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Effects of exercise and horticultural intervention on the brain and mental health in older adults with… Makizako, Hyuma; Tsutsumimoto, Kota; Doi, Takehiko; Hotta, Ryo; Nakakubo, Sho; Liu-Ambrose, Teresa; Shimada, Hiroyuki Nov 4, 2015

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STUDY PROTOCOL Open AccessEffects of exercise and horticulturalintervention on the brain and mentalhealth in older adults with depressivesymptoms and memory problems: studyprotocol for a randomized controlled trial[UMIN000018547]Hyuma Makizako1*, Kota Tsutsumimoto1, Takehiko Doi1,2, Ryo Hotta1, Sho Nakakubo1, Teresa Liu-Ambrose3and Hiroyuki Shimada1AbstractBackground: Depressive symptoms and memory problems are significant risk factors for dementia. Exercise can reducedepressive symptoms and improve cognitive function in older people. In addition, the benefits of horticultural activityon physical and mental well-being have been demonstrated in people with dementia. Although evidence of suchnon-pharmacological interventions is mounting, no studies have examined whether physical exercise and horticulturalactivity exert a positive impact on brain and mental health (e.g., depressive symptoms) in non-demented older adults athigh risk of cognitive impairment and depression. Therefore, we propose a randomized controlled trial to assess the efficacyand efficiency of physical exercise and horticultural activity in improving brain and mental health in community-dwellingolder adults with memory problems and depressive symptoms.Methods/Design: The 20-week randomized controlled trial will include 90 community-dwelling adults aged 65 yearsor older with memory problems and depressive symptoms. Participants will be randomized to one of three experiments:exercise, horticultural activity, or educational control group, using a 1:1:1 allocation ratio. The combined exercise programand horticultural activity program will consist of 20 weekly 90-minute sessions. Participants in the exercise group will practiceaerobic exercise, muscle strength training, postural balance retraining, and dual-task training. The horticultural activityprogram will include crop-related activities, such as field cultivation, growing, and harvesting. Participants in the educationalcontrol group will attend two 90-minute educational classes during the 6-month trial period. Depressive symptoms andmemory performance will be measured by the Geriatric Depression Scale-15, and the Logical Memory subtests of theWechsler Memory Scale-Revised will be used to measure depressive symptoms and memory performance as primaryoutcomes, at baseline (prior to randomization), immediately following intervention (6 months from baseline), and 6 monthsafter intervention. Hippocampal volume will be measured at baseline and immediately after intervention, using magneticresonance imaging. Secondary outcomes will comprise cognitive function, including language, attention/executiveperformance, and processing speed; brain-derived neurotrophic-factor serum levels; and health-related quality of life.(Continued on next page)* Correspondence: makizako@ncgg.go.jp1Department of Preventive Gerontology, Center for Gerontology and SocialScience, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho,Obu, Aichi 474-8551, JapanFull list of author information is available at the end of the articleTRIALS© 2015 Makizako et al. 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.Makizako et al. Trials  (2015) 16:499 DOI 10.1186/s13063-015-1032-3(Continued from previous page)Discussion: This intervention study will determine the clinical importance and efficacy of physical exercise andhorticultural activity as non-pharmacological interventions in community-dwelling older adults at high risk of poorbrain and mental health.Trial registration: UMIN000018547; registered 7 August 2015.Keywords: Cognition, Depression, Exercise, Hippocampal volume, HorticultureBackgroundDepressive symptoms constitute a significant risk factor forAlzheimer’s disease (AD) [1]. Epidemiological studies havereported an association between depressive symptoms andcognitive decline, and depressive symptoms have beenshown to predict cognitive decline in old age [2–4]. Severalfactors affect cognitive functioning in old age, and olderpeople with memory problems are considered to be at ahigher risk of developing dementia, particularly AD, rela-tive to those without memory problems [5, 6]. In addition,cognitive impairment is more common in older peoplewith depression [7]. Therefore, older adults with combinedmemory decline and depressive symptoms may be at ahigher risk of dementia, and they should be the focus of in-terventions designed to improve brain and mental healthand address issues such as memory problems and depres-sive symptoms.Exercise can improve cognitive function and reducedepressive symptoms in older people. Specifically, aerobicexercise has been shown to produce mild-to-moderatecognitive gains in healthy adults [8]. Cognitive improve-ment has also been observed following aerobic exercise inolder adults with mild cognitive impairment (MCI) [9, 10].However, evidence concerning the effects of aerobic exer-cise on memory in older adults with a higher risk of cogni-tive impairment is limited [11]. Some studies have shownmemory