Brain White Matter: A Substrate for Resilience and a Substance for Subcortical Small Vessel Disease

Age-related brain white matter disease is a form of small vessel disease (SVD) that may be associated with lacunar and other small subcortical infarcts, cerebral microbleeds, and perivascular spaces. This common form of cerebrovascular disease may manifest clinically as cognitive impairment of varying degrees and difficulty with mobility. Whereas some persons show cognitive decline and mobility failure when there are brain white matter hyperintensities (WMH) and acute stroke, others recover, and not everyone with brain white matter disease is disabled. Thus, repair or compensation of brain white matter may be possible, and furthermore, certain vascular risks, such as raised blood pressure, are targets for prevention of white matter disease or are administered to reduce the burden of such disease. Vascular risk modification may be useful, but alone may not be sufficient to prevent white matter disease progression. In this chapter, we specifically focus on WMH of vascular origin and explore white matter development, plasticity, and enduring processes of myelination across the health span in the context of experimental and human data, and compare and contrast resilient brain white matter propensity to a diseased white matter state. We conclude with thoughts on novel ways one might study white matter resilience, and predict future healthy cognitive and functional outcomes.

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

10.31234/osf.io/692bf ◽

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.

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CNS small vessel disease

Neurology ◽

10.1212/wnl.0000000000007654 ◽

2019 ◽

Vol 92 (24) ◽

pp. 1146-1156 ◽

Cited By ~ 31

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.

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Collateral Recruitment Is Impaired by Cerebral Small Vessel Disease

Stroke ◽

10.1161/strokeaha.119.027661 ◽

2020 ◽

Vol 51 (5) ◽

pp. 1404-1410 ◽

Cited By ~ 3

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.

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Evaluation of Cerebral Blood Flow Measured by 3D PCASL as Biomarker of Vascular Cognitive Impairment and Dementia (VCID) in a Cohort of Elderly Latinx Subjects at Risk of Small Vessel Disease

Frontiers in Neuroscience ◽

10.3389/fnins.2021.627627 ◽

2021 ◽

Vol 15 ◽

Author(s):

Kay Jann ◽

Xingfeng Shao ◽

Samantha J. Ma ◽

Steven Y. Cen ◽

Lina D’Orazio ◽

...

Keyword(s):

At Risk ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Cognitive Impairment ◽

White Matter ◽

Small Vessel Disease ◽

Vascular Cognitive Impairment ◽

Small Vessel ◽

Vessel Disease ◽

Brain White Matter

Cerebral small vessel disease (cSVD) affects arterioles, capillaries, and venules and can lead to cognitive impairments and clinical symptomatology of vascular cognitive impairment and dementia (VCID). VCID symptoms are similar to Alzheimer’s disease (AD) but the neurophysiologic alterations are less well studied, resulting in no established biomarkers. The purpose of this study was to evaluate cerebral blood flow (CBF) measured by 3D pseudo-continuous arterial spin labeling (pCASL) as a potential biomarker of VCID in a cohort of elderly Latinx subjects at risk of cSVD. Forty-five elderly Latinx subjects (12 males, 69 ± 7 years) underwent repeated MRI scans ∼6 weeks apart. CBF was measured using 3D pCASL in the whole brain, white matter and 4 main vascular territories (leptomeningeal anterior, middle, and posterior cerebral artery (leptoACA, leptoMCA, leptoPCA), as well as MCA perforator). The test-retest repeatability of CBF was assessed by intra-class correlation coefficient (ICC) and within-subject coefficient of variation (wsCV). Absolute and relative CBF was correlated with gross cognitive measures and domain specific assessment of executive and memory function, vascular risks, and Fazekas scores and volumes of white matter hyperintensity (WMH). Neurocognitive evaluations were performed using Montreal Cognitive Assessment (MoCA) and neuropsychological test battery in the Uniform Data Set v3 (UDS3). Good to excellent test-retest repeatability was achieved (ICC = 0.77–0.85, wsCV 3–9%) for CBF measurements in the whole brain, white matter, and 4 vascular territories. Relative CBF normalized by global mean CBF in the leptoMCA territory was positively correlated with the executive function composite score, while relative CBF in the leptoMCA and MCA perforator territory was positively correlated with MoCA scores, controlling for age, gender, years of education, and testing language. Relative CBF in WM was negatively correlated with WMH volume and MoCA scores, while relative leptoMCA CBF was positively correlated with WMH volume. Reliable 3D pCASL CBF measurements were achieved in the cohort of elderly Latinx subjects. Relative CBF in the leptomeningeal and perforator MCA territories were the most likely candidate biomarker of VCID. These findings need to be replicated in larger cohorts with greater variability of stages of cSVD.

