Pathogenesis of white matter changes in cerebral small vessel diseases: beyond vessel-intrinsic mechanisms

2017 ◽  
Vol 131 (8) ◽  
pp. 635-651 ◽  
Author(s):  
Anne Joutel ◽  
Hugues Chabriat
Keyword(s):  
White Matter ◽  
Current Knowledge ◽  
Large Population ◽  
Clinical Importance ◽  
Magnetic Resonance Images ◽  
Cerebrovascular Reactivity ◽  
Small Vessel ◽  
Oligodendrocyte Progenitor Cells ◽  
Perivascular Spaces ◽  
Cerebral Small Vessel Diseases

Cerebral small vessel diseases (SVDs) are a leading cause of age and hypertension-related stroke and dementia. The salient features of SVDs visible on conventional brain magnetic resonance images include white matter hyperintensities (WMHs) on T2-weighted images, small infarcts, macrohemorrhages, dilated perivascular spaces, microbleeds and brain atrophy. Among these, WMHs are the most common and often the earliest brain tissue changes. Moreover, over the past two decades, large population- and patient-based studies have established the clinical importance of WMHs, notably with respect to cognitive and motor disturbances. Here, we seek to provide a new and critical look at the pathogenesis of SVD-associated white matter (WM) changes. We first review our current knowledge of WM biology in the healthy brain, and then consider the main clinical and pathological features of WM changes in SVDs. The most widely held view is that SVD-associated WM lesions are caused by chronic hypoperfusion, impaired cerebrovascular reactivity (CVR) or blood–brain barrier (BBB) leakage. Here, we assess the arguments for and against each of these mechanisms based on population, patient and experimental model studies, and further discuss other potential mechanisms. Specifically, building on two recent seminal studies that have uncovered an anatomical and functional relationship between oligodendrocyte progenitor cells and blood vessels, we elaborate on how small vessel changes might compromise myelin remodelling and cause WM degeneration. Finally, we propose new directions for future studies on this hot research topic.

scholarly journals Cerebral Small Vessel Disease

2020 ◽  
Vol 21 (24) ◽  
pp. 9729
Author(s):  
Jakub Litak ◽  
Marek Mazurek ◽  
Bartłomiej Kulesza ◽  
Paweł Szmygin ◽  
Joanna Litak ◽  
...  
Keyword(s):  
Small Vessel Disease ◽  
Current Knowledge ◽  
Cerebral Small Vessel Disease ◽  
Cerebral Vessels ◽  
Small Vessel ◽  
Epithelial Layer ◽  
Small Arteries ◽  
Vessel Disease ◽  
The Impact ◽  
Cerebral Small Vessel Diseases

Cerebral small vessel disease (CSVD) represents a cluster of various vascular disorders with different pathological backgrounds. The advanced vasculature net of cerebral vessels, including small arteries, capillaries, arterioles and venules, is usually affected. Processes of oxidation underlie the pathology of CSVD, promoting the degenerative status of the epithelial layer. There are several classifications of cerebral small vessel diseases; some of them include diseases such as Binswanger’s disease, leukoaraiosis, cerebral microbleeds (CMBs) and lacunar strokes. This paper presents the characteristics of CSVD and the impact of the current knowledge of this topic on the diagnosis and treatment of patients.

scholarly journals Body mass index, time of day, and genetics affect perivascular spaces in the white matter

2020 ◽  
Author(s):  
Giuseppe Barisano ◽  
Farshid Sepehrband ◽  
Nasim Sheikh-Bahaei ◽  
Meng Law ◽  
Arthur W. Toga
Keyword(s):  
Body Mass Index ◽  
White Matter ◽  
Body Mass ◽  
Structural Changes ◽  
Large Population ◽  
Time Of Day ◽  
Perivascular Spaces ◽  
Healthy Human ◽  
Magnetic Resonance Imaging Mri

