Riluzone in Patients with Cognitive Disorders
Bruce McEwen, Ph.D; Ana C. Pereira, M.D.
Rockefeller University
Grant Program:
Clinical Neuroscience Research
Funded in:
April 2012, for 3 years
Funding Amount:
$200,000
Lay Summary
Riluzole may prevent conversion of mild cognitive impairment to Alzheimer's.
Goal: Investigators will conduct an initial clinical study of the drug Riluzole in a small number of adults with mild cognitive impairment to see whether it decreases metabolic changes in the brain that may be associated with progression to Alzheimer’s disease. They also will correlate the drug’s metabolic effects with participants’ cognitive performance.
Background: Mild Cognitive Impairment (MCI) is a transitional stage between normal aging and early Alzheimer’s disease (AD). A person with MCI has notable changes in cognition and impaired memory as reflected in lower neuropsychological test scores than would be expected based on the person’s age and educational background. While people with MCI do not have trouble in daily functioning or dementia, a significant percent will begin to develop these problems and progress to AD. Scientists do not yet know what precipitates this decline to dementia, but autopsy studies implicate excess amounts of the neurotransmitter glutamate in the brain. Glutamate transmits excitatory messages when it is released from the axon of one brain cell to its neighbor at the junction between the two cells, called a synapse.
In MCI, there are excess stores of glutamate in axons, while in Alzheimer’s disease brain cells fail to take up released glutamate. Its uptake is blocked by amyloid, a protein that builds up in spaces between brain cells in AD. Moreover, excessive glutamate is associated with another hallmark of Alzheimer’s disease, increased “tau” protein that builds up inside brain cells. Taken together, these findings suggest that the conversion from MCI to AD occurs when too much glutamate is released by axons and not enough is taken up by neighboring brain cells, causing a cascade of metabolic events, including the destructive effects of oxidation, which leads to loss of brain cells and their synapses. These events are thought to occur primarily in two brain areas: the hippocampus, where memory is transformed from short to long-term; and the pre-frontal cortex, which is involved in “executive” functions of planning and carrying out plans.
The investigators hypothesize that the drug Riluzole will prevent this adverse cascade of metabolic events in MCI, and that improved metabolic outcomes may be associated with enhanced cognitive functioning. Riluzole, approved by the Food and Drug Administration as safe and effective for treating fatal Amyotrophic Lateral Sclerosis (ALS) where it increases median survival time, decreases glutamate release by axons, increases its uptake by neurons, and increases oxidative metabolism. They will test Riluzole versus placebo in 28 people with MCI, randomized into two groups of 14 participants each, over a six-month period. Participants will be assessed at baseline and after three and six months of clinical testing. The researchers will see whether those given Riluzole compared to placebo show improved metabolic changes as reflected by biomarkers that are measured primarily by MRS and PET imaging. They anticipate that those on Riluzole will show: increased neuronal viability, as reflected by the biomarker NAA (a metabolite in the central nervous system); increased levels of the antioxidant glutathione which inhibits the destructive effects of oxidation; and decreased glutamate levels. Any associated improvements in cognitive functioning will be assessed by neuropsychological test measures.
Significance: If promising, this study will lead to the large-scale determination of whether Riluzole is a safe and effective drug for preventing the conversion of MCI to Alzheimer’s disease. If so, it will be the first effective therapeutic intervention for preventing AD.
Abstract
Riluzone in patients with cognitive disorders
Cognitive aging is a major source of disability in an increasingly aging population. The paucity of effective treatments for cognitive aging disorders, and most importantly in Alzheimer’s disease instigates a need for further research into novel therapeutic possibilities. Alzheimer’s disease is the most common neurodegenerative disorder and its prevalence steeply increases. Glutamate-mediated excitotoxicity in neuropsychiatric disorders and in particular in Alzheimer’s disease has been shown to cause significant cerebral damage. Early effective therapeutic intervention in Alzheimer’s disease is critical in order to prevent or at least retard neuropathological progression that will lead to widespread irreversible neuronal loss and significant cognitive dysfunction. We will perform a parallel study in humans and rodents** using a medication that is a glutamate modulator to evaluate for in vivo imaging biomarkers of metabolic brain improvement along with cognitive changes in patients in the earliest stages of Alzheimer’s disease and we will be using state-of-the-art high resolution morphological methods in a rodent model of brain aging to measure dendritic spines which represent the primary site of structural plasticity in the adult brain after treatment with the glutamate modulator.
**We are also going to perform a parallel rodent study with riluzole (which is also being used in humans)
Investigator Biographies
Bruce McEwen, Ph.D; Ana C. Pereira, M.D.
Bruce McEwen, PhD received his bachelor’s degree in chemistry from Oberlin College in 1959 and his Ph.D. in cell biology from Rockefeller University in 1964. He was a United States Public Health Service Postdoctoral Fellow at the Institute of Neurobiology in Göteborg, Sweden, from 1964 to 1965, worked as an assistant professor in the zoology department at the University of Minnesota and then returned to Rockefeller in 1966 as assistant professor. He was appointed associate professor in 1971 and professor and head of laboratory in 1981 and was named Alfred E. Mirsky Professor in 1999. Dr. McEwen is a past president of the Society for Neuroscience. He is a member of the National Academy of Sciences, the American Academy of Arts and Sciences and the Institute of Medicine. In 2010, he received a share of the IPSEN Fondations Prize in Neuroplasticity. In 2009, he received the Gold Medal award from the Society for Biological Psychiatry. In 2005 he received the Pasarow Award in Neuropsychiatry. He is a recipient of the Dale Medal of the British Endocrine Society, and in 2005 he received the Goldman-Rakic Prize for Cognitive Neuroscience from the National Alliance for Research for Schizophrenia and Depression and the Karl Spencer Lashley Award from the American Philosophical Society. Dr. McEwen has over 800 publications on how hormones alter behavior and mood, regulate neuroendocrine activity, protect the brain from stress and regulate brain aging and certain disease processes.
Ana C. Pereira, M.D. graduated in Medicine at Universidade Federal de Sao Paulo, Brazil in December 2004 in the top 1% of the class. She was a Post-Doctoral Research Scientist at Columbia University at the Taub Institute for Alzheimer’s disease between 2005-2007. Afterwards she became a resident in Neurology at Harvard University graduating in the end of June 2011. She has been a Clinical Investigator at Rockefeller University, in New York City ever since. She has published “An in vivo correlate of exerciseinduced neurogenesis in the adult dentate gyrus” in Proceedings of the National Academy of Science in 2007 which has had over 250 citations, the review article “Imaging-guided Microarray: Molecular profiles dissociating Alzheimer’s disease from normal aging” in Annals of the New York Academy of Sciences, “The Anterior Disconnection Syndrome revisited using modern technologies” in the journal Neurology, articles in Brazilian magazines and the book in Portuguese “Em torno da mente” (“Around the mind”), which intertwines the relationship between neuroscience and philosophy. At the Rockefeller University, she has been studying the glutamatergic excitotoxic events that occur in the brains of patients in the earliest stages of Alzheimer’s disease with the use of state-of-the-art brain imaging techniques. She is also testing potential therapeutic interventions with glutamate modulators that can retard the progression of the disorder. In addition, Dr. Pereira studies the mechanisms of age-related cognitive decline in rats and humans investigating genetic and environmental underdetermined risk factors, such as sleep-disordered breathing, for pathological brain aging.
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