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Promotion of the mind through exercise (PROMoTE): a proof-of-concept randomized controlled trial of aerobic… Liu-Ambrose, Teresa; Eng, Janice J; Boyd, Lara A; Jacova, Claudia; Davis, Jennifer C; Bryan, Stirling; Lee, Philip; Brasher, Penny; Hsiung, Ging-Yuek R Feb 17, 2010

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STUDY PROTOCOL Open AccessPromotion of the mind through exercise(PROMoTE): a proof-of-concept randomizedcontrolled trial of aerobic exercise training inolder adults with vascular cognitive impairmentTeresa Liu-Ambrose1,2*, Janice J Eng1, Lara A Boyd1, Claudia Jacova3, Jennifer C Davis2,4,5, Stirling Bryan5,Philip Lee6, Penny Brasher5, Ging-Yuek R Hsiung3AbstractBackground: Sub-cortical vascular ischaemia is the second most common etiology contributing to cognitiveimpairment in older adults, and is frequently under-diagnosed and under-treated. Although evidence is mountingthat exercise has benefits for cognitive function among seniors, very few randomized controlled trials of exercisehave been conducted in populations at high-risk for progression to dementia. Aerobic-based exercise training maybe of specific benefit in delaying the progression of cognitive decline among seniors with vascular cognitiveimpairment by reducing key vascular risk factors associated with metabolic syndrome. Thus, we aim to carry out aproof-of-concept single-blinded randomized controlled trial primarily designed to provide preliminary evidence ofefficacy aerobic-based exercise training program on cognitive and everyday function among older adults with mildsub-cortical ischaemic vascular cognitive impairment.Methods/Design: A proof-of-concept single-blinded randomized trial comparing a six-month, thrice-weekly,aerobic-based exercise training group with usual care on cognitive and everyday function. Seventy older adultswho meet the diagnostic criteria for sub-cortical ischaemic vascular cognitive impairment as outlined by Erkinjunttiand colleagues will be recruited from a memory clinic of a metropolitan hospital. The aerobic-based exercisetraining will last for 6 months. Participants will be followed for an additional six months after the cessation ofexercise training.Discussion: This research will be an important first step in quantifying the effect of an exercise intervention oncognitive and daily function among seniors with sub-cortical ischaemic vascular cognitive impairment, arecognized risk state for progression to dementia. Exercise has the potential to be an effective, inexpensive, andaccessible intervention strategy with minimal adverse effects. Reducing the rate of cognitive decline among seniorswith sub-cortical ischaemic vascular cognitive impairment could preserve independent functioning and healthrelated quality of life in this population. This, in turn, could lead to reduced health care resource utilization costsand avoidance of early institutional care.Trial Registration: ClinicalTrials.gov Protocol Registration System: NCT01027858.* Correspondence: tlambrose@exchange.ubc.ca1Department of Physical Therapy, University of British Columbia, Vancouver,CanadaLiu-Ambrose et al. BMC Neurology 2010, 10:14http://www.biomedcentral.com/1471-2377/10/14© 2010 Liu-Ambrose et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.BackgroundCerebrovascular disease is the second most commonetiology contributing to dementia in older adults [1-4]and may be the most under-diagnosed and yet mosttreatable form of cognitive dysfunction in older adults[5]. Vascular cognitive impairment is defined as the lossof cognitive function resulting from ischaemic, ischae-mic-hypoxic, or hemorrhagic brain lesions as a result ofcerebrovascular disease and cardiovascular pathologicchanges. As vascular cognitive impairment is predomi-nantly a sub-cortical frontal form of cognitive disorderwith prominent executive dysfunction [6], it directlyimpairs everyday function [7], such as managingfinances, transportation, or the telephone. Takentogether, vascular cognitive impairment has the potentialto severely impact the ability to function autonomouslywithin society [8].A number of epidemiological studies suggest thatmodification of vascular risk factors, such as hyperten-sion, diabetes mellitus, and hypercholesterolemia may behelpful in slowing down the progression of vascular cog-nitive impairment [9-12]. Hence, one promisingapproach to delay the progression of vascular cognitiveimpairment is aerobic-based exercise training. Critically,evidence is mounting that exercise has benefits for cog-nitive function among seniors. Aerobic-based