AbstractThe analysis of cerebral perivascular spaces (PVS) using magnetic resonance imaging (MRI) allows to explore in vivo their contributions to neurological disorders. To date the normal amount and distribution of PVS in healthy human brains are not known, thus hampering our ability to define with confidence pathogenic alterations. Furthermore, it is unclear which biological factors can influence the presence and size of PVS on MRI. We performed exploratory data analysis of PVS volume and distribution in a large population of healthy individuals (n = 897, age = 28.8 ± 3.7). Here we describe the global and regional amount of PVS in the white matter, which can be used as a reference for clinicians and researchers investigating PVS and may help the interpretation of the structural changes affecting PVS in pathological states. We found a relatively high inter-subject variability in the PVS amount in this population of healthy adults (range: 1.31-14.49 cm3). We then identified body mass index, time of day, and genetics as new elements significantly affecting PVS in vivo under physiological conditions, offering a valuable foundation to future studies aimed at understanding the physiology of perivascular flow.

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 Body mass index, time of day, and genetics affect perivascular spaces in the white matter

2020 ◽  
pp. 0271678X2097285
Author(s):  
Giuseppe Barisano ◽  
Nasim Sheikh-Bahaei ◽  
Meng Law ◽  
Arthur W Toga ◽  
Farshid Sepehrband
Keyword(s):  
Body Mass Index ◽  
White Matter ◽  
Body Mass ◽  
Structural Changes ◽  
Large Population ◽  
Time Of Day ◽  
Perivascular Spaces ◽  
Healthy Human ◽  
Magnetic Resonance Imaging Mri

The analysis of cerebral perivascular spaces (PVS) using magnetic resonance imaging (MRI) allows to explore in vivo their contributions to neurological disorders. To date the normal amount and distribution of PVS in healthy human brains are not known, thus hampering our ability to define with confidence pathogenic alterations. Furthermore, it is unclear which biological factors can influence the presence and size of PVS on MRI. We performed exploratory data analysis of PVS volume and distribution in a large population of healthy individuals (n = 897, age = 28.8 ± 3.7). Here we describe the global and regional amount of PVS in the white matter, which can be used as a reference for clinicians and researchers investigating PVS and may help the interpretation of the structural changes affecting PVS in pathological states. We found a relatively high inter-subject variability in the PVS amount in this population of healthy adults (range: 1.31–14.49 cm3). The PVS volume was higher in older and male individuals. Moreover, we identified body mass index, time of day, and genetics as new elements significantly affecting PVS in vivo under physiological conditions, offering a valuable foundation to future studies aimed at understanding the physiology of perivascular flow.

scholarly journals Collateral Recruitment Is Impaired by Cerebral Small Vessel Disease

Stroke ◽  
2020 ◽  
Vol 51 (5) ◽  
pp. 1404-1410 ◽  
Author(s):  
Michelle P. Lin ◽  
Thomas G. Brott ◽  
David S. Liebeskind ◽  
James F. Meschia ◽  
Kevin Sam ◽  
...  
Keyword(s):  
White Matter ◽  
White Matter Hyperintensities ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Cerebral Microbleeds ◽  
Large Vessel ◽  
Small Vessel ◽  
Perivascular Spaces ◽  
Vessel Disease ◽  
Poor Recruitment

