Clinical trial NCT02446314: An Investigation Into the Effects of a Wild Blueberry Powder and a Wild Blueberry Extract on Cognition in Older Adults
Official title: A Randomized, Double-blind, Placebo-controlled Study Investigating the Effects of a Wild Blueberry Powder and a Wild Blueberry Extract on Cognition in Older Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Cognitive Decline
Lead sponsor: University of Reading
Sponsor class: OTHER
Collaborators: name: Naurex, Inc, an affiliate of Allergan plc
First posted: 2015-05-18
Enrollment: 122
Sex: ALL
Minimum age (years): 65
Maximum age (years): 80
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: The purpose of this study is to determine whether a 6 month dietary intervention with wild blueberry powder and extract stabilised with L-cysteine and L-glutathione have an effect on cognitive performance in participants aged between 65 - 80.

Detailed description: Interventions: A placebo and two different wild blueberry products will be used in this study (see Table 1). A wild blueberry powder at two different doses and a single wild blueberry extract. The wild blueberry powder will be used at a 450 mg-dose, to which 45 mg of L-Cysteine and 5 mg of L-Glutathione will be added (wild blueberry powder-450), as well as at a 900 mg-dose, to which 90 mg of L-Cysteine and 10 mg of L-Glutathione will also be added (wild blueberry powder-900). The wild blueberry extract will consist of 100 mg of wild blueberry extract supplemented with 10 mg of L-Cysteine and 1 mg of L-Glutathione. Participants will be asked to consume two capsules daily with their normal breakfast. The capsules will be packed in blister packs with 4 capsules per blister. Each box contains 4 blisters (or a total of 16 capsules) in order to provide for 1 week of study medication, with 2 capsules remaining. Participants will be instructed to return the left-over investigational product weekly (i.e two capsules) using stamped addressed envelopes supplied by the experimenters. Weekly assessment of left-over investigational product will allow for continued compliance verification.

Procedure: The study comprises of a telephone screen and then six visits, including a familiarization visit (week T-1), three test visits (week 0, 12 and 24), and two control visits (week 6 and 18). Participants may stop the study treatment without stating any reason at any time during the study. In addition, a participant will be withdrawn from the study if: a subject requests discontinuation, he/she exhibits a serious adverse event to any component of the test product, the participant significantly violates the inclusion or exclusion criteria, an intercurrent illness emerges and/or the investigator's opinion is that withdrawal is appropriate and in the best interest of the participant. If a participant withdraws from the study, he/she will be encouraged to make a final visit as soon as possible, irrespective of the reason for withdrawal, to complete a final battery of cognitive tasks.

1. Screening: once a participant has indicated that they wish to join the trial they will be contacted by telephone for a brief screening session. The research associate (RA) will give a brief overview of the study and will ascertain that each interested volunteer is willing to participate for the entire duration of the study and to check that they fulfill our inclusion/exclusion criteria. Once confirmation of suitability for the study is confirmed, the RA will schedule their familiarization visit.
2. Familiarization Visit: Volunteers will be asked to attend the Nutritional Psychology Unit at the University of Reading where they will receive a detailed explanation on the study by the participating research associate and will be asked to sign the informed consent form before any study procedure starts. A log will be kept identifying all participants having signed the informed consent form (ICF) and the participant will be allocated a participant number. Once consent has been given, the inclusion/exclusion criteria will be checked once again and vital signs (blood pressure and heart rate) and anthropometric measurements (height, weight, BMI) will be taken. The participants will then be asked to complete a number of questionnaires and cognitive tasks comprising: (i) Yale Physical Activity Questionnaire; (ii) Frequency of Forgetting Questionnaire to give a baseline assessment of their memory performance; and (iii) Computerized Global Cognitive Health Assessments (NART, CERAD, MMSE, letter and category fluency; unless as a member of the Older Adult Panel these data have been collected from them in the preceding 3 months). Finally, participants will be given training on the cognitive test battery (tasks outlined below) that will be used during the study to reduce the chances of 'practice' adversely effecting performance on subsequent test days. Before leaving the laboratory, participants will be asked to keep a 72 hour food diary (consisting of 2 week days \& 1 weekend day) so that background flavonoid intakes can be measured prior to the start of the intervention.
3. Test Visits (Weeks 0, 12 and 24): All of these sessions will be held in the morning (typically 8am-10am arrival time to suit participants individual needs). Participants will attend the laboratory in a fasted state and on arrival at the laboratory we will check participants still fulfill our inclusion/exclusion criteria, their general well-being, notification of any adverse events, any issues with compliance, and to check whether there have been changes to any concomitant medication. Blood pressure and heart rate will also be measured, and the food diary will be collected (week 0 and 24 only). They will then receive a standard low-flavonoid breakfast and will complete the battery of cognitive tasks (see below). Subjects will then be given their intervention (sufficient quantity until their next test session, in blister packs, weeks 0 and 12 only), and will then be requested to consume 2 capsules each day. At week 24 only, the Yale Physical Activity and Frequency of Forgetting questionnaires will also be administered, and weight will be measured.
4. Control Visits (weeks 6 \& 18): These sessions can take place at any time of day to suit the participant. Participants will attend the laboratory at the University of Reading to collect the next 6 week supply of their intervention. During these visits we will check that participants still fulfill our inclusion/exclusion criteria, informally check their well-being, inquire whether there have been any adverse events, and confirm that there have not been any changes to their concomitant medication. At week 18 only participants will be given another copy of the 72 hour food diary (consisting of 2 week days \& 1 weekend day and asked to complete this before they return for their test visit in week 24.