exercisetraining may be of specific benefit in slowing the pro-gression of cognitive decline among seniors with vascu-lar cognitive impairment by reducing key vascular riskfactors associated with metabolic syndrome. Aerobicexercise may also act specifically on disease pathophy-siology [13], for example, by improving capillarization ormodulating brain neurotrophic factors [14-16], and mayeven decrease brain amyloid load in the brain [17].Finally, aerobic-based exercise training as an interven-tion strategy for individuals with vascular cognitiveimpairment is attractive as it could be delivered at apopulation-level.The growing consensus is that small vessel diseaseshave an important role in vascular cognitive impairment[18,19]. Small vessel disease often presents as unde-tected “covert” strokes in the sub-cortical white matter.Compared to other forms of vascular cognitive impair-ment, the sub-cortical ischaemic vascular disease sub-type is a more homogenous form of the disease with amore predictable outcome [20]. While mild Sub-corticalIschaemic Vascular Cognitive Impairment (SIVCI)describes those individuals whose symptoms are notassociated with substantial functional impairment [18],persons with mild SIVCI have a high risk of progressionto dementia [18,21]. Seniors with mild SIVCI are also atrisk for executive dysfunction [18], and subsequently atrisk for decline in everyday function (i.e., ability toperform instrumental activities of daily living [ADLs])[7]. Instrumental ADLs refer to capacities that arerequired for autonomous function within society [8]; theability to perform instrumental ADLs is a key aspect offunctional independence and health related quality oflife [8]. Thus, persons with mild SIVCI represent anideal target population for intervention strategies, aspreservation of their cognitive and functional status willlikely maintain and prolong their ability to live indepen-dently and with quality. To our knowledge, no rando-mized controlled trial has assessed the effect of aerobic-based exercise training on cognitive and everyday func-tion among seniors with mild SIVCI. Thus, we aim tocarry out a proof-of-concept single-blinded randomizedcontrolled trial primarily designed to provide prelimin-ary evidence of efficacy of a six-month, thrice-weekly,aerobic-based exercise training program on cognitiveand everyday function among older adults with mildSIVCI. In addition, this proof-of-concept study will aimto explore the effect of aerobic-based exercise trainingon: 1) serum glucose, hemoglobin A1c, and lipids; 2)inflammatory biomarkers; 3) physical function; 4) healthrelated quality of life; and 5) health resource utilization.Finally, this study will demonstrate the feasibility of deli-vering the intervention in this population, determine therecruitment rate, determine the rate of withdrawal, andprovide estimates of the variances, co-variances andeffect sizes of the proposed outcome measures to informthe sample size for a larger definitive trial.Methods/DesignDesign OutlineWe will conduct a six-month proof-of-concept single-blinded randomized trial and follow our study cohortfor an additional six months of follow-up (see Figure 1).RecruitmentWe will recruit seniors with mild SIVCI through theUniversity of British Columbia Hospital Clinic for Alz-heimer Disease and Related Disorders (UBCH-CARD).All individuals who receive care at the UBCH-CARDhave the option to sign a consent form providing accessto their records for research purposes and indicatingtheir willingness to be approached for research studies.One trained research assistant will review the charts ofpatients at the UBCH-CARD who have expressed inter-ests to participate in research studies. Clinicians at theUBCH-CARD will also be informed of this study andthey will assist in recruitment by flagging the charts oftheir current patients who may qualify for this study toour research assistants. Those who appear eligible basedon detailed chart review will be mailed an informationpackage regarding the study, including the consent form.Liu-Ambrose et al. BMC Neurology 2010, 10:14http://www.biomedcentral.com/1471-2377/10/14Page 2 of 9For those who are interested in participating, a onehour consent and screening session will be arranged.Once informed consent is obtained, we will perform thescreening tests. Those who remain eligible after thescreening session and who later provide written recom-mendation from their physician indicating their appro-priateness to participate in an aerobic-based exercisetraining program will proceed to baseline assessments.EligibilityWe will recruit individuals who fulfill