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Dietary Flavanols and Dentate Gyrus Function

Primary Purpose

Memory Loss

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Cocoa Flavanol
Sponsored by
New York State Psychiatric Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Memory Loss

Eligibility Criteria

50 Years - 75 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Columbia University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

F 0 mg

F 260 mg

F 510 mg

F 770 mg

Arm Description

daily consumption of capsules containing 0 mg cocoa flavanol for 12 weeks

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

daily consumption of capsules containing 510 mg cocoa flavanol for 12 weeks

daily consumption of capsules containing 770 mg cocoa flavanol for 12 weeks

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.
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
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.
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.

Full Information

First Posted
December 5, 2014
Last Updated
June 1, 2020
Sponsor
New York State Psychiatric Institute
Collaborators
Mars, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT02312310
Brief Title
Dietary Flavanols and Dentate Gyrus Function
Official Title
Dietary Cocoa Flavanols and Age-Related Memory Decline
Study Type
Interventional

2. Study Status

Record Verification Date
June 2020
Overall Recruitment Status
Completed
Study Start Date
December 2015 (Actual)
Primary Completion Date
November 2018 (Actual)
Study Completion Date
April 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
New York State Psychiatric Institute
Collaborators
Mars, Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Memory Loss

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
211 (Actual)

8. Arms, Groups, and Interventions

Arm Title
F 0 mg
Arm Type
Placebo Comparator
Arm Description
daily consumption of capsules containing 0 mg cocoa flavanol for 12 weeks
Arm Title
F 260 mg
Arm Type
Active Comparator
Arm Description
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
Arm Title
F 510 mg
Arm Type
Active Comparator
Arm Description
daily consumption of capsules containing 510 mg cocoa flavanol for 12 weeks
Arm Title
F 770 mg
Arm Type
Active Comparator
Arm Description
daily consumption of capsules containing 770 mg cocoa flavanol for 12 weeks
Intervention Type
Dietary Supplement
Intervention Name(s)
Cocoa Flavanol
Intervention Description
12 weeks administration of cocoa flavanol
Primary Outcome Measure Information:
Title
Modified Benton Recognition Task (ModBent)
Description
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
Secondary Outcome Measure Information:
Title
Dentate Gyrus Cerebral Blood Volume
Description
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
Title
Modified Benton Recognition Task (ModBent)
Description
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
Title
Modified Rey Auditory Verbal Learning Test
Description
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
Title
NIH Toolbox Cognition Battery (NIHTB-CB): The List Sorting Test
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
50 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Scott A Small, MD
Organizational Affiliation
Columbia University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
25344629
Citation
Brickman AM, Khan UA, Provenzano FA, Yeung LK, Suzuki W, Schroeter H, Wall M, Sloan RP, Small SA. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat Neurosci. 2014 Dec;17(12):1798-803. doi: 10.1038/nn.3850. Epub 2014 Oct 26.
Results Reference
background
PubMed Identifier
31932823
Citation
Bussy U , May BR , Olanrewaju Y , Hewitt G , Anderson N , Crozier A , Ottaviani JI , Kwik-Uribe C . Reliable, accessible and transferable method for the quantification of flavanols and procyanidins in foodstuffs and dietary supplements. Food Funct. 2020 Jan 29;11(1):131-138. doi: 10.1039/c9fo02762a.
Results Reference
background
PubMed Identifier
29959422
Citation
Ottaviani JI, Fong R, Kimball J, Ensunsa JL, Britten A, Lucarelli D, Luben R, Grace PB, Mawson DH, Tym A, Wierzbicki A, Khaw KT, Schroeter H, Kuhnle GGC. Evaluation at scale of microbiome-derived metabolites as biomarker of flavan-3-ol intake in epidemiological studies. Sci Rep. 2018 Jun 29;8(1):9859. doi: 10.1038/s41598-018-28333-w.
Results Reference
background

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Dietary Flavanols and Dentate Gyrus Function

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