Publications by authors named "Sabrina Schilling"

15 Publications

  • Page 1 of 1

Cerebral small vessel disease genomics and its implications across the lifespan.

Nat Commun 2020 12 8;11(1):6285. Epub 2020 Dec 8.

University of Alabama at Birmingham School of Medicine, Birmingham, AL, 35233, USA.

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.
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http://dx.doi.org/10.1038/s41467-020-19111-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722866PMC
December 2020

High dilated perivascular space burden: a new MRI marker for risk of intracerebral hemorrhage.

Neurobiol Aging 2019 12 10;84:158-165. Epub 2019 Sep 10.

Univ. Bordeaux, Inserm U1219, Bordeaux Population Health Research Center, Bordeaux, France; CHU de Bordeaux, Department of Neurology, Bordeaux, France. Electronic address:

Commonly observed in older community persons, dilated perivascular spaces (dPVSs) are thought to represent an emerging MRI marker of cerebral small vessel disease, but their clinical significance is uncertain. We examined the longitudinal relationship of dPVS burden with risk of incident stroke, ischemic stroke, and intracerebral hemorrhage (ICH) in the 3C-Dijon population-based study (N = 1678 participants, mean age 72.7 ± 4.1 years) using Cox regression. dPVS burden was studied as a global score and according to dPVS location (basal ganglia, white matter, hippocampus, brainstem) at the baseline. During a mean follow-up of 9.1 ± 2.6 years, 66 participants suffered an incident stroke. Increasing global dPVS burden was associated with a higher risk of any incident stroke (hazard ratio [HR], 1.24; 95% CI, [1.06-1.45]) and of incident ICH (HR, 3.12 [1.78-5.47]), adjusting for sex and intracranial volume. Association with ICH remained significant after additionally adjusting for vascular risk factors and for other cerebral small vessel disease MRI markers. High dPVS burden in basal ganglia and hippocampus, but not in white matter or brainstem, were associated with higher risk of any stroke and ICH.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.08.031DOI Listing
December 2019

Triple and quadruple cervical artery dissections: a systematic review of individual patient data.

J Neurol 2019 Jun 23;266(6):1383-1388. Epub 2019 Mar 23.

Department of Neurology, Amsterdam UMC, Location AMC, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.

Background And Purpose: Simultaneous dissection of three or four cervical arteries rarely occurs. As a result, limited information is available on clinical characteristics, underlying causes, treatment, and outcome of these patients.

Methods: We performed a systematic review of individual patient data on triple and quadruple cervical artery dissection (CeAD). We included all cases for whom, at minimum, data on age, sex and affected cervical arteries were available.

Results: Out of 1396 publications identified in the initial search, 52 were included, with data available on 96 patients. Mean age was 42 years and 66% were women. 63% had triple CeAD. The most common manifestations were headache (69%), neck pain (44%), motor deficit (36%), and Horner syndrome (34%). 57% had an ischemic stroke, in the majority of these patients the stroke was confined to the vascular territory of a single artery. 83% were managed medically (antiplatelets or anticoagulants) and 11% underwent endovascular treatment. An underlying disease or triggering event was identified in 71%, most commonly trauma (35%, cervical manipulative therapy in 13%), infection (18%), fibromuscular dysplasia (16%), and hereditary connective tissue disorder (8%). In-hospital mortality was 1%. 80% of patients had a good functional outcome (mRS 0-1) at follow-up. Two recurrences (3%) were reported.

Conclusions: Triple or quadruple CeAD mostly affected young women, and underlying disease or triggering event could be identified in more than two-thirds of patients. Less than two-thirds of triple or quadruple CeAD patients suffered ischemic stroke. Most patients were managed medically and the majority had a favorable outcome.
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http://dx.doi.org/10.1007/s00415-019-09269-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517349PMC
June 2019

Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting.

Neurology 2019 Jan 16. Epub 2019 Jan 16.

Objective: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.

Methods: 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.

Results: 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, = 1.77 × 10; and LINC00539/ZDHHC20, = 5.82 × 10. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits ( value for BI, = 9.38 × 10; = 5.23 × 10 for hypertension), smoking ( = 4.4 × 10; = 1.2 × 10), diabetes ( = 1.7 × 10; = 2.8 × 10), previous cardiovascular disease ( = 1.0 × 10; = 2.3 × 10), stroke ( = 3.9 × 10; = 3.2 × 10), and MRI-defined white matter hyperintensity burden ( = 1.43 × 10; = 3.16 × 10), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI ( ≤ 0.0022), without indication of directional pleiotropy.