the diagnostic cri-teria for SIVCI as outlined by Erkinjuntti and colleagues[22], which requires the presence of both cognitive syn-drome (as defined in Section A below) and small vesselischaemic disease (as defined in Section B below).A. Cognitive Syndrome defined as:1. Dysexecutive Syndrome: Some impairment in goalformulation, initiation, planning, organizing, sequencing,executing, set-shifting and maintenance, or abstracting.2. Memory Deficit: Some impairment in recall in thepresence of relatively intact recognition and benefitfrom cueing.3. Progression: Deterioration of A1 and A2 from a pre-vious higher level of functioning that are not per seinterfering with complex occupational and socialactivities.B. Small Vessel Ischaemic Disease defined as:1. Evidence of relevant cerebrovascular disease bybrain imaging (in the last 12 months) defined as thepresence of both:i. Periventricular and deep white matter lesions: Pat-chy areas of low attenuation (intermediate densitybetween that of normal white matter and that ofintraventricular cerebrospinal fluid) or diffuse sym-metrical areas of low attenuation with ill definedmargins extending to the centrum semiovale, plus atleast one lacunar infarct (correlating to the whiteFigure 1 Overview of the flow of participants through the Promotion of the Mind Through Exercise (PROMoTE) Trial.Liu-Ambrose et al. BMC Neurology 2010, 10:14http://www.biomedcentral.com/1471-2377/10/14Page 3 of 9matter grading scale greater than 3 from the Cardio-vascular Health Study) [23,24]; andii. Absence of cortical and/or cortico-sub-corticalnon-lacunar territorial infarcts and watershedinfarcts, haemorrhages indicating large vessel disease,signs of normal pressure hydrocephalus, or otherspecific causes of white matter lesions (e.g., multiplesclerosis, leukodystrophies, sarcoidosis, brain irradia-tion, etc).2. Presence or a history of neurological signs as evi-dence for cerebrovascular disease such as lower facialweakness, Babinski sign, sensory deficit, dysarthria, gaitdisorder, or extrapyramidal signs consistent with sub-cortical brain lesion(s).In addition, individuals must meet the following inclu-sion criteria: 1) Montreal Cognitive Assessment (MoCA)[25] score less than 26 at screening; 2) Mini-MentalState Examination (MMSE) [26] score of ≥ 20 at screen-ing; 3) Community-dwelling; 4) Live in Metro Vancou-ver; 5) Have a caregiver, family member, or friend whointeracts with him/her on a weekly basis; 6) Able tocomply with scheduled visits, treatment plan, and othertrial procedures; 7) Must be able to read, write, andspeak English in which psychometric tests are providedwith acceptable visual and auditory acuity; 8) Stable ona fixed dose of cognitive medications (e.g., donepezil,galantamine, rivastigmine, memantine, etc.) that is notexpected to change during the 12-month study period,or, if they are not on any of these medications, they arenot expected to start them during the 12-month studyperiod; 9) Provide a personally signed and datedinformed consent document indicating that the indivi-dual (or a legally acceptable representative) has beeninformed of all pertinent aspects of the trial. In addition,an assent form will be provided at baseline and again atregular intervals; 10) Able to walk independently; and11) Must be in sufficient health to participate in thestudy’s aerobic-based exercise training program. Thiswill be based on medical history, vital signs, physicalexamination by study physicians, and written recom-mendation by family physician indicating one’s appropri-ateness to participate in an aerobic-based exercisetraining program.The exclusion criteria are: 1) Absence of relevantsmall vessel ischaemic lesions on an existing brain com-puted tomography (CT) or magnetic resonance imaging(MRI); 2) Diagnosed with another type of neurodegen-erative (e.g. AD) or neurological condition (e.g., multiplesclerosis, Parkinson’s disease, etc.) that affects cognitionand mobility; 3) At high risk for cardiac complicationsduring exercise and/or unable to self-regulate activity orto understand recommended activity level (i.e., Class Cof the American Heart Risk Stratification Criteria); 4)Have clinically significant peripheral neuropathy orsevere musculoskeletal or joint disease that impairsmobility; 5) Taking medications that may negativelyaffect cognitive function, such as anticholinergics,including agents with pronounced anticholinergic prop-erties (e.g., amitriptyline), major tranquilizers (typicaland atypical antipsychotics), and anticonvulsants (e.g.,gabapentin, valproic acid, etc.); or 6) Planning to partici-pate, or already enrolled