ORCID Profile
0000-0001-5185-6384
Current Organisation
The University of Edinburgh
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Publisher: Cold Spring Harbor Laboratory
Date: 13-10-2020
DOI: 10.1101/2020.10.08.20205245
Abstract: Low-level chronic inflammation increases with age and is associated with cognitive decline. DNA methylation (DNAm) levels may provide more stable reflections of cumulative inflammatory burden than traditional serum approaches. Using structural and diffusion MRI data from 521 in iduals aged 73, we demonstrate that a DNAm proxy of C-Reactive Protein (CRP) shows significantly (on average 6.4-fold) stronger associations with brain structural outcomes than serum CRP. We additionally find that DNAm CRP has an inverse association with global and domain-specific (speed, visuospatial and memory) cognitive functioning, and that brain structure partially mediates this CRP-cognitive association (up to 29.4%), dependent on lifestyle and health factors. These data support the hypothesis that chronic systemic inflammation may contribute to neurodegenerative brain changes which underlie differences in cognitive ability in later life. DNA methylation-based predictors could be used as proxies for chronic inflammatory status.
Publisher: Cambridge University Press (CUP)
Date: 02-10-2015
DOI: 10.1017/THG.2015.71
Abstract: Structural brain magnetic resonance imaging (MRI) traits share part of their genetic variance with cognitive traits. Here, we use genetic association results from large meta-analytic studies of genome-wide association (GWA) for brain infarcts (BI), white matter hyperintensities, intracranial, hippoc al, and total brain volumes to estimate polygenic scores for these traits in three Scottish s les: Generation Scotland: Scottish Family Health Study (GS:SFHS), and the Lothian Birth Cohorts of 1936 (LBC1936) and 1921 (LBC1921). These five brain MRI trait polygenic scores were then used to: (1) predict corresponding MRI traits in the LBC1936 (numbers ranged 573 to 630 across traits), and (2) predict cognitive traits in all three cohorts (in 8,115–8,250 persons). In the LBC1936, all MRI phenotypic traits were correlated with at least one cognitive measure, and polygenic prediction of MRI traits was observed for intracranial volume. Meta-analysis of the correlations between MRI polygenic scores and cognitive traits revealed a significant negative correlation (maximal r = 0.08) between the HV polygenic score and measures of global cognitive ability collected in childhood and in old age in the Lothian Birth Cohorts. The lack of association to a related general cognitive measure when including the GS:SFHS points to either type 1 error or the importance of using prediction s les that closely match the demographics of the GWA s les from which prediction is based. Ideally, these analyses should be repeated in larger s les with data on both MRI and cognition, and using MRI GWA results from even larger meta-analysis studies.
Publisher: Springer Science and Business Media LLC
Date: 03-10-2016
DOI: 10.1038/NN.4398
Publisher: Springer Science and Business Media LLC
Date: 08-01-2014
Publisher: Springer Science and Business Media LLC
Date: 13-10-2016
Publisher: Elsevier BV
Date: 12-2014
Publisher: Springer Science and Business Media LLC
Date: 04-2023
DOI: 10.1038/S41591-023-02268-W
Abstract: Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of 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 in the white matter. These were associated with white matter PVS already in young adults ( N = 1,748 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort ( N = 2,862 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippoc al PVS, and of basal ganglia PVS and hippoc al PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-01-2019
DOI: 10.1212/WNL.0000000000006851
Abstract: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10 −8 and LINC00539/ZDHHC20, p = 5.82 × 10 −9 . Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follow-up s le or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits ( p value for BI, p [BI] = 9.38 × 10 −25 p [SSBI] = 5.23 × 10 −14 for hypertension), smoking ( p [BI] = 4.4 × 10 −10 p [SSBI] = 1.2 × 10 −4 ), diabetes ( p [BI] = 1.7 × 10 −8 p [SSBI] = 2.8 × 10 −3 ), previous cardiovascular disease ( p [BI] = 1.0 × 10 −18 p [SSBI] = 2.3 × 10 −7 ), stroke ( p [BI] = 3.9 × 10 −69 p [SSBI] = 3.2 × 10 −24 ), and MRI-defined white matter hyperintensity burden ( p [BI] = 1.43 × 10 −157 p [SSBI] = 3.16 × 10 −106 ), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( p ≤ 0.0022), without indication of directional pleiotropy. In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.
Publisher: Elsevier BV
Date: 07-2019
Publisher: Springer Science and Business Media LLC
Date: 18-01-2017
DOI: 10.1038/NCOMMS13624
Abstract: The hippoc al formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippoc al volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippoc al structure here we perform a genome-wide association study (GWAS) of 33,536 in iduals and discover six independent loci significantly associated with hippoc al volume, four of them novel. Of the novel loci, three lie within genes ( ASTN2 , DPP4 and MAST4 ) and one is found 200 kb upstream of SHH . A hippoc al subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippoc al volume are also associated with increased risk for Alzheimer’s disease ( r g =−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippoc al volume and risk for neuropsychiatric illness.
