Levodopa Response and Gut Microbiome in Patients With Parkinson's Disease

Study Overview
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Brief Summary
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Levodopa (LD) is an effective treatment to control symptoms of Parkinson's disease (PD). However, the response to (the effectiveness) LD changes over time and patients require higher and more frequent LD doses for treatment. The purpose of this study is to identify what reasons or causes might influence the changes in LD effectiveness, particularly if intestinal bacteria contribute to the breakdown of LD in patients with PD. This study is an observational cohort proof-of-concept study that follows PD patients who take PD at high-frequency doses and low-frequency doses. . Each PD patient will have a household healthy control/spouse enrolled into the study. Single patients with no spouse will still be eligible to enroll.

Detailed Description
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Levodopa (LD) is an effective treatment to control symptoms of Parkinson's disease (PD) and during the first few years of LD treatment patients are said to experience a 'honeymoon' period, reflective of a sustained beneficial response to this dopamine pro-drug. However, the response to LD changes over time and patients require higher and more frequent LD doses. Most patients develop motor response complications such as frequent periods of immobility and involuntary movements. The major unmet need is to preserve the initial, stable, response to LD and prevent the development of motor response complications. It is therefore essential to identify the underlying mechanism for the changes in LD effectiveness. This study involves only 1 study visit. Prior to the study visit, participants will be asked to complete questionnaires and will receive an at-home stool collection kit. At the time of the study visit, participants will turn in their questionnaires and their at-home stool sample. On the day of the study visit, the patient will have fasted (overnight for 8 hours) and taken their last LD medication 12 hours prior to the visit. Each patient (and healthy control) will bring a home collected stool sample to their scheduled research visit which will be taken and stored in -80 freezers for the microbiota analysis. Oral swab will be collected for oral microbiota analysis. For PD patients only, an indwelling catheter for blood draws will be placed by one of the highly experienced GI infusion nurses and a fasting blood sample will be drawn. At the time of the visit, each patient will be given their morning LD dose (1.5 times their usual dose as they did not take LD for 12 hours), and then both patients and their controls will be given lactulose (20 mg) and have their breath collected every 10 minutes for the first hour, and then every 15 minutes for the following 3 hours (total 4 hours) for measurement of breath hydrogen and methane to assess mouth to cecum transit and presence/absence of small bowel bacteria overgrowth. PD patients will also have a blood sample drawn every 30 minutes, for 4 hours (total 8 draws) to measure LD and LD metabolites in the plasma Patients and controls will be provided a light breakfast (2 white wheat bread toasts with thin layer of butter and coffee). Each patient and control will complete a detailed dietary questionnaire (FFQ and 24 hour diet recall), a food timing questionnaire and screener and a structured demographic questionnaire. PD patients will also complete a questionnaire that includes PD-related information. Patients will also perform a simple finger tapping task to asses and quantify speed of movement before, during and after completion of study. Finger tapping task will be done using 2 mechanical counters mounted on a board. The patients go back and forth between these two counters and the number of taps in 30 seconds will be automatically recorded. In addition, patients will log their motor state (OFF versus ON) every half an hour on a PD diary.

Official Title
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Levodopa Response and Gut Microbiome in Patients With Parkinson's Disease

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: Low dose levodopa
* Drug: High dose levodopa


