[Recurrent depressive disorder associated with an atypical CADASIL syndrome]. / Recidiverende depressieve stoornis bij een atypisch CADASIL-syndroom.

A 55-year-old man with recurrent depressive episodes, with onset at age 45, was admitted to hospital after a suicide attempt. Due to a recent stroke as well as a family history of stroke and depression, CADASIL (prevalence of 2-5 per 100.000) was considered as a possible diagnosis. Although depression is common in CADASIL, the initial presentation is not typically comprised of recurrent depressions. Brain MRI, however, did not show the characteristic white matter lesions in the anterior temporal lobe. Genetic analysis revealed a cysteine-sparing mutation (Arg61Trp) in the NOTCH3 gene. Recently, several such mutations have been associated with CADASIL presenting with an atypical phenotype including a lower prevalence of recurrent stroke. This suggests that the prevalence of CADASIL may be higher than estimated in depressed patients. This case demonstrates the importance of considering CADASIL as a possible etiology of depression as this has consequences for prognosis, treatment and genetic counseling.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with multiple different onset forms of frequent recurrent attacks: A case report and literature review.

INTRODUCTION: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one kind of monogenic hereditary small-vessel disease in the brain caused by mutations in the NOTCH3 gene. However, it is rare for CADASIL to recur with different clinical manifestations in 1 patient, and some atypical clinical manifestations can easily lead to misdiagnosis by clinical physicians. CASE CONCERN: A 34-year-old male presented with transient speech disorder accompanied by weakness in the left side of the body for 1 day in June 2020. Magnetic resonance imaging showed acute ischemic infarction in right centrum semiovale, along with multiple abnormal white matter hyperintensities in the brain. Genetic sequencing identified a heterozygous mutation in the NOTCH3 gene. The patient experienced recurrent episodes in 2021 and 2023, with varying clinical symptoms including visual blurring, abnormal limb sensation, and sudden cognitive dysfunction. DIAGNOSIS: The diagnoses of CADASIL is based on clinical manifestations, imaging results, and genetic reports. INTERVISION AND OUTCOMES: The patient was received symptomatic treatment including antiplatelet aggregation therapy, lipid regulation, and plaque stabilization, resulting in improved symptoms. OUTCOMES: During the course of the disease, after medication treatment and rehabilitation exercise, the patient clinical symptoms have significantly improved. Currently, the patient is closely following up and regularly undergoing relevant examinations. LESSONS: In this rare case, we found that CADASIL can recur multiple times in a patient with different clinical symptoms, which can easily lead to clinical misdiagnosis. Clinicians should consider the possibility of CADASIL in young patients with sudden typical neurological dysfunction.

Peculiar CADASIL phenotype in monozygotic twins carrying a novel NOTCH3 pathogenetic variant.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominantly inherited cerebral small vessel disease caused by Neurogenic locus notch homolog protein 3 (NOTCH3) gene mutations. The main clinical features include migraine with aura, recurrent ischemic strokes and dementia. Brain MRI typically shows multiple small lacunar infarcts and severe, diffuse, symmetrical white matter hyperintensities (WMHs), with characteristic involvement of the anterior temporal pole, external capsule, and superior frontal gyrus. Reports of twins with CADASIL are scarce. Herein we describe a pair of monozygotic twins with peculiar CADASIL phenotype, carrying a new NOTCH3 variant. CASE PRESENTATION: Twin A was a 45-year-old male suffering from migraine, obesity, arterial hypertension, and polycythemia (with negative genetic analysis), who complained of a transient, short-lasting (~ 5 minutes) episode of speech difficulties. Brain MRI showed diffuse, symmetrical, confluent periventricular WMHs involving frontal, parietal, and temporal lobes and external capsules, with sparing of anterior temporal poles. Genetic analysis of NOTCH3 gene demonstrated the presence of missense c.3329G>A, p.(Cys1110Tyr) variant, confirming CADASIL diagnosis. Twin B, affected by migraine and polycythemia, as well as his monozygotic twin, presented with a 2-month history of trigeminal neuralgia. Brain MRI demonstrated diffuse WMHs with a pattern of distribution like his twin. Genetic analysis revealed the same NOTCH3 pathogenic variant. CONCLUSIONS: Our monozygotic twins have a strikingly similar neuroimaging picture with sparing of anterior temporal poles. They also have a peculiar phenotype, both presenting polycythemia without genetically confirmed cause. Twin B had trigeminal neuralgia, that is unusual in CADASIL. The possible association of the peculiar findings with the newly reported NOTCH3 variant needs to be confirmed with further observations.

