SYNchronizing Exercises, Remedies in GaIt and Cognition

Study Overview
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Brief Summary
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The proposed SYNERGIC trial is uniquely designed to evaluate the effect of aerobic and progressive resistance training exercises, combined with cognitive training and Vitamin D3 supplementation, in cognition and mobility in older adults with Mild Cognitive Impairment (MCI).

Detailed Description
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Exercises, specifically resistance and aerobic training, have been demonstrated to improve cognitive outcomes, along with improved physical capacity and mobility. Both aerobic and resistance training trials of different duration have revealed positive results, with the most consistent findings being observed after combined interventions of 6 months to one year. Although the training benefits of progressive resistance training (PRT) have been well documented, PRT has been studied far less extensively in older adults with Mild Cognitive Impairment (MCI). Exercise training has proven to be beneficial for cognition even in vulnarable populations like in frail older adults, and those with mobility issues. The exact mechanism supporting the benefits of exercise for cognition in humans needs to be further explored, as numerous studies in animals and humans have demonstrated that aerobic exercise may have neuroprotective and neurorestorative effects. The rationale of combining aerobic and PRT as multimodal exercise intervention is supported by research that has revealed potential beneficial effects. In addition, multimodal exercise interventions have shown positive effects on muscle/lean mass, cognition and brain structure, functionality, and brain volume. Similarly cognitive training, i.e. computer based cognitive process training, has also shown positive results in improving cognition, mobility, and postural control. Several recent systematic reviews on the topic support the benefits of cognitive training. In line with exercise training, recent research on cognitive training has also supported important improvements in brain plasticity post-intervention. Finally, Vitamin D3 deficiency in older adults has been linked to cognitive dysfunction, dementia, and mobility decline. Besides its very well-known effects on muscle and bone physiology, several studies have shown a potential beneficial role of Vitamin D3 on cognitive function. Robustly designed trials, with longitudinal follow-up, have been recommended in older adults with MCI to investigate the comparative benefits of isolated Vitamin D3 supplementation, and combined with physical and cognitive training. To date, the effect of adding cognitive training and/or Vitamin D3 to a multimodal progressive exercise training for improving global cognition, executive function, memory, and gait in MCI has not been assessed.

Official Title
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SYNchronizing Exercises, Remedies in GaIt and Cognition (SYNERGIC): A Randomized Controlled Double Blind Trial

Conditions
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Mild Cognitive Impairment

Intervention / Treatment
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* Dietary Supplement: Vitamin D3
* Other: Exercises (E)
* Other: Cognitive Training (CT)
* Other: placebo D3
* Other: control cognitive training
* Other: Placebo exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 60 years of age Self-reported levels of proficiency in English (French for Montreal site only) for speaking and understanding spoken language. Able to comply with scheduled visits, treatment plan, and other trial procedures Able to ambulate at least 10 meters independently Having MCI operationalized using Albert et al. criteria as: objective cognitive impairment in one of the following four cognitive domains: memory, executive function, attention, and language evaluated by the Montreal Cognitive Assessment (MoCA) test with scores ranging from 13-24/30. Preserved activities of daily living on the disability scale confirmed by clinician interview Having normal or corrected to normal vision in at least one eye so that they can identify symbols and stimuli presented on a computer screen in front of them. Must be in sufficient health to participate in the study's aerobic-based exercise training program, based on medical history, vital signs, physical examination by study physicians, or written recommendation by family physician indicating one's appropriateness to participate in aerobic-based exercise training program. Exclusion Criteria: Serious underlying disease (such as active cancer, or recent heart attack) which, in the opinion of the investigator, may preclude engagement in interventions or may interfere with the participant's ability to participate fully in the study. Diagnosis of dementia using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Participant with uncontrolled major depression, schizophrenia, severe anxiety and substance abuse. Current parkinsonism or any neurological disorder with residual motor deficits (e.g. stroke with motor deficit), active musculo-skeletal disorders (e.g. severe osteoarthritis of lower limbs) or history of knee/hip replacement affecting gait performance at clinical evaluation. Intention to enroll in other clinical trials during the same time period Pre-existing exercise structured training program involving aerobic or resistance training in previous 6 months. Taking cognitive enhancers, neuroleptics, anticholinergics or Vitamin D3 in doses more than 1000IU/day or equivalent.

