Art therapy and music reminiscence activity in the prevention of cognitive decline: study protocol for a randomized controlled trial

STUDY PROTOCOL Open Access A he apy and music eminiscence ac i i y in he p e en ion o cogni i e decline: s udy p o ocol o a andomized con olled ial Ra hi Mahend an 1,2,3* , I is Raw ae 1,2 , Johnson Fam 1,2 , Jona han Wong 1 , Alan P em Kuma 4,5,6,7 , Mihi Gandhi 8,9,10 , Kenny Xu Jing 8 , Lei Feng 1,2 and Ee Heok Kua 1,2 Abs ac Backg ound: A en ion has shi ed o he use o non-pha macological in e en ions o p e en cogni i e decline as a p e en i e s a egy, as well as o hose a isk and hose wi h mild cogni i e impai men . Ea ly in oduc ion o psycho-social in e en ions can add ess cogni i e decline and signi ican ly impac quali y o li e and he wellbeing o elde ly indi iduals. This pilo s udy explo es he easibili y o using a he apy and music eminiscence ac i i y o imp o e he cogni ion o communi y li ing elde ly wi h mild cogni i e impai men . Me hods/Design: This open-label, in e en ional s udy in ol es a pa allel andomized con olled ial design wi h h ee a ms ( wo in e en ion a ms and a con ol g oup) o e a nine-mon h pe iod. Pa icipan s will be communi y- li ing elde ly indi iduals aged 60–85 yea s, bo h gende s, who mee p ede ined inclusion and exclusion c i e ia. In he ini ial h ee mon hs, in e en ions will be p o ided weekly and o he emaining six mon hs o nigh ly. A sample size o 90 pa icipan s is a ge ed based on expec ed neu opsychological es pe o mance, a p ima y ou come measu e, and d op-ou a es. The andomiza ion p ocedu e will be ca ied ou ia a web-based andomiza ion sys em. In e en ions will be p o ided by ained s a wi h a con ol g oup no ecei ing any in e en ion bu con inuing li e as usual. Assessmen s will be done a baseline, h ee mon hs, and nine mon hs, and include neu oimaging o measu e ce eb al changes and neu opsychological es s o measu e o changes in cogni ion. Seconda y ou come measu es will include mood changes in anxie y and dep ession and elome e leng hs. S a is ical analysis will be unde aken by s a is icians; all e icacy analysis will be ca ied ou on an in en ion- o- ea basis. P ima y and seconda y ou comes will be modeled using he linea mixed model o epea ed measu emen s and u he analysis may be unde aken o adjus o po en ial con ounde s. Discussion: This will be he i s s udy o compa e he e ec i eness o a he apy and music eminiscence ac i i y in a andomized con olled ial. We expec ha he ial will p o ide use ul e idence o de eloping psychosocial in e en ions o he elde ly wi h mild cogni i e impai men . T ial egis a ion: The s udy was egis e ed on 7 July 2016 a Clinical T ials.go , a se ice o he US Na ional Ins i u e o Heal h (NCT02854085), e ospec i ely. Keywo ds: A he apy, Music eminiscence ac i i y, Mild cogni i e impai men , Randomized con olled ial * Co espondence: [email p o ec ed] 1 Depa men o Psychological Medicine, Yong Loo Lin School o Medicine, Na ional Uni e si y o Singapo e, Singapo e, Republic o Singapo e 2 Depa men o Psychological Medicine, Na ional Uni e si y Hospi al, Towe Block, Le el 9, 1E Ken Ridge Road, Singapo e, Republic o Singapo e Full lis o au ho in o ma ion is a ailable a he end o he a icle © The Au ho (s). 