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SYNERGIC TRIAL (SYNchronizing Exercises, Remedies in Gait and Cognition) a multi-Centre randomized controlled… Montero-Odasso, Manuel; Almeida, Quincy J; Burhan, Amer M; Camicioli, Richard; Doyon, Julien; Fraser, Sarah; Li, Karen; Liu-Ambrose, Teresa; Middleton, Laura; Muir-Hunter, Susan; McIlroy, William; Morais, José A; Pieruccini-Faria, Frederico; Shoemaker, Kevin; Speechley, Mark; Vasudev, Akshya; Zou, G. Y; Berryman, Nicolas; Lussier, Maxime; Vanderhaeghe, Leanne; Bherer, Louis Apr 16, 2018

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STUDY PROTOCOL Open AccessSYNERGIC TRIAL (SYNchronizing Exercises,Remedies in Gait and Cognition) a multi-Centre randomized controlled double blindtrial to improve gait and cognition in mildcognitive impairmentManuel Montero-Odasso1,2,3* , Quincy J. Almeida4, Amer M. Burhan5, Richard Camicioli6, Julien Doyon7,Sarah Fraser8, Karen Li9, Teresa Liu-Ambrose10, Laura Middleton11, Susan Muir-Hunter12, William McIlroy13,José A. Morais14, Frederico Pieruccini-Faria1,3, Kevin Shoemaker15, Mark Speechley2, Akshya Vasudev16, G. Y. Zou2,17,Nicolas Berryman18,19, Maxime Lussier18,20, Leanne Vanderhaeghe21 and Louis Bherer9,18,20,22AbstractBackground: Physical exercise, cognitive training, and vitamin D are low cost interventions that have the potential toenhance cognitive function and mobility in older adults, especially in pre-dementia states such as Mild CognitiveImpairment (MCI). Aerobic and progressive resistance exercises have benefits to cognitive performance, thoughevidence is somewhat inconsistent. We postulate that combined aerobic exercise (AE) and progressive resistancetraining (RT) (combined exercise) will have a better effect on cognition than a balance and toning control (BAT)intervention in older adults with MCI. We also expect that adding cognitive training and vitamin D supplementation tothe combined exercise, as a multimodal intervention, will have synergistic efficacy.Methods: The SYNERGIC trial (SYNchronizing Exercises, Remedies in GaIt and Cognition) is a multi-site, double-blinded,five-arm, controlled trial that assesses the potential synergic effect of combined AE and RT on cognition and mobility,with and without cognitive training and vitamin D supplementation in older adults with MCI. Two-hundred participantswith MCI aged 60 to 85 years old will be randomized to one of five arms, four of which include combined exercise pluscombinations of dual-task cognitive training (real vs. sham) and vitamin D supplementation (3 × 10,000 IU/wk. vs. placebo)in a quasi-factorial design, and one arm which receives all control interventions. The primary outcome measure is theADAS-Cog (13 and plus modalities) measured at baseline and at 6 months of follow-up. Secondary outcomes includeneuroimaging, neuro-cognitive performance, gait and mobility performance, and serum biomarkers of inflammation(C reactive protein and interleukin 6), neuroplasticity (brain-derived neurotropic factor), endothelial markers (vascularendothelial growth factor 1), and vitamin D serum levels.Discussion: The SYNERGIC Trial will establish the efficacy and feasibility of a multimodal intervention to improvecognitive performance and mobility outcomes in MCI. These interventions may contribute to new approaches tostabilize and reverse cognitive-mobility decline in older individuals with MCI.(Continued on next page)* Correspondence: mmontero@uwo.ca1Department of Medicine, Division of Geriatric Medicine, Schulich School ofMedicine & Dentistry, University of Western Ontario, London, Canada2Department of Epidemiology and Biostatistics, Schulich School of Medicine& Dentistry, University of Western Ontario, London, CanadaFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Montero-Odasso et al. BMC Geriatrics  (2018) 18:93 https://doi.org/10.1186/s12877-018-0782-7(Continued from previous page)Trial Registration: Identifier: NCT02808676. https://www.clinicaltrials.gov/ct2/show/NCT02808676.Keywords: MCI, Exercise, Cognitive training, Vitamin D, Cognition, Gait, DementiaBackgroundOver 46 million people lived with dementia worldwidein 2015, with 1 new case every 4.1 s [1]. The cost associ-ated with these dementia cases is over $800 billion US[1]. There is no cure for dementia. Recently, there hasbeen an important shift in interventional studies ondementia to targeting early stages or pre-dementiastates. Mild cognitive impairment (MCI) is thought tobe an intermediate state between normal cognition ofaging and very early dementia and, as a pre-dementiastate, is commonly regarded as the optimal stage tointervene with preventive strategies and early treatments[2, 3]. Promising interventions for people with MCIinclude physical exercise, cognitive training, and vitaminD supplementation.Physical exercise, specifically aerobic exercise (AE) andprogressive resistance training (RT), have been demon-strated to improve cognitive outcomes, along withimproved physical capacity and mobility in older adults[4, 5]. Both, AE [6] and RT [7] trials have reported posi-tive results in improving cognitive performance, withconsistent findings also observed after AE interventionslasting more than 3 months [4, 8]. RT has been studiedless extensively than aerobic training in older adults,particularly in Mild Cognitive Impairment (MCI).Similarly, cognitive training (e.g., computer based cogni-tive process training) may improve cognition, mobility,and postural control in older adults. Recent systematicreviews have shown cognitive benefits of computer-basedcognitive training [9, 10]. Notably, a dual-task cognitivetraining regimen designed by our group has demonstratedthat this type of training can also improve balance inhealthy older adults [11]. Recent research suggests thatimprovements in brain plasticity occur after cognitivetraining [12, 13].Vitamin D deficiency has been associated with cognitivedysfunction, dementia and mobility decline in older adults[4, 14–16]. Vitamin D is a neurosteroid hormone thatexhibits neuroprotective attributes through antioxidativemechanisms, neuronal calcium regulation, immunomodu-lation, enhanced nerve conduction, and detoxificationmechanisms [14, 17–20]. Compelling evidence from animalmodels and epidemiological studies supports a potentialbeneficial role for vitamin D on cognitive function [18, 21].Robustly designed trials with longitudinal follow-uphave been recommended to investigate the comparativebenefits of isolated and multi-domain interventions inMCI to improve cognition and function [22]. To date,the effect of combined AE and RT in MCI is unknown.Moreover, the added value of adding cognitive trainingand vitamin D supplementation to physical exercisefor improving global cognition, executive function,and memory in MCI has not been assessed. [22] TheSYNERGIC TRIAL (SYNchronizing Exercises, Remed-ies in GaIt and Cognition) is designed to evaluate theeffect of the combined exercise (AE and RT), alone orin combination with cognitive training and vitamin Dsupplementation, in older adults with MCI. This trial isbeing conducted by the