UBC Faculty Research and Publications

Buying time: a proof-of-concept randomized controlled trial to improve sleep quality and cognitive function… Falck, Ryan S; Davis, Jennifer C; Best, John R; Li, Linda C; Chan, Patrick C Y; Wyrough, Anne B; Landry, Glenn J; Liu-Ambrose, Teresa Aug 17, 2018

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Item Metadata


52383-13063_2018_Article_2837.pdf [ 806.77kB ]
JSON: 52383-1.0371141.json
JSON-LD: 52383-1.0371141-ld.json
RDF/XML (Pretty): 52383-1.0371141-rdf.xml
RDF/JSON: 52383-1.0371141-rdf.json
Turtle: 52383-1.0371141-turtle.txt
N-Triples: 52383-1.0371141-rdf-ntriples.txt
Original Record: 52383-1.0371141-source.json
Full Text

Full Text

STUDY PROTOCOL Open AccessBuying time: a proof-of-conceptrandomized controlled trial to improvesleep quality and cognitive function amongolder adults with mild cognitiveimpairmentRyan S. Falck1, Jennifer C. Davis2, John R. Best1, Linda C. Li3, Patrick C. Y. Chan1, Anne B. Wyrough1,Glenn J. Landry1 and Teresa Liu-Ambrose1*AbstractBackground: Current evidence suggests that good quality sleep is associated with preserved cognitive functionand reduced dementia risk in older adults. Sleep complaints are especially common among older adults with mildcognitive impairment (MCI), and this may contribute to their increased risk for progression to dementia. Thus,improving their sleep may be important for maintaining their cognitive health. Chronotherapy is a set of interventionstrategies that can improve sleep quality through strengthening the entrainment of the biological clock to the solarlight-dark cycle, and includes strategies such as (1) bright light therapy (BLT); (2) physical activity (PA); and (3) goodsleep hygiene. Of these strategies, BLT is the most potent and is based on providing individualized timing to entraincircadian rhythms. Thus, a personalized chronotherapy intervention of individually timed BLT and individually tailoredPA promotion, in conjunction with general sleep hygiene education may promote older adult sleep quality. Wetherefore aim to carry out a proof-of-concept randomized controlled trial (RCT) to examine the efficacy of such apersonalized chronotherapy intervention to improve sleep quality among older adults with MCI.Methods/design: This was a 24-week RCT of a personalized chronotherapy intervention aimed to primarily improvesleep quality as measured by the MotionWatch8©. Participants in the personalized chronotherapy group (INT) willreceive four once-weekly, general sleep hygiene education classes, followed by 20 weeks of (1) individually timed BLTand (2) bi-weekly, individually tailored PA counseling phone calls in conjunction with receiving a consumer-availablePA tracker—the Fitbit® Flex™. Ninety-six adults (aged 65–85 years) classified as having MCI (i.e., Mini-Mental State Exam(MMSE)≥ 24; Montreal Cognitive Assessment (MoCA)≤ 26; without dementia or significant functional impairment) willbe randomized to either INT or a waitlist control group (CON).Discussion: The results of this trial will help determine if a personalized chronotherapy intervention that includesindividually timed BLT and individually tailored PA promotion, along with general sleep hygiene education canpromote sleep quality among older adults at increased risk for dementia. Our results will help inform best practices forpromoting sleep quality among older adults with MCI.Trial registration: ClinicalTrials.gov, NCT02926157. Registered on 6 October 2016.Keywords: Sleep, Cognitive function, Bright light therapy, Physical activity, Older adults* Correspondence: teresa.ambrose@ubc.ca1Department of Physical Therapy, Aging, Mobility and CognitiveNeuroscience Laboratory, Faculty of Medicine, University of British Columbia,Vancouver, BC, 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.Falck et al. Trials  (2018) 19:445 https://doi.org/10.1186/s13063-018-2837-7BackgroundWorldwide, there is one new case of dementia detectedevery 4 s [1] and the costs of treating this epidemic arestaggering. As of 2015 the estimated worldwide costs fordementia treatment were US$818 billion, and in 2018the costs are expected to balloon to over US$1 trillion [2].There is not yet a cure for dementia, and thus interveningwith lifestyle strategies on known risk factors for cognitiveimpairment is an important strategy for reducing demen-tia risk—or at least delaying its onset [3].Older adults with mild cognitive impairment (MCI)are at increased risk for dementia [4]. MCI is a clinicalentity characterized by cognitive decline greater thanexpected for an individual’s age and education level, butwhich does not interfere notably with everyday function[5]. Importantly, 30% of older adults diagnosed withMCI develop dementia within 5 years [6], while in thesame 5-year timespan only 2% of older adults withoutMCI are diagnosed with dementia [7]. There is currentlya lack of effective pharmaceutical options for treatingMCI, and thus lifestyle modifications to reshape thecognitive trajectory of older adults with MCI are animportant line of scientific inquiry [8].Improving older adult sleep quality is a promising strategyfor maintaining older adult cognitive health. More than halfof adults over 65 years report at least one chronic sleepcomplaint—the most common being the inability to stayasleep at night [9]. Poor sleep quality is also an importantrisk factor for Alzheimer’s disease (the most common formof dementia) [10], and older adults with MCI are more likelyto experience poor sleep quality than healthy older adults[11]. Moreover, epidemiological evidence suggests poorsleep quality is associated with an increased risk of conver-sion from MCI to dementia [12], and thus improving sleepquality among individuals with MCI may help reducedementia risk.Sleep quality is closely