improvement following exercise interventions in-volving physical and cognitive activities in participants withMCI [12, 13]. Interestingly, moderate-intensity physical ex-ercise may increase hippocampal volume in cognitivelyhealthy community-dwelling older adults [14] and thosewith MCI [15]. Hippocampal volume is the primary deter-minant of memory decline [16], and geriatric depressionmagnifies hippocampal atrophy and the risk of AD [17].Exercise could also improve mood in older people.Antidepressant effects have been observed with exercisein people with mild depression [18]. A systematic reviewindicated that exercise was moderately more effectivethan a control intervention in reducing symptoms of de-pression, but analysis of methodologically robust trialsshowed a smaller effect in favor of exercise [19]. Resultsof another review were consistent with the suggestionthat, for older people who present with clinically mean-ingful symptoms of depression, prescribing structuredexercise with mixed elements of endurance and strengthtraining tailored to individual ability is likely to reducethe severity of depression [20].Another non-pharmacological intervention strategy forreducing depression is horticultural activity, which is ex-pected to increase social and behavioral activation andmental well-being, and moderate levels of physical activityin a nature-based environment [21]. In addition, interven-tion studies, randomized controlled trials (RCTs), andpre–post design studies have been conducted to examinethe effects of horticultural activity on physical andmental well-being in people with dementia, and the re-sults showed reductions in levels of agitation [22].However, the quantitative studies were of poor qualitywith respect to sample size and study design. In addition,there have been no well-designed intervention studiesconducted to examine the effects of horticultural activityon brain and mental health (e.g., depressive symptoms,cognitive function, and brain volume) in non-dementedadults with a higher risk of dementia.We hypothesize that physical exercise and horticulturalactivity may exert a positive impact on brain (e.g., cognitivefunction and brain volume in the hippocampus) and men-tal health (e.g., depressive symptoms) in older adults with ahigher risk of cognitive impairment and depression. How-ever, this hypothesis has not been tested. Therefore, wepropose a 20-week RCT involving community-dwellingadults aged 65 years or older with mild memory problemsand depressive symptoms. Further, we aim to explore therelative importance of hippocampal volume changes withrespect to improvements in cognitive function and mood.Given the immense health and financial burdens imposedby dementia and depression, the results of our pro-posed RCT could exert a significant impact on the health ofJapanese seniors and the country’s long-term care system.Methods/DesignStudy designThe proposed study is a randomized single-blind con-trolled community-based trial with a parallel designand a 1:1:1 allocation ratio. The study design is shownin Fig. 1. We will recruit 90 community-dwelling adultsaged 65 years or older with memory problems and de-pressive symptoms. Informed consent will be obtainedfrom all participants prior to their inclusion in thestudy. The study protocol was approved by the EthicsMakizako et al. Trials  (2015) 16:499 Page 2 of 7Committee of the National Center for Geriatrics andGerontology (#839).SettingThis study will be conducted in the Japanese communityin Obu city, a suburb of Nagoya, Japan. Obu city has apopulation of 88,550, of whom 17,354 (19.6 %) are aged65 or older (in April 2014). We have been conducting anobservational study, including face-to-face interviews andmeasures of physical and cognitive function, in thiscommunity since 2011 [23]. Pre-intervention and post-intervention participant screening and data collection willbe performed at the community center. Magnetic reson-ance imaging (MRI) scanning will be conducted at theResearch Institute at the National Center for Geriatricsand Gerontology.Study populationThe study population will include community-dwellingolder adults with mild memory decline and depressivesymptoms. Participants will be required to meet the fol-lowing inclusion criteria: (1) independent adults aged65 years or older living within the community; (2) memoryproblems (subjective memory complaints or objective mildmemory decline indicated via an age-adjusted word listmemory score at least 1.0 SD below the reference thresh-old); and (3) presence of depressive symptoms (GeriatricDepression Scale-15 [GDS-15] score of ≥5) [24]. Partici-pants will be excluded if they meet the following exclusioncriteria: (1) support or care certified by the Japanese publiclong-term care insurance system; (2) dementia diagnosis orMini-Mental State Examination score of ≤18; (3) a historyof major psychiatric illness (e.g., bipolar disorder) or otherserious neurological or musculoskeletal diagnoses; (4)disability in basic activities of daily living; (5) incapable ofundertaking cognitive performance tests; (6) physical exer-cise contraindication; and (7) use of walking aids in dailylife. Participants will also be excluded if they cannot signthe informed consent form.Sample sizeThe required sample size for this study was calculatedusing predictions of 6-month