Risk factors for progression of brain atrophy in aging
Six-year follow-up of normal subjects
C. Enzinger, MD,
F. Fazekas, MD,
P. M. Matthews, MD, DPhil, FRCP,
S. Ropele, PhD,
H. Schmidt, MD,
S. Smith, DPhil and
R. Schmidt, MD
From the Departments of Neurology (Drs. Enzinger, Fazekas, Ropele, and R. Schmidt) and Radiology, Section of Neuroradiology (Dr. Fazekas), MR Research Unit (Dr. Ropele), and the Institute of Medical Biochemistry and Molecular Genetics (Dr. H. Schmidt), Medical University of Graz, Austria; and the Centre for Functional MRI of the Brain (Drs. Matthews and Smith), John Radcliffe Hospital, University of Oxford, UK.
Address correspondence and reprint requests to Dr. Christian Enzinger, Department of Neurology, Medical University Graz, Auenbruggerplatz 22, A-8036 Graz, Austria; e-mail: chris.enzinger{at}meduni-graz.at
Objectives: To determine the rate of brain atrophy in neurologicallyasymptomatic elderly and to investigate the impact of baselinevariables including conventional cerebrovascular risk factors,APOE4, and white matter hyperintensity (WMH) on its progression.
Methods: We assessed the brain parenchymal fraction at baselineand subsequent annual brain volume changes over 6 years for201 participants (F/M = 96/105; 59.8 ± 5.9 years) inthe Austrian Stroke Prevention Study from 1.5-T MRI scans usingSIENA (structural image evaluation using normalization of atrophy)/SIENAX(an adaptation of SIENA for cross-sectional measurement)(www.fmrib.ox.ac.uk/fsl).Hypertension, cardiac disease, diabetes mellitus, smoking, andregular alcohol intake were present in 64 (31.8%), 60 (29.9%),5 (2.5%), 70 (39.3%), and 40 (20.7%) subjects, respectively.Plasma levels of fasting glucose (93.7 ± 18.6 mg/dL),glycated hemoglobin A (HbA1c; 5.6 ± 0.7%), total cholesterol(228.3 ± 40.3 mg/dL), and triglycerides (127.0 ±75.2 mg/dL) were determined. WMH was rated as absent (n = 56),punctate (n = 120), early confluent (n = 14), and confluent(n = 11).
Results: The baseline brain parenchymal fraction of the entirecohort was 0.80 ± 0.02 with a mean annual brain volumechange of –0.40 ± 0.29%. Univariate analysis demonstrateda higher rate of brain atrophy in older subjects (p = 0.0001),in those with higher HbA1c (p = 0.0001), higher body mass index(p = 0.02), high alcohol intake (p = 0.04), severe WMH (p =0.03), and in APOE4 carriers (p = 0.07). Multivariate analysissuggested that baseline brain parenchymal fraction, HbA1c, andWMH score explain a major proportion of variance in the ratesof brain atrophy in the cohort (corrected R2 = 0.27; p = 0.0001).
Conclusions: Neurologically asymptomatic elderly experiencecontinuing brain volume loss, which appears to accelerate withage. Glycated hemoglobin A (HbA1c) was identified as a riskfactor for a greater rate of brain atrophy. Clustering of factorsassociated with the so-called metabolic syndrome in subjectswith high HbA1c suggests a link between this syndrome and late-lifebrain tissue loss.
Supported by grants P15158 (S.R.), P13180, and J2373-B02 (C.E.)from the FWF Austrian Science Fund (Vienna), and by the AustrianNational Bank Jubilaeumsfonds (projects 3905, 4484, and 7776).P.M.M. acknowledges support from the MS Society of Great Britainand Northern Ireland and the MRC. S.S. is supported by an ERSRCAdvanced Research Fellowship. The sponsors of the study hadno role in study design, data collection, data analysis, datainterpretation, or writing of the report.
Presented in part at the 56th Annual Meeting of the AmericanAcademy of Neurology, San Francisco, CA, April 2004, and atthe 14th Meeting of the European Neurological Society, Barcelona,Spain, June 2004.
Received August 13, 2004. Accepted in final form February 8,2005.
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4, and white matter hyperintensity (WMH) on its progression. 