Conclusion: 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.
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http://dx.doi.org/10.1212/WNL.0000000000006851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369905PMC
January 2019

Clinical Significance of Magnetic Resonance Imaging Markers of Vascular Brain Injury: A Systematic Review and Meta-analysis.

JAMA Neurol 2019 01;76(1):81-94

Stroke Research Group, Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.

Importance: Covert vascular brain injury (VBI) is highly prevalent in community-dwelling older persons, but its clinical and therapeutic implications are debated.

Objective: To better understand the clinical significance of VBI to optimize prevention strategies for the most common age-related neurological diseases, stroke and dementia.

Data Source: We searched for articles in PubMed between 1966 and December 22, 2017, studying the association of 4 magnetic resonance imaging (MRI) markers of covert VBI (white matter hyperintensities [WMHs] of presumed vascular origin, MRI-defined covert brain infarcts [BIs], cerebral microbleeds [CMBs], and perivascular spaces [PVSs]) with incident stroke, dementia, or death.

Study Selection: Data were taken from prospective, longitudinal cohort studies including 50 or more adults.

Data Extraction And Synthesis: We performed inverse variance-weighted meta-analyses with random effects and z score-based meta-analyses for WMH burden. The significance threshold was P < .003 (17 independent tests). We complied with the Meta-analyses of Observational Studies in Epidemiology guidelines.

Main Outcomes And Measures: Stroke (hemorrhagic and ischemic), dementia (all and Alzheimer disease), and death.

Results: Of 2846 articles identified, 94 studies were eligible, with up to 14 529 participants for WMH, 16 012 participants for BI, 15 693 participants for CMB, and 4587 participants for PVS. Extensive WMH burden was associated with higher risk of incident stroke (hazard ratio [HR], 2.45; 95% CI, 1.93-3.12; P < .001), ischemic stroke (HR, 2.39; 95% CI, 1.65-3.47; P < .001), intracerebral hemorrhage (HR, 3.17; 95% CI, 1.54-6.52; P = .002), dementia (HR, 1.84; 95% CI, 1.40-2.43; P < .001), Alzheimer disease (HR, 1.50; 95% CI, 1.22-1.84; P < .001), and death (HR, 2.00; 95% CI, 1.69-2.36; P < .001). Presence of MRI-defined BIs was associated with higher risk of incident stroke (HR, 2.38; 95% CI, 1.87-3.04; P < .001), ischemic stroke (HR, 2.18; 95% CI, 1.67-2.85; P < .001), intracerebral hemorrhage (HR, 3.81; 95% CI, 1.75-8.27; P < .001), and death (HR, 1.64; 95% CI, 1.40-1.91; P < .001). Presence of CMBs was associated with increased risk of stroke (HR, 1.98; 95% CI, 1.55-2.53; P < .001), ischemic stroke (HR, 1.92; 95% CI, 1.40-2.63; P < .001), intracerebral hemorrhage (HR, 3.82; 95% CI, 2.15-6.80; P < .001), and death (HR, 1.53; 95% CI, 1.31-1.80; P < .001). Data on PVS were limited and insufficient to conduct meta-analyses but suggested an association of high PVS burden with increased risk of stroke, dementia, and death; this requires confirmation.

Conclusions And Relevance: We report evidence that MRI markers of VBI have major clinical significance. This research prompts careful evaluation of the benefit-risk ratio for available prevention strategies in individuals with covert VBI.
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http://dx.doi.org/10.1001/jamaneurol.2018.3122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439887PMC
January 2019

Determinants and outcome of multiple and early recurrent cervical artery dissections.

Neurology 2018 08 1;91(8):e769-e780. Epub 2018 Aug 1.