Motor Exercise and CognitionTeam (MEC Team 12) of the Canadian Consortium onNeurodegeneration in Aging (CCNA), part of the CanadaDementia Strategy.Hypotheses1. Twenty weeks of supervised combined exercise (AEand RT) will significantly improve cognitivefunction in older adults with MCI, as assessed byprimary outcome Alzheimer’s Disease AssessmentScale-Cognitive (ADAS-Cog 13 and plus modalities)and secondary outcomes, compared to a balance andtoning (BAT) control.2. Adding cognitive training to combined exercise willsignificantly improve primary and secondary outcomescompared to combined exercise without cognitivetraining.3. Adding vitamin D supplementation to combinedexercise will significantly improve primary andsecondary outcomes compared to combinedexercise without vitamin D supplementation.4. The multi-domain intervention (combined exercise+ cognitive training + vitamin D supplementation)will significantly improve primary and secondaryoutcomes compared to the control intervention.Methods/DesignDesignThe SYNERGIC TRIAL (SYNchronizing Exercises,Remedies in GaIt and Cognition) is a randomized,phase II, five-arm, double-blind controlled study evalu-ating the effect of combined exercise with and withoutcognitive training and vitamin D supplementation oncognitive function. A total of 200 participants withMCI, aged 60 and older will be enrolled and random-ized into one of five arms:Montero-Odasso et al. BMC Geriatrics  (2018) 18:93 Page 2 of 15Arm 1: combined AE and RT exercise + cognitivetraining + vitamin D.Arm 2: combined AE and RT exercise + cognitivetraining + placebo D.Arm 3: combined AE and RT exercise + control cogni-tive training + vitamin D.Arm 4: combined AE and RT exercise + control cogni-tive training+ placebo D;Arm 5: BAT exercise + control cognitive training +placebo D.Note: The active interventions are in bold. Arm 5includes only control interventions.Figure 1 illustrates the trial design and Fig. 2 summa-rizes the timeline of the trial consisting of an approxi-mate 12–18 months enrolment period, and 12 monthsof follow-up. The trial adheres to the ConsolidatedStandards of Reporting Trials guidelines for the conductand reporting of clinical trials, as extended to non-pharmacologic interventions [23].SettingInterventions will be done across five sites: London (leadand sponsor site), Waterloo-University of Waterloo,Waterloo-Wilfrid Laurier University, Montreal, andVancouver. Participants will be recruited primarilyfrom the community and from clinics serving MCIpopulations.ParticipantsEligibilityThe target recruitment is 200 older adults aged 60 to85 years old with MCI who meet inclusion and exclusioncriteria as outlined here (London target recruitment: 40participants, Waterloo-University of Waterloo targetrecruitment: 20, Waterloo-Wilfred Laurier Universitytarget recruitment: 20, Montreal target recruitment: 50,and Vancouver-University of British Columbia targetrecruitment: 70). Although age, sex, and education willbe included as covariates in the analytical models,recruitment will not be stratified.Inclusion criteriaParticipants must meet each of the following criteria forenrolment into the study:1. Age 60 to 85 years old.2. Self-reported levels of proficiency in English, orFrench (at Montreal site only), for speaking andunderstanding spoken language.Fig. 1 Consortium flowchart for the SYNERGIC TrialMontero-Odasso et al. BMC Geriatrics  (2018) 18:93 Page 3 of 153. Able to comply with scheduled visits, treatmentplan, and other trial procedures.4. Able to ambulate at least 10 m independently.5. Having MCI defined following Albert et al. [2]criteria:a- Subjective cognitive complains,b- Objective cognitive impairment in one of thefollowing four cognitive domains: memory,executive function, attention, and language,operationalized using one or more of thefollowing: MoCA Test (Montreal CognitiveAssessment) with scores ranging from 13 to 24/30, Logical Memory below Alzheimer’s DiseaseNeuroimaging Initiative (ADNI) cut-offs (< 9 for16+ years of education; < 5 for 8–15 years ofeducation; < 3 for 0–7 years of education),Consortium to Establish a Registry for Alzheimer’sDisease (CERAD) word list recall < 6.c- Preserved activities of daily living operationalized asa Score > 14/23 on the Lawton-Brody InstrumentalActivities Of Daily Living (IADL) [24] scale andconfirmed by clinician’s interviews.d- Absence of dementia using criteria from theDiagnostic and Statistical Manual of MentalDisorders, Fifth Edition [25] and/or GlobalClinical Dementia Rating (CDR) ≤ 0.5 [26].6. Having normal or corrected to normal vision inat least one eye so that they can identify symbolsand stimuli presented on a computer screen infront of them.7. Must be in sufficient health to participate in thestudy’s exercise training program as determinedusing the Physical Activity ReadinessQuestionnaire-Plus (PARQ+) screening tool,coupled with evaluation by a certified exercisephysiologist and/or a physician for clearance toparticipate in combined exercise training program.Fig. 2 Schematic Timeline of the SYNERGIC Trial. a Recruitment of participants will be an on-going process with individuals being assigned to groups asthey are enrolled. Recruitment is expected to be finished between 12 to 18 months. b Baseline assessments (T0) will be completed within one-week ofparticipant starting the specific intervention/placebo. Participants will return to the clinic six months (c) after starting the specific intervention/placebo tocomplete the post intervention assessment (T6). After six months participants will return to the clinic again (T12) at which time their final assessment willbe completed (d). 9 months after their first baseline assessment (T0) i.e. 3 months post-intervention, there will be a follow-up phone callMontero-Odasso et al. BMC Geriatrics  (2018) 18:93 Page 4 of 15Exclusion criteriaParticipants who exhibit any of the following conditionsare to be excluded from the study:1. Serious underlying disease which, in the opinion ofthe investigator, may preclude engagement ininterventions or may interfere with the participant’sability to participate fully in the study.2. Participant with uncontrolled major depression,schizophrenia, severe anxiety or drug abuse.3. Current parkinsonism or any neurological disorderwith residual motor deficits (e.g. stroke with motordeficit), active musculoskeletal disorders (e.g. severeosteoarthritis of lower limbs) or history of knee/hipreplacement affecting gait performance at clinicalevaluation.4. Intention to enroll in other clinical trials during thesame time period.5. Active participation in an exercise programinvolving AE or RT regimen 2 or more times perweek in previous 6 months.6. Taking vitamin D, cognitive enhancers,neuroleptics, or anticholinergics.7. Known hypercalcemia and/or disorder that is causeof hypercalcemia (e.g. hyperparathyroidism/ Paget’sdisease/ Sarcoidosis).8. Known renal/kidney insufficiency.9. Uncontrolled hypertension.10. Uncontrolled diabetes.Sample sizeSample size calculation is based on changes in ourprimary outcome: global cognitive function measuredusing the Alzheimer