changes in GDS-15 results.Based on the results of our previous work, conducted inthe same town, we predict that a change of 1.5 GDS-15points would indicate differences and assume that the SDsfor the GSD-15 would be 2.5 in our sample. Assuming anon-consent and dropout rate of 20–30 %, 30 participantsare required per group. The study design necessitatespower of at least 80 % and an α level of <.05 to assess theeffects of the interventions.RandomizationParticipants will be randomly assigned (1:1:1) to an exer-cise intervention (EI), a horticultural intervention (HI), oran educational (control) group upon completion of base-line assessments. The randomization sequence will becomputer generated [25, 26]. A researcher who is unawareof the aims of the study will perform the randomizationprocedure.Planned trial interventionsExercise intervention groupThe combined exercise program will involve 20 weekly90-minute sessions involving physical and cognitive ac-tivities. Approximately 10–15 individuals will participatein each class at a fitness facility. Trained instructors willconduct the exercise sessions, which will involve aerobicFig. 1 Overview of the flow of participantsMakizako et al. Trials  (2015) 16:499 Page 3 of 7exercise, muscle strength training, postural balance retrain-ing, and dual-task training. Each session will begin witha 10-minute warm-up period and stretching exercisesfollowed by 20 minutes of muscle strength exercise andpostural balance retraining. The exercises will be con-ducted under multitask conditions that will includephysical and cognitive tasks; we have called this com-bination training “cognicize.” For example, participantsplay word games while engaging in stepping exercises.The participants will also undertake daily home-based ex-ercises and walking, which will require self-monitoringusing a booklet and pedometer. To improve health behav-ior, physiotherapists will deliver lectures to inform the par-ticipants about cognitive health, exercise methods, therisks associated with dementia, effects of exercise on de-mentia, and ways in which to self-monitor regular physicalactivities.Horticultural intervention groupThe HI program will involve 20 weekly 90-minute ses-sions involving nature-based activities. The program willinclude crop-related activities such as cultivating a field,growing, and harvesting. Individuals in this group willengage in gardening activities including group planting(known as Yoseue style bonsai), which involves the com-bination of different plant varieties or shapes, and plant-ing flowers in the public garden. The vegetable expertswill lecture the participants with nutritional informationand recipes for the field crops that will be grown in theprogram.Educational control groupParticipants in the educational control group will attendtwo 90-minute education classes during the 6-month trialperiod. The classes will include topics that experts con-sider less likely to influence study outcomes (e.g., effectiveremedies for crime or traffic accidents in older people).OutcomesOutcomes will be measured at the community center byresearch assistants who are blinded to the randomizationstatus. Participants will be required to take part in baselinedata collection lasting approximately 2 hours. Subsequentdata collection will occur immediately following the inter-vention (6 months after baseline) and 6 months afterintervention for all outcomes. All outcome measures willbe assessed by independent examiners who are unawareof group allocation.Primary outcomesPrimary outcomes will include a reduction in depressivesymptoms, based on changes in GDS-15 scores, and animprovement in memory performance, assessed via wordlist memory [27] and the Logical Memory subtests of theWechsler Memory Scale-Revised (WMS-R) [28]. TheGDS-15 consists of 15 items. A score of 5 or higher willbe used to identify clinical depressive symptoms [29, 30].The word list memory tasks will involve immediaterecognition and delayed recall of a 10-word target list[27]. Participants are instructed to memorize 10 words,which are presented on a tablet personal computer. Eachof the 10 target words is presented for 2 seconds. A totalof 30 words, including 10 target and 20 distracter words,is then presented, and participants are asked to choosethe 10 target words immediately (Word-List Memory TaskI); this is repeated for three trials. The average number ofcorrect answers is calculated to produce a score within arange of 0–10. In addition, participants are instructed torecall (and record in writing) the 10 target words after ap-proximately 20 minutes (Word-List Memory Task II). Thetotal number of target words recalled is then calculated.In the WMS-R Logical Memory subtests, two short stor-ies (A and B) are read aloud to the participant, who isinstructed to recall the details of the stories immediately(Logical Memory Task I) and after 30 minutes (LogicalMemory Task II) [28]. Total scores are calculated (i.e., sumof scores for stories A and B) for WMS-R Logical MemoryTasks I and II.Secondary outcomesSecondary outcomes will include whole-brain and hippo-campal volume, evaluated using MRI; cognitive function,assessed using verbal fluency tests (VFTs) [31] and tabletversions of the trail-making test (TMT) [27] and symboldigit substitution test (SDST) [27]; brain-derived neuro-trophic