scholarly journals Endothelial CXCL5 negatively regulates myelination and repair after white matter stroke

2019 ◽  
Author(s):  
Guanxi Xiao ◽  
Rosie Kumar ◽  
Yutaro Komuro ◽  
Jasmine Burguet ◽  
Visesha Kakarla ◽  
...  
Keyword(s):  
Risk Factors ◽  
Endothelial Cells ◽  
White Matter ◽  
Signaling Pathway ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Oligodendrocyte Progenitor ◽  
Vessel Disease ◽  
Cerebral Endothelial Cells

AbstractCerebral small vessel disease and resulting white matter pathologies are worsened by cardiovascular risk factors including obesity. The molecular changes in cerebral endothelial cells caused by chronic cerebrovascular risk factors remain unknown. We developed a novel approach for molecular profiling of chronically injured cerebral endothelial cells using cell-specific translating ribosome affinity purification (RiboTag) with RNA-seq in Tie2-Cre:RiboTag mice. We used this approach to identify the transcriptome of white matter endothelial cells after the onset of diet-induced obesity (DIO). DIO induces an IL-17B signaling pathway that acts on the cerebral endothelia through IL-17Rb to increase levels of both circulating CXCL5 and local endothelial expression of CXCL5 in both the DIO mouse model and in humans with imaging or pathologic evidence of cerebral small vessel disease. In the white matter, endothelial CXCL5 acts as a chemoattractant and promotes the association of oligodendrocyte progenitor cells (OPCs) with cerebral endothelia increasing vessel-associated OPC cell number and triggers OPC gene expression programs regulating migration and chemokine receptor activation. Targeted blockade of IL-17B with peripheral antibody administration reduced the population of vessel-associated OPCs by reducing endothelial CXCL5 expression. CXCL5-mediated sequestration of OPCs to white matter vasculature impairs OPC differentiation after a focal white matter ischemic lesion. DIO promotes a unique white matter endothelial-to-oligodendrocyte progenitor cell signaling pathway that compromises brain repair after stroke.

scholarly journals Cerebral Small Vessel Disease, Risk Factors, and Cognition in Tenants of Precarious Housing

Stroke ◽  
2020 ◽  
Vol 51 (11) ◽  
pp. 3271-3278
Author(s):  
Lily W. Zhou ◽  
William J. Panenka ◽  
Ghadeer Al-Momen ◽  
Kristina M. Gicas ◽  
Allen E. Thornton ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Risk Factors ◽  
White Matter ◽  
Odds Ratio ◽  
White Matter Hyperintensities ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Resonance Imaging ◽  
Vessel Disease

Background and Purpose: We aim to describe the burden, characteristics, and cognitive associations of cerebral small vessel disease in a Canadian sample living with multimorbidity in precarious housing. Methods: Participants received T1, T2-fluid-attenuated inversion recovery, and susceptibility-weighted imaging 3T magnetic resonance imaging sequences and comprehensive clinical, laboratory, and cognitive assessments. Cerebral small vessel disease burden was characterized using a modified Small Vessel Disease (mSVD) score. One point each was given for moderate-severe white matter hyperintensities, ≥1 cerebral microbleeds, and ≥1 lacune. Multivariable regression explored associations between mSVD score, risk factors, and cognitive performance. Results: Median age of the 228 participants (77% male) was 44.7 years (range, 23.3–63.2). In n=188 participants with consistent good quality magnetic resonance imaging sequences, mSVD scores were 0 (n=127, 68%), 1 (n=50, 27%), and 2 (n=11, 6%). Overall, one-third had an mSVD ≥1 n=61 (32%); this proportion was unchanged when adding participants with missing sequences n=72/228 (32%). The most prevalent feature was white matter hyperintensities 53/218 (24%) then cerebral microbleed 16/191 (8%) and lacunes 16/228 (7%). Older age (odds ratio, 1.10 [95% CI, 1.05–1.15], P <0.001), higher diastolic blood pressure (odds ratio, 1.05 [95% CI, 1.01–1.09], P =0.008), and a history of injection drug use (odds ratio, 3.13 [95% CI, 1.07–9.16], P =0.037) had significant independent associations with a mSVD score of ≥1 in multivariable analysis. mSVD ≥1 was associated with lower performance on tests of verbal memory, sustained attention, and decision-making, contributing 4% to 5% of the variance in each cognitive domain. Conclusions: The 32% prevalence of cerebral small vessel disease in this young, socially marginalized cohort was higher than expected for age and was associated with poorer cognitive performance.

