Untreated Parkinson's Disease Work-up Assessing Resident Microbiota and Duodenal Barrier Function

Official title

Multimodal Characterization of Gastrointestinal Structure, Function, and Microbiome in Drug-Naïve Parkinson's Disease

Overview

The UPWARD study is a prospective hypothesis-generating study in individuals with untreated Parkinson's disease (PD) and age-matched healthy controls (HCs). The objective of the study is to characterise disease-driven gastrointestinal (GI) changes that occur prior to initiation of treatment. The main questions this study aims to answer are: 1. Are there changes in duodenal permeability in people with untreated PD? 2. Are there changes in the gut microbiome in people with untreated PD? 3. Are these gut changes linked to prodromal features, or movement and non-movement symptoms of PD? The study consists of a screening visit, followed by a six-day home phase and one subsequent study visit at UZ Leuven. During the home phase, participants collect a stool sample, ingest radiopaque markers to assess gut transit time, and complete questionnaires. During the study visit, participants undergo an abdominal X-ray, a clinical assessment, and blood sampling. An upper GI endoscopy with duodenal biopsies is offered as an optional component of the study. This study does not test a therapeutic intervention. Examinations as part of the study are not standard clinical care. The findings are expected to improve understanding of early GI involvement in PD and to inform future mechanistic and clinical research.

Detailed description

This is a hypothesis-generating study aimed at characterising gut microbiome composition and intestinal permeability in patients with drug-naïve Parkinson's disease (PD), compared to age-matched healthy controls (HCs). Drug-naïve PD patients and HCs will be prospectively recruited. After a screening visit, participants will undergo a single study visit; no longitudinal follow-up is planned.

Participants will undergo standardized assessments across five domains: (1) gut microbiome and fecal read-outs, (2) duodenal barrier function assessed using optional duodenal biopsies, (3) whole-gut transit time measured with radiopaque markers, (4) clinical features assessed using validated questionnaires and rating scales, and (5) laboratory parameters obtained from blood sampling.

For the main study procedures (stool collection, radiopaque pellet ingestion with abdominal X-ray, clinical assessments, questionnaires, and blood sampling), approximately 75 drug-naïve PD patients will be included. Approximately one third are expected to consent to the optional gastroduodenoscopy, resulting in an estimated subgroup of 25 PD patients with duodenal biopsies. Age-matched healthy controls will be recruited in comparable numbers for the respective study components. All analyses will be cross-sectional.

Interventions

• Other Invasive sampling procedures
  Invasive sampling procedures in the study include an (optional) gastroduodenoscopy with duodenal biopsies, and venous blood sampling.
• Other Non-invasive sampling procedures
  Non-invasive sampling procedures in this study include a clinical examination, radiopaque pellet test with an abdominal X-ray (to assess whole-gut transit time), stool sample collection, and questionnaires.

Primary outcome measures

• Paracellular flux [Time frame: On day 7 (Follow-up visit)]
• Transepithelial electrical resistance (TEER) [Time frame: On day 7 (Follow-up visit)]
• Fecal microbiota composition [Time frame: Analyses wil be performed after storage of stool samples, collected during the at-home phase (day 1-6) preceding the Follow-up visit on day 7.]
• Duodenal microbiota composition [Time frame: Analyses wil be performed after storage of duodenal samples, collected during the gastroduodenoscopy on day 7 (Follow-up visit).]

Eligibility criteria

\* Inclusion criteria:

Patients eligible for inclusion in this study must meet all of the following criteria:

• Diagnosis of Parkinson's Disease by a neurologist according to the Movement Disorder Society Clinical Diagnostic Criteria for PD
• Signed informed consent form
• Aged 18-75 years old
• Able to understand the study and questionnaires, and comply with study requirements

Controls eligible for inclusion in this study must meet all of the following criteria:

• Aged 40-75 years old
• Signed informed consent form
• Able to understand the study and questionnaires, and comply with study requirements

• Exclusion criteria:

Participants eligible for this study must not meet any of the following criteria:

Patients and controls:

• Gastrointestinal: diagnosis of organic gastrointestinal diseases potentially affecting the assessments during the study (e.g. inflammatory bowel disease (IBD), celiac disease, eosinophilic diseases of the gastro-intestinal tract, gastro-intestinal cancer, diverticulitis in the last 6 months, GI infection in the last 3 months, …).
• Surgery: major abdominal surgery (including, but not limited to: cholecystectomy, colectomy, hiatal hernia repair, …) except for uncomplicated appendectomy, splenectomy and inguinal hernia repair.
• Medication use:

• Any previous exposure to medication used in the treatment of motor symptoms of Parkinson's disease (levodopa, dopamine agonists, MAO-B inhibitors, COMT-inhibitors, NMDA-receptor antagonists, anticholinergics)
• Antibiotics use in the last 3 months.
• Use of PPI in the last month.
• Use of NSAID in the last month.
• Use of anticoagulation4 (including vitamin K antagonists (VKA), direct oral anticoagulants (DOAC) or low-molecular weight heparins (LMWH)) or dual antiplatelet therapy4 (DUAPT; Acetylsalicilic acid (Asaflow®) + P2Y12-inhibitor (Clopidogrel®)).
• Pregnancy and breastfeeding.
• Other: Cancer and/or adjuvant treatment within the last 6 months
• Exposures:

• Food intoxication in the last 3 months.
• Consumptom of more than 2 standard units of alcohol per day.

Patients (additional criteria)

1\. Neurological: any major neurological disorder other than Parkinson's disease.

Controls (additional criteria)

• Neurological:

• A diagnosis of Parkinson's disease or any other major neurological disorder other than Parkinson's disease.
• Clinical signs of parkinsonism.
• First degree relative(s) with Parkinson's disease.
• Gastrointestinal: subjects fulfilling a clinical diagnosis of either Functional dyspepsia, Functional constipation, or Irritable bowel syndrome based on the ROME-IV diagnostic criteria.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Cohort

Study locations

Belgium · 1 center

• UZ Leuven — Leuven

Identifiers

NCT: NCT07418658 · s71449

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