A Multi-Center Randomized Proof-of-Concept Clinical Trial Applying [¹⁸F]FDG-PET for Evaluation of Metabolic Therapy with Rosiglitazone XR in Mild to Moderate Alzheimer's Disease

Article type: Research Article

Authors: Tzimopoulou, Sofia^a | Cunningham, Vincent J.^a | Nichols, Thomas E.^b | Searle, Graham^a | Bird, Nick P.^c | Mistry, Prafull^c | Dixon, Ian J.^c | Hallett, William A.^a | Whitcher, Brandon^a | Brown, Andrew P.^a | Zvartau-Hind, Marina^d | Lotay, Narinder^d | Lai, Robert Y. K.^e | Castiglia, Mary^f | Jeter, Barbara^f | Matthews, Julian C.^g | Chen, Kewei^{h; j; l} | Bandy, Dan^{h; l} | Reiman, Eric M.^{i; k; l} | Gold, Michael^f | Rabiner, Eugenii A.^{a; m} | Matthews, Paul M.^{a; m; *}

Affiliations: [a] GlaxoSmithKline Clinical Imaging Centre, Hammersmith Hospital, London, UK | [b] Department of Statistics & Warwick Manufacturing Group, University of Warwick, Coventry, UK | [c] GlaxoSmithKline Discovery Biometrics, Harlow, UK | [d] GlaxoSmithKline Neurosciences Medicine Development Centre, London, UK | [e] GlaxoSmithKline Neurosciences Discovery Medicine, Harlow, UK | [f] GlaxoSmithKline Neurosciences Medicine Development Centre, Research Triangle Park, NC, USA | [g] School of Cancer and Enabling Sciences, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK | [h] Banner Alzheimer's Institute and Positron Emission Tomography Centre, Banner Good Samaritan Medical Centre, Phoenix, AZ, USA | [i] Department of Psychiatry, University of Arizona, Phoenix, AZ, USA | [j] Department of Mathematics and Statistics, Arizona State University, Tempe, AZ, USA | [k] Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA | [l] Arizona Alzheimer's Consortium, Phoenix, AZ, USA | [m] Department of Clinical Neuroscience, Imperial College, London, UK

Correspondence: [*] Correspondence to: Professor P.M. Matthews, GSK Clinical Imaging Centre, Hammersmith Hospital, DuCane Road, London W12 0NN UK. Tel.: +44 208 008 6036; Fax: +44 208 008 6491; E-mail: [email protected].

Abstract: Here we report the first multi-center clinical trial in Alzheimer's disease (AD) using fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARγ agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Secondary objectives included testing for reduction in the progression of brain atrophy and improvement in cognition. Active treatment was associated with a sustained but not statistically significant trend from the first month for higher mean values in Kiindex and CMRgluindex, novel quantitative indices related to the combined forward rate constant for [18F]FDG uptake and to the rate of cerebral glucose utilization, respectively. However, neither these nor another analytical approach recently validated using data from the Alzheimer's Disease Neuroimaging Initiative indicated that active treatment decreased the progression of decline in brain glucose metabolism. Rates of brain atrophy were similar between active and placebo groups and measures of cognition also did not suggest clear group differences. Our study demonstrates the feasibility of using [18F]FDG-PET as part of a multi-center therapeutics trial. It suggests that Rosiglitazone is associated with an early increase in whole brain glucose metabolism, but not with any biological or clinical evidence for slowing progression over a 1 year follow up in the symptomatic stages of AD.

Keywords: ¹⁸F-FDG, Alzheimer's disease, analysis, dementia, PPARγ, rosiglitazone

DOI: 10.3233/JAD-2010-100939

Journal: Journal of Alzheimer's Disease, vol. 22, no. 4, pp. 1241-1256, 2010