Rare NOTCH3 Variants in a Chinese Population-Based Cohort and Its Relationship With Cerebral Small Vessel Disease

Stroke ◽  
2021 ◽  
Author(s):  
Jing-Yi Liu ◽  
Ming Yao ◽  
Yi Dai ◽  
Fei Han ◽  
Fei-Fei Zhai ◽  
...  
Keyword(s):  
Chinese Population ◽  
White Matter Hyperintensities ◽  
Rare Variants ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Vessel Disease ◽  
Age Related ◽  
Whole Exome ◽  
General Chinese Population

Background and Purpose: Researches on rare variants of NOTCH3 in the general Chinese population are lacking. This study aims to describe the spectrum of rare NOTCH3 variants by whole-exome sequencing in a Chinese community-based cohort and to investigate the association between rare NOTCH3 variants and age-related cerebral small vessel disease. Methods: The cross-sectional study comprised 1065 participants who underwent whole-exome sequencing and brain magnetic resonance imaging. NOTCH3 variants with minor allele frequency<1% in all 4 public population databases (1000 Genomes, ESP6500siv2_ALL, GnomAD_ALL, and GnomAD_EAS) were defined as rare variants. Multivariable linear and logistic regressions were used to investigate the associations between rare NOTCH3 variants and volume of white matter hyperintensities and cerebral small vessel disease burden. Clinical and imaging characteristics of rare NOTCH3 variant carriers were summarized. Results: Sixty-five rare NOTCH3 variants were identified in 147 of 1065 (13.8%) participants, including 57 missense single nucleotide polymorphisms (SNPs), 5 SNPs in splice branching sites, and 3 frameshift deletions. A significantly higher volume of white matter hyperintensities and heavier burden of cerebral small vessel disease was found in carriers of rare NOTCH3 EGFr (epidermal growth factor-like repeats)-involving variants, but not in carriers of EGFr-sparing variants. The carrying rate of rare EGFr-involving NOTCH3 variants in participants with dementia or stroke was significantly higher than those without dementia or stroke (12.4% versus 6.6%, P =0.041). Magnetic resonance imaging signs suggestive of CADASIL were found in 3.4% (5/145) rare EGFr cysteine-sparing NOTCH3 variant carriers but not in 2 cysteine-altering NOTCH3 variant carriers. Conclusions: Carriers of rare NOTCH3 variants involving the EGFr domain may be genetically predisposed to age-related cerebral small vessel disease in the general Chinese population.

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

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.

scholarly journals Associations between blood and cerebrospinal fluid flow impairments assessed with phase-contrast MRI and brain damage in patients with age-related cerebral small vessel disease

2019 ◽  
pp. 16-23
Author(s):  
E.I. Kremneva ◽  
B.M. Akhmetzyanov ◽  
L.A. Dobrynina ◽  
M.V. Krotenkova
Keyword(s):  
Cerebrospinal Fluid ◽  
Brain Damage ◽  
Phase Contrast ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Csf Flow ◽  
Phase Contrast Mri ◽  
Vessel Disease ◽  
Age Related

Hemodynamic parameters of blood and cerebrospinal fluid (CSF) flow can be measured in vivo using phase-contrast MRI (PC-MRI). This opens new horizons for studying the mechanisms implicated in the development and progression of age-related cerebral small vessel disease (SVD). In this paper, we analyze associations between cerebral arterial, venous and CSF flow impairments and SVD features visible on MRI. The study was carried out in 96 patients with SVD (aged 60.91 ± 6.57 years) and 23 healthy volunteers (59.13 ± 6.56 years). The protocol of the MRI examination included routine MRI sequences (T2, FLAIR, T1, SWI, and DWI) applied to assess the severity of brain damage according to STRIVE advisory standards and PC-MRI used to quantify blood flow in the major arteries and veins of the neck, the straight and upper sagittal sinuses, and CSF flow at the aqueduct level. We analyzed the associations between linear and volumetric parameters of blood/CSF flow and the degree of brain matter damage using the Fazekas scale. We observed a reduction in tABF, stVBF, sssVBF, aqLF, Saq, and ICC values and a rise in Pi associated with WMH progression, as well as a gradual decline in tABF and an increase in Pi, Saq and ICC associated with a growing number of lacunes (р < 0.05). Patients with early (< 5) MB had lower sssVBF and stVBF rates in comparison with patients without MB; aqLF, Saq, and ICC values were elevated in patients with 5 to 10 MB, as compared to patients without MB or early (< 5) MB. The established associations between MRI findings in patients with SVD and blood/CSF flow impairments suggest the important role of mechanisms implicated in the disruption of Monro–Kellie intracranial homeostasis in promoting SVD.

scholarly journals Contributions of Aging to Cerebral Small Vessel Disease

2020 ◽  
Vol 82 (1) ◽  
pp. 275-295 ◽  
Author(s):  
T. Michael De Silva ◽  
Frank M. Faraci
Keyword(s):  
Recent Progress ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Brain Health ◽  
Vessel Disease ◽  
Age Related ◽  
The Face ◽  
Basic Biology ◽  
The Impact

