SYNchronizing Exercises, Remedies in GaIt and Cognition

Mild Cognitive Impairment Clinical Trial

— SYNERGIC  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02808676
• Other study ID #: 107670
• Status: Terminated
• Phase: N/A
• Start date: July 14, 2016
• Est. completion date: November 24, 2020

Study information

• Verified date: September 2021
• Source: Lawson Health Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 176
• Est. completion date: November 24, 2020
• Est. primary completion date: November 24, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 60 Years and older

Eligibility

Inclusion Criteria:

1. At least 60 years of age

2. Self-reported levels of proficiency in English (French for Montreal site only) for speaking and understanding spoken language.

3. Able to comply with scheduled visits, treatment plan, and other trial procedures

4. Able to ambulate at least 10 meters independently

5. 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

6. 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.

7. 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:

1. 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.

2. Diagnosis of dementia using criteria from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.

3. Participant with uncontrolled major depression, schizophrenia, severe anxiety and substance abuse.

4. 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.

5. Intention to enroll in other clinical trials during the same time period

6. Pre-existing exercise structured training program involving aerobic or resistance training in previous 6 months.

7. Taking cognitive enhancers, neuroleptics, anticholinergics or Vitamin D3 in doses more than 1000IU/day or equivalent.

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Mild Cognitive Impairment

Intervention

Dietary Supplement:
• Vitamin D3
Dose: 10000 IU, three times per week, orally.

Other:
• Exercises (E)
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.
• Cognitive Training (CT)
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).
• placebo D3
matching placebo for Vitamin D3
• control cognitive training
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.
• Placebo exercise
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

Locations

Country	Name	City	State
Canada	St. Joseph's Health Care London, Parkwood Hospital	London	Ontario
Canada	Université de Montréal	Montréal	Quebec
Canada	University of British Columbia	Vancouver	British Columbia
Canada	University of Waterloo	Waterloo	Ontario
Canada	Wilfrid Laurier University	Waterloo	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
Lawson Health Research Institute

Country where clinical trial is conducted

Canada, 

References & Publications (23)

Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011 May;7(3):270-9. doi: 10.1016/j.jalz.2011.03.008. Epub 2011 Apr 21. — View Citation

Annweiler C, Beauchet O, Bartha R, Hachinski V, Montero-Odasso M; WALK Team (Working group Angers-London for Knowledge). Vitamin D and caudal primary motor cortex: a magnetic resonance spectroscopy study. PLoS One. 2014 Jan 31;9(1):e87314. doi: 10.1371/journal.pone.0087314. eCollection 2014. — View Citation

Annweiler C, Montero-Odasso M, Muir SW, Beauchet O. Vitamin D and Brain Imaging in the Elderly: Should we Expect Some Lesions Specifically Related to Hypovitaminosis D? Open Neuroimag J. 2012;6:16-8. doi: 10.2174/1874440001206010016. Epub 2012 Feb 28. — View Citation

Annweiler C, Schott AM, Rolland Y, Blain H, Herrmann FR, Beauchet O. Dietary intake of vitamin D and cognition in older women: a large population-based study. Neurology. 2010 Nov 16;75(20):1810-6. doi: 10.1212/WNL.0b013e3181fd6352. — View Citation

Ballesteros S, Prieto A, Mayas J, Toril P, Pita C, Ponce de León L, Reales JM, Waterworth J. Brain training with non-action video games enhances aspects of cognition in older adults: a randomized controlled trial. Front Aging Neurosci. 2014 Oct 14;6:277. doi: 10.3389/fnagi.2014.00277. eCollection 2014. Erratum in: Front Aging Neurosci. 2015;7:82. — View Citation

Beauchet O, Annweiler C, Verghese J, Fantino B, Herrmann FR, Allali G. Biology of gait control: vitamin D involvement. Neurology. 2011 May 10;76(19):1617-22. doi: 10.1212/WNL.0b013e318219fb08. Epub 2011 Apr 6. — View Citation

Bherer L, Erickson KI, Liu-Ambrose T. Physical exercise and brain functions in older adults. J Aging Res. 2013;2013:197326. doi: 10.1155/2013/197326. Epub 2013 Sep 17. — View Citation

Chapman SB, Aslan S, Spence JS, Hart JJ Jr, Bartz EK, Didehbani N, Keebler MW, Gardner CM, Strain JF, DeFina LF, Lu H. Neural mechanisms of brain plasticity with complex cognitive training in healthy seniors. Cereb Cortex. 2015 Feb;25(2):396-405. doi: 10.1093/cercor/bht234. Epub 2013 Aug 28. — View Citation

Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: a meta-analytic study. Psychol Sci. 2003 Mar;14(2):125-30. — View Citation

Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007 Sep;30(9):464-72. Epub 2007 Aug 31. Review. Erratum in: Trends Neurosci. 2007 Oct;30(10):489. — View Citation

