke or transient ischaemic attack (TIA) were obtained from 45 sites of the Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events (CHANCE) trial. We assessed the associations of burdens of CSVD and ICAS with new strokes and bleeding events using multivariate Cox regression models and those with modified Rankin Scale (mRS) scores using ordinal logistic regression models.ResultsAmong the 1045 patients, CSVD was present in 830 cases (79.4%) and ICAS in 460 (44.0%). Patients with >1 ICAS segment showed the highest risk of new strokes (HR 2.03, 95% CI 1.15 to 3.56, p=0.01). No association between CSVD and the occurrence of new strokes was found. The presence of severe CSVD (common OR (cOR) 2.01, 95% CI 1.40 to 2.89, p<0.001) and >1 ICAS segment (cOR 2.15, 95% CI 1.57 to 2.93, p<0.001) was associated with higher mRS scores. Severe CSVD (HR 10.70, 95% CI 1.16 to 99.04, p=0.04), but not ICAS, was associated with a higher risk of bleeding events. Six-point modified CSVD score improved the predictive power for bleeding events and disability.InterpretationCSVD is associated with more disability and bleeding events, and ICAS is associated with an increased risk of stroke and disability in patients with minor stroke and TIA at 3 months. CSVD and ICAS may represent different vascular pathologies and play distinct roles in stroke outcomes.Trial registration numberNCT00979589

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Abstract WMP59: White Matter Hyperintensities Play a Pivotal Role in Progression of Cerebral Small Vessel Disease: A 7-Year Chinese Urban Community Study

Stroke ◽

10.1161/str.51.suppl_1.wmp59 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Yiwei Xia ◽

Yi Shen ◽

Yi Wang ◽

Lumeng Yang ◽

Yiqing Wang ◽

...

Keyword(s):

Executive Function ◽

Small Vessel Disease ◽

Urban Community ◽

Cerebral Small Vessel Disease ◽

Pivotal Role ◽

Small Vessel ◽

Community Study ◽

Perivascular Spaces ◽

Vessel Disease ◽

Increased Risk

Objective: To explore the role of WMH in progression of CSVD in an urban community in China over a period of 7 years, and to investigate associations between WMH volume (baseline & progression) and cognitive impairment. Methods: CSVD markers and neuropsychological tests at baseline and follow-up of 191 participants of the Shanghai Aging Study (SAS) were assessed. WMH volume were assessed by automatic segmentation based on U-net model. Lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces (ePVS) were rated manually. SVD score was rated as the total burden of CSVD markers. We performed multivariate linear regression and binominal logistic regression. We plotted progression of markers by baseline WMH volume in tertile. Results: Participants with higher baseline WMH volume developed more progression of WMH volume, increased risk of incident lacunes, incident CMBs, and ePVS progression. Mean change of WMH volume over 7 years was 4.27mL (0.62mL/y) for all participants, 3.21mL for participants with 1st tertile WMH volume at baseline, 4.19mL for those with 2nd tertile WMH, and 5.43mL for those with 3rd tertile WMH. Incident lacunes and incident CMBs were predominantly seen in participants with 2nd and 3rd tertile WMH. WMH (baseline & progression) were associated with decline of executive function. Conclusions: WMH play a pivotal role in progression of cerebral small vessel disease and are associated with decline of executive function in a Chinese urban community study over a period of 7 years.

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The SNP43 (G/A) polymorphism in CAPN10 gene confers an increased risk of cognitive impairment in cerebral small vessel disease

Journal of Clinical Laboratory Analysis ◽

10.1002/jcla.22615 ◽

2018 ◽

Vol 32 (9) ◽

Cited By ~ 3

Author(s):

Kai Wu ◽

Ying Cai

Keyword(s):

Cognitive Impairment ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Vessel Disease ◽

Increased Risk ◽

Capn10 Gene

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Increased Levels of Circulating Angiogenic Cells and Signaling Proteins in Older Adults With Cerebral Small Vessel Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.711784 ◽

2021 ◽

Vol 13 ◽

Author(s):

Arunima Kapoor ◽

Aimée Gaubert ◽

Anisa Marshall ◽

Irene B. Meier ◽

Belinda Yew ◽

...

