Precision Probiotic Supplementation in Individuals With Mild Cognitive Impairment

Precision Probiotic Supplementation in Individuals With Mild Cognitive Impairment: a Randomized Controlled Trial

The overarching goal of this randomized-controlled trial is to investigate the role and mechanism of the microbiota-gut-brain axis in MCI. The main questions it aims to answer are:

Aim 1: To investigate the association between gut microbiota, MCI and AD biomarkers. Investigators plan to compare gut microbiota profiles in a well-characterized cohort between individuals with MCI and cognitively normal adults using metagenomics sequencing data. Also, the relationship between gut microbiota and AD biomarkers, such as amyloid PET and plasma tau, will be explored in MCI and cognitively normal adults.

Aim 2: To determine the efficacy of precision probiotic supplementation on cognitive decline (primary outcome) and functional brain changes (secondary outcome) in individuals with MCI due to AD using a randomized, double-blind, placebo-controlled trial. Investigators plan to recruit 120 individuals with MCI due to AD, i.e., MCI with positive amyloid biomarkers. Participants will be randomized to a 12-month supplement of precision probiotics based on the individual gut probiotic profile or placebo. The primary outcome measure will be the changes in cognitive functions over 6 months (primary endpoint) and 12 months. The secondary outcome measure will be resting-state functional brain changes.

Aim 3: To investigate potential mediators underlying the effect of probiotic supplementation. The most apparent mediator will be a shift or changes in gut microbiota. Other potential mediators will be related to decreased lipopolysaccharide, proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6 and IL-10, and increased brain- derived neurotrophic factor, short-chain fatty acid, etc.

Study Overview

• Status: Not yet recruiting
• Conditions: Mild Cognitive Impairment
• Intervention / Treatment: Dietary supplement: Precision probiotics

Detailed Description

Given the rapidly aging trend worldwide and in Taiwan, the disease burden and economic impact of dementia on families, healthcare systems, and society are expected to increase unprecedentedly. It is estimated that interventions that could delay the clinical onset of dementia by a modest one year would significantly reduce the prevalence of dementia. Mild cognitive impairment (MCI) presents an early stage of cognitive impairment with a much higher risk of progression to dementia and a unique stage, potentially amenable to intervention, preventing further decline to dementia.

The microbiota-gut-brain axis is one of the most-studied gut-organ systems, and accumulating evidence shows gut microbiota might play a critical role in the pathogenesis of Alzheimer's disease (AD). However, the role of gut microbiota in the early stage of the AD spectrum, such as MCI, is unclear. Also, the effects of the probiotic supplements on cognition in patients with AD or MCI from several small randomized-controlled trials were inconsistent. Fixed regimens of probiotics were used in all these trials, and patients with MCI diagnosed by diverse research frameworks were included. As a result, the overarching goal of this proposal is to investigate the role and mechanism of the microbiota-gut-brain axis in MCI. Investigators will use data from a well-characterized cohort and a randomized controlled trial with a "precision" probiotic supplementation, i.e., a probiotic supplement based on individual gut probiotic profile, in a group of MCI due to AD, i.e., MCI with positive amyloid biomarkers.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Chi-Chuan Wei; Phone Number: 65227 +886-2-2826-7000; Email: chichuan20708@gmail.com
• Study Contact Backup: Name: Yi-Fang Chuang; Phone Number: 7981 +886-2-2826-7000; Email: chuangy@nycu.edu.tw

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• 60 years old and above
• Diagnosis of MCI based on 2011 NIA-AA criteria
• Amyloid (+) measured by either amyloid PET imaging or CSF amyloid markers
• No dietary supplements, including other probiotics, yogurts with live, active cultures or supplements, and immune-enhancing supplements in the past three months (or wash-out period for three months for individuals taking supplements)
• No use of antibiotics, anti-inflammatory medications, gastrointestinal medicine within the past three months (or wash-out period for three months for individuals taking medications)
• Consenting to be randomly assigned intervention

Exclusion criteria:

• Currently undergoing cancer treatment.
• The anticipated life expectancy of less than six months.
• Suffering from severe mental disorders such as schizophrenia, bipolar disorder, or major depressive disorder.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Precision probiotics; The precision probiotics will be designed based on the results of probiotic signatures and consensus clustering described in the PRELIMINARY AND SUPPORTING Data section and available probiotics from GenMont Biotech Inc. (https://www.genmont.com.tw/)	Dietary supplement: Precision probiotics; The precision probiotics will be designed based on the results of probiotic signatures and consensus clustering described in the PRELIMINARY AND SUPPORTING Data section and available probiotics from GenMont Biotech Inc. (https://www.genmont.com.tw/) The individual gut microbiota will determine the supplement and composition of probiotics.
Placebo Comparator: Placebo (wait-list group); Placebo packets or capsules will be composed of maize starch only and be identical in appearance, weight, and smell. After completing trials, the Placebo group will be provided with a 6- month precision probiotic supplement.	Dietary supplement: Precision probiotics; The precision probiotics will be designed based on the results of probiotic signatures and consensus clustering described in the PRELIMINARY AND SUPPORTING Data section and available probiotics from GenMont Biotech Inc. (https://www.genmont.com.tw/) The individual gut microbiota will determine the supplement and composition of probiotics.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The changes in attention	The primary outcome measure is the change in standardized scores (z-scores) for attention after 12 months. The average of the standardized scores of forward and backward digit Span subtest, digit symbol substitution subtests and symbol Searching subtest of the Wechsler Adult Intelligence Scale-III (WAIS-3) will represent the score for that domain, with higher scores indicating better performance.	baseline, 3 months, 6 months, 12 months postintervention
The changes in memory	The primary outcome measure is the change in scores for the memory after 12 months. In the memory domain, the Logical Memory subset of the Wechsler Memory Scale (Hua et al., 1997) will be used, with higher scores indicating better performance.	baseline, 3 months, 6 months, 12 months postintervention
The changes in executive function	The primary outcome measure is the change in standardized scores (z-scores) for executive function after 12 months. The average of the standardized scores of the color trails test, stroop color and word test, and verbal fluency test will represent the score for that domain, with higher scores indicating better performance.	baseline, 3 months, 6 months, 12 months postintervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The changes in global cognition at the 12th month from baseline.	Mental State Examination measures global cognition and screening tools for cognitive impairment in older, community-dwelling, hospitalized, and institutionalized adults. The education adjusted cut-off was used to indicate impaired global cognition. It has been translated into Chinese for clinical use in Taiwan. It has a maximum score of 30 points, with higher scores indicating better global cognition.	baseline, 6months, 12 months postintervention
The changes in brain imaging at the 12th month from baseline.	The brain Magnetic Resonance Imaging (MRI) will be performed on a 3-Tesla Magnetom Scanner in the Far-Eastern Memorial Hospital or the Cardinal Tien Hospital. The scanning protocol will consist of the following: whole-brain T1 magnetization-prepared rapid gradient-echo sequence, T2-weighted turbo spin-echo sequence, FLAIR pulse sequence, diffusion tensor imaging, and 6-min resting-state fMRI imaging using gradient-echo echo-planar imaging. During the resting-state fMRI, patients will be told to relax with closed eyes without concentrating on anything particular.	baseline, 6months, 12 months postintervention

Collaborators and Investigators

• Sponsor: National Yang Ming University
• Collaborators: Far Eastern Memorial Hospital; National Science and Technology Council
• Investigators: Study Chair: Yen-Ling Chiu, Far Eastern Memorial Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): March 18, 2024
• Primary Completion (Estimated): July 31, 2025
• Study Completion (Estimated): July 31, 2027

Study Registration Dates

• First Submitted: November 13, 2023
• First Submitted That Met QC Criteria: February 19, 2024
• First Posted (Estimated): February 26, 2024

Study Record Updates

• Last Update Posted (Estimated): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 19, 2024
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction
• Other Study ID Numbers: 112R10438Y

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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