Background and Purpose— Cerebral small vessel disease (SVD) is associated with increased stroke risk and poor stroke outcomes. We aimed to evaluate whether chronic SVD burden is associated with poor recruitment of collaterals in large-vessel occlusive stroke. Methods— Consecutive patients with middle cerebral artery or internal carotid artery occlusion presenting within 6 hours after stroke symptom onset who underwent thrombectomy from 2012 to 2017 were included. The prespecified primary outcome was poor collateral flow, which was assessed on baseline computed tomographic angiography (poor, ≤50% filling; good, >50% filling). Markers of chronic SVD on brain magnetic resonance imaging were rated for the extent of white matter hyperintensities, enlarged perivascular spaces, chronic lacunar infarctions and cerebral microbleeds using the Standards for Reporting Vascular Changes on Neuroimaging criteria. Severity of SVD was quantified by adding the presence of each SVD feature, with a total possible score of 0 to 4; each SVD type was also evaluated separately. Multivariable logistic regression analyses were performed to evaluate the relationships between SVD and poor collaterals, with adjustment for potential confounders. Results— Of the 100 eligible patients, the mean age was 65±16 years, median National Institutes of Health Stroke Scale score was 15, and 68% had any SVD. Poor collaterals were observed in 46%, and those with SVD were more likely to have poor collaterals than patients without SVD (aOR, 1.9 [95% CI, 1.1–3.2]). Of the SVD types, poor collaterals were significantly associated with white matter hyperintensities (aOR, 2.9 per Fazekas increment [95% CI, 1.6–5.3]) but not with enlarged perivascular spaces (adjusted odds ratio [aOR], 1.3 [95% CI, 0.4–4.0]), lacunae (aOR, 2.1 [95% CI, 0.6–7.1]), or cerebral microbleeds (aOR, 2.1 [95% CI, 0.6–7.8]). Having a greater number of different SVD markers was associated with a higher odds of poor collaterals (crude trend P <0.001; adjusted P =0.056). There was a dose-dependent relationship between white matter hyperintensity burden and poor collaterals: adjusted odds of poor collaterals were 1.5, 3.0, and 9.7 across Fazekas scores of 1 to 3 ( P trend=0.015). No patient with an SVD score of 4 had good collaterals. Conclusions— Chronic cerebral SVD is associated with poor recruitment of collaterals in large vessel occlusive stroke. A prospective study to elucidate the potential mechanism of how SVD may impair the recruitment of collaterals is ongoing.

scholarly journals Cerebrovascular reactivity measurement in cerebral small vessel disease: Rationale and reproducibility of a protocol for MRI acquisition and image processing

2017 ◽  
Vol 13 (2) ◽  
pp. 195-206 ◽  
Author(s):  
Michael J Thrippleton ◽  
Yulu Shi ◽  
Gordon Blair ◽  
Iona Hamilton ◽  
Gordon Waiter ◽  
...  
Keyword(s):  
White Matter ◽  
Grey Matter ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Cerebrovascular Reactivity ◽  
Small Vessel ◽  
Minor Stroke ◽  
Reactivity Measurement ◽  
Vessel Disease ◽  
History Of

Background Impaired autoregulation may contribute to the pathogenesis of cerebral small vessel disease. Reliable protocols for measuring microvascular reactivity are required to test this hypothesis and for providing secondary endpoints in clinical trials. Aims To develop and assess a protocol for acquisition and processing of cerebrovascular reactivity by MRI, in subcortical tissue of patients with small vessel disease and minor stroke. Methods We recruited 15 healthy volunteers, testing paradigms using 1- and 3-min 6% CO2 challenges with repeat scanning, and 15 patients with history of minor stroke. We developed a protocol to measure cerebrovascular reactivity and delay times, assessing tolerability and reproducibility in grey and white matter areas. Results The 3-min paradigm yielded more reproducible data than the 1-min paradigm (CV respectively: 7.9–15.4% and 11.7–70.2% for cerebrovascular reactivity in grey matter), and was less reproducible in white matter (16.1–24.4% and 27.5–141.0%). Tolerability was similar for the two paradigms, but mean cerebrovascular reactivity and cerebrovascular reactivity delay were significantly higher for the 3-min paradigm in most regions. Patient tolerability was high with no evidence of greater failure rate (1/15 patients vs. 2/15 volunteers withdrew at the first visit). Grey matter cerebrovascular reactivity was lower in patients than in volunteers (0.110–0.234 vs. 0.172–0.313%/mmHg; p < 0.05 in 6/8 regions), as was the white matter cerebrovascular reactivity delay (16.2–43.9 vs. 31.1–47.9 s; p < 0.05 in 4/8 regions). Conclusions An effective and well-tolerated protocol for measurement of cerebrovascular reactivity was developed for use in ongoing and future trials to investigate small vessel disease pathophysiology and to measure treatment effects.

scholarly journals Probing brain developmental patterns of myelination and associations with psychopathology in youth using gray/white matter contrast

