Ignite Creation Date:
2024-07-17 @ 10:47 AM
Last Modification Date:
2024-10-26 @ 3:34 PM
Study NCT ID:
NCT06495190
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-07-10
First Post:
2024-07-03
Brief Title:
Cognition Flavonoids Exercise Gut Microbiome
Sponsor:
Appalachian State University
Organization:
Appalachian State University
Study Overview
Official Title:
Age-related Cognitive Changes Effects of Combined Flavonoid Intake and Physical Exertion Mediated by the Gut Microbiome
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This NIH project will examine the effects of routine flavonoid-rich blueberry intake 12-weeks combined with or in the absence of regular moderate exercise on cognitive function in a clinical population of older participants identified as experiencing age-related cognitive changes This projects hypothesis is that the combination of flavonoid-rich diet and routine physical activity may potentiate cognitive benefits and reduce cognitive decline in an aging population via mechanisms mediated by the gut microbiome
Detailed Description:
This randomized clinical trial RCT is designed to investigate the effect of 12-weeks blueberry ingestion 52 g freeze dried powder per day equivalent to 2 cups fresh blueberries per day with or without brisk walking five 45-minute supervised sessions per week on cognitive function in healthy older adult participants An important aim is to determine if this potential benefit is mediated through changes in the gut microbiome profile and an increase in gut-derived phenolics Older adult participants n240 with a goal of 200 completing all procedures will be randomized to one of four groups blueberry-walking blueberry-stretching placebo-walking and placebo-stretching The blueberry and placebo powder supplements will be ingested using double blind procedures Blood urine and stool samples will be collected pre-study and then again after 6- and 12-weeks Cognitive function and cardiorespiratory fitness will be measured at the same time points Participants will be assessed for processing speed episodic memory working memory and sustained attention using the Cambridge Neuropsychological Test Assessment Battery CANTAB Cambridge Cognition Ltd laboratory of Dr Carol Cheatham UNC Chapel Hill Urine samples will be analyzed for gut-derived phenolic metabolites via liquid chromatography tandem MSMS lab of Dr Mary Ann Lila NCSU Taxonomic and functional profiles from metagenomic sequencing of the stool samples will be acquired UNC Chapel Hill
Recruitment Healthy older adult participants 240 to start 200 to finish will be recruited from the Charlotte NC metropolitan area Healthy nonsmoking physically inactive male and female participants targeting 65-85 years of age BMI less than 35 with cognitive changes will be selected who match the inclusion and exclusion criteria
Design This study will employ a randomized double blind placebo controlled parallel group research design with participants 60 assigned to one of 4 arms for the 12 week trial period blueberry and walking blueberry and stretching placebo and walking placebo and stretching
Schedule LAB TESTING VISIT 1 Orientation and ConsentBaseline Cognitive Testing approximately 2 hours
A ORIENTATION AND CONSENT 15 min Potential study participants responding to recruitment messages will come to the AppState Human Performance Lab at an assigned time Study procedures will be thoroughly explained by the Research Manager Dr Camila Olson Human Performance Lab HPL during the consent process Subjects will voluntarily sign the consent form
B MoCA 5 min Participants will report to the lab of Dr Cheatham UNC Chapel Hill Nutrition Research Institute NCRC where they will undergo cognitive testing using the MoCA Participants will be tested for cognitive decline using the Montreal Cognitive Assessment MoCA MoCA consists of eight sections to test recall memory executive function attention orientation abstraction visuospatial skills and naming Mild cognitive decline will be defined as a score of 1 - 15 SD below the norm on the MoCA This criterion was employed in previous work at the NCRC with great success PMID 36066009 Those who score below the 15 SD cutoff will be referred to their family physicians Subjects that score within 1 SD of the norm will not be allowed to enter into the study and will be excused from further participation C CANTAB 30 min Subjects that qualify for the study using the MoCA criteria will be further tested at Cheathams lab for cognitive function using the Cambridge Neuropsychological Test Assessment Battery CANTAB Cambridge Cognition Ltd The CANTAB is a standardized and computerized instrument with automated data capture Participants will be assessed for processing speed episodic memory working memory and sustained attention The CANTAB has been validated for assessment of cognitive decline and will be used to validate the findings from the other assessments The chosen CANTAB collection of subtests see below has been designed at Cambridge to assess cognitive decline and has been shown to be sensitive to deterioration of cognitive abilities even in the short-term Completion of the 5 subtests requires about 30 minutes The tasks are completed on a touch screen computer Subtests of the CANTAB to be included in the battery Motor Control Task -to familiarize participant with the touch screen Rapid Visual Information Processing -test of sustained visual attention Paired Associate Learning -test of memory and learning Reaction Time -test of simple choice reaction time Spatial Working Memory -test of spatial information retention
