Vascular Dysfunction in Leukoaraiosis

Sam, Kevin; Crawley, Adrian; Poublanc, Julien; Conklin, John; Sobczyk, Olivia; Mandell, Daniel M.; Duffin, James; Venkatraghavan, Lashmi; Fisher, Joseph A.; Black, Sandra E.; Mikulis, David J.

doi:10.3174/ajnr.a4888

Cited by 37 publications

(44 citation statements)

References 53 publications

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“…(14) Lower CVR, FA, CBF and increased T2 and MD were observed in WMH compared with contralateral normal white matter. (16)…”

Section: Discussionmentioning

confidence: 99%

“…(9,10) Magnetic resonance imaging (MRI) techniques measure CVR in all brain tissues, including the subcortical areas commonly affected by SVD. (11) So far, MRI-based CVR has been assessed in relatively few small studies in SVD, but used different CVR challenges,(12-16) and did not account for clinically-relevant variables (e.g. age, blood pressure [BP], gender) that could confound CVR associations with SVD features.…”

Section: Introductionmentioning

confidence: 99%

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Intracranial functional haemodynamic relationships in patients with cerebral small vessel disease

Blair

Thrippleton

Shi

et al. 2019

Preprint

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BackgroundCerebral small vessel disease (SVD) is a major cause of stroke and dementia. The underlying cerebrovascular dysfunction is poorly understood. We investigated cerebrovascular reactivity, blood flow, vascular and cerebrospinal fluid (CSF) pulsatility, and their independent relationship to SVD features, in patients with minor ischaemic stroke and MRI evidence of SVD.MethodsWe recruited patients with minor ischaemic stroke and assessed CVR using Blood Oxygen Level Dependent (BOLD) MRI during a hypercapnic challenge, cerebral blood flow, vascular and CSF pulsatility using phase contrast MRI, and structural MR brain imaging to quantify white matter hyperintensities (WMH) and perivascular spaces (PVS). We quantified CVR in seven white matter and six subcortical grey matter regions, measured blood flow in carotid and vertebral arteries, intracranial venous sinuses, internal jugular veins and CSF flow at the aqueduct and foramen magnum. We used multiple regression to identify SVD features, blood flow and pulsatility parameters associated with CVR, controlling for patient characteristics.ResultsIn 53 of 60 patients with complete data (age 68.0±8.8, 74% male, 75% hypertensive), CVR in grey and white matter decreased with increasing blood pressure (BP, respectively −0.001%/mmHg, p=0.01 and −0.006%/mmHg, p=0.01, per mmHg increase in BP). After controlling for age, gender and systolic BP, white matter CVR decreased with increasing WMF volume (−0.01%/mmHg per log10 increase in WMH volume, p=0.02) and basal ganglia PVS (−0.01%/mmHg per point increase in PVS score, p=0.02). White matter CVR decreased with increasing venous pulsatility (superior sagittal sinus −0.03%/mmHg, p=0.02, per unit increase in pulsatility index) but not with cerebral blood flow (p=0.58). Lower foramen magnum CSF stroke volume was associated with worse white matter CVR (0.04%/mmHg per ml increase in stroke volume, p=0.04) and increased basal ganglia PVS.ConclusionsContemporaneous assessment of CVR, intracranial vascular and CSF pulsatility demonstrates important interrelationships of these vascular functions in humans. Decreased CVR, increased venous pulsatility and reduced foramen magnum CSF stroke volume suggests that dynamic vascular dysfunctions underpin PVS dysfunction and WMH development. Improved understanding of microvascular dysfunction and CSF dynamics offers new intervention targets to reduce SVD lesion development and their impact on cognitive dysfunction and stroke.

