{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:26:40Z","timestamp":1793413600853,"version":"4.5.0"},"reference-count":45,"publisher":"American Medical Association (AMA)","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Neurol"],"published-print":{"date-parts":[[2025,8,1]]},"abstract":"\n Importance<\/jats:title>\n Carrying a variation in the gene for \u03b2-glucocerebrosidase is a major risk factor for Parkinson disease dementia (PDD), and raising \u03b2-glucocerebrosidase levels lowers \u03b1-synuclein in cell and animals. Ambroxol is a chaperone for \u03b2-glucocerebrosidase, which increases the levels of \u03b2-glucocerebrosidase.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To examine the safety and tolerability of ambroxol in PDD, test the efficacy of ambroxol in improving or slowing the progression of cognitive deficits, and acquire pharmacological data.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This was a 52-week, phase 2, double-blind, placebo-controlled, randomized clinical trial conducted from February 2015 to June 2023. The study took place at a single center and was referral based. Included were patients with PDD who were older than 50 years, had Parkinson disease for at least 1 year before cognitive impairment, had mild to moderate dementia, were taking stable medications, and had a study partner.<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Ambroxol low dose (525 mg per day), high dose (1050 mg per day), or placebo.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n Safety and tolerability outcomes were adverse events. Primary efficacy outcomes were the Alzheimer Disease Assessment Scale\u2013cognitive subscale, version 13 (ADAS-Cog-13) and Clinician\u2019s Global Impression of Change (CGIC).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 75 patients were screened, and 55 were randomized. Thirty-one individuals received ambroxol, with 8 patients (mean [SD] age, 78.8 [3.4] years, all male) in the low-dose group and 22 patients (mean [SD] age, 70.7 [7.6]; 19 male [86.4%]) in the high-dose group. One patient was excluded from the high-dose group due to a diagnosis of progressive supranuclear palsy. A total of 24 patients (mean [SD] age, 72.7 [6.3] years; 19 male [79.2%]) were included in the placebo group. Participants receiving ambroxol (23 of 193 adverse events [12%]) showed more gastrointestinal adverse events than those receiving placebo (9 of 172 adverse events [5%]). Statistical analyses compared ambroxol high dose vs placebo. There was no evidence to suggest differences between groups on primary or secondary outcomes. Mean (SD) ambroxol high-dose concentrations were 7.48\u03bcM (3.17\u03bcM; 95% CI, 6.08-8.87\u03bcM) in plasma and 0.73\u03bcM (0.07\u03bcM; 95% CI, 0.64-0.81\u03bcM) in cerebrospinal fluid at the end of titration. Mean (SD) \u03b2-glucocerebrosidase levels were higher at week 26 (ambroxol, 12.45 [1.97] nmol\/h\/mg; 91% CI, 11.54-13.36 nmol\/h\/mg); placebo, 8.50 [1.96] nmol\/h\/mg; 91% CI, 7.65-9.34 nmol\/h\/mg;\n P<\/jats:italic>\n \u2009=\u2009.05) in the ambroxol group compared with placebo.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n Results of this randomized clinical trial reveal that ambroxol was safe, well-tolerated, and demonstrated target engagement. However, the effect of ambroxol on cognition was not confirmed.<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT02914366<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaneurol.2025.1687","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T11:00:31Z","timestamp":1751281231000},"page":"797","source":"Crossref","is-referenced-by-count":31,"title":["Ambroxol as a Treatment for Parkinson Disease Dementia"],"prefix":"10.1001","volume":"82","author":[{"given":"Carolina R. A.","family":"Silveira","sequence":"first","affiliation":[{"name":"Cognitive Neurology and Alzheimer\u2019s Disease Research Centre, Parkwood Institute, London, Ontario, Canada"},{"name":"Lawson Research Institute, St Joseph\u2019s Health Care London, London, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy K. 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