tied to the function of circadianrhythms (i.e., ~ 24-h biological clock [13]), which coordi-nates physiology and behavior with the solar light-darkcycle [14–16]. Briefly, the process by which the biologicalclock is synchronized with the solar light-dark cycle isknown as entrainment [17], and is regulated by the activityof the suprachiasmatic nuclei (SCN) which serves as “themaster biological clock” of the central nervous system[18]. This process of entrainment occurs through certainexternal stimuli, known as zeitgebers (from the Germantime-givers), and helps to prevent inadvertent driftingor divergence from the 24-h day [19]. Of particularimportance, aging is associated with (1) the biologicalclock initiating sleep-promoting mechanisms earlier inthe day [20, 21]; and (2) decreased amplitude in circadiansignals that increase sleep need [22, 23]. The weakening ofcircadian regulation that occurs with aging likely plays aprominent role in the fragmentation of sleep-wake rhythmsobserved in older adults during (1) the wake maintenancezone, which occurs 2–3 h before habitual bedtime and (2)the sleep maintenance zone, which occurs 2–3 h beforehabitual wake time [24]. Because aging appears to be linkedto the divergence of the biological clock, chronotherapiesthat use effectively timed zeitgebers to help strengthen theentrainment of the SCN to the solar light-dark cycle mayimprove older adult sleep quality [25].The principal entraining zeitgeber for the human bio-logical clock is light [25, 26], which exerts its influence onblue-light-sensitive receptors in the retina [27]. Retinallight exposure directly stimulates greater activity of theSCN, which phase delays the biological clock such thatthe desire for sleep decreases and wakefulness increases(or is maintained); reduced retinal light exposure resultsin less activity of the SCN and increases the desire to sleepby phase advancing the biological clock [17]. While theimportance of light is thus integral for the proper functionof the SCN and the biological clock, older adults havereduced sensitivity to light, which leads to poorer functionof the SCN and divergence of the biological clock fromthe solar light-dark cycle [28]. Behavioral changes in olderadulthood—such as spending less time outdoors—couldalso further decrease bright light exposure, which may bea key factor in decreased amplitude of circadian rhythms[24]. Thus, older adults in particular may benefit fromeffectively timed bright light to strengthen the entrainmentof the SCN to the solar light-dark cycle.Bright light therapy (BLT) is an increasingly popularchronotherapy strategy [24]. While the efficacy of BLT asan intervention strategy is currently inconclusive [29, 30],the biological clock is not equally amenable to shifts ateach phase in the circadian rhythm [17]. Indeed, anyzeitgeber can cause the biological clock to phase advance,phase delay, or be entirely phase neutral depending on thebiological clock time at which a zeitgeber is administered.As such, successful BLT requires an individualized approachwhere proper timing is essential [24].Another potential zeitgeber for use as chronotherapy isphysical activity (PA) [28, 31, 32]. Briefly, PA performed inthe morning or early afternoon does not appear to have aconsistent effect on phase shifts of the biological clock;however, engaging in PA in the late afternoon causes aphase advance of the biological clock, while late night PAcauses phase delay of the biological clock [31, 32]. Thetime-based response to how PA can impact the SCN ishypothesized to coincide with the timing of the openingof the “sleep gate”—the shift of the biological clock fromgenerating a waking signal that reduces sleep need, togenerating a signal that facilitates sleep [33].However, the use of PA in chronotherapy is challenging.The current evidence describing the effects of PA as azeitgeber comes from controlled laboratory experiments,where the timing and intensity of PA in the form ofFalck et al. Trials  (2018) 19:445 Page 2 of 9exercise is tightly controlled. Conducting an interventionwhere participants would be asked to engage in regularlytimed PA at a prescribed intensity would (1) be burden-some to participants and (2) require enormous resourcesto ensure participant adherence. More importantly,evidence suggests that regular PA—regardless of timing—isassociated with better sleep quality [34, 35]. Less than 5% ofolder adults meet the current guidelines of 150 min/weekof PA [36], and older adults with MCI are less active thantheir cognitively healthy peers [37]. Given that individually-timed BLT appears to be the most powerful chronothera-peutic [24], promoting older adult PA in conjunction withBLT may be a feasible approach to providing personalizedchronotherapy.In addition to the potential benefit of combining indi-vidually timed BLT with PA, improving sleep hygiene canpositively impact sleep quality and aid chronotherapy [38].Poor sleep hygiene exacerbates or even causes poor sleep,whereas good sleep hygiene results in feeling more restedand alert upon awakening—as well as a greater ability tofunction throughout the day. Sleep hygiene education,which teaches behavioral strategies to promote healthysleep (e.g., avoiding watching television before bed), canalso be useful as a strategy to promote behaviors whichmay improve circadian regulation—including light expos-ure and PA [39]. Current recommendations for improvingolder adult sleep quality therefore suggest combining (1)BLT; (2) PA; and (3) sleep hygiene education [40]. Import-antly, preliminary evidence suggests combined BLT andPA in the form of exercise training, and sleep hygiene canimprove sleep quality in older adults with insomnia [41].While these results are promising, there remains a gap inour understanding of