Role of Nasal Dysbiosis in Parkinson Disease (SMELLPARK)

• ClinicalTrials.gov Identifier: NCT04249245
• Recruitment Status: Recruiting
• First Posted: January 30, 2020
• Last Update Posted: February 17, 2020
• Sponsor: Institut Pasteur
• Information provided by (Responsible Party): Institut Pasteur

Study Description

Brief Summary:

Olfactory dysfunction is frequent in Parkinson Disease (PD) and may be present years before the motor symptoms appear. The early olfactory dysfunction could result from environmental factors acting through the nasal cavity such as microbial communities. In across-sectional bicentric study, groups of 160 PD patients and 160 controls will be compared for nasal microbiota composition according to their geographical origin. We will search an association between microbiota and the presence of an olfactory deficit, cognitive deficit and thymic disorder.

Condition or disease	Intervention/treatment
Parkinson Disease	Other: Nasal Swab

Detailed Description:

Olfactory dysfunction is frequent in Parkinson Disease (PD) and may be present years before the motor symptoms appear. The early olfactory dysfunction could result from environmental factors acting through the nasal cavity such as microbial communities. Local inflammation induced by a nasal bacterial dysbiosis (microbiota imbalance) could lead to early neuronal dysfunctions in the olfactory system propagating in all the brain, thus inducing motor, cognitive and emotional manifestations in PD, in keeping with the Braak's stage hypothesis. We propose a translational project aiming at investigating the potential influence of nasal dysbiosis in PD pathogenesis. First, we will analyze both olfaction and nasal microbiota in a large series of PD patients and test the link between olfactory deficits and nasal dysbiosis. Then, we will take advantage of studying two populations of subjects with a very different environmental exposure (in mainland France and French West Indies) to isolate the abnormalities of the nasal microbiota that could be specific for PD. The study will be performed in 160 patients and 160 healthy volunteers. Patients will be enrolled in two investigators sites of which different environmental exposure: 1) Guadeloupe Hospital, French West Indies and 2) Pitie-Salpetriere Hospital, Paris, France. The patient selection will be conducted in consultation with the physician and it will be proposed to the spouse to participate as controls. The study subjects will be enrolled after collecting their informed consent.

As soon as the study subjects are included, the following measurements will be done at once at the inclusion:

• Neurological assessment: Idiopathic PD. Severity of the disease will be evaluated using the Hoehn and Yahr staging. Non-motor manifestations of the disease will be assessed using the Non-Motor Symptoms Scale (NMSS). Severity of REM behavior disorder will be evaluated using the Innsbruck REM sleep behaviour disorder inventory .
• Olfactory function: Olfactory performance will be measured using (a) the Sniffin' Stick test battery (Burghardt, Wedel, Germany) following a standardized procedure and (b) a discrimination test of odorant mixtures developed by the Research Unit.
• Global cognitive performance and executive functions: The Montreal Cognitive Assessment (MoCA) will be used to assess global cognitive performance. Frontal Assessment Battery (FAB) will be used to detect executive dysfunction.
• Memory: The delayed paragraph recall index from the Wechsler Memory Scale IV-Revised will be employed as a valid, sensitive measure of verbal declarative memory and a surrogate marker of hippocampal function.
• Mood disorders: Two self-questionnaires will be used: the Snaith-Hamilton pleasure scale to assess anhedonia severity, and the Quick inventory of depressive symptomatology-self-rated for depression intensity evaluation. Two clinician rating tests for depression severity will also be used: the Hamilton Depression Rating Scale 17 and the MINI.

Sampling of human microbiota will be performed at the end. Subjects will undergo nasal brushing from anterior nares after local epinephrine application with a sterile flocked swab inserted and gently rolled around the inside of both nostrils. Swabs (one per nostril) will be placed on ice immediately after collection and then frozen at -80°C before shipment to the Research Unit (Institut Pasteur) where analyses will be carried out:

• Immunohistochemistry analysis: The levels of Neuroinflammation and aSyn proteins will be analyzed in the nasal tissue samples.
• Microbiome analysis: Microbial composition will be determined by metagenomic (pan-bacterial 16S rRNA gene sequencing).

Study Design

• Study Type: Observational
• Estimated Enrollment: 320 participants
• Observational Model: Case-Control
• Time Perspective: Cross-Sectional
• Official Title: Role of Nasal Dysbiosis in Parkinson Disease
• Actual Study Start Date: February 14, 2020
• Estimated Primary Completion Date: February 28, 2022
• Estimated Study Completion Date: July 30, 2023

Groups and Cohorts

Group/Cohort	Intervention/treatment
Parkinson Patients; These patients are Hospitalized or consult in the participating hospitals of the Pointe à Pitre (Guadeloupe), or at the Pitié-Salpêtrière hospital (Paris). They were diagnosed Idiopathic PD (Parkinson Disease). The diagnosis is made according to the MDS criteria described in Postuma and al. 2015.	Other: Nasal Swab; All
Control Subjects; They are Spouse of Parkinson Patients group , with an age difference <5 years compared to the patient concerned. If the Spouse can't be included, a corresponding control subject could be recruited in the consultation with an age difference <5 years compared to the patient concerned, in respecting the final gender ratio of the PD group.	Other: Nasal Swab; All

Outcome Measures

Primary Outcome Measures :

1. Bacterial composition of the nasal swab samples based on 16S sequencing of DNA [ Time Frame: 3 years ]
   The operational taxonomic units (OTU) will be constructed and comparison between groups will be performed.

