Dietary Flavanols and Dentate Gyrus Function

Study Overview
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Brief Summary
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to assess the effect of differing amounts of a cocoa-derived dietary flavanol (epicatechin ) on dentate gyrus function and corresponding cognitive function

Detailed Description
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In this double blinded trial, the participants, age 50-75 years, will be randomized to receive 0, 260, 510, or 770 mg daily* for 12 weeks and will be tested before and after the intervention. Cognitive testing will be conducted prior to randomization, and at weeks 4, 12, and 20 of the study. In an optional substudy, fMRI (functional magnetic resonance imaging) with gadolinium contrast will be conducted to measure dentate gyrus function before randomization and then after completion of the 12-week intervention portion of the trial. *see note in Record Log regarding the change in the method of assessment of cocoa flavanol content of the capsules

Official Title
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Dietary Cocoa Flavanols and Age-Related Memory Decline

Conditions
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Memory Loss

Intervention / Treatment
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* Dietary Supplement: Cocoa Flavanol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1. Signed and dated informed consent obtained before any trial-related activities. (Trial-related activities are any procedure that would not have been performed during normal management of the subject). Telephone Screen 2. Healthy Male or Female subjects. (Females must be post-menopausal) Telephone Screen 3. Age between 50 and 75 years, both inclusive. Telephone Screen 4. Body mass index between 18.0 and 35 kg/m², both inclusive. Telephone Screen Exclusion Criteria: Currently undergoing medical treatment, including prescription drugs/medication. Medical History Interview Clinically significant abnormal hematology, biochemistry, urinalysis, or coagulation screening tests, as judged by the Investigator. Medical History Interview History or presence of cancer (except basal cell skin cancer or squamous cell skin cancer), or any clinically significant cardiovascular, respiratory, metabolic, renal, hepatic, gastrointestinal, endocrinological (with the exception euthyroid struma), haematological, dermatological, venereal, neurological, psychiatric diseases or other major disorders as judged by the Investigator. Medical History Interview Seated blood pressure at screening (after resting for 5 min in seated position) outside the range of 90-140 mmHg for systolic or 50-90 mmHg for diastolic (excluding white-coat hypertension; therefore, if a repeated measurement shows values within the range, the subject can be included in the trial) and/or resting supine heart rate outside the range 50-90 beats per minute. Measurement taken at consent before eligibility is determined Current Depression or Anxiety Symptoms using PHQ-8 (eight-item Patient Health Questionnaire depression scale) and GAD-7 (Generalized Anxiety Disorder 7-item scale). PHQ-8 score >= 10 and/or GAD-7 score >= 10 are excluded. (Past history of disorders not exclusionary). Interview Currently taking SSRI (selective serotonin reuptake inhibitor) medications for any reason. Interview Heart Diseases. Medical History Interview Hepatitis B or C positive status. Medical History Interview HIV positive status. Medical History Interview History of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reaction. Medical History Interview Use of non-prescription medication, herbal products or nutritional supplements during the study, and within the last 4 weeks before the start of the study (screening), as judged by the Investigator; occasional use of aspirin, ibuprofen, acetaminophen is permitted. Interview Adherence to a vegan or vegetarian diet or to specialty/uncommon diets. Interview Food Allergies to tree nuts, soy, cocoa and cocoa-containing products. Interview People who choose to avoid caffeine intake. Interview Current or history of alcoholism or drug/chemical abuse as per Investigator's judgment. Medical History Interview Hormone Replacement Therapy; Currently pregnant; Pregnant or lactating within past 6 mos; Hormonal birth control (pill). Interview Smoking. Interview Unwilling to have blood drawn or anxiety/nausea during a blood draw. Interview. Uncomfortable completing memory and attention tasks in the English language. Interview MoCA (Montreal Cognitive Assessment) score less than 26. Montreal Cognitive Assessment Inability to swallow study capsules. Interview (at consent). Did not complete the two weeks Run-In Period (Participants who missed more than 2 intake occasions out of 14 days (28 occasions total) or if there are > 8 capsules left in the bottle after the two weeks will be excluded). Run-In Period. MRI RELATED Cardiac Pacemaker Interview Internal Pump Interview Insulin Pump Interview Tattoo eyeliner Interview Wire sutures Interview Internal Metal Objects Interview Metal Slivers in Eye Interview Prosthesis Interview Hearing Aid Implants Interview Neurostimulator Interview Metal Fragments Interview Brain Aneurysm Clips Interview Vascular Clips Interview Breast Expander Interview Vena Cava Filter Interview Heart Valve Interview Metal Stents Interview Asthma Interview Hay-Fever Interview Sickle Cell Disease Interview Kidney Disease Interview Pregnant Interview Claustrophobic Interview Wheelchair bound Interview Machinist or ever worked with heavy metals Interview Contraindication to Gadolinium, including prior adverse reaction to gadolinium, past or current history of severe breathing difficulty that has been treated by a physician (e.g. asthma, COPD (Chronic obstructive pulmonary disease), etc) and sickle cell disease. History of renal impairment or estimated glomerular filtration rate <30 L/min.1.732m2 is also exclusionary Interview; Glomerular filtration rate assessed with creatinine via StatSensor monitor Had more than one previous MRI scans with Gadolinium Interview

