Gut-brain Health Effects of PREbiotics in Older Adults With Suspected COgnitive DEcline

Subjective Cognitive Decline Clinical Trial

— PRECODE  

Official title:

Gut-brain Health Effects of PREbiotics in Older Adults With Suspected COgnitive DEcline: The PRECODE Study

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06433037
• Other study ID #: NL85910.091.23
• Status: Not yet recruiting
• Phase: N/A
• Start date: June 2024
• Est. completion date: September 2026

Study information

• Verified date: May 2024
• Source: Wageningen University
• Contact: Yannick Vermeiren, PhD
• Phone: +31618520620
• Email: yannick.vermeiren[@]wur.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

As people around the world are living longer, the number of individuals with dementia, particularly Alzheimer's disease (AD), is expected to triple by 2050. There's growing evidence suggesting that our gut health might play a role in the prevention of dementia. The connection between our gut and brain, known as the gut-brain axis, is becoming an important area of study. Research in animals has shown that different types of dietary fibre can improve gut health, brain function, mood, blood sugar level and the immune system and may even prevent certain harmful brain changes seen in Alzheimer's disease. Subjective Cognitive Decline (SCD) is a condition where individuals notice a decline in their mental abilities, and it can be an early sign of Alzheimer's disease.

The goal of this clinical trial is to learn if dietary fibres can improve gut and brain health in older individuals, between the ages of 60 and 79 years, who notice problems in their mental abilities, and meet the criteria of SCD. Three different dietary fibres will be given, and researchers will compare three different fibres to a placebo product to see if there is a difference between the fibres and the placebo.

The main questions it aims to answer are:

1. Does dietary fibre improve working memory?

2. Does dietary fibre improve other markers of brain function?

3. Does dietary fibre improve gut health?

4. Does dietary fibre improve the immune system and blood glucose levels?

5. Does dietary fibre improve mood?

Participants will:

• Consume dietary fibres twice a day, mixed in water, tea or coffee, for a period of 26 weeks

• Have two functional MRI scans, and three additional study visits, where blood, urine and feces will be collected

• Undergo a number of neuropsychological tests, aimed at evaluating brain function

• Fill out questionnaires on their general health, mood, dietary habits, gut health

• Wear smartwatches for one week, at the beginning and the end of the study

Description:

Rationale: Due to the greying of society, a triplication of the number of people with dementia worldwide, with Alzheimer's disease (AD) as the commonest form, is expected by 2050. Compelling evidence points towards a crucial role of intestinal health as one potential etiological modifier of dementia, with the (microbiota) gut-brain axis (MGBA) receiving increasing attention. A number of preclinical studies have demonstrated benefit of various sources of dietary fibre for their capacity to improve gut health, cognitive functioning, general mood, glycaemia, immunogenicity, and, to inhibit tau phosphorylation, the latter which is a hallmark in AD brain. Subjective cognitive decline (SCD) lies on the continuum of AD, and subjects with this condition are at increased risk of further conversion to mild cognitive impairment (MCI) or AD. Currently, no cure is available for AD. Various symptomatic and a few disease-modifying treatments are available, but these treatments only have very limited or mild clinical effects and are often accompanied by severe side effects. Clinical follow-up studies to evaluate the effect of dietary fibre in older adults with suspected cognitive decline are required, but are still lacking to date.

Objective: The primary objective of this study is to investigate the effect of 26 weeks of supplementation with three different dietary fibres (chicory inulin, resistant dextrin, and seaweed polysaccharide) compared to a placebo (maltodextrin) on microbiota gut-brain health effects in older adults (aged 60-79) with Subjective Cognitive Decline Plus (SCD+) by assessing changes in brain function and working memory by blood oxygen level dependant (BOLD) signal activity and task accuracy during n-back task functional magnetic resonance imaging (fMRI) assessment.

The secondary objectives are to investigate the effects of 26 weeks of supplementation with dietary fibre (chicory inulin, resistant dextrin, and, seaweed polysaccharide) compared to placebo (maltodextrin) in older adults on the following parameters related to potential gut-brain pathways:

1. neuropsychological test battery scoring,

2. other relevant brain health parameters,

3. relevant intestinal health parameters, and

4. immune and metabolic parameters.

Study population: 164 older adults (60-79 years) with SCD+.

Study design implementation:

Participants will undergo assessments at baseline (T0), mid-study (T1/2, after 13 weeks) and at study end (T1, after 26 weeks. Each participant will have five study visits in total: two at T0, one at T1/2 and two at T1.

At each of the timepoints the following will be collected/performed at WUR: Sample collection (blood, urine (omitted in week 13), faeces); general cognitive assessments (see NTB; Cognitive Failure Questionnaire (CFQ) (baseline and end only), GDS-15, GAD-7); general physiological measures (blood pressure, BMI, grip-strength); dietary assessment (MIND-adjusted Eetscore, FFQ). At ZGV working memory will be evaluated using BOLD fMRI signalling and task accuracy using an n-back task paradigm. Additionally, high-resolution T1- and T2-weighted anatomical images of main regions of interest (hippocampi, (pre)frontal-, and temporal cortices) will be acquired.