Disease Assessment Scale Cognitive13 and the plus modality (ADAS-Cog 13 and plus).Changes in the ADAS-Cog test has been used asprimary outcome in pharmacological clinical trials indementia [27] and in 2 previous studies testing the effectof exercises on cognition in MCI participants [28, 29]. Atotal of 200 participants, with 160 in the combinedexercise (pooled from the first 4 arms in one group)and 40 participant in the BAT control group, wouldhave 80% power to detect an effect size (mean differ-ence divided by the standard deviation) of 0.5 at2-sided, 5% significance level. In addition, two-groupcomparisons with 80 participants per group wouldhave 88% power to detect an effect size of 0.5 at the5% significance level. The effect size of 0.5 wasselected based on previous studies showing an effectsize of exercise on ADAS-Cog ranging from 0.6 to 0.3in MCI populations. [28–30]. The sample size estima-tions may be regarded as conservative, as the finaldata will be analyzed using analysis of covariance(ANCOVA) to adjust for baseline ADAS-Cog scoresand other important patient characteristics.MeasuresTest performed in the screening session, and duringthree visits (baseline, 6 months, and 12 months) areitemised in Table 1. Information concerning demograph-ics, chronic diseases, comorbidities, chronic medications,history of previous falls, fear of falling, and balance con-fidence will be recorded using valid questionnaires atbaseline. Additional descriptors to be tested include theactivities of daily living using the Alzheimer DiseaseCooperative Study Activities of Daily Living inventory(ADCS-ADL), Lawton-Brody IADL, the Short Form qual-ity of life questionnaire (SF-36), the Generalized AnxietyDisorder 7 (GAD 7), Geriatric Depression Scale (GDS-30),CDR, the physical activity scale for the elderly (PASE), andthe Mini Mental State Examination (MMSE).Primary outcomeChanges in cognitive function will be assessed using theADAS-Cog in two modalities, the 13 items modality(ADAS-Cog 13) and the plus modality (ADAS-Cog plus,Table 1) [25]. Improvement in either modality is consid-ered evidence of efficacy. The ADAS-Cog 13 is a scale thatconsists of 13 brief cognitive tests assessing memory,language, attention, concentration and praxis. Scoresrange from 0 to 84, with higher scores indicating higherseverity of cognitive impairment [25]. The ADAS-Cog hasbeen used a primary outcome measure in numerous trialswith MCI and Alzheimer’s Disease (AD) [28, 29]. TheADAS-Cog plus has marked advantages over the ADAS-Cog 13 as an outcome measure in MCI populations sinceit incorporates items concerning executive function [25].The following tests are adding to the ADAS-Cog 13 tocomprise the plus modality: Trail-Making Test (TMT) A& B, the WAIS-R Digit Symbol Substitution Test (DSST),the Digit Span forward & backward, and CategoryFluency. In brief, the TMT (A & B) is a two part test,which assesses attention, speed, and mental flexibility andhas been widely used clinically for assessing deficits inattention and executive functioning [31]. Trails A, whereparticipants connect numbers in ascending order is trun-cated at 3 min and Trails B, where participants connectnumbers and letters in ascending and alternating order istruncated at 5 min. Psychomotor speed is assessed withthe DSST [32], which evaluates the speed with whichparticipants copy arbitrary symbols associated with corre-sponding digits, by referring to a number-symbol key atthe top of the page. The Digit Span test is an auditoryattention task, where participants are asked to recall aseries of numbers forward and backward. For categoryfluency, a measure of speed and flexibility of verbalthought, participants are asked to name as many items asMontero-Odasso et al. BMC Geriatrics  (2018) 18:93 Page 5 of 15possible in a specified category (vegetables & animals);unique responses during the first minute in each categoryare counted.We expect that our interventions, over 20 weeks, willshow improvement and/or less decline in cognition asmeasured by the ADAS-Cog (13 and plus modalities) atmonth 6 and at month 12. Significant changes in eithertime points will be considered preliminary evidence ofefficacy. Additionally, reducing the proportion of partici-pants, expressed as percentages per allocated group, withabnormal ADAS-Cog scores (dichotomous variable,cut-off score to be determined with ADAS-Cog litera-ture) after intervention will be considered evidence ofefficacy. Furthermore, we expect a significant statisticalimprovement in the transformed score of ADAS-Cogplus using an algorithm validated by Crane et al. [33].Secondary outcomesSecondary outcomes include neuropsychological assess-ments, gait and mobility outcomes (including incidenceof fall), neuroimaging, and blood biomarkers.Cognitive outcomesSecondary cognitive outcomes will include MoCA testfor global cognition, the recall list from the ADAS-Cogto evaluate verbal semantic memory, TMT A and B,DSST, Digit Span Test (Forward and Backwards), BostonNaming Test, Verbal fluency (animals and vegetables),Table 1 Assessments across study visits for SYNERGIC TrialProcedure Visit 1ScreeningVisit 2BaselineVisit 36 monthTelephone Follow-upat 9 monthVisit 412 monthWritten Informed Consent XDemographic Information XMini Mental State Examination (MMSE) XPhysical Activity Readiness Questionnaire Plus (PARQ +) XLogical Memory 1 & 2 XCERAD Word List Recall XPASE Questionnaire XMontreal Cognitive Assessment (MoCA) X X XGeneralized Anxiety Disorder 7 (GAD-7) X X XGeriatric Depression Scale (GDS-30) X X XClinical Dementia Rating (CDR) X X XActivities of Daily Living (ADCS-ADL and IADL) X X XClinical Medical Questionnaire X X XDual Task Control Assessment X X XADAS-Cog 13 (+ tests a) X X XTrail Making Test A & B a X X XDigit Symbol Test a X X XDigit Span Forward and Backward WAIS-III a X X XBoston Naming Test a X X XVerbal Fluency Test a X X XColour Word Interference Test X X XQuality of Life Questionnaire (SF-36) X X XShort Physical Performance Battery (SPPB) X X XGait Assessment using Gait Mat and accelerometers(when available)X X XSix Minute Walk Test (6MWT) b X X XNeuroimaging (MRI) X XBlood Draw X XFalls Calendar c X X X Xa Testing included in the ADAS-Cog plusb This test may be completed at the gym facility on the first day of interventionc Calendar will be given to participant to complete and will be submitted to Research Staff at exercise trainingMontero-Odasso et al. BMC Geriatrics  (2018) 18:93 Page 6 of 15and Colour Word Interference Test (Table 1). We expectimprovement in participants of the active intervention inthese cognitive tests, with the larger improvement in themultimodal intervention.Gait outcomesGait velocity and variability under single and dual-taskingGait velocity will be assessed as the time taken to walk6 m using an electronic walkway system (ProtoKinetic®and/or GAITRite® Systems, Inc.). Gait variability ofspatial and temporal gait variables (stride time, stridelength, double support time and step width) will be cal-culated using the coefficient of variation (CV = (standarddeviation / mean) × 100). The CV is a