2017 Open Access This a icle is dis ibu ed unde he e ms o he C ea i e Commons A ibu ion 4.0 In e na ional License (h p://c ea i ecommons.o g/licenses/by/4.0/), which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided you gi e app op ia e c edi o he o iginal au ho (s) and he sou ce, p o ide a link o he C ea i e Commons license, and indica e i changes we e made. The C ea i e Commons Public Domain Dedica ion wai e (h p://c ea i ecommons.o g/publicdomain/ze o/1.0/) applies o he da a made a ailable in his a icle, unless o he wise s a ed. Mahend an e al. T ials (2017) 18:324 DOI 10.1186/s13063-017-2080-7 Backg ound Popula ion aging is a global public heal h conce n and demen ia is one o he majo causes o disabili y and de- pendency in he elde ly popula ion wo ldwide [1]. Re- sea ch now a ge s he p e en ion o delay o cogni i e decline as a mo e bene icial app oach and a en ion has shi ed o non-pha macological in e en ions and p e- en i e s a egies o cogni i ely no mal elde ly and hose exhibi ing mild cogni i e p oblems. Mild cogni i e impai men (MCI, DSM-5 Mino Neu o- cogni i e Diso de ) [2] is associa ed wi h high bu den wi h abou 50% o indi iduals going on o de elop demen ia wi hin i e yea s. While 14–40% may e u n o no mal cogni i e unc ioning o e ime, o he s may exhibi a pe - sis en o m o MCI wi hou con e sion [3, 4]. In e en- ions om s imula ing leisu e ac i i ies and an ac i e cogni i e li es yle o add ess cogni i e decline a his s age, ha e a signi ican impac on he quali y o li e and well- being o elde ly indi iduals and also illness p og ession [5]. E idence sugges s ha he causes o aging a e mul i- ac o ial, anging om inc eased in lamma ion and oxida- i e s ess o dec eased mi ochond ial unc ion, ho monal le els, and genome ins abili y [6]. Howe e , he aging b ain s ill exhibi s plas ici y which allows in e en ions and cogni i e aining o b ing abou al e a ions in ce e- b al mo phology and unc ion [7]. A sys ema ic e iew o psycho-social in e en ions (69 p ospec i e con olled ials) ound posi i e e ec s on quali y o li e and posi i e men al heal h [8] and engaging in s imula ing ac i i ies a leas wice a week educed he isk o demen ia by 50% [9]. In e en ions ocusing mainly on li es yle modi ica ions, no ably he FINGER ial, ha e epo ed signi ican bene i s om a mul i ace ed in e en- ion ha included die , exe cise, cogni i e aining, and ascula moni o ing [10]. Ou ea lie wo k in an open-label ial o a he apy (AT), music eminiscence, mind ulness p ac ice, and Tai Chi exe cise wi h communi y-li ing elde ly, e ealed imp o emen s in sub-synd omal anxie y and dep essi e symp oms [11]. This was ollowed by a andomized con- olled ial (RCT) o examine Mind ulness Awa eness P ac ice ( he con ol g oup ecei ed Heal h Educa ion) in he elde ly wi h MCI and designed wi h a nine-mon h du a ion deemed su icien o in e en ion esponse [12]. In e en ions we e p o ided weekly o h ee mon hs and hen mon hly o six mon hs and a ange o “psychobio- ma ke s”we e in es iga ed [13]. Telome e leng h was one o hose measu ed as i is widely accep ed as a bioma ke o cellula aging and cogni i e de- cline wi h changes om a ious ac i i ies esul ing in longe elome es [14–16]. P elimina y indings om he Mind ul- ness Awa eness P ac ice RCT ha e e ealed changes in unc- ional b ain ac i i y, neu opsychological es s, elome e leng hs, and oxida i e s ess ma ke s a e jus h ee mon hs o weekly in e en ion (manusc ip in p epa a ion). Impo - an ly, he equency o he ac i i y had a signi ican impac on he sus ainabili y o gains p oduced by he in e en ion [17]. Exis ing esea ch on AT and music eminiscence ac i - i y (MRA), howe e , is limi ed, especially on he e icacy o hese in e en ions on cogni ion. Kim has shown ha AT imp o es mood and o e all wellbeing o elde ly indi iduals, bu he cogni i e s a us o he pa icipan s was unknown [18]. While