Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Original Research Article Dement Geriatr Cogn Disord 2011;31:341–348 DOI: 10.1159/000328118 Elevated Plasma Homocysteine Is Associated with Increased Brain Atrophy Rates in Older Subjects with Mild Hypertension Sunil K. Narayan   a Michael J. Firbank   a Brian K. Saxby   c Gerard Stansby   b Monica Hansrani   b John T. O’Brien   a Gary A. Ford   a   a  Institute for Ageing and Health, Newcastle University, b  Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, and c  Cognitive Drug Research Ltd, Goring on Thames, UK dementia, associations with both Alzheimer’s disease and vascular dementia have been shown [2, 3]. Subclinical ce- rebral pathologies which have been found to precede these clinical conditions, such as white matter lesions (WMLs) [4] and silent brain infarcts (SBIs) [5] have been associated with hyperhomocysteinaemia. While several cross-sectional studies demonstrate a significant associa- tion between homocysteine and reduced brain volumes in elderly populations [6, 7], it remains unknown wheth- er homocysteine directly determines the rate of brain at- rophy, and if so, through what mechanism. WMLs are often seen on brain magnetic resonance imaging (MRI) in healthy elderly subjects and are associated with cogni- tive decline and dementia. WMLs are also associated with cardiovascular risk factors [8]. SBIs are also fre- quently seen on brain MRI in the otherwise healthy el- derly and are associated with an increased risk of stroke, cognitive decline and dementia, as well as with several cardiovascular risk factors such as hypertension and dia- betes [5]. Elevated homocysteine is associated with the presence of SBI [5], but it is not clear if it is an independent risk factor for SBI. Folate and B12 concentrations are in- versely related to homocysteine levels due to the role these vitamins play in homocysteine metabolism. An indepen- dent association of vitamin B12 concentrations with cog- nitive decline, dementia [9] and brain atrophy has been reported [10]. It remains unclear whether the association Key Words Homocysteine  Folate  B12  Brain atrophy  White matter lesions  Hypertension Abstract We determined using serial MR imaging whether raised plas- ma homocysteine levels are associated with increased brain atrophy, white matter lesion (WML) progression or incidence of silent brain infarcts (SBIs) in older hypertensive subjects. Brain atrophy rates (0.58 8 0.48% per year, mean 8 SD) were significantly correlated with homocysteine (  = 0.46, p = 0.001 homocysteine;  = 0.44, p = 0.007 homocysteine/fo- late/B12 models) but not with folate or B12 levels. Progres- sion of WML (0.08 8 0.16%) was not associated with homo- cysteine level (B = 0.01, p = 0.29). New SBIs were uncommon. In older hypertensive individuals, plasma homocysteine lev- els are associated with increased rates of whole-brain atro- phy but not WML progression. Copyright © 2011 S. Karger AG, Basel Introduction Elevated homocysteine concentrations have been as- sociated with stroke, dementia, cognitive decline [1] and depression in several case-control and cohort studies. In Accepted: April 4, 2011 Published online: May 18, 2011 Prof. G.A. Ford Level 6 Leazes Wing Royal Victoria Infirmary Newcastle upon Tyne NE1 4LP (UK) Tel. +44 191 222 7744, E-Mail g.a.ford  @  ncl.ac.uk © 2011 S. Karger AG, Basel 1420–8008/11/0315–0341$38.00/0 Accessible online at: www.karger.com/dem