D ERP 30 min Subjects will also be assessed using electrophysiological procedures ERP in Cheathams lab To collect ERP data the participant will be fitted with a Geodesic Sensor Net GSN Electrical Geodesic Inc consisting of a 128-sensor array The GSN is easy to apply comfortable and relatively non-invasive The GSN is comprised of AgAgCl sensors in an elastic-webbed geodesic tension structure The participants head is measured to insure the proper net is used and to mark the scalp at the vertex for proper placement of net The GSN is soaked in a potassium chloride and warm water solution
Excess solution is blotted from the net so that it does not drip in the participants eyes The net is carefully stretched over the participants head matching the vertex electrode to the vertex mark and the ear electrodes with the preauricular points The chinstrap and side tension straps are tightened and the sensors are all checked to insure that they are perpendicular to and in contact with the scalp Application of the net requires only about 5 minutes and is well tolerated A picture will be taken of the net placement and impedances are then checked Any sensors that are not reading well are adjusted and a small amount of electrolyte solution is applied to the sensors sponge with a pipette When impedances are within accepted limits the participant will be seated in front of the monitor in the participant room separate from the control room A camera which is time-locked to the data being acquired will record the participant during presentation of the pictures Using the Smart-Eye eye-tracking system the investigators will collect information on gaze direction and eyeblinks This system is the only system on the market to offer integrated dense array EEG and remote head- and eye-tracking for linking attention time-on-task pupillometry and eye blinks to the ongoing EEG Data will be recorded continuously and epoched into windows around the stimuli presentation offline Once the net is in place the participant will participate in the three cognitive tests For the n-back working memory task participants will watch a series of letters appearing on the computer screen and will press a button when the target is detected The target in a 2-back task is identified as a letter that matches the letter that appeared letter-before-last 2-back Letters that do not match the definition require no response Use of this task has been shown to predict those in which cognitive decline will be rapid To assess visual mismatch negativity component of the N200 attention the participant will be instructed to focus on the center of the screen At a ratio of 1611 standardstargetsdeviants the computer will randomly cycle through the task When a defined target appears the participant will press the button All other stimuli do not require a response This task requires sharp attentional focus and has been shown to be sensitive to mild cognitive impairment
E Stress questionnaires 15 min Subjects will complete questionnaires that assess anxiety and stressful life events
F Human Performance Lab questionnaires and kits 15 min Subjects will return to the Human Performance Lab and complete a physical activity survey International Physical Activity Questionnaire IPAQ and the medical health questionnaire MHQ Subjects will receive from Dr Olson a 3-day food record stool collection kit and the 24-hour urine collection kit with complete instructions see attached documents The 3-d food record will be completed on the Thursday Friday and Saturday period before Lab Visit 2 Urine and stool samples will be collected the day before Lab Visit 2 Subjects will receive datestimes for additional lab visits
LAB TESTING VISIT 2 Pre-Study Fitness Testing and Sample Collection and Initiation of BlueberryPlacebo Supplementation 15 h
A BLOOD URINE STOOL SAMPLES Approximately one week after Lab Visit 2 participants will report to the HPL in the morning in an overnight fasted state at their assigned times Participants will turn in their 3-day food records and stool and 24-hour urine samples Blood samples maximum of 35 mL will be collected from an arm vein by a trained phlebotomists while participants are seated
B BODY COMPOSITION Height and weight will be measured using a stadiometer and balance beam weight scale The seca medical Body Composition Analyzer mBCA Hanover MD will be used to measure body composition through 8 point BIA while participants stand on foot electrodes with bare feet and grasp electrodes with both hands on side rails The seca mBCA provides several measurements of interest including fat mass fat free mass skeletal muscle mass visceral fat total body water and extracellular water