whether personalized chronotherapyis an effective approach to improving sleep quality amongolder adults with MCI. Thus, we propose a proof-of-con-cept randomized controlled trial (RCT) to examine the effi-cacy of a personalized chronotherapy interventioncombining (1) individually timed BLT; (2) individually tai-lored PA promotion; and (3) general sleep hygiene educa-tion to improve the sleep quality of older adults with MCI.We will use a multimodal personalized chronotherapyintervention for improving the sleep quality of olderadults with MCI, which may ultimately help in maintain-ing cognitive function and reduce dementia risk in thispopulation.MethodsDesignWe propose a proof-of-concept RCT of 96 community-dwelling older adults with MCI, aged 65 to 85 years. Partici-pants randomized to the personalized chronotherapy group(INT) will receive the intervention over a 24-week period.There will be three measurement sessions with monthlymonitoring (Fig. 1). Briefly, at each monthly monitoringparticipants will complete by telephone (1) the EuroQol 5D(EQ5D), a standardized instrument for measuring generichealth status [42] and (2) the ICECAP index of capabilityfor older people, which examines older adult quality oflife [43]. Ethical approval has been obtained from theUniversity of British Columbia's Clinical Research Eth-ics Board (H16-01029, 22 September 2016). All partici-pants will provide a personally signed and datedinformed consent document indicating that the individ-ual has been informed of all pertinent aspects of thetrial.RecruitmentWe will recruit from the community and from our owndatabase of individuals who have consented to be contactedabout future research. Briefly, participants who have beenpreviously involved in our research and have consented tobeing contacted about future research will be contacted. Inaddition, we will recruit participants by advertisementsplaced in local community centers, newspapers, and word-of-mouth referrals. Interested individuals will first bescreened by telephone to check for general eligibility ac-cording to our criteria, and then screened using the PhysicalActivity Readiness Questionnaire (PAR-Q) [44]. Briefly, thePAR-Q is a simple screening tool for determining readi-ness to begin a PA program and for uncovering any po-tential health risks that may be associated with anincrease in PA. Those who appear eligible will attendan information session.EligibilityInclusion criteriaWe will include community-dwelling men and womenwho (1) are aged between 65 and 85 years and are livingin their own home; (2) have preserved general cognitionas indicated by a Mini-Mental State Examination (MMSE[45]) score ≥ 24/30; (3) have a baseline Montreal CognitiveAssessment (MoCA [46]) score < 26/30; (4) do not havedementia of any type; (5) do not have any significantimpairment in daily function; (6) are currently experi-encing poor sleep quality as indicated by a PittsburghSleep Quality Index (PSQI [47]) score > 5; (7) scored < 5/15on the 15-item Geriatric Depression Scale [48, 49]; (8) areable to walk independently and are in sufficient health toparticipate in regular PA as indicated by the PAR-Q [44];and (9) understand, speak, and read English with acceptablevisual and auditory acuity.Exclusion criteriaWe will exclude individuals who are (1) diagnosed withobstructive sleep apnea; (2) receiving continuous positiveair pressure (CPAP) treatment; (3) at high risk for cardiaccomplications during PA or unable to self-regulate activityor to understand recommended PA level; and (4) haveFalck et al. Trials  (2018) 19:445 Page 3 of 9clinically important peripheral neuropathy or severemusculoskeletal or joint disease that impairs mobility.Sample size calculationOur primary outcome measure is sleep efficiency asmeasured by the MotionWatch8© wrist-worn acti-graphy unit (MW8) (CamNtech; Cambridge, UK)[50]. Sleep efficiency is one of several validated ob-jective sleep parameters [51], and it is the goldstandard in evaluating insomnia treatment efficiency[52]. Our pilot data suggested that sleep hygieneeducation alone had a small effect on sleep efficiencyafter 6 months (d = 0.16). As the proposed INT pro-gram is multifaceted (i.e., sleep hygiene education +individually timed BLT + individually tailored PAcounseling), we anticipate a larger effect size in thisRCT. Thus, assuming a two-sided alpha of 0.05, cor-relation across adjacent time points of 0.88 (esti-mated from pilot data), 40 participants per groupwill provide power of 0.85 to detect an effect size of0.50 at the end of the intervention [53]. To allow fora drop-out rate of 15%, we will recruit a total of 96older adults (i.e., 48 per group).MeasurementsBaseline measurements will be obtained prior to ran-domization. There will be three measurement sessions:baseline, 12 weeks, and 24 weeks.DescriptorsWe will measure height using a wall-mounted stadiometerand measure weight using a calibrated digital scale. Gen-eral health and socioeconomic status will be ascertained byquestionnaire. In addition, we will survey participants atbaseline for obstructive sleep apnea risk using the Snoring,Tiredness, Observed apnea, Blood pressure, Body massindex, Age, Neck circumference and Gender (STOP-BANG) questionnaire [54].Primary outcomeWe will measure sleep efficiency using the MW8. Briefly,the MW8 is a uni-axial, lightweight, wrist-worn accelerom-eter designed to observe acceleration ranging in magnitudefrom 0.01 to 8 G, with a frequency of 3–11 Hz. The filteredacceleration signal is digitized and the magnitude is summedover a user-specified time interval, or “epoch”. At the end ofeach interval, the summed value or activity “count” is storedFig. 