in, a clinical drug trial concur-rent to this study.Ethical approval has been obtained from the Vancou-ver Coastal Health Research Institute (V07-01160) andthe University of British Columbia’s Clinical ResearchEthics Board (H07-01160).Sample SizePrior to launching a definitive randomized controlledtrial, it is essential that the feasibility of conducting sucha trial be demonstrated. A sample for a definitive studywith multiple end-points and outcome variables willrequire several hundred participants and warrant amulti-site study. Given that no study has examined theeffect of exercise on cognitive function in SIVCI, wehave selected a sample size of 30 participants per group.Studies have suggested a standard deviation of changeof 6 to 7 [27-29] in Alzheimer Disease Assessment ScaleCognitive (ADAS-Cog) scores among individuals withvascular cognitive impairment. We highlight that arecent exercise trial among seniors at risk for AD withADAS-Cog as the primary outcome measure demon-strated an effect size of 0.60 [30]. Thus, assuming analpha of 0.05, 30 participants per group will provide apower of 0.75 to 0.80. We estimate a drop-out rate of10% during a 12-month period. Hence, we are aiming torecruit 35 participants per group (i.e., 70 participants intotal) which will accommodate a conservative 15% drop-out rate.MeasurementsBaseline measurements will be obtained prior to rando-mization. There will be three measurement sessions:baseline, 6 months, and 12 months (Figure 1). Out-comes will be assessed by trained assessors blinded togroup allocation.Screening SessionFor the screening session, we will administer the Physi-cal Activity Readiness Questionnaire (PAR-Q) [31], ascreening measure of physical readiness for exercise.Global cognitive function will be assessed using theMMSE [26] and the MoCA [25].DescriptorsUsing a wall mounted stadiometer, standing height willbe measured as stretch stature to the 0.1 cm per stan-dard protocol. Weight will be measured twice to the 0.1Liu-Ambrose et al. BMC Neurology 2010, 10:14http://www.biomedcentral.com/1471-2377/10/14Page 4 of 9kg on a calibrated digital scale. General health andsocioeconomic status will be ascertained by a question-naire. Participants will undergo a clinical assessmentwith neurologist and study physicians (G-YRH and PL)at baseline to confirm current health status and eligibil-ity for study, including clinical impressions of overallcognitive and functional status. The NeuropsychiatricInventory (NPI), an informant-rated instrument, will beused to evaluate behavioural and neuropsychiatric symp-toms [32].Physical activity, not including the study-assignedexercise classes, will be determined by the valid and reli-able Physical Activities Scale for the Elderly (PASE)questionnaire [33,34]. Designed for those aged 65 yearsand older, participants use a 12-item scale to self-reportthe average number of hours per day spent participatingin leisure, household, and occupational physical activ-ities over the previous seven-day period. Accounting forextracurricular physical activities throughout the rando-mized trial is essential to ascertain the specific effects ofthe delivered interventions on cognition and function.Primary OutcomesCognitive Function We will assess cognitive functionusing the cognitive section of the Alzheimer DiseaseAssessment Scale (ADAS-Cog) [35]. The scale consistsof 11 brief cognitive tests assessing memory, language,and praxis. Scores range from 0 to 70, with higherscores indicating greater severity of cognitive impair-ment. The ADAS-Cog has been a significant outcomemeasure in numerous trials with AD [27,36,37] but alsowith vascular dementia [29,38]. The ADAS-Cog hasmarked advantages as an outcome measure, based on itssubstantial data confirming both reliability and validityand its use in measuring longitudinal change togetherwith sensitivity to treatment effects [39].Global Executive Function Because executive dysfunc-tion is common among those with SIVCI [6], we willuse the Executive Interview (EXIT-25) [40] to assessglobal executive function. The EXIT 25 provides a stan-dardized clinical assessment of executive functions. Itcontains 25 items designed to elicit signs of frontal sys-tem pathology. Performance on the EXIT25 correlateswell with standard neuropsychological tests of executivefunctions. The EXIT25 scores range from 0 to 50, withhigh scores indicating impaired global executive func-tion. A cut point of 15 out of 50 is recommended [40].Everyday FunctionBecause executive dysfunction isassociated with impaired everyday function [7], we willuse the ADCS-ADL to assess the ability to