standardizedmeasure of variability allowing comparison of gait vari-ables measured in different units, having different meansand range of values. Gait walks will be performed 3times under single-task conditions, and one time undereach of the three dual-task conditions (described below),and one time as fast gait. Dual-tasking assessments willpermit calculation of dual-task cost for all gait variablesof interest [34, 35]. Specifically, we expect participants inthe combined exercise intervention to increase their gaitvelocity, decrease their gait variability and reduce theirdual-task cost for the gait variables of interest.Gait performance will be recorded using electronicwalkway systems which automatically determine spatio-temporal gait parameters from imbedded sensors acti-vated by foot pressure [36]. The gait mat will be locatedin a well-lit room with start and end points marked onthe floor 1 m from either end of the mat. Participantswill perform three main tasks: 1) preferred walkingspeed, 2) dual-task walking (counting backwards by 1’s,subtracting 7’s, and naming animals out loud while walk-ing) and 3) fast walking. In all walks, participants willstart 1 m before the beginning of the 6-m walkway andcontinue to travel 1 m past the end of the walkway. Thisprocedure is in place to ensure steady-state walkingand to minimize any effects of acceleration and de-acceleration during the course of the walk [37, 38].The dual-task conditions selected are based on previ-ous research which demonstrated that counting back-wards requires both working memory and attention[39] and naming animals is related to verbal fluency,which relies on semantic memory [39, 40]. The evalu-ator will record any counting errors during walking sothat it can be compared with the same mental taskswhile seated. The seated assessments will be timed at10 s and will be performed in the beginning of all cog-nitive assessments (before ADAS-Cog) to preventpractice effects in dual-task gait performance. Reliabil-ity has been previously established for this protocol inpeople with MCI [41] and an instructive video can befound at the “www.gaitandbrain.com/resources” as the“Guidelines for Gait Assessments in CCNA”.FallsA fall is defined as ‘unintentionally coming to rest onthe ground, floor, or other lower level and not due to aseizure, syncope, or an acute stroke’ [42]. Events causedby overwhelming environmental hazards (e.g., beingstruck by a moving object) are not considered a fall.Recurrent falls are defined as ‘two or more events in a12-month period’. Falls will be recorded throughout the12-month trial, participants will be provided with a fallscalendars, on which they will record any falls that haveoccurred, and they will be asked to bring them monthlyto the training sessions to review with a research staffmember. After the completion of the intervention, par-ticipants will be contacted at month 9 and 12 to reportincidental falls. We expect participants in the combinedintervention to reduce the number of falls compared tothe sham intervention.Mobility assessmentsTo further evaluate mobility, participants will be per-forming the Short Physical Performance Battery (SPPB),and the 6 min walk test (6MWT). We expect partici-pants in the active intervention to present the largerimprovements.NeuroimagingBrain Magnetic Resonance Imaging (MRI) will be per-formed at baseline and 6-month visit. The imaging protocolwill follow the Canadian Dementia Imaging Protocol devel-oped for CCNA and available at http://www.cdip-pcid.ca.Pre-post regional patterns of brain plasticity will beassessed using structural (high-resolution 3D T1-weightedimages = 7 min) in order to get voxel-based volumetric andcortical thickness measures, as well as diffusion tensorimaging (DTI, 30 directions, with AP/PA correction scan =7 min) to calculate fractional anisotropy and diffusivity inwhite matter tracts as well as derive tract-based statistics.Cerebrovascular integrity and pathology will be assessedusing the following contrasts: PD/T2 = 5 min; FLAIR =7 min, and T2* = 5 min). Functional magnetic resonanceimaging at rest (rsfMRI plus field map = 12 min) will alsobe acquired to measure change in data-driven functionalnetworks. Scanning time will take 1.3 h. We expect that allactive interventions will improve brain morphology (struc-tural MRI), chemistry (spectroscopy MRI), and function(resting state MRI) compared with control interventionsas defined by: increased hippocampal volume (mm3) byMRI scanning; positive localized Voxel-Based Morphom-etry (VBM) brain changes (z-score relative change); de-creased total volume of White Matter Hyper-intensities(WMHs) (mm3); and lead to beneficial hippocampal andMontero-Odasso et al. BMC Geriatrics  (2018) 18:93 Page 7 of 15anterior and posterior cingulate MRS metabolite changes(% increase in N-acetylaspartate, and increase in phospho-creatine metabolites) and resting state MRI prefrontalactivation.Biological markersA blood draw will take place at baseline and 6-month visitin fasting conditions. Serum biomarkers of inflammation(C reactive protein, and interleukin 6), neuroplasticity(brain-derived neurotropic factor), endothelial health (vas-cular endothelial growth factor 1), and vitamin D serumlevels will be measured before and after intervention.Samples will be collected, processed and stored securely atthe respective site in a − 80 C freezer used for researchpurposes. We expect that active interventions willpreferentially decrease inflammatory markers, increasebrain-derived neurotrophic factor (BDNF) levels [29],and decrease vascular endothelial growth factor(VEGF-1) compared to either cognitive or controlconditions.Study proceduresThe screening visit (visit 1) will determine participant’seligibility. There will be three assessment sessions: base-line, post-intervention at 6 months, and 12-monthfollow-up (Fig. 1). The baseline assessment will occurprior to randomization. Outcomes will be assessed bytrained assessors blinded to group allocation. The mea-sures at each assessment are described in Table 1 andtimelines are shown in Fig. 2.RandomizationUpon completion of the screening and baseline assess-ments, participants will be randomized and allocated toone of the 5 study arm. The randomization sequence ofthe participants will be generated centrally by the researchpharmacist of the sponsor site using a central, web-basedrandomization service (www.randomizer.org) and will bespecific for each site. The research pharmacy will assignthe investigational product (vitamin D/matching placebo,as “kits”) in compliance with the randomization list(s) andallocate a sequential randomization number to eachparticipant. A block randomization by 5 will be applied toensure an appropriate balance of the characteristics ofparticipants between each arm. Permuted blocks will beemployed to ensure balance over time. After the baselineassessment, research personnel not involved in measure-ment or intervention will access the randomization list(s)to determine the arm allocation and institute the corre-sponding study interventions.BlindingIn order to minimize a source