First report of a p.Cys484Tyr Notch3 mutation in a CADASIL patient with acute bilateral multiple subcortical infarcts-case report and brief review.

BACKGROUND: CADASIL(Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)is an inherited small vessel disease caused by mutations in NOTCH3 gene. Although NOTCH3 has numerous hotspots of gene mutations, mutations in exons 9 are rare. The p.C484T gene mutation type associated with it has not been reported in any relevant cases yet. Furthermore, CADASIL patients rarely present with acute bilateral multiple subcortical infarcts. CASE PRESENTATION: We report the case of a Chinese female patient with CADASIL who experienced "an acute bilateral subcortical infarction" because of"hemodynamic changes and hypercoagulability". In genetic testing, we discovered a new Cys484Tyr mutation in exon 9, which has also been found in the patient's two daughters. CONCLUSIONS: It is important to note that this discovery not only expands the mutation spectrum of Notch3 mutations in CADASIL patients, but also examines the mechanism behind acute bilateral subcortical infarction in CADASIL patients via case reviews and literature reviews, in order to provide some clinical recommendations for early intervention, diagnosis, and treatment in similar cases in the future.

Protein aggregates containing wild-type and mutant NOTCH3 are major drivers of arterial pathology in CADASIL.

Loss of arterial smooth muscle cells (SMCs) and abnormal accumulation of the extracellular domain of the NOTCH3 receptor (Notch3ECD) are the 2 core features of CADASIL, a common cerebral small vessel disease caused by highly stereotyped dominant mutations in NOTCH3. Yet the relationship between NOTCH3 receptor activity, Notch3ECD accumulation, and arterial SMC loss has remained elusive, hampering the development of disease-modifying therapies. Using dedicated histopathological and multiscale imaging modalities, we could detect and quantify previously undetectable CADASIL-driven arterial SMC loss in the CNS of mice expressing the archetypal Arg169Cys mutation. We found that arterial pathology was more severe and Notch3ECD accumulation greater in transgenic mice overexpressing the mutation on a wild-type Notch3 background (TgNotch3R169C) than in knockin Notch3R170C/R170C mice expressing this mutation without a wild-type Notch3 copy. Notably, expression of Notch3-regulated genes was essentially unchanged in TgNotch3R169C arteries. We further showed that wild-type Notch3ECD coaggregated with mutant Notch3ECD and that elimination of 1 copy of wild-type Notch3 in TgNotch3R169C was sufficient to attenuate Notch3ECD accumulation and arterial pathology. These findings suggest that Notch3ECD accumulation, involving mutant and wild-type NOTCH3, is a major driver of arterial SMC loss in CADASIL, paving the way for NOTCH3-lowering therapeutic strategies.

Progress to Clarify How NOTCH3 Mutations Lead to CADASIL, a Hereditary Cerebral Small Vessel Disease.

Notch signaling is conserved in C. elegans, Drosophila, and mammals. Among the four NOTCH genes in humans, NOTCH1, NOTCH2, and NOTCH3 are known to cause monogenic hereditary disorders. Most NOTCH-related disorders are congenital and caused by a gain or loss of Notch signaling activity. In contrast, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 is adult-onset and considered to be caused by accumulation of the mutant NOTCH3 extracellular domain (N3ECD) and, possibly, by an impairment in Notch signaling. Pathophysiological processes following mutant N3ECD accumulation have been intensively investigated; however, the process leading to N3ECD accumulation and its association with canonical NOTCH3 signaling remain unknown. We reviewed the progress in clarifying the pathophysiological process involving mutant NOTCH3.

Border-Zone Cerebral Infarcts Associated with COVID-19 in CADASIL: A Report of 3 Cases and Literature Review.