Cerebral Small Vessel Disease In Patients With Sickle Cell Disease: Initial Findings With Ultra-High Field 7T MRI

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1011-1011
Author(s):  
Veronica van der Land ◽  
Jaco J.M. Zwanenburg ◽  
Bart J Biemond ◽  
Jeroen Hendrikse ◽  
Henk-Jan Mutsaerts ◽  
...  
Keyword(s):  
Risk Factors ◽  
White Matter ◽  
Sickle Cell Disease ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Imaging Features ◽  
Cell Disease ◽  
Deep White Matter ◽  
Vessel Disease

Abstract Introduction Almost 40% of patients with a severe form of sickle cell disease (SCD) develop small silent cerebral infarctions (SCIs), often located in the deep white matter, that may be associated with cognitive impairment. In patients with cardiovascular disease or risk factors, occurrence of these SCIs is a well known phenomenon, and considered as part of ‘cerebral small vessel disease’. Currently, it is unknown whether small vessel disease is the underlying cause of SCIs in sickle cell disease. If we can identify imaging features supporting the hypothesis that cerebral small vessel disease occurs in patients with SCD, this may provide new targets for therapeutic interventions. The aim of the present study is to investigate the brain imaging features of neurologically asymptomatic young SCD patients with ultra-high field 7T MRI. Methods Ten consecutive, neurological asymptomatic patients with SCD (homozygous hemoglobin S) without other cardiovascular risk factors were included (mean age 23 years, range 19-25). Brain lesions were scored using a 3D magnetization prepared fluid attenuated inversion recovery scan (MP-FLAIR) and a dual-echo T2*-weighted scan for the visualization of small arteries and veins. Results With the exception of two patients, all displayed round and circumscript infarcts in the deep white matter of the frontal or parietal lobe (Table). Most lesions (82%) were <5 mm. In one patient (A) we identified 164 white matter infarcts (Figure 1). Strikingly, one patient (patient B) had several cortical micro-infarcts (Figure 2) although she had no neurological symptoms. These were associated with an occluded A1 and A2 segment of the anterior cerebral artery. In addition, this patient had unique pattern of white matter lesions, consisting of irregular shaped white matter infarcts, some located periventricular, and others close to the cortical infarcts. In two other patients (patients C and D) we identified an isolated cortical micro-infarct despite the absence of large vessel vasculopathy. In patient C, we found numerous hypo-intense areas symmetrically distributed in the deep white matter of the frontal and parietal lobe (Figure 3). These areas were associated with prominent transmedullary veins. Conclusion In our series of young and neurological asymptomatic SCD patients, we found the typical imaging features of SCIs in 8 out of 10 patients. Our findings suggest that patients with SCD may have manifestations of cerebral small vessel disease before the occurrence of symptoms, even at a young age and without other cardiovascular risk factors. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Serum alkaline phosphatase level is correlated with the incidence of cerebral small vessel disease

2019 ◽  
Vol 42 (1) ◽  
pp. E47-E52 ◽  
Author(s):  
Piao Xiangyu ◽  
Jie Zhao ◽  
Yue Wu
Keyword(s):  
Risk Factors ◽  
Alkaline Phosphatase ◽  
White Matter ◽  
Vascular Calcification ◽  
Small Vessel Disease ◽  
Serum Alkaline Phosphatase ◽  
Cerebral Small Vessel Disease ◽  
Lacunar Infarct ◽  
Small Vessel ◽  
Vessel Disease

