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

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.

2020 ◽  
pp. 1-8
Author(s):  
Yousef Hannawi ◽  
Lisa R. Yanek ◽  
Brian G. Kral ◽  
Lewis C. Becker ◽  
Dhananjay Vaidya ◽  
...  

<b><i>Introduction:</i></b> We have demonstrated that asymptomatic cerebral small vessel disease (cSVD) measured by white matter hyperintensity volume is associated with reduced manipulative manual dexterity on the Grooved Peg Board Test (GPBT) in middle-aged healthy individuals with a family history of early coronary artery disease. In this current study, we aim to identify the association of subcortical white matter microstructural impairment measured by diffusion tensor imaging, manual dexterity measured by GPBT and circulating serums ceramide, another marker for white matter injury. We hypothesize that lower regional fractional anisotropy (rFA) is associated with worse performance on GPBT and elevated serum ceramides in the same study population. <b><i>Methods:</i></b> rFA of 48 regions representing the subcortical white matters were analyzed in GeneSTAR participants in addition to serum ceramides and GPBT scores. Unadjusted univariable analyses with Bonferroni correction for multiple comparisons were completed using Spearman correlation for testing the associations between ceramides, rFA of subcortical white matter, and GPBT performance. Subsequently, sensitivity analyses were performed after excluding the participants that had any physical limitation that may influence their performance on GPBT. Finally, in the adjusted analysis using generalized estimating equation, linear regression models were performed for the areas that met significance threshold in the unadjusted analyses. <b><i>Results:</i></b> 112 subjects (age [49 ± 11], 51% female, 39.3% African American) were included. Adjusted analyses for the significant correlations that met the Bonferroni correction threshold in the unadjusted univariable analyses identified significant negative associations between rFA of the right fornix (RF) and log-GPBT score (β = −0.497, <i>p</i> = 0.037). In addition, rFA of RF negatively correlated with log serum ceramide levels (C18: β = −0.03, <i>p</i> = 0.003, C20: β = −0.0002, <i>p</i> = 0.004) and rFA of left genu of corpus callosum negatively correlated with log C18 level (β = −0.0103, <i>p</i> = 0.027). <b><i>Conclusions:</i></b> These results demonstrate that subcortical microstructural white matter disruption is associated with elevated serum ceramides and reduced manual dexterity in a population with cSVD. These findings suggest that injury to white matter tracts undermines neural networks, with functional consequences in a middle-aged population with cardiovascular risk factors.


Author(s):  
Emilia Salvadori ◽  
Fabio Fierini ◽  
Leonardo Pantoni

Cerebral small vessel disease (SVD) is well recognized as a highly prevalent disorder that plays an important role in stroke and cognitive impairment. This chapter deals with the relationship between SVD and cognition in longitudinal studies and aims at clarifying the role of SVD as a marker and determinant of neurocognitive impairment. This chapter discusses the prognostic role of magnetic resonance imaging (MRI)-based SVD features (i.e., white matter hyperintensities, small lacunar infarcts, microbleeds, and perivascular spaces) as predictors of dementia or cognitive decline. The evidence reviewed in this chapter provides strong supports for the impact of white matter hyperintensities and small lacunar infarcts in increasing the risk of dementia and cognitive decline. Microbleeds and perivascular spaces have been more recently targeted as MRI features of SVD, and this chapter will review the increasing evidence of their role in cognitive decline.


Author(s):  
Salvatore Rudilosso ◽  
Luis Mena ◽  
Diana Esteller ◽  
Marta Olivera ◽  
Juan José Mengual ◽  
...  

2018 ◽  
Author(s):  
Ayan Dey ◽  
Vessela Stamenova ◽  
Agnes Bacopulos ◽  
Nivethika Jeyakumar ◽  
Gary R. Turner ◽  
...  

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.


Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Kayla Navarro ◽  
Ka-ho Wong ◽  
Majd M Ibrahim ◽  
Adam H De Havenon ◽  
Eric Goldstein

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.


Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Susanna Melkas ◽  
Sami Curtze ◽  
Gerli Sibolt ◽  
Niku K Oksala ◽  
Jukka Putaala ◽  
...  

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.