of bias, this is a double-blinded study. Research personnel performing the outcomeassessments at 6 and 12 month follow-ups will be blindedto group allocation. Participants will be blinded to the“active” intervention and study hypotheses. If it was medic-ally necessary to un-blind a participant, the central researchpharmacy will be contacted by the principal investigator toobtain the code.Study interventionsAll participants will participate in three (3) group-training sessions per week for 20 weeks, under thesupervision of trainers. Each session will last approxi-mately 90 min and will be comprised of 30 min cogni-tive training or the cognitive training control followedby approximately 60 min of combined AE and RT orBAT control exercise. All participants will receive amonthly supply of either a vitamin D supplement (tablet10,000 IU) or a placebo to be taken three times perweek. All arms will have an equal volume and frequencyof contact with trainers over the 12 months of the study.Interventions will be delivered in small groups of up toeight individuals. Each training group will have 1–2trainers present each session to ensure a ratio of onetrainer per four participants. To avoid potential imbal-ances in exposure time, control conditions for exerciseand cognitive training will have the same duration as theactive interventions.Combined AE and RT exerciseThe combined exercise intervention will be held in appro-priate fitness facilities and take place between Mondayand Friday, ensuring that it is not on three consecutivedays. Staff trained and certified in exercise training willsupervise all sessions. Difficulty of aerobic and resistanceexercise will be tailored to their individual functioninglevel, with constant monitoring by the trainers.Participants will start with a 10 min warm up, whichincludes: marching in place with arm swings, bum kicks,dynamic hamstring stretching, hula hoop circles, shouldercircles, arm reaches, torso twists, ankle circles, dynamiccalf stretching, side stepping with wrist circles, split-stepknee bends, and quarter squats. The RT portion will occurnext and includes 5 exercises: leg press & leg flexion(lower body), chest press, lat pull, and seated row (upperbody). These exercises are performed alternating betweenlower and upper body exercises, with the number of repe-titions, sets, and rest being modified every 4 weeks to in-crease muscular strength. RT will progress from loads andvolumes appropriate for endurance (first 8 weeks) to thoseappropriate for maximal strength gains (last 12 weeks).Training volume, intensity, and rest are standardized anddescribed in Additional file 1: Table S1. Participantsshould reach exhaustion at the last prescribed repetitionof the last set. Training prescription for all exercisesMontero-Odasso et al. BMC Geriatrics  (2018) 18:93 Page 8 of 15follows American College of Sport Medicine guidelinesfor strength development in older adults.Following the RT portion of each session, partici-pants will complete 2 sets of 10 min of aerobic exer-cise. The mode of exercise can vary and may includewalking, a variety of ergometers (treadmill, ellipticalmachines, cycling ergometers, rowing machines, etc.),and other forms of free aerobic exercises, as long asthe cognitive load is minimized. Intensity will be mon-itored using a Borg scale (0–10) with a target of 5–6for weeks 1–8, 6–7 for weeks 9–16, and 7–8 for thelast 4 weeks (Additional file 2: Table S2).Each session will end with a ten-minute cool down,which will consist of the following stretches (each heldfor 20–30 s); quadriceps stretch, hamstring stretch, calfstretch, 2 hip stretches, static torso rotation, seated sidebend, back and shoulder stretch, chest stretch, tricepsstretch, neck stretch.BAT control exercisesParticipants assigned to the BAT control exercise con-dition will take part in balance and toning exercisesin groups of up to eight participants, supervised by atrainer [43–48]. The exercises will be devoted to im-proving muscle tone and flexibility, without improvingstrength, and cardiorespiratory capacity. Resistant loadand number of repetitions will not progress acrossexercise sessions, unless participants were unable tocomplete required repetitions at the beginning of theintervention. The session will start with the same10-min warm-up completed in the combined AE andRT group. This will be followed by 40 min of avariety of balance and toning exercises that will targetthe entire body. The sessions will include functionaltraining (wall squats, standing calf raises, standing legabduction/adduction, standing ball walk up & down,seated back row with resistance tube, shoulder retrac-tions, wall push-ups, toe walking, heel walking, quar-ter squats, gluteus kickback holds, standing balltwists, shoulder circuits, yoga ball chest press, yogaball shoulder abduction, yoga ball leg adductionsqueeze), balance training (standing leg circumduc-tion, tandem stance, single leg stance, tandem stanceball relay pass, partner ball pass in tandem stance,tandem forward & backward walking, toe taps onbench), agility training (4 step zig zag in place, 4 stepzig zag walking, line and cone drills), and core train-ing (core contractions seated on exercise ball, exerciseball seated ball pass, seated exercise ball marching,modified & full bug on floor). Exercises will be cycledin and out every 3 weeks to maintain variety anddecrease likelihood of progression. The session willend with the same 10 min cool down stretches as forthe exercise group.Cognitive trainingThe cognitive training intervention will involve tabletbased (iPad®, held on a stand on a table) dual-task trainingthat requires participants to maintain and prepare formany response alternatives (working memory) and toshare attention between two concurrent tasks (divided at-tention). Difficulty of cognitive training is tailored to theirindividual functioning level. The training uses a custom-written program developed for neuro-rehabilitation andhas been used in previous research trials for cognitive [39,40] and mobility outcomes [12].Cognitive training will take place in groups of up toeight participants before the exercise training session.Cognitive training will be 30 min, at maximum, and eachparticipant will complete the cognitive training at anindividual desk space, in a quiet room, wearing head-phones. Each session, participants will perform a twodifferent visuo-motor tasks, each with their respectivesets of visual stimuli (e.g., letters, numbers, animals,vehicles, fruits, celestial bodies) and respective hand-button correspondences (i.e., buttons that are to betapped with the thumbs on either the right or the leftside of the tablet). Participants are instructed to performas fast as possible, while maintaining accuracy. Tasks willbe performed both separately and concurrently so thattask-set cost and dual-task cost can be isolated. At eachsession, task combination for the sets of stimuli willchange (from a total 18 combinations). Training will alsoinclude online feedback as well as histogram of dailyperformances to encourage improvement.Control cognitive