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: F 0 mg<br>daily consumption of capsules containing 0 mg cocoa flavanol for 12 weeks | Dietary Supplement: Cocoa Flavanol<br>* 12 weeks administration of cocoa flavanol<br>|
| Active Comparator: F 260 mg<br>daily consumption of capsules containing 260 mg* cocoa flavanol for 12 weeks *see note in Record Log regarding the change in the method of assessment of cocoa flavanol content of the capsules | Dietary Supplement: Cocoa Flavanol<br>* 12 weeks administration of cocoa flavanol<br>|
| Active Comparator: F 510 mg<br>daily consumption of capsules containing 510 mg cocoa flavanol for 12 weeks | Dietary Supplement: Cocoa Flavanol<br>* 12 weeks administration of cocoa flavanol<br>|
| Active Comparator: F 770 mg<br>daily consumption of capsules containing 770 mg cocoa flavanol for 12 weeks | Dietary Supplement: Cocoa Flavanol<br>* 12 weeks administration of cocoa flavanol<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Benton Recognition Task (ModBent) | The ModBent task is divided into two parts. During the matching trials (top), participants were shown a complex stimulus for 10 s. Following a 1-s inter-trial interval, they were required to select, via a key press, which of two stimuli matched the one they had just studied, as quickly and as accurately as possible. Following 41 matching trials, participants were shown a series of 82 stimuli (bottom), 41 of which appeared on the initial study set during the matching trials and 41 of which were foils. They were required to indicate, as quickly as possible, whether each stimulus appeared earlier (yes response) or was new (no response). The primary variable of the ModBent task is the mean RT for correct rejections of foils during the recognition trials | baseline and 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dentate Gyrus Cerebral Blood Volume | measured in functional MRI. we generated high-resolution CBV brain maps using gadolinium-enhanced T1-weighted scans acquired perpendicular to the hippocampal long-axis, with sub-millimeter in-plane resolution of 0.68 × 0.68 mm and slice thickness of 3 mm. To perform group-wise voxel-based analyses on the whole hippocampal circuit, we first isolated hippocampal subfields using FreeSurfer segmentations and thresholded posterior probabilities to generate a composite mask of the bilateral hippocampal formation. These masked T1-weighted images were then used to generate a group-wise template to which individual images were co-registered using a diffeomorphic technique that maximizes cross-correlation among images. | baseline and 12 weeks | 
| Modified Benton Recognition Task (ModBent) | The ModBent task is divided into two parts. During the matching trials (top), participants were shown a complex stimulus for 10 s. Following a 1-s inter-trial interval, they were required to select, via a key press, which of two stimuli matched the one they had just studied, as quickly and as accurately as possible. Following 41 matching trials, participants were shown a series of 82 stimuli (bottom), 41 of which appeared on the initial study set during the matching trials and 41 of which were foils. They were required to indicate, as quickly as possible, whether each stimulus appeared earlier (yes response) or was new (no response). The primary variable of the ModBent task is the mean RT for correct rejections of foils during the recognition trials | 20 weeks | 
| Modified Rey Auditory Verbal Learning Test | In learning Trials 1 to 3 the participant is read 20 unique, semantically/phonemically unrelated words (List A) and is to free recall those words after each trial. Next the participant is read a list of 20 unique words (List B) and is to recall as many as possible. This trial is followed by a short delay free recall trial: the participant is to recall as many words as possible from List A. After a 1.5-hour, the participant is asked to long delay free recall words from List A and then from List B. This is followed by a 66-item forced recognition trial: the participant is read a list of 66 words and asked to distinguish List A words from semantic and phonemic distractors, including words from List B. Finally, a source memory trial is administered: the examiner serially reads words from List A and B. The participant is to specify from which list each word came.Higher score indicates better performance. score ranges from 0 to 60. | Baseline and 12 Weeks | 
| NIH Toolbox Cognition Battery (NIHTB-CB): The List Sorting Test | Participants are presented with a series of stimuli, each of which is both visually and auditorily presented by computer. A picture of each stimulus is displayed on the computer monitor for 2 seconds while the name of the stimulus is simultaneously being read via a computerized voice; stimuli are presented one after another. The participant must remember each stimulus in a series, mentally reorder them from smallest to largest, and recite the names of the stimuli in this order. List Sorting scores are based upon Total Score. Higher score indicated better performance.Score ranges from 0-100. | Baseline and 12 Weeks |