The Effects of a Multidomain Lifestyle Intervention on Brain Functioning and Its Relation With Immunometabolic Markers in Ageing

Study Overview
=================
Brief Summary
-----------------
HELI is a multicenter, randomised controlled trial in two Dutch research centres (Donders Centre for Cognitive Neuroimaging, Nijmegen, and the department of Human Nutrition & Health at Wageningen University) among 104 older adults aged 60-75 years who are at risk for cognitive decline with an intervention duration of 26 weeks (roughly 6 months). Participants are randomized in a 1:1 ratio to a multidomain lifestyle intervention characterized by group-sessions and guidance (high-intensity intervention group) versus online access to general lifestyle-related health information in the form of biweekly leaflets (low-intensity intervention group).

Official Title
-----------------
The Effects of a Multidomain Lifestyle Intervention on Brain Functioning and Its Relation With Immunometabolic Markers in Ageing: the HELI Study

Conditions
-----------------
Life Style, Risk Reduction, Cognitive Decline, Aging

Intervention / Treatment
-----------------
* Behavioral: Multidomain lifestyle intervention


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent; Age between 60-75 years (at pre-screening); Fluency in Dutch (speaking, reading and writing); Lives near study centres in Nijmegen and Wageningen (max. 50 kilometers of travelling, to ensure study centre visits are possible without excessive travel burden); Presence of ≥2 self-reported risk factors for cognitive decline (BMI of 30 or higher, physical inactivity according to World Health Organization guidelines, hypertension [not using hypertensive drugs counts as an additional risk factor], hypercholesterolemia, diabetes type-II, non-symptomatic cardiovascular disease). Exclusion Criteria: Concurrent participation in other intervention trials; Technologically illiterate (complete incompetence in working with computers, apps, online questionnaires, etc.); No internet access from home; Clinical diagnosis of ≥1 of the following: vascular event (CVA), neurological pathology (e.g. mild cognitive impairment, dementia, multiple sclerosis, Parkinson's, epilepsy), current malignant disease(s) (with or without current treatment), current psychiatric disorder(s) (e.g. depression, psychosis, bipolar episodes), symptomatic cardiovascular disease (e.g. stroke, angina pectoris, heart failure, myocardial infarction), revascularisation surgery in the last 12 months at pre-screening, inflammatory bowel disease (characterised with diarrhoea), visual impairment (e.g. blindness), hearing or communicative impairment; Unable to undergo MRI (e.g. metal objects in upper body, past brain surgery, active implants, claustrophobic); Cognitive impairment as determined by the Telephone Interview for Cognitive Status (TICS-M1), performed during pre-screening before inclusion.

