Study of Mental Activity and Regular Training

15 Pages·2011·2.07 MB·English

Gatesetal.BMCGeriatrics2011,11:19
http://www.biomedcentral.com/1471-2318/11/19
STUDY PROTOCOL Open Access
Study of Mental Activity and Regular Training
(SMART) in at risk individuals: A randomised
double blind, sham controlled, longitudinal trial
Nicola J Gates1*, Michael Valenzuela1,2,3, Perminder S Sachdev1,2,4, Nalin A Singh5,6, Bernhard T Baune7,
Henry Brodaty1,2,8, Chao Suo1, Nidhi Jain9, Guy C Wilson9, Yi Wang9, Michael K Baker9, Dominique Williamson9,
Nasim Foroughi9 and Maria A Fiatarone Singh9,10
Abstract
Background: Theextenttowhichmentalandphysicalexercisemayslowcognitivedeclineinadultswithearlysigns
ofcognitiveimpairmentisunknown.Thisarticleprovidestherationaleandmethodologyofthefirsttrialtoinvestigate
theisolatedandcombinedeffectsofcognitivetraining(CT)andprogressiveresistancetraining(PRT)ongeneral
cognitivefunctionandfunctionalindependenceinolderadultswithearlycognitiveimpairment:StudyofMentaland
RegularTraining(SMART).Oursecondaryaimistoquantifythedifferentialadaptationstotheseinterventionsinterms
ofbrainmorphologyandfunction,cardiovascularandmetabolicfunction,exercisecapacity,psychologicalstateand
bodycomposition,toidentifythepotentialmechanismsofbenefitandbroaderhealthstatuseffects.
Methods: SMARTisadouble-blindrandomized,doublesham-controlledtrial.Onehundredandthirty-twocommunity-
dwellingvolunteerswillberecruited.Primaryinclusioncriteriaare:atriskforcognitivedeclineasdefinedby
neuropsychologyassessment,lowphysicalactivitylevels,stabledisease,andageover55years.Thetwoactive
interventionsarecomputerizedCTandwholebody,highintensityPRT.Thetwoshaminterventionsareeducational
videosandseatedcalisthenics.Participantsarerandomizedinto1of4supervisedtraininggroups(2d/wk×6mo)ina
fullyfactorialdesign.Primaryoutcomesmeasuredatbaseline,6,and18monthsaretheAlzheimer’sDiseaseAssessment
Scale(ADAS-Cog),neuropsychologicaltestscores,andBayerInformantInstrumentalActivitiesofDailyLiving(B-IADLs).
Secondaryoutcomesarepsychologicalwell-being,qualityoflife,cardiovascularandmusculoskeletalfunction,body
composition,insulinresistance,systemicinflammationandanabolic/neurotrophichormones,andbrainmorphology
andfunctionviaMagneticResonanceImaging(MRI)andSpectroscopy(fMRS).
Discussion: SMART will provide a novel evaluation of the immediate and long term benefits of CT, PRT, and
combined CT and PRT on global cognitive function and brain morphology, as well as potential underlying
mechanisms of adaptation in older adults at risk of further cognitive decline.
Trial Registration: Australia and New Zealand Clinical Trials Register (ANZCTR): ANZCTRN12608000489392
Background five-year delay in dementia onset and progression could
With a forecast 100 million persons with dementia by halve disease prevalence [2] and would have a significant
2050, this disorder presents a major challenge to suf- impact on disease burden. The efficacy of pharmacologi-
ferers, their caregivers, and the health care system, and cal treatments to date have been limited to symptom
delay of disease onset and progression is amongst the control [3] and have not been effective in reducing dis-
most pressing challenges for medical research [1]. A ease onset, and so non-pharmacological preventative
interventions are of great interest.
There is strong evidence from cross-sectional and pro-
*Correspondence:[email protected]
spective cohort studies that participation in mentally
1SchoolofPsychiatry,UniversityofNewSouthWales,RandwickNSW2031,
Australia
Fulllistofauthorinformationisavailableattheendofthearticle
©2011Gatesetal;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommons
AttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproductionin
anymedium,providedtheoriginalworkisproperlycited.
