Effect of Nordic Berries on Cognitive Function, Cardiometabolic Risk Markers and Gut Microbiota in Adults With Mild Cognitive Impairment

Study Overview
=================
Brief Summary
-----------------
The aim of the current study is to investigate whether daily intake of Nordic berries for 12 weeks can improve cognitive abilities of adults with mild cognitive impairment, and whether the effect can be linked to changes in metabolic parameters.

Detailed Description
-----------------
The study will be conducted with a randomized, double-blind, parallel-group (2 arms) placebo-controlled, single-center interventional design. The aim is to investigate the effects on cognitive function and cardiometabolic risk markers after 12 weeks intake of a berry product vs. a reference product. The reference will be isocaloric and matched in taste, appearance, volume and macronutrient composition to the active berry product. Two groups, each of 50 volunteers, are studied. Volunteers will be patients attending the Cognitive medicine unit at Ängelholm hospital, who have mild cognitive impairment (but not dementia). One group of volunteers will consume the berry product while the other group act as control and will consume the reference product. Each volunteer will be seen for a screening visit as well as one pre- and one post-intervention visit at the clinic. In addition, there will be 2 follow-up calls in between visits. Pre- and post-intervention visits will include cognitive assessment with the CANTAB battery (episodic memory and verbal recognition memory), as well as additional cognitive and behavioral tests. Cardiometabolic parameters will be addressed (plasma glucose, insulin, inflammatory markers, blood lipids, body composition) and fecal samples collected.

Official Title
-----------------
A Randomized, Double-blind, Placebo-controlled Intervention Study to Evaluate the Effect of Nordic Berries on Cognitive Function, Cardiometabolic Risk Markers and Gut Microbiome in Adults With Mild Cognitive Impairment The MINDBERRY Trial

Conditions
-----------------
Cognitive Impairment, Mild, Memory Impairment

Intervention / Treatment
-----------------
* Other: Active berry product
* Other: Reference product


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age of 55 years or older. Cognitive impairment in accordance with the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria and global deterioration scale (GDS) stage 3. Capable and willing to give written informed consent. Capable and willing to perform cognitive testing (mastering the Swedish language, functional vision and hearing or the use of visual or hearing aids during testing). Capable and willing to ingest the study beverage for 12 weeks and to follow the instructions given. Exclusion Criteria: MMSE (Mini-Mental State Examination) <24 (at screening or in the last 3 months). Cognitive disease (e.g. dementia) according to Global Deterioration Scale (GDS) stage 4 and up. Severe affective disorder with current symptoms Severe mental disorder. Newly diagnosed or poorly regulated thyroid disease (unstable dose since 3 months back). Ongoing insulin therapy. Ongoing treatment for malignancy*. Conditions with major impact on the gastrointestinal tract (such as Crohn's disease, ulcerative colitis, diagnosed gluten intolerance, undertaken intestinal resection or weight loss surgery). Planned major intervention in health care over the next 3 months (the study period). Undergoing antibiotic therapy for the last 3 months prior to inclusion in the study. Allergy / intolerance to berries or other ingredients in the study products (i.e., colorants, aromas, starch). Vegetarians / vegans. Smoking. Abuse of alcohol or psychoactive substance. Significant change in medication over the last 3 months. Daily, regular high consumption of berries or juices / marmalade / product with high content of these berries (guideline no more than 5 grams per day). (Can be recruited for the study if this intake ceases before visit 1. High consumes (approximately 1 dl of berries per day) has to cease with this at least one month before visit 1.) Taking supplements with potential cognitive effects (e.g. omega-3, ginko biloba), or containing grape and berry extracts or probiotics (capsules or other). (Can be recruited if this intake ceases at least one month before visit 1). Planned longer absence/vacation during the next 3 months (the study period). Concurrent participation in other clinical intervention trials (dietary/pharmacological). Other reasons that make the Study investigator in consultation with the responsible physician deem the person inappropriate to include. basalioma exempt from exclusion criteria.