For two periods of one week, corresponding with the baseline and week 26 visits, participants will wear smartwatches. These watches will be worn continuously and data will be gathered regarding cardiovascular functioning (heart rate), physical activity and mood (push messages).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 164
• Est. completion date: September 2026
• Est. primary completion date: September 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years to 79 Years

Eligibility

Inclusion Criteria:

1. Written informed consent

2. Fluency in Dutch (speaking, reading, writing)

3. Age between 60-79 years (at screening)

4. Subjective cognitive decline plus (SCD+), (criteria of Jessen et al.):

4.1 Self-reported worsening of memory; 4.2 Indication of repetitive concerns (worries) associated with SCD; 4.3 With at least one of the following two features present: (i) onset of SCD within the last 5 years; (ii) age at onset =60 years of age;

5. Presence of at least 2 self-reported risk factors for cognitive decline (based on LIBRA criteria): (i) Diabetes mellitus type II (ii) High cholesterol (iii) Hypertension (iv) High BMI (v) Heart disease (vi) Unhealthy diet (lower regular adherence to Mediterranean diet components such as fish, vegetables, olive oil, pasta and red wine)

Exclusion Criteria:

1. Current participation in other intervention trials

2. Technologically illiterate (complete incompetence in working with computers, apps, online questionnaires, smartwatches etc.)

3. No internet access from home

4. Clinical diagnosis of =1 of the following:

• Neurological pathology (e.g. MCI, dementia, multiple sclerosis, Parkinson's disease, epilepsy);

• Current malignant disease(s), with or without treatment;

• Current psychiatric disorder(s) (e.g. major depressive disorder, bipolar disorder, schizophrenia, anxiety, psychosis, PTSD);

• Symptomatic/decompensated cardiovascular disease (e.g. stroke, angina pectoris, heart failure, recent myocardial infarction);

• Severe visual impairment or blindness

• Hearing or communicative impairment.

• Gastrointestinal tract disorder such as irritable bowel syndrome or inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis).

5. Current or recent (<6 weeks) use of prebiotic, probiotic, or dietary fibre supplement that may modulate the microbiota, or unwilling to stop the use of supplements during the study

6. Current or recent (<6 weeks) of algae/phytoplankton supplements such as spirulina or chlorella, or unwilling to stop the use of supplements during the study

7. Use of psychotropic medication (anti-depressants, anti-psychotics)

8. Use of antibiotics in the 3 months before starting the study or planned use during the study

9. Being an employee of the Human Nutrition and Health Division of Wageningen University.

10. Significant cognitive impairment assessed using the Modified Telephone Interview for Cognitive Status battery (TICS-m score <23)

11. Request to have Apo-E genotype result disclosed

12. Allergies to fish or shellfish

13. Having a contra-indication to MRI scanning including:

• Ferromagnetic implants:

• Active implantable medical devices such as: insulin pump / medicine pump / neurostimulator; pacemaker / defibrillator;

• Other passive implants such as: punctured port-a-cath; synthetic heart valve

• Intra-orbital or intra-ocular metallic fragments

• Claustrophobia

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Subjective Cognitive Decline

Intervention

Dietary Supplement:
• Chicory inulin
Chicory inulin (12g/day) divided over two dosages (6g per dose)
• Resistant dextrin
Resistant dextrin (14g/day) divided over two dosages (7g per dose)
• Seaweed polysaccharide
Seaweed polysaccharide (1g/day) divided over two dosages (0.5g per dose). Additionally contains 7g/day of placebo as a volumetric and isocaloric filler.
• Placebo
Maltodextrin (7g/day) will be provided in two divided doses (3.5g per dose)

Locations

Country	Name	City	State
Netherlands	Wageningen University	Wageningen

Sponsors (6)

Lead Sponsor	Collaborator
Wageningen University	Cosun Nutrition Center, Oceanium Ltd., Roquette Frères, Sensus BV, Technical University of Eindhoven (TU/e)