2018 ◽  
Author(s):  
Linn B. Norbom ◽  
Nhat Trung Doan ◽  
Dag Alnæs ◽  
Tobias Kaufmann ◽  
Torgeir Moberget ◽  
...  
Keyword(s):  
Individual Differences ◽  
White Matter ◽  
Cognitive Ability ◽  
Large Population ◽  
Population Based ◽  
Magnetic Resonance Images ◽  
Childhood And Adolescence ◽  
Cognitive Components ◽  
Age Related ◽  
Regional Associations

AbstractBackgroundCerebral myeloarchitecture shows substantial development across childhood and adolescence, and aberrations in these trajectories are relevant for a range of mental disorders. Differential myelination between intracortical and subjacent white matter can be approximated using signal intensities in T1-weighted magnetic resonance images (MRI).MethodsTo test the sensitivity of gray/white matter contrast (GWC) to age and individual differences in psychopathology and general cognitive ability in youth (8-23 years), we formed data-driven psychopathology and cognitive components using a large population-based sample, the Philadelphia Neurodevelopmental Cohort (PNC) (n=6487, 52% females). We then tested for associations with regional GWC defined by an independent component analysis (ICA) in a subsample with available MRI data (n=1467, 53% females).ResultsThe analyses revealed a global GWC component, which showed an age-related decrease from late childhood and across adolescence. In addition, we found regional anatomically meaningful components with differential age associations explaining variance beyond the global component. When accounting for age and sex, both higher symptom levels of anxiety or prodromal psychosis and lower cognitive ability were associated with higher GWC in insula and cingulate cortices and with lower GWC in pre- and postcentral cortices. We also found several additional regional associations with anxiety, prodromal psychosis and cognitive ability.ConclusionIndependent modes of GWC variation are sensitive to global and regional brain developmental processes, possibly related to differences between intracortical and subjacent white matter myelination, and individual differences in regional GWC are associated with both mental health and general cognitive functioning.

Abstract W P364: Relationships Between Endothelial Function, Biological Markers and Cerebral Small Vessel Diseasein Patients with Chronic Cerebrovascular Disease and Comorbidity

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Tomohisa Nezu ◽  
Naohisa Hosomi ◽  
Shiro Aoki ◽  
Tetsuya Takahashi ◽  
Takamichi Sugimoto ◽  
...  
Keyword(s):  
White Matter ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Cerebrovascular Disease ◽  
Progenitor Cells ◽  
Small Vessel Disease ◽  
White Matter Lesions ◽  
Magnetic Resonance Images ◽  
Small Vessel ◽  
Partial Regression Coefficient

Background and Purpose: Pathogenesis of white matter lesions is thought to be associated with endothelial dysfunction and inflammation. Ultrasound assessment of brachial artery flow mediated dilation (FMD) as a noninvasive and useful method has been recently used as an index of endothelium-dependent vasodilation. The aim of this study was to investigate the associations between endothelial function which was evaluated by FMD and the severity of white matter lesions in patients with chronic cerebrovascular disease and comorbidity. Additionally, we evaluated association between FMD and the number of circulating progenitor cells. Methods: Patients with cerebrovascular diseases history and other untypical neurological problems were enrolled in this study (n=63; 39 male, 69.8±10.0 years). Patients were classified according to periventricular hyperintensities (PVH) and deep white matter hyperintensities (DWMH) scores by fluid-attenuate inversion recovery image of magnetic resonance images (Fazekas gradings). Endothelial dysfunction was defined as a FMD≤4.5%. The numbers of CD34+/CD133+ cells defined as circulating progenitor cells were evaluated by flow cytometry. Results: The patients with endothelial dysfunction (n=39, 61.9%) were older (72.4±7.6 vs. 65.5±11.8, P=0.007), more frequently male (74.4% vs. 41.7%, P=0.016) and more frequently had hypertension (89.7% vs. 37.5%, P<0.001) than the patients without. FMD was negatively correlated with age, the severity of PVH and the severity of DWMH (R 2 =0.120, p=0.006, R 2 =0.280, p<0.001 and R 2 =0.234, p<0.001, respectively). In addition, FMD was positively correlated with the number of circulating progenitor cell (R 2 =0.078, p=0.034). After multivariate analysis with age, sex, presence of stroke and comorbidities, endothelial dysfunction was independently associated with the severity of PVH (standardized partial regression coefficient [β] 0.703, p=0.002), as well as DWMH (β 0.589, p=0.042). Conclusion: Endothelial dysfunction which was evaluated by FMD might be predictive for the grade of cerebral small vessel disease.