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and physically stimulating activities is associated with and combined benefits of cognitive training and resis-
decreased dementia prevalence and/or incidence [4-9]. tance training, and to provide novel, comprehensive
Experimental trials indicate that cognitive training can data on possible proposed links between cognitive
significantly improve performance in healthy adults on a improvement and brain and whole-body-adaptation to
range of cognitive tasks, with an average moderate effect resistance and cognitive training.
size (ES) of 0.6 [10-13]; and that exercise interventions Most cognitive and exercise training trials have tar-
of as little as one week of aerobic exercise can result in geted healthy, cognitively intact adults. The most vul-
improved memory, attention, and reaction time [14]. nerable individuals at highest risk for cognitive decline,
Sustained improvements, particularly in executive func- however, are those with early cognitive impairment
tion, have been shown after aerobic training (ES = 0.41), and co-morbid diseases such as cardiovascular disease,
combined aerobic and resistance training (ES = 0.59), type 2 diabetes, obesity, and hypertension (i.e. meta-
and resistance training alone (ES = 0.53), even after bolic syndrome). We are therefore deliberately exclud-
exercise was withdrawn in some cases [15]. ing high functioning volunteers and targeting a highly
Two studies to directly compare single and combined clinically relevant population, with evidence of early
physical and mental exercise found effect sizes across a cognitive impairment and various cardiovascular risk
range of cognitive outcomes to be much larger in the factors. These individuals may not be capable of the
combined condition [12,16]. Both of these studies had moderate or high intensity aerobic training that has
design flaws, including very small sample sizes [16] and been shown to be effective in animal and human trials.
high dropout rates [12], limiting conclusions. Therefore, Resistance training, which has a larger effect size in
a robustly designed trial is required to investigate the the literature (0.53) than isolated aerobic training
comparative benefits of isolated and combined physical (0.41), and comparable to combined aerobic/resistance
and mental training. training (0.59), may be a more realistic exercise option
The mechanisms of benefit from physical and mental in this cohort, as it is more feasible in elders with
interventions are not clear, it has been postulated that frailty and mobility impairment, thus having the poten-
physical and mental activity may therefore have poten- tial for long-term adherence. We [23] and others have
tial to stimulate plasticity of the brain and possibly shown that resistance training results in many benefi-
reduce dementia onset. Animal studies have demon- cial adaptations in older adults that may be relevant to
strated a range of positive neurobiological outcomes, the mechanisms underlying its putative cognitive bene-
including decreased inflammatory cytokines, decreased fits. These adaptations (see Figure 1), many of which
cortisol response to stressors, increased insulin-like will be studied in this proposal (particularly changes in
growth factor-1 (IGF-1) into the brain, increased cere- fitness, inflammation, and body composition) would
bral blood flow and angiogenesis, and increased hippo- not be anticipated after exposure to cognitive training
campal volume, brain derived neurotrophic factor alone, consequently the SMART trial will enable inves-
(BDNF), neurogenesis, and synaptic density after mem- tigation of the efficacy of combining these two dis-
ory-enhancing cognitive and exercise training [7,17]. tinctly different training paradigms.
Human data are more limited, but observations of The SMART trial is a long term study that will mea-
responses to training have included increased blood sure evidence of both immediate and sustained benefits
flow, aerobic capacity, and region brain volume after of training, one year after withdrawal of active treat-
behavioural and aerobic training [18,19] and improved ment. In addition to the selection of general cognitive,
brain chemistry using magnetic resonance spectrometry functional, physical, mood symptoms and quality of life
(MRS) in our pilot work with cognitive training [20]. outcome measures will also be assessed to identify the
There are fewer human data available on the possible extent of transfer of benefits of our interventions.
cognitive-enhancing mechanisms of resistance training,
with findings of no changes in BDNF [21], and increases Objectives and Hypothesis
in IGF-1 [22]. Animal and human exercise trials indicate The primary objective of the SMART trial is to deter-
that exercise may improve brain function via two path- mine whether cognitive, physical or combined cognitive
ways; directly through the induction and regulation of and physical training can prevent or slow cognitive and
growth factors (e.g., BDNF, IGF-1), and/or indirectly via functional decline in vulnerable older adults at high risk
the modulation of systemic inflammation [7]. However, of dementia. Our secondary aim is to explore adaptation
rigorous clinical trials investigating the central and per- to these two interventions in the brain, as well as iden-
ipheral synergistic benefits of exercise for improved tify potential mechanisms of benefit, in particular modu-
brain function are lacking [7]. Consequently the Study lation of cardiovascular risk profile, systemic
of Mental Activity and Regime Training trial (SMART) inflammatory cytokines, growth factors, fitness levels,
was designed and implemented to examine the isolated and body composition.
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Figure1Theoreticalmodelofmechanismslinkagebetweenprogressiveresistancetraining,cognitivetraining,andcognitiveand
functionaloutcomes.BDNF=brain-derivedneuralgrowthfactorIGF-1=insulin-likegrowthfactor-1.
