Cerebral Small Vessel Disease, Hypertension, and Vascular Contributions to Cognitive Impairment and Dementia

Hypertension, Journal Year: 2023, Volume and Issue: 81(1), P. 75 - 86

Published: Nov. 29, 2023

Hypertension-associated cerebral small vessel disease is a common finding in older people. Strongly associated with age and hypertension, found at autopsy over 50% of people aged ≥65 years, spectrum clinical manifestations. It the main cause lacunar stroke major source vascular contributions to cognitive impairment dementia. The brain areas affected are subcortical periventricular white matter deep gray nuclei. Neuropathological sequelae diffuse lesions (seen as hyperintensities on T2-weighted magnetic resonance imaging), ischemic foci (lacunes or microinfarcts), less commonly, microhemorrhages. most form concentric, fibrotic thickening penetrating arteries (up 300 microns outer diameter) termed arteriolosclerosis. Less forms artery atheroma lipohyalinosis (the described by C. Miller Fisher adjacent lacunes). Other microvascular that not reviewed here include amyloid angiopathy venous collagenosis. Here, we review epidemiology, neuropathology, management, genetics, preclinical models, pathogenesis hypertensive disease. Knowledge gaps initiating factors, molecular pathogenesis, relationships between arterial pathology tissue damage, possible reversibility, pharmacological targets, biomarkers. Progress anticipated from multicell transcriptomic proteomic profiling, novel experimental models further target-finding interventional studies.

Language: Английский

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Cerebral small vessel disease: Pathological mechanisms and potential therapeutic targets

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: Aug. 12, 2022

Cerebral small vessel disease (CSVD) represents a diverse cluster of cerebrovascular diseases primarily affecting arteries, capillaries, arterioles and venules. The diagnosis CSVD relies on the identification subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds using neuroimaging. is observed in 25% strokes worldwide most common pathology cognitive decline dementia elderly. Still, due to poor understanding pathophysiology CSVD, there not an effective preventative or therapeutic approach for CSVD. widely accepted treatment mitigate vascular risk factors adopt healthier lifestyle. Thus, deeper pathogenesis may foster more specific therapies. Here, we review underlying mechanisms pathological characteristics development, with focus endothelial dysfunction, blood-brain barrier impairment change. We also describe inflammation whose role contributing gaining interest. Finally, update current treatments measures as well discuss potential targets novel strategies treatment.

Language: Английский

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Genomics of perivascular space burden unravels early mechanisms of cerebral small vessel disease

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(4), P. 950 - 962

Published: April 1, 2023

Abstract Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly the white matter. These were associated with matter already young adults ( N = 1,748; 22.1 2.3 yr) enriched early-onset leukodystrophy genes expressed fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% loci showed nominally associations (27% after multiple-testing correction) Japanese cohort 2,862; 68.3 5.3 yr). Mendelian randomization supported causal high blood pressure basal ganglia hippocampal PVS, stroke, accounting for pressure. Our findings provide insight into biology pointing pathways involving extracellular matrix, membrane transport developmental processes, potential genetically informed prioritization drug targets.

Language: Английский

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Endothelial cells as key players in cerebral small vessel disease

Nature reviews. Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Language: Английский

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Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 134(2)

Published: Nov. 28, 2023

Vascular aging impacts multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how specifically affects brain vasculature, along with molecular read-outs, remain vastly incomplete. Here we demonstrate that is associated marked decline in Notch3 signaling both murine and human vessels. To clarify consequences loss used single-cell transcriptomics uncovered inactivation alters regulation calcium, contractile function, promotes notable increase extracellular matrix. These alterations adversely impact reactivity, manifesting as dilation, tortuosity, microaneurysms, decreased cerebral blood flow, observed by MRI. Combined, these impairments hinder glymphatic flow result buildup glycosaminoglycans within parenchyma. Remarkably, this phenomenon mirrors key pathological feature found brains CADASIL patients – hereditary dementia NOTCH3 missense mutations. Additionally, RNA sequencing neuronal compartment null mice has unveiled patterns reminiscent those neurodegenerative diseases. findings offer direct evidence age-related deficiencies trigger progressive subsequently affecting culminating neurodegeneration.