1 Standard protocol items: recommendation for interventional trials (SPIRIT) figureFalck et al. Trials  (2018) 19:445 Page 4 of 9in memory and the integrator is reset. Estimates of sleepquality parameters can then be extracted from the devicebased on the number of counts for a given epoch. For thepresent study, we will use 60-s epochs, which is consistentwith current guidelines for estimating sleep quality [55].Participants will first be fitted with the MW8 on thenon-dominant wrist and provided detailed information onits features (i.e., the light sensor, event marker button, andstatus indicator). Participants will be instructed to pressthe event marker button each night when they start tryingto sleep, and again each morning when they are finishedtrying to sleep. We will also provide participants with theConsensus Sleep Diary (CSD)—which they will be askedto complete upon awakening each morning [56]. Afterwearing the MW8 continuously for at least 14 days,participants will return the MW8 and completed CSD.We will subsequently download and analyze the MW8data using MotionWare software 1.0.27 (CamNtech). Theresponses from the CSD will be used to confirm sleepwindows identified by participants (as determined bytime-stamped event markers). In cases where the eventmarker and CSD entries disagree for the start time ofthe sleep window, we will use the light sensor data todetermine “lights out”. Similarly, when the event markerand CSD entry disagree for the end of the sleep window,we will use “lights on” and activity onset to determine theend of the sleep window. The MotionWare software willbe used to estimate sleep efficiency (i.e., time asleepexpressed as a percentage of time in bed).Secondary outcomesObjective sleep quality In addition to estimating ourprimary outcome of sleep efficiency, we will use theMW8 and MotionWare software to estimate differentparameters of sleep quality including: sleep duration(total time spent sleeping), sleep latency (time between“lights out” and falling asleep), and fragmentation index.Briefly, fragmentation index is defined by MotionWareas the sum of (1) the total time spent sleeping catego-rized as mobile in the epoch-by-epoch mobile/immobilecategorization expressed as a percentage of the timespent asleep and (2) the number of immobile bouts thatwere ≤ 1 min in length expressed as a percentage of thetotal number of immobile bouts during time spent sleep-ing. The MW8 provides validated estimates for measuresof sleep quality for the following indices: sleep duration,efficiency, fragmentation, and latency [50, 57].Subjective sleep quality We will also use the PSQI as ameasure of subjective sleep quality [47]. This 19-itemquestionnaire assesses sleep quality using subjective ratingsbased on the summation of 7 different component scores(i.e., sleep quality, sleep latency, sleep duration, habitualsleep efficiency, sleep disturbance, use of sleeping medica-tion, and daytime dysfunction). Respondents will be askedto answer the questionnaire retrospectively, surveyingsleep components spanning the previous month.Cognitive function We will use a comprehensive neu-ropsychological battery to examine changes in cognitivefunction including (1) the 13-item Alzheimer’s DiseaseAssessment Scale [58], (2) Trail Making (parts A and B)[59]; (3) the Digit Symbol Substitution Test [60]; and (4)category fluency (i.e., vegetables) [60].Treatment allocationRandomizationParticipants will be randomly assigned (1:1) to either theINT or the waitlist control group (CON). We will usepermuted blocks of varying size to ensure balance overtime. To ensure concealment of the treatment allocation,the randomization sequences will be generated and heldby a central web-based randomization service.Allocation concealmentRecruitment and enrollment of participants will bemanaged by the research coordinator who will screenfor study eligibility, obtain informed consent, and conductbaseline assessment. Following completion of baselineassessment, the research coordinator will access the web-based randomization service and the participant will beassigned a participant number and allocated to the INTor the CON group. Research personnel performing theoutcome assessment and data analysis will be blindedto group allocation. We will not be able to blind partici-pants or personnel delivering the interventions to groupallocation.Experimental groupsPersonalized chronotherapy group (INT)Participants allocated to the INT group will receive fouronce-weekly general sleep hygiene education classes,followed by 20 weeks of (1) individually timed BLT basedon the participant’s sleep profile and (2) individuallytailored PA promotion.General sleep hygiene education Following baselineassessment, participants in the INT group will receive a4-week general sleep hygiene education course (weeks1–4; 1×/week; 2 h/session). These courses will provideparticipants with an understanding of (1) how sleep isregulated; (2) the relationship between sleep and cognition;(3) how sleep changes as we age; and (4) why preservingsleep quality is fundamental to healthy aging. Participantswill learn strategies to protect sleep including the im-portance of individually timed BLT (i.e., seek brightFalck et al. Trials  (2018) 19:445 Page 5 of 9light exposure during the day, while avoiding light atnight) and regular PA.At the completion of the 4-week sleep hygiene educationcourse, INT group participants will receive 20 weeks of (1)individually timed BLT based on the participant’s sleepprofile and (2) individually tailored PA promotion.Individually timed bright light therapy (BLT) In week5, participants in the INT group will meet with atrained research assistant to develop a daily BLTschedule designed to improve sleep quality and addresssleep complaints. Using the results from the STOP-BANG questionnaire, we will first counsel participantswith moderate-to-high risk of sleep apnea to see