Primary Hypotheses of Daily Living (BIADL) [26] at both 6- and 18- month
1. Six months of supervised cognitive training (CT) will follow-up, relative to a sham training control condition.
significantly improve cognitive function, as assessed by 2. Six months of supervised high intensity progressive
the Alzheimer’s Disease Assessment Scale Cognitive resistance training (PRT) will significantly improve cog-
subscale (ADAS-Cog) [24,25], and independence of nitive function, as assessed by the ADAS-Cog, and inde-
function as assessed by the Bayer Informant -Activities pendence of function as assessed by the Bayer
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Informant -Activities of Daily Living (BIADL), at both 6- Study Population and Eligibility Criteria
and 18-month follow-up, relative to a sham training Participants are community-dwelling persons aged 55 or
control condition. above, with primary inclusion criteria being self-reported
3. The combination of CT and PRT will be signifi- memory complaint, a Clinical Dementia Rating (CDR)
cantly superior to either intervention in isolation for [28] of ≤ 1.0; Mini-Mental Status Examination (MMSE)
cognitive and functional benefits. [29] score of 23-29; and willing to have multiple cogni-
Secondary Hypotheses tive, physical and imaging assessments over 18 months.
1. All active training interventions will improve brain Complete inclusion and exclusion criteria are listed in
morphology and biochemistry compared to the sham Table 1.
control condition, as defined by: increased hippocampal
volume (mm3) by MRI scanning; positive localised Recruitment
Voxel-Based Morphometry (VBM) brain changes (z- Participants are to be recruited from October 2008 until
score relative change); decreased whole brain volume of December 2011 from media publicity on state radio,
White Matter Hyper-intensities (WMHs) (mm3); and advertisements in local newspapers and businesses, a
lead to beneficial hippocampal and posterior cingulate mail campaign using the electoral roll, contact with par-
MRS metabolite changes (% increase in N-acetylaspar- ticipants from previous studies who provided consent
tate, and increase in phosphocreatine metabolites). for such contact, general practitioner lists, aged care and
2. All active training interventions will improve sec- health service facilities, community programs for seniors
ondary cognitive outcomes, in the domains of attention, and word of mouth.
memory, fluency, and executive function, relative to the Sample size estimates
sham control condition, and combined training will be Sample size estimates (alpha 0.05, beta 0.20) are based
superior to either single intervention. on planned comparisons for the main effects of PRT
3. All active training interventions will maintain global and CT, as well as the effect of combined training vs.
clinical impression scores, as defined by the Clinical either intervention in isolation on our primary outcome:
Dementia Rating (CDR) scale, relative to the sham con- global cognitive function as assessed by ADAS-Cog. The
trol condition. assumptions are as follows: our meta-analyses [30] and
4. PRT exercise will preferentially decrease inflamma- review of published RCTs in older adults [15] reveal
tory markers, insulin resistance, and central adiposity Effect Sizes (ES) for a range of cognitive outcomes of
and increase fitness (strength and aerobic capacity), approximately 0.60 for cognitive training, 0.59 for aero-
muscle mass, and functional mobility, compared to bic/resistance training, and 0.53 for resistance training,
either cognitive or sham control condition. compared to 0.15 for control groups. However, as we
5. Cognitive and physical training will produce positive are enrolling a cohort with early cognitive impairment,
effects on psychological health and quality of life above we anticipate a decline of approximately this magnitude
and beyond the non-specific effects seen after sham (ES = 0.15) over 12 months in our sample, so that the
control condition. sham control condition would merely offset that decline
(ES = 0.0). Thus, we have conservatively powered the
Methods study to show an ES of 0.53 for the main effects of both
Study Design and Setting CT and PRT vs. control (n rounded up to 30/group × 4
The SMART trial is a longitudinal double-blind, sham = 120 required for 4-cell factorial design).