performeveryday activities of daily living [41]. The ADCS-ADLis a 23-item informant-rated questionnaire that mea-sures, in a range of 0 to 78, an individual’s performanceof activities of daily living.Secondary OutcomesBlood Biomarkers Serum glucose, Hgb A1c, and lipidlevel will be measured by conventional methods. SerumHSC, CRP, and IL-6 will be determined by standardELISA methods [42].Physical Function Physical function will be assessedusing a three-instrument performance battery thatincludes:1) Six-Minute WalkThis is a walking test of physical status to assess gen-eral cardiovascular capacity in seniors [43]. The totaldistance walked in meters in six minutes is recorded inmeters.2) Balance and MobilityGeneral balance and mobility will be assessed with theNational Institute on Aging (NIA) Balance Scale [44].For this Scale, participants are assessed on performancesof standing balance, walking, and sit-to-stand. Eachcomponent is rated out of four points, for a maximumof 12 points. Poor performance on this scale predictssubsequent disability [44].3) Physiological Falls RiskWe will use the Physiological Profile Assessment(PPA)© [45] (Prince of Wales Medical Research Insti-tute, Randwick, Sydney, NSW, Australia) to assess forphysiological falls risk. The PPA is a valid and reliabletool for assessing fall risk in older people. Based on theperformance of five physiological domains (posturalsway, hand reaction time, quadriceps strength, proprio-ception, and edge contrast sensitivity), the PPA com-putes a fall risk score for each individual and thismeasure has a 75% predictive accuracy for falls in olderpeople [45]. A PPA z-score of 0-1 indicates mild risk, 1-2 indicates moderate risk, 2-3 indicates high risk, and 3and above indicates marked risk [46].4) Quality of LifeWe will evaluate health related quality of life using theEuroQol 5D (EQ-5D) – a preference-based generic uti-lity instrument that provides weightings for qualityadjusted life year (QALYs). QALYs are defined as thebenefit of a health intervention in terms of time in aseries of quality-weighted health states, in which thequality weights reflect the desirability of living in thestate, typically from “perfect” health (weighted 1.0) todead (weighted 0.0) [47]. QALYs are calculated basedon the quality of life of a patient (measured using healthutilities) in a given health state and the time spent inthat health state. The EQ-5D captures 243 uniquehealth states based on the following domains: 1) mobi-lity; 2) self-care; 3) usual activities; 4) pain and 5) anxi-ety or depression. We will calculate QALYs using thehealth state utility values from the EQ-5D to determineif there is a statistically significant difference in theLiu-Ambrose et al. BMC Neurology 2010, 10:14http://www.biomedcentral.com/1471-2377/10/14Page 5 of 9incremental cost per QALY change for participantsreceiving the aerobic-based training compared withthose who are not.5) Health Resource UtilizationThe health resource utilization questionnaire asksparticipants to report the following visits over a speci-fied time period: 1) health care professionals; 2) admis-sions or visits to hospital; and 3) laboratory work. Thehealth resource utilization questionnaire has been pre-viously described and supported in previous studies[48]. We will estimate total health care related costsover the 12 months from a Canadian health care sys-tem perspective. Participants will be instructed to spe-cify total health care expenditure and report thereason for each item. Additionally, participants will beinstructed to report health care expenditure due to anyadverse events associated with the aerobic-based train-ing program; this is not anticipated to be a major costdriver. On a per participant basis, costs will beassigned to health care resource utilization using afully allocated hospital cost model (for in-patient costs)and the British Columbia provincial guide to medicalfees (for outpatient costs). Our base case analysis willconsider the costs of all health care resource use andour sensitivity analyses will include only interventionrelated health care resource costs and a complete caseanalysis.Treatment AllocationRandomizationParticipants will be randomly assigned (1:1) to either theaerobic-based exercise training (AT) group or the usualcare (CON) group. The randomization sequence will begenerated by a central, web-based randomization servicehttp://www.randomization.net; permuted blocks of vary-ing size will be employed to ensure balance over time.After baseline assessment, research personnel notinvolved in measurement or intervention will access theweb-based randomization