Memory Loss
Conditions
Brief summary
to assess the effect of differing amounts of a cocoa-derived dietary flavanol (epicatechin ) on dentate gyrus function and corresponding cognitive function
Detailed description
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
Interventions
DIETARY_SUPPLEMENTCocoa Flavanol
12 weeks administration of cocoa flavanol
Sponsors
Mars, Inc.
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
Yes
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
1. Currently undergoing medical treatment, including prescription drugs/medication. Medical History Interview 2. Clinically significant abnormal hematology, biochemistry, urinalysis, or coagulation screening tests, as judged by the Investigator. Medical History Interview 3. 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 4. 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 5. 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 6. Currently taking SSRI (selective serotonin reuptake inhibitor) medications for any reason. Interview 7. Heart Diseases. Medical History Interview 8. Hepatitis B or C positive status. Medical History Interview 9. HIV positive status. Medical History Interview 10. History of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reaction. Medical History Interview 11. 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 12. Adherence to a vegan or vegetarian diet or to specialty/uncommon diets. Interview 13. Food Allergies to tree nuts, soy, cocoa and cocoa-containing products. Interview 14. People who choose to avoid caffeine intake. Interview 15. Current or history of alcoholism or drug/chemical abuse as per Investigator's judgment. Medical History Interview 16. Hormone Replacement Therapy; Currently pregnant; Pregnant or lactating within past 6 mos; Hormonal birth control (pill). Interview 17. Smoking. Interview 18. Unwilling to have blood drawn or anxiety/nausea during a blood draw. Interview. 19. Uncomfortable completing memory and attention tasks in the English language. Interview 20. MoCA (Montreal Cognitive Assessment) score less than 26. Montreal Cognitive Assessment 21. Inability to swallow study capsules. Interview (at consent). 22. 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 1. Cardiac Pacemaker Interview 2. Internal Pump Interview 3. Insulin Pump Interview 4. Tattoo eyeliner Interview 5. Wire sutures Interview 6. Internal Metal Objects Interview 7. Metal Slivers in Eye Interview 8. Prosthesis Interview 9. Hearing Aid Implants Interview 10. Neurostimulator Interview 11. Metal Fragments Interview 12. Brain Aneurysm Clips Interview 13. Vascular Clips Interview 14. Breast Expander Interview 15. Vena Cava Filter Interview 16. Heart Valve Interview 17. Metal Stents Interview 18. Asthma Interview 19. Hay-Fever Interview 20. Sickle Cell Disease Interview 21. Kidney Disease Interview 22. Pregnant Interview 23. Claustrophobic Interview 24. Wheelchair bound Interview 25. Machinist or ever worked with heavy metals Interview 26. 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 27. Had more than one previous MRI scans with Gadolinium Interview
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Modified Benton Recognition Task (ModBent) | baseline and 12 weeks | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dentate Gyrus Cerebral Blood Volume | baseline and 12 weeks | 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. |
| Modified Benton Recognition Task (ModBent) | 20 weeks | 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 |
| Modified Rey Auditory Verbal Learning Test | Baseline and 12 Weeks | 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. |
| NIH Toolbox Cognition Battery (NIHTB-CB): The List Sorting Test | Baseline and 12 Weeks | 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. |
Countries
United States
Participant flow
Recruitment details
first consent; 1/13/2016 Final data collection session: 11/21/2018 All data collected at Columbia University Medical Center
