Hereditary cerebral small vessel disease and the role of genetic factors

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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The role of small diffusion-weighted imaging lesions in cerebral small vessel disease

Neurology ◽

10.1212/wnl.0000000000008364 ◽

2019 ◽

pp. 10.1212/WNL.0000000000008364 ◽

Cited By ~ 1

Author(s):

Kim Wiegertjes ◽

Annemieke ter Telgte ◽

Pedro B. Oliveira ◽

Esther M.C. van Leijsen ◽

Mayra I. Bergkamp ◽

...

Keyword(s):

Diffusion Weighted Imaging ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Small Diffusion ◽

Vessel Disease ◽

Diffusion Weighted

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Oxidative stress in cerebral small vessel disease. Role of reactive species

Free Radical Research ◽

10.1080/10715762.2017.1402304 ◽

2017 ◽

Vol 52 (1) ◽

pp. 1-13 ◽

Cited By ~ 21

Author(s):

Cezary Grochowski ◽

Jakub Litak ◽

Piotr Kamieniak ◽

Ryszard Maciejewski

Keyword(s):

Oxidative Stress ◽

Small Vessel Disease ◽

Reactive Species ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Vessel Disease

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Advances in biomarkers of cerebral small vessel disease

Journal of Neurorestoratology ◽

10.26599/jnr.2019.9040021 ◽

2019 ◽

Vol 07 (04) ◽

pp. 171-183

Author(s):

Xue Peng ◽

Jianhua Zhao ◽

Junli Liu ◽

Shaomin Li

Keyword(s):

Genetic Factors ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Research Progress ◽

Imaging Biomarkers ◽

Gene Markers ◽

Vessel Disease ◽

Cerebrovascular Risk ◽

Perforating Arteries

Cerebral small vessel disease (CSVD) refers to a type of syndrome caused by lesions in perforating arteries, small veins, small arteries, or capillaries, resulting in clinical, imaging, or pathological alterations. The occurrence and development of CSVD are related to various cerebrovascular risk factors, such as metabolism and genetic factors. CSVD is diagnosed based on brain imaging biomarkers; however, biomarkers capable of predicting and diagnosing CSVD early in its progression have not been found. Exploring biomarkers closely related to disease progression is of great significance for early diagnosis, prognosis, prevention, and treatment of CSVD. This article examines the research progress of CSVD biomarkers, from inflammatory biomarkers, coagulation and fibrinolysis markers, biomarkers of endothelial dysfunction, biomarkers related to cerebrospinal fluid, and gene markers.

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Cerebral Small Vessel Disease in subclinical and clinical stages, role of inflammation for risk prediction and potential treatment targets, and management strategies

Internal Medicine Review ◽

10.18103/imr.v2i11.265 ◽

2016 ◽

Vol 2 (11) ◽

Author(s):

C. Frances Fan ◽

José R Romero

Keyword(s):

Clinical Outcomes ◽

Small Vessel Disease ◽

Brain Mri ◽

Management Strategies ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Potential Treatment ◽

Treatment Targets ◽

Vessel Disease

Stroke and dementia are the most common neurological disorders worldwide. Cerebrovascular disease, particularly cerebral small vessel disease (CSVD) is implicated in both, and the two main types of CSVD (hypertensive vasculopathy and cerebral amyloid angiopathy) account for the majority of cerebrovascular contributions to stroke and dementia. Current knowledge of CSVD may influence treatment decisions and preventive efforts. Although the causes of CSVD are not entirely elucidated, ongoing research of the pathophysiology of CSVD, such as the role of inflammation, is helping identify potential treatment targets, evaluate prediction models and develop preventive strategies. Given the detectability of CSVD in preclinical stages using brain MRI, a long window of opportunity is presented to implement existent preventive measures. This review considers CSVD including its subclinical manifestations detected using brain MRI, clinical manifestations, use of markers of CSVD as predictors of clinical outcomes such as dementia and stroke, and presents potential management strategies when seeing patients with cerebral small vessel disease to reduce its disease burden and clinical consequences. Clinical trials have evaluated some aspects of CSVD treatment and are beginning to recognize CSVD as endpoint in subclinical stages. Future studies will clarify if this approach is able to delay onset of dementia and prevent stroke occurrence, meanwhile implementation of existent recommendations for the prevention and treatment of stroke and dementia may reduce disability and clinical outcomes related to CSVD.

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Investigating the origin and evolution of cerebral small vessel disease: The RUN DMC – InTENse study

European Stroke Journal ◽

10.1177/2396987318776088 ◽

2018 ◽

Vol 3 (4) ◽

pp. 369-378 ◽

Cited By ~ 5

Author(s):

Annemieke ter Telgte ◽

Kim Wiegertjes ◽

Anil M Tuladhar ◽

Marlies P Noz ◽

José P Marques ◽

...

Keyword(s):

Temporal Dynamics ◽

Small Vessel Disease ◽

Clinical Importance ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Acute Ischaemia ◽

Origin And Evolution ◽

Vessel Disease ◽

And Function

Background Neuroimaging in older adults commonly reveals signs of cerebral small vessel disease (SVD). SVD is believed to be caused by chronic hypoperfusion based on animal models and longitudinal studies with inter-scan intervals of years. Recent imaging evidence, however, suggests a role for acute ischaemia, as indicated by incidental diffusion-weighted imaging lesions (DWI+ lesions), in the origin of SVD. Furthermore, it becomes increasingly recognised that focal SVD lesions likely affect the structure and function of brain areas remote from the original SVD lesion. However, the temporal dynamics of these events are largely unknown. Aims (1) To investigate the monthly incidence of DWI+ lesions in subjects with SVD; (2) to assess to which extent these lesions explain progression of SVD imaging markers; (3) to investigate their effects on cortical thickness, structural and functional connectivity and cognitive and motor performance; and (4) to investigate the potential role of the innate immune system in the pathophysiology of SVD. Design/methods The RUN DMC – InTENse study is a longitudinal observational study among 54 non-demented RUN DMC survivors with mild to severe SVD and no other presumed cause of ischaemia. We performed MRI assessments monthly during 10 consecutive months (totalling up to 10 scans per subject), complemented with clinical, motor and cognitive examinations. Discussion Our study will provide a better understanding of the role of DWI+ lesions in the pathophysiology of SVD and will further unravel the structural and functional consequences and clinical importance of these lesions, with an unprecedented temporal resolution. Understanding the role of acute, potentially ischaemic, processes in SVD may provide new strategies for therapies.

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