2018 ◽  
Vol 10 (448) ◽  
pp. eaam9507 ◽  
Author(s):  
Rikesh M. Rajani ◽  
Sophie Quick ◽  
Silvie R. Ruigrok ◽  
Delyth Graham ◽  
Sarah E. Harris ◽  
...  

Brain ◽  
2010 ◽  
Vol 134 (1) ◽  
pp. 73-83 ◽  
Author(s):  
K. F. de Laat ◽  
A. M. Tuladhar ◽  
A. G. W. van Norden ◽  
D. G. Norris ◽  
M. P. Zwiers ◽  
...  

Diagnostics ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 720
Author(s):  
Larisa A. Dobrynina ◽  
Zukhra Sh. Gadzhieva ◽  
Kamila V. Shamtieva ◽  
Elena I. Kremneva ◽  
Bulat M. Akhmetzyanov ◽  
...  

Introduction: Cerebral small vessel disease (CSVD) is the leading cause of vascular and mixed degenerative cognitive impairment (CI). The variability in the rate of progression of CSVD justifies the search for sensitive predictors of CI. Materials: A total of 74 patients (48 women, average age 60.6 ± 6.9 years) with CSVD and CI of varying severity were examined using 3T MRI. The results of diffusion tensor imaging with a region of interest (ROI) analysis were used to construct a predictive model of CI using binary logistic regression, while phase-contrast magnetic resonance imaging and voxel-based morphometry were used to clarify the conditions for the formation of CI predictors. Results: According to the constructed model, the predictors of CI are axial diffusivity (AD) of the posterior frontal periventricular normal-appearing white matter (pvNAWM), right middle cingulum bundle (CB), and mid-posterior corpus callosum (CC). These predictors showed a significant correlation with the volume of white matter hyperintensity; arterial and venous blood flow, pulsatility index, and aqueduct cerebrospinal fluid (CSF) flow; and surface area of the aqueduct, volume of the lateral ventricles and CSF, and gray matter volume. Conclusion: Disturbances in the AD of pvNAWM, CB, and CC, associated with axonal damage, are a predominant factor in the development of CI in CSVD. The relationship between AD predictors and both blood flow and CSF flow indicates a disturbance in their relationship, while their location near the floor of the lateral ventricle and their link with indicators of internal atrophy, CSF volume, and aqueduct CSF flow suggest the importance of transependymal CSF transudation when these regions are damaged.


2019 ◽  
Vol 20 (3) ◽  
pp. 776 ◽  
Author(s):  
Michael Thrippleton ◽  
Gordon Blair ◽  
Maria Valdes-Hernandez ◽  
Andreas Glatz ◽  
Scott Semple ◽  
...  

A protocol for evaluating ultrasmall superparamagnetic particles of iron oxide (USPIO) uptake and elimination in cerebral small vessel disease patients was developed and piloted. B1-insensitive R1 measurement was evaluated in vitro. Twelve participants with history of minor stroke were scanned at 3-T MRI including structural imaging, and R1 and R2* mapping. Participants were scanned (i) before and (ii) after USPIO (ferumoxytol) infusion, and again at (iii) 24–30 h and (iv) one month. Absolute and blood-normalised changes in R1 and R2* were measured in white matter (WM), deep grey matter (GM), white matter hyperintensity (WMH) and stroke lesion regions. R1 measurements were accurate across a wide range of values. R1 (p < 0.05) and R2* (p < 0.01) mapping detected increases in relaxation rate in all tissues immediately post-USPIO and at 24–30 h. R2* returned to baseline at one month. Blood-normalised R1 and R2* changes post-infusion and at 24–30 h were similar, and were greater in GM versus WM (p < 0.001). Narrower distributions were seen with R2* than for R1 mapping. R1 and R2* changes were correlated at 24–30 h (p < 0.01). MRI relaxometry permits quantitative evaluation of USPIO uptake; R2* appears to be more sensitive to USPIO than R1. Our data are explained by intravascular uptake alone, yielding estimates of cerebral blood volume, and did not support parenchymal uptake. Ferumoxytol appears to be eliminated at 1 month. The approach should be valuable in future studies to quantify both blood-pool USPIO and parenchymal uptake associated with inflammatory cells or blood-brain barrier leak.


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