Dataset Information

Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease.

ABSTRACT: Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3'-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3'-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association.

SUBMITTER: Schmidt H

PROVIDER: S-EPMC3212720 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease.

Schmidt Helena H Zeginigg Marion M Wiltgen Marco M Freudenberger Paul P Petrovic Katja K Cavalieri Margherita M Gider Pierre P Enzinger Christian C Fornage Myriam M Debette Stephanie S Rotter Jerome I JI Ikram Mohammad A MA Launer Lenore J LJ Schmidt Reinhold R

Brain : a journal of neurology 20111017 Pt 11

Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leuco ...[more]

PMID: 22006983

Similar Datasets

Project description:ImportanceWith advancing age, an increased visibility of perivascular spaces (PVSs) on magnetic resonance imaging (MRI) is hypothesized to represent impaired drainage of interstitial fluid from the brain and may reflect underlying cerebral small vessel disease (SVD). However, whether large perivascular spaces (L-PVSs) (>3 mm in diameter) visible on MRI are associated with SVD and cognitive deterioration in older individuals is unknown.ObjectiveTo examine whether L-PVSs are associated with the progression of the established MRI markers of SVD, cognitive decline, and increased risk of dementia.Design, setting, and participantsThe prospective, population-based Age, Gene/Environment Susceptibility-Reykjavik Study assessed L-PVSs at baseline (September 1, 2002, through February 28, 2006) on MRI studies of the brain in 2612 participants. Participants returned for additional MRI from April 1, 2007, through September 30, 2011, and underwent neuropsychological testing at the 2 time points a mean (SD) of 5.2 (0.2) years apart. Data analysis was conducted from August 1, 2016, to May 4, 2017.ExposuresThe presence, number, and location of L-PVSs.Main outcomes and measuresIncident subcortical infarcts, cerebral microbleeds, and progression of white matter hyperintensities detected on MRI; cognitive decline defined as composite score changes between baseline and follow-up in the domains of memory, information processing speed, and executive function; and adjudicated incident dementia cases diagnosed according to international guidelines.ResultsOf the 2612 study patients (mean [SD] age, 74.6 [4.8] years; 1542 [59.0%] female), 424 had L-PVSs and 2188 did not. The prevalence of L-PVSs was 16.2% (median number of L-PVSs, 1; range, 1-17). After adjusting for age, sex, and interval between baseline and follow-up scanning, the presence of L-PVSs was significantly associated with an increased risk of incident subcortical infarcts (adjusted risk ratio, 2.54; 95% CI, 1.76-3.68) and microbleeds (adjusted risk ratio, 1.43; 95% CI, 1.18-1.72) and a greater 5-year progression of white matter hyperintensity volume. The presence of L-PVSs was also associated with a steeper decline in information processing speed and more than quadrupled the risk of vascular dementia. All associations persisted when further adjusted for genetic and cerebrovascular risk factors. The associations with cognitive outcomes were independent of educational level, depression, and other SVD MRI markers.Conclusions and relevanceLarge PVSs are an MRI marker of SVD and associated with the pathogenesis of vascular-related cognitive impairment in older individuals. Large PVSs should be included in assessments of vascular cognitive impairment in the older population and as potential targets for interventions.

Project description:BackgroundTwenty-four-hour and nighttime blood pressure (BP) levels are more strongly associated with cardiovascular risk than office or daytime BP measurements. However, it remains undocumented which of the office and ambulatory BP measurements have the strongest association and predictive information in relation to the presence of type I, or arteriolosclerosis type, cerebral small vessel diseases (CSVD).MethodsA subset of 429 participants from the Maracaibo Aging Study [aged ≥40 years (women, 73.7%; mean age, 59.3 years)] underwent baseline brain magnetic resonance imaging (MRI) to visualize CSVD, which included log-transformed white matter hyperintensities (log-WMH) volume and the presence (yes/no) of lacunes, cerebral microbleeds (CMB), or enlarged perivascular spaces (EPVS). Linear and logistic regression models were applied to examine the association between CSVD and each +10-mmHg increment in the office and ambulatory systolic BP measurements. Improvement in the fit of nested logistic models was assessed by the log-likelihood ratio and the generalized R 2 statistic.ResultsOffice and ambulatory systolic BP measurements were related to log-WMH (β-correlation coefficients ≥0.08; P < 0.001). Lacunes and CMB were only associated with ambulatory systolic BP measurements (odds ratios [OR] ranged from 1.31 [95% confidence interval, 1.10-1.55] to 1.46 [1.17-1.84], P ≤ 0.003). Accounted for daytime systolic BP, both the 24-h (β-correlation, 0.170) and nighttime (β-correlation, 0.038) systolic BP measurements remained related to log-WMH. When accounted for 24-h or daytime systolic BP levels, the nighttime systolic BP retained the significant association with lacunes (ORs, 1.05-1.06; 95% CIs, ≥1.01 to ≤ 1.13), whereas the 24-h and daytime systolic BP levels were not associated with lacunes after adjustments for nighttime systolic BP (ORs, ≤ 0.88; 95% CI, ≥0.77 to ≤ 1.14). On top of covariables and office systolic BP, ambulatory systolic BP measurements significantly improved model performance (1.05% ≥ R 2 ≤ 3.82%). Compared to 24-h and daytime systolic BP, nighttime systolic BP had the strongest improvement in the model performance; for WMH (1.46 vs. 1.05%) and lacunes (3.06 vs. ≤ 2.05%).ConclusionsTwenty-four-hour and nighttime systolic BP were the more robust BP measurements associated with CSVD, but the nighttime systolic BP level had the strongest association. Controlling ambulatory BP levels might provide additional improvement in the prevention of CSVD.

Dataset Information

Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease.

Publications

Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets