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Exploring the Gut-Brain Axis in Ageing and Neurodegeneration

Study Purpose

Neurodegenerative diseases are a major health concern due to their growing societal implications and economic costs. The identification of early markers of pathogenic mechanisms is one of the current main challenges. The gut-brain axis has become a primary target because of its transversal role across the neurodegenerative spectrum and its effect on cognition. However, despite recent progress, how changes in the gut-microbiota composition can affect the human brain is still unclear. The goal of this observational study is to characterise the gut-microbiota composition associated with alterations in brain structure and function during the ageing process and across neurodegenerative disorders. This is based on recent studies showing that changes in the human brain and in the microbiota composition, can indicate very sensitively and in a predictive way pathological development and, consequently, be used as markers of neurodegenerative diseases. The main questions it aims to answer are:

- How variation in the gut-microbiota composition correlates with the normal brain ageing trajectory? - How dysregulation in the gut-microbiota correlates with pathological changes in brain regions in specific neurodegenerative disorders? - Can the impact of the gut-microbiota on the brain be modulated by blood biomarkers? The investigators will recruit 40 young healthy participants, 40 old healthy participants, 40 participants with prodromal Alzheimer's Disease, 40 participants with Parkinson's Disease and 40 participants with Multiple Sclerosis.

Participants will undergo the following examinations:

- Magnetic Resonance Imaging.

- Analysis of a stool sample.

- Analysis of a blood sample.

- Neuropsychological assessment.

- Questionnaires on eating habits

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	Yes
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Observational
Eligible Ages	20 Years - 90 Years
Gender	All

More Inclusion & Exclusion Criteria

INCLUSION CRITERIA:

Healthy Young and Old Subjects:

- 20-50 or 60-90 years old.

- Cognitively healthy (Mini-Mental State examination ≥ 26) - Absence of significant neurological disorders.

Patients with prodromal Alzheimer's Disease:

- Subjective cognitive complaint (corroborated by the informant) - Episodic memory deficit on neuropsychological testing.

- Clinical Dementia Rating = 0.5.

- Mini-Mental State Examination (MMSE) > 23.

- Independently functioning in activities of daily living.

Patients with Parkinson's Disease:

- Recent diagnosis of Parkinson's Disease.

- Mild-moderate score at the Unified Parkinson's Disease Rating Scale (UPDRS) - Cognitively healthy (Mini-Mental State examination ≥ 26) - In case of taking medications for Parkinson's Disease: stable dosage for at least 6 months.

Patients with Multiple Sclerosis:

- Recent diagnosis of relapsing-remitting Multiple Sclerosis.

- Expanded Disability Status Scale score ≤ 4.0.

- Cognitively healthy (Mini-Mental State examination ≥ 26) - In case of taking medications for Multiple Sclerosis: stable dosage for at least 6 months.

EXCLUSION CRITERIA:

For both healthy participants and patients:

- Contraindications to magnetic resonance imaging (metal implant in body, known claustrophobia, pacemakers) - Severe comorbidities.

- Antibiotics treatments over the last 3 months

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT05934188
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	IRCCS San Camillo, Venezia, Italy
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Nicola Filippini
Principal Investigator Affiliation	IRCCS San Camillo, Venezia, Italy
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Recruiting
Countries	Italy
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Healthy, Prodromal Alzheimer's Disease, Parkinson Disease, Multiple Sclerosis