Cerebral small vessel disease (SVD) is characterized by changes in the pial and parenchymal microcirculations. SVD produces reductions in cerebral blood flow and impaired blood-brain barrier function, which are leading contributors to age-related reductions in brain health. End-organ effects are diverse, resulting in both cognitive and noncognitive deficits. Underlying phenotypes and mechanisms are multifactorial, with no specific treatments at this time. Despite consequences that are already considerable, the impact of SVD is predicted to increase substantially with the growing aging population. In the face of this health challenge, the basic biology, pathogenesis, and determinants of SVD are poorly defined. This review summarizes recent progress and concepts in this area, highlighting key findings and some major unanswered questions. We focus on phenotypes and mechanisms that underlie microvascular aging, the greatest risk factor for cerebrovascular disease and its subsequent effects.

scholarly journals A population neuroscience approach to the study of cerebral small vessel disease in midlife and late life: an invited review

2018 ◽  
Vol 314 (6) ◽  
pp. H1117-H1136 ◽  
Author(s):  
Dana R. Jorgensen ◽  
C. Elizabeth Shaaban ◽  
Clayton A. Wiley ◽  
Peter J. Gianaros ◽  
Joseph Mettenburg ◽  
...  
Keyword(s):  
Risk Factors ◽  
Small Vessel Disease ◽  
Later Life ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Cross Sectional ◽  
Vessel Disease ◽  
Age Related ◽  
Cerebral Microvasculature ◽  
Study Designs

Aging in later life engenders numerous changes to the cerebral microvasculature. Such changes can remain clinically silent but are associated with greater risk for negative health outcomes over time. Knowledge is limited about the pathogenesis, prevention, and treatment of potentially detrimental changes in the cerebral microvasculature that occur with advancing age. In this review, we summarize literature on aging of the cerebral microvasculature, and we propose a conceptual framework to fill existing research gaps and advance future work on this heterogeneous phenomenon. We propose that the major gaps in this area are attributable to an incomplete characterization of cerebrovascular pathology, the populations being studied, and the temporality of exposure to risk factors. Specifically, currently available measures of age-related cerebral microvasculature changes are indirect, primarily related to parenchymal damage rather than direct quantification of small vessel damage, limiting the understanding of cerebral small vessel disease (cSVD) itself. Moreover, studies seldom account for variability in the health-related conditions or interactions with risk factors, which are likely determinants of cSVD pathogenesis. Finally, study designs are predominantly cross-sectional and/or have relied on single time point measures, leaving no clear evidence of time trajectories of risk factors or of change in cerebral microvasculature. We argue that more resources should be invested in 1) developing methodological approaches and basic science models to better understand the pathogenic and etiological nature of age-related brain microvascular diseases and 2) implementing state-of-the-science population study designs that account for the temporal evolution of cerebral microvascular changes in diverse populations across the lifespan.

scholarly journals Cognitive consequences of regression of cerebral small vessel disease

2018 ◽  
Vol 4 (1) ◽  
pp. 85-89 ◽  
Author(s):  
Esther MC van Leijsen ◽  
Mayra I Bergkamp ◽  
Ingeborg WM van Uden ◽  
Sjacky Cooijmans ◽  
Mohsen Ghafoorian ◽  
...  
Keyword(s):  
Executive Function ◽  
White Matter ◽  
Cognitive Decline ◽  
White Matter Hyperintensities ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Vessel Disease ◽  
Disease Markers ◽  
Total Brain

Introduction Recent studies have shown that neuroimaging markers of cerebral small vessel disease can also regress over time. We investigated the cognitive consequences of regression of small vessel disease markers. Patients and methods Two hundred and seventy-six participants of the RUNDMC study underwent neuroimaging and cognitive assessments at three time-points over 8.7 years. We semi-automatically assessed white matter hyperintensities volumes and manually rated lacunes and microbleeds. We analysed differences in cognitive decline and accompanying brain atrophy between participants with regression, progression and stable small vessel disease by analysis of variance. Results Fifty-six participants (20.3%) showed regression of small vessel disease markers: 31 (11.2%) white matter hyperintensities regression, 10 (3.6%) vanishing lacunes and 27 (9.8%) vanishing microbleeds. Participants with regression showed a decline in overall cognition, memory, psychomotor speed and executive function similar to stable small vessel disease. Participants with small vessel disease progression showed more cognitive decline compared with stable small vessel disease (p < 0.001 for cognitive index and memory; p < 0.01 for executive function), although significance disappeared after adjusting for age and sex. Loss of total brain, gray matter and white matter volume did not differ between participants with small vessel disease regression and stable small vessel disease, while participants with small vessel disease progression showed more volume loss of total brain and gray matter compared to those with stable small vessel disease (p < 0.05), although significance disappeared after adjustments. Discussion Regression of small vessel disease markers was associated with similar cognitive decline compared to stable small vessel disease and did not accompany brain atrophy, suggesting that small vessel disease regression follows a relatively benign clinical course. Future studies are required to validate these findings and to assess the role of vascular risk factor control on small vessel disease regression and possible recovery of clinical symptoms. Conclusion Our findings of comparable cognitive decline between participants with regression and stable small vessel disease might suggest that small vessel disease regression has a relative benign cognitive outcome.