From the Department of Neuro-oncology (A.C.), Netherlands Cancer Institute/Antoni van Leeuwenhoek; Department of Neurology (A.C.), MC Slotervaart, Amsterdam, the Netherlands; University of Bordeaux (S.S., S.D.); Bordeaux Population Health (S.S., S.D.), INSERM Center U1219, France; Department of Neurology (C.J.V., B.G.-S., H.S., S.J., U.F., M.A.), University Hospital Inselspital and University of Bern; Division of Neuropediatrics (B.G.-S.), San Giovanni Hospital Bellinzona, Switzerland; Department of Neurology (T.M.M., T.T.), Helsinki University Central Hospital, Finland; Departments of Neurology and Public Health Sciences (A.S., B.B.W.), University of Virginia, Charlottesville; Department of Clinical and Experimental Sciences (A.P.), Neurology Clinic, University of Brescia, Italy; Department of Neurology (M.K., C.G.-G., C.L.), Heidelberg University Hospital, Germany; Normandie Université (E.T.), Unicaen, CHU Caen, Inserm U1237; Université Paris Descartes (E.T.), CH Ste Anne, Inserm U894, Paris, France; Stroke Division (V.T.), Florey Institute for Neuroscience and Mental Health, University of Melbourne; Department of Neurology (V.T.), Austin Health, Heidelberg, Victoria, Australia; Department of Neurology (Y.B.), Dijon University Hospital; Department of Neurology (P.R., H.C., M.-G.B.), Lariboisière Hospital, Paris 7 University, DHU Neurovasc Sorbonne Paris Cité, France; Cerebrovascular Unit (A.B.), IRCCS Foundation C. Besta Neurological Institute, Milan, Italy; Suva/Swiss National Accident Insurance Fund (T.B.), Lucerne, Switzerland; Stroke Unit and Division of Internal and Cardiovascular Medicine (V.C.), University of Perugia, Italy; Department of Neurology and Stroke Center (P.A.L., C.T., S.T.E.), Department of Clinical Research, University Hospital and University of Basel, Switzerland; Neurology Clinic (C.L.), Memmingen Hospital, Germany; Department of Neurology (J.J.M.), Sanatorio Allende, Cordoba, Argentina; Department of Neurology (D.L.), Lille University, INSERM U1171, France; NeuroCentre (R.W.B.), Clinic Hirslanden Zürich, Switzerland; Neurorehabilitation Unit (S.T.E.), University Center for Medicine of Aging and Rehabilitation, Felix Platter Hospital, University of Basel, Switzerland; INSERM 1176 (J.D.), Institut Pasteur de Lille, France; Department of Clinical Neuroscience (T.T.), Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg; Department of Neurology (T.T.), Sahlgrenska University Hospital, Gothenburg, Sweden; and Department of Neurology-Memory Clinic (S.D.), Bordeaux University Hospital, France.

Objective: To assess putative risk factors and outcome of multiple and early recurrent cervical artery dissection (CeAD).

Methods: We combined data from 2 multicenter cohorts and compared patients with multiple CeAD at initial diagnosis, early recurrent CeAD within 3 to 6 months, and single nonrecurrent CeAD. Putative risk factors, clinical characteristics, functional outcome, and risk of recurrent ischemic events were assessed.

Results: Of 1,958 patients with CeAD (mean ± SD age 44.3 ± 10 years, 43.9% women), 1,588 (81.1%) had single nonrecurrent CeAD, 340 (17.4%) had multiple CeAD, and 30 (1.5%) presented with single CeAD at admission and had early recurrent CeAD. Patients with multiple or early recurrent CeAD did not significantly differ with respect to putative risk factors, clinical presentation, and outcome. In multivariable analyses, patients with multiple or early recurrent CeAD more often had recent infection (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.29-2.53), vertebral artery dissection (OR 1.82, 95% CI 1.34-2.46), family history of stroke (OR 1.55, 95% CI 1.06-2.25), cervical pain (OR 1.36, 95% CI 1.01-1.84), and subarachnoid hemorrhage (OR 2.85, 95% CI 1.01-8.04) at initial presentation compared to patients with single nonrecurrent CeAD. Patients with multiple or early recurrent CeAD also had a higher incidence of cerebral ischemia (hazard ratio 2.77, 95% CI 1.49-5.14) at 3 to 6 months but no difference in functional outcome compared to patients with single nonrecurrent CeAD.

