Primary Objective: Determining the prevalence in advanced-stage PD patients of increased bacterial TDC activity in faeces and the prevalence of increased AADC activity in serum.Secondary Objectives:- Correlating TDC activity and AADC activity to…
ID
Source
Brief title
Condition
- Malabsorption conditions
- Movement disorders (incl parkinsonism)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Prevalence of increased TDC activity in faeces and increased AADC activity in
serum.
Secondary outcome
Correlation of TDC activity in faeces / AADC activity in serum to:
- Treatment response, which is defined as the magnitude of the difference
between the MDS-UPDRS part III score in the ON state versus the
practically-defined OFF state (ΔOFF-ON)
- MDS-UPDRS part III (baseline score)
- MDS-UPDRS part IV (single moment of measurement)
- TUG (baseline score and ΔOFF-ON)
- Purdue Pegboard Test (baseline score and ΔON-OFF)
- Composite Clinical Motor Score, which is a composite of MDS-UPDRS-III, TUG
and pegboard test scores (baseline score and ΔOFF-ON)
- modified Hoehn & Yahr score (baseline score and ΔON-OFF)
- subjective clinimetrics scores (WOQ-9, SIBO questionnaire, Schwab&England
scale, self-reported medication effect)
- medication use (levodopa equivalent dose (LED), dosage frequency, use of
non-levodopa dopaminergic medication, total duration of use of PD medication)
- duration of disease (time since diagnosis)
- comorbidities
- diet
Correlation of abundance of TDC-producing bacteria in faeces to:
- TDC activity in faeces;
- the dependent variables described above;
- factors associated with socioeconomic status (ethnicity, type of dwelling,
paid work, main daily activity, highest completed education, total number of
years of education).
Correlating factors associated with socioeconomic status to treatment response.
Background summary
Many persons with Parkinson*s disease (PD), estimated at 20% in our centre,
develop a progressive resistance to levodopa, which is the pharmacological
mainstay of PD treatment. These persons gradually lose responsiveness to
levodopa and develop an aberrant response with delayed effect and unpredictable
fluctuations. 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. Compared to normal subjects, PD patients are prone to
alterations in gut microbiota, including an increased abundance of Akkermansia,
Lactobacillus and Bifidobacterium and a decreased abundance of Prevotella. Of
these, Lactobacillus brevis is a TDC-producing species. Additionally,
accumulation of bacterial TDC in the small intestine may occur in the context
of small-intestinal bacterial overgrowth (SIBO) for which persons with PD have
an increased risk and which has been reported to be present in 46% of PD
patients. Bacterial TDC 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 (PDI). This enzyme normally converts levodopa to
dopamine, which is unable to cross the blood-brain barrier. Therefore, in a
therapeutic setting levodopa is combined with a PDI which inhibits AADC
peripherally, greatly increasing the bioavailability of levodopa to the brain.
It has, however, been found that chronic use of levodopa/PDI can lead to a
paradoxical induction of AADC activity, leading to a premature breakdown of
levodopa and limitation of its bioavailability and effect.
Studies examining a possible relationship between TDC and AADC activity on one
hand, and clinical characteristics of PD patients on the other, have thus far
been small and/or examined few variables. In a separate study, we will be using
the large (n=520) Personalized Parkinson Project (PPP) cohort to examine this
relationship. However, the PPP cohort consists entirely of persons in whom the
PD diagnosis is fairly recent (up to 5 years before inclusion). Levodopa
resistance is more likely to develop later in the disease course. Therefore, a
sample of patients with more advanced PD is needed.
As detailed above, it has been well-described that persons with PD have a
different composition of the intestinal microbiome as compared to healthy
individuals. Indeed, an altered gut microbiome might be a prerequisite for the
development of PD. More recently, indications have been found that within PD
patients, the microbiome differs between patients with and without motor
complications (possibly related to bacterial TDC production, as described
above). A possible risk factor for an altered gut microbiome appears to be
socioeconomic status. Given the above, this may influence the risk of
developing PD and/or the risk of developing motor complications of PD.
Data and biospecimen samples from this cross-sectional study can be used to
further explore the relationship between gut microbiome composition on the one
hand, and TDC activity, motor complications and socioeconomic status on the
other.
Study objective
Primary Objective: Determining the prevalence in advanced-stage PD patients of
increased bacterial TDC activity in faeces and the prevalence of increased AADC
activity in serum.
Secondary Objectives:
- Correlating TDC activity and AADC activity to clinical parameters;
- Correlating abundance of TDC-producing bacteria in advanced-stage PD patients
to bacterial TDC activity;
- Correlating abundance of TDC-producing bacteria in advanced-stage PD patients
to clinical markers associated with levodopa unresponsiveness / motor
complications;
- Correlating abundance of TDC-producing bacteria in advanced-stage PD patients
to socio-economic status, and by extension, correlating socio-economic status
to response fluctuations.
Study design
Cross-sectional, observational with invasive measurements.
Study burden and risks
Although in a separate study, we will investigate AADC and TDC enzyme activity
and their clinical correlates in already-collected data and biosamples, those
were collected in patients with a recent PD diagnosis. There are indications
that increased enzyme activity, and related levodopa resistance, are more
likely to occur in patients with more advanced PD. A new study is therefore
necessary to examine this, in order to obtain a better external validity for
the PD population as a whole. The risks associated with this study are deemed
to be negligible. There are no specific benefits for the subjects associated
with participation in this study. As unintended advantages, OFF/ON-scoring may
provide subjects with more insight into the effect levodopa has on their
symptoms, and the results of their enzyme assays (if they would request these
to be shared with them) may provide subjects with insight into a reason for
their levodopa (un)responsiveness. Also, for external participants in whom
there is uncertainty over the correctness of the diagnosis, the screening visit
may provide them with more diagnostic certainty.
Reinier Postlaan 4
NIJMEGEN 6525 GC
NL
Reinier Postlaan 4
NIJMEGEN 6525 GC
NL
Listed location countries
Age
Inclusion criteria
- Subject has Parkinson*s disease of at least 5 years duration, defined as time
since diagnosis made by a neurologist;
- Subject is an adult, at least 25 years of age;
- Subject can read and understand Dutch;
- Subject has completed the METC-approved Informed Consent;
- Subject 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 allergy or contraindication to either levodopa or 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.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| ClinicalTrials.gov | NCT05558787 |
| CCMO | NL82727.091.22 |