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exercises+CognitiveTraining+Vitamin D3<br>Exercises will combine aerobic+resistance training. Cognitive training will be performed before exercise intervention and using using an ad-hoc software developed by us for tablets. Vitamin D3 (10000IU) will be provided orally three time per week for 20 weeks. | Dietary Supplement: Vitamin D3<br>* Dose: 10000 IU, three times per week, orally.<br>* Other names: Cholecalciferol;Other: Exercises (E)<br>* All participants will complete three (3) group training sessions per week (total 20 weeks), under the supervision of trainers. Each exercise session will last approximately 60 minutes and will happen after the cognitive training/control (CT cCT) session. The exercise session will be a combined aerobic and progressive strengthening exercise. Within each small group of four to eight individuals, participants follow the program tailored to their individual functioning level, with constant monitoring by the trainers. Participants are expected to attend all training sessions and research staff will strongly encourage them to do so.<br>Other: Cognitive Training (CT)<br>* CT intervention will involve computer-based multimodal and multi-domain dual-task training with memory load. A custom-written program, developed for neuro-rehabilitation and used in previous research trials for cognitive and mobility outcomes will be used. Training sessions will take place in groups of four to eight participants before each of the fitness-training session for duration of 30 min max. Participants will perform a concurrent visuo-motor task (dual-task combination) composed of different sets of visual stimuli that have to be identified by tapping designated figures on an digital tablet (IOS or Android system). Participants will perform discrimination tasks involving sets of items (e.g. letters, numbers, animals, vehicles, fruits, celestial bodies).<br>|
| Experimental: Exercises+CognitiveTraining+Placebo D3<br>Exercises will combine aerobic+resistance training. Cognitive training will be performed before exercise intervention and using using an ad-hoc software developed by us for tablets. Matching placebo of vitamin D3 will be provided orally three time per week for 20 weeks. | Other: Exercises (E)<br>* All participants will complete three (3) group training sessions per week (total 20 weeks), under the supervision of trainers. Each exercise session will last approximately 60 minutes and will happen after the cognitive training/control (CT cCT) session. The exercise session will be a combined aerobic and progressive strengthening exercise. Within each small group of four to eight individuals, participants follow the program tailored to their individual functioning level, with constant monitoring by the trainers. Participants are expected to attend all training sessions and research staff will strongly encourage them to do so.<br>Other: Cognitive Training (CT)<br>* CT intervention will involve computer-based multimodal and multi-domain dual-task training with memory load. A custom-written program, developed for neuro-rehabilitation and used in previous research trials for cognitive and mobility outcomes will be used. Training sessions will take place in groups of four to eight participants before each of the fitness-training session for duration of 30 min max. Participants will perform a concurrent visuo-motor task (dual-task combination) composed of different sets of visual stimuli that have to be identified by tapping designated figures on an digital tablet (IOS or Android system). Participants will perform discrimination tasks involving sets of items (e.g. letters, numbers, animals, vehicles, fruits, celestial bodies).<br>Other: placebo D3<br>* matching placebo for Vitamin D3<br>|
| Experimental: Exercises+Control CogTraining+Vitamin D3<br>Exercises will combine aerobic+resistance training. Control cognitive training will be performed before exercise intervention and will consist in computer skills training courses. Each session will consist of introductory exercises for computers and different software (e.g., Word, Excel), as well as an initiation to the Internet (search engines, websites, games, etc.). Vitamin D3 (10000IU) will be provided orally three time per week for 20 weeks | Dietary Supplement: Vitamin D3<br>* Dose: 10000 IU, three times per week, orally.<br>* Other names: Cholecalciferol;Other: Exercises (E)<br>* All participants will complete three (3) group training sessions per week (total 20 weeks), under the supervision of trainers. Each exercise session will last approximately 60 minutes and will happen after the cognitive training/control (CT cCT) session. The exercise session will be a combined aerobic and progressive strengthening exercise. Within each small group of four to eight individuals, participants follow the program tailored to their individual functioning level, with constant monitoring by the trainers. Participants are expected to attend all training sessions and research staff will strongly encourage them to do so.<br>Other: control cognitive training<br>* As a control activity to ensure the same time exposure as in the interventions arms, participant in the control arm will receive a 30 min computer skills training.<br>|