Secondary Outcome Measures :

1. Epidemiological characteristics of patients PD [ Time Frame: 3 years ]
   Demographic variables (locations of residence and types of housing), risk factors (activities, diet, history family).
2. Olfactory function [ Time Frame: 3 years ]
   Olfactory performance will be measured using the Sniffin' Stick test battery (Burghardt, Wedel, Germany) following a standardized procedure and a discrimination test of odorant mixtures developed by the Research Unit
3. Neurological assessment: Idiopathic PD - Hoehn and Yahr staging. [ Time Frame: 3 years ]
   Severity of the disease will be evaluated using the Hoehn and Yahr staging.
4. Neurological assessment: Idiopathic PD - Non-Motor Symptoms Scale (NMSS) [ Time Frame: 3 years ]
   Severity of non-motor manifestations of the disease will be assessed using the Non-Motor Symptoms Scale (NMSS).
5. Neurological assessment: Idiopathic PD - the Innsbruck REM sleep behaviour disorder inventory [ Time Frame: 3 years ]
   Severity of REM behavior disorder will be evaluated using the Innsbruck REM sleep behaviour disorder inventory .
6. Global cognitive performance - MoCA [ Time Frame: 3 years ]
   The Montreal Cognitive Assessment (MoCA) will be used to assess global cognitive performance.
7. Executive functions [ Time Frame: 3 years ]
   Frontal Assessment Battery (FAB) will be used to detect executive dysfunction.
8. Memory Function [ Time Frame: 3 years ]
   The delayed paragraph recall index from the Wechsler Memory Scale IV-Revised will be employed as a valid, sensitive measure of verbal declarative memory and a surrogate marker of hippocampal function.
9. Mood disorders - the Snaith-Hamilton pleasure scale [ Time Frame: 3 years ]
   The Snaith-Hamilton pleasure scale (self-questionnaire) will be used to assess anhedonia severity,
10. Mood disorders - the Quick inventory of depressive symptomatology-self-rated [ Time Frame: 3 years ]
    The Quick inventory of depressive symptomatology-self-rated will be used for depression intensity evaluation.
11. Mood disorders - the Hamilton Depression Rating Scale 17 [ Time Frame: 3 years ]
    The Hamilton Depression Rating Scale 17, a clinician rating test, will also be used to assess depression severity.
12. Mood disorders - the MINI [ Time Frame: 3 years ]
    The MINI, a clinician rating test, will also be used to assess depression severity.

Biospecimen Retention:   Samples With DNA

Nasal bacterial swab sample

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes
• Sampling Method: Non-Probability Sample

Study Population

Parkinson patients and control subjects (spouse or matched controls)

Criteria

Inclusion Criteria:

Patients (PD)

• Age > 18 years
• Idiopathic PD
• In Guadeloupe (N=80) : living for more than 15 years in Caribbean, including the 5 first years.
• In Paris (N=80): living for more than 15 years in mainland France, including the 5 first years.

Controls

• Age > 18 years
• Spouse of enrolled PD patient or matched controls, with age difference between spouses <5 years. When the spouse cannot be included, a matched control respecting the PD group's final sex ratio and with an age difference <5 years relative to the concerned PD case will be enrolled.

Exclusion Criteria (both PD patients and controls)

• Presence of a cold or acute pathology which could explain an original olfactory disorder other than Parkinson's disease
• Use of nasal antiseptics within the last 3 months
• Refusal of or contraindication to nasal microbiota sampling

Contacts and Locations

Contacts

Contact: Annie LANNUZEL, MD, PhD; + 33 (0) 5 90 89 14 30; annie.lannuzel@chu-guadeloupe.fr

Contact: Françoise LAZARINI, PhD; + 33 (0) 1 44 38 92 74; francoise.lazarini-serandour@pasteur.fr

Locations

France

Pitie-Salpetriere Hospital; Recruiting

Paris, France, 75013

Contact: Emmanuel ROZE, MD, PhD emmanuel.flamand-roze@aphp.fr

Guadeloupe

Centre Hospitalier Universitaire; Not yet recruiting

Pointe-à-Pitre, Guadeloupe

Contact: Annie LANNUZEL, MD, PhD annie.lannuzel@chu-guadeloupe.fr

Sponsors and Collaborators

Institut Pasteur

More Information

• Responsible Party: Institut Pasteur
• ClinicalTrials.gov Identifier: NCT04249245
• Other Study ID Numbers: 2019-030
• First Posted: January 30, 2020
• Last Update Posted: February 17, 2020
• Last Verified: February 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Institut Pasteur:

Olfaction; Microbiota; Dysbiosis; Metagenomic analysis

Additional relevant MeSH terms:

Parkinson Disease; Dysbiosis; Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Neurodegenerative Diseases; Pathologic Processes