Background: Vascular calcification is one of the mechanisms underlying the pathogenesis of cerebral small vessel disease (CSVD). Whether higher levels of serum alkaline phosphatase (ALP), a predictor of vascular calcification, are independently associated with CSVD remains inconclusive. Purpose: The present study explored the link between levels of circulating ALP and CSVD in a Chinese population. Methods: A total of 568 participants were recruited from the healthcare center at the affiliated Zhongshan Hospital of Dalian University and the Fifth People Hospital of Dalian between January 2010 and December 2016. The subjects were divided into three groups based on the infarct and severity of white matter hyper-intensities (WMH) as categorized by brain magnetic resonance imaging (MRI) analysis and Fazekas rating scales: no/mild cerebral WMH (nm-WMH); moderate-to-severe WMH (MS-WMH); and silent lacunar infarct (SLI). The subjects were also divided into three tertiles based on circulating levels of ALP: ≤64, 65–105 and ≥106 (IU/L). Information regarding the risk factors, such as coronary artery disease, diabetes mellitus, hypertension and serum ALP level, C-reactive protein, homocysteine (HCY), and other laboratory results, were collected. The associations of ALP with WMH and SLI were evaluated using logistic regression analysis. Results: After adjustment for vascular risk factors, subjects with MS-WMH and SLI were more likely to have ALP levels ≥106 IU/L than ≤64 IU/L. The mean circulating level of ALP was substantially increased in patients with MS-WMH or SLI compared with patients with nm-WMH. The multivariate model revealed that this significant difference remained when MS-WMH or SLI was added to the model, after adjustment for confounding factors. Conclusion: The circulating level of ALP was positively correlated with a high risk of silent lacunar infarct and white matter hyperintensity; important indicators of small vessel disease.

Higher Cerebral Small Vessel Disease Burden in Patients with White Matter Recent Small Subcortical Infarcts

2021 ◽  
Vol 30 (7) ◽  
pp. 105824
Author(s):  
Salvatore Rudilosso ◽  
Luis Mena ◽  
Diana Esteller ◽  
Marta Olivera ◽  
Juan José Mengual ◽  
...  
Keyword(s):  
White Matter ◽  
Disease Burden ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Vessel Disease

scholarly journals Cognitive heterogeneity among community-dwelling older adults with Cerebral Small Vessel Disease

2018 ◽  
Author(s):  
Ayan Dey ◽  
Vessela Stamenova ◽  
Agnes Bacopulos ◽  
Nivethika Jeyakumar ◽  
Gary R. Turner ◽  
...  
Keyword(s):  
White Matter ◽  
Subjective Experience ◽  
Small Vessel Disease ◽  
Neuropsychological Testing ◽  
Cerebral Small Vessel Disease ◽  
Community Dwelling ◽  
Small Vessel ◽  
Vessel Disease ◽  
Age Related ◽  
Subjective Complaints

Some degree of ischemic injury to white matter tracts occurs naturally with age and is visible on magnetic resonance imaging as focal or confluent white matter hyperintensities (WMHs). Its relationship to cognition, however, remains unclear. To explore this, community-dwelling adults between the ages 55-80 years old completed structural imaging, neuropsychological testing, and questionnaires to provide objective measures and subjective experience of executive functioning. Volumetric lesion burden derived from structural MRI identified those with significant WMH burden (~10 cubic cm). Half of those recruited met this criterion and were designated as the cerebral small vessel disease (CSVD) group. Subjective complaints but not objective test scores differentiated adults with and without CSVD. Hierarchical clustering revealed two CSVD subgroups that differentiated those with impaired versus preserved executive function relative to controls. Overall these results provide some explanation for behavioural heterogeneity often observed in studies of age-related white matter changes. They also support the use of questionnaires to assess subjective complaints that may be able to detect subtle effects of pathology not evident on standardized cognitive scores.

