Clinical trial NCT05558787: AADC/TDC in Advanced Parkinson's Disease
Official title: Aromatic L-amino Acid Decarboxylase Activity, Tyrosine Decarboxylase Activity and Gut Microbiome in Patients With Advanced Parkinson's Disease
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Parkinson Disease
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: University of Groningen
name: Predica Diagnostics
name: ParkinsonNL
name: Maag Lever Darm Stichting
name: Stichting Woelse Waard
name: Stichting Alkemade-Keuls
First posted: 2022-09-28
Enrollment: 48
Sex: ALL
Minimum age (years): 25
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
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).

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Prevalence of increased TDC activity in feces
timeFrame: through study completion, an average of 2 weeks
measure: Prevalence of increased AADC activity in serum
timeFrame: through study completion, an average of 2 weeks
Secondary outcomes:
measure: Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III
timeFrame: through study completion, an average of 2 weeks
measure: Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part IV
timeFrame: through study completion, an average of 2 weeks
measure: Timed up-and-go test
timeFrame: through study completion, an average of 2 weeks
measure: Purdue Pegboard Test
timeFrame: through study completion, an average of 2 weeks
measure: Composite Clinical Motor Score
timeFrame: through study completion, an average of 2 weeks
measure: modified Hoehn & Yahr score
timeFrame: through study completion, an average of 2 weeks
measure: 9-item Wearing-Off Questionaire (WOQ-9)
timeFrame: through study completion, an average of 2 weeks
measure: SIBO questionnaire
timeFrame: through study completion, an average of 2 weeks
measure: Schwab and England Activities of Daily Living Scale
timeFrame: through study completion, an average of 2 weeks
measure: Medication questionnaire
timeFrame: through study completion, an average of 2 weeks
measure: Demographics questionnaire
timeFrame: through study completion, an average of 2 weeks
measure: Diet questionnaire
timeFrame: through study completion, an average of 2 weeks
measure: Prevalence of increased COMT activity in urine
timeFrame: through study completion, an average of 2 weeks
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboudumc Centre of Expertise for Parkinson & Movement Disorders
Study officials:
References: