AADC/TDC in 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.


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.