Keyword(s):

Older Adults ◽

Small Vessel Disease ◽

Brain Magnetic Resonance Imaging ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Signaling Proteins ◽

Angiogenic Growth Factors ◽

Vessel Disease ◽

Increased Risk ◽

Age And Sex

Background: Cerebral small vessel disease (SVD) is associated with increased risk of stroke and dementia. Progressive damage to the cerebral microvasculature may also trigger angiogenic processes to promote vessel repair. Elevated levels of circulating endothelial progenitor cells (EPCs) and pro-angiogenic signaling proteins are observed in response to vascular injury. We aimed to examine circulating levels of EPCs and proangiogenic proteins in older adults with evidence of SVD.Methods: Older adults (ages 55–90) free of dementia or stroke underwent venipuncture and brain magnetic resonance imaging (MRI). Flow cytometry quantified circulating EPCs as the number of cells in the lymphocyte gate positively expressing EPC surface markers (CD34+CD133+CD309+). Plasma was assayed for proangiogenic factors (VEGF-A, VEGF-C, VEGF-D, Tie-2, and Flt-1). Total SVD burden score was determined based on MRI markers, including white matter hyperintensities, cerebral microbleeds and lacunes.Results: Sixty-four older adults were included. Linear regression revealed that older adults with higher circulating EPC levels exhibited greater total SVD burden [β = 1.0 × 105, 95% CI (0.2, 1.9), p = 0.019], after accounting for age and sex. Similarly, a positive relationship between circulating VEGF-D and total SVD score was observed, controlling for age and sex [β = 0.001, 95% CI (0.000, 0.001), p = 0.048].Conclusion: These findings suggest that elevated levels of circulating EPCs and VEGF-D correspond with greater cerebral SVD burden in older adults. Additional studies are warranted to determine whether activation of systemic angiogenic growth factors and EPCs represents an early attempt to rescue the vascular endothelium and repair damage in SVD.

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Increased Risk for Cerebral Small Vessel Disease is Associated with Quantitative Susceptibility Mapping in HIV Infected and Uninfected Individuals

NeuroImage Clinical ◽

10.1016/j.nicl.2021.102786 ◽

2021 ◽

pp. 102786

Author(s):

Kyle D. Murray ◽

Md. Nasir Uddin ◽

Madalina E. Tivarus ◽

Bogachan Sahin ◽

Henry Z. Wang ◽

...

Keyword(s):

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Susceptibility Mapping ◽

Small Vessel ◽

Quantitative Susceptibility Mapping ◽

Vessel Disease ◽

Increased Risk

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Haptoglobin Hp1 Variant Does Not Associate with Small Vessel Disease

Brain Sciences ◽

10.3390/brainsci10010018 ◽

2019 ◽

Vol 10 (1) ◽

pp. 18

Author(s):

Juha Lempiäinen ◽

Petra Ijäs ◽

Teemu J. Niiranen ◽

Markku Kaste ◽

Pekka J. Karhunen ◽

...

Keyword(s):

Stroke Patient ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Diabetic Patients ◽