aphysician. The participant will then work with the researchassistant to determine the best regularly scheduled bedtime and wake time in order for the participant to dedicate8 h to sleeping each night (i.e., sleep window). Using theresults from the MW8 sleep recordings (i.e., the partici-pant’s current sleep window), and the participant’s rec-ommended sleep window, we will classify participantsas (1) phase advanced (falls asleep earlier than intended);(2) phase delayed (falls asleep later than intended or wakesup later than intended); or (3) phase neutral (falls asleepwhen intended). Participants will then be provided with acommercially available BLT device (Philips goLITE BLU)and be provided a personalized BLT schedule based ontheir phase classification. The goLITE BLU emits short-wave blue light (~ 200 lx), which possesses greater phase-shifting properties than the rest of the visible lightspectrum [61–64]. All BLT doses will be 1 h in duration,twice daily for 20 weeks (i.e., week 5–24). The time anddose-dependent effects of BLT have been well-describedelsewhere [65–69].Phase advanced: Participants will be counseled touse BLT 2 h after waking, and again 11 h later (e.g.,morning BLT dose, 8:00–9:00 a.m.; evening BLT dose,7:00–8:00 p.m.). Participants will be instructed to avoidlight 1.5 h before sleep window onset. Participants canotherwise continue their normal light routine at night.Phase delayed: Participants will be counseled to useBLT 30 min after waking, and again 11 h later. Partici-pants will be counseled to avoid all light 3 h before sleepwindow onset.Phase neutral: participants with a neutral sleep phasewill be further sub-categorized based on their currentwaking routine.Participants who wake up earlier than intended willbe counseled to use BLT 2 h after waking, and again11 h later. Participants will be counseled to avoidlight 1.5 h before sleep window onset. Participantscan otherwise continue their normal light routine atnight.Participants who wake up when intended will becounseled to use BLT 1 h after waking, and again 11 hlater. Participants will be instructed to avoid lightbeginning 2 h before sleep window onset. Participantscan otherwise continue their normal light routine atnight.Individually tailored physical activity (PA) promotionINTgroup participants will also meet with a certified fitnessprofessional (i.e., the coach) in week 5 to review theircurrent PA level, and develop an individualized PA plan.We will use the brief action planning approach to helpparticipants develop their individualized PA plan [70].Briefly, this approach requires the coach to guide partici-pants to (1) set an activity goal; (2) develop an action plan;(3) identify barriers and solutions; and then (4) rate theirconfidence in the plan. This process will be repeated untilthe confidence rating reaches > 7/10, indicating that theperson is confident about implementing the plan. Partici-pants will be counseled to engage in PA at least 4 h beforetheir regularly scheduled bed time.Participants will then be provided a Fitbit® Flex™ to beworn on the non-dominant wrist 24 h/day—except duringwater-based activity or when charging the device. TheFitbit® Flex™ is one of the most common wireless PAtrackers in the consumer market and is capable of col-lecting PA data, uploading it to the web, and producingsimple graphs and charts of an individual’s activity. PAdata from the device will be wirelessly synchronizedwith the Fitbit online Dashboard, which can be viewedonly by the participants and their fitness professional.During weeks 5–24, the fitness professional will reviewthe individual’s PA on the Dashboard and progressivelymodify the activity goals during nine bi-weekly phonecalls.Waitlist group (CON)Participants in the CON group will receive access tofour optional weekly health enrichment lectures duringweeks 1–4 of the intervention period. These lectures willprovide educational material for participants on healthyweight management, diet, mindful meditation, and goalsetting. This group will not receive specific informationon PA during these lectures. During weeks 5–24, partici-pants will not receive any intervention and will go abouttheir usual activity. After 6 months follow up, CON partic-ipants will receive (1) the sleep hygiene education courseand (2) PA counseling and a Fitbit® Flex™.Intervention compliance and compliance measuresFor INT participants, we will track compliance to boththe BLT prescription and PA promotion program. Briefly,INT participants will receive monthly calendars monitoringFalck et al. Trials  (2018) 19:445 Page 6 of 9their BLT use, which they will complete and send by mail.Monthly BLT calendars will be reviewed upon receipt fromparticipants and we will follow up with INT participantswho do not appear to be following their BLT prescription(i.e., < 50% compliance or did not mail their most recentmonthly BLT calendar). We will also monitor weekly PAfor each INT participant using the Fitbit online Dashboard,and we will follow up with participants who do not appearto be logging their PA using their Fitbt (i.e., no PA minuteslogged on the Fitbit Dashboard within the past 2 weeks).As an additional measure to increase participant com-pliance and understanding, we will maintain a bi-weeklyphone call schedule with participants and will follow upon all missed appointments or missed phone calls.Adverse events monitoringWe will have a Data Safety Monitoring Committee (TeresaLiu-Ambrose, Jennifer C. Davis, and Linda Li). All adverseevents will be reviewed by the monitoring board. They willstop the study if the adverse event data demonstrate anyhazards directly due to the intervention (e.g., increased fallsrate) based on monthly report.Statistical analysesThe primary objective of this study is to provide evi-dence