trainingThe cognitive training control group sessions will last amaximum of 30 min to align with the same time frameas the cognitive training group. Participants will alter-nate between 2 different tasks (touristic searching usinginternet and video watching) completed using the sametablet (iPad®) as in the cognitive training group. Sessionswill be held in groups of up to eight participants, and inthe first session they will receive a short introductorylesson on the use of the tablet and how to navigate theinternet. For the touristic searching using internet, par-ticipants will be required to find 3 hotels, 3 touristicplaces, and 3 restaurants of their own preference in acity assigned by the instructor (a new city will beselected each session). They will also need to include therespective addresses of those places on their log sheet.For the video watching task, participants will watch aNational Geographic video on YouTube selected by theinstructor with a different video selected each session.They will watch the video for 20 min and during theremaining 10 min they will answer the following ques-tions on their log sheet; 1) what is the video about; 2)what is the most important information in your opinion;Montero-Odasso et al. BMC Geriatrics  (2018) 18:93 Page 9 of 153) create a question based on the video and answer yourown question. Despite completion of the tasks, partici-pants will be stopped at 30 min.Vitamin D supplementationParticipants will receive vitamin D supplementation (1tablet of 10,000 IU of vitamin D3) three times per weekin order to reach a weekly cumulative dose of 30,000 IUper week (equivalent of 4258 IU daily). The vitamin Dcapsules will be provided by the research coordinator invials at the first session and every 4 weeks for a total offive vials during the training period. Vials will bereturned by the participants to the research coordinatorat the end of each 4 week block. Rationale and bio-safety of the dose: The dose of 10,000 IU/day is currentlyapproved by Health Canada as a supplementation forolder adults. Heaney et al. have administered doses of30,000 IU/day vitamin D3 to adult men for 5 months,with no significant changes in serum calcium concentra-tions or adverse reactions [49–51]. A comprehensivereview of toxic effects of vitamin D found that the low-est level at which an adverse effect was observed was aserum calcidiol concentration of 200 nmol/l, corre-sponding to a daily intake of 40,000 IU. Therefore,weekly doses of 30,000 IU have a 9-fold weekly marginof safety of the established safe dose.Placebo vitamin D supplementationParticipants allocated to placebo vitamin D will receive aplacebo capsule that will perfectly match the vitamin Dtablets. They will take one tablet three times per week,to match what the active vitamin D participants will betaking. The vials will be dispensed on a 4 week basis inthe same manner as the vitamin D tablets.Data analysisPlanned analysisDescriptive statistics for demographic and baseline char-acteristics will be provided with means and standarddeviations, or medians and the interquartile range whereappropriate, for continuous characteristics, and frequen-cies and percentages for categorical variables. Analysiswill be conducted as intention-to-treat (ITT) and asper-protocol analysis (PPA). Observation of a statisticallysignificant difference in the primary outcome at post-intervention time point will be considered preliminaryevidence of efficacy. Contrasts from linear mixed modelscontaining the variable for intervention arm, the cat-egorical variable for time points, and their interactionterm will be used for comparing continuous outcomessuch as ADAS-Cog scores, adjusting for baseline out-come values and patient characteristics including age,sex, and education. This approach can readily handlethree time points (baseline, 6 months and 12 months)and thus may be regarded as a generalization of theANCOVA. Similar analyses for binary outcomes such asreduction of prevalence rate of abnormal ADAS-Cogplus score will be performed with generalized linearmixed effect models. Specific contrasts from the mixed-effects models will be constructed to test the followinghypotheses. The first hypothesis (exercise intervention)will be evaluated by collapsing arms 1–4 (exercise inter-vention, n = 160) and comparing them with arm 5 (noexercise intervention, n = 40). For the second hypothesis(cognitive intervention), arms 1–2 (cognitive interven-tion, n = 80) and arms 3–4 (no cognitive intervention,n = 80) will be collapsed and compared. For the thirdhypothesis (vitamin D intervention), we will collapsearms 1 and 3 (vitamin D intervention, n = 80) and com-pare them with collapsed arms 2 and 4 (no vitamin D,n = 80). For the fourth hypothesis (synergic effect), arm1 (all active interventions, n = 40) will be comparedwith arm 5 (all control interventions, n = 40).For the secondary outcomes, 6 month changes in gaitperformance and secondary cognitive outcomes of inter-est will be performed using one way analyses of variance.For group comparisons that are statistically significant,pairwise comparisons will be made using Tukey’s mul-tiple comparisons tests. Secondary analyses will be alsoperformed according to an intention-to-treat principleand per-protocol analysis. An economic analysis will alsobe performed.All statistical tests will be two-tailed, and a p-value ofless than 0.05 will be considered to indicate statisticalsignificance. All calculations will be made using SPSS(SPSS version 23.0, SPSS Inc., Chicago, IL) and Stata(Stata Statistical Software: Release 14. College Station,TX: StataCorp LP.).Frequency of the analysesPreliminary analysis will be performed after finishingrecruitment to ascertain descriptive characteristics atbaseline assessment. Interim efficacy analyses will beperformed when recruitment is reaching 50% of targetsample and final efficacy analysis will be performed atthe end of the trial since no safety issues are anticipatedin this study.Adverse event and serious adverse event reportingAdverse events will be recorded for subjects starting atthe time of signing the Informed Consent until their dis-continuation of the study. All adverse events will be re-corded on an ongoing paper log, which will be reviewedby each site leader and forwarded to the team leader atLondon site, who will determine both the intensity ofthe event and the relationship of the event to studyprocedures, and monitored until resolved. Based on theoutcome it will be up to the team leader to medicallyMontero-Odasso et al. BMC Geriatrics  (2018) 18:93 Page 10 of 15determine if it is justified for the participant to continuein the study or terminate their participation. A seriousadverse event is defined as any incident that is unex-pected, and related or possibly related to participation inthe research study.Rescue medication and risk managementHigher doses of vitamin D may lead to hypervitaminosisD manifested by hypercalcemia and its sequelae. Treat-ment of acute or chronic intoxication includes withdrawalof vitamin D3 and any calcium supplements, maintenanceof a low calcium