Pre-assignment details
1. consent: exclusions: 5 BMI too high; 66 MOCA too low; 4 elevated blood pressure; 16 other; 17 lost to follow-up 2. two week run-in period: exclusions: 24 failed, 17 withdrew or lost to follow-up 3. baseline assessments: exclusions: 1 lost to follow-up
Participants by arm
| Arm | Count |
|---|---|
| 0 mg daily consumption of capsules containing 0 mg cocoa flavanol for 12 weeks | 53 |
| 260 mg daily consumption of capsules containing 260 mg cocoa flavanol for 12 weeks; | 53 |
| 510 mg daily consumption of capsules containing 510 mg cocoa flavanol for 12 weeks; | 53 |
| 770 mg daily consumption of capsules containing 770 mg cocoa flavanol for 12 weeks; | 52 |
| Total | 211 |
Baseline characteristics
| Characteristic | 0 mg | Total | 770 mg | 510 mg | 260 mg |
|---|---|---|---|---|---|
| 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (gVLM) | 19.7 nM STANDARD_DEVIATION 24.23 | 30.44 nM STANDARD_DEVIATION 55.84 | 36.59 nM STANDARD_DEVIATION 72.06 | 44.32 nM STANDARD_DEVIATION 72.4 | 20.98 nM STANDARD_DEVIATION 34.28 |
| Age, Continuous | 61.47 years STANDARD_DEVIATION 6.78 | 61.13 years STANDARD_DEVIATION 6.47 | 61.23 years STANDARD_DEVIATION 6.37 | 61 years STANDARD_DEVIATION 6.15 | 60.81 years STANDARD_DEVIATION 6.71 |
| alternative Healthy Eating Index (aHEI) | 65.09 units on a scale STANDARD_DEVIATION 11.44 | 66.36 units on a scale STANDARD_DEVIATION 12 | 66.74 units on a scale STANDARD_DEVIATION 10.84 | 64.83 units on a scale STANDARD_DEVIATION 14.3 | 68.78 units on a scale STANDARD_DEVIATION 10.82 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 20 Participants | 4 Participants | 8 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants | 191 Participants | 48 Participants | 45 Participants | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 13 Participants | 3 Participants | 4 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 30 Participants | 8 Participants | 8 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 7 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 41 Participants | 160 Participants | 41 Participants | 38 Participants | 40 Participants |
| Region of Enrollment United States | 53 Participants | 211 Participants | 52 Participants | 53 Participants | 53 Participants |
| Sex: Female, Male Female | 31 Participants | 120 Participants | 29 Participants | 30 Participants | 30 Participants |
| Sex: Female, Male Male | 22 Participants | 91 Participants | 23 Participants | 23 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 0 / 53 | 0 / 53 | 0 / 52 |
| other Total, other adverse events | 0 / 53 | 0 / 53 | 0 / 53 | 0 / 52 |
| serious Total, serious adverse events | 0 / 53 | 0 / 53 | 0 / 53 | 0 / 52 |
Outcome results
Primary
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
Time frame: baseline and 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0 mg Cocoa Flavanol | Modified Benton Recognition Task (ModBent) | Baseline | 2807.98 ms | Standard Deviation 1733.36 |
| 0 mg Cocoa Flavanol | Modified Benton Recognition Task (ModBent) | 12 Weeks | 2671.50 ms | Standard Deviation 1431.17 |
| 260 mg Cocoa Flavanol | Modified Benton Recognition Task (ModBent) | 12 Weeks | 2489.84 ms | Standard Deviation 1135.4 |
| 260 mg Cocoa Flavanol | Modified Benton Recognition Task (ModBent) | Baseline | 2579.94 ms | Standard Deviation 1026.18 |
| 510 mg Cocoa Flavanol | Modified Benton Recognition Task (ModBent) | Baseline | 2603.65 ms | Standard Deviation 999.31 |
| 510 mg Cocoa Flavanol | Modified Benton Recognition Task (ModBent) | 12 Weeks | 2381.68 ms | Standard Deviation 929.14 |
| 770 mg Cocoa Flavanol | Modified Benton Recognition Task (ModBent) | Baseline | 2732.79 ms | Standard Deviation 1367.96 |
| 770 mg Cocoa Flavanol | Modified Benton Recognition Task (ModBent) | 12 Weeks | 2653.01 ms | Standard Deviation 1289.18 |
p-value: 0.393Mixed Models Analysis
Secondary
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.
