Volume of white matter hyperintensities in healthy adults: contribution of age, vascular risk factors, and inflammation-related genetic variants

Abstract

Aging is associated with appearance of white matter hyperintensities (WMH) on MRI scans. Vascular risk and inflammation, which increase with age, may contribute to white matter deterioration and proliferation of WMH. We investigated whether circulating biomarkers and genetic variants associated with elevated vascular risk and inflammation are associated with WMH volume in healthy adults (144 volunteers, 44-77 years of age). We examined association of WMH volume with age, sex, hypertension, circulating levels of total plasma homocysteine (tHcy), cholesterol (low-density lipoprotein), and C-reactive protein (CRP), and four polymorphisms related to vascular risk and inflammation: Apolipoprotein ε (ApoE ε2,3,4), Angiotensin-Converting Enzyme insertion/deletion (ACE I/D), methylenetetrahydrofolate reductase (MTHFR) C677T, C-reactive protein (CRP)-286C>A>T, and interleukin-1β (IL-1β) C-511T. We found that larger WMH volume was associated with advanced age, hypertension, and elevated levels of homocysteine and CRP but not with low-density lipoprotein levels. Homozygotes for IL-1β-511T allele and carriers of CRP-286T allele that are associated with increased inflammatory response had larger WMH than the other allelic combinations. Carriers of the APOE ε2 allele had larger frontal WMH than ε3 homozygotes and ε4 carriers did. Thus, in healthy adults, who are free of neurological and vascular disease, genetic variants that promote inflammation and elevated levels of vascular risk biomarkers can contribute to brain abnormalities. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

Copyright © 2011 Elsevier B.V. All rights reserved.

Figures

Figure 1

Volume of the white matter hyperintense regions in frontal, parietal, temporal and occipital lobes in carriers of the ancestral C allele and TT homozygotes of the single nucleotide polymorphism IL-1β C-511T. Bars are standard errors; stars indicate significant differences between the lobes.

Figure 2

Volume of frontal, parietal, temporal and occipital white matter hyperintensities grouped according to hypertension diagnosis and presence of CRP-286T allele that is associated with highest homocysteine levels. Bars are standard errors; stars indicate significant differences between the lobes.

Figure 3

Surface response plots of the tri-variate associations among age, plasma total homocysteine (log-transformed, μmol/l), and white matter hyperintensities volume (log-transformed, cm3) in four cerebral lobes (the response variable, color coded). Color temperature scale corresponds to the WMH volume: hotter colors reflect larger volumes.