Overview

The most common genetic risk factor for Parkinson's Disease is a heterozygous mutation of the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase (GCase). Reduced GCase activity is associated with aggregation of the protein alpha synucleine (aSyn) in the central nervous system, which is related to the pathological cause of PD. Ambroxol is a mucolytic expectorant that appears to facilitate the refolding of the misfolded GBA protein thats acts as a chaperone for GCase.

This randomized placebo-controlled trial aims to investigate the disease-modifying properties of ambroxol in PD patients with a GBA1-mutation. Patients will undergo motor and cognitive tests, as well as imaging and blood tests.

Eligibility

Inclusion Criteria:

• Diagnosis of Parkinson's disease, according to Movement Disorders Society (MDS) criteria (27)
• Disease duration of 10 years or less at time of inclusion
• PD patients carrying a GBA1 mutation
• Able to write written informed consent, understanding study protocol and perform protocol related actions
• Willing and able to self-administer oral ambroxol or placebo medication

Exclusion Criteria:

• The refusal to be informed about an unforeseen clinical finding
• Use of an implanted Deep Brain Stimulation (DBS) system
• Confirmed dysphagia that would preclude self-administration of ambroxol or placebo tablets
• History of known sensitivity to the study medication
• Pregnant or breastfeeding women
• Participants of childbearing potential that would not use adequate birth control, consisting of a negative pregnancy test at the screening visit and use of accepted contraceptive methods defined as highly effective while participating in the study
• MRI incompatible implants in the body
• Any clinically significant or unstable medical or surgical condition that in the opinion of the principal investigator may put the participant at risk when participating in the study or may influence the results of the study or affect the participant's ability to take part in the study, as determined by medical history, physical examinations, electrocardiogram (ECG), or laboratory tests. Such conditions may include:
  1. Impaired renal function (a positive urine dipstick test, and laboratory values below or above: a eGFR <45 ml/min 1,73M2, Sodium 135-145 mmol/L, Potassium 3.5-5.0 mmol/L, Urea 2.5-7.5mmol/L).
  2. Moderate/severe hepatic impairment (laboratory values below or above: ASAT 0- 80U/L, ALAT0-90 U/L, GGT > 80 U/L, Alkaline Phosphatase 35-210 U/L).