Riluzole, a Glutamate Modulator, Slows Cerebral Glucose Metabolism Decline in Patients With Alzheimer's Disease

Dawn C. Matthews; Xiangling Mao; Kathleen Dowd; Diamanto Tsakanikas; Caroline S. Jiang; Caroline Meuser; Randolph D. Andrews; Ana S. Lukic; Jihyun Lee; Nicholas Hampilos; Neeva Shafiian; Mary Sano; P. David Mozley; Howard Fillit; Bruce S. McEwen; Dikoma C. Shungu; Ana C. Pereira


Brain. 2022;144(12):3742-3755. 

In This Article

Abstract and Introduction


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 ageing 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, 50 participants who 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 end points were baseline to 6 months changes in (i) cerebral glucose metabolism as measured with fluorodeoxyglucose-PET in prespecified regions of interest (hippocampus, posterior cingulate, precuneus, lateral temporal, inferior parietal, frontal); and (ii) 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 prespecified 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 participants in comparison to the 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 × 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 provide a rationale for more powered, longer duration studies of riluzole as a potential intervention for Alzheimer's disease.


Alzheimer's disease is the most common neurodegenerative disorder, affecting over 43 million people worldwide with an enormous psychosocial and economic impact on society.[1] Without effective therapies and given a high rate of clinical trial failures, an urgent need remains to identify treatment strategies that can slow progression of Alzheimer's disease neurodegeneration. In this exploratory clinical trial, we evaluated the potential of riluzole, a glutamate modulator that exhibits neuroprotective properties and is approved for amyotrophic lateral sclerosis (ALS), to provide benefit in Alzheimer's disease.

Glutamatergic pyramidal neurons that furnish corticocortical connections between association cortical areas and the excitatory hippocampal connections that subserve memory and cognition are the most vulnerable to damage and loss in Alzheimer's disease.[2,3] The entorhinal cortex, an early site of tau accumulation, consists primarily of pyramidal cells that use glutamate as an excitatory neurotransmitter.[4] The hippocampal and neocortical atrophy characteristic of Alzheimer's disease progression demonstrate degeneration predominantly in large glutamatergic pyramidal neurons.[3,5,6] Glutamate-mediated toxicity has been implicated as one potential mechanism of neuronal loss in Alzheimer's disease.[7] Glutamate overflow to extrasynaptic space and activation of extrasynaptic N-methyl-D-aspartate (NMDA) receptors has been hypothesized to allow excessive sodium and calcium influx, degrading mitochondrial function and leading to apoptosis.[8] We have previously shown that downregulation of the major glutamate transporter EAAT2 (or GLT-1) accelerates age-related cognitive decline, and conditional heterozygous astrocytic EAAT2 knockout mice have dysregulated immune signalling that correlated with cognitive performance.[9] The neuropathophysiological hallmarks of Alzheimer's disease, amyloid-β plaques and neurofibrillary tangles formed of hyperphosphorylated tau, have been implicated in glutamatergic dysfunction. Neurofibrillary tangles tend to preferentially accumulate in excitatory pyramidal neurons.[10–12] Tau gene expression and phosphorylation are increased in the setting of glutamate toxicity[13,14] and tau release and propagation through interconnected neural circuits are dependent on neuronal activity.[15–17] Oligomers of amyloid-β disrupt glutamate transporters,[18] leading to spillover and activation of extrasynaptic NMDA receptors, implicated in glutamate-mediated toxicity and inhibition of long term potentiation.[19] Amyloid-β release is dependent on neuronal activity[20] and decreases surface expression of synaptic NMDA receptors,[21] critical for physiological neurotransmission. Glutamatergic dysregulation thus forms a cycle of toxicity in Alzheimer's disease. We have proposed that pharmacological modulation of glutamatergic neural circuits in Alzheimer's disease could diminish toxicity through one or more of these pathways, with the potential to preserve or increase neuronal function. Particularly relevant would be the protection of the pyramidal neurons that are most vulnerable in Alzheimer's disease, through reduced glutamate overflow to extrasynaptic space, reducing glutamate-mediated toxicity and potentially allowing increased synaptic activity.

Our group has previously shown that riluzole can prevent age-related cognitive decline in rodents through clustering of dendritic spines,[22] strengthening neural communication.[23,24] Furthermore, we have shown that riluzole rescues gene expression profiles related to ageing and Alzheimer's disease, and that the most affected pathways were related to neurotransmission and neuroplasticity.[25] More recently, we have demonstrated that riluzole prevented hippocampal-dependent spatial memory decline in an early-onset aggressive mouse model of Alzheimer's disease (5XFAD), reduced amyloid pathology and reversed many of the gene expression changes in immune pathways.[26] These reversals involved microglia-related genes[26] thought to be critical mediators of Alzheimer's disease pathophysiology,[27–29] including a recently identified unique population of disease-associated microglia.[30] Riluzole has also been reported to reduce total tau,[31] which in clinical studies correlates with glucose metabolism and cognition.[32] Riluzole has been demonstrated to modulate ion channels,[33,34] and to increase neurotrophic factors.[35,36]

Previous research suggests that riluzole-related improvements in astrocytic function and glutamate uptake may produce changes detectable with fluorodeoxyglucose (FDG) PET measurement of glucose metabolism and with magnetic resonance spectroscopy (1H MRS).[37] This may occur through increased activity of the main glutamate transporter in the brain, EAAT2 and glutamate uptake.[31,38–40] In rodent models, riluzole increases glutamate uptake by astrocytes and mitigates astrocytic dysfunction.[38] A tight coupling between glutamatergic activity and cerebral glucose metabolism with stoichiometry close to 1:1 has been demonstrated.[41] Glutamatergic transmission accounts for more than 80% of ATP generated from brain metabolism.[42] In one pathway, astrocytic uptake of glutamate released by neuronal synaptic activity leads to conversion of glucose to lactate by the astrocyte, which is transported to neurons and converted to pyruvate for ATP production.[43] Direct metabolism of glucose by neurons has been described and likewise supports the 1:1 relationship between increases in the glutamate–glutamine cycle and neuronal glucose oxidation.[44] In a 1H-13C MRS study conducted in rats, riluzole administration increased glutamate-C4, GABA-C2 and glutamine-C4 in hippocampus and prefrontal cortex, demonstrating increased glucose oxidative metabolism and glutamate/glutamine cycling between neurons and astroglia.[37]

In the current study, we aimed to translate preclinical findings to human Alzheimer's disease through a pilot phase 2 randomized, double-blind, placebo-controlled clinical trial of riluzole in patients with a diagnosis of mild Alzheimer's disease. We tested the hypotheses that (i) riluzole would mitigate the decline of regional cerebral glucose metabolism in Alzheimer's disease as measured with FDG-PET, a well-established biomarker in Alzheimer's disease; (ii) FDG-PET metabolic brain maps would correlate with cognitive measures; and (iii) riluzole would alter the neuronal viability marker, N-acetylaspartate (NAA), and glutamate levels as a marker of target engagement, both measured with 1H MRS.