Objective White matter hyperintensities (WMH) detectable by magnetic resonance imaging (MRI)are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMH are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified. Methods We performed a meta-analysis of genome-wide association studies (GWAS) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts. Results We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs)in one locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (Pdiscovery= 4.0×10−9; Preplication =1.3×10−7; Pcombined =4.0×10−15). Other SNPs in this region also reaching genome-wide significance are rs9894383 (P=5.3×10−9), rs11869977 (P=5.7×10−9), rs936393 (P=6.8×10−9), rs3744017 (P=7.3×10−9), and rs1055129 (P=4.1×10−8). Variant alleles at these loci conferred a small increase in WMH burden (4–8% of the overall mean WMH burden in the sample). Interpretation This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
Background and Purpose— It is unknown whether white matter lesions (WML) develop abruptly in previously normal brain areas, or whether tissue changes are already present before WML become apparent on MRI. We therefore investigated whether development of WML is preceded by quantifiable changes in normal-appearing white matter (NAWM). Methods— In 689 participants from the general population (mean age 67 years), we performed 2 MRI scans (including diffusion tensor imaging and Fluid Attenuation Inversion Recovery [FLAIR] sequences) 3.5 years apart using the same 1.5-T scanner. Using automated tissue segmentation, we identified NAWM at baseline. We assessed which NAWM regions converted into WML during follow-up and differentiated new WML into regions of WML growth and de novo WML. Fractional anisotropy, mean diffusivity, and FLAIR intensity of regions converting to WML and regions of persistent NAWM were compared using 3 approaches: a whole-brain analysis, a regionally matched approach, and a voxel-wise approach. Results— All 3 approaches showed that low fractional anisotropy, high mean diffusivity, and relatively high FLAIR intensity at baseline were associated with WML development during follow-up. Compared with persistent NAWM regions, NAWM regions converting to WML had significantly lower fractional anisotropy (0.337 vs 0.387; P <0.001), higher mean diffusivity (0.910×10 –3 mm 2 /s vs 0.729×10 –3 mm 2 /s; P <0.001), and relatively higher normalized FLAIR intensity (1.233 vs –0.340; P <0.001). This applied to both NAWM developing into growing and de novo WML. Conclusions— White matter changes in NAWM are present and can be quantified on diffusion tensor imaging and FLAIR before WML develop. This suggests that WML develop gradually, and that visually appreciable WML are only the tip of the iceberg of white matter pathology.
C erebral white matter lesions (WMLs) are highly prevalent in the elderly population and increase the risk of dementia and stroke.1 Although believed to be vascular in origin, the exact etiology of WMLs is still unknown. On the basis of pathological and epidemiological studies, blood pressure is considered to be one of the most important factors by damaging the cerebral small vessels.2,3 Because blood pressure is modifiable, blood pressure control seems an important candidate for the prevention of WML progression.The earliest studies demonstrating an association between high blood pressure and WMLs were cross-sectional by design, which limits causal inferences. [4][5][6][7][8][9][10][11][12][13] More recently, studies have used longitudinal designs and found similar results.14-23 Yet, because WML progression is strongly influenced by the WML load at baseline, 15 it is unknown to what extent associations of blood pressure with WML progression are affected by the baseline WML load. Moreover, to provide stronger evidence for a temporal relationship, blood pressure should preferably be measured before the window in which WML progression is determined, instead of during this window. In addition, the use of different MRI scanners or scanning protocols when measuring WML progression can possibly lead to systematic biases. Previous studies have addressed 1 or 2 of these issues, but none of them addressed all.It is also unknown whether the associations between blood pressure and WML progression are present for systolic, diastolic, and pulse pressure. Moreover, the influence of medication use and control of hypertension on WML progression remains unclear. We hypothesized that blood pressure would relate to WML progression even when taking baseline WML load into account and that medication use and adequate control of hypertension would reduce this progression.We tested this hypothesis in a population-based longitudinal MRI study in which we measured systolic, diastolic, and pulse pressure before MRI scanning; evaluated the influence of the WML load at baseline; and used exactly the same scanners and scanning protocol at baseline and follow-up.Abstract-High blood pressure is considered an important risk factor for cerebral white matter lesions (WMLs) in the aging population. In a longitudinal population-based study of 665 nondemented persons, we investigated the longitudinal relationship of systolic blood pressure, diastolic blood pressure, and pulse pressure with annual progression of WMLs.Means of blood pressure were calculated over a 5-year period before longitudinal MRI scanning. WML progression was subsequently measured on 2 scans 3.5 years apart. We performed analyses with linear regression models and evaluated adjustments for age, sex, cardiovascular risk factors, and baseline WML volume. In addition, we evaluated whether treatment of hypertension is related to less WML progression. Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.