Alde s and Le ine-Mado i ha e esul s ha seem o sugges ha AT is use ul in imp o ing cogni i e pe o m- ance [19], he s udy me hodology was no igo ous. The ex- pe imen al g oup could choose he ac i i y o pa icipa e in and could a end as ew as h ee o he en AT sessions. The s udy by Rus ed e al. [20] did no clea ly explain he con ol g oup ac i i y and ec ui ed a wide ange o demen ia pa ic- ipan s. None o he s udies ha e been o su icien igo o ocused on elde ly wi h MCI. Lis ening o music e ec i ely s imula es he audi o y co ex and o he b ain a eas ela ed o a en ion, seman ic p ocessing, memo y, mo o unc ion, and emo ional p o- cessing [21]. Ye s udies on he speci ic use o MRA and i s e icacy o elde ly wi h MCI a e a e. Mos o he esea ch has examined music he apy, wi h componen s o eminis- cence, o mood symp oms, whe e lis ening o music hey p e e ed [22] and choosing he ype o music o lis en o educed anxie y and dep ession in he elde ly [23, 24]. Pe o sky e al. did a e iew o he u ili y o music in e en- ions on mood in he elde ly wi h mild demen ia and ound ha many o he s udies we e no me hodologically s ong, indica ing ha he e idence was inconclusi e [25]. The esea ch on music he apy and cogni i e changes howe e has shown posi i e imp o emen s on Mini- Men al S a e Examina ion (MMSE) sco es, e en one mon h pos in e en ion [24] and on he sho - e m o wo king memo y and quali y o li e in elde ly wi h mild o mode a e demen ia [26]. Howe e , he e icacy o music he apy o cogni i e imp o emen is s ill deba ed and he e is a gap in he li e a u e o music eminis- cence ac i i ies in elde ly wi h MCI. Me hods/Design Aims o s udy This pilo s udy aims o explo e he easibili y o using AT and MRA o imp o e he cogni ion o communi y li ing elde ly wi h MCI (Diagnos ic and S a is ical Manual-5: Mild Neu ocogni i e Diso de ) [2]. The p ima y ou comes will be he s uc u al ce eb al changes ha occu wi h he wo in e en ions and he ex en o which he he apies may e e se cogni i e impai men and/o p e en u he cogni i e decline on neu opsychological es s o cogni ion. This will be based on pa icipan s’p e-, h ee-mon h and nine-mon h neu o- psychological es sco es, compa ed wi h indi iduals in he con ol a m who do no pa icipa e in ac i e in e en ions. Mahend an e al. T ials (2017) 18:324 Page 2 o 10 Seconda y ou comes comp ise changes in blood bio- ma ke s, psychological wellbeing, and mood symp oms. We hypo hesize ha pa icipan s in bo h ac i e in e - en ion a ms will ha e (1) imp o ed unc ional connec - i i y, (2) imp o ed neu opsychological cogni i e es sco es, (3) inc eased elome e leng hs, and (4) enhanced psychological wellbeing and educ ions in anxie y and dep essi e symp oms compa ed wi h he con ol g oup. No a p io i hypo heses we e de eloped as o whe he AT o MRA is mo e e ec i e as he compa ison is explo a o y. S udy design This is an open-label, in e en ional s udy in ol ing a pa - allel RCT design wi h h ee a ms and un o e nine mon hs. The du a ion o nine mon hs was used in p e i- ous RCTs o psychosocial in e en ions a ou cen e and p o ided a ial leng h o su icien du a ion which yielded measu able changes. The p o ocol was p epa ed acco ding o he S anda d P o ocol I ems: Recommenda ions o In e en ional T ials (SPIRIT) guidelines (see Fig. 1, Addi ional ile 1, and Fig. 2). In e en ions will be weekly o he i s h ee mon hs, hen o nigh ly o he emaining six mon hs. Weekly in e en ions p o ide g ea e p ac ice e ec s and imp o emen s in cogni ion and b ain unc ion, i any, can be de ec ed by h ee mon hs. In he subsequen