scholarly journals Collateral Recruitment Is Impaired by Cerebral Small Vessel Disease

Stroke ◽  
2020 ◽  
Vol 51 (5) ◽  
pp. 1404-1410 ◽  
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.

scholarly journals Cell Senescence and Cerebral Small Vessel Disease in the Brains of People Aged 80 Years and Older

2019 ◽  
Vol 78 (11) ◽  
pp. 1066-1072 ◽  
Author(s):  
Emma J Norton ◽  
Leslie R Bridges ◽  
Lawrence C Kenyon ◽  
Margaret M Esiri ◽  
Dorothy C Bennett ◽  
...  
Keyword(s):  
Cell Density ◽  
Older Persons ◽  
Small Vessel Disease ◽  
Subcortical White Matter ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Mural Cell ◽  
Mural Cells ◽  
Vessel Disease ◽  
Age Related

Abstract Cerebral small vessel disease (cSVD) in penetrating arteries is a major cause of age-related morbidity. Cellular senescence is a molecular process targeted by novel senolytic drugs. We quantified senescence in penetrating arteries and tested whether myocyte senescence was associated with cSVD. We immunolabeled subcortical white matter of older persons (age 80–96 years, n = 60) with minimal AD, using antibodies to 2 established senescence markers (H3K9me3, γH2AX) and a myocyte marker (hSMM). Within the walls of penetrating arteries (20–300 µm), we quantified senescence-associated heterochromatic foci (SAHF)-positive nuclei, cell density (nuclei/µm2), and sclerotic index (SI). Senescent-appearing mural cells were present in small arteries of all cases. cSVD cases exhibited a lower proportion of senescent-appearing cells and lower area fraction (AF%) of SAHF-positive nuclei compared to controls (p = 0.014, 0.016, respectively). cSVD severity and SI both correlated negatively with AF% (p = 0.013, 0.002, respectively). Mural cell density was lower (p < 0.001) and SI higher (p < 0.001) in cSVD, relative to controls. In conclusion, senescent myocyte-like cells were universal in penetrating arteries of an AD-free cohort aged 80 years and older. Senescent-appearing nuclei were more common in persons aged 80 years and older without cSVD compared to cSVD cases, indicating caution in senolytic drug prescribing. Myocyte senescence and cSVD may represent alternative vessel fates in the aging human brain.

Adverse effects of pre-existing cerebral small vessel disease on cognitive improvement after carotid endarterectomy

2019 ◽  
Vol 15 (6) ◽  
pp. 657-665 ◽  
Author(s):  
Jun Yoshida ◽  
Fumio Yamashita ◽  
Makoto Sasaki ◽  
Kunihiro Yoshioka ◽  
Shunrou Fujiwara ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
White Matter ◽  
Carotid Endarterectomy ◽  
White Matter Hyperintensities ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Cognitive Improvement ◽  
Vessel Disease

Background Although patients with improved cognition after carotid endarterectomy usually exhibit postoperative restoration of cerebral blood flow, less than half of patients with such cerebral blood flow change have postoperatively improved cognition. Cerebral small vessel disease on magnetic resonance imaging is associated with irreversible cognitive impairment. Aims The purpose of the present prospective study was to determine whether pre-existing cerebral small vessel disease affects cognitive improvement after carotid endarterectomy. Methods Brain MR imaging was performed preoperatively, and the number or grade of each cerebral small vessel disease was determined in 80 patients undergoing carotid endarterectomy for ipsilateral internal carotid artery stenosis (≥70%). The volume of white matter hyperintensities relative to the intracranial volume was also calculated. Brain perfusion single-photon emission computed tomography and neuropsychological testing were performed preoperatively and two months postoperatively. Based on these data, a postoperative increase in cerebral blood flow and postoperative improved cognition, respectively, were determined. Results Logistic regression analysis using the sequential backward elimination approach revealed that a postoperative increase in cerebral blood flow (95% confidence interval [CI], 10.74–3730.00; P = 0.0004) and the relative volume of white matter hyperintensities (95% CI, 0.01–0.63; P = 0.0314) were significantly associated with postoperative improved cognition. Although eight of nine patients with postoperative improved cognition exhibited both a relative volume of white matter hyperintensities <0.65% and a postoperative increase in cerebral blood flow, none of patients with a relative volume of white matter hyperintensities ≥0.65% had postoperative improved cognition regardless of any postoperative change in cerebral blood flow. Conclusion Pre-existing cerebral white matter hyperintensities on magnetic resonance imaging adversely affect cognitive improvement after carotid endarterectomy.

Automated detection of white matter hyperintensities of all sizes in cerebral small vessel disease

2016 ◽  
Vol 43 (12) ◽  
pp. 6246-6258 ◽  
Author(s):  
Mohsen Ghafoorian ◽  
Nico Karssemeijer ◽  
Inge W. M. van Uden ◽  
Frank-Erik de Leeuw ◽  
Tom Heskes ◽  
...  
Keyword(s):  
White Matter ◽  
White Matter Hyperintensities ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Automated Detection ◽  
Small Vessel ◽  
Vessel Disease
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