for the efficacy of a personalized chronotherapyintervention in improving sleep quality. Our primaryanalyses will therefore follow the intention-to-treatprinciple (i.e., all individuals will be analyzed accordingto their group allocation regardless of compliance). Wewill evaluate between-group differences (INT vs. CON)in sleep quality using mixed linear models. Maximumlikelihood estimation will be used in order to includeall randomized participants to estimate treatment effects,regardless of loss to follow up. Time will be considered asa repeated, categorical variable and will be included as afixed effect in addition to group and group-by-time inter-action. The intercept will be specified as a random effect.Primary and secondary outcomes will be analyzed usingthis same analytic model.DiscussionOur research team will use a multi-pronged approachto explore the utility of personalized chronotherapy toimprove sleep quality and cognitive function among olderadults with MCI. This proposed trial may have importantpublic health and mechanistic implications.Public healthCurrent guidelines for sleep recommend older adultsshould sleep 7–8 h/night [71]. Given that older adultswith MCI experience poor sleep [24], our study mayprovide an evidence-based chronotherapy approach toimproving sleep quality in older adults with MCI. Ourapproach to improving sleep quality in older adults withMCI may also help maintain the cognitive health ofthese individuals at risk for dementia.MechanisticSeveral lifestyle approaches to maintaining the cognitivehealth of older adults with MCI have been proposed suchas (1) exercise [72] and (2) cognitive training [73]. However,no study has yet examined if changes in sleep qualitycan improve cognitive health among older adults withMCI. Should our intervention prove to be efficacious atimproving cognitive function through improved sleepquality, it would be a major contribution towards ourunderstanding of how to maintain the cognitive healthof older adults with MCI.Trial statusAt 1 October 2017 we have obtained ethical approval,have registered the trial, and have successfully recruited38 participants.AcknowledgementsRSF is funded by the University of British Columbia Rehabilitation SciencesScholarship. LCL is a Canada Research Chair in Patient-Oriented KnowledgeTranslation. GJL is a Canadian Institutes of Health Research Postdoctoral Fel-low. TLA is a Canada Research Chair in Physical Activity, Mobility, and Cogni-tive Health.FundingThis study is funded by Vancouver Coastal Health Research InstituteInnovation and Translational Research Awards (F16–01717), the Alzheimer’sSociety Research Program, and by the Jack Brown and Family AlzheimerResearch Foundation to TLA. These funding agencies did not play a role instudy design, data collection, analysis, interpretation of data, or in writing themanuscript.Availability of data and materialsThe datasets used and/or analyzed during the current study are availablefrom the corresponding author on reasonable request.Authors’ contributionsTLA (Principal Investigator), LL, and GJL wrote the grant application, whichwas funded by Vancouver Coastal Health Research Institute. RSF, JCD, GJL,and TLA jointly drafted the Buying Time protocol. RSF, JCD, JRB, LL, PCYC,ABW, GJL, and TLA are part of the Buying Time research team and criticallyreviewed the manuscript. RSF wrote the first draft of the manuscript. JCD,JRB, and TLA all wrote part of the manuscript and provided critical review.All authors read and approved the final manuscript.Ethics approval and consent to participateEthical approval for this study was provided by the University of BritishColumbia Clinical Research Ethics Board (H16–01029). All participants for thisstudy will provide written consent.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Falck et al. Trials  (2018) 19:445 Page 7 of 9Author details1Department of Physical Therapy, Aging, Mobility and CognitiveNeuroscience Laboratory, Faculty of Medicine, University of British Columbia,Vancouver, BC, Canada. 2Department of Management, University of BritishColumbia – Okanagan Campus, Kelowna, BC, Canada. 3Department ofPhysical Therapy, Arthritis Research Canada, Faculty of Medicine, University ofBritish Columbia, Vancouver, BC, Canada.Received: 1 February 2018 Accepted: 4 August 2018References1. World Health Organization. Alzheimer’s Disease International. Dementia: APublic Health Authority; 2012. p. 112.2. Wimo A, Guerchet M, Ali G-C, Wu Y-T, Prina AM, Winblad B, Jönsson L, LiuZ, Prince M. The worldwide costs of dementia 2015 and comparisons with2010. Alzheimers Dement. 2017;13(1):1–7.3. Barnes DE, Yaffe K. The projected effect of risk factor reduction onAlzheimer’s disease prevalence. Lancet Neurol. 2011;10(9):819–28.4. Petersen RC. Mild cognitive impairment: transition from aging toAlzheimer's disease. In: Iqbal K, Sisodia SS, Winblad B, editors. Alzheimer'sDisease: Advances in etiology, pathogenesis and therapeutics. Hoboken;2001. p. 141-51.5. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mildcognitive impairment: clinical characterization and outcome. Arch Neurol.1999;56(3):303–8.6. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med.2004;256(3):183–94.7. Busse A, Bischkopf J, Riedel-Heller SG, Angermeyer MC. Mild cognitiveimpairment: prevalence and incidence according to different diagnosticcriteria. Results of the Leipzig longitudinal study of the aged (LEILA75+). Br JPsychiatry. 2003;182:449–54.8. Petersen RC, Lopez O, Armstrong MJ, Getchius TS, Ganguli M, Gloss D,Gronseth GS, Marson D, Pringsheim T, Day GS. Practice guideline updatesummary: mild cognitive impairment: Report of the Guideline Development,Dissemination, and Implementation Subcommittee of the AmericanAcademy of Neurology. Neurology. 