Summary: A clinical trial has revealed that Ambroxol, a common cough medicine in Europe, may help slow cognitive decline in people with Parkinson’s disease dementia. The 12-month study found that the drug stabilized psychiatric symptoms, protected against brain damage, and even improved cognition in genetically at-risk participants.
Ambroxol boosts an enzyme called GCase, which is often deficient in Parkinson’s patients, contributing to brain cell damage. While not yet approved for use in North America, the drug’s safety profile and early benefits make it a compelling candidate for further study.
Key Facts:
- Stabilized Symptoms: Ambroxol halted psychiatric decline seen in the placebo group.
- Genetic Benefit: Cognition improved in those with GBA1 gene variants.
- Brain Protection: GFAP, a marker of brain damage, remained stable on Ambroxol.
Source: Lawson Research Institute
Dementia poses a major health challenge with no safe, affordable treatments to slow its progression.
Researchers at Lawson Research Institute (Lawson), the research arm of St. Joseph’s Health Care London, are investigating whether Ambroxol – a cough medicine used safely for decades in Europe – can slow dementia in people with Parkinson’s disease.
Published today in the prestigious JAMA Neurology, this 12-month clinical trial involving 55 participants with Parkinson’s disease dementia (PDD) monitored memory, psychiatric symptoms and GFAP, a blood marker linked to brain damage.
Parkinson’s disease dementia causes memory loss, confusion, hallucinations and mood changes. About half of those diagnosed with Parkinson’s develop dementia within 10 years, profoundly affecting patients, families and the health care system.
Led by Cognitive Neurologist Dr. Stephen Pasternak, the study gave one group daily Ambroxol while the other group received a placebo.
“Our goal was to change the course of Parkinson’s dementia,” says Pasternak. “This early trial offers hope and provides a strong foundation for larger studies.”
Key findings from the clinical trial include:
• Ambroxol was safe, well-tolerated and reached therapeutic levels in the brain
• Psychiatric symptoms worsened in the placebo group but remained stable in those taking Ambroxol.
• Participants with high-risk GBA1 gene variants showed improved cognitive performance on Ambroxol
• A marker of brain cell damage (GFAP) increased in the placebo group but stayed stable with Ambroxol, suggesting potential brain protection.
Although Ambroxol is approved in Europe for treating respiratory conditions and has a long-standing safety record – including use at high doses and during pregnancy – it is not approved for any use in Canada or the U.S.
“Current therapies for Parkinson’s disease and dementia address symptoms but do not stop the underlying disease,” explains Pasternak.
“These findings suggest Ambroxol may protect brain function, especially in those genetically at risk. It offers a promising new treatment avenue where few currently exist.”
Ambroxol supports a key enzyme called glucocerebrosidase (GCase), which is produced by the GBA1 gene. In people with Parkinson’s disease, GCase levels are often low. When this enzyme doesn’t work properly, waste builds up in brain cells, leading to damage.
Pasternak learned about Ambroxol during a fellowship at The Hospital for Sick Children (SickKids) in Toronto, where it was identified as a treatment for Gaucher disease – a rare genetic disorder in children caused by a deficiency of GCase.
He is now applying that research to explore whether boosting GCase with Ambroxol could help protect the brain in Parkinson’s-related diseases.
“This research is vital because Parkinson’s dementia profoundly affects patients and families,” says Pasternak. “If a drug like Ambroxol can help, it could offer real hope and improve lives.”
Funded by the Weston Foundation, this study is an important step toward developing new treatments for Parkinson’s disease and other cognitive disorders, including dementia with Lewy bodies. Pasternak and his team plan to start a follow-up clinical trial focused specifically on cognition later this year.
About this neuropharmacology and Parkinson’s disease research news
Author: Debora Flaherty
Source: Lawson Research Institute
Contact: Debora Flaherty – Lawson Research Institute
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Ambroxol as a Treatment for Parkinson Disease Dementia A Randomized Clinical Trial” by Stephen Pasternak et al. JAMA Neurology
Abstract
Ambroxol as a Treatment for Parkinson Disease Dementia A Randomized Clinical Trial
Importance
Carrying a variation in the gene for β-glucocerebrosidase is a major risk factor for Parkinson disease dementia (PDD), and raising β-glucocerebrosidase levels lowers α-synuclein in cell and animals. Ambroxol is a chaperone for β-glucocerebrosidase, which increases the levels of β-glucocerebrosidase.
Objective
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.
Design, Setting, and Participants
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.
Interventions
Ambroxol low dose (525 mg per day), high dose (1050 mg per day), or placebo.
Main Outcomes and Measures
Safety and tolerability outcomes were adverse events. Primary efficacy outcomes were the Alzheimer Disease Assessment Scale–cognitive subscale, version 13 (ADAS-Cog-13) and Clinician’s Global Impression of Change (CGIC).
Results
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 7.48μM (3.17μM; 95% CI, 6.08-8.87μM) in plasma and 0.73μM (0.07μM; 95% CI, 0.64-0.81μM) in cerebrospinal fluid at the end of titration.
Mean (SD) β-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; P = .05) in the ambroxol group compared with placebo.
Conclusions and Relevance
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.
Trial Registration
ClinicalTrials.gov Identifier: NCT02914366