Eligibility criteria: Inclusion Criteria:

* Overall healthy volunteers as proven by medical history and/or physical examination and of all ethnicity and socioeconomic status
* Free-living
* Subjects with subjective memory complaints
* MMSE: 24-30
* Subjects are willing to maintain their normal eating habits and exercise habits to avoid changes in body weight over the duration of the study
* Being willing to complete the food diaries and questionnaires
* Able to give signed written informed consent
* Signed informed consent form

Exclusion Criteria:

* Use of complementary and alternative medicine
* History of metabolic disorder, diabetes, substance abuse
* Subjects diagnosed with psychiatric or neurological conditions
* Subjects using medications that might affect the outcome measures (such as antidepressant and sleeping medication), or planned changes

Primary outcomes:
measure: Proportion of Words Correctly Recognised.
timeFrame: 12, and 24 weeks
measure: Total Number of Correct Sequences Recalled
timeFrame: 12, and 24 weeks
measure: Combined Z Score of Delayed Words Recalled, Words Recognised, and Pictures Recognised.
timeFrame: 12, and 24 weeks
Secondary outcomes:
measure: Combined Z Score of Mean Reaction Time Scores for Incongruent Attention Network and Stroop Task Trials.
timeFrame: 12, and 24 weeks
measure: Combined Z Score of Proportion of Immediate Words Recalled, Number of Correct Serial 3 and Serial 7 Subtractions, Sternberg Task Coefficent of the Line
timeFrame: 12, and 24 weeks
measure: Systolic Blood Pressure
timeFrame: 12, and 24 weeks.
measure: Diastolic Blood Pressure
timeFrame: 12, and 24 weeks
measure: Heart Rate
timeFrame: 12, and 24 weeks.
measure: Positive Affect Score
timeFrame: 12, and 24 weeks
measure: Negative Affect Score
timeFrame: 12, and 24 weeks.
Other outcomes:
Locations:
city: Reading
country: United Kingdom
facility: University of Reading
state: Berkshire
Study officials:
affiliation: University of Reaiding
name: Claire M Williams, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: NATURIEX-DBS,, LLC
name: Emilie Fromentin, PhD
role: STUDY_DIRECTOR
References:
citation: How, P.S., Ellis, J.A., Neshatdoust, S., Spencer, J.P.E. (2008). The impact of plant-derived flavonoids on mood, memory and motor skills in healthy older UK adults. Proceedings of the Nutrition Society, 67, E316.
citation: Krikorian R, Shidler MD, Nash TA, Kalt W, Vinqvist-Tymchuk MR, Shukitt-Hale B, Joseph JA. Blueberry supplementation improves memory in older adults. J Agric Food Chem. 2010 Apr 14;58(7):3996-4000. doi: 10.1021/jf9029332.
citation: Macready AL, Kennedy OB, Ellis JA, Williams CM, Spencer JP, Butler LT. Flavonoids and cognitive function: a review of human randomized controlled trial studies and recommendations for future studies. Genes Nutr. 2009 Dec;4(4):227-42. doi: 10.1007/s12263-009-0135-4. Epub 2009 Aug 13.
citation: Rendeiro C, Vauzour D, Kean RJ, Butler LT, Rattray M, Spencer JP, Williams CM. Blueberry supplementation induces spatial memory improvements and region-specific regulation of hippocampal BDNF mRNA expression in young rats. Psychopharmacology (Berl). 2012 Oct;223(3):319-30. doi: 10.1007/s00213-012-2719-8. Epub 2012 May 9.
citation: Rendeiro C, Vauzour D, Rattray M, Waffo-Teguo P, Merillon JM, Butler LT, Williams CM, Spencer JP. Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor. PLoS One. 2013 May 28;8(5):e63535. doi: 10.1371/journal.pone.0063535. Print 2013.
citation: Whyte AR, Cheng N, Fromentin E, Williams CM. A Randomized, Double-Blinded, Placebo-Controlled Study to Compare the Safety and Efficacy of Low Dose Enhanced Wild Blueberry Powder and Wild Blueberry Extract (ThinkBlue) in Maintenance of Episodic and Working Memory in Older Adults. Nutrients. 2018 May 23;10(6):660. doi: 10.3390/nu10060660.