Cognitive Decline, Cognitive Dysfunction
Conditions
Keywords
Polyphenols, Mediterranean Diet, Gut Microbiome, Alzheimer Disease
Brief summary
Globally, populations are ageing increasing the prevalence of Alzheimer's disease (AD), due to lack of effective treatments. The traditional Mediterranean diet, rich in fibre and polyphenols (PPs) can help prevent or delay cognitive dysfunction and preserve healthy brain structure and function. Cognitive decline is inversely associated with higher PP intakes (\>421mg/day) i.e., total flavonoids, flavan-3-ols and flavonoid oligomers. The positive brain effects of flavonoid intake are likely mediated in part by gut microbial PP metabolites, consistent with the emerging role of the brain-gut microbiome (BGM) system in neurodegeneration. Our preliminary data indicate that circulating phenyl-γ-valerolactones (PVL), neuroprotective compounds exclusively produced by gut microbiota from flavan-3-ol rich foods18 are associated with delaying cognitive dysfunction. Intake of PPs change gut microbial composition and function, altering the physiology of the host's secondary bile acid (BA) pool through modulation of bacterial 7α-dehydroxylation of de-conjugated primary BAs into secondary BAs. This is noteworthy as 7α-dehydroxylation of BAs does not happen in the brain and because gut microbial BA metabolites have regulatory and signalling functions in the brain. The ratio between certain primary and secondary BAs is also dysregulated in AD with significantly lower serum concentrations of cholic acid (a primary BA) and increased levels of deoxycholic acid (a bacterially produced secondary BA). The increased ratio of cholic acid to deoxycholic acid is correlated with cognitive decline. Increased levels of tyrosine, tryptophan, purine, and tocopherol have also been identified in postmortem AD brains. However, specific pathways and mechanisms underlying these associations are unclear. In this multi-PI application by leaders in the field of BGM interactions, we leverage the collectively (NIH, HSC, SFI) funded Tripartite US-Ireland R&D Partnership Program to determine the mechanisms involved in PP intake on maintaining healthier cognitive and brain function, as mediated by gut microbiota metabolites of PP and BAs in 50+ year old elderly with enhanced AD risk.
Interventions
DIETARY_SUPPLEMENTPolyphenol Supplement
Juice Plus Essentials, Berry Blend Capsules
DIETARY_SUPPLEMENTPlacebo Supplement
Micronutrient matched placebo
Sponsors
University of Parma
University College Cork
National Institute on Aging (NIA)
University of California, Los Angeles
University of Ulster
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
Interventional Model
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* 50+ years * BMI ≥ 25 kg/m2 * Enhanced risk of AD - defined as family history of AD, 1st degree family member * Habitually consume suboptimal diets such as typical Western diet (i.e., high in animal products, refined carbohydrates and processed food). * Subjects capable of and willing to comply with the protocol and to give their written informed consent.
Exclusion criteria
* Cognitive impairment at time of recruitment into the study, as measured by the Mini Mental Status Exam (MMSE, score 25-30), and Clinical Dementia Rating (CDR, score=0) or Everyday Cognition Scale-12 (ECog-12, score\<1.36 included). * Pre-existing psychosis or psychiatric conditions. * Currently receiving treatment for dementia. * History of substance abuse or cerebrovascular events. * Heavy use of tobacco (\>1/2 pack per day) * Any intolerance or allergy documented or suspected to one of the components of the study products. * Have taken probiotics or antibiotic therapy within the last 1 month * Change in medication use in the last 3 months. * Frailty, malnutrition, or food allergy/intolerance requiring special diets will also be excluded. * Following any specific diet (vegetarian, vegan, etc.) * Body weight at enrolment greater than 400lbs due to weight restrictions on the MRI table. * Pregnant, breastfeeding, postpartum for less than 6 months, or unwilling to practice birth control during participation in the study. * Unable to safely participate in the MRI (claustrophobia, presence of devices affected by MRI such as pacemakers, neurostimulators, or metallic foreign body, etc.) * Chronic pain. * Presence of a condition or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data. * Having a psychological or linguistic inability to sign the informed consent; * Under legal protection (guardianship, wardship) or deprived from his rights following administrative or judicial decision; * Subject participating in another biomedical study or participation in another study within the 3 months before entry into this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Differences in Cognitive Measures pre, mid, & post intervention | Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12). | The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) |
| Differences in Polyphenol-derived metabolite concentrations pre, mid, & post intervention - stool | Collected three times by the participant at home, once at baseline (week 0), once at mid-study (month 6), and once at the final 12month appointment (month 12) | Measurement of metabolomics via stool specimen. |
| Differences in Polyphenol-derived metabolite concentrations pre, mid, & post intervention - blood | Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12). | Measurement of metabolomics via blood specimen. |
| Differences in microbiome levels pre, mid, & post intervention - Stool | Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12). | 16S RNA sequencing to measure microbiome levels via stool specimen. |
| Differences in microbiome levels pre & post intervention - Blood | Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12). | 16S RNA sequencing to measure microbiome levels via blood specimen. |
| Differences in microbiome levels pre, mid, & post intervention - Blood | Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12). | Shotgun metagenomics, sequencing to measure microbiome levels via stool specimen. |
| Differences in Cognitive Measures pre, mid, & post intervention - Executive Function | Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12). | Administration of a standardized Stroop Neuro-psychological test; participants ability to correctly identify colours when words are printed in conflicting ink colours. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Monthly Questionnaire Data | Collected 3 times (1) before beginning the dietary supplement, (2) mid-study month 6, (3) end of study month 12. | Collected once a month for the duration of the study (12months). |
| Systolic and Diastolic Blood Pressure | Measured three times, once at each in-clinic appointment (week 0, month 6, month 12). | Measurement of the pressure of circulating blood at rest |
| Anthropometrics - waist and hip circumference | Measured three times, once at each in-clinic appointment (week 0, month 6, & month 12) | Measurement of waist and hip circumference (cm) |
| Differences in tryptophan-associated metabolite profiles pre, mid, and post intervention - Stool | Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12). | Measurement of tryptophan-associate metabolite profiles via stool specimen. |
| Differences in Bile Acid's (BA's) pre, mid, & post intervention - Stool | Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12). | Measurement of BA's via stool specimen. |
| Differences in Inflammatory markers pre, mid, & post intervention - Blood | Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12). | Measurement of inflammatory markers via blood specimen. |
| Differences in Alzheimer's Disease (AD) markers pre, mid, & post intervention - Blood [Time | Collected three times, once at baseline appointment (week 0), once at mid-study appointment (month 6), and once at the final 12month appointment (month 12). | Measurement of AD markers via blood specimen. |
| Anthropometrics - BMI | Measured three times, once at each in-clinic appointment (week 0, month 6, month 12) | Measurement of height(in) and weight(lbs), used to calculate body mass index (BMI) |
| Questionnaire Data | Collected 3 times (1) before beginning the dietary supplement, (2) mid-study month 6, (3) end of study month 12. | Use of validated surveys to assess ingestive behaviours, social isolation, stress, health, physical activity, etc., self-reported by the participant at home. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Differences in Multimodal Brain Signatures pre, mid, & post intervention | Measured thrice, once at baseline (week 0), mid-study (month 6), and final 12month appointment (month 12) visit. | Neuroimaging of participants brain via magnetic resonance imaging (MRI) procedure. |
Countries
United Kingdom
Contacts
Primary ContactChris Gill, PhD
Backup ContactAoife Caffrey, PhD
Outcome results
None listed