2017; https://doi.org/10.1212/WNL.0000000000004826.9. Foley DJ, Monjan AA, Brown SL, Simonsick EM. Sleep complaints amongelderly persons: an epidemiologic study of three communities. Sleep. 1995;18(6):425-32.10. Lim AS, Yu L, Kowgier M, Schneider JA, Buchman AS, Bennett DA.Modification of the relationship of the apolipoprotein E ε4 allele to the riskof Alzheimer disease and neurofibrillary tangle density by sleep. JAMANeurol. 2013;70(12):1544–51.11. Naismith SL, Hickie IB, Terpening Z, Rajaratnam SW, Hodges JR, Bolitho S,Rogers NL, Lewis SJ. Circadian misalignment and sleep disruption in mildcognitive impairment. J Alzheimers Dis. 2014;38(4):857–66.12. Tranah GJ, Blackwell T, Stone KL, Ancoli-Israel S, Paudel ML, Ensrud KE,Cauley JA, Redline S, Hillier TA, Cummings SR. Circadian activity rhythmsand risk of incident dementia and mild cognitive impairment in olderwomen. Ann Neurol. 2011;70(5):722–32.13. Moore RY. The suprachiasmatic nucleus and the circadian timing system.Prog Mol Biol Transl Sci. 2013;119:1–28.14. Golombek DA, Rosenstein RE. Physiology of circadian entrainment. PhysiolRev. 2010;90(3):1063–102.15. Daan S, Beersma D, Borbély AA. Timing of human sleep: recovery processgated by a circadian pacemaker. Am J Phys Regul Integr Comp Phys. 1984;246(2):R161–83.16. Borbély AA, Achermann P, Trachsel L, Tobler I. Sleep initiation and initialsleep intensity: interactions of homeostatic and circadian mechanisms. J BiolRhythm. 1989;4(2):37–48.17. Shirani A, Louis EKS. Illuminating rationale and uses for light therapy. J ClinSleep Med. 2009;5(2):155.18. Mintz EM, Marvel CL, Gillespie CF, Price KM, Albers HE. Activation of NMDAreceptors in the suprachiasmatic nucleus produces light-like phase shifts ofthe circadian clock in vivo. J Neurosci. 1999;19(12):5124–30.19. Czeisler CA, Duffy JF, Shanahan TL, Brown EN, Mitchell JF, Rimmer DW,Ronda JM, Silva EJ, Allan JS, Emens JS. Stability, precision, and near-24-hourperiod of the human circadian pacemaker. Science. 1999;284(5423):2177–81.20. Czeisler CA, Dumont M, Duffy JF, Steinberg JD, Richardson GS, Brown EN,Sanchez R, Rios CD, Ronda JM. Association of sleep-wake habits in olderpeople with changes in output of circadian pacemaker. Lancet. 1992;340(8825):933–6.21. Duffy JF, Dijk DJ, Klerman EB, Czeisler CA. Later endogenous circadiantemperature nadir relative to an earlier wake time in older people. Am JPhys. 1998;275(5 Pt 2):R1478–87.22. Dijk DJ, Duffy JF, Riel E, Shanahan TL, Czeisler CA. Ageing and the circadianand homeostatic regulation of human sleep during forced desynchrony ofrest, melatonin and temperature rhythms. J Physiol. 1999;516(Pt 2):611–27.23. van Someren EJ, Mirmiran M, Swaab DF. Non-pharmacological treatment ofsleep and wake disturbances in aging and Alzheimer's disease:chronobiological perspectives. Behav Brain Res. 1993;57(2):235–53.24. Landry GJ, Liu-Ambrose T. Buying time: a rationale for examining the use ofcircadian rhythm and sleep interventions to delay progression of mildcognitive impairment to Alzheimer’s disease. Front Aging Neurosci. 2014;6:325.25. Sharma VK, Chandrashekaran M: Zeitgebers (time cues) for biologicalclocks. 2005.26. Roenneberg T, Foster RG. Twilight times: light and the circadian system.Photochem Photobiol. 1997;66(5):549–61.27. Schmidt TM, Chen S-K, Hattar S. Intrinsically photosensitive retinal ganglioncells: many subtypes, diverse functions. Trends Neurosci. 2011;34(11):572–80.28. Neikrug AB, Ancoli-Israel S. Sleep disorders in the older adult–a mini-review.Gerontology. 2010;56(2):181–9.29. Montgomery P, Dennis JA. Bright light therapy for sleep problems in adultsaged 60+. Cochrane Database of Systematic Reviews. 2002. https://doi.org/10.1002/14651858.CD003403.30. Morgenthaler TI, Lee-Chiong T, Alessi C, Friedman L, Aurora RN, BoehleckeB, Brown T, Chesson AL Jr, Kapur V, Maganti R. Practice parameters for theclinical evaluation and treatment of circadian rhythm sleep disorders. Sleep.2007;30(11):1445–59.31. Buxton OM, Lee CW, L'Hermite-Balériaux M, Turek FW, Van Cauter E. Exerciseelicits phase shifts and acute alterations of melatonin that vary withcircadian phase. Am J Phys Regul Integr Comp Phys. 2003;284(3):R714–24.32. Baehr EK, Eastman CI, Revelle W, Olson SHL, Wolfe LF, Zee PC. Circadianphase-shifting effects of nocturnal exercise in older compared with youngadults. Am J Phys Regul Integr Comp Phys. 2003;284(6):R1542–50.33. Dijk D-J, Edgar DM. Circadian and homeostatic control of wakefulness andsleep. In: Turek F, Zee P, editors. Regulation of sleep and circadian rhythms.New York: Dekker; 1999.34. Youngstedt SD. Effects of exercise on sleep. Clin Sports Med. 2005;24(2):355–65.35. Kredlow MA, Capozzoli MC, Hearon BA, Calkins AW, Otto MW. The effects ofphysical activity on sleep: a meta-analytic review. J Behav Med. 2015;38(3):427–49.36. Troiano RP, Berrigan D, Dodd KW, Masse LC, Tilert T, McDowell M. Physicalactivity in the United States measured by accelerometer. Med Sci SportsExerc. 2008;40(1):181–8.37. Falck RS, Landry GJ, Best JR, Davis JC, Chiu BK, Liu-Ambrose T. Cross-sectional relationships of physical activity and sedentary behavior withcognitive function in older adults with probable mild cognitive impairment.Phys Ther. 2017;97(10):975–84.38. Stepanski EJ, Wyatt JK. Use of sleep hygiene in the treatment of insomnia.Sleep Med Rev. 2003;7(3):215–25.39. Irish LA, Kline CE, Gunn HE, Buysse DJ, Hall MH. The role of sleep hygiene inpromoting public health: a review of empirical evidence. Sleep Med Rev.2015;22:23–36.40. Zee PC, Vitiello MV. Circadian rhythm sleep disorder: irregular sleep wakerhythm. Sleep Med Clin. 2009;4(2):213–8.41. Richter K, Myllymaeki J, Scharold-Schaefer S, Tomova I, Mayrer R, NiklewskiG. Treating comorbid insomnia in older adults via cognitive-behaviouraltreatment, bright light and exercise. Health (N Y). 