Conclusion: Patients with multiple and early recurrent CeAD share similar risk factors, clinical characteristics, and functional outcome. Compared to patients with single nonrecurrent CeAD, they are more likely to have recurrent cerebral ischemia at 3 to 6 months, possibly reflecting an underlying transient vasculopathy.
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http://dx.doi.org/10.1212/WNL.0000000000006037DOI Listing
August 2018

Burden of Dilated Perivascular Spaces, an Emerging Marker of Cerebral Small Vessel Disease, Is Highly Heritable.

Stroke 2018 02 8;49(2):282-287. Epub 2018 Jan 8.

From the Inserm, Bordeaux Population Health Research Center (M-G.D., C.T., M.S., A.S., S.S., G. C., S.D.) and Institut des Maladies Neurodégénératives, CNRS-CEA UMR 5293 (B.M.), University of Bordeaux, France; Pole de santé publique (C.T.) and Department of Neurology (S.D.), Centre Hospitalier Universitaire de Bordeaux, France; Inserm U1167, Lille, France (P.A.); Department of Epidemiology and Public Health, Pasteur Institute of Lille, France (P.A.); Department of Public Health, Lille University Hospital, France (P.A.); Centre for Brain Research, Indian Institute of Science, Bangalore, India (G.C.); and Department of Neurology, Pekin Union Medical College Hospital, Beijing, China (Y.-C.Z.).

Background And Purpose: The genetic contribution to dilated perivascular space (dPVS) burden-an emerging MRI marker of cerebral small vessel disease-is unknown. We measured the heritability of dPVS burden and its shared heritability with other MRI markers of cerebral small vessel disease.

Methods: The study sample comprised 1597 participants from the population-based Three City (3C) Dijon Study, with brain MRI and genome-wide genotyping (mean age, 72.8±4.1 years; 61% women). dPVS burden and lacunar brain infarcts were rated on a semiquantitative scale, whereas an automated algorithm generated white matter hyperintensity volume (WMHV). We estimated dPVS burden heritability and shared heritability with WMHV and lacunar brain infarcts using the genome-wide complex trait analysis tool, on unrelated participants, adjusting for age, sex, intracranial volume, and principal components of population stratification.

Results: dPVS burden was significantly correlated with WMHV and lacunar brain infarcts, the strongest correlation being found between WMHV and dPVS in basal ganglia. Heritability estimates were h=0.59±0.24 (=0.007) for dPVS burden, h=0.54±0.24 (=0.010) for WMHV, and h=0.48±0.81 (=0.278) for lacunar brain infarcts. We found a nonsignificant trend toward shared heritability between dPVS and WMHV (r=0.41±0.28; =0.096), which seemed driven by dPVS in basal ganglia (r=0.72±0.61; =0.126) and not dPVS in white matter (r=-0.10±0.36; =0.393). A genetic risk score for WMHV based on published loci was associated with increased dPVS burden in basal ganglia (=0.031).

Conclusions: We provide evidence for important genetic contribution to dPVS burden in older community-dwelling people, some of which may be shared with WMHV. Differential heritability patterns for dPVS in white matter and basal ganglia suggest at least partly distinct underlying biological processes.
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http://dx.doi.org/10.1161/STROKEAHA.117.019309DOI Listing
February 2018

Differential associations of plasma lipids with incident dementia and dementia subtypes in the 3C Study: A longitudinal, population-based prospective cohort study.

PLoS Med 2017 Mar 28;14(3):e1002265. Epub 2017 Mar 28.

University of Bordeaux, Bordeaux, France.

Background: Vascular risk factors have been proposed as important targets for the prevention of dementia. As lipid fractions represent easily modifiable targets, we examined the longitudinal relationship of baseline lipid fractions with 13-y incident dementia and its subtypes (Alzheimer disease [AD] and mixed or vascular dementia) in older community-dwelling persons.