diet and if needed corticosteroids or cal-ciuric diuretics, such as furosemide and ethacrymic acidto decrease serum calcium concentrations. All participantswill be monitored by site physicians and trained staff, andshould any adverse events arise, participants will haveaccess to a phone number and e-mail address provided onthe copy of their signed consent form. They will beinformed to use these contacts to notify the PrincipalInvestigator about concerns that may be associated withtreatment received in each site.Ethical considerationsThis study is conducted in compliance with InternationalConference on Harmonization Good Clinical Practice(ICH-GCP) and all applicable regulatory requirements.Sponsor site obtained approval of the Research EthicsBoard at the University of Western Ontario (REB# 107670),the Lawson Health Research Institute’s Clinical ResearchImpact Committee (R-15-038), and Health Canada (HC file- HC6–24-c195918 / HC protocol #201619) prior to initiat-ing study-related activities. Each intervention site has alsoobtained local ethical approval.DiscussionOlder adults with MCI are at a high risk of progressionto dementia syndromes with incident rates often tentimes higher than the cognitive healthy counterparts.Additionally, older adults with MCI have an increasedrisk of falling and mobility decline [52, 53]. Physicalexercise, cognitive training, and vitamin D supplementa-tion are emerging and promising non-pharmacologicalinterventions to enhance mobility and cognitive func-tioning in older adults, especially in pre-dementia statessuch as MCI.These three interventions have been tested separately,with positive results for physical exercise and cognitivetraining in improving cognitive function, and controver-sial evidence for vitamin D supplementation [8, 19].Importantly, it is currently unknown whether combiningAE with RT exercise has a better impact on cognitiveperformance than a BAT exercise modality, and if an in-tegrated approach including combined AE and RT exer-cise in addition to cognitive training and vitamin D willpose a synergistic efficacy for improving cognition andmobility when compared with combined exercise alone.Mechanistically, AE and RT exercises can provoke a cas-cade of biochemical, physiological, and structural changesin the brain, as summarised in Fig. 3. For example, AEincreases blood flow, neurotrophic factor release, neurogen-esis, immune system efficacy and metabolism. These effectsof exercise could combat inflammatory processes and theatrophy of brain structures both often associated with agingand dementias [6, 22]. Interventions using RT exerciseshave found substantial improvements in high-order cogni-tion (e.g. executive functions), whereas low-order cognition(e.g. attention, processing speed) is less benefited [6]. Thereason for this selective improvement in cognition is un-known, but it is hypothesized that areas in the brain thatmodulate executive functions are more susceptible to bothaging and physical exercises interventions. Mechanism sug-gested involve modulation of insulin-like growth factor-1and insulin sensitivity, decreasing inflammation, enhancingrelease of brain-derived neurotrophic factor pathways, andeven decrease brain amyloid load [7, 54, 55]. Combinedexercise interventions have also shown increased brainvolume and muscle mass in older adults [44].Cognitive training can also improve cognition throughenhancing brain functioning. Individuals who practicedmonitoring of two tasks at the same time (i.e. dual-tasktraining) on computer devices presented improved con-nectivity between prefrontal and temporal cortices, areasknown to be important for executive functioning andmemory, when compared to control participants [13].Furthermore, imaging in these participants showed in-creased activity in these cortical areas during restingstate, as shown by increased blood flow. With this,implementing a dual-task cognitive training program inolder adults has the potential to selectively improvehigh-order cognitive functioning through brain plasticityand improved activation.Epidemiological evidence suggests that serum levels of25-hydroxyvitamin D below 50 nmol is associated withimpaired executive functions and the development ofdementia [18]. Similarly, vitamin D levels in serum havebeen associated with worse performance in the cognitivemotor interface in MCI populations. The reason of thisassociation remains to be determined; however, vitaminD (25-hydroxyvitamin D) supplementation has beenhypothesized to cause enhancement of neuroprotectiveagents that decrease biochemical processes in the brainthat accelerate cell death [19]. Activation of vitamin Dreceptor inhibits the production of amyloid-β (Aβ) pro-tein in the brain. Deregulated production of Aβ proteininfluences a chain of biochemical mechanisms that in-creases the rate of hippocampal cell death and synapticloss. Calcium function can also be regulated by vitaminD via down regulation of L-type voltage-sensitive calciumMontero-Odasso et al. BMC Geriatrics  (2018) 18:93 Page 11 of 15channels decreasing apoptosis. Finally, vitamin D canstabilize mitochondria leading to a reduction in oxidativedamage. Thus, we hypothesized that vitamin D couldmodulate cognitive functioning through three major path-ways: Aβ inhibition, calcium metabolism and mitochon-drial activity [56]. Additionally, we have also hypothesizedthat as a consequence of cognitive enhancement withvitamin D supplementation, motor function may also beimproved [16, 57].This randomized controlled trial is the first of its kindto test whether a multimodal intervention combiningAE and RT with or without cognitive training or vitaminD supplementation can improve cognition and mobilityrelated outcomes in older adults with MCI. Strengths ofour protocol include the selection of a comprehensivebattery of assessments sensitive to mobility-cognitivechanges, as determined in a previous Pan-CanadianConsensus in Gait and Cognition (available at www.gai-tandbrain.com/resources), and a population target, olderadults with MCI, which is thought to be the ideal stageto intervene to delay cognitive decline before dementia.Results for this study will provide data concerning theeffect size of the proposed multimodal interventionscompared with isolated interventions in cognitive andmobility outcomes in MCI. We expect that the com-bined exercise intervention will provide the larger effectsize contributing in the changes in cognitive outcomesfollowed by the effects of cognitive training and vitaminD supplementation.In conclusion, the SYNERGIC Trail may contributeto establish the efficacy of an integrated therapeuticstrategy, a multimodal approach, to stabilize andreverse cognitive decline in older individuals withMCI, and help to delay progression to dementia syn-dromes. The proposed interventions are aimed atimproving the quality of life of many older adultswith significant cognitive decline and also alleviateeconomic burdens on health care. It is estimated that500,000 older Canadians have MCI [1] and even amodest one-year delay in dementia incidence couldsave the Canadian