AADC/TDC in Advanced Parkinson's Disease (AADCTDC)

Aromatic L-amino Acid Decarboxylase Activity, Tyrosine Decarboxylase Activity and Gut Microbiome in Patients With Advanced Parkinson's Disease

Rationale: Many persons with Parkinson's disease (PD) develop a progressive resistance to levodopa, which is the pharmacological mainstay of PD treatment. Recently, two enzymatic pathways have been identified that could be (partially) responsible for this: 1) breakdown of levodopa by bacterial tyrosine decarboxylase (TDC), an enzyme which normally decarboxylates dietary tyrosine but which is also able to decarboxylate levodopa. Accumulation of bacterial TDC in the small intestine, such as in the context of small-intestinal bacterial overgrowth (SIBO) - for which persons with PD are at increased risk - has the potential to prematurely metabolize levodopa, hence limiting its bioavailability and effect. 2) paradoxical induction of activity of the enzyme aromatic L-amino acid decarboxylase (AADC) in chronic users of levodopa combined with a peripheral decarboxylase inhibitor, also leading to a premature breakdown of levodopa and limitation of its bioavailability and effect.

Primary objective: in a cross-sectional sample of advanced (≥5 years) Parkinson's disease determining the prevalence of increased bacterial TDC activity in feces, and the prevalence of increased AADC activity in serum.

Secondary objective: correlating these biomarkers to clinical parameters, correlating composition of the microbiome to TDC activity, to the presence of levodopa resistance, and to factors related to socio-economic status.

Study design: using feces, serum and urine samples and clinical data from n=50 participants, the relevant enzymes' activity will be measured and the composition of the gut microbiome will be determined. These will be correlated to the clinical and demographic parameters.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease

• Study Type: Observational
• Enrollment (Actual): 48

Contacts and Locations

Study Locations

• Netherlands
  • Nijmegen, Netherlands, 6525 GC
    • Radboudumc Centre of Expertise for Parkinson & Movement Disorders

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

50 adult patients with Parkinson's disease (diagnosed by a neurologist), with a disease duration of at least 5 years (since diagnosis).

Description

Inclusion Criteria:

• Participant has Parkinson's disease of at least 5 years duration, defined as time since diagnosis made by a neurologist;
• Participant is an adult, at least 25 years of age;
• Participant can read and understand Dutch;
• Participant has completed the Ethics Committee-approved Informed Consent;
• Participant is willing, competent, and able to comply with all aspects of the protocol, including not taking their PD medication during a 12-hour period, and biospecimen collection.

Exclusion Criteria:

• Co-morbidities that would hamper interpretation of parkinsonian disability, such as coincident musculoskeletal abnormalities, as judged by the investigators;
• Significant doubt over the correctness of the diagnosis PD, as judged by the investigators;
• Not able to stand or walk without the assistance of another person (walking aids are not an exclusion criterion);
• Never having used levodopa;
• No current use of levodopa due to lack of effect, despite never having used at least 600mg/day during at least 1 month;
• Documented allergic reaction or severe side effect to levodopa or benserazide;
• History of narrow-angle glaucoma (unless specific permission by the treating ophthalmologist for use of levodopa/benserazide);
• History of malignant melanoma (unless specific permission by the treating dermatologist for use of levodopa/benserazide);
• History of psychiatric disease with a psychotic component (unless specific permission by the treating psychiatrist for use of levodopa/benserazide);
• Known current uncompensated cardiovascular, endocrine, renal, hepatic, hematologic, or pulmonary disease (unless specific permission by the treating physician for use of levodopa/benserazide);
• Documented severe and debilitating dyskinesias on levodopa, to such an extent that levodopa treatment was terminated;
• Current pregnancy or breastfeeding;
• Co-morbidity with primary gastrointestinal pathology associated with altered gut microbiota and/or altered absorption (such as inflammatory bowel disease, celiac disease, colorectal carcinoma);
• Antibiotic use at any time during the 12 months leading up to the clinic visit;
• Current or recent (less than 1 month before clinic visit) use of (non-parkinson) drugs known or suspected to influence AADC activity, including amphetamine, dexamethasone, dopamine receptor antagonists, monoamine oxidase (MAO) inhibitors (including MAO-B inhibitors which are infrequently used as antiparkinsonian drugs), prostaglandin E2, and vigabatrin.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Prevalence of increased TDC activity in feces	through study completion, an average of 2 weeks
Prevalence of increased AADC activity in serum	through study completion, an average of 2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III	Baseline score and score after levodopa administration	through study completion, an average of 2 weeks
Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part IV	Baseline score and score after levodopa administration	through study completion, an average of 2 weeks
Timed up-and-go test	TUG. Baseline score and score after levodopa administration	through study completion, an average of 2 weeks
Purdue Pegboard Test	Baseline score and score after levodopa administration	through study completion, an average of 2 weeks
Composite Clinical Motor Score	This is a composite of MDS-UPDRS-III, TUG and pegboard test scores. Baseline score and score after levodopa administration.	through study completion, an average of 2 weeks
modified Hoehn & Yahr score	Ordinal scale of Parkinson's disease severity. Baseline score and score after levodopa administration.	through study completion, an average of 2 weeks
9-item Wearing-Off Questionaire (WOQ-9)	Questionnaire on wearing-off symptoms	through study completion, an average of 2 weeks
SIBO questionnaire	15-item scale on gastrointestinal symptoms associated with small-intestinal bacterial overgrowth (SIBO)	through study completion, an average of 2 weeks
Schwab and England Activities of Daily Living Scale	Single-question scale on the ability to perform activities of daily living	through study completion, an average of 2 weeks
Demographics questionnaire	14-item questionnaire on demographic parameters	through study completion, an average of 2 weeks
Medication questionnaire	9-item questionnaire on (current and past) medication use for Parkinson's disease, and their effect on symptoms	through study completion, an average of 2 weeks
Diet questionnaire	18-item questionnaire on diet	through study completion, an average of 2 weeks
Prevalence of increased COMT activity in urine	Catechol-O-methyltransferase	through study completion, an average of 2 weeks

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: University of Groningen; Maag Lever Darm Stichting; Predica Diagnostics; ParkinsonNL; Stichting Woelse Waard; Stichting Alkemade-Keuls

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2023
• Primary Completion (Actual): August 14, 2024
• Study Completion (Actual): August 14, 2024

Study Registration Dates

• First Submitted: September 9, 2022
• First Submitted That Met QC Criteria: September 25, 2022
• First Posted (Actual): September 28, 2022

Study Record Updates

• Last Update Posted (Actual): August 19, 2024
• Last Update Submitted That Met QC Criteria: August 15, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: 113707

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No