| Experimental: Exercises+Control CogTraining+Placebo D3<br>Exercises will combine aerobic+resistance training.Control cognitive training will be performed before exercise intervention and will consist in computer skills training courses. Each session will consist of introductory exercises for computers and different software (e.g., Word, Excel), as well as an initiation to the Internet (search engines, websites, games, etc. Matching placebo of vitamin D3 will be provided orally three time per week for 20 weeks. | Other: Exercises (E)<br>* All participants will complete three (3) group training sessions per week (total 20 weeks), under the supervision of trainers. Each exercise session will last approximately 60 minutes and will happen after the cognitive training/control (CT cCT) session. The exercise session will be a combined aerobic and progressive strengthening exercise. Within each small group of four to eight individuals, participants follow the program tailored to their individual functioning level, with constant monitoring by the trainers. Participants are expected to attend all training sessions and research staff will strongly encourage them to do so.<br>Other: placebo D3<br>* matching placebo for Vitamin D3<br>Other: control cognitive training<br>* As a control activity to ensure the same time exposure as in the interventions arms, participant in the control arm will receive a 30 min computer skills training.<br>|
| Placebo Comparator: Placebo exercise+Control Cog+Placebo D3<br>This will be the comparator arm with control/placebo activities. | Other: placebo D3<br>* matching placebo for Vitamin D3<br>Other: control cognitive training<br>* As a control activity to ensure the same time exposure as in the interventions arms, participant in the control arm will receive a 30 min computer skills training.<br>Other: Placebo exercise<br>* As a control activity to ensure the same time exposure as in the interventions arms, participant in the control arm will receive a 60 min of a tone exercise regimen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in global cognition assessed using the ADASCog(13 and Plus modalities). | Global cognition will be assessed using the cognitive section of the Alzheimer Disease Assessment Scale-plus EF+FA (ADAS-Cog-plus). This scale consists of 10 brief cognitive tests assessing memory, language, executive function, praxis, and instrumental activities of daily living. The ADAS-Cog has been a significant outcome measure in numerous trials with MCI and AD. The ADAS-Cog-plus has marked advantages as an outcome measure in MCI populations since incorporates items concerning executive function (EF) and functional abilities (FA). Scores in the ADASCog-plus (EF+FA) range from 0 to 90, with higher scores indicating better cognitive performance. | baseline and at 20 weeks (after interventions finalised) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in cognition assessed as the CCNA Cognitive Battery. | The Canadian Consortium on Neurodegeneration in Ageing (CCNA) has established a battery of neuropsychological test which will used as secondary outcomes | baseline at 20 weeks (after interventions finalised) | 
| Change in gait velocity (cm/s). | Gait will be assessed under single and dual-task conditions | baseline at 20 weeks (after interventions finalised) | 
| Change in gait variability (%CoV). | Gait will be assessed under single and dual-task conditions | baseline at 20 weeks (after interventions finalised) | 
| Brain structure (sMRI) | Structural 3 Tesla MRI will be performed at baseline and 20 weeks in all participants who do no present contra-indication for imaging studies | baseline and at 20 weeks (after interventions finalised) | 
| Brain function (fMRI) | Functional 3 Tesla MRI will be performed at baseline and at 20 weeks 6 in all participants who do no present contra-indication for imaging studies. | baseline and at 20 weeks (after interventions finalised) | 
| Changes in BDNF serum levels | Changes in brain derived neurotrophic factor (BDNF) serum levels will be assessed and measured in international units | baseline and at 20 weeks (after interventions finalised) | 
| Combined Score of Cognition and Functionality (Pooled Index) | This index will include cognitive test, gait velocity, dual task gait and the ability to perform activities of daily living. Therefore, treatments are considered successful if they slow down the progression of cognitive decline and maintain functionality and independency | baseline and at 20 weeks (after interventions finalised) | 
| Changes in serum levels Interleukin 1. | Changes in IL-1 will be assessed in serum and measured in international units. | baseline and at 20 weeks (after interventions finalised) | 
| Changes in serum levels Interleukin 6. | Changes in IL-6 will be assessed in serum and measured in international units. | baseline and at 20 weeks (after interventions finalised) | 
| Changes in serum High Sensitive C reactive protein (CRP). | Serum levels of C reactive protein (CRP) 1 will be determined by standardized ELISA methods. | baseline and at 20 weeks (after interventions finalised). | 
| Changes in serum levels of VEGF receptor 1. | Serum levels of VEGF receptor 1 will be determined by standardized ELISA methods. | baseline and at 20 weeks (after interventions finalised) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cognitive training, Vitamin D, Exercise