Participation Criteria
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Eligibility Criteria
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FOR PATIENTS WITH PD: Inclusion Criteria: Documented diagnosis of Parkinson's disease On Levodopa treatment Exclusion Criteria: History of GI diseases [except for hemorrhoids or occasional (<3 times a week) heartburn] like Inflammatory bowel disease or Celiac disease Antibiotic use within last 12 weeks Use of probiotic supplement over the prior 2 weeks except yogurt Intentional change in diet Chronic use of NSAIDS. A washout period of 3 weeks is needed before the subject could be enrolled into the study. Low does aspirin is allowed. FOR CONTROL GROUP: Inclusion Criteria: No clinical evidence of neurological disorders including Parkinson's disease Live in the same household as the Parkinson's Disease patient or is a first degree relative of the PD patient. Exclusion Criteria: History of GI diseases [except for hemorrhoids or occasional (<3 times a week) heartburn] like Inflammatory bowel disease or Celiac disease Antibiotic use within last 12 weeks Use of probiotic supplement over the prior 2 weeks except yogurt Intentional change in diet Chronic use of NSAIDS. A washout period of 3 weeks is needed before the subject could be enrolled into the study. Low does aspirin is allowed.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1<br>PD patients receiving low frequency dose of levodopa. | Drug: Low dose levodopa<br>* Low frequency is defined as ≤ 3 LD doses a day<br>|
| Group 2<br>PD patients receiving high frequency dose of levodopa. | Drug: High dose levodopa<br>* High frequency dosage is defined as ≥ 5 LD doses per day<br>|
| Control Group<br>Spouses of PD patients without PD diagnosis | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fecal microbial community structure and functional changes for phylum, genus and species taxonomic level bacteria, virus, fungi, and archaea. | Quantitative polymerase chain reaction (qPCR), 16S rRNA Sequencing and Shotgun Metagenomics | During the study visit,1 day | 
| Oral microbial community structure and functional changes for phylum, genus and species taxonomic level bacteria, virus, fungi, and archaea. | Quantitative polymerase chain reaction (qPCR), 16S rRNA Sequencing and Shotgun Metagenomics | During the study visit,1 day | 
| Change in the measurement of blood biomarker levodopa (ng/mL) over 12 time frames | ELISA (enzyme-linked immunosorbent assay) | During the study visit,1 day | 
| Change in the measurement of blood biomarker glucagon-like peptide-1 (GLP-1) (pm) over 12 time frames | ELISA (enzyme-linked immunosorbent assay) | During the study visit,1 day | 
| Change in the measurment scores of breath hydrogen and methane to assess mouth to cecum transit and presence or absence of small bowel bacteria overgrowth over 16 time frames. | Lactulose Breath Scoring Test | During the study visit,1 day | 
| Change in the measurement of blood levodopa metabolomics concentrations (ug/mL) across 12 time frames. | Gas Chromatography - Tandem Mass Spectrometry (GC-MS/MS) | During the study visit,1 day | 
| Changes in the measurement of blood targeted short chain fatty acids (SCFA) metabolomics concentrations (ug/mL) for acetate, propionate, butyrate and total SCFA across 12-time frames | Gas Chromatography - Tandem Mass Spectrometry (GC-MS/MS) | During the study visit,1 day | 
| Change in the measurement of blood targeted trimethylamine N-oxide (TMAO) concentrations (uM) across 12 time frames | Liquid Chromatography-Mass Spectrometry (LC-MS/MS) | During the study visit,1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Food Timing Screener | Food Timing Screener (FTS) questionnaire. A structured food demographics questionnaire was therefore developed to access food timing. The questionnaire consists of eight questions asking subjects' eating habits on work days and non-work days. Questions include the time of the main meal during work and non-work days, time of last meal before bed, consistency of dinner within work and non-work days, and consistency of breakfast, lunch, and dinner between work and non-work days. | During the study visit,1 day | 
| Food and Frequency of Consumption | Food Timing Questionnaires (FTQ) consists of a list of foods and the frequency in which these foods are consumed. | During the study visit,1 day | 
| Single day food recall | Automated Self-Administered 24-Hour Recall (ASA24) Dietary Assessment. Total nutrients from all supplements reported in a given day. | During the study visit,1 day | 
| Gastrointestinal Symptom and Severity | Patient-Reported Outcomes Measurements Information System (PROMIS) gastrointestinal questionnaire for Belly Pain (6 questions), Bowel Incontinence (4 questions), Constipation (9 questions), and Gas & Bloating (12 questions). Higher score denoted more GI symptoms. Lower score denotes less GI symptoms. Scores range from 20 (low) to 80 (high). A score of 50 is denoted as the general population. | During the study visit,1 day | 
| Diet change | Vioscreen Food Frequency Questionnaire (FFQ). Total of 19 measured food components. Vioscreen captures comprehensive dietary behaviors in just 30 minutes. It is a unique dietary questionnaire, management and analysis system that efficiently gathers and manages data that immediately identifies dietary habits and counsel for lifestyle changes. | During the study visit,1 day | 
| REM Sleep Behavior Disorder assessment | RBD1Q questionnaire that consists of a single question, answered yes or no, as follows: Have you ever been told, or suspected yourself, that you seem to 'act out your dreams' while asleep (for example, punching, flailing your arms in the air, making running movements, etc.)? | During the study visit,1 day | 
| Sleep Disturbance | The Patient Reported Outcomes Measurement Information System (PROMIS) is a self-reported questionnaire that assess the sleep-wake function in adults. | During the study visit,1 day | 
| Chronotype | The Munich ChronoType Questionnaire (MCTQ) uses a self-rated scale to assess individual phase of entrainment on work and work-free days; it is a tool to collect primary sleep times, such as bed- and rise-times, plus the clock time of becoming fully awake as well as sleep latency and inertia, in addition to other time points. | During the study visit,1 day | 
| Functional status in patients with Parkinson's Disease | The On-Off Parkinson's Disease Diary by Hauser assesses troublesome and non-troublesome dyskinesia through self-reported time markers. | During the study visit,1 day | 
| Motor speed and lateralized coordination | PD patients will take a Finger-Tapping Test (FTT) where hands are laid flat and fingers are lifted one at a time onto two mechanical counters mounted on a board. The patients go back and forth between these two counters and the number of taps in 30 seconds will be recorded. | During the study visit,1 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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levodopa