factor (BDNF) serum levels; and health-relatedquality of life (QOL).Whole-brain and hippocampal volume will be deter-mined using a 3-T system (TM Trio, Siemens, Germany).Three-dimensional volumetric acquisition of a T1-weightedgradient echo sequence will be performed to produce agapless series of thin sagittal sections using a magnetizationpreparation rapid-acquisition gradient-echo sequence (in-version time [TI] 800 ms; repetition time [TR] 1800 ms;echo time [TE] 1.98 ms; and 1.1 mm slice thickness). AxialT2-weighted spin-echo images (TR 4200 ms; TE 89.0 ms;and 5.0 mm slice thickness) and axial fluid-attenuatedinversion-recovery images (TI 2500 ms; TR 9000 ms; TE100 ms; 5 mm slice thickness) will then be obtained fordiagnosis.Verbal fluency will be assessed according to the numberof words generated across 60-second trials [32]. Both theletter VFT (which assesses phonemic verbal fluency) andthe animal naming test (which assesses semantic verbalfluency) will be performed. In the letter VFT, participantswill be instructed to retrieve as many words (excludingproper names) as possible within a 60-second period,beginning with the Japanese syllabic characters (hiragana)Makizako et al. Trials  (2015) 16:499 Page 4 of 7“Shi,” “I,” and “Re” [33]. The total number of words gener-ated for all three letters will be used as a measure ofperformance. In the animal naming test, participants willbe instructed to generate a list of animal names within60 seconds [31]. The tablet version of the TMT, consistingof parts A and B, will be used to determine attentionand executive function [27]. In the tablet version of theTMT-A, participants are required to touch target num-bers (1–15), which are presented randomly on thepanel, in consecutive order as rapidly as possible. In thetablet version of the TMT-B, participants touch targetnumbers or letters, alternating between consecutive num-bers and letters (Japanese Kana characters). We will recordthe time (in seconds) taken to complete each task; ashorter time represents superior performance. In the tabletversion of the SDST, nine pairs of numbers and symbolsare presented at the top of the display, and a target symbolis shown in the center of the display. Participants thenchoose a number that corresponds to a target symbol,which is presented at the bottom of the display, as rapidlyas possible. The number of correct numbers chosen within90 seconds constitutes the score. One point is awarded foreach number that is chosen correctly within the time limit.The tablet versions of the TMT and SDST have demon-strated reliability and validity in a sample of community-dwelling older adults [27].Serum BDNF levels will be measured using theQuantikine Human Kit (R & D Systems, Inc. Minneapolis,MN, USA) and used as a biomarker [12].Health-related QOL will be assessed using the Short-Form Health Survey-12, a standardized instrument withestablished psychometric validity, which measures eighthealth domains: physical functioning, role limitationsdue to physical health, bodily pain, general health, vital-ity (energy/fatigue), social functioning, role limitationsdue to emotional health, and mental health (psycho-logical distress and wellbeing) [34].Other outcomesOther outcomes will include physical performance testssuch as handgrip strength, walking speed, and the two-minute walking test [35]; social network, assessed usingthe abbreviated version of the Lubben Social NetworkScale (LSNS-6) [36]; Life-Space Assessment (LSA) [37];subjective sleep quality, assessed using the PittsburghSleep Quality Index [38]; and daily physical activity level,assessed using a triaxial accelerometer [39]. We willmonitor adherence to the intervention programs andrecord adverse events.Physical performance tests will include handgrip strengthto measure muscle strength, normal and maximum walk-ing speed to measure general gait ability, and the two-minute walking test to assess exercise tolerance. Handgripstrength and walking speed are simple, easy to implementin community settings, and strong predictors of health out-comes [40]. In the two-minute walking test, participantswill be asked to walk, covering as much ground as possiblein a demarcated area within 2 minutes. The distancewalked within 2 minutes will be measured [35].Social network will be measured using the LSNS-6,which is a six-item scale (simple sum scoring with a rangeof 0–30) consisting of three items that evaluate kinship tiesand three items that evaluate non-kin ties [36]. Life-spacemobility will be measured via the LSA, which is used toobtain a score based on the reported distance travelledduring the 4 weeks preceding assessment. Scores rangefrom 0 (“totally roombound”) to 120 (“travelled out oftown every day without assistance”), with lower scoresreflecting lower life-space mobility [37, 41]. Sleep qualitywill be evaluated using the Pittsburgh Sleep Quality Index,which consists of 19 items that produce a global sleepquality score and scores for the following seven compo-nents: sleep quality, latency, duration, disturbance, habitualsleep efficiency, use of soporific medication, and daytimedysfunction. The sum of these seven component scoresyields one global score for subjective sleep quality (range0–21), with higher scores reflecting poorer subjective sleepquality [42]. Daily physical activity level, including