C GRADED EXERCISE TEST Participants will be tested for maximal aerobic capacity VO2max during a graded treadmill test with the Cosmed CPET metabolic cart Participants will first warm up on the treadmill to demonstrate that they can freely walk on the treadmill Participants will walk against a gradually increasing workload Bruce protocol until maximal effort is reached and the participant voluntarily stops exercising The main outcome measure is peak VO2 or the milliliters of oxygen that can be consumed for each kilogram of body mass at peak effort The Cosmed CPET metabolic system Rome Italy will be attached via a facemask to the participant for continuous measurement of metabolic factors oxygen consumption ventilation rate respiratory rate respiratory exchange ratio A chest heart rate monitor will provide heart rates in beats per minute The rating of perceived exertion RPE will be assessed using a 6 to 20 scale Data will be recorded at the end of each 3 minute stage and at the point of maximal exertion and submaximalmaximal changes pre to post 12 weeks training will be used as criteria for assessing changes in cardiorespiratory fitness The aerobic exercise prescription for the 12 week training program will be based on the maximal heart rate MHR and resting heart rate RHR measured during baseline testing Testing and safety procedures will be under IRB guidance for healthy elderly participants and the study MD will provide oversight of testing procedures
D SUPPLEMENTS Each participant will be given a 6-weeks supply of vacuum-sealed packets of coded lyophilized wild blueberry powder or placebo 52 g daily The lowbush wild blueberry freeze-dried powder will be provided from the Wild Blueberry Association of North America Old Town ME and freeze-dried by FutureCeuticals Momence IL The fiber and carbohydrate-matched placebo blueberry powder will be developed by NCSU using a formula from previous studies blueberry flavoring and aroma 89 coloring 105 purple lake 075 red lake 045 blue 2 lake 003 red dye 0008 blue 2 dye glucose 32 fructose 355 citric acid 077 cellulose 15 fibersol-2 18 xanthan gum 1 pectin 109 and silica 099 The blueberry and placebo powders will be packaged at the NCRC NC Food Innovation Lab Participants will be instructed that the blueberry or placebo powders should be stored in a freezer in the supplied packets until use Instructions will be provided to consume the supplements in split doses half with breakfast and half with lunch mixed in beverages yogurt or other foods If a study participant fails to take the supplement dose on a given day or two they will be asked to add 1 extra packet per day until they are back on schedule Study participants will contact the Research Manager ASU-NCRCappstateedu if they fail to consume the supplement for 3 days or longer and discuss whether or not they wish to dropout of the study Compliance to the supplementation regimen will be assessed through regular email messages and a count of returned packets at the 6- and 12-week time points
LAB TESTING VISITS 3 4 and 5 6 These same basic procedures will be repeated after 6- and 12-weeks except that visits 3 and 5 will not involve subjects going through the consent process and completing the medical health questionnaire and that visit 6 will not include providing subjects with additional supplement packets
12-WEEK RANDOMIZED CLINICAL TRIAL 60 TRAINING SESSIONS AT THE NORTH CAROLINA RESEARCH CAMPUS NCRC Kannapolis NC
Participants will engage in supervised physical activity sessions 5 SESSIONS PER WEEK 45 MIN PER SESSION and consume 52 grams per day of freeze-dried blueberry powder or placebo
Participants will engage in 45 minutes per day supervised exercise brisk walking with heart rate monitors or non aerobic stretching floor exercises for 5 days per week during a 12-week period Exercise sessions will be conducted in small groups under supervision Exercise supervisors will be trained in CPR and an AED device will be located at the door of the Human Performance Lab in the building adjacent to the walking oval
Walking sessions will be held outdoors under supervision on the NCRC track Training heart rates and total distance walked will be recorded On days with inclement weather subjects will walk under cover NCRC parking garage or on treadmills in the Human Performance Lab
Heart rate during the physical activity sessions will be monitored with a FitBit Inspire Walkers will gradually increase intensity with a goal of 60 of the heart rate reserve based on data from the graded exercise test
