| 1. |
|
|
| 2. |
|
|
| 3. |
- Jia, TY, et al.
(författare)
-
Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group
- 2021
-
Ingår i: Molecular psychiatry. - : Springer Science and Business Media LLC. - 1476-5578 .- 1359-4184. ; 26:8, s. 3884-3895
-
Tidskriftsartikel (refereegranskat)abstract
- DNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)—three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.
|
|
| 4. |
|
|
| 5. |
- Traylor, Matthew, et al.
(författare)
-
Genetic basis of lacunar stroke : a pooled analysis of individual patient data and genome-wide association studies
- 2021
-
Ingår i: The Lancet Neurology. - 1474-4422. ; 20:5, s. 351-361
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. Methods: We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. Findings: Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254 798 controls, of which 2987 cases (matched with 29 540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42 310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0·05). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. Interpretation: Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-β signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. Funding: British Heart Foundation.
|
|
| 6. |
- Ball, Emily L., et al.
(författare)
-
Predicting post-stroke cognitive impairment using acute CT neuroimaging : A systematic review and meta-analysis
- 2022
-
Ingår i: International Journal of Stroke. - : Sage Publications. - 1747-4930 .- 1747-4949. ; 17:6, s. 618-627
-
Forskningsöversikt (refereegranskat)abstract
- Background Identifying whether acute stroke patients are at risk of cognitive decline could improve prognostic discussions and management. Structural computed tomography neuroimaging is routine in acute stroke, and may identify those at risk of post-stroke dementia or post-stroke cognitive impairment (PSCI).Aim To systematically review the literature to identify which stroke or pre-stroke features on brain computed tomography scans, performed at the time of stroke, are associated with post-stroke dementia or PSCI.Summary of review We searched electronic databases to December 2020. We included studies reporting acute stroke brain computed tomography, and later diagnosis of a cognitive syndrome. We created summary estimates of size of unadjusted association between computed tomography features and cognition. Of 9536 citations, 28 studies (41 papers) were eligible (N = 7078, mean age 59.8-78.6 years). Cognitive outcomes were post-stroke dementia (10 studies), PSCI (17 studies), and one study analyzed both. Fifteen studies (N = 2952) reported data suitable for meta-analyses. White matter lesions (WML) (six studies, N = 1054, OR = 2.46, 95% CI = 1.25-4.84), cerebral atrophy (four studies, N = 558, OR = 2.80, 95% CI = 1.21-6.51), and pre-existing stroke lesions (three studies, N = 352, OR = 2.38, 95% CI = 1.06-5.32) were associated with post-stroke dementia. WML (four studies, N = 473, OR = 3.46, 95% CI = 2.17-5.52) were associated with PSCI. Other computed tomography features were either not associated with cognitive outcome, or there were insufficient data.Conclusions Cognitive impairment following stroke is of great concern to patients and carers. Features seen on visual assessment of acute stroke computed tomography brain scans are strongly associated with cognitive outcomes. Clinicians should consider when and how this information should be discussed with stroke survivors.
|
|
| 7. |
- Ball, Emily Louise, et al.
(författare)
-
Predictors of post-stroke cognitive impairment using acute structural MRI neuroimaging : A systematic review and meta-analysis
- 2023
-
Ingår i: International Journal of Stroke. - : Sage Publications. - 1747-4930 .- 1747-4949. ; 18:5, s. 543-554
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Stroke survivors are at an increased risk of developing post-stroke cognitive impairment and post-stroke dementia; those at risk could be identified by brain imaging routinely performed at stroke onset.AIM: This systematic review aimed to identify features which are associated with post-stroke cognitive impairment (including dementia), on magnetic resonance imaging (MRI) performed at stroke diagnosis.SUMMARY OF REVIEW: We searched the literature from inception to January 2022 and identified 10,284 records. We included studies that performed MRI at the time of stroke (0-30 days after a stroke) and assessed cognitive outcome at least three months after stroke. We synthesised findings from 26 papers, comprising 27 stroke-populations (N=13,114, average age range=40-80 years, 19-62% female). When data were available, we pooled unadjusted (ORu) and adjusted (ORa) odds ratios.We found associations between cognitive outcomes and presence of cerebral atrophy (3 studies, N=453, ORu=2.48, 95%CI=1.15-4.62), presence of microbleeds (2 studies, N=9151, ORa=1.36, 95%CI=1.08-1.70), and increasing severity of white matter hyperintensities (3 studies, N=704, ORa=1.26, 95%CI=1.06-1.49). Increasing cerebral small vessel disease score was associated with cognitive outcome following unadjusted analysis only (2 studies, N=499, ORu=1.34, 95%CI=1.12-1.61; 3 studies, N=950, ORa=1.23, 95%CI=0.96-1.57). Associations remained after controlling for pre-stroke cognitive impairment. We did not find associations between other stroke features and cognitive outcome, or there were insufficient data.CONCLUSIONS: Acute stroke MRI features may enable healthcare professionals to identify patients at risk of post-stroke cognitive problems. However, there is still substantial uncertainty about the prognostic utility of acute MRI for this.
|
|
| 8. |
- Hachinski, Vladimir, et al.
(författare)
-
Preventing dementia by preventing stroke : The Berlin Manifesto
- 2024
-
Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949.
-
Forskningsöversikt (refereegranskat)abstract
- The incidence of stroke and dementia are diverging across the world, rising for those in low-and middle-income countries and falling in those in high-income countries. This suggests that whatever factors cause these trends are potentially modifiable. At the population level, neurological disorders as a group account for the largest proportion of disability-adjusted life years globally (10%). Among neurological disorders, stroke (42%) and dementia (10%) dominate. Stroke and dementia confer risks for each other and share some of the same, largely modifiable, risk and protective factors. In principle, 90% of strokes and 35% of dementias have been estimated to be preventable. Because a stroke doubles the chance of developing dementia and stroke is more common than dementia, more than a third of dementias could be prevented by preventing stroke. Developments at the pathological, pathophysiological, and clinical level also point to new directions. Growing understanding of brain pathophysiology has unveiled the reciprocal interaction of cerebrovascular disease and neurodegeneration identifying new therapeutic targets to include protection of the endothelium, the blood-brain barrier, and other components of the neurovascular unit. In addition, targeting amyloid angiopathy aspects of inflammation and genetic manipulation hold new testable promise. In the meantime, accumulating evidence suggests that whole populations experiencing improved education, and lower vascular risk factor profiles (e.g., reduced prevalence of smoking) and vascular disease, including stroke, have better cognitive function and lower dementia rates. At the individual levels, trials have demonstrated that anticoagulation of atrial fibrillation can reduce the risk of dementia by 48% and that systolic blood pressure lower than 140 mmHg may be better for the brain. Based on these considerations, the World Stroke Organization has issued a proclamation, endorsed by all the major international organizations focused on global brain and cardiovascular health, calling for the joint prevention of stroke and dementia. This article summarizes the evidence for translation into action.
|
|
| 9. |
- Ingala, Silvia, et al.
(författare)
-
Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort.
- 2021
-
Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17:7, s. 1189-1204
-
Tidskriftsartikel (refereegranskat)abstract
- We classified non-demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles.From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut-offs of 1000 pg/mL for amyloid beta (Aß)1-42 and 27 pg/mL for p-tau181 were validated using Gaussian mixture models. Given strong correlation of p-tau and t-tau (R2 =0.98, P<0.001), neurodegeneration was defined by age-adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages.Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A-T-N-, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non-Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P<0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T-N- compared to A-T-N- (P<0.001).In non-demented individuals along the AD continuum, p-tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.
|
|
| 10. |
|
|
