Drug That Slows Progression of ALS May Provide the Same Benefit for People With Alzheimer’s

Summary: Riluzole, a drug commonly prescribed to slow the progression of ALS, appears to slow brain metabolic decline and improve cognitive performance in those with mild Alzheimer’s disease.

Source: ADDF

Riluzole, a drug that has been used for more than 20 years to slow the progression of ALS, commonly known as Lou Gehrig’s disease, was shown in a pilot phase 2 study to slow brain metabolic decline and have a positive effect on cognitive performance versus placebo in people with mild Alzheimer’s disease.

The study was pre-published in a recent online issue of the journal Brain.

The Alzheimer’s Drug Discovery Foundation (ADDF) provided funding and expertise to study investigators, helping to bring this research into phase 2 clinical testing.

“Using two types of brain scans as biomarkers—this study was able to measure improvements in brain metabolism among treated patients and correlate those improvements with cognitive changes and disease progression,” said study co-author Howard Fillit, M.D., ADDF’s Founding Executive Director and Chief Science Officer.

“Riluzole represents many of the ADDF’s research priorities. It is a repurposed drug, which helps speed the research process. It targets an important and understudied biological mechanism that goes awry with aging, and the rigorous design of this trial measured both biomarker and clinical outcomes.”

The trial randomly assigned 50 patients aged 50 to 90 years to receive either the active drug (n=26) or placebo (n=24) twice daily for six months. Riluzole works by modulating a neurotransmitter in the brain called glutamate, which plays an essential role in the ability of nerve cells to send signals to one another. Glutamate dysregulation is thought to begin a cycle of toxicity that underlies the development of Alzheimer’s disease.

The study met its main primary outcome, confirming a difference in brain metabolic changes between patients on active treatment and placebo.

The changes were measured and analyzed using a specialized PET scan that measures glucose metabolism called FDG PET. Changes in FDG PET scans correlated with cognitive decline and predicted Alzheimer’s disease progression.

In this trial, FDG PET progression scores also correlated with changes in patients’ cognitive functions, including memory, attention, language, and visual-spatial skills.

Secondary outcomes were also met, including significant changes in glutamate levels measured through magnetic resonance spectroscopy, correlations between cognitive measures assessed through neuropsychological testing and neuroimaging biomarkers.

Another primary endpoint, change in N-acetylaspartate, a marker of neuron health, was not met. Finally, several regions of the brain showed preserved glucose metabolism, but most prominently a region called the posterior cingulate which is a hub network for Alzheimer’s disease.

The study found no difference in adverse events between the treatment and placebo groups. Using repurposed drugs like riluzole comes with the benefit of having, in this case, two decades of experience showing the drug’s safety. This helps to speed and streamline costs of the drug testing process.

This shows a brain
Finally, several regions of the brain showed preserved glucose metabolism, but most prominently a region called the posterior cingulate which is a hub network for Alzheimer’s disease. Image is in the public domain

Lead investigator Dr. Ana Pereira, Assistant Professor of Neurology and Neuroscience at the Icahn School of Medicine at Mount Sinai in New York, NY, said the promising results support moving the drug into a phase 3 trial with larger numbers of patients followed for a longer time for further testing of safety and efficacy.

 “We are deeply appreciative to the ADDF not just for their investment in our work, but for their commitment to novel scientific approaches to Alzheimer’s research,” said Dr. Pereira.

Thanks to its deep connections throughout the Alzheimer’s research community, the ADDF was able to connect Dr. Pereira with another of its funded investigators, Dawn Matthews, Chief Executive Officer at ADM Diagnostics, an ADDF-funded company. The two worked together on designing the trial to take advantage of new technology from ADM that allowed for a more robust analysis of the PET scan data.

About this Alzheimer’s disease research news

Source: ADDF
Contact: Emily Berkowitz – ADDF
Image: The image is in the public domain

Original Research: Closed access.
Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer’s disease” by Howard Fillit et al. Brain


Abstract

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.

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