2014;6(10):960.42. The EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. Health Policy. 1990;16(3):199–208.43. Coast J, Flynn TN, Natarajan L, Sproston K, Lewis J, Louviere JJ, Peters TJ.Valuing the ICECAP capability index for older people. Soc Sci Med. 2008;67(5):874–82.44. Canadian Society for Exercise Physiology. Par-Q and You. Gloucester:Canadian Society of Exercise Physiology; 1994. p. 1–2.45. Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practicalmethod for grading the cognitive state of patients for the clinician. JPsychiatr Res. 1975;12(3):189–98.Falck et al. Trials  (2018) 19:445 Page 8 of 946. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I,Cummings JL, Chertkow H. The Montreal cognitive assessment, MoCA: abrief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695–9.47. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburghsleep quality index: a new instrument for psychiatric practice and research.Psychiatry Res. 1989;28(2):193–213.48. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, Leirer VO.Development and validation of a geriatric depression screening scale: apreliminary report. J Psychiatr Res. 1983;17(1):37–49.49. Van Marwijk H, Wallace P, de Bock GH, Hermans J, Kaptein AA, Mulder JD.Evaluation of the feasibility, reliability and diagnostic value of shortenedversions of the geriatric depression scale. Br J Gen Pract. 1995;45(393):195–9.50. Elbaz M, Yauy K, Metlaine A, Martoni M, Leger D. Validation of a newactigraph motion watch versus polysomnography on 70 healthy andsuspected sleep-disordered subjects. J Sleep Res. 2012;21:218.51. Krystal AD, Edinger JD. Measuring sleep quality. Sleep Med. 2008;9:S10–7.52. Roth T. Measuring treatment efficacy in insomnia. J Clin Psychiatr. 2004;65:8–12.53. Faul F, Erdfelder E, Lang A-G, Buchner A. G* Power 3: a flexible statisticalpower analysis program for the social, behavioral, and biomedical sciences.Behav Res Methods. 2007;39(2):175–91.54. Chung F, Subramanyam R, Liao P, Sasaki E, Shapiro C, Sun Y. HighSTOP-Bang score indicates a high probability of obstructive sleep apnoea.Br J Anaesth. 2012;108(5):768–75.55. Van Someren EJ. Improving actigraphic sleep estimates in insomnia anddementia: how many nights? J Sleep Res. 2007;16(3):269–75.56. Carney CE, Buysse DJ, Ancoli-Israel S, Edinger JD, Krystal AD, Lichstein KL,Morin CM. The consensus sleep diary: standardizing prospective sleepself-monitoring. Sleep. 2012;35(2):287–302.57. Ancoli-Israel S, Cole R, Alessi C, Chambers M, Moorcroft W, Pollak CP. Therole of actigraphy in the study of sleep and circadian rhythms. Sleep. 2003;26(3):342–92.58. Weyer G, Erzigkeit H, Kanowski S, Ihl R, Hadler D. Alzheimer's diseaseassessment scale: reliability and validity in a multicenter clinical trial. IntPsychogeriatr. 1997;9(2):123–38.59. Spreen O, Strauss E. A compendium of neurological tests. 2nd ed. NewYork: Oxford University Press, Inc.; 1998.60. Wechsler D: WAIS-R manual: Wechsler adult intelligence scale-revised:Psychological Corporation; 1981.61. Lockley SW, Brainard GC, Czeisler CA. High sensitivity of the humancircadian melatonin rhythm to resetting by short wavelength light. J ClinEndocrinol Metab. 2003;88(9):4502–5.62. Warman VL, Dijk D-J, Warman GR, Arendt J, Skene DJ. Phase advancing humancircadian rhythms with short wavelength light. Neurosci Lett. 2003;342(1):37–40.63. Wright HR, Lack LC, Kennaway DJ. Differential effects of light wavelength inphase advancing the melatonin rhythm. J Pineal Res. 2004;36(2):140–4.64. Cajochen C, Munch M, Kobialka S, Krauchi K, Steiner R, Oelhafen P, Orgul S,Wirz-Justice A. High sensitivity of human melatonin, alertness,thermoregulation, and heart rate to short wavelength light. J ClinEndocrinol Metab. 2005;90(3):1311–6.65. Czeisler CA, Kronauer RE, Allan JS, Duffy JF, Jewett ME, Brown EN, Ronda JM.Bright light induction of strong (type 0) resetting of the human circadianpacemaker. Science. 1989;244(4910):1328–33.66. Khalsa SBS, Jewett ME, Cajochen C, Czeisler CA. A phase response curve tosingle bright light pulses in human subjects. J Physiol. 2003;549(3):945–52.67. Revell VL, Molina TA, Eastman CI. Human phase response curve tointermittent blue light using a commercially available device. J Physiol.2012;590(19):4859–68.68. St Hilaire MA, Gooley JJ, Khalsa SBS, Kronauer RE, Czeisler CA, Lockley SW.Human phase response curve to a 1 h pulse of bright white light. J Physiol.2012;590(13):3035–45.69. Rüger M, St Hilaire MA, Brainard GC, Khalsa SBS, Kronauer RE, Czeisler CA,Lockley SW. Human phase response curve to a single 6.5 h pulse ofshort-wavelength light. J Physiol. 2013;591(1):353–63.70. Gutnick D, Reims K, Davis C, Gainforth H, Jay M, Cole S. Brief actionplanning to facilitate behavior change and support patient self-management. JCOM. 2014;21(1):18–29.71. Hirshkowitz M, Whiton K, Albert SM, Alessi C, Bruni O, DonCarlos L, Hazen N,Herman J, Katz ES, Kheirandish-Gozal L. National Sleep Foundation’s sleeptime duration recommendations: methodology and results summary. SleepHealth. 2015;1(1):40–3.72. Zheng G, Xia R, Zhou W, Tao J, Chen L. Aerobic exercise amelioratescognitive function in older adults with mild cognitive impairment: asystematic review and meta-analysis of randomised controlled trials. Br JSports Med. 2016; https://doi.org/10.1136/bjsports-2015-095699.73. Martin M, Clare L, Altgassen AM, Cameron M. Cognition-based interventionsfor older people and people with mild cognitive impairment. CochraneDatabase of Systematic Reviews. 2011. https://doi.org/10.1002/14651858.CD006220.pub2.Falck et al. Trials  (2018) 19:445 Page 9 of 9


Citation Scheme:


Citations by CSL (citeproc-js)

Usage Statistics



Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            async >
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:


Related Items