training-controlled, randomized clinical trial adhering The only two published studies of combined mental
precisely to CONSORT guidelines http://www.consort- and physical training [12,16] showed average ES = 0.94
statement.org for the conduct and reporting of clinical for combined training compared to mental training
trials, as extended to non-pharmacological interventions alone and ES = 1.27 for combined training compared to
[27]. Ethical approval was obtained from the Sydney exercise training alone. Therefore, we have ample power
South West Area Health Service (HREC Ref.08/RPAH/ (99.7%) to find a difference of this magnitude between
106), University of Sydney Human Research Ethics our combined training (n = 30) and isolated training
(HREC: 06-2008/11094), University of New South Wales groups (n = 30). Reported dropout from drug trials in
(HREC: 08152), and signed informed consent was MCI is 28% [31] however our experience in fully super-
obtained from all participants. Participants are from the vised training of older adults with frailty/chronic disease
greater Sydney metropolitan area, and the study is con- dropout averages 10-15% over 12 months. Therefore, we
ducted at Cumberland Campus of the University of Syd- will inflate sample size needs for approximately10%
ney in Lidcombe NSW Australia. MRI scans are drop out rate to account for anticipated attrition (n =
performed at the Clinical Research Imaging Centre in 132), and we will recalculate these sample size needs in
Randwick NSW Australia. interim analysis after the first 50 participants have
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Table 1Inclusion andexclusion criteria forthe SMART trial
Inclusioncriteria Exclusioncriteria
Age≥55 Unstablemedicalcondition*
CompetencyinEnglishsufficientforassessmentandtraining Participationinanycognitivetrainingactivity
Community-dwelling Participationin>150min/wkofmoderateorgreaterintensityplannedexerciseof
MMSE^23-29 anykind
CDR^^≤1.0 Rapidlyprogressiveorterminalillness
TICS#<30 Pre-existingdiagnosisofdementia
Nounstablediseaseprecludingplannedexercise* Psychoticillness(DSM-IV)**
Absenceofsignificantcognitivedeclinein5years Degenerativeneurologicaldisorder
Absenceofknownorganicorpsychiatricconditionaffecting DiagnosisofstrokeorTIA+withinlast12months,strokewithresidualneurological
cognition deficit,twoormorestrokesorTIAsatanytime,OnestrokeorTIAwithresidual
Abletoseeandhearsufficientlytoparticipateinplanned deficitsthatprecludeparticipation.
physicalandcomputer-basedcognitivetraining TBI±withinpastyear,orwithresidualdeficitsthatprecludeparticipation.
Diagnosisofdepression(DSM-IV)GDS++>9orcurrenttreatmentwithantidepressant
medications,greaterthan3episodesofdepressioninthelast5years("episode":
requiringtreatment),>10episodesrequiringtreatmentoverlifetime,pastsuicide
attempts,currentbipolardiagnosisandtreatment,>3pastepisodesrequiring
treatmentinlast5years.
Currentalcoholordrugabuse(DSM-IV)
Unrepairedabdominalorotherknownaneurysm
Myocardialinfarctionorcardiacsurgerywithinpast6months
NYHAClassIVCHF±±
Unstableanginaoruncontrolledmalignantarrhythmiasatrestoronexercisestress
testing
Recentretinalhaemorrhageordetachment/proliferativeretinopathy
Seizures(>2inpast12months)
*Examplesofunstableconditionsincludeuncontrolledarrhythmias,hypertension,hyperglycemia,symptomaticenlarginghernia,acutepulmonaryembolism,
deepvenousthrombosis,recentorunstablefracture,inflammatoryortraumaticjointinjuries,etc.Suchindividualsmaybecomeeligibleifmedicalorsurgical
treatmentstabilizestheircondition.
^MMSEMiniMentalStatusExamination27
^^CDRClinicalDementiaRating26
#TICSTelephoneInterviewforCognitiveStatus-Modified30
**DSM-IVDiagnosticandStatisticalManualofMentalDisorders4thedition
+TIATransIschemicAttack
±TBITraumaticbrainInjury
++GDSGeriatricDepressionScale[49]
±±NYHAClassIVCHFNewYorkHeartAssociationClassIVClassofHeartFailureindicatingsymptomsevidentatrestwithanyphysicalactivityincreasing
symptoms,precludingabilitytocompletephysicalactivityandcausingseverelimitations.
completed 6 months intervention and revise ES and remainder of the baseline physical performance testing
sample size needs if required. is completed, followed by baseline cognitive tests and
Screening procedure MRI scan. If following screening a participant was
Potential participants undergo initial telephone interview excluded for low vitamin D, acute illness, or abnormal
and screening using the 13-item modified Telephone stress test or raised blood pressure, he or she may enter
Interview for Cognitive Status (TICS-M) [32], inclusion the study following appropriate treatment and medical
score between 21-30/39 to exclude high cognitively review. Participants are randomised at the completion of
functioning individuals. Health status and lifestyle beha- all baseline assessments.