INTRODUCTION: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common inherited cerebral small vessel disease and is a cause of early onset ischemic lacunar stroke. COVID-19 infection may lead, in addition to acute respiratory syndrome, to vascular complications including stroke. Herein, we report three CADASIL patients presenting with cerebral border-zone infarcts concomitant to COVID-19 infection and summarize similar cases previously published in literature. METHODS: Clinical and radiological features of the 3 patients were collected and described. A narrative review of literature was performed in PubMed and Google Scholar by the end of 2022 using the "CADASIL" AND "COVID-19" AND "stroke" terms. RESULTS: In our 3 patients, aged 40-58 years, stroke symptoms occurred one to 11 days after the first COVID-19 manifestations. Pulmonary symptoms were mild or absent. One patient presented with hemodynamic failure presumably related to acute cardiomyopathy. Brain magnetic resonance imaging revealed in all cases, ischemic lesions within border-zone areas in both cerebral hemispheres, lesions in the genu of the corpus callosum or in the medium cerebellar peduncles in two cases. The watershed pattern of ischemic lesions was detected in two cases despite any blood pressure drop or severe respiratory dysfunction. Seven CADASIL patients presenting with acute brain infarcts (multiple in 4/7) in context of SARS-CoV-2 infection were identified in literature, despite no fall in blood pressure except for one of them. CONCLUSION: Our observations, in line with previous reports, further suggest that COVID-19 infection may alter blood flow autoregulation in the deepest cerebral white matter in CADASIL patients. The thrombocytopathy and endotheliopathy developing during COVID-19 infection may participate to the underlying vascular processes.

Treatment with Cerebrolysin Prolongs Lifespan in a Mouse Model of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare familial neurological disorder caused by mutations in the NOTCH3 gene and characterized by migraine attacks, depressive episodes, lacunar strokes, dementia, and premature death. Since there is no therapy for CADASIL the authors investigate whether the multi-modal neuropeptide drug Cerebrolysin may improve outcome in a murine CADASIL model. Twelve-month-old NOTCH3R169C mutant mice (n=176) are treated for nine weeks with Cerebrolysin or Vehicle and histopathological and functional outcomes are evaluated within the subsequent ten months. Cerebrolysin treatment improves spatial memory and overall health, reduces epigenetic aging, and prolongs lifespan, however, CADASIL-specific white matter vacuolization is not affected. On the molecular level Cerebrolysin treatment increases expression of Calcitonin Gene-Related Peptide (CGRP) and Silent Information Regulator Two (Sir2)-like protein 6 (SIRT6), decreases expression of Insulin-like Growth Factor 1 (IGF-1), and normalizes the expression of neurovascular laminin. In summary, Cerebrolysin fosters longevity and healthy aging without specifically affecting CADASIL pathology. Hence, Cerebrolysin may serve a therapeutic option for CADASIL and other disorders characterized by accelerated aging.

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

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

Clinical and neuroimaging review of monogenic cerebral small vessel disease from the prenatal to adolescent developmental stage.

Cerebral small vessel disease (cSVD) refers to a group of pathological processes with various etiologies affecting the small vessels of the brain. Most cases are sporadic, with age-related and hypertension-related sSVD and cerebral amyloid angiopathy being the most prevalent forms. Monogenic cSVD accounts for up to 5% of causes of stroke. Several causative genes have been identified. Sporadic cSVD has been widely studied whereas monogenic cSVD is still poorly characterized and understood. The majority of cases of both the sporadic and monogenic types, including cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), typically have their onset in adulthood. Types of cSVD with infantile and childhood onset are rare, and their diagnosis is often challenging. The present review discusses the clinical and neuroimaging findings of monogenic cSVD from the prenatal to adolescent period of development. Early diagnosis is crucial to enabling timely interventions and family counseling.

Modifiable vascular risk factors contribute to stroke in 1080 NOTCH3 R544C carriers in Taiwan Biobank.