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“…(14) Lower CVR, FA, CBF and increased T2 and MD were observed in WMH compared with contralateral normal white matter. (16)…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intracranial functional haemodynamic relationships in patients with cerebral small vessel disease

Blair

Thrippleton

Shi

et al. 2019

Preprint

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“…Animal models demonstrated cerebrovascular dysfunction appeared months ahead of the rst histological evidence of white matter injury, including oligodendrocyte loss and glial activation [35,36]. Previous clinical studies followed up moderate-severe WMH patients for one year and found in comparison with contralateral normal appearing white matter (NAWM) that did not progress, NAWM that progressed to WMH had signi cantly decreased CVR value [30,31]. This result suggested that impaired dynamic cerebrovascular response to hypercapnia precedes the occurrence of WMH and may result in the development of WMH.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, rs-fMRI has been applied to explore CVR in cerebral large vessel diseases including carotid artery stenosis carotid or occlusion, Moyamoya disease [24,[27][28][29]. Furthermore, emerging studies used BOLD signal technology to evaluate CVR in WMH individuals and found that impaired CVR was associated with WMH [20,30,31]. However, all these studies didn't further explore whether impaired CVR can leads to cognitive decline through WMH.…”

Section: Introductionmentioning

confidence: 99%

Decreased Cerebrovascular Reserve is the Initial Cause of White Matter Hyperintensity Related Cognitive Decline

Yang

Chu

et al. 2020

Preprint

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Abstract Background: Increasing evidences have demonstrated the progressions of white matter hyperintensity (WMH) are associated with cerebrovascular reserve(CVR) and cognitive decline.The present study hypothesized that impaired CVR is associated with WMH progression and may lead to cognitive decline through WMH.Methods:A total of 244 WMH subjects were recruited and were categorized into WMH-I (n=112), WMH-II (n=76)and WMH-III(n=56) groups according to Fazekas rating scale.The individual CVR was measured using blood-oxygenation level-dependent (BOLD) signal fluctuations obtained from resting-state functional MRI(rs-fMRI). We compared maps of the CVR and clinical features among the three groups. Multiple linear regression analysis was performed to investigate the correlations of WMH volume with impaired CVR and cognitive functions indifferent domains controlling for age, sex, years of education, vascular risk factors, numbers of lacunas and cerebral microbleeds in all WMH individuals.Results: Compared with the WMH-I group, both WMH-II and WMH-III groups showed CVR decline in the left frontal and occipital areas. Multiple linear regression analysis showed WMH volumewas negatively associated with CVR impairments in left frontal/occipital areas and cognitive functions including global cognitive function (GCF), executive function (EF), information processing speed (IPS), memory and visuospatial processing function (VPF)(all P<0.05). Additionally, mediation analysis revealed CVR impairments in left frontal and occipital areas didn’t directly lead to cognitive decline, but indirectly caused cognitive decline in multiple domains through increasing WMH burdens (all 95% confidence intervals didn’t contain zero). Conclusion:The CVR decline initially resulted in WMH progression, which is responsible for the following development of cognitive decline. This study shed lights on exploring the pathogenesis of WMH progression and underlying mechanisms of WMH-related cognitive decline.

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“…The observed sparing of cortical U-fibres, which are supplied by shorter arteries, is consistent with such a mechanism. Several cerebral blood flow (CBF) and perfusion studies employing a variety of techniques have shown that resting CBF within WMHs is lower than that in normal-appearing WM in elderly subjects [75,76]. A recent meta-analysis of 28 cross-sectional CBF studies in 1161 elderly individuals showed that CBF was globally reduced in subjects with more WMHs [77].…”

Section: Chronic Cerebral Hypoperfusionmentioning

confidence: 99%

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

2017

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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.

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Vascular Dysfunction in Leukoaraiosis

Cited by 37 publications

References 53 publications

Intracranial functional haemodynamic relationships in patients with cerebral small vessel disease

Intracranial functional haemodynamic relationships in patients with cerebral small vessel disease

Decreased Cerebrovascular Reserve is the Initial Cause of White Matter Hyperintensity Related Cognitive Decline

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

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