viours are also assessed via telephone. Informants are
interviewed using the Bayer-Activities of Daily Living Randomisation, concealment, and allocation
(B-IADL) [26], Informant KATZ Index of ADL [33], and A concealed, computer-generated sequence of randomly
informant ratings of memory decline and concern. A permuted blocks (block size = 8), stratified by gender
subset of informants complete an in-person B-IADL and age, is generated by a statistician not otherwise
form to validate the telephone version. involved in the study (http://www.randomization.com,
Participants provide signed informed consent prior to created by Dr Gerard E. Dallal, Tufts University). Ran-
completing a series of in-person screening assessments. domization occurs at the completion of the entire base-
A flow of assessment procedures is presented in Figure line assessment. Where randomization occurs in person,
2. A structured clinical interview including psychiatric assignments will be placed in sealed opaque envelopes
screening is completed by a neuropsychologist, and and delivered to subjects by the recruitment officer with
CDR score is calculated prior to physician and physical subjects designated to 6 months of cognitive training,
screening. If eligible after physician screening, the progressive resistance training, combined cognitive and
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Monday
Baseline
1 week (minimum) Next week
Thursday
(or later)
Thursday
Friday Friday
Monday Tuesday (or later)
6 Months
1 week 72 hours
96 hours
Thursday
Friday Monday Tuesday (or later)
18 Months
72 hours
96 hours
Figure2SMARTassessmentschedule.
progressive resistance training, or stretching and video- women in the targeted cohort, and potential age effects
quiz control group in a 1:1:1:1 ratio. Flow of subjects on adaptation to training.
through the study to date is presented in Figure 3.
Blinding
Stratification Subjects are informed that they will be randomly
Stratification by gender and age group (55-74; 75+) is assigned to one of four treatment groups by the recruit-
carried out, in anticipation of the greater prevalence of ment officer, and will be blinded to the investigators’
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Recruitment Pool n=1926
Ineligible n=46
On hold n=155
Not interested n=1510
No contact n=61
Assessment for eligibility n=154
t
n Ineligible n=44
e
m On hold n=21
oll Withdrawals n=11
nr Baseline Assessment n=78
E
Withdrawals n=0
On hold n=2
Randomisation n=76
n Cognitive (CT) and PRT and sham CT and SCOG and SPEX
tio Progressive Cognitive (SCOG) Sham physical n=20
a Resistance n= 17 (SPEX) n=18
c
o Training (PRT) n=20
All Did not start n=0 Did not start n=1 Did not start n=0 Did not start n=0
CT and PRT PRT and SCOG SCOG and SPEX
h Up interventionsn=14 interventions n=12 CT and SPEX n=17
t Interventions n=15
n-
ow
mo Discontinued n=3 Discontinued n=1 Discontinued n=1
6 oll Adverse events n=1 Adverse events n=0 Discontinued n=1 Adverse events n=0
F Adverse events n=0
Drop out n=2
onth w-Up CT and PRT n=3 Pn=R6T and SCOG CnT= 6and SPEX SnC=O8G and SPEX
mo Discontinued n=0
8 oll Lost n=0 Discontinued n=0 Discontinued n=0 Discontinued n=0
1F Lost n=0
Lost n=0 Lost n=0
Figure3ParticipantflowthroughSMARTtodate.
hypothesis as to which is the preferred intervention arm. trainers. Each session lasts 90 minutes and comprises
All groups will have an equal volume and frequency of approximately 45 minutes PRT or sham physical exer-
contact with trainers over the 18 months of the study. cise (sham physical) and 45 minutes CT or sham cogni-
All primary and secondary outcomes will be obtained tive exercise (sham CT). In order to take advantage of
and analyzed by blinded assessors on different days to the enhanced attention and learning exhibited after an
the training programs. acute bout of exercise in both animal and human stu-
dies [34], but not enhance adaptation to sham cognitive
Interventions training, PRT will proceed CT, and will follow sham CT.
All participants complete two group training sessions Within each small group (maximum 10) participants
per week (total 26 weeks), under the supervision of follow the program tailored to their individual
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functioning level, with constant oversight by trainers. 10computerworkstations,andsimple touchscreensto
Make-up sessions are allowed for participants who miss avoidtrainingdifficultiesinthecomputer-naïve.
CT and PRT sessions to achieve as close to 52 (26 × 2) Progressive Resistance Training (+ Sham cognitive)
sessions as possible within the 26 week intervention per- Progressive resistance training (PRT) is supervised by
iod. Each training group will have 1-2 trainers present at experiencedresearchassistants(exercisephysiologistsand
the session. The background of the trainers is in exer- physiotherapists)inamedically-supervisedclinic(Univer-
cise physiology or physiotherapy, and the specific tech- sityofSydneyHealthSciences)ataratioof1trainerfor4-
niques of CT and PRT to be administered are learned 5 subjects. The specifics of the high intensity training
from the investigators of this study (NG, MV, MFS). intervention are summarised in Table 2. Participantsare
Throughout the 18- month trial participants are pro- progressed continuously throughout the 6-month inter-
vided with log books to document their social and vention,guidedbydailyratingsofperceivedexertion(15-
recreational activities per day and are called weekly for 18 on the Borg Scale [37] and 1RM’s every 3 weeks to
telephone administration of a health status checklist. At maintainintensityat3%from80to92%ofcurrentmaxi-
the completion of the 6- month intervention partici- mum capacity). Maximization of potential cognitive-
pants are not given ongoing access to the training or enhancingeffectsofthePRTissupportedbyintroduction
advice as to what to do. Following assessments at 6 and of novel exercise after every 8 sessions and encouraging
18 months participants receive a token reward (movie visualisation,countingoutloud,andimageryofthemus-
tickets or store voucher) for their participation. clerepetitionscontractingduringrestintervals.