Abstract P369: Cerebral Small Vessel Disease and Enlarged Cardiac Ventricles

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Kayla Navarro ◽  
Ka-ho Wong ◽  
Majd M Ibrahim ◽  
Adam H De Havenon ◽  
Eric Goldstein
Keyword(s):  
White Matter ◽  
Ejection Fraction ◽  
Right Ventricular ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Right Atrial ◽  
Ventricular Ejection Fraction ◽  
Vessel Disease ◽  
Atrial Area

Introduction: White matter hyperintensities (WMH) are a radiographic marker for cerebral small vessel disease (CSVD). Conditions altering cerebral venous outflow such as elevated central venous pressure and right atrial pressure in individuals with cardiac valvular disease have been implicated in the development of WMH. Hypothesis: We hypothesize that increased right-heart chamber size in individuals without significant cardiac valvular disease is associated with worse WMH. Methods: A retrospective chart review of adults with a brain MRI and a 2-dimensional transthoracic echocardiogram (TTE) was performed. Worst burden of WMH by way of Fazekas score, either periventricular or deep white matter, served as the primary outcome. Statistical analysis was performed using a multivariate ordinal logistic regression model. Results: A total of 132 individuals were included. Right atrial area (OR 0.93, 95% CI 0.87 to 1.00, p = 0.0041), right ventricular internal diameter (OR 0.48, 95%CI 0.27 to 0.83, p = 0.008) and left atrial area (OR 0.93, 95%CI 0.88 to 0.98, p = 0.007) was identified as being significant. Cardiac functional markers were not significant, including tricuspid annular plane systolic excursion (OR 0.99, 95%CI 0.93 to 1.05, p = 0.670), right ventricular ejection fraction (OR 0.99, 95%CI 0.96 to 1.02, p = 0.670) and left ventricular ejection fraction (OR 0.99, 95%CI 0.96 to 1.02, p = 0.567). Analysis of isolated DWM or PVWM Fazekas scores did not find significant predictors in relation to cardiac structure or function. Conclusions: Through non-invasive cardiac imaging, we identified that cardiac structural abnormalities as opposed to functional abnormalities were associated with worse WMH. Mechanistically this may result from altered intracerebral arteriovenous coupling or a shared pathophysiologic pathway between WMH and coronary microvascular disease.

Abstract TMP119: High Homocysteine Level is not Associated With White Matter Changes, Dementia nor Mortality After Ischemic Stroke

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Susanna Melkas ◽  
Sami Curtze ◽  
Gerli Sibolt ◽  
Niku K Oksala ◽  
Jukka Putaala ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
White Matter ◽  
Homocysteine Level ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Cross Sectional ◽  
White Matter Changes ◽  
Vessel Disease

Background: Association between high homocysteine level and cerebral small-vessel disease has been implicated in cross-sectional studies, but results from longitudinal studies have been less clear. The aim of this study was to investigate whether homocysteine level at 3-months poststroke relates to the occurrence of white matter changes (WMC), the surrogate of cerebral small-vessel disease. We also investigated whether it relates to the prognosis after ischemic stroke regarding the risk of dementia at 3-months and mortality in long-term follow-up. Methods: A total of 321 consecutive acute ischemic stroke patients aged 55 to 85 were included in the study and followed up to 12 years. Plasma homocysteine level and occurrence of WMC in MRI were measured 3 months poststroke and dementia according to DSM-III was evaluated at the same time. Findings: The median homocysteine level was 13.50 μmol/l (interquartile range [IQR] 10.60-18.50 μmol/l). Total of 81 patients (25.2%) had homocysteine level above 18.50 μmol/l. In logistic regression analysis, homocysteine level above 18.50 μmol/l was not associated with severe WMC nor with dementia at 3 months poststroke. In Kaplan-Meier analysis, homocysteine level above 18.50 μmol/l was not associated with survival in 12-year follow-up. For further analysis, the group was divided in quartiles according to homocysteine level. The quartiles did not differ in occurrence of severe WMC at baseline, in the risk of dementia at 3 months, nor in the risk of mortality in 12-year follow-up. Interpretation: In our poststroke cohort homocysteine level is not associated with WMC. Further, it does not relate to impaired prognosis manifested as dementia at 3 months or mortality in 12-year follow-up.