six mon hs, he equency o he in e en ions has been inc eased o o nigh ly, based on p e ious ial expe ience ha mon hly in e en ions do no sus ain he ea ly gains. S udy e alua ions will be done by compa ing he wo in e en ion g oups (AT and MRA) and a con ol g oup. Pa icipan s will ha e w i en in- o med consen aken, sc eening, and baseline measu es comple ed be o e andomiza ion in o one o he h ee s udy a ms. In e en ion A m 1: Pa icipan s will ecei e AT In e en ion A m 2: Pa icipan s will ecei e MRA Con ol A m: Pa icipan s will no ecei e any in e - en ion bu con inue hei li e as usual. Eligibili y c i e ia The inclusion c i e ia a e: 1. Aged 60–85 yea s, bo h gende s, and li ing in he communi y and ul ils he ope a ional de ini ion/ c i e ia o MCI: (a) a leas one age-educa ion adjus ed neu opsychological es Z sco e < −1.5; (b) do no mee DSM V c i e ia o a majo neu ocogni- i e diso de ; (c) memo y/cogni i e complain p e e ably co obo a ed by a eliable in o man ; 2. Func ions independen ly as assessed wi h Ba hel’s Ac i i ies o Daily Li ing and ins umen al Ac i i ies o Daily Li ing; 3. Able o a el o he da a collec ion si e on hei own and pa icipa e in he ac i i y weekly o 12 weeks and hen o nigh ly o six mon hs. The exclusion c i e ia a e: 1. Those who do no mee he abo e inclusion c i e ia (i.e. do no ha e MCI diagnosis); 2. Those wi h demen ia/majo neu ocogni i e diso de o no mal aging; 3. P esence o a neu ological condi ion, e.g. epilepsy, Pa kinson’s disease, s oke; 4. P esence o a majo psychia ic diso de , e.g. majo dep ession, psychoses; 5. Te minal illness, e.g. cance ; 6. P esence o signi ican isual and/o hea ing impai men and colo blindness; 7. Pa icipan s in ano he in e en ion s udy a he same ime. Randomiza ion p ocedu e Pa icipan s will be andomized (on he same day a e aking w i en in o med consen , sc eening, and com- ple ing baseline measu es) o he AT, MRA, o con ol g oups a a 1:1:1 alloca ion a io. Balanced in e en ion assignmen s will be achie ed using pe mu ed block andomiza ion s a i ied by gende . Block size will be de e mined by he s a is ician esponsible o gene a ing he andomiza ion lis and will no be made known o he clinical in es iga o o si e pe sonnel. Consen aking, sc eening and eligibili y c i e ia Demog aphy ques ionnai e, basic heal h sc een, unc ional assessmen , neu opsychological es s, neu oimaging and blood in es iga ions Baseline P e-baseline 12x Weekly sessions A /Music in e en ions Li e as Usual Con ols 9 Mon hs (End) Basic heal h sc een (excluding heigh ), unc ional assessmen , neu opsychological es s and blood in es iga ions Basic heal h sc een (excluding heigh ), unc ional assessmen , neu opsychological es s and neu oimaging. Only A /Music in e en ions unde go blood in es iga ions 3 Mon hs 12x Fo nigh ly sessions Li e as Usual Con ols A /Music in e en ions Fig. 1 Wo k low plan o pa icipan s Mahend an e al. T ials (2017) 18:324 Page 3 o 10 Implemen a ion o he andomiza ion p ocess will be ca ied ou ia a web-based andomiza ion sys em by Singapo e Clinical Resea ch Ins i u e. The andomiza ion sys em will hen de e mine he in e en ion a m and p o ide a unique pa icipa ion numbe o be used o he pa icipan . Deli e y o in e en ions The in e en ions will be deli e ed by ained a and music he apis s. Ac i i ies in each in e en ion is s uc- u ed and planned o he whole s udy pe iod. A he apy The AT ac i i y was de eloped by he eam in consul a ion wi h a he apis s. I will ha e wo componen s: c ea ion o a pieces; and iewing and discussing a pieces wi h na a ion o hough