Type I ◽

Patient Cohort ◽

Vessel Disease ◽

Number Of Patients ◽

Increased Risk

Haptoglobin (Hp) is a plasma protein that binds free hemoglobin and protects tissues from oxidative damage. An Hp2 allele has been associated with an increased risk of cardiovascular complications. On the other hand, recent studies have suggested that Hp1 allele increases risk to develop severe cerebral small vessel disease. We aimed to replicate this finding in a first-ever stroke patient cohort. Hp was genotyped by PCR and gel electrophoresis in the Helsinki Stroke Aging Memory Study in patients with DNA and magnetic resonance imaging (MRI) available (SAM; n = 316). Lacunar infarcts and white matter lesions (WML) classified by Fazekas grading from brain MRI were associated with Hp genotypes. As population controls, we used participants of Cardiovascular diseases—a sub study of Health 2000 Survey (n = 1417). In the SAM cohort, 63.0% of Hp1-1 carriers (n = 46), 52.5% of Hp1-2 carriers (n = 141) and 51.2% of Hp2-2 carriers (n = 129) had severe WML (p = 0.372). There was no difference in severe WMLs between Hp1-1 vs. Hp1-2 and Hp2-2 carriers (p = 0.201). In addition, 68.9% of Hp1-1 carriers (n = 45), 58.5% of Hp1-2 carriers (n = 135), and 61.8% of Hp2-2 carriers (n = 126) had one or more lacunar lesions (p = 0.472). There was no difference in the number of patients with at least one lacunar infarct between Hp1-1 vs. Hp1-2 and Hp2-2 groups (p = 0.322). Neither was there any difference when diabetic patients (type I and II) were examined separately. Hp1 allele is not associated with an increased risk for cerebral small vessel disease in a well-characterized Finnish stroke patient cohort.

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TOTAL MRI BURDEN OF CEREBRAL SMALL-VESSEL DISEASE IS ASSOCIATED WITH COGNITIVE DECLINE AND AN INCREASED RISK OF DEMENTIA IN OLDER PEOPLE: THE AGES-REYKJAVIK STUDY

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.07.084 ◽

2017 ◽

Vol 13 (7) ◽

pp. P211-P212

Author(s):

Jie Ding ◽

Sigurdur Sigurdsson ◽

Mark van Buchem ◽

Vilmundur Gudnason ◽

Lenore J. Launer

Keyword(s):

Older People ◽

Cognitive Decline ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Vessel Disease ◽

Increased Risk

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Abstract W P345: Increased Risk of Gastrointestinal Bleeding Associated With Antiplatelet Therapy in Patients With Cerebral Small Vessel Disease

Stroke ◽

10.1161/str.45.suppl_1.wp345 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Sang-mi Noh ◽

Jong S. Kim

Keyword(s):

White Matter ◽

White Matter Hyperintensities ◽

Small Vessel Disease ◽

Bleeding Risk ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Gi Bleeding ◽

Stroke Patients ◽

Vessel Disease ◽

Increased Risk

Background: Gastrointestinal (GI) bleeding is a major complication of aniplatelets in patients with stroke. Although underlying gastrointestinal disease is an important factor for increased bleeding risk, the presence of cerebral small vessel disease (SVD) may also be a factor because it may indicate systemic small vessel pathologies. We assessed the association of cerebral SVD and GI bleeding in patients who are under treatment with antiplatelets for secondary stroke prevention. Methods: We compared stroke patients who visited our clinic between May 2007 and May 2013 who developed GI bleeding while receiving antiplatelets with age and sex matched patients who did not. Control subjects were randomly selected among those who were visited out-patients clinic on the same day as the study subjects. Patients who received anticoagulants were excluded. MRIs were evaluated for the presence of white matter changes (Fazeka scale) and microbleeds. Results: During the study period, 47 patients in the bleeding group and 94 patients in the control group were enrolled. No differences were found in baseline characteristics between the two groups including stroke subtypes and the number of antiplatelets (mono vs dual therapy). The prevalence of SVD (microbleeds or white matter hyperintensities) (p = 0.004), white matter hyperintensities (p = 0.008), but not microbleeds alone (p = 0.221), were significantly higher in the bleeding group. Multivariate analysis showed that the presence of SVD was independently associated with increased GI bleeding risk (OR 3.3, 95% confidence interval 1.5-7.3). Conclusions: Our data show the presence of cerebral SVD is a marker for increased GI bleeding risk in patients receiving antiplatelets in stroke patients, perhaps related with systemic small vessel pathology in this group of patients. Physicians may have to consider this association when antiplatelets are used for the secondary prevention of stroke.

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