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Schwartz Award for Physician Scientist"},{"name":"Karen Strauss Cook Research Scholar Award","award":["1 R01 MH075895"],"award-info":[{"award-number":["1 R01 MH075895"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,31]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Dysregulation of glutamatergic neural circuits has been implicated in a cycle of toxicity, believed among the neurobiological underpinning of Alzheimer\u2019s 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\u2019s 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\u2019s disease as compared to placebo.<\/jats:p><jats:p>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\u2009years of age, with a clinical diagnosis of probable Alzheimer\u2019s 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\u2009mg riluzole (n\u2009=\u200926) or placebo (n\u2009=\u200924) twice a day. Twenty-two riluzole-treated and 20 placebo participants completed the study. Primary end points were baseline to 6\u2009months 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.<\/jats:p><jats:p>Measures of cerebral glucose metabolism, a well-established Alzheimer\u2019s 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 \u00d7 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.<\/jats:p><jats:p>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\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awab222","type":"journal-article","created":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T19:11:18Z","timestamp":1623957078000},"page":"3742-3755","source":"Crossref","is-referenced-by-count":94,"title":["Riluzole, a glutamate modulator, slows cerebral glucose metabolism decline in patients with Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9452-2245","authenticated-orcid":false,"given":"Dawn C","family":"Matthews","sequence":"first","affiliation":[{"name":"ADM Diagnostics Inc., Northbrook, IL 60062, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangling","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Radiology, Weill Cornell Medicine, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Dowd","sequence":"additional","affiliation":[{"name":"The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diamanto","family":"Tsakanikas","sequence":"additional","affiliation":[{"name":"The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline S","family":"Jiang","sequence":"additional","affiliation":[{"name":"The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Meuser","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randolph D","family":"Andrews","sequence":"additional","affiliation":[{"name":"ADM Diagnostics Inc., Northbrook, IL 60062, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana S","family":"Lukic","sequence":"additional","affiliation":[{"name":"ADM Diagnostics Inc., Northbrook, IL 60062, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihyun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Radiology, Weill Cornell Medicine, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Hampilos","sequence":"additional","affiliation":[{"name":"Department of Radiology, Weill Cornell Medicine, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neeva","family":"Shafiian","sequence":"additional","affiliation":[{"name":"Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Sano","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"David Mozley","sequence":"additional","affiliation":[{"name":"Department of Radiology, Weill Cornell Medicine, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard","family":"Fillit","sequence":"additional","affiliation":[{"name":"Alzheimer's Drug Discovery Foundation, New York, NY 10019, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce S","family":"McEwen","sequence":"additional","affiliation":[{"name":"The Rockefeller University, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dikoma C","family":"Shungu","sequence":"additional","affiliation":[{"name":"Department of Radiology, Weill Cornell Medicine, New York, NY 10021, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana C","family":"Pereira","sequence":"additional","affiliation":[{"name":"The Rockefeller University, New York, NY 10065, USA"},{"name":"Department of Neurology, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Ronald M. 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