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Strategic white matter tracts for processing speed deficits in age-related small vessel disease

Neurology ◽

10.1212/wnl.0000000000000475 ◽

2014 ◽

Vol 82 (22) ◽

pp. 1946-1950 ◽

Cited By ~ 57

Author(s):

M. Duering ◽

B. Gesierich ◽

S. Seiler ◽

L. Pirpamer ◽

M. Gonik ◽

...

Keyword(s):

White Matter ◽

Processing Speed ◽

Small Vessel Disease ◽

Small Vessel ◽

White Matter Tracts ◽

Vessel Disease ◽

Age Related

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Validation and comparison of two automated methods for quantifying brain white matter hyperintensities of presumed vascular origin

Journal of International Medical Research ◽

10.1177/0300060519880053 ◽

2019 ◽

Vol 48 (2) ◽

pp. 030006051988005

Author(s):

Jennifer M.J. Waymont ◽

Chariklia Petsa ◽

Chris J. McNeil ◽

Alison D. Murray ◽

Gordon D. Waiter

Keyword(s):

White Matter ◽

White Matter Hyperintensities ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Manual Segmentation ◽

Lesion Segmentation ◽

Vessel Disease ◽

Brain White Matter ◽

Automated Methods

Objectives White matter hyperintensities (WMH) are a common imaging finding indicative of cerebral small vessel disease. Lesion segmentation algorithms have been developed to overcome issues arising from visual rating scales. In this study, we evaluated two automated methods and compared them to visual and manual segmentation to determine the most robust algorithm provided by the open-source Lesion Segmentation Toolbox (LST). Methods We compared WMH data from visual ratings (Scheltens’ scale) with those derived from algorithms provided within LST. We then compared spatial and volumetric WMH data derived from manually-delineated lesion maps with WMH data and lesion maps provided by the LST algorithms. Results We identified optimal initial thresholds for algorithms provided by LST compared with visual ratings (Lesion Growth Algorithm (LGA): initial κ and lesion probability thresholds, 0.5; Lesion Probability Algorithm (LPA) lesion probability threshold, 0.65). LGA was found to perform better then LPA compared with manual segmentation. Conclusion LGA appeared to be the most suitable algorithm for quantifying WMH in relation to cerebral small vessel disease, compared with Scheltens’ score and manual segmentation. LGA offers a user-friendly, effective WMH segmentation method in the research environment.

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Neuroimaging in cerebral small vessel disease: Update and new concepts

Dementia & Neuropsychologia ◽

10.1590/1980-57642016dn11-040002 ◽

2017 ◽

Vol 11 (4) ◽

pp. 336-342 ◽

Cited By ~ 3

Author(s):

Mika Shibuya ◽

Claudia da Costa Leite ◽

Leandro Tavares Lucato

Keyword(s):

Endothelial Dysfunction ◽

Small Vessel Disease ◽

Systemic Disease ◽

Significant Proportion ◽

Small Vessel ◽

White Matter Hyperintensity ◽

Perivascular Spaces ◽

Imaging Features ◽

Vessel Disease ◽

Vascular Origin

ABSTRACT. In recent years, small vessel disease (SVD) has been recognized for its major impact on cognitive impairment in elderly people, where it is often difficult to separate its effects from those of neurodegenerative diseases individually. SVD is a systemic disease, probably related to diffuse endothelial dysfunction, which affects the perforating arterioles, capillaries and venules in the brain. Although often asymptomatic, it is responsible for almost half of all dementia cases and a significant proportion of stroke cases. Imaging features found on magnetic resonance include recent small subcortical infarctions, lacunes of presumed vascular origin, white matter hyperintensity of presumed vascular origin, prominent perivascular spaces and cerebral microbleeds. The recognition of these imaging findings as a spectrum of the same disease caused by endothelial dysfunction of small cerebral vessels can allow an overall analysis of the disease and thus the development of more effective preventive and therapeutic strategies.