service to determine thegroup allocation.Allocation ConcealmentRecruitment and enrolment of participants will be man-aged by the research coordinator who will screen forstudy eligibility, obtain informed consent, and conductbaseline assessment. Following completion of baselineassessment, the research coordinator will access theweb-based randomization service and the participantwill be assigned a participant number and allocated tothe intervention or the control group. Research person-nel performing the outcome assessment and data analy-sis will be blinded to group allocation but it is notpossible to blind participants and personnel deliveringinterventions to group allocation.Experimental GroupsAerobic-Based Training (AT) GroupAll AT group classes will be led by instructors certifiedto instruct seniors. Each 60-minute class will include a10 minute warm-up, a target of 40 minutes of walking,and a 10-minute cool down. Class attendance will berecorded for each participant by the instructorsthroughout the six-month intervention period.Over the six month intervention period, we will usethree complimentary techniques to monitor and pro-gress exercise intensity of the AT program. Each partici-pant will:1) Wear a heart rate monitor and will be asked towork initially at approximately 40% of his/her age speci-fic target heart rate (i.e., heart rate reserve; HRR) andgradually progress to reach the target of 60% of HRR.Once the target of 60% of HRR is achieved, it will besustained by the participant for the remainder of theintervention period;2) Subjectively monitor the intensity of each workoutusing the Borg’s Rating of Perceived Exertion (RPE)[49]. Participants will be gradually progressed to a targetRPE of 14 to 15; and3) Use the simple “talk” test [50,51]. Participants willbe asked to initially walk at a pace where they can con-verse comfortably without effort and gradually progressto a pace where conversation requires a bit of effort.In addition to the formal group classes, all individualsin the AT group will be given a pedometer to serve asboth an incentive and reminder to partake in walkingon a daily basis. Participants will be asked to record thenumber of steps each day. All pedometers will bereturned to the study coordinator at the 6 month assess-ment session.Usual Care (CON) GroupParticipants in the CON group will receive educationalmaterial about vascular cognitive impairment and aboutstress management, healthful diet, and smoking. How-ever, this group will not receive specific informationregarding physical activity. Participants in the AT groupwill also be offered these educational materials.Adverse Events MonitoringDr. Philip Lee, in addition to a physician and statisticianexternal to the research team, will review all adverseevents reported in the study on a monthly basis. Theywill inform us to stop the study if the adverse eventsdata are of sufficient concern.Statistical AnalysesAs a primary objective of this study is to provide preli-minary evidence of efficacy we will compare partici-pants of the AT group who are compliant with theLiu-Ambrose et al. BMC Neurology 2010, 10:14http://www.biomedcentral.com/1471-2377/10/14Page 6 of 9intervention (defined as attending 60% of the total exer-cise sessions) to the CON group rather than using anintention-to-treat analysis as would be appropriate in apivotal clinical trial. In addition, no adjustment for mul-tiple endpoints will be made since in a proof-of-conceptstudy a Type II error is of more concern than a Type Ierror [52]. For each of the three primary endpoints (i.e.,ADAS-Cog, EXIT-25, ADCS-ADL), the change frombaseline to six months and 12 months will be assessedusing an analysis of covariance model incorporating thebaseline measurement. Observing a statistically signifi-cant difference on any of the three primary outcomeswill be considered preliminary evidence of efficacy.We will also report variances, co-variances, and effectsizes, as well as sampling feasibility (i.e., ease of recruit-ment, recruitment rate, withdrawal rate). This informa-tion will inform sampling for future trials.Economic AnalysisOur economic evaluation will explore incremental costsand health benefits comparing the aerobic-based train-ing intervention with usual care using both cost effec-tiveness and cost utility analyses. A cost utility analysisis a specific type of cost effectiveness analysis wherehealth benefits are measured using QALYs. The out-come of our cost effectiveness analysis is the incremen-tal cost effectiveness ratio (ICER). By definition, anICER is the difference between the mean costs of pro-viding the competing