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

Abstract

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.

Keywords: Alzheimer’s disease; FDG PET; cerebral brain metabolism; glutamate; riluzole.

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1 Neuroimaging measures for the study: FDG-PET (left) and 1H MRS (right).

[A(i)] Prespecified regions of interest, which were masked with each participant’s grey tissue segment. [A(ii)] Alzheimer’s disease progression classifier pattern, in which increasing progression scores reflect increasing expression of the pattern (subset shown) of hypometabolism (blue) and preservation (red) relative to whole brain. The progression scores of 517 test participants from amyloid negative cognitively normal status through amyloid-positive early mild cognitive impairment (EMCI), late MCI (LMCI) and Alzheimer’s dementia (AD) are shown, with mean and standard error, illustrating the correspondence between increased score and worsening clinical severity (data derived using FDG-PET scans from ADNI, www.adni-info.org, as described in Matthews et al.51). [B(i)] Axial, (ii) sagittal and (iii) coronal magnetic resonance images of a human brain, with depiction of the size and placement of the voxel of interest in the posterior cingulate cortex (PC). PC voxel dimensions: 2.0 cm (anterior–posterior) × 2.0 cm (left–right) × 2.0 cm (superior–inferior) or 8 cm3. [B(iv)] Sample CT-PRESS MRS data from the PC voxel, showing (a) an experimental spectrum with a clearly resolved C-4 glutamate (Glu) resonance at 2.35 ppm, as well as the resonances for NAA, total creatine (tCr), total choline (tCho) and combined resonances of C-2 glutamate and C-2 glutamine (Glx); (b) model fitting of spectrum in a to obtain the metabolite peak areas of interest; (c) individual components of the model-fitted spectrum in a; (d) residuals of the difference between spectra in a and in b.

Figure 2

Enrolment, randomization and trial completion.

Figure 3 Comparison of changes in FDG-PET in PC over 6 months.

(A) PC region of interest (representative sagittal slice) in FDG-PET. (B) Comparison between placebo and riluzole-treated arms of the absolute and percentage change in PC FDG SUVR over the 6-month treatment period. (C) Individual change from baseline to follow up in PC SUVR in placebo (left) and riluzole (right) treated arms. (D) Comparison of change in PC SUVR by APOE ɛ4 carrier and non-carrier subgroups, and by younger and older age groups. Individual values are shown with mean and standard error bars.

Figure 4 Comparison of changes in FDG-PET in prespecified regions of interest over 6 months.

(A) Region of interest boundaries shown in representative slices, colour-coded to indicate the significance levels in comparisons between placebo and riluzole-treated arms of the 6 month change in FDG SUVR. (B) Comparison between placebo and riluzole-treated arms of the 6 month change in FDG SUVR for posterior cingulate (PC = PostCing), combined PC and precuneus (PCC), lateral temporal (LatTemp), right hippocampus (Hip), orbitofrontal (OrbFrontal), frontal, parietal and subcortical white matter (as a comparator, expected to remain stable). For each region, data-points are shown for the placebo group on the left and for the riluzole-treated group on the right. Individual values are shown with mean and standard error bars.

Figure 5 Comparison of FDG-PET progression score changes over 6 months.

(A) Comparison between placebo and riluzole-treated arms of the change in FDG progression score. (B) Correlation between Alzheimer’s disease progression score at baseline and ADAS-cog score at baseline (left) and between the 6-month change in Alzheimer’s disease progression score and in ADAS-cog (right) for all study participants.

Figure 6

Correlations between FDG-PET measures and cognitive performance. Correlations at baseline between: (A) FDG Alzheimer’s disease progression score and MMSE score; (B) posterior cingulate-precuneus (PCC) score and MMSE score; (C) lateral temporal FDG SUVR and ADAS-cog score; and (D) orbitofrontal FDG SUVR and NPI score.

Figure 7 Comparison of changes in 1H MRS measures.

(A) 1H MRS measures of Glu/W (top) and Glu/tCr (bottom) levels changes in PC at baseline, 3 and 6 months. (B) Correlations at baseline, midpoint and end point between NAA/W and Glu/W in riluzole and placebo groups (top) and NAA/tCr and Glu/tCr in riluzole and placebo groups (bottom). (C) Correlations at baseline between Glu/W and MMSE (top) and Glu/W and ADAS-cog (bottom) across participants.