s and inne expe iences. S udies ha e shown ha isual a p oduc ion in e en ions and cogni- i e a e alua ion g oups bene i he indi idual bu in sligh ly di e en ways [27]. Hence, his s udy will include bo h ac i i ies and conside hem as one in e en ion. The guided iewing and making o isual images and alk he apy wi h an a he apis con ibu es o ex e naliza ion o hough s and eelings which may o he wise emain unexp essed. Each weekly session will begin wi h mind ul elaxa ion o help he pa icipan s ocus on he ask ahead. They will be asked o d aw any- hing hey wan o wha hey hink is ele an o he opic o each session. They will hen be asked o sha e abou he pic u e hey ha e c ea ed, eelings, and pe - spec i es, i s in pai s and hen wi h he g oup whe e image app ecia ion ac i i ies will be used o help pa ici- pan s gain insigh s and discuss hei eelings. In addi ion, pa icipan s will isi bo h he Na ional A Galle y and he Na ional Uni e si y o Singapo e A Museum once a mon h in he i s h ee mon hs. They will iew displayed a wo ks in guided sessions and will be in i ed o sha e hei iews and eelings abou he Fig. 2 S anda d P o ocol I ems: Recommenda ion o In e en ional T ials (SPIRIT) igu e: he schedule o en olmen , in e en ions, and assessmen s. Mmon hs, VAS isual analog scale, ADL Ba hel Index (Ac i i ies o Daily Li ing), iADL ins umen al Ac i i ies o Daily Li ing, PDQ Pe cei ed De ici s Ques ionnai e, MMSE Mini-Men al S a e Examina ion, CDR Clinical Demen ia Ra ing, GDS-15 Ge ia ic Dep ession Scale (15-i em), GAI-20 Ge ia ic Anxie y In en o y, MRI unc ional magne ic esonance imaging, ZBI Za i Bu den In en o y Mahend an e al. T ials (2017) 18:324 Page 4 o 10 a e ac s. Each o he AT sessions will las 1 h (inclusi e o 5 min o mind ul elaxa ion and a 15-min b eak). F om he ou h o nin h mon h, o nigh ly AT sessions a e p o ided wi h sessions a he s udy cen e al e na ing wi h sessions a he Na ional A Galle y o Na ional Uni- e si y o Singapo e A Museum. Pa icipan s will isi he A Galle y and A Museum, i s , because he a pieces canno be emo ed om hese places and b ough o he esea ch cen e ; second, wo si es a e in ol ed because nei he one o he si es has su icien docen s o manage he numbe o isi s alone. Wi h wo si es, each si e will hos he pa icipan s’ isi only once a mon h in he i s h ee mon hs and hen in al e na e mon hs o he nex six mon hs. Pa icipan s will be aken o he A Galle y and Museum by coach and will be accompanied by esea ch s a du ing he 15-min jou ney. Con en o he a he apy in e en ion Weekly sessions: Session 1: A and exp ession Session 2: F iendship Session 3: Visi o he NUS A Museum Session 4: Visi o he Na ional A Galle y Session 5: Emo ions and eelings Session 6: Family Session 7: Visi o he NUS A Museum Session 8: Visi o he Na ional A Galle y Session 9: Happiness Session 10: Hopes and wishes Session 11: Visi o he NUS A Museum Session 12: Visi o he Na ional A Galle y Fo nigh ly sessions: Session 13: A ac i i y Session 14: Visi o he NUS A Museum Session 15: A ac i i y Session 16: Visi o he Na ional A Galle y Session 17: A ac i i y Session 18: Visi o he NUS A Museum Session 19: A ac i i y Session 20: Visi o he Na ional A Galle y Session 21: A ac i i y Session 22: Visi o he NUS A Museum Session 23: A ac i i y Session 24: Visi o he Na ional A Galle y Music eminiscence ac i i y Reminiscence he apy wi h music en ails lis ening and discussing ac i i ies, e en s, and expe iences ela ed o he music. Sessions will be p esen ed as music ideos, wi h addi ional p omp s in he o m o pho og aphs, o acili a e he