interventions divided by the differ-ence in effectiveness, where ICER = Δ Cost/Δ Effect[53]. We will determine the incremental cost of theaerobic-based training intervention per person experien-cing a clinically significant improvement in cognitiveperformance relative to usual care. Further, for our costutility analysis, we will estimate the incremental cost perquality adjusted life year gained (QALY). We will use acombination of imputation and bootstrapping to quan-tify uncertainty due to missing values and the finitestudy sample size60 61.Time FrameRecruitment will commence in December 2009. Finalfollow-up assessment is expected to conclude in Febru-ary 2012.DiscussionAlthough exercise therapy holds promise for delayingthe onset and slowing down the progression of bothcognitive and functional decline, very few randomizedcontrolled trials of exercise have been conducted inpopulations at high-risk for dementia [30]. This researchwill be an important first step in quantifying the effectof an exercise intervention on cognitive and daily func-tion among seniors with SIVCI, as vascular cognitiveimpairment is the second most common cause ofdementia in older adults [1-4]. Exercise has the potentialto be an effective, inexpensive, and accessible interven-tion strategy with minimal adverse effects. Retarding therate of cognitive decline among seniors with SIVCIcould preserve independent functioning and quality oflife in this population. This, in turn, could lead toreduced health care utilization costs and avoidance ofearly institutional care. Delaying the onset or retardingthe progression of dementia by only one year wouldreduce the number of clinical cases of dementia by 9.2million by 2050 in the US alone [54].Our interdisciplinary research team will use a multi-pronged approach to explore the utility of aerobic-basedexercise training among seniors with mild SIVCI. Theimpact of our proposed work may be significant forseniors with mild SIVCI.AcknowledgementsThis study is jointly funded by the Canadian Stroke Network and the Heartand Stroke Foundation of Canada.TLA and LAB are Michael Smith Foundation for Health Research (MSFHR)Scholars. LAB is also a Canada Research Chair in Neurobiology of MotorLearning. JJE is a MSFHR Senior Scholar.Sponsor’s Role: None.Author details1Department of Physical Therapy, University of British Columbia, Vancouver,Canada. 2Centre for Hip Health and Mobility, Vancouver Coastal ResearchInstitute, Vancouver, Canada. 3Division of Neurology, University of BritishColumbia, Vancouver, Canada. 4Experimental Medicine, University of BritishColumbia, Vancouver, Canada. 5Centre for Clinical Epidemiology andEvaluation, Vancouver Coastal Research Institute, Vancouver, Canada.6Division of Geriatric Medicine, University of British Columbia, Vancouver,Canada.Authors’ contributionsTLA, JJE, LAB, G-YRH, CJ, and JB wrote the grant application that was jointlyfunded by the Canadian Stroke Network and the Heart and StrokeFoundation of Canada in 2009. JCD, PhD candidate is affiliated with thePromotion of the Mind Through Exercise (PROMoTE) Trial. The grantapplication formed the bases for the manuscript, which was jointly draftedby TLA and JCD with all other authors contributing to its critical review andapproving the final draft.Competing interestsThe authors declare that they have no competing interests.Received: 18 December 2009Accepted: 17 February 2010 Published: 17 February 2010References1. Rockwood K, Wentzel C, Hachinski V, Hogan DB, MacKnight C, McDowell I:Prevalence and outcomes of vascular cognitive impairment. VascularCognitive Impairment Investigators of the Canadian Study of Health andAging. Neurology 2000, 54(2):447-451.2. Desmond DW, Erkinjuntti T, Sano M, Cummings JL, Bowler JV, Pasquier F,Moroney JT, Ferris SH, Stern Y, Sachdev PS, et al: The cognitive syndromeof vascular dementia: implications for clinical trials. Alzheimer disease andassociated disorders 1999, 13(Suppl 3):S21-29.3. 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Alzheimer’s and Dementia 2007,3:186-191.Pre-publication historyThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/10/14/prepubdoi:10.1186/1471-2377-10-14Cite this article as: Liu-Ambrose et al.: Promotion of the mind throughexercise (PROMoTE): a proof-of-concept randomized controlled trial ofaerobic exercise training in older adults with vascular cognitiveimpairment. BMC Neurology 2010 10:14.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitLiu-Ambrose et al. BMC Neurology 2010, 10:14http://www.biomedcentral.com/1471-2377/10/14Page 9 of 9


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