Role of Nasal Dysbiosis in Parkinson Disease (SMELLPARK)

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.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease
• Intervention / Treatment: 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 Type: Observational
• Enrollment (Estimated): 320

Contacts and Locations

• Study Contact: Name: Annie LANNUZEL, MD, PhD; Phone Number: + 33 (0) 5 90 89 14 30; Email: annie.lannuzel@chu-guadeloupe.fr
• Study Contact Backup: Name: Françoise LAZARINI, PhD; Phone Number: + 33 (0) 1 44 38 92 74; Email: francoise.lazarini-serandour@pasteur.fr

Study Locations

• France
  • Paris, France, 75013
    • Recruiting
    • Pitie-Salpêtrière Hospital
    • Contact: Emmanuel ROZE, MD, PhD; Email: emmanuel.flamand-roze@aphp.fr
• Guadeloupe
  • Pointe-à-Pitre, Guadeloupe
    • Not yet recruiting
    • Centre Hospitalier Universitaire
    • Contact: Annie LANNUZEL, MD, PhD; Email: annie.lannuzel@chu-guadeloupe.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Parkinson patients and control subjects (spouse or matched controls)

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Epidemiological characteristics of patients PD	Demographic variables (locations of residence and types of housing), risk factors (activities, diet, history family).	3 years
Olfactory function	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 years
Neurological assessment: Idiopathic PD - Hoehn and Yahr staging.	Severity of the disease will be evaluated using the Hoehn and Yahr staging.	3 years
Neurological assessment: Idiopathic PD - Non-Motor Symptoms Scale (NMSS)	Severity of non-motor manifestations of the disease will be assessed using the Non-Motor Symptoms Scale (NMSS).	3 years
Neurological assessment: Idiopathic PD - the Innsbruck REM sleep behaviour disorder inventory	Severity of REM behavior disorder will be evaluated using the Innsbruck REM sleep behaviour disorder inventory .	3 years
Global cognitive performance - MoCA	The Montreal Cognitive Assessment (MoCA) will be used to assess global cognitive performance.	3 years
Executive functions	Frontal Assessment Battery (FAB) will be used to detect executive dysfunction.	3 years
Memory Function	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.	3 years
Mood disorders - the Snaith-Hamilton pleasure scale	The Snaith-Hamilton pleasure scale (self-questionnaire) will be used to assess anhedonia severity,	3 years
Mood disorders - the Quick inventory of depressive symptomatology-self-rated	The Quick inventory of depressive symptomatology-self-rated will be used for depression intensity evaluation.	3 years
Mood disorders - the Hamilton Depression Rating Scale 17	The Hamilton Depression Rating Scale 17, a clinician rating test, will also be used to assess depression severity.	3 years
Mood disorders - the MINI	The MINI, a clinician rating test, will also be used to assess depression severity.	3 years

Collaborators and Investigators

• Sponsor: Institut Pasteur

Study record dates

Study Major Dates

• Study Start (Actual): February 14, 2020
• Primary Completion (Estimated): April 30, 2024
• Study Completion (Estimated): April 30, 2024

Study Registration Dates

• First Submitted: January 20, 2020
• First Submitted That Met QC Criteria: January 29, 2020
• First Posted (Actual): January 30, 2020

Study Record Updates

• Last Update Posted (Actual): October 2, 2023
• Last Update Submitted That Met QC Criteria: September 29, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Microbiota; Olfaction; Dysbiosis; Metagenomic analysis
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Dysbiosis
• Other Study ID Numbers: 2019-030

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No