Cognitive Training Intervention (+ Sham physical) Combined CT and PRT
Cognitivetraining(CT)interventioninvolvescomputer- This group will receive both the cognitive training inter-
based multimodal and multi-domain exercises targeting vention and progressive resistance training intervention,
memory,executivefunction,attentionandspeedofinfor- delivered on the same day within 90-minute sessions.
mation processing. The training uses the COGPACK Sham Cognitive and Sham Physical Exercise Control Group
program [35], developed for neuro-rehabilitation and In this group, subjects will receive versions of cognitive
used in a previous research trial with MCI [36]. A total and physical exercise that are considered to be ineffec-
setof14exerciseshavebeen selectedincludingsixtasks tive with regards to the cognitive, neurological and phy-
ofvisualandverbalexplicitmemory(’Reading’,‘Memory sical outcomes of this trial. The total session length will
for names’, ‘Memory for shopping list’, ‘Memory for be 90 minutes, and all training will be supervised in
forms’, ‘Memory for route’, ‘Memory for traffic signs’), groups of up to 10.
fourtasksofexecutive function(’Anagrams’,‘Sequence’, Sham Cognitive
‘Logicblocks’,‘Logic’)andfourattentionandspeedtasks Sham CT involves video exposure to a variety of general
(’Reaction’, ‘Connect’ UFOs’ and ‘Search’). The training interest documentary topics, such as travel, culture, and
schedule was pre programmed with 4 exercises being history (National Geographic), and tailored to suit the
administered at each 45-minute training session. Train- audience and their expectation of training, are followed
ing sessions are completed in a group settingwith upto by a set of simple questions regarding the presented
Table 2ProgressiveResistance TrainingMethodology
Exercise Equipment Frequency Volume Intensityprogression
Routine SeatedChestpress DigitalK400Keiserpneumaticresistance 2sessions/ 3setsof 80%ofthemostrecentlymeasured1RM
machines(KeiserSportshealth wk 8per progressedeachsessionstoleratedusingRPE*
Equipments,Inc.Fresno,CA) session 15-18(approximately3%persession)
Seatedlegpress
Seatedrow
Standinghip
abduction
Kneeextension
Novel Lateralraise Freeweights(dumbbells) 4weeksor 3setsof 15-18RPE
8sessions 8per
session
Hipflexion Keiser
Calfraise Keiser
Hipextension Keiser
Bicepcurls Freeweights(dumbbells)
*RPERatingsofperceivedExertionBorgScale[37]
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material. Previous CT trials used this type of active con- aerobic activity, such a regimen has been shown
trol condition [38] with minimal impact on cognitive recently to have no effects on brain volume in older
outcomes. adults [18].
Sham Physical
Sham physical exercise (Sham physical) will include Adverse Events
stretching and seated calisthenics designed so as not to Monitoring of adverse events will be achieved by weekly
notably increase heart rate or aerobic capacity, improve questionnaire/interview- and proxy information will be
balance, or enhance strength. No use of equipment and obtained whenever necessary to minimize missing data.
no progression will be included. This regime allows for Adverse events will include any exacerbation of underly-
maintenance of the double blind design as it is similar ing disease, or new onset musculoskeletal, cardiovascu-
to what older adults anticipate receiving in senior lar, or metabolic abnormality attributed directly to study
group exercise classes. Furthermore, in contrast to protocols.
Table 3Primaryandsecondary cognitive andfunctional outcome measures
Outcome Explanation Description
measure
Primary Alzheimer’sDiseaseAssessmentScale ThissubscaleoftheADAS,measuresseverityofcognitivedysfunctionassociatedwith
Cognitive (ADAS-Cog)[25] Alzheimer’sdiseaseandiswidelyusedinpharmacologicalstudiesofdementiaandMCI
[51].TheADAS-Coghasexcellentpsychometricpropertiesbeingvalidandreliable,and
isendorsedasastandardoutcomemeasure[26].