BACKGROUND AND AIM: Previous studies have suggested cardiovascular risk factors increase the risk of not only common sporadic stroke but also of stroke in patients with monogenic stroke disorders including CADASIL. We investigated the effects of the NOTCH3 Arg544Cys (R544C) variant and associated vascular risk factors on stroke in the Taiwanese population. METHODS: This study was conducted using data from the Taiwan Biobank, consisting of at least 130,000 Han Chinese participants. The genotype was derived from customized genome-wide arrays for 650,000 to 750,000 single-nucleotide polymorphisms (SNPs). Individuals with NOTCH3 R544C were subsequently matched with noncarriers based on the propensity score at a 1:10 ratio by demographic and cardiovascular risk factors. The odds ratio (OR) for stroke or other phenotypes in NOTCH3 R544C carriers and matched noncarriers was then calculated. Univariate and multivariate regression analyses were performed on cardiovascular risk factors in NOTCH3 R544C carriers with and without stroke. The polygenic risk score (PRS) model, adopted from the UK Biobank, was then applied to evaluate the role of NOTCH3 R544C in stroke. RESULTS: From the 114,282 participants with both genotype and questionnaire results, 1080 (0.95%) harbored the pathogenic NOTCH3 R544C variant. When compared to the matched controls (n = 10,800), the carriers presented with a history of stroke (OR: 2.52, 95% confidence interval (CI) (1.45, 4.37)), dementia (OR: 30.1, 95% CI (3.13, 289.43)), and sibling history of stroke (OR: 2.48, 95% CI (1.85, 3.34)) phenotypes. The risk of stroke increased with every 10-year increase in age (p = 0.006, Cochran-Mantel-Haenszel test). Among NOTCH3 R544C carriers, 16 (1.3%) of the 1080 carriers with a stroke history were older, male, and more likely to have hypertension, diabetes, dyslipidemia, and a family history of stroke. In the stepwise multivariate analysis, hypertension (OR: 11.28, 95% CI (3.54, 43.3)) and diabetes mellitus (OR: 4.10, 95% CI (1.31, 12.4)) were independently associated with stroke. Harboring the NOTCH3 R544C variant in the Taiwan Biobank is comparable with a 6.74 standard deviations increase in individual's polygenic risk score for stroke. CONCLUSION: While the NOTCH3 R544C variant alone increased the risk of stroke, modifiable vascular risk factors also played a role in the occurrence of stroke in Taiwanese community-dwelling individuals carrying the NOTCH3 variant.

Bioinformatic Identification of Signaling Pathways and Hub Genes in Vascular Dementia

Background: Vascular dementia (VaD) is a prevalent neurodegenerative disease characterized by cognitive impairment due to cerebrovascular factors, affecting a significant portion of the aging population and highlighting the critical need to understand specific targets and mechanisms for effective prevention and treatment strategies. We aimed to identify pathways and crucial genes involved in the progression of VaD through bioinformatics analysis and subsequently validate these findings. Methods: We conducted differential expression analysis, Weighted Gene Co-expression Network Analysis (WGCNA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and Protein-Protein Interaction (PPI) analysis. We utilized pheochromocytoma 12 (PC12) cells to create an in vitro oxygen-glucose deprivation (OGD) model. We investigated the impact of overexpression and interference of adrenoceptor alpha 1D (ADRA1D) on OGD PC12 cells using TdT-mediated dUTP nick-end labeling (TUNEL), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot (WB), and Fluo-3-pentaacetoxymethyl ester (Fluo-3 AM) analysis. Results: We found 187 differentially expressed genes (DEGs) in the red module that were strongly associated with VaD and were primarily enriched in vasoconstriction, G protein-coupled amine receptor activity, and neuroactive ligand-receptor interaction, mitogen-activated protein kinase (MAPK) signaling pathway, and cell adhesion. Among these pathways, we identified ADRA1D as a gene shared by vasoconstriction, G protein-coupled amine receptor activity, and neuroactive ligand-receptor interaction. The TUNEL assay revealed a significant decrease in PC12 cell apoptosis with ADRA1D overexpression (p < 0.01) and a significant increase in apoptosis upon silencing ADRA1D (p < 0.01). RT-qPCR and WB analysis revealed elevated ADRA1D expression (p < 0.001) ... (AU)

Enfermedad de CADASIL: ictus familiares / Cadasil disease: Family strokes

El CADASIL es una microangiopatía cerebral de herencia autosómica dominante. Si bien su epidemiologia y patogénesis son poco conocidas, se sabe que está causada por una mutación del gen NOTCH3. Su expresión clínica es variable, dominada por episodios de migraña con aura seguido de episodios isquémicos cerebrales recurrentes, demencia y trastornos neuropsiquiátricos. El diagnóstico final se hace fundamentalmente con resonancia magnética desde la fase presintomática. El manejo del CADASIL es multidisciplinar. A continuación, exponemos el caso de un paciente que presenta múltiples accidentes cerebrovasculares. En la resonancia magnética se observa extensa afectación de sustancia blanca en ambos hemisferios cerebrales y en el estudio genético mutación compatible con enfermedad de CADASIL. (AU)