Methods And Findings: Non-institutionalized persons aged 65+ y (n = 9,294) were recruited for the Three-City Study (3C Study), a population-based cohort study from the electoral rolls of the cities of Dijon, Bordeaux, and Montpellier, France, between March 1999 and March 2001. Follow-up examinations were performed every 2 y after the baseline assessment. The final study sample comprised 7,470 participants from the 3C Study (mean age ± standard deviation [SD] 73.8 ± 5.3 y, 61.0% women) who were prospectively followed up for up to 13 y. Fasting lipid fractions (triglycerides [TGs], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC]) were studied as continuous variables, and results are reported per SD increase of each lipid fraction. Incident dementia and its subtypes were studied as censored variables using Cox models with age as time scale. Analyses were adjusted for sex, study center, and educational level, as well as vascular risk factors and apolipoprotein E (APOE) ε4 genotype. We corrected for multiple testing, yielding a significance threshold of 0.0169. p-Values above the significance threshold but less than 0.05 were considered nominally significant. During a mean (± SD) follow-up period of 7.9 ± 3.6 y, 779 participants developed incident dementia (n = 532 AD and n = 154 mixed or vascular dementia). Higher LDL-C and TC concentrations at baseline were associated with an increased risk of AD (hazard ratio [HR] per SD increase = 1.13 [95% CI 1.04-1.22], p = 0.0045, and HR = 1.12 [1.03-1.22], p = 0.0072, respectively). These associations were largely unchanged after adjustment for vascular risk factors and were attenuated after adjustment for APOEε4 (HR per SD increase = 1.12 [1.03-1.23], p = 0.0110, and HR = 1.12 [1.02-1.23], p = 0.0171, respectively). Higher TG concentrations at baseline were associated with an increased risk of all dementia (HR per SD increase = 1.11 [1.03-1.19], p = 0.0044) and mixed or vascular dementia (HR = 1.21 [1.04-1.41], p = 0.0163). However, these associations disappeared after adjusting for vascular risk factors (HR = 1.07 [0.98-1.17], p = 0.1374, and HR = 1.17 [0.96-1.42], p = 0.1206, respectively). Main limitations of the study include interval censoring of incident dementia cases, potential selective survival bias, and the fact that variation in lipid concentrations during follow-up could not be accounted for in the analyses.

Conclusions: In a large population-based sample of older community-dwelling persons with up to 13 y of follow-up, we observed that higher LDL-C and TC concentrations were associated with an increased risk of AD. This result was independent of vascular risk factors and was attenuated after adjustment for APOEε4 carrier status. TG and HDL-C concentrations were not associated with risk of incident dementia or its subtypes after accounting for vascular risk factors.
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http://dx.doi.org/10.1371/journal.pmed.1002265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369688PMC
March 2017

White Matter Lesion Progression: Genome-Wide Search for Genetic Influences.

Stroke 2015 Nov 8;46(11):3048-57. Epub 2015 Oct 8.

From the Department of Neurology (E.H., M.C., H.S., R.S.) and Institute for Medical Informatics, Statistics and Documentation (E.H.), Medical University of Graz, Graz, Austria; Cardiovascular Health Research Unit, Departments of Medicine (J.C.B., B.M.P.), Radiology (D.K.S.), and Neurology and Epidemiology (W.T.L.), University of Washington, Seattle; Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento (C.D.C., O.M.); Brown Foundation Institute of Molecular Medicine (M.F.) and Human Genetics Center (M.F.), University of Texas Health Science Center, Houston; Icelandic Heart Association, Kopavogur, Iceland (S.S., V.G., A.S.); Stroke and Ageing Research Group, Department of Medicine, Southern Clinical School, Monash University, Melbourne, Victoria, Australia (V.S., M.C., C.M., T.P., R.B.); Departments of Cardiology (S.T., J.W.J.), Gerontology and Geriatrics (S.T., A.J.M.C., R.G.J.W.), Molecular Epidemiology (P.E.S.), and Radiology (M.B.), Leiden University Medical Center, Leiden, The Netherlands; Departments of Epidemiology (B.F.J.V., H.H.H.A., C.M.D., A.H., M.W.V., M.A.I.), Radiology (B.F.J.V., H.H.H.A., M.W.V., M.A.I.), and Medical Informatics (W.J.N.), Erasmus Medical Center, Rotterdam, The Netherlands; INSERM U897 (C.W., G.C., C.D., S.S., S.D.), CNRS-CEA UMR5296 (B.M.), and INSERM U708 (C.T.), Université Bordeaux Segalen, Bordeaux, France; Department of Statistical Genetics, Max Planck Institute of Psychiatry, Munich, Germany (C.W.); Department of Biostatistics, Boston University School of Public Health, MA (Q.Y., A.B., J.W.); INSERM U744, Pasteur Institute, Lille, France (P.A.); Department of Pharmacology and Therapeutics, University College Cork, Cork, Ireland (B.M.B.); INSERM U1161 and Lariboisière Hospital, Paris 7 University, Paris, France (G.C., S.S., S.D.); Centre for Medical Systems Biology, Leiden, The Netherlands (C.M.D.); Robertson Center for Biostatistics, University of Glasgow, Glasgow, United Kingdom (I.F

Background And Purpose: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

Methods: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.