The stretching program will be supervised and conducted in the Human Performance Lab on mats The session will start with 5 to 10 minutes warm up of light activity eg easy walking with light calisthenics After the warm up participants will engage in 8 to 10 stretching exercises per session under the guidance of an exercise supervisor Each stretching exercise will be held for 10 to 30 seconds at the point of slight discomfort The flexibility exercise will be repeated for two to four repetitions with participants aiming for 60 seconds of total stretching time per flexibility exercise eg four 15 second stretches Exercise supervisors will provide a complete orientation to the stretching exercises during the first session
Two primary cohorts 40 each walking and stretching groups will be scheduled each semester during a 3-month period September through November and February through April during a 3-year period Of 240 participants entered into the study each year 200 are expected to successfully complete all phases Retention will be maximized by regular contact with participants during supervised exercise sessions and through regular email messages Three exercise session times will be offered each day of the work week 700 am 900 am 400 pm If participants miss an exercise session there will be weekly opportunities to attend make up sessions Saturday mornings If a study participant misses 3 or more days of exercise training the Research Manager will contact the participant and discuss whether or not they want to drop out of the study
Recruitment Healthy older adult participants 240 to start 200 to finish will be recruited from the Charlotte NC metropolitan area Healthy nonsmoking physically inactive male and female participants targeting 65-85 years of age BMI less than 35 with cognitive changes will be selected who match the inclusion and exclusion criteria
Design This study will employ a randomized double blind placebo controlled parallel group research design with participants 60 assigned to one of 4 arms for the 12 week trial period blueberry and walking blueberry and stretching placebo and walking placebo and stretching
Schedule LAB TESTING VISIT 1 Orientation and ConsentBaseline Cognitive Testing approximately 2 hours
A ORIENTATION AND CONSENT 15 min Potential study participants responding to recruitment messages will come to the AppState Human Performance Lab at an assigned time Study procedures will be thoroughly explained by the Research Manager Dr Camila Olson Human Performance Lab HPL during the consent process Subjects will voluntarily sign the consent form
B MoCA 5 min Participants will report to the lab of Dr Cheatham UNC Chapel Hill Nutrition Research Institute NCRC where they will undergo cognitive testing using the MoCA Participants will be tested for cognitive decline using the Montreal Cognitive Assessment MoCA MoCA consists of eight sections to test recall memory executive function attention orientation abstraction visuospatial skills and naming Mild cognitive decline will be defined as a score of 1 - 15 SD below the norm on the MoCA This criterion was employed in previous work at the NCRC with great success PMID 36066009 Those who score below the 15 SD cutoff will be referred to their family physicians Subjects that score within 1 SD of the norm will not be allowed to enter into the study and will be excused from further participation C CANTAB 30 min Subjects that qualify for the study using the MoCA criteria will be further tested at Cheathams lab for cognitive function using the Cambridge Neuropsychological Test Assessment Battery CANTAB Cambridge Cognition Ltd The CANTAB is a standardized and computerized instrument with automated data capture Participants will be assessed for processing speed episodic memory working memory and sustained attention The CANTAB has been validated for assessment of cognitive decline and will be used to validate the findings from the other assessments The chosen CANTAB collection of subtests see below has been designed at Cambridge to assess cognitive decline and has been shown to be sensitive to deterioration of cognitive abilities even in the short-term Completion of the 5 subtests requires about 30 minutes The tasks are completed on a touch screen computer Subtests of the CANTAB to be included in the battery Motor Control Task -to familiarize participant with the touch screen Rapid Visual Information Processing -test of sustained visual attention Paired Associate Learning -test of memory and learning Reaction Time -test of simple choice reaction time Spatial Working Memory -test of spatial information retention
D ERP 30 min Subjects will also be assessed using electrophysiological procedures ERP in Cheathams lab To collect ERP data the participant will be fitted with a Geodesic Sensor Net GSN Electrical Geodesic Inc consisting of a 128-sensor array The GSN is easy to apply comfortable and relatively non-invasive The GSN is comprised of AgAgCl sensors in an elastic-webbed geodesic tension structure The participants head is measured to insure the proper net is used and to mark the scalp at the vertex for proper placement of net The GSN is soaked in a potassium chloride and warm water solution