scholarly journals CNS small vessel disease

Neurology ◽  
2019 ◽  
Vol 92 (24) ◽  
pp. 1146-1156 ◽  
Author(s):  
Rocco J. Cannistraro ◽  
Mohammed Badi ◽  
Benjamin H. Eidelman ◽  
Dennis W. Dickson ◽  
Erik H. Middlebrooks ◽  
...  
Keyword(s):  
Risk Factors ◽  
White Matter ◽  
Small Vessel Disease ◽  
Blood Oxygenation ◽  
Small Vessel ◽  
Imaging Biomarkers ◽  
Amyloid Angiopathy ◽  
Perivascular Spaces ◽  
Advanced Imaging ◽  
Vessel Disease

CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. Prevalence increases with age, affecting about 5% of people aged 50 years to almost 100% of people older than 90 years. Known causes and risk factors include age, hypertension, branch atheromatous disease, cerebral amyloid angiopathy, radiation exposure, immune-mediated vasculitides, certain infections, and several genetic diseases. CSVD can be asymptomatic; however, depending on location, lesions can cause mild cognitive dysfunction, dementia, mood disorders, motor and gait dysfunction, and urinary incontinence. CSVD is diagnosed on the basis of brain imaging biomarkers, including recent small subcortical infarcts, white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy. Advanced imaging modalities can detect signs of disease even earlier than current standard imaging techniques. Diffusion tensor imaging can identify altered white matter connectivity, and blood oxygenation level-dependent imaging can identify decreased vascular reactivity. Pathogenesis is thought to begin with an etiologically specific insult, with or without genetic predisposition, which results in dysfunction of the neurovascular unit. Uncertainties regarding pathogenesis have delayed development of effective treatment. The most widely accepted approach to treatment is to intensively control well-established vascular risk factors, of which hypertension is the most important. With better understanding of pathogenesis, specific therapies may emerge. Early identification of pathologic characteristics with advanced imaging provides an opportunity to forestall progression before emergence of symptoms.

scholarly journals A Systematic Review of WNT Signaling in Endothelial Cell Oligodendrocyte Interactions: Potential Relevance to Cerebral Small Vessel Disease

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1545
Author(s):  
Narek Manukjan ◽  
Zubair Ahmed ◽  
Daniel Fulton ◽  
W. Matthijs Blankesteijn ◽  
Sébastien Foulquier
Keyword(s):  
White Matter ◽  
Small Vessel Disease ◽  
Clinical Manifestations ◽  
Cell Types ◽  
Cerebral Small Vessel Disease ◽  
White Matter Injury ◽  
Small Vessel ◽  
Limited Attention ◽  
Vessel Disease

Key pathological features of cerebral small vessel disease (cSVD) include impairment of the blood brain barrier (BBB) and the progression of white matter lesions (WMLs) amongst other structural lesions, leading to the clinical manifestations of cSVD. The function of endothelial cells (ECs) is of major importance to maintain a proper BBB. ECs interact with several cell types to provide structural and functional support to the brain. Oligodendrocytes (OLs) myelinate axons in the central nervous system and are crucial in sustaining the integrity of white matter. The interplay between ECs and OLs and their precursor cells (OPCs) has received limited attention yet seems of relevance for the study of BBB dysfunction and white matter injury in cSVD. Emerging evidence shows a crosstalk between ECs and OPCs/OLs, mediated by signaling through the Wingless and Int-1 (WNT)/β-catenin pathway. As the latter is involved in EC function (e.g., angiogenesis) and oligodendrogenesis, we reviewed the role of WNT/β-catenin signaling for both cell types and performed a systematic search to identify studies describing a WNT-mediated interplay between ECs and OPCs/OLs. Dysregulation of this interaction may limit remyelination of WMLs and render the BBB leaky, thereby initiating a vicious neuroinflammatory cycle. A better understanding of the role of this signaling pathway in EC–OL crosstalk is essential in understanding cSVD development.

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