Results: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.

Conclusions: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.
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http://dx.doi.org/10.1161/STROKEAHA.115.009252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749149PMC
November 2015

Epidemiology, pathophysiology, diagnosis, and management of intracranial artery dissection.

Lancet Neurol 2015 Jun;14(6):640-54

Department of Neurosurgery, Showa University, Tokyo, Japan.

Spontaneous intracranial artery dissection is an uncommon and probably underdiagnosed cause of stroke that is defined by the occurrence of a haematoma in the wall of an intracranial artery. Patients can present with headache, ischaemic stroke, subarachnoid haemorrhage, or symptoms associated with mass effect, mostly on the brainstem. Although intracranial artery dissection is less common than cervical artery dissection in adults of European ethnic origin, intracranial artery dissection is reportedly more common in children and in Asian populations. Risk factors and mechanisms are poorly understood, and diagnosis is challenging because characteristic imaging features can be difficult to detect in view of the small size of intracranial arteries. Therefore, multimodal follow-up imaging is often needed to confirm the diagnosis. Treatment of intracranial artery dissections is empirical in the absence of data from randomised controlled trials. Most patients with subarachnoid haemorrhage undergo surgical or endovascular treatment to prevent rebleeding, whereas patients with intracranial artery dissection and cerebral ischaemia are treated with antithrombotics. Prognosis seems worse in patients with subarachnoid haemorrhage than in those without.
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http://dx.doi.org/10.1016/S1474-4422(15)00009-5DOI Listing
June 2015

Familial occurrence and heritable connective tissue disorders in cervical artery dissection.

Neurology 2014 Nov 29;83(22):2023-31. Epub 2014 Oct 29.

Authors' affiliations are listed at the end of the article.

Objective: In a large series of patients with cervical artery dissection (CeAD), a major cause of ischemic stroke in young and middle-aged adults, we aimed to examine frequencies and correlates of family history of CeAD and of inherited connective tissue disorders.

Methods: We combined data from 2 large international multicenter cohorts of consecutive patients with CeAD in 23 neurologic departments participating in the CADISP-plus consortium, following a standardized protocol. Frequency of reported family history of CeAD and of inherited connective tissue disorders was assessed. Putative risk factors, baseline features, and 3-month outcome were compared between groups.

Results: Among 1,934 consecutive patients with CeAD, 20 patients (1.0%, 95% confidence interval: 0.6%-1.5%) from 17 families (0.9%, 0.5%-1.3%) had a family history of CeAD. Family history of CeAD was significantly more frequent in patients with carotid location of the dissection and elevated cholesterol levels. Two patients without a family history of CeAD had vascular Ehlers-Danlos syndrome with a mutation in COL3A1. This diagnosis was suspected in 2 additional patients, but COL3A1 sequencing was negative. Two patients were diagnosed with classic and hypermobile Ehlers-Danlos syndrome, one patient with Marfan syndrome, and one with osteogenesis imperfecta, based on clinical criteria only.

Conclusions: In this largest series of patients with CeAD to date, family history of symptomatic CeAD was rare and inherited connective tissue disorders seemed exceptional. This finding supports the notion that CeAD is a multifactorial disease in the vast majority of cases.
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http://dx.doi.org/10.1212/WNL.0000000000001027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248448PMC
November 2014

Plasma lipids and cerebral small vessel disease.

Neurology 2014 Nov 15;83(20):1844-52. Epub 2014 Oct 15.