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.SLEEP.2019.07.015
Abstract: Sleep is important for brain health. We analysed associations between usual sleep habits and magnetic resonance imaging (MRI) markers of neurodegeneration (brain atrophy), vascular damage (white matter hyperintensities, WMH) and waste clearance (perivascular spaces, PVS) in older community-dwelling adults. We collected self-reported usual sleep duration, quality and medical histories from the Lothian Birth Cohort 1936 (LBC1936) age 76 years and performed brain MRI. We calculated sleep efficiency, measured WMH and brain volumes, quantified PVS, and assessed associations between sleep measures and brain markers in multivariate models adjusted for demographic and medical history variables. In 457 subjects (53% males, mean age 76 ± 0.65 years), we found: brain and white matter loss with increased weekend daytime sleep (β = -0.114, P = 0.03 β = -0.122, P = 0.007 respectively), white matter loss with less efficient sleep (β = 0.132, P = 0.011) and PVS increased with interrupted sleep (OR 1.84 95% CI, P = 0.025). Cross-sectional associations of sleep parameters with brain atrophy and more PVS suggest adverse relationships between usual sleep habits and brain health in older people that should be evaluated longitudinally.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2012
DOI: 10.1038/NG.2250
Publisher: Springer Science and Business Media LLC
Date: 25-04-2017
DOI: 10.1038/MP.2017.62
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-12-2021
DOI: 10.1212/WNL.0000000000012997
Abstract: To investigate chronic inflammation in relation to cognitive aging by comparison of an epigenetic and serum biomarker of C-reactive protein and their associations with neuroimaging and cognitive outcomes. At baseline, participants (n = 521) were cognitively normal, around 73 years of age (mean 72.4, SD 0.716), and had inflammation, vascular risk (cardiovascular disease history, hypertension, diabetes, smoking, alcohol consumption, body mass index), and neuroimaging (structural and diffusion MRI) data available. Baseline inflammatory status was quantified by a traditional measure of peripheral inflammation—serum C-reactive protein (CRP)—and an epigenetic measure (DNA methylation [DNAm] signature of CRP). Linear models were used to examine the inflammation–brain health associations mediation analyses were performed to interrogate the relationship between chronic inflammation, brain structure, and cognitive functioning. We demonstrate that DNAm CRP shows significantly (on average 6.4-fold) stronger associations with brain health outcomes than serum CRP. DNAm CRP is associated with total brain volume (β = −0.197, 95% confidence interval [CI] −0.28 to −0.12, p FDR = 8.42 × 10 −6 ), gray matter volume (β = −0.200, 95% CI −0.28 to −0.12, p FDR = 1.66 × 10 −5 ), and white matter volume (β = −0.150, 95% CI −0.23 to −0.07, p FDR = 0.001) and regional brain atrophy. We also find that DNAm CRP has an inverse association with global and domain-specific (speed, visuospatial, and memory) cognitive functioning and that brain structure partially mediates this CRP–cognitive association (up to 29.7%), dependent on lifestyle and health factors. These results support the hypothesis that chronic inflammation may contribute to neurodegenerative brain changes that underlie differences in cognitive ability in later life and highlight the potential of DNAm proxies for indexing chronic inflammatory status. This study provides Class II evidence that a DNAm signature of CRP levels is more strongly associated with brain health outcomes than serum CRP levels.
Publisher: SAGE Publications
Date: 10-09-2018
Abstract: Neuroimaging and clinical studies have defined human sporadic cerebral small vessel disease but the pathophysiology remains relatively poorly understood. To develop effective therapies and preventative strategies, we must better understand the heterogeneity and development of small vessel disease at a cellular level. Small vessel disease lesions as seen on neuroimaging have specific neuropathological correlates. Standard histological s les are taken from strategic areas of the brain typically affected by small vessel disease, in cases with a range of disease from mild to severe and controls. Tissue is formalin fixed, scanned using 7-tesla magnetic resonance imaging and processed for histology. Histological slides are digitalized then registered with the corresponding magnetic resonance image. Small vessel disease burden is assessed and lesions are precisely identified on the ex vivo imaging and microscopy independently then compared. The tissue can be interrogated using multiple magnetic resonance sequences and histological methods targeting the gliovascular unit. The primary outcome is identifying and defining the cellular characteristics of small vessel disease lesions compared to imaging. Secondary outcomes are related to obtaining information about abnormalities of protein expression in the gliovascular unit, defining groups of small vessel disease severity in our cohorts for future analysis and developing a reliable, reproducible protocol for accurate radiological–histological lesion comparison, which can be applied to other neurological diseases in the future. Comprehensive, precise pathological–radiological–clinical correlations in small vessel disease will provide greater insight into associations and pathophysiology underlying magnetic resonance imaging findings in normal- and abnormal-appearing tissue, ex vivo and in vivo.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Susana Muñoz Maniega.