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Inflammatory biomarkers are associated with total brain volume

The Framingham Heart Study

From the Departments of Neurology (A.L.J., P.A.W., S.S., R.A.) and Preventive Medicine (R.S.V., E.J.B.), Whitaker Cardiovascular Institute (R.S.V., J.F.K., I.L., E.J.B.), Boston University School of Medicine; National Heart, Lung and Blood Institute's Framingham Heart Study (J.M.M., P.A.W., S.S., R.A., R.S.V., M.G.L., S.K., E.J.B.), Framingham, MA; Department of Biostatistics (J.M.M.), Boston University School of Public Health; Department of Mathematics and Statistics (M.G.L.), Boston University; General Medical Division (J.B.M.) and Cardiovascular Disease Prevention Center (S.K.), Massachusetts General Hospital and Harvard Medical School, Boston, MA; and Department of Neurology, Center for Neuroscience, and Imaging of Dementia and Aging Laboratory (C.D.), University of California at Davis.

Address correspondence and reprint requests to Dr. Angela L. Jefferson, Department of Neurology, Boston University School of Medicine, 715 Albany Street, B-7800, Boston, MA 02118; e-mail: angelaj{at}bu.edu

Background: Systemic inflammation is associated with ischemia and Alzheimer disease (AD). We hypothesized that inflammatory biomarkers would be associated with neuroimaging markers of ischemia (i.e., white matter hyperintensities [WMH]) and AD (i.e., total brain volume [TCB]).

Methods: MRI WMH and TCB were quantified on 1,926 Framingham Offspring participants free from clinical stroke, TIA, or dementia (mean age 60 ± 9 years; range 35 to 85 years; 54% women) who underwent measurement of a circulating inflammatory marker panel, including CD40 ligand, C-reactive protein, interleukin-6 (IL-6), soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, myeloperoxidase, osteoprotegerin (OPG), P-selectin, tumor necrosis factor-alpha (TNF), and tumor necrosis factor receptor II. To account for head size, both TCB (TCBV) and WMH (WMH/TCV) were divided by total cranial volume. We used multivariable linear regression to relate 10 log-transformed inflammatory biomarkers to brain MRI measures.

Results: In multivariable models, inflammatory markers as a group were associated with TCBV (p < 0.0001) but not WMH/TCV (p = 0.28). In stepwise models adjusted for clinical covariates with backwards elimination of markers, IL-6 and OPG were inversely associated with TCBV; TNF was inversely related to TCBV in a subset of 1,430 participants. Findings were similar in analyses excluding individuals with prevalent cardiovascular disease. The relations between TCBV and inflammatory markers were modified by both sex and age, and generally were more pronounced in men and in older individuals.

Conclusions: Although our observational cross-sectional data cannot establish causality, they are consistent with the hypothesis that higher inflammatory markers are associated with greater atrophy than expected for age.

*These authors contributed equally to the article.

Supported by the NHLBI's Framingham Heart Study N01-HC-25195; AG022773 and HD043444 (A.L.J.); AG08122, NS017950, and AG16495 (P.A.W.); HL004334, HL067288, HL077447, and HV28178 (R.S.V.); HL081587, HL067266, and AG027081 (J.F.K.); an American Diabetes Association Career Development Award and NCRR GCRC M01-RR-01066 (J.B.M.); Doris Duke Charitable Foundation and HL083102 (S.K.); HL064753, HL076784, and AG028321 (E.J.B.); and AG021028 and AG010129 (C.D.).

Disclosure: The authors report no conflicts of interest.

Received May 1, 2006. Accepted in final form November 27, 2006

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