Primary Bayer-InstrumentalActivitiesofdailyLiving TheB-IADLinitiallydevelopedforpharmaceuticalclinicaltrialstoassessdeficitsinthe
Functional (B-ADL)[26,52] activitiesofdailylifeincommunity-dwellingindividualswithMCIandresponseto
pharmacologicalagents[26],isa25-iteminformantorproxyquestionnaire.
Secondary Mini-MentalStateExamination(MMSE)[29] Internationallyknownbriefmeasuretoscreenforcognitiveimpairment[41],withvalid
Cognitive andreliablequantitativeassessmentofseverityofcognitiveimpairment,andissensitive
tochangesincognitivefunctionovertime[53].
GP-Cog[54] Sixitemselfreportscaleidentifyingwhetherpatientshavegreaterdifficultyfunctioning
in6areasofdailylifecomparedtotheirleveloffunctioning5-10yearsearlier.
ClinicalDementiaRating(CDR)[28] Acommonlyusedclinicaltoolfortheglobalassessmentofdementiaseverity,is
completedbyaclinicianaftersynthesizinginformationobtainedfromthepatient,
informantsandanyothersources[28].
SubjectiveMemoryComplaint(SMC) EightquestionsweredevelopedtomeasureSMCincludingtypeofmemorydifficulty,
concernlevel,duration,comparisontopeers,andreportedbyinformant,meeting
criteriafortheassessmentofSMC[55].
LifeExperienceQuestionnaire(LEQ)[19] Questionnaireisaselfreportquestionnaireexaminingtheamountandqualityofmental
activityapersonhasengagedinovertheirlifetime[19].
Matrices Matrices,aperceptualsubtestoftheWechslerAdultIntelligenceScale-III(WAIS-III)
assessesexecutivefunctionsandrequiresvisualperception,organization,andsynthesis
ofvisualspatialinformation[56].
Similarities ThisverbalsubtestfromtheWAIS-IIIisusedtomeasureverbalconceptionformation
andabstraction[56].
TrailMakingTest(TMT)[40]AandB TrialsAandBtestspeedofattention,sequencingandvisualsearch,andincludesa
motorresponsecomponent,whilstBalsoassessesmentalflexibility,anexecutive
function[57].
LogicalMemory TheLogicalMemorysubtestoftheWechslerMemoryScale3rdedition(WMS-III)isused
tomeasurebothimmediateanddelayedmemoryforverbalinformation.
BentonVisualRetentionTest(BVRT)[42] Thiswidelyusedvisualmemorytestassessesvisualperceptionandvisualconstructive
abilitiesasparticipantsarerequiredtodrawfrommemorysimpledesigns[41].
SymbolDigitModalitiesTest(SDMT) SDMT,firstpublishedin1973byAaronSmithandsubsequentlyrevisedin1982[41]
measuresdividedattention,visualscanning,tracking,andmotorspeed.Itusesa
substitutionformatpresentingsymbolswithmatchingnumbers,andparticipantsare
requiredtonamethenumberscorrespondingtoeachgivensymbol.
CategoryFluency CategoryVerbalFluencymeasuresverbalproductionofanimalnamesfromsemantic
memory[58].
ControlledOralWordAssociationTest COWATisalanguagebasedtaskassessesassociationfluency,andisoftenusedasa
(COWAT) measureofexecutivefunctioning.ThemostcommonlyusedlettersareF.A.S.orC.F.
andL.baseduponwordprevalencerates[58].
MemoryAwarenessRatingScale-Memory TheMARS-MFisan11itemselfreportratingscaleofeverydaymemoryfunctioning.
Functioning(MARS-MF)[43] Ratingsaremadeona0-4scalewhere0=neverand4=always,andisusually
administeredinaninterviewformat[43].
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Specificadverseeventsthatwillberoutinelymonitored Mini-Mental Status Examination (MMSE) [29]. Specific
include: falls, cardiac events during physical testing and cognitive functions are assessed by Trail Making Test A
exercise training (angina, arrhythmias, blood pressure and B [40], Matrices and Similarities subtests of the
excursions,clinicallysignificantECGchanges);fatigueand Wechsler Adult Intelligence Scale 3rd Edition (WAIS-
musclesorenessormusculoskeletalinjuryafterresistance III), Symbol Digit Modalities Test (SDMT) [41], Logical
orshamphysicaltraining;anxietyduringMRIscanorcog- Memory I and II subtests of the Wechsler Memory
nitiveorshamcognitivetraining;painorinjuryrelatedto Scale 3rd Edition (WMS-III), Benton Visual Retention
movement of ferromagnetic devices, implants, shrapnel Test-Revised 5th Edition (BVRT-R) [42] and verbal flu-
during MRI scan; and pain, bruising, or infection at the ency (Controlled oral words association test, and animal
venipuncture site. In addition, subjects will be asked to names). Subjective perception of memory capacity is
report allchanges inmedication,healthcareprofessional assessed by the Memory Functioning Scale of the Mem-
visits,newdiagnoses,acuteillnesses,oranynewsymptoms. ory Awareness Rating Scale (MARS-MFS) [43]. Cogni-
tive domain scores will be calculated on the basis of
Outcome Measures sum of z-scores of index tests, referenced to whole-
All outcome measures (see Tables 3, 4, 5, 6 and 7) will group baseline results.
