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

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.

Risk factors associated with abnormal cognition in Japanese outpatients with diabetes, hypertension or dyslipidemia

“…Moreover, pioglitazone prevented the accumulation of amyloid-b by increasing cerebral blood flow in patients with diabetes and Alzheimer's disease, which resulted in a significant improvement in MMSE scores [27]. Effective prevention of dementia onset by improvement in insulin resistance has been reported in several studies [28,29]. These studies may support our finding that pioglitazone was associated with a reduced risk of abnormal cognition by 50 %.…”

Evaluation of a Calibrated 18F-FDG PET Score as a Biomarker for Progression in Alzheimer Disease and Mild Cognitive Impairment

“…Typically these were short trials of a few weeks or up to 3 mo active treatment duration with 18 F-FDG PET before and during treatment (20)(21)(22). Trials that were extended for at least 6 mo also showed evidence of disease progression by further reduction of glucose metabolism in association cortices (23)(24)(25)(26). However, these trials had not been designed to assess progression.…”

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research

“…In a small number of AD non-diabetic patients, 18-month treatment with pioglitazone (45 mg/day) as add-on therapy to the AChE inhibitors produced no significant treatment effect on cognition (Geldmacher et al 2011). Regardless the APOE status, no evidence of statistically or clinically significant efficacy in cognition or global function was detected for 2 mg or 8 mg rosiglitazone-extended release formulation (PPAR γ agonist) as adjunctive therapy to ongoing AChEIs in the two clinical phase III studies on AD patients (Harrington et al 2010;Tzimopoulou et al 2010). …”