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Effect on heart rate	Heart rate as determined by wearable Samsung Active 2.0 Smartwatches	Measured at baseline and week 26
Other	Effect on physical activity	Physical activity (pedometer) as determined by wearable Samsung Active 2.0 Smartwatches	Measured at baseline and week 26
Other	Effect on BMI	Measured in kg/m^2	Measured at baseline, week 13 and week 26
Other	Effect on blood pressure	Systolic and diastolic blood pressure as measured by sphygmomanometer	Measured at baseline, week 13 and week 26
Other	Effect on mood as measured by Samsung Active 2.0 Smartwatches	Mood determined by push notifications (sad, stressed, neutral, happy, or angry) as determined by wearable Samsung Active 2.0 Smartwatches	Measured at baseline, week 13 and week 26
Other	Effect on mood as determined by GDS-15 questionnaire	Self-reported depressive symptoms by Geriatric Depression Scale-15 (GDS-15) questionnaire	Measured at baseline, week 13 and week 26
Other	Effect on mood as determined by GAD-7 questionnaire	Self-reported anxiety symptoms by Generalised Anxiety Disorder-7 (GAD-7) questionnaire	Measured at baseline, week 13 and week 26
Primary	Effect on working memory during n-back task fMRI	Effects on working memory will be assessed by blood-oxygen level dependant (BOLD) signal activity during 2-back task performed during fMRI scanning	Measured at baseline and week 26
Primary	Effect on working memory performance during n-back task fMRI	Effects on working memory performance will be assessed by task accuracy during 2-back task performed during fMRI scanning	Measured at baseline and week 26
Secondary	Effect on cognitive functioning as measured by a neuropsychological test battery	Effect on z-scoring of cognitive domains- episodic memory, executive function and working memory as measured by Cognitive Function Composite test battery	Measured at baseline, week 13 and week 26
Secondary	Effect on ADAS-Cog Word Recall cognitive assessment (episodic memory)	Mean number of correct responses across three trials; Score 0 to 10. Higher score indicates better outcome.	Measured at baseline, week 13 and week 26
Secondary	Effect on ADAS-Cog Word Recognition cognitive assessment (episodic memory)	Mean number of correct responses across three trials. Score 0 to 12. Higher score indicates better outcome.	Measured at baseline, week 13 and week 26
Secondary	Effect on Digit Symbol Substitution Test cognitive assessment (executive function)	Amount of symbols correctly substituted. Score 0 - 90. Higher score indicates better outcome	Measured at baseline, week 13 and week 26
Secondary	Effect on Digit Span Backward Task cognitive assessment (working memory)	Longest span of digits correctly recalled. Score 2-8. Higher score indicates better outcome	Measured at baseline, week 13 and week 26
Secondary	Effect on Category Fluency Test cognitive assessment (executive function)	Number of uniquely named items from category within 60 seconds. Higher score indicates better outcome	Measured at baseline, week 13 and week 26
Secondary	Effect on ADAS-Cog Orientation cognitive assessment (episodic memory)	The number of correct responses on orientation. Score 0 to 8. Higher score indicates better outcome	Measured at baseline, week 13 and week 26
Secondary	Effect on tryptophan metabolites	Tryptophan related neurotransmitters and metabolites (plasma)	Measured at baseline and week 26
Secondary	Effect on amyloid-beta (Aß) biomarker	Aß1-42/Aß1-40 ratio (plasma)	Measured at baseline and week 26
Secondary	Effect on neuroplasticity	Brain-derived neurotrophic factor (BDNF) levels (serum)	Measured at baseline and week 26
Secondary	Effect on brain regions of interest	Structural MRI with T1- and T2-weighted anatomical images of regions of interest (hippocampi, (pre)frontal-and temporal cortices)	Measured at baseline and week 26
Secondary	Effect on hypothalamic-pituitary adrenal axis	Cortisol levels (serum)	Measured at baseline and week 26
Secondary	Effect on intestinal barrier integrity	Assay-based panel of intestinal barrier integrity markers measured in blood	Measured at baseline, week 13 and week 26
Secondary	Effect on intestinal inflammation	Assay-based panel of intestinal inflammatory markers measured in faeces	Measured at baseline, week 13 and week 26
Secondary	Effect on gastrointestinal transit time	Gut transit time measured by blue muffin consumption and appearance of blue colour in faeces	Measured at baseline, week 13 and week 26
Secondary	Effect on gastrointestinal symptoms	Self-rated gastrointestinal symptoms as measured by the Gastrointestinal Symptom Rating Scale (GSRS) questionnaire	Measured at baseline, week 13 and week 26
Secondary	Effect on self-reported stool consistency	Effect on stool consistency as measured by Bristol Stool Scale (BSS)	Measured at baseline, week 13 and week 26
Secondary	Effect on stool consistency	Effect on stool consistency as measured by faecal water content	Measured at baseline, week 13 and week 26
Secondary	Effect on qualitative faecal microbiota composition	Qualitative faecal microbiota composition as measured by 16s rRNA sequencing	Measured at baseline, week 13 and week 26
Secondary	Effect on quantitative faecal microbiota composition	Quantitative faecal microbiota composition as measured by digital droplet PCR	Measured at baseline, week 13 and week 26
Secondary	Effect on faecal metabolites	Faecal short-chain fatty acids (acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, heptanoic acid) and branched-chain fatty acids (isobutyric acid, isovaleric acid, 4-methyl valeric acid) as measured by gas chromatography-flame ionization detection (GC-FID)	Measured at baseline, week 13 and week 26
Secondary	Effect on faecal pH	Faecal pH measurement	Measured at baseline, week 13 and week 26
Secondary	Effect on immune parameters	Inflammatory cytokine panel measured in blood	Measured at baseline, week 13 and week 26
Secondary	Effect on glucose homeostasis	Assay-based panel of markers to evaluate glucose homestasis in blood	Measured at baseline, week 13 and week 26
Secondary	Effect on lipid profile	Assay-based panel of markers to analyse lipid profile in blood	Measured at baseline, week 13 and week 26

External Links

•   PRECODE study Wageningen University