Association of total cerebral small vessel disease burden with the cavitation of recent small subcortical infarcts

2021 ◽  
pp. 028418512110665
Author(s):  
Meimei Wang ◽  
Yunfei Li ◽  
Yingjie Song ◽  
Yingyu Zhao ◽  
Xiaohu Zhao
Keyword(s):  
White Matter ◽  
White Matter Hyperintensities ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Perivascular Spaces ◽  
Vessel Disease ◽  
Multivariable Regression ◽  
Total Burden

Background Recent small subcortical infarcts (RSSIs) could evolve into cavitation (lacunes) or non-cavitation (white matter hyperintensities or disappearance) during the chronic period, but the factors involved remain unclear. Purpose To explore the association between total cerebral small vessel disease (CSVD) burden and lesion cavitation. Material and Methods We retrospectively selected 202 inpatients with an isolated RSSI who underwent baseline and follow-up magnetic resonance imaging (median interval = 16.6 months; interquartile range [IQR]=8.2–30.1). Inpatients were divided into cavitation and non-cavitation groups depending on whether a fluid-filled cavity formed. Data including demographic, clinical, and radiological features were collected and analyzed. To determine total CSVD burden, four imaging markers, including lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces, were rated and summed as a final practical score between 0 and 4. Results Overall, 137 (67.8%) patients progressed to cavitation and 65 (32.2%) to non-cavitation. Binary multivariable regression analysis showed that the baseline total CSVD burden ( P  = 0.005) and infarct diameter ( P  = 0.002) were independent risk factors for cavitation. A severe total burden (scores of 3–4) at baseline was independently related to cavitation ( P = 0.001). Moreover, the total CSVD burden score varied from 2 (IQR=1–3) at baseline to 3 (IQR=2–4) at follow-up. The extent of the increase in total burden was correlated with cavitation ( r = 0.201; P = 0.004). Conclusion Total CSVD burden, both the baseline value and extent of increase, was positively associated with cavitation. RSSIs with severe total CSVD burden at baseline have a greater potential to become cavitated.

scholarly journals Magnetic resonance imaging for assessment of cerebrovascular reactivity in cerebral small vessel disease: A systematic review

2016 ◽  
Vol 36 (5) ◽  
pp. 833-841 ◽  
Author(s):  
Gordon W Blair ◽  
Fergus N Doubal ◽  
Michael J Thrippleton ◽  
Ian Marshall ◽  
Joanna M Wardlaw
Keyword(s):  
Magnetic Resonance Imaging ◽  
White Matter ◽  
Magnetic Resonance ◽  
White Matter Hyperintensities ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Cerebrovascular Reactivity ◽  
Small Vessel ◽  
Resonance Imaging ◽  
Vessel Disease

Cerebral small vessel disease (SVD) pathophysiology is poorly understood. Cerebrovascular reactivity (CVR) impairment may play a role, but evidence to date is mainly indirect. Magnetic resonance imaging (MRI) allows investigation of CVR directly in the tissues affected by SVD. We systematically reviewed the use of MRI to measure CVR in subjects with SVD. Five studies (total n = 155 SVD subjects, 84 controls) provided relevant data. The studies included different types of patients. Each study used blood oxygen level dependent (BOLD) MRI to assess CVR but a different vasoactive stimulus and method of calculating CVR. CVR decreased with increasing white matter hyperintensities in two studies ( n = 17, 11%) and in the presence of microbleeds in another. Three studies ( n = 138, 89%) found no association of CVR with white matter hyperintensities. No studies provided tissue-specific CVR values. CVR decreased with age in three studies, and with female gender and increasing diastolic blood pressure in one study. Safety and tolerability data were limited. Larger studies using CVR appear to be feasible and are needed, preferably with more standardized methods, to determine if specific clinical or radiological features of SVD are more or less associated with impaired CVR.

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