Ages Eligible for Study
-----------------
Minimum Age: 60 Years
Maximum Age: 75 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: Multidomain lifestyle intervention. Participants are randomized in a 1:1 ratio to a multidomain lifestyle intervention characterized by group-sessions and supervision (high-intensity intervention group) versus access to general lifestyle-related health information in the form of biweekly leaflets which are provided through e-mail (low-intensity intervention group).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High-intensity group<br>The high-intensity group receives a supervised multidomain lifestyle intervention consisting of weekly group meetings. During the weekly group meetings, information and exercises are provided, and participants are able to exchange experiences and advice with other group members. | Behavioral: Multidomain lifestyle intervention<br>* A multidomain lifestyle intervention including the following lifestyle domains: (1) diet, (2) physical activity, (3) sleep, (4) stress/mindfulness, and (5) cognitive training.<br>|
| No Intervention: Low-intensity group<br>The low-intensity group only receives access to general lifestyle-related health information through biweekly leaflets, which are provided through e-mail. | |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in brain activity during working memory | Blood-oxygen level dependent activity during N-back (2-back) fMRI task | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in working memory performance | Task accuracy during N-back (2-back) fMRI task | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in cerebral perfusion levels | Cerebral perfusion measured using arterial spin labelling (ASL) | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in inflammatory profile in blood plasma | Blood plasma analysis to measure hs-CRP, IL-6 and TNF-α concentrations | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in microbiota profile | 16S rRNA based profile of gut microbiota in faeces | Change between Baseline (T0) and Follow-up after 6 months (T1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body mass index | Measured in kg/m^2 | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Waist circumference | Measured in cm | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Hip circumference | Measured in cm | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Blood pressure | Measured by blood pressure monitor. Scores range from approximately (for diastolic) 60-120 and (for systolic) 100-180 mmHg, with higher scores indicating higher blood pressure. | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Abdominal fat distribution (neuroimaging) | Visceral adipose tissue(VAT)/subcutaneous adipose tissue (SAT) ratio measured by abdominal T1-weighted MRI scan | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Brain structure volume profile (neuroimaging) | Brain structure volumes (grey matter, white matter, brain vesicles), measured by MP2RAGE structural sequence | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Brain myo-inositol levels (neuroimaging) | Brain myo-inositol levels reflecting local neuroinflammation in dorsolateral prefrontal cortex and hippocampus, measured by magnetic resonance spectroscopy (MRS) | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Intracranial iron deposition (neuroimaging) | Local aggregation of iron deposition within the brain, measured by quantitative susceptibility mapping (QSM) | Baseline (T0) | 
| Change in Neuropsychological test battery scoring | Z-scoring of cognitive assessments targeting cognitive domains predominantly affected by cognitive ageing: executive function (incl. working memory), episodic memory and processing speed | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Trail Making Test A (TMT-A) Numbers : trial time (cognitive assessment) | Discrete number; score 0 - no maximum (seconds to assessment completion). Lower score indicates a better outcome | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Trail Making Test A (TMT-A) Numbers: errors (cognitive assessment) | Discrete number; score 0 - no maximum (amount of errors). Lower score indicates a better outcome | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Trail Making Test B (TMT-B) Numbers and Letters : trial time (cognitive assessment) | Discrete number; score 0 - no maximum (seconds to assessment completion). Lower score indicates a better outcome | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Trail Making Test B (TMT-B) Numbers and Letters: errors (cognitive assessment) | Discrete number; score 0 - no maximum (amount of errors). Lower score indicates a better outcome | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Verbal Fluency Test (VFT) (cognitive assessment) | Word count in one minute; score 0 - no maximum. Higher score indicates a better outcome | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Rey Auditory Verbal Learning Test (RAVLT): learning trials (cognitive assessment) | Discrete number; score 0 - 15 (amount of words remembered during learning trial 1 to 5). Higher score indicates a better score | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Rey Auditory Verbal Learning Test (RAVLT): delayed recall (cognitive assessment) | Discrete number; score 0 - 15 (amount of words remembered during delayed recall). Higher score indicates a better score | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Digit Symbol Substitution Test (DSST) (cognitive assessment) | Discrete number; score 0 - 90 (amount of symbols correctly substituted). Higher score indicates better outcome | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Wechsler Adult Intelligence Scale (WAIS) digit span (cognitive assessment) | Discrete number; score 0 - 90 (amount of digit spans correctly repeated). Higher score indicates better outcome | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Five Facet Mindfulness Questionnaire (questionnaire) | Self-assessment of mindfulness; score 24 - 120. Higher score indicate more mindfulness | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Sedentary Behaviour Questionnaire (questionnaire) | Average hours and minutes of sedentary behavior a day; score 0 - 24 hours. Higher score (more hours) indicates more sedentary behavior | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Eetscore food questionnaire (questionnaire) | Dutch Healthy Diet Index 2015; score 0 - 160. Higher score indicates a better outcome | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Perceived Stress Scale (questionnaire) | Stress perception; score 0 - 40. Higher score indicate more perceived stress | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Pittsburgh Sleep Quality Index (PSQI) (questionnaire) | Sleep quality; score 0 - 21. Higher score (referred to as global or total score) indicates worse sleep quality | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in SQUASH (questionnaire) | Physical activity. METs derived from the Ainsworth's compendium of physical activity will be used to classify physical activity intensity (<1.5METs- sedentary, 1.6-2.9 METs- light, 3.0-5.9METs- moderate, >6.0- vigorous physical activity) | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Cognitive Failures Questionnaire (questionnaire) | Subjective cognitive functioning; score 0 - 100. A higher score indicates more subjective cognitive failure | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Memory Self-Efficacy MIA (questionnaire) | Self-evaluation and confidence of memory. Sum of Part 1 + Part 2A and B. Part 1: Strategy (scores 10 - 50, higher scores indicate more use of strategies), Part 2A: Subjective memory functioning (score 23 - 115, higher score indicates better memory self-efficacy) and Part 2B: Locus (score 7 - 35, higher scores indicate better perceived personal control over remembering abilities) | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in total amount of bacteria, fungi and specific bacterial strains (faeces) | Total amount of bacteria, fungi and specific bacterial strains are quantified using digital droplet PCR in faecal samples | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in individual short-chain fatty acids (SCFAs) profile (faeces) | GC-MS and LC-MS measurements to assess profile of individual SCFAs in faecal samples (acetic acid, formic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid, valeric acid, 4-methyl valeric acid, hexanoic acid, heptanoic acid) | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in microbiome-derived bioactive compounds (faeces) | Amount of microbiome-derived bioactive compounds is measured by untargeted LC-MS microbiota-derived metabolite analysis in faecal samples | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in intestinal inflammation profile (faeces) | Assay-based profile of intestinal inflammation measured in faecal samples | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in Gut transit time | Gut transit time measured by blue muffin consumption and appearance in faeces | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in metabolic profile (blood) | Assay-based profile of (energy) metabolism measured in plasma samples | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in inflammation profile (blood) | Assay-based profile of systemic inflammation measured in plasma samples | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in intestinal integrity profile (blood) | Assay-based profile of intestinal integrity measured in plasma samples | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in brain health profile (blood) | Assay-based profile of brain health measured in plasma samples | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in white blood cell count (blood) | White blood cell count measured via finger prick analysis | Change between Baseline (T0) and Follow-up after 6 months (T1) | 
| Change in small intestinal bacterial overgrowth (SIBO) (breath) | Measurement of total exhaled hydrogen gas after glucose consumption in breath samples | Change between Baseline (T0) and Follow-up after 6 months (T1) |