Excess solution is blotted from the net so that it does not drip in the participants eyes The net is carefully stretched over the participants head matching the vertex electrode to the vertex mark and the ear electrodes with the preauricular points The chinstrap and side tension straps are tightened and the sensors are all checked to insure that they are perpendicular to and in contact with the scalp Application of the net requires only about 5 minutes and is well tolerated A picture will be taken of the net placement and impedances are then checked Any sensors that are not reading well are adjusted and a small amount of electrolyte solution is applied to the sensors sponge with a pipette When impedances are within accepted limits the participant will be seated in front of the monitor in the participant room separate from the control room A camera which is time-locked to the data being acquired will record the participant during presentation of the pictures Using the Smart-Eye eye-tracking system the investigators will collect information on gaze direction and eyeblinks This system is the only system on the market to offer integrated dense array EEG and remote head- and eye-tracking for linking attention time-on-task pupillometry and eye blinks to the ongoing EEG Data will be recorded continuously and epoched into windows around the stimuli presentation offline Once the net is in place the participant will participate in the three cognitive tests For the n-back working memory task participants will watch a series of letters appearing on the computer screen and will press a button when the target is detected The target in a 2-back task is identified as a letter that matches the letter that appeared letter-before-last 2-back Letters that do not match the definition require no response Use of this task has been shown to predict those in which cognitive decline will be rapid To assess visual mismatch negativity component of the N200 attention the participant will be instructed to focus on the center of the screen At a ratio of 1611 standardstargetsdeviants the computer will randomly cycle through the task When a defined target appears the participant will press the button All other stimuli do not require a response This task requires sharp attentional focus and has been shown to be sensitive to mild cognitive impairment
E Stress questionnaires 15 min Subjects will complete questionnaires that assess anxiety and stressful life events
F Human Performance Lab questionnaires and kits 15 min Subjects will return to the Human Performance Lab and complete a physical activity survey International Physical Activity Questionnaire IPAQ and the medical health questionnaire MHQ Subjects will receive from Dr Olson a 3-day food record stool collection kit and the 24-hour urine collection kit with complete instructions see attached documents The 3-d food record will be completed on the Thursday Friday and Saturday period before Lab Visit 2 Urine and stool samples will be collected the day before Lab Visit 2 Subjects will receive datestimes for additional lab visits
LAB TESTING VISIT 2 Pre-Study Fitness Testing and Sample Collection and Initiation of BlueberryPlacebo Supplementation 15 h
A BLOOD URINE STOOL SAMPLES Approximately one week after Lab Visit 2 participants will report to the HPL in the morning in an overnight fasted state at their assigned times Participants will turn in their 3-day food records and stool and 24-hour urine samples Blood samples maximum of 35 mL will be collected from an arm vein by a trained phlebotomists while participants are seated
B BODY COMPOSITION Height and weight will be measured using a stadiometer and balance beam weight scale The seca medical Body Composition Analyzer mBCA Hanover MD will be used to measure body composition through 8 point BIA while participants stand on foot electrodes with bare feet and grasp electrodes with both hands on side rails The seca mBCA provides several measurements of interest including fat mass fat free mass skeletal muscle mass visceral fat total body water and extracellular water
C GRADED EXERCISE TEST Participants will be tested for maximal aerobic capacity VO2max during a graded treadmill test with the Cosmed CPET metabolic cart Participants will first warm up on the treadmill to demonstrate that they can freely walk on the treadmill Participants will walk against a gradually increasing workload Bruce protocol until maximal effort is reached and the participant voluntarily stops exercising The main outcome measure is peak VO2 or the milliliters of oxygen that can be consumed for each kilogram of body mass at peak effort The Cosmed CPET metabolic system Rome Italy will be attached via a facemask to the participant for continuous measurement of metabolic factors oxygen consumption ventilation rate respiratory rate respiratory exchange ratio A chest heart rate monitor will provide heart rates in beats per minute The rating of perceived exertion RPE will be assessed using a 6 to 20 scale Data will be recorded at the end of each 3 minute stage and at the point of maximal exertion and submaximalmaximal changes pre to post 12 weeks training will be used as criteria for assessing changes in cardiorespiratory fitness The aerobic exercise prescription for the 12 week training program will be based on the maximal heart rate MHR and resting heart rate RHR measured during baseline testing Testing and safety procedures will be under IRB guidance for healthy elderly participants and the study MD will provide oversight of testing procedures