durationof light, moderate, and total physical activity, and the num-bers of steps taken during the 2-week periods subsequentto pre-intervention and post-intervention assessments, willbe measured using a triaxial accelerometer [39].Statistical analysesStatistical analyses will be conducted to assess the effectsof interventions according to the intention-to-treatprinciple, which states that data for all individuals shouldbe analyzed according to their group allocation, regardlessof compliance. Data will be entered according to a multipleimputation method. Between-group differences in primaryoutcomes subsequent to intervention will be comparedusing multiple linear regression analysis. Baseline scores,experimental groups, and characteristics (e.g., age, sex,diagnoses, and medical conditions) will be included in themodels as covariates. If the effects of the intervention aresignificant, two planned simple contrasts will be performedto assess differences between the EI and control groupsand the HI and control groups. Contrasts will also beperformed within each intervention group to determinewhether intervention benefits are observed for the primaryoutcomes. The analysis performed for the primary out-comes will also be performed for the secondary and otheroutcome measures.DiscussionThis RCT will determine the clinical importance and effi-cacy of non-pharmacological interventions in community-dwelling older adults at a higher risk of poor brain andMakizako et al. Trials  (2015) 16:499 Page 5 of 7mental health, with MRI data and biomarkers used to as-sess the biological mechanisms of action in multidimen-sional exercise and horticultural activity.Improved understanding of the primary mechanismsunderlying exercise and horticultural activity wouldincrease our capacity to refine and develop non-pharmacological interventions for dementia and depressionprevention in the aging population. If interactions betweenmemory improvement, brain atrophy control, and depres-sion reduction are clarified, these results could make amajor contribution to knowledge in this field.One of strengths of our study is that the findings couldeasily be translated into evidence-based intervention strat-egies that both professionals and the lay public could useto engage older adults in exercise and horticultural activ-ity. If this study provides evidence of a potential treatmentthat could increase brain health, including improvementsin cognitive function and mental health and reductions inbrain atrophy, our findings could be used immediately asnon-pharmacological interventions for dementia and de-pression prevention in the community.Trial statusAt the time of manuscript submission, we have obtainedethical approval, registered the trial, and successfullyrecruited 29 participants, and the status of the trial is openfor enrollment.AbbreviationsAD: Alzheimer’s disease; BDNF: Brain-derived neurotrophic factor; EI: Exerciseintervention; GDS-15: Geriatric Depression Scale-15; HI: Horticulturalintervention; LSA: Life-Space Assessment; LSNS-6: Lubben Social NetworkScale; MCI: Mild cognitive impairment; MRI: Magnetic resonance imaging;QOL: health-related quality of life; RCT: Randomized controlled trial;SDST: Symbol Digit Substitution Test; TMT: Trail-Making Test; VFT: VerbalFluency Test; WMS-R: Wechsler Memory Scale-Revised.Competing interestsThe authors declare that they have no competing interests.Authors’ contributionsHM designed and supervised all aspects of the study implementation anddrafted the manuscript. HS participated in the design of the study and providedfeedback concerning the implementation of the study. KT participated in thedesign of the study and contributed to participant recruitment and screening.RH and SN contributed to participant recruitment and screening. TD contributedto participant recruitment and helped with the design of cognitive outcomemeasures and MRI data collection. TLA helped to draft the manuscript andcritically reviewed the manuscript. All authors participated in drafting themanuscript and critical revision for important intellectual content. All authorshave read and approved the final manuscript.AcknowledgementsThis study is funded by a grant-in-aid for Young Scientists (A; grant number26702033) from the Japan Society for the Promotion of Science. It is alsosupported in part by a grant from the National Center for Geriatrics andGerontology (Research Funding for Longevity Sciences; grant number 26–33).Author details1Department of Preventive Gerontology, Center for Gerontology and SocialScience, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho,Obu, Aichi 474-8551, Japan. 2Japan Society for the Promotion of Science,Kojimachi Business Center Building, 5-3-1 Kojimachi, Chiyoda-ku, Tokyo102-0083, Japan. 3Aging, Mobility, and Cognitive Neuroscience Laboratory,Djavad Mowafaghian Centre for Brain Health, University of British Columbia,212-2177 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.Received: 14 September 2015 Accepted: 23 October 2015References1. Barnes DE, Yaffe K. The projected effect of risk factor reduction on Alzheimer’sdisease prevalence. Lancet Neurol. 2011;10:819–28.2. Paterniti S, Verdier-Taillefer MH, Dufouil C, Alperovitch A. Depressive symptomsand cognitive decline in elderly people. 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