Additional Details

Recent studies show that alterations in the microbiota profile has been observed in the ageing process and across neurodegenerative disorders and it has been associated with cognitive decline and disease-specific clinical symptoms. The objective of this multicenter observational cross-sectional cohort study is to characterise how changes in the gut-microbiota profile may affect brain changes during the physiological ageing processes and across neurodegenerative disorders with different etiopathogenesis. The investigators will combine novel magnetic resonance imaging and biological techniques to test these hypotheses: 1. Specific functional and structural changes, which reflect unsuccessful compensatory mechanisms to counteract ageing, are associated with changes in the gut-microbiota composition. 2. Neurodegenerative disorders (prodromal Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis) show unique changes in the gut-microbiome profile, associated with specific structural and functional brain changes. 3. The microbiota profile characterizing the unsuccessful ageing and different neurodegenerative diseases is associated with alterations in blood biomarkers. For this study the investigators plan to recruit 80 healthy subjects divided into two groups (40 subjects aged 20-50 years and 40 subjects aged 60-90 years) and 120 patients divided into three groups (40 patients with prodromal Alzheimer's Disease, 40 patients with Parkinson's Disease and 40 patients with Multiple Sclerosis). All participants will undergo a multimodal Magnetic Resonance Imaging protocol to study the brain structure and function and a detailed neuropsychological protocol to assess cognitive functioning. In addition, stool and blood samples will be collected to investigate the gut-microbiota composition and the presence of inflammatory markers, respectively. Participants will also be asked to fill out questionnaires on eating habits. There are no known risks or long-term side effects related to Magnetic Resonance Imaging. The performance of the examination does not involve physical or mental impairment. The study does not directly benefit the participant. However, participation in the study will increase knowledge in the area of the relationship between the gut microbiota and the brain, providing potential new knowledge useful for preventing the risk of developing neurodegenerative processes. The study takes place at San Camillo IRCCS S.r.l. (70 Alberoni street, Lido VE, 30126, Italy IT). The study started on 01/05/2023 and the end is planned for 30/04/2026. The submitted study is funded by the Ministry of Health through a finalized research call won by Principal Investigator, Dr. Nicola Filippini, and approved by Ethics Committee for Clinical Trials of the Province of Venice and IRCCS San Camillo, Azienda ULSS 3 Serenissima.

Arms & Interventions

Arms

: Young Healthy Subjects (N = 40)

20-50 years old Cognitively healthy (Mini-Mental State examination ≥ 26) Absence of significant neurological disorders

: Old Healthy Subjects (N = 40)

60-90 years old Cognitively healthy (Mini-Mental State examination ≥ 26) Absence of significant neurological disorders

: Patients with prodromal Alzheimer's Disease (N = 40)

Subjective cognitive complaint (corroborated by the informant) Episodic memory deficit on neuropsychological testing Clinical Dementia Rating = 0.5 Mini-Mental State Examination (MMSE) > 23 Independently functioning in activities of daily living

: Patients with Parkinson's Disease (N = 40)

Recent diagnosis of Parkinson's Disease Mild-moderate score at the Unified Parkinson's Disease Rating Scale (UPDRS) Cognitively healthy (Mini-Mental State examination ≥ 26) In case of taking medications for Parkinson's Disease: stable dosage for at least 6 months

: Patients with Multiple Sclerosis (N = 40)

Recent diagnosis of relapsing-remitting Multiple Sclerosis Expanded Disability Status Scale score ≤ 4.0 Cognitively healthy (Mini-Mental State examination ≥ 26) In case of taking medications for Multiple Sclerosis: stable dosage for at least 6 months

Interventions

Diagnostic Test: - Magnetic Resonance Imaging

The Magnetic Resonance Imaging protocol will comprise both structural and functional sequences.

Behavioral: - Neuropsychological protocol

Neuropsychological tests will be administered to participants to assess general cognitive state and a range of high-level cognitive functions (memory, executive, language). In addition, disease-specific tests will be administered to patients to investigate disease staging and the level of disability and autonomy.

Behavioral: - Eating habits

Information on eating habits will be derived from food questionnaires.

Diagnostic Test: - Microbiome analyses

The Microbiome analyses will be derived from a stool sample (16S rRNA sequencing targeted metagenomic analyses).

Diagnostic Test: - Inflammatory markers

Inflammatory markers will be evaluated in terms RNA expression level in plasma blood sample.

Diagnostic Test: - Alzheimer's Disease biomarkers

The Alzheimer's Disease biomarkers will be measured in the plasma of prodromal Alzheimer's Disease patients.

Contact a Trial Team

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