Time frame: baseline and 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0 mg Cocoa Flavanol | Dentate Gyrus Cerebral Blood Volume | 12 Weeks | 2.25 % cerebral blood volume | Standard Deviation 0.57 |
| 0 mg Cocoa Flavanol | Dentate Gyrus Cerebral Blood Volume | Baseline | 2.44 % cerebral blood volume | Standard Deviation 0.81 |
| 260 mg Cocoa Flavanol | Dentate Gyrus Cerebral Blood Volume | Baseline | 2.17 % cerebral blood volume | Standard Deviation 0.69 |
| 260 mg Cocoa Flavanol | Dentate Gyrus Cerebral Blood Volume | 12 Weeks | 2.11 % cerebral blood volume | Standard Deviation 0.52 |
| 510 mg Cocoa Flavanol | Dentate Gyrus Cerebral Blood Volume | Baseline | 2.11 % cerebral blood volume | Standard Deviation 0.47 |
| 510 mg Cocoa Flavanol | Dentate Gyrus Cerebral Blood Volume | 12 Weeks | 2.01 % cerebral blood volume | Standard Deviation 0.71 |
| 770 mg Cocoa Flavanol | Dentate Gyrus Cerebral Blood Volume | 12 Weeks | 2.23 % cerebral blood volume | Standard Deviation 0.59 |
| 770 mg Cocoa Flavanol | Dentate Gyrus Cerebral Blood Volume | Baseline | 1.85 % cerebral blood volume | Standard Deviation 0.67 |
Secondary
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
Time frame: 20 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0 mg Cocoa Flavanol | Modified Benton Recognition Task (ModBent) | 2542.76 ms | Standard Deviation 1278.87 |
| 260 mg Cocoa Flavanol | Modified Benton Recognition Task (ModBent) | 2475.35 ms | Standard Deviation 1512.88 |
| 510 mg Cocoa Flavanol | Modified Benton Recognition Task (ModBent) | 2373.78 ms | Standard Deviation 934.84 |
| 770 mg Cocoa Flavanol | Modified Benton Recognition Task (ModBent) | 2550.18 ms | Standard Deviation 1165.92 |
Secondary
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.
Time frame: Baseline and 12 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0 mg Cocoa Flavanol | Modified Rey Auditory Verbal Learning Test | Baseline | 38.91 units on a scale | Standard Deviation 8.45 |
| 0 mg Cocoa Flavanol | Modified Rey Auditory Verbal Learning Test | 12 Weeks | 39.49 units on a scale | Standard Deviation 9.7 |
| 260 mg Cocoa Flavanol | Modified Rey Auditory Verbal Learning Test | 12 Weeks | 38.69 units on a scale | Standard Deviation 9.3 |
| 260 mg Cocoa Flavanol | Modified Rey Auditory Verbal Learning Test | Baseline | 37.25 units on a scale | Standard Deviation 8.19 |
| 510 mg Cocoa Flavanol | Modified Rey Auditory Verbal Learning Test | Baseline | 39.75 units on a scale | Standard Deviation 7.38 |
| 510 mg Cocoa Flavanol | Modified Rey Auditory Verbal Learning Test | 12 Weeks | 41.10 units on a scale | Standard Deviation 8.5 |
| 770 mg Cocoa Flavanol | Modified Rey Auditory Verbal Learning Test | Baseline | 39.96 units on a scale | Standard Deviation 9.62 |
| 770 mg Cocoa Flavanol | Modified Rey Auditory Verbal Learning Test | 12 Weeks | 41.92 units on a scale | Standard Deviation 8.48 |
Secondary
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.
Time frame: Baseline and 12 Weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0 mg Cocoa Flavanol | NIH Toolbox Cognition Battery (NIHTB-CB): The List Sorting Test | Baseline | 52.89 units on a scale | Standard Deviation 8.85 |
| 0 mg Cocoa Flavanol | NIH Toolbox Cognition Battery (NIHTB-CB): The List Sorting Test | 12 Weeks | 53.34 units on a scale | Standard Deviation 7.44 |
| 260 mg Cocoa Flavanol | NIH Toolbox Cognition Battery (NIHTB-CB): The List Sorting Test | 12 Weeks | 56.10 units on a scale | Standard Deviation 8.47 |
| 260 mg Cocoa Flavanol | NIH Toolbox Cognition Battery (NIHTB-CB): The List Sorting Test | Baseline | 56.81 units on a scale | Standard Deviation 8.91 |
| 510 mg Cocoa Flavanol | NIH Toolbox Cognition Battery (NIHTB-CB): The List Sorting Test | Baseline | 54.60 units on a scale | Standard Deviation 9.15 |
| 510 mg Cocoa Flavanol | NIH Toolbox Cognition Battery (NIHTB-CB): The List Sorting Test | 12 Weeks | 54.86 units on a scale | Standard Deviation 8.56 |
| 770 mg Cocoa Flavanol | NIH Toolbox Cognition Battery (NIHTB-CB): The List Sorting Test | Baseline | 55.18 units on a scale | Standard Deviation 8.65 |
| 770 mg Cocoa Flavanol | NIH Toolbox Cognition Battery (NIHTB-CB): The List Sorting Test | 12 Weeks | 53.46 units on a scale | Standard Deviation 9.23 |