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

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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Cognitive consequences of regression of cerebral small vessel disease

European Stroke Journal ◽

10.1177/2396987318820790 ◽

2018 ◽

Vol 4 (1) ◽

pp. 85-89 ◽

Cited By ~ 6

Author(s):

Esther MC van Leijsen ◽

Mayra I Bergkamp ◽

Ingeborg WM van Uden ◽

Sjacky Cooijmans ◽

Mohsen Ghafoorian ◽

...

Keyword(s):

Executive Function ◽

White Matter ◽

Cognitive Decline ◽

White Matter Hyperintensities ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Vessel Disease ◽

Disease Markers ◽

Total Brain

Introduction Recent studies have shown that neuroimaging markers of cerebral small vessel disease can also regress over time. We investigated the cognitive consequences of regression of small vessel disease markers. Patients and methods Two hundred and seventy-six participants of the RUNDMC study underwent neuroimaging and cognitive assessments at three time-points over 8.7 years. We semi-automatically assessed white matter hyperintensities volumes and manually rated lacunes and microbleeds. We analysed differences in cognitive decline and accompanying brain atrophy between participants with regression, progression and stable small vessel disease by analysis of variance. Results Fifty-six participants (20.3%) showed regression of small vessel disease markers: 31 (11.2%) white matter hyperintensities regression, 10 (3.6%) vanishing lacunes and 27 (9.8%) vanishing microbleeds. Participants with regression showed a decline in overall cognition, memory, psychomotor speed and executive function similar to stable small vessel disease. Participants with small vessel disease progression showed more cognitive decline compared with stable small vessel disease (p < 0.001 for cognitive index and memory; p < 0.01 for executive function), although significance disappeared after adjusting for age and sex. Loss of total brain, gray matter and white matter volume did not differ between participants with small vessel disease regression and stable small vessel disease, while participants with small vessel disease progression showed more volume loss of total brain and gray matter compared to those with stable small vessel disease (p < 0.05), although significance disappeared after adjustments. Discussion Regression of small vessel disease markers was associated with similar cognitive decline compared to stable small vessel disease and did not accompany brain atrophy, suggesting that small vessel disease regression follows a relatively benign clinical course. Future studies are required to validate these findings and to assess the role of vascular risk factor control on small vessel disease regression and possible recovery of clinical symptoms. Conclusion Our findings of comparable cognitive decline between participants with regression and stable small vessel disease might suggest that small vessel disease regression has a relative benign cognitive outcome.

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Cerebral small vessel disease: Capillary pathways to stroke and cognitive decline

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x15606723 ◽

2015 ◽

Vol 36 (2) ◽

pp. 302-325 ◽

Cited By ~ 102

Author(s):

Leif Østergaard ◽

Thorbjørn S Engedal ◽

Fiona Moreton ◽

Mikkel B Hansen ◽

Joanna M Wardlaw ◽

...

Keyword(s):

Cognitive Decline ◽

Capillary Flow ◽

Small Vessel Disease ◽

Genetic Disorders ◽

The Elderly ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Vascular Pathology ◽

Vessel Disease ◽

Capillary Dysfunction

Cerebral small vessel disease (SVD) gives rise to one in five strokes worldwide and constitutes a major source of cognitive decline in the elderly. SVD is known to occur in relation to hypertension, diabetes, smoking, radiation therapy and in a range of inherited and genetic disorders, autoimmune disorders, connective tissue disorders, and infections. Until recently, changes in capillary patency and blood viscosity have received little attention in the aetiopathogenesis of SVD and the high risk of subsequent stroke and cognitive decline. Capillary flow patterns were, however, recently shown to limit the extraction efficacy of oxygen in tissue and capillary dysfunction therefore proposed as a source of stroke-like symptoms and neurodegeneration, even in the absence of physical flow-limiting vascular pathology. In this review, we examine whether capillary flow disturbances may be a shared feature of conditions that represent risk factors for SVD. We then discuss aspects of capillary dysfunction that could be prevented or alleviated and therefore might be of general benefit to patients at risk of SVD, stroke or cognitive decline.

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x221074223 ◽

2022 ◽

pp. 0271678X2210742

Author(s):

Xue-Qing Zhang ◽

Yu-Xiang Yang ◽

Can Zhang ◽

Xin-Yi Leng ◽

Shi-Dong Chen ◽

...

Keyword(s):

Mendelian Randomization ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Fat Free Mass ◽

Small Vessel ◽

Sensitivity Analyses ◽

Vessel Disease ◽

Increased Risk ◽

Lobar Hemorrhage ◽

Health Rating

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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