D SUPPLEMENTS Each participant will be given a 6-weeks supply of vacuum-sealed packets of coded lyophilized wild blueberry powder or placebo 52 g daily The lowbush wild blueberry freeze-dried powder will be provided from the Wild Blueberry Association of North America Old Town ME and freeze-dried by FutureCeuticals Momence IL The fiber and carbohydrate-matched placebo blueberry powder will be developed by NCSU using a formula from previous studies blueberry flavoring and aroma 89 coloring 105 purple lake 075 red lake 045 blue 2 lake 003 red dye 0008 blue 2 dye glucose 32 fructose 355 citric acid 077 cellulose 15 fibersol-2 18 xanthan gum 1 pectin 109 and silica 099 The blueberry and placebo powders will be packaged at the NCRC NC Food Innovation Lab Participants will be instructed that the blueberry or placebo powders should be stored in a freezer in the supplied packets until use Instructions will be provided to consume the supplements in split doses half with breakfast and half with lunch mixed in beverages yogurt or other foods If a study participant fails to take the supplement dose on a given day or two they will be asked to add 1 extra packet per day until they are back on schedule Study participants will contact the Research Manager ASU-NCRCappstateedu if they fail to consume the supplement for 3 days or longer and discuss whether or not they wish to dropout of the study Compliance to the supplementation regimen will be assessed through regular email messages and a count of returned packets at the 6- and 12-week time points
LAB TESTING VISITS 3 4 and 5 6 These same basic procedures will be repeated after 6- and 12-weeks except that visits 3 and 5 will not involve subjects going through the consent process and completing the medical health questionnaire and that visit 6 will not include providing subjects with additional supplement packets
12-WEEK RANDOMIZED CLINICAL TRIAL 60 TRAINING SESSIONS AT THE NORTH CAROLINA RESEARCH CAMPUS NCRC Kannapolis NC
Participants will engage in supervised physical activity sessions 5 SESSIONS PER WEEK 45 MIN PER SESSION and consume 52 grams per day of freeze-dried blueberry powder or placebo
Participants will engage in 45 minutes per day supervised exercise brisk walking with heart rate monitors or non aerobic stretching floor exercises for 5 days per week during a 12-week period Exercise sessions will be conducted in small groups under supervision Exercise supervisors will be trained in CPR and an AED device will be located at the door of the Human Performance Lab in the building adjacent to the walking oval
Walking sessions will be held outdoors under supervision on the NCRC track Training heart rates and total distance walked will be recorded On days with inclement weather subjects will walk under cover NCRC parking garage or on treadmills in the Human Performance Lab
Heart rate during the physical activity sessions will be monitored with a FitBit Inspire Walkers will gradually increase intensity with a goal of 60 of the heart rate reserve based on data from the graded exercise test
The stretching program will be supervised and conducted in the Human Performance Lab on mats The session will start with 5 to 10 minutes warm up of light activity eg easy walking with light calisthenics After the warm up participants will engage in 8 to 10 stretching exercises per session under the guidance of an exercise supervisor Each stretching exercise will be held for 10 to 30 seconds at the point of slight discomfort The flexibility exercise will be repeated for two to four repetitions with participants aiming for 60 seconds of total stretching time per flexibility exercise eg four 15 second stretches Exercise supervisors will provide a complete orientation to the stretching exercises during the first session
Two primary cohorts 40 each walking and stretching groups will be scheduled each semester during a 3-month period September through November and February through April during a 3-year period Of 240 participants entered into the study each year 200 are expected to successfully complete all phases Retention will be maximized by regular contact with participants during supervised exercise sessions and through regular email messages Three exercise session times will be offered each day of the work week 700 am 900 am 400 pm If participants miss an exercise session there will be weekly opportunities to attend make up sessions Saturday mornings If a study participant misses 3 or more days of exercise training the Research Manager will contact the participant and discuss whether or not they want to drop out of the study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None