Fraser SA, Li KZ, DeMont RG, Penhune VB. Effects of balance status and age on muscle activation while walking under divided attention. J Gerontol B Psychol Sci Soc Sci. 2007 May;62(3):P171-8. — View Citation

Kueider AM, Parisi JM, Gross AL, Rebok GW. Computerized cognitive training with older adults: a systematic review. PLoS One. 2012;7(7):e40588. doi: 10.1371/journal.pone.0040588. Epub 2012 Jul 11. Review. — View Citation

Langlois F, Vu TT, Chassé K, Dupuis G, Kergoat MJ, Bherer L. Benefits of physical exercise training on cognition and quality of life in frail older adults. J Gerontol B Psychol Sci Soc Sci. 2013 May;68(3):400-4. doi: 10.1093/geronb/gbs069. Epub 2012 Aug 28. — View Citation

Liu-Ambrose T, Nagamatsu LS, Voss MW, Khan KM, Handy TC. Resistance training and functional plasticity of the aging brain: a 12-month randomized controlled trial. Neurobiol Aging. 2012 Aug;33(8):1690-8. doi: 10.1016/j.neurobiolaging.2011.05.010. Epub 2011 Jul 7. — View Citation

Montero-Odasso M, Almeida QJ, Burhan AM, Camicioli R, Doyon J, Fraser S, Li K, Liu-Ambrose T, Middleton L, Muir-Hunter S, McIlroy W, Morais JA, Pieruccini-Faria F, Shoemaker K, Speechley M, Vasudev A, Zou GY, Berryman N, Lussier M, Vanderhaeghe L, Bherer — View Citation

Montero-Odasso M, Bherer L, Studenski S, Gopaul K, Oteng-Amoako A, Woolmore-Goodwin S, Stoole P, Wells J, Doherty T, Zecevic AA, Galinsky D, Rylett RJ, Jutai J, Muir-Hunter S, Speechley M, Camicioli R. Mobility and Cognition in Seniors. Report from the 2008 Institute of Aging (CIHR) Mobility and Cognition Workshop. Can Geriatr J. 2015 Sep 30;18(3):159-67. doi: 10.5770/cgj.18.188. eCollection 2015 Sep. Review. — View Citation

Montero-Odasso M, Hachinski V. Preludes to brain failure: executive dysfunction and gait disturbances. Neurol Sci. 2014 Apr;35(4):601-4. doi: 10.1007/s10072-013-1613-4. Epub 2013 Dec 24. — View Citation

Montero-Odasso M, Verghese J, Beauchet O, Hausdorff JM. Gait and cognition: a complementary approach to understanding brain function and the risk of falling. J Am Geriatr Soc. 2012 Nov;60(11):2127-36. doi: 10.1111/j.1532-5415.2012.04209.x. Epub 2012 Oct 30. Review. — View Citation

Nagamatsu LS, Handy TC, Hsu CL, Voss M, Liu-Ambrose T. Resistance training promotes cognitive and functional brain plasticity in seniors with probable mild cognitive impairment. Arch Intern Med. 2012 Apr 23;172(8):666-8. doi: 10.1001/archinternmed.2012.379. Erratum in: Arch Intern Med. 2013 Aug 12;173(15):1477. — View Citation

Reijnders J, van Heugten C, van Boxtel M. Cognitive interventions in healthy older adults and people with mild cognitive impairment: a systematic review. Ageing Res Rev. 2013 Jan;12(1):263-75. doi: 10.1016/j.arr.2012.07.003. Epub 2012 Jul 25. Review. — View Citation

Sage MD, Almeida QJ. A positive influence of vision on motor symptoms during sensory attention focused exercise for Parkinson's disease. Mov Disord. 2010 Jan 15;25(1):64-9. doi: 10.1002/mds.22886. — View Citation

Sage MD, Almeida QJ. Symptom and gait changes after sensory attention focused exercise vs aerobic training in Parkinson's disease. Mov Disord. 2009 Jun 15;24(8):1132-8. doi: 10.1002/mds.22469. — View Citation

Skinner J, Carvalho JO, Potter GG, Thames A, Zelinski E, Crane PK, Gibbons LE; Alzheimer's Disease Neuroimaging Initiative. The Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-Plus): an expansion of the ADAS-Cog to improve responsiveness in MCI. Brain Imaging Behav. 2012 Dec;6(4):489-501. doi: 10.1007/s11682-012-9166-3. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	Change in gait velocity (cm/s).	Gait will be assessed under single and dual-task conditions	baseline at 20 weeks (after interventions finalised)
Secondary	Change in gait variability (%CoV).	Gait will be assessed under single and dual-task conditions	baseline at 20 weeks (after interventions finalised)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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).
Secondary	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)