From the University of Bordeaux Ségalen (S.S., C.T., C.D., Y.Z., A.A., S.D.), INSERM U897 Neuroepidemiology, Bordeaux, France; Pekin Union Medical College Hospital (Y.Z.), China; Inserm U1061(C.B.), Montpellier; University Montpellier I (C.B.); University Pierre et Marie Curie-Paris 6 (A.A.); CNRS-CEA UMR5296 (F.C., B.M.), Université Bordeaux Segalen, Bordeaux; University of Versailles Saint-Quentin-en-Yvelines (S.D.); Department of Neurology (S.D.), Lariboisière Hospital, Paris; INSERM UMR S-1161 (S.D.), Paris 7 University, France; Department of Neurology (S.D.), Bordeaux University Hospital, Bordeaux; and Department of Neurology (S.D.), Boston University School of Medicine, Framingham Heart Study, Boston, MA.

Objectives: We examined the cross-sectional association between lipid fractions and 2 MRI markers of cerebral small vessel disease, white matter hyperintensity volume (WMHV) and lacunes, representing powerful predictors of stroke and dementia.

Methods: The study sample comprised 2,608 participants from the 3C-Dijon Study (n = 1,842) and the Epidemiology of Vascular Aging Study (EVA) (n = 766), 2 large French population-based cohorts (72.8 ± 4.1 and 68.9 ± 3.0 years; 60.1% and 58.4% women, respectively). Analyses were performed separately in each study and combined using inverse variance meta-analysis. Lipid fractions (triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol) were studied as continuous variables. WMHV was studied both in a continuous and dichotomous manner, the latter reflecting the age-specific top quartile of WMHV (EXT-WMHV). Analyses were adjusted for age and sex.

Results: Increasing triglycerides were associated with larger WMHV in the 3C-Dijon Study (β ± SE = 0.0882 ± 0.0302, p = 0.0035), in the EVA Study (β ± SE = 0.1062 ± 0.0461, p = 0.021), and in the combined analysis (β ± SE = 0.0936 ± 0.0252, p = 0.0002) and with higher frequency of lacunes in the 3C-Dijon Study (odds ratio [OR] = 1.65 [95% confidence interval 1.10-2.48], p = 0.015), in the EVA Study (OR = 1.58 [95% confidence interval 0.93-2.70], p = 0.09), and in the combined analysis (OR = 1.63 [95% confidence interval 1.18-2.25], p = 0.003). Associations were attenuated but maintained after adjusting for other vascular risk factors or for inflammatory markers. Associations were present and in the same direction both in participants taking and those not taking lipid-lowering drugs but tended to be stronger in the former for EXT-WMHV. Increasing low-density lipoprotein cholesterol tended to be associated with a decreased frequency and severity of all MRI markers of cerebral small vessel disease in both studies.

Conclusions: Increasing triglycerides but not other lipid fractions were associated with MRI markers of cerebral small vessel disease in older community persons.
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http://dx.doi.org/10.1212/WNL.0000000000000980DOI Listing
November 2014

Abdominal obesity and lower gray matter volume: a Mendelian randomization study.

Neurobiol Aging 2014 Feb 31;35(2):378-86. Epub 2013 Aug 31.

INSERM, Neuroepidemiology U708, Paris and Bordeaux, France; Department of Epidemiology, University of Versailles Saint-Quentin-en-Yvelines, Garches, France; Department of Neurology, Boston University School of Medicine, Boston, MA, USA; Department of Neurology, Lariboisière Hospital, Paris 7 University, Paris, France. Electronic address:

We investigated the relationship of anthropometric markers of obesity with quantitative magnetic resonance imaging markers of brain aging, including measures of total brain volume (TBV), gray matter volume (GMV), hippocampal volume, white matter hyperintensity volume (WMHV), and brain infarcts, and examined causality using Mendelian randomization (MR). Analyses were performed in 1779 individuals (60.4% women, 72.8 ± 4.1 years of age) from the 3C-Dijon population-based cohort study (N = 1555 for the MR). Larger waist-to-hip-ratio (WHR) and waist circumference (WC) were associated with lower TBV (p = 0.0001 and p = 0.005), and lower GMV (p = 0.0008 and p = 0.003), independently of age, gender, body mass index (BMI), and vascular risk factors. Higher BMI, WC, and WHR were associated with larger WMHV and WC with brain infarcts, before adjusting for vascular risk factors only. We used MR to investigate the inverse relationship between WHR and GMV. One valid instrumental variable was available in women only (rs6905288), which was associated with GMV (p = 0.015). Age and BMI-adjusted effect estimates from the MR analysis confirmed the inverse association between GMV and WHR and are in favor of a causal association.
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http://dx.doi.org/10.1016/j.neurobiolaging.2013.07.022DOI Listing
February 2014

APOE genotype and MRI markers of cerebrovascular disease: systematic review and meta-analysis.