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An intrinsic endothelial dysfunction causes cerebral small vessel disease

10.1101/2021.12.13.472377 ◽

2021 ◽

Author(s):

Sophie Quick ◽

Tessa V. Procter ◽

Jonathan Moss ◽

Angus Lawson ◽

Serena Baker ◽

...

Keyword(s):

White Matter ◽

Endothelial Dysfunction ◽

Blood Brain Barrier ◽

Small Vessel Disease ◽

Brain Barrier ◽

Small Vessel ◽

Extrinsic Factors ◽

Vessel Disease ◽

Brain White Matter ◽

Blood Brain

Small Vessel Disease (SVD) is the leading cause of vascular dementia, causes a quarter of strokes, and worsens stroke outcomes(1, 2). The disease is characterised by cerebral small vessel and white matter pathology, but the underlying mechanisms are poorly understood. Classically, the microvascular and tissue damage has been considered secondary to extrinsic factors, such as hypertension, consisting of microvessel stiffening, impaired vasoreactivity and blood-brain barrier dysfunction identified in human sporadic SVDs. However, increasing evidence points to an underlying vulnerability to SVD-related brain damage, not just extrinsic factors. Here, in a novel normotensive transgenic rat model where the phospholipase flippase Atp11b is deleted, we show pathological, imaging and behavioural changes typical of those in human sporadic SVD, but that occur without hypertension. These changes are due to an intrinsic endothelial cell dysfunction, identified in vessels of the brain white matter and the retina, with pathological evidence of vasoreactivity and blood-brain barrier deficits, which precipitate a secondary maturation block in oligodendroglia and myelin disruption around the small vessels. This highlights that an intrinsic endothelial dysfunction may underlie vulnerability to human sporadic SVD, providing alternative therapeutic targets to prevent a major cause of stroke and dementia.

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

Acta Radiologica ◽

10.1177/02841851211066583 ◽

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.

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Small vessel disease burden in cerebral amyloid angiopathy without symptomatic hemorrhage

Neurology ◽

10.1212/wnl.0000000000003655 ◽

2017 ◽

Vol 88 (9) ◽

pp. 878-884 ◽

Cited By ~ 16

Author(s):

Gregoire Boulouis ◽

Andreas Charidimou ◽

Michael J. Jessel ◽

Li Xiong ◽

Duangnapa Roongpiboonsopit ◽

...

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Small Vessel Disease ◽

Summary Score ◽

Small Vessel ◽

Amyloid Angiopathy ◽

Perivascular Spaces ◽

Cognitive Symptoms ◽

Vessel Disease ◽

Age Related ◽

Cerebral Amyloid

Objective:Cerebral amyloid angiopathy (CAA) is a common age-related small vessel disease (SVD). Patients without intracerebral hemorrhage (ICH) typically present with transient focal neurologic episodes (TFNEs) or cognitive symptoms. We sought to determine if SVD lesion burden differed between patients with CAA first presenting with TFNEs vs cognitive symptoms.Methods:A total of 647 patients presenting either to a stroke department (n = 205) or an outpatient memory clinic (n = 442) were screened for eligibility. Patients meeting modified Boston criteria for probable CAA were included and markers of SVD were quantified, including cerebral microbleeds (CMBs), perivascular spaces, cortical superficial siderosis (cSS), and white matter hyperintensities (WMHs). Patients were classified according to presentation symptoms (TFNEs vs cognitive). Total CAA-SVD burden was assessed using a validated summary score. Individual neuroimaging markers and total SVD burden were compared between groups using univariable and multivariable models.Results:There were 261 patients with probable CAA included. After adjustment for confounders, patients first seen for TFNEs (n = 97) demonstrated a higher prevalence of cSS (p < 0.0001), higher WMH volumes (p = 0.03), and a trend toward higher CMB counts (p = 0.09). The total SVD summary score was higher in patients seen for TFNEs (adjusted odds ratio per additional score point 1.46, 95% confidence interval 1.16–1.84, p = 0.013).Conclusions:Patients with probable CAA without ICH first evaluated for TFNEs bear a higher burden of structural MRI SVD-related damage compared to those first seen for cognitive symptoms. This study sheds light on neuroimaging profile differences across clinical phenotypes of patients with CAA without ICH.

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