Language: Английский

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Pathophysiology of cerebral small vessel disease: a journey through recent discoveries

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(10)

Published: May 14, 2024

Cerebral small vessel disease (cSVD) encompasses a heterogeneous group of age-related pathologies that affect multiple regions. Disease manifestations range from lesions incidentally detected on neuroimaging (white matter hyperintensities, deep infarcts, microbleeds, or enlarged perivascular spaces) to severe disability and cognitive impairment. cSVD accounts for approximately 25% ischemic strokes the vast majority spontaneous intracerebral hemorrhage is also most important vascular contributor dementia. Despite its high prevalence potentially long therapeutic window, there are still no mechanism-based treatments. Here, we provide an overview recent advances in this field. We summarize data highlighting remarkable continuum between monogenic multifactorial cSVDs involving NOTCH3, HTRA1, COL4A1/A2 genes. Taking vessel-centric view, discuss possible cause-and-effect relationships risk factors, structural functional changes, manifestations, underscoring some major knowledge gaps. Although endothelial dysfunction rightly considered central feature cSVD, contributions smooth muscle cells, pericytes, other cells warrant continued investigation.

Language: Английский

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Salidroside promotes pro-angiogenesis and repair of blood brain barrier via Notch/ITGB1 signal path in CSVD Model

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 1, 2024

Salidroside (SAL), extracted from Rhodiola rosea, has been widely used in coronary heart disease and myocardial ischemia for decades. Previous studies have demonstrated that SAL could reduce arteriosclerosis, thus combat ischemic brain damage. However, the in-depth function of salidroside Cerebral Small Vascular Disease (CSVD) not discovered, related molecular mechanism is still unclear. The present study aims to explore effects angiogenesis as well repair blood barrier (BBB) its possible mechanisms. We established a rat model SHR via 2-vessel gradual occlusion (SHR-2VGO) mimic CSVD. Subsequently, MRI, pathomorphism, Morriss water maze test were conducted determine CSVD-related indicators. 8 weeks post-surgery, animals randomly administered SAL, DAPT, ATN161 or saline.The aim was protective CSVD mechanism. Here we found attenuate cerebral hypoperfusion-induced BBB disruption, promote pro-angiogenesis through enhancing cell budding. Further investigations significantly increase expression Notch1, Hes1, Hes5, ITGB1. In addition, confirmed activate Notch signal path, then up-regulate ITGB1 protect disruption. aforementioned findings integrity Notch-ITGB1 signaling path CSVD, which indicated be potential medicine candidate treatment.

Language: Английский

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A cell-autonomous role for border-associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(11), P. 2138 - 2151

Published: Sept. 18, 2024

Language: Английский

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CADASIL: A NOTCH3-associated cerebral small vessel disease

Journal of Advanced Research, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary cerebral small vessel disease (CSVD), pathologically characterized by a non-atherosclerotic non-amyloid diffuse angiopathy primarily involving to medium-sized penetrating arteries leptomeningeal arteries. In 1996, mutation in notch receptor 3 gene (NOTCH3) was identified as cause of CADASIL. However, since that time other genetic CSVDs have been described, including HtrA serine peptidase 1 gene-associated CSVD cathepsin A CSVD, clinically mimic original phenotype. Though NOTCH3-associated now well-recognized disorder number studies investigating this increasing, role NOTCH3 pathogenesis CADASIL remains elusive.

Language: Английский

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Vascular cognitive impairment and dementia: Mechanisms, treatment, and future directions

International Journal of Stroke, Journal Year: 2024, Volume and Issue: 19(8), P. 838 - 856

Published: Sept. 16, 2024

Worldwide, around 50 million people live with dementia, and this number is projected to triple by 2050. It has been estimated that 20% of all dementia cases have a predominant cerebrovascular pathology, while perhaps another vascular diseases contribute mixed picture. Therefore, the contribution affects 20 currently will increase markedly in next few decades, particularly lower- middle-income countries. In review, we discuss mechanisms cognitive impairment (VCI) review management. VCI refers spectrum pathologies any degree impairment, ranging from subjective decline, mild dementia. While acute decline occurring soon after stroke most recognized form VCI, chronic disease, particular cerebral small-vessel can cause insidious absence stroke. Moreover, disease not only commonly co-occurs Alzheimer’s (AD) increases probability AD pathology result clinical but may also etiologically development pathologies. Despite its enormous health economic impact, neglected research area, adequately powered trials therapies, resulting proven treatments. Current management emphasizes prevention treatment risk factors, evidence for intensive hypertension control. Reperfusion therapies attenuate VCI. Associated behavioral symptoms such as apathy poststroke emotionalism are common. We highlight novel strategies hopefully lead new course-modifying therapies. Finally, importance including endpoints large cardiovascular need an increased focus funding important area.

Language: Английский

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