Neurology 2013 Jul;81(3):292-300

Department of Epidemiology, Raymond Poincaré Hospital, University of Versailles St Quentin en Yvelines, Versailles, France.

Objective: We aimed to examine the association of APOE ε genotype with MRI markers of cerebrovascular disease (CVD): white matter hyperintensities, brain infarcts, and cerebral microbleeds.

Methods: We performed a systematic review and meta-analysis of 42 cross-sectional or longitudinal studies identified in PubMed from 1966 to June 2012 (n = 29,965). This included unpublished data from 3 population-based studies: 3C-Dijon, Framingham Heart Study, and Sydney Memory and Ageing Study. When necessary, authors were contacted to provide effect estimates for the meta-analysis.

Results: APOE ε4 carrier status and APOE ε44 genotype were associated with increasing white matter hyperintensity burden (sample size-weighted z score meta-analysis [meta]-p = 0.0034 and 0.0030) and presence of cerebral microbleeds (meta odds ratio [OR] = 1.24, 95% confidence interval [CI] [1.07, 1.43], p = 0.004, and 1.87 [1.26, 2.78], p = 0.002), especially lobar. APOE ε2 carrier status was associated with increasing white matter hyperintensity load (z score meta-p = 0.00053) and risk of brain infarct (meta OR = 1.41[1.09, 1.81], p = 0.008).

Conclusions: APOE ε4 and APOE ε2 were associated with increasing burden in MRI markers for both hemorrhagic and ischemic CVD. While the association of APOE ε4 with an increased burden of CVD could be partly contributing to the relationship between APOE ε4 and AD, APOE ε2 was associated with MRI markers of CVD in the opposite direction compared to AD.
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http://dx.doi.org/10.1212/WNL.0b013e31829bfda4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770168PMC
July 2013

Large-vessel correlates of cerebral small-vessel disease.

Neurology 2013 Feb 23;80(7):662-9. Epub 2013 Jan 23.

Inserm U708, Neuroepidemiology, Paris, France.

Objective: Our aim was to investigate the relationship of carotid structure and function with MRI markers of cerebral ischemic small-vessel disease.

Methods: The study comprised 1,800 participants (aged 72.5 ± 4.1 years, 59.4% women) from the 3C-Dijon Study, a population-based, prospective cohort study, who had undergone quantitative brain MRI and carotid ultrasound. We used multivariable logistic and linear regression adjusted for age, sex, and vascular risk factors.

Results: Presence of carotid plaque and increasing carotid lumen diameter (but not common carotid artery intima-media thickness) were associated with higher prevalence of lacunar infarcts: odds ratio (OR) = 1.60 (95% confidence interval [CI]: 1.09-2.35), p = 0.02 and OR = 1.24 (95% CI: 1.02-1.50), p = 0.03 (by SD increase). Carotid plaque was also associated with large white matter hyperintensity volume (WMHV) (age-specific top quartile of WMHV distribution): OR = 1.32 (95% CI: 1.04-1.67), p = 0.02, independently of vascular risk factors. Increasing Young elastic modulus and higher circumferential wall stress, reflecting augmented carotid stiffness, were associated with increasing WMHV (effect estimate [β] ± standard error: 0.0003 ± 0.0001, p = 0.024; β ± standard error: 0.005 ± 0.002, p = 0.008). Large WMHV was also associated with increasing Young elastic modulus (OR = 1.22 [95% CI: 1.04-1.42], p = 0.01) and with decreasing distensibility coefficient (OR = 0.83 [95% CI: 0.69-0.99], p = 0.04), independently of vascular risk factors. Associations of carotid lumen diameter with lacunar infarcts and of carotid stiffness markers with WMHV were independent of carotid plaque.

Conclusions: In addition to and independently of carotid plaque, increasing carotid lumen diameter and markers of carotid stiffness were associated with increasing prevalence of lacunar infarcts and increasing WMHV, respectively.
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http://dx.doi.org/10.1212/WNL.0b013e318281ccc2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590057PMC
February 2013