CADASIL is a brain microangiopathy with autosomal dominant inheritance. Although its epidemiology and pathogenesis are poorly understood, it is known to be caused by a mutation of the Notch3 gene. Its clinical expression is variable, dominated by episodes of migraine with aura followed by recurrent cerebral ischemic episodes, dementia and neuropsychiatric disorders. Final diagnosis is made fundamentally with magnetic resonance imaging from the pre-symptomatic phase. CADASIL is managed in a multidisciplinary way. Below, we report a case of a patient who presented multiple cerebrovascular accidents. Magnetic resonance imaging revealed extensive white matter involvement in both cerebral hemispheres and in the genetic study mutation compatible with CADASIL disease. (AU)

Comparison of models for stroke-free survival prediction in patients with CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, which is caused by mutations of the NOTCH3 gene, has a large heterogeneous progression, presenting with declines of various clinical scores and occurrences of various clinical event. To help assess disease progression, this work focused on predicting the composite endpoint of stroke-free survival time by comparing the performance of Cox proportional hazards regression to that of machine learning models using one of four feature selection approaches applied to demographic, clinical and magnetic resonance imaging observational data collected from a study cohort of 482 patients. The quality of the modeling process and the predictive performance were evaluated in a nested cross-validation procedure using the time-dependent Brier Score and AUC at 5 years from baseline, the former measuring the overall performance including calibration and the latter highlighting the discrimination ability, with both metrics taking into account the presence of right-censoring. The best model for each metric was the componentwise gradient boosting model with a mean Brier score of 0.165 and the random survival forest model with a mean AUC of 0.773, both combined with the LASSO feature selection method.

Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial.

BACKGROUND: Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease. METHODS: We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated. FINDINGS: Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10-4%/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10-4%/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10-4%/mm Hg [19·6; -45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10-4%/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10-4%/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10-4%/mm Hg [27·5; -77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10-4%/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10-4%/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake. INTERPRETATION: 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research. FUNDING: EU Horizon 2020 programme.

Associations between neurovascular coupling and cerebral small vessel disease: A systematic review and meta-analysis.

PURPOSE: The pathogenesis of cerebral small vessel disease (cSVD) remains elusive despite evidence of an association between white matter hyperintensities (WMH) and endothelial cerebrovascular dysfunction. Neurovascular coupling (NVC) may be a practical alternative measure of endothelial function. We performed a systematic review of reported associations between NVC and cSVD. METHODS: EMBASE and PubMed were searched for studies reporting an association between any STRIVE-defined marker of cSVD and a measure of NVC during functional magnetic resonance imaging, transcranial Doppler, positron emission tomography, near-infrared spectroscopy or single-photon emission computed tomography, from inception to November 3rd, 2022. Where quantitative data was available from studies using consistent tests and analyses, results were combined by inverse-variance weighted random effects meta-analysis. FINDINGS: Of 29 studies (19 case-controls; 10 cohorts), 26 reported decreased NVC with increasing severity of cSVD, of which 18 were individually significant. In 28 studies reporting associations with increasing WMH, 25 reported reduced NVC. Other markers of cSVD were associated with reduced NVC in: eight of nine studies with cerebral microbleeds (six showing a significant effect); three of five studies with lacunar stroke; no studies reported an association with enlarged perivascular spaces. Specific SVD diseases were particularly associated with reduced NVC, including six out of seven studies in cerebral amyloid angiopathy and all four studies in CADASIL. In limited meta-analyses, %BOLD occipital change to a visual stimulus was consistently reduced with more severe WMH (seven studies, SMD -1.51, p < 0.01) and increasing microbleeds (seven studies, SMD -1.31, p < 0.01). DISCUSSION AND CONCLUSION: In multiple, small studies, neurovascular coupling was reduced in patients with increasing severity of all markers of cSVD in sporadic disease, CAA and CADASIL. Cerebrovascular endothelial dysfunction, manifest as impaired NVC, may be a common marker of physiological dysfunction due to small vessel injury that can be easily measured in large studies and clinical practice.