Health System over $109 billionover 30 years [58].Fig. 3 Conceptual model for individual and synergistic effects of planned interventions in the SYNERGIC TrialMontero-Odasso et al. BMC Geriatrics  (2018) 18:93 Page 12 of 15Additional filesAdditional file 1: Table S1. Participants in the SYNERGIC Trial willcomplete the following resistance training three times per week for20-weeks. (DOCX 14 kb)Additional file 2: Table S2. Participants in the SYNERGIC Trial willcomplete the following aerobic training three times per week for20-weeks. (DOCX 14 kb)Additional file 3: Table S3. Members and affiliations of the CanadianGait and Cognition Network. (DOCX 16 kb)Abbreviations6MWT: 6 Minute Walk Test; AD: Alzheimer’s disease; ADAS-Cog: Alzheimer’sdisease assessment scale-cognitive; ADCS-ADL: Alzheimer disease cooperativestudy activities of daily living; ADNI: Alzheimer’s disease neuroimaging initiative;AE: Aerobic exercise; ANCOVA: Analysis of covariance; Aβ: amyloid-β;BAT: Balance and toning; BDNF: Brain-derived neurotrophic factor;CCNA: Canadian consortium in neurodegeneration and aging;CDR: Clinical dementia rating; CERAD: Consortium to establish a registryfor alzheimer’s disease; CV: Coefficient of variation; DSST: Digit symbolsubstitution test; GAD 7: Generalized anxiety disorder 7; GDS-30: Geriatricdepression scale; IADL: Instrumental activities of daily living; ICH-GCP: International conference on harmonization good clinical practice;ITT: Intention-to-treat; MCI: Mild cognitive impairment; MMSE: Minimental state examination; MoCA: Montreal cognitive assessment;MRI: Magnetic resonance imaging; PARQ+: Physical activity readinessquestionnaire-plus; PASE: Physical activity scale for the elderly;PPA: Per-protocol analysis; rsfMRI: Functional magnetic resonanceimaging at rest; RT: Resistance training; SF-36: Short form quality of lifequestionnaire; SPPB: Short physical performance battery; SYNERGIC: SYNchronizingExercises, and Remedies in GaIt and Cognition; TMT: Trail-making test; VBM: Voxel-based morphometry; VEGF: Vascular endothelial growth factor; WMHs: Whitematter hyper-intensitiesAcknowledgementsThe authors thank Dr. Yanina Sarquis-Adamson, Alanna Black MSc CCRP, SynergicTrial National Research Coordinator, and Kayla Regan MSc, University of WaterlooResearch Coordinator for their valuable edits and comments in the manuscript.Collaborating members of the Canadian Gait and Cognition Network can be foundin Additional file 3: Table S3.FundingThe SYNERGIC Trial is funded by Canadian Consortium on Neurodegenerationin Aging (CCNA Grant# “FRN” CNA 137794). The CCNA is supported by a grantfrom the Canadian Institutes of Health Research with funding from severalpartners.Authors’ contributionsMMO: Principal investigator, study conception and design, obtaining funding,and drafting first version of the manuscript. QA, AB, RC, JD, SF, KL, TLA, LM, SMH,WM, JM, KS, MS, AV: Drafting the manuscript or revising it critically for importantintellectual content. FPF: Mobility assessments, logistics, relevant intellectualcontributions to project and manuscript. GY: statistical design, drafting themanuscript or revising it critically for important intellectual content. NB: Revisingthe manuscript for important intellectual content and co-design the exercisetraining program. ML: Revising the manuscript for important intellectual contentand develop the cognitive training protocol. LV: created the randomizationsequences, and dispensed the Vitamin D and matching placebo. LB: Drafting themanuscript and revising for important intellectual content, provide the cognitivetraining protocol, and co-design the exercise training program. All authors readand approved the final manuscript.Ethics approval and consent to participateThis study is conducted in compliance with International Conference onHarmonization Good Clinical Practice (ICH-GCP) and all applicable regulatoryrequirements. Sponsor site obtained approval of the Research Ethics Board atthe University of Western Ontario (REB# 107670), the Lawson Health ResearchInstitute’s Clinical Research Impact Committee (R-15-038), and Health Canada(HC file - HC6–24-c195918 / HC protocol #201619) prior to initiating study-related activities. Each intervention site has also obtained local ethical approval.Written consent to participate was obtained when participants signed the letterof information and consent. Capacity to consent was determined on the basisof direct observation of the participant and/or from information obtainedfrom their family. Participants in this study do not have a degree ofcognitive impairment (such as advanced dementia) that would preventthem from understanding the information given and appreciating theconsequences of their decision.Competing interestsThe authors declare they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1Department of Medicine, Division of Geriatric Medicine, Schulich School ofMedicine & Dentistry, University of Western Ontario, London, Canada.2Department of Epidemiology and Biostatistics, Schulich School of Medicine& Dentistry, University of Western Ontario, London, Canada. 3Gait and BrainLab, Parkwood Institute, Lawson Health Research Institute, London, Canada.4Sun Life Financial Movement Disorders Research Centre, Wilfrid LaurierUniversity, Waterloo, Canada. 5Schulich School of Medicine and Dentistry,University of Western Ontario, London, Canada. 6Geriatric and CognitiveNeurology, University of Alberta, Edmonton, Canada. 7FunctionalNeuroimaging Unit, University of Montreal, Montreal, Canada. 8Departmentof Psychology-University of Ottawa, Ottawa, Canada. 9Department ofPsychology and PERFORM Centre, Concordia University, Montreal, Canada.10Department of Physical Therapy, University of British Columbia, Centre forHip Health and Mobility, and Djavad Mowafaghian Centre for Brain Health,Vancouver Coastal Research Institute, University of British Columbia,Vancouver, Canada. 11Department of Kinesiology, University of Waterloo,Waterloo, Canada. 12School of Physical Therapy, University of WesternOntario, London, Canada. 13Division of Neurology and Department ofMedicine, University of Toronto. Tanz Centre for Research inNeurodegenerative Diseases, University of Toronto, Toronto, Canada.14Division of Geriatrics and Centre of Excellence in Aging and ChronicDisease, McGill University, Montreal, Canada. 15Department of Kinesiology,University of Western Ontario, London, Canada. 16Department of Psychiatry,Division of Geriatric Psychiatry and Department of Medicine, Division ofClinical Pharmacology, University of Western Ontario, London, Canada.17Robarts Clinical Trials Inc, London, Canada. 18Centre de Recherche, InstitutUniversitaire de Gériatrie de Montréal, Montréal, Canada. 19Department ofSports Studies, Bishop’s University, Sherbrooke, Canada. 20Faculty ofMedicine, University of Montreal, Montréal, Canada. 21St. Joseph’s HealthCare, London, Canada. 22Montreal Heart Institute, Research Centre, Montreal,Canada.Received: 5 February 2018 Accepted: 3 April 2018References1. Alzheimer Disease International. 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