Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA1 beta-glucosylceramidase gene (GBA). Heterozygous GBA mutations are recognized as the most frequent genetic risk factor for Parkinson's disease (PD),with an overall carrier frequency of about 10% in PD. Heterozygous carriers of GBA mutations are at increased odds for developing PD and even higher for PD Dementia and Dementia with Lewy Bodies. In GBA carriers, PD usually occurs at earlier age at onset, higher risk for dementia, visual hallucinations, autonomic dysfunction and faster progression of motor symptoms than noncarriers, culminating in an overall reduced survival.~GBA1 mutations reduce the enzymatic function of GCase, ultimately promoting the toxic accumulation of alpha-synuclein (alpha-syn) fibrils throughout the central nervous system. The toxic conversion of physiological alpha-syn conformers by glycosphingolipids should be reversible at a stage prior to incorporation into fibrils. Therefore, the use of agents able to enhance GCase activity might hold a therapeutic potential. Ambroxol is a metabolite of bromhexine which has been used for over 30 years as an over-the-counter mucolytic, with an excellent safety profile with few side effects. The brain penetrance of Ambroxol in vivo and its ability to increase GCase activity and reduce alpha-syn levels has been consistently confirmed in several in vitro and in vivo studies, but only at a higher dose (1.2 g/day in humans).~The investigators hypothesize that the greatest impact of Ambroxol as a disease-modifying agent will be on cognitive performance, because it is the clinical feature that showed the greatest difference between PD carriers vs. non-carriers.~Sixty patients diagnosed with PD and carriers of GBA mutations will be recruited and randomly allocated to either Ambroxol 1.2 g/day or Placebo. Galenic formulation of Ambroxol 200 mg per tablet and similar Placebo tablets have been manufactured ad hoc and their use in this study has been authorized by the Italian Medicines Agency (AIFA; Provvedimento 2021-004565-13 SC23119).~The investigators will administer clinical and cognitive assessments to determine if there is any difference in the progression of cognitive dysfunction (primary endpoint) as well as other motor and non-motor features between the two treatment arms.~Pharmacokinetics (Ambroxol drug levels) and pharmacodynamics (GCase enzyme activity) of the experimental drug in blood and cerebrospinal fluid samples will be measured as well as neurodegeneration biomarkers in the cerebrospinal fluid (alpha-synuclein, Tau, phospho-Tau and beta amyloid-42) at baseline and after the intake of oral Ambroxol for 12 months.
The present multicenter, randomized, double-blind, placebo-controlled clinical trial will investigate whether the prolonged administration of high-dose oral Ambroxol over 52 weeks is safe, tolerable, able to change Glucocerebrosidase enzyme activity and alpha-synuclein levels in the central nervous system and, ultimately, to reduce the progression of cognitive decline and motor disability in 60 individuals with Parkinson's disease with mutations of the glucocerebrosidase gene (GBA1; OMIM 606463).~Participants will undergo clinical, biomarker blood and cerebrospinal fluid analysis, neuropsychological, neuroimaging assessment throughout the course of the study.