Ages Eligible for Study
-----------------
Minimum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active berry product<br>Once daily consumption over the period of the study | Other: Active berry product<br>* Subjects should consume the active product containing nordic berries daily during the 12 week intervention period.<br>|
| Placebo Comparator: Reference product<br>Once daily consumption over the period of the study | Other: Reference product<br>* Subjects should consume a reference product (isocaloric to active product) daily during the 12 week intervention period.<br>* Other names: inactive control;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CANTAB - Paired Associate Learning test (PAL28) | To investigate how daily berry intake affects cognitive function (primary objective) measured by episodic memory | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Episodic memory (test verbal recognition memory (VRM) (free-, immediate- and delayed recall) |  | 12 weeks | 
| Attention, psychomotor speed and executive function (Trail making test (TMT) A and B) |  | 12 weeks | 
| Selective attention and processing speed (Stroop color-word test) |  | 12 weeks | 
| Verbal fluency (letter S word fluency test) | Number of novel words on letter S during 60 seconds. | 12 weeks | 
| Behavior and quality of life (AES, Apathy evaluation score (self)) | Answers given by the participants on 18 questions reflect apathy including behavioral, cognitive and emotional indicators on a scale 18-72 where higher scores reflect more apathy. | 12 weeks | 
| Behavior and quality of life (Apathy evaluation score (informant)) | Answers given by someone close to the participant on 18 questions reflect apathy including behavioral, cognitive and emotional indicators on a scale 18-72 where higher scores reflect more apathy. | 12 weeks | 
| EuroQol five dimension (EQ-5D) life quality score. | Participant marks on a visual analogue scale from 0 to 100 how they value their current health status where 0 represents the lowest, and 100 highest, health status and quality of life. | 12 weeks | 
| Hospital Anxiety Depression (HAD) Score. | Self-assessment with 14 items that assess anxiety and depression symptoms before and after the intervention on a scale from 0 to 21, with higher scores indication the presence of symptoms. | 12 weeks | 
| Systolic blood pressure | Change in systolic blood pressure in mm/Hg | 12 weeks | 
| Diastolic blood pressure | Change in diastolic blood pressure in mm/Hg | 12 weeks | 
| Heart rate | Change in bpm (beats per minute) | 12 weeks | 
| Body weight | Change in body weight (kg) | 12 weeks | 
| BMI | Change in body weight index (kg/m^2) | 12 weeks | 
| Body fat composition | Body fat composition (% body fat, fat free mass (kg), basal metabolic rate (BMR) measured with TANITA scale. | 12 weeks | 
| Waist-to-hip ratio | Waist circumference/hip circumference | 12 weeks | 
| Fasting glucose (mM) |  | 12 weeks | 
| Fasting insulin |  | 12 weeks | 
| HOMA-IR | Homeostasis model assessment of insulin resistance (HOMA-IR) | 12 weeks | 
| Lipid metabolism: total cholesterol mg/dl |  | 12 weeks | 
| Lipid metabolism: LDL-cholesterol mg/dl |  | 12 weeks | 
| Lipid metabolism: HDL-cholesterol mg/dl |  | 12 weeks | 
| Lipid metabolism: triglycerides mg/dl |  | 12 weeks | 
| Lipid metabolism: apolipoprotein B/ apolipoprotein A1 ratio |  | 12 weeks | 
| Lipid metabolism: oxLDL | Oxidized LDL-cholesterol | 12 weeks | 
| Liver function: alanine aminotransferase (ALAT) (ukat/L) |  | 12 weeks | 
| Inflammation: hsCRP (mg/L) | high sensitive c-reactive protein | 12 weeks | 
| Inflammation: plasma serum amyloid A (mg/L) |  | 12 weeks | 
| Inflammation: IL-6 ng/L |  | 12 weeks | 
| Inflammation: TNFalfa ng/L |  | 12 weeks | 
| Inflammation: IL-12 ng/L |  | 12 weeks | 
| Inflammation: IL-15 ng/L |  | 12 weeks | 
| Inflammation: MCP-1 ng/L |  | 12 weeks | 
| Inflammation: sVCAM-1 (ukat/L) |  | 12 weeks | 
| Inflammation: IFN-g |  | 12 weeks | 
| Biomarker related to cognitive function: BDNF | Change in plasma brain-derived neurotrophic factor (BDNF) | 12 weeks | 
| PAL scores (PALTEA) | Change in PALTEA score at different levels of the test | 12 weeks | 
| VRM scores | Change in VRM scores at different levels of the test | 12 weeks |