be administered by blinded assessors at baseline, 6 Psychosocial and quality of life Psycho-social well-
months and at 18 months follow-up. Each test is chosen being and quality of life are assessed via the Life Satis-
because of excellent psychometric properties and mini- faction Scale (LSS) [44], Physical and Mental Health
mal sensitivity to practice effects. Cognitive testing takes Short-36 (SF-36>)[45], Quality of Life Scales (QOLS)
place in a fed state (after breakfast), and before any phy- [46], Scale of Psychological Well Being (SPWB) [47],
sical testing on that day to standardize known effects of Depression, Anxiety, Stress Scales (DASS) [48], the Ger-
fasting and acute exercise on cognitive performance. iatric Depression Scale (GDS) [49], and Duke Social
Primary outcomes Support (DSS) [50].
Cognitive function is measured via the Alzheimer’s Dis- Physical status and level of functional capacity Physi-
ease Assessment Scale-Cognitive (ADAS-Cog) [25], and cal status and exercise capacity are assessed across
capacity to perform daily tasks by the Bayer-Activities of seven domains: body composition; cardio vascular pro-
Daily Living (B-IADL) [26] which has been found to dif- file; exercise capacity; functional performance; nutri-
ferentiate between normal ageing and mild to moderate tional status; health status; and inflammatory and
dementia [39]. anabolic profile, with measures described in Table 4.
Secondary Outcomes Neuroimaging MRI data are acquired at baseline, 6
Cognitive function Global cognitive function is assessed months follow up and 18 months follow up, using a 3.0-
via the Clinical Dementia Rating scale (CDR) [28], and Tesla Philips Achieva System (see Table 7). For each
Table 4Secondaryoutcome measures continued: Psycho-social status
Outcome Nameofscale Description
Measure
Psycho- GeriatricDepressionScale(GDS) TheGDSisusedtoassessanolderperson’slevelofdepressionwithsimpleyes/noresponseset
social 15-items[49] [59],andthefifteenitemscreeningtesthasbeenreportedtobesatisfactory[49].
DepressionAnxietyandStress 21-itemself-reportmeasureofseverityofdepression,anxiety,andstresspsychologicalsymptoms.
Scale21(DASS)[60] OverallDistresscanbecalculatedbysummingeachofthesub-scalescoreswithpossiblescores
rangingfrom0-63,withhigherscoresindicatinghigherdistress[48].
ScaleofPsychologicalWellbeing TheSPWBmeasureswell-beingandpsychologicalfunctioningincludessixsubscales:autonomy;
(SPWB)[47] environmentalmastery;personalgrowth;positiverelationswithothers;purposeinlife;andself-
acceptance[47].Participantsarerequiredtorateagreementonasixpointagreementscale,with
higherscoresindicatinggreaterwellbeing.
DukeSocialSupport(DSS)[50] TheDSSisusedtoassessperceivedadequacyandsizeofsocialsupportnetworkona3pointscale
withhighertotalscoresreflectinghigherlevelsofsocialsupport[50].
Qualityof LifesatisfactionScale(LSS)[44] Thissingleitem7pointdelighted-terribleratingscaleprovidesagestaltmeasureoflifesatisfaction,
life andcanyieldreliableandvaliddata[61].
PhysicalandMentalHealth ThePhysical&MentalHealthSummaryScalesincludeeightgenerichealthconcepts,selectedfrom
SummaryScales(SF36)® 40includedintheMedicalOutcomesStudy(MOS),andMOSresearchersselectedandadapted
questionnaireitemsanddevelopednewmeasuresfora149-itemFunctioningandWell-Being
Profile[62]thesourceforSF-36®items.
QualityofLifeScales(QoLS)[46] This16item7Likerttypedelighted-terribleselfreportscalemeasuressatisfactionwithfive
conceptualaspectsoflifenotablymaterialandphysicalwellbeing;relationshipswithotherpeople,
social,communityandcivicactivities;personaldevelopmentandfulfilment;andrecreation[46].