Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer's disease.

Dysregulation of glutamatergic neural circuits has been implicated in a cycle of toxicity, believed among the neurobiological underpinning of Alzheimer's disease. Previously, we reported preclinical evidence that the glutamate modulator riluzole, which is FDA-approved for the treatment of amyotrophic lateral sclerosis, has potential benefits on cognition, structural and molecular markers of aging and Alzheimer's disease. The objective of this study was to evaluate in a pilot clinical trial, using neuroimaging biomarkers, the potential efficacy and safety of riluzole in patients with Alzheimer's disease as compared to placebo. A 6-month phase 2 double-blind, randomized, placebo-controlled study was conducted at two sites. Participants consisted of males and females, 50 to 95 years of age, with a clinical diagnosis of probable Alzheimer's disease, and Mini-Mental State Examination between 19 and 27. Ninety-four participants were screened, fifty subjects that met inclusion criteria were randomly assigned to receive 50 mg riluzole (n = 26) or placebo (n = 24) twice a day. Twenty-two riluzole-treated and 20 placebo participants completed the study. Primary endpoints were baseline to 6 months changes in a) cerebral glucose metabolism as measured with fluorodeoxyglucose-positron emission tomography in pre-specified regions of interest (hippocampus, posterior cingulate, precuneus, lateral temporal, inferior parietal, frontal) and b) changes in posterior cingulate levels of the neuronal viability marker N-acetylaspartate as measured with in vivo proton magnetic resonance spectroscopy. Secondary outcome measures were neuropsychological testing for correlation with neuroimaging biomarkers and in vivo measures of glutamate in posterior cingulate measured with magnetic resonance spectroscopy as a potential marker of target engagement. Measures of cerebral glucose metabolism, a well-established Alzheimer's disease biomarker and predictor of disease progression, declined significantly less in several pre-specified regions of interest with the most robust effect in posterior cingulate, and effects in precuneus, lateral temporal, right hippocampus and frontal cortex in riluzole-treated subjects in comparison to placebo group. No group effect was found in measures of N-acetylaspartate levels. A positive correlation was observed between cognitive measures and regional cerebral glucose metabolism. A group by visit interaction was observed in glutamate levels in posterior cingulate, potentially suggesting engagement of glutamatergic system by riluzole. In vivo glutamate levels positively correlated with cognitive performance. These findings support our main primary hypothesis that cerebral glucose metabolism would be better preserved in the riluzole treated group than in the placebo group and investigations in future larger and longer studies to test riluzole as a potential novel therapeutic intervention for Alzheimer's disease.