apy. Pa icipan s who ag ee will be asked o b ing 10–20 pho og aphs and also choose songs o music o he ideos. Reminiscence p o okes sha ed eel- ings and boos s sel -es eem while he g oup p ocess p o- ides alida ion o each membe [28]. The s uc u ed ac i i y was p e iously planned by he eam and used e - ec i ely in he ea lie na u alis ic s udy [11]. Pa icipan s will mee weekly o he i s h ee mon hs and hen o nigh ly o six mon hs. As in he AT in e en ion g oup, each session will begin wi h a 5-min mind ul e- laxa ion and he 1-h session will include a 15-min b eak. Con en o he music eminiscence ac i i y Weekly sessions: Session 1: In oduc ion and ice-b eaking session Session 2: Family o o igin Session 3: House/Place I g ew up in Session 4: Childhood Session 5: Childhood games Session 6: School Session 7: My a o i e eache , subjec , classma e Session 8: Occupa ion Session 9: Signi ican e en s/achie emen s Session 10: F iendships Session 11: My bes iend Session 12: Family/Ma iage Fo nigh ly sessions: Session 13: Pa en s/Child en Session 14; Hobbies, spo s and games Session 15: Holidays and a el Session 16: My a o i e place in Singapo e Session 17: Fa o i e ood Session 18: Memo able songs Session 19: Fes i als Session 20: Famous ac o s/singe s Session 21: Rec ea ional places Session 22: Old mo ies Session 23: Fa o i e pa ks Session 24: Te mina ion; g oup discussion Con ol g oup The con ol g oup will no ecei e any in e en ion bu con inue hei li e as usual. S udy se ing Da a collec ion will be done by ained nu ses and esea ch assis an s blinded o he g oup assignmen a a communi y esea ch cen e used by he uni e si y, named he T aining and Resea ch Academy a Ju ong Poin (TaRA@JP). Mahend an e al. T ials (2017) 18:324 Page 5 o 10 Measu es A ques ionnai e on demog aphy will include a basic heal h sc een (weigh , heigh , BP, and PR a baseline and epea ed [wi h he excep ion o heigh ] a h ee and nine mon hs). Func ional assessmen will be done using he Ac i i ies o Daily Li ing (ADL) ques ionnai e and he ins umen al ADL (iADL). Subjec i e cogni i e impai men will be assessed using he Pe cei ed De ici s Ques ionnai e (PDQ). I consis s o 20 ques ions answe ed on a i e-poin Like scale. Sco es ange om 0 o 80, wi h highe sco es indica ing se e e impai men . Cogni i e assessmen s will be done wi h he ollowing alida ed assessmen scales: (1)Mini-Men al S a e Examina ion (MMSE), a b ie 30-poin ques ionnai e, will be used o sc een o cogni i e impai men . Sco es ange om 0 o 30, wi h highe sco es indica ing less impai men ; (2)Clinical Demen ia Ra ing (CDR) Scale is a i e-poin scale used o cha ac e ize six domains o cogni i e and unc ional pe o mance applicable o Alzheime ’s disease and o he demen ias: memo y, o ien a ion, judgmen and p oblem-sol ing, commu- ni y a ai s, home and hobbies, and pe sonal ca e; (3)Neu opsychological es s: (a)Rey Audi o y Ve bal Lea ning Tes (RAVLT) e alua es decla a i e e bal lea ning and memo y; (b)Digi Span Task consis s o a Digi Span Fo wa d (DSF) and Digi Span Backwa d (DSB) and is used o assess a en ion and e bal wo king memo y; (c)Colo T ails Tes (CTT) 1 and 2 assess sus ained a en ion and memo y; (d)Block Design, a sub es o he Wechsle In elligence Tes s, measu es isual–spa ial and o ganiza ional p ocessing abili ies and non- e bal p oblem-sol ing skills. Psychological wellbeing assessmen will be assessed wi h he: (1)Ge ia ic Dep ession Scale (GDS): a 15-i em “yes/ no”ques ionnai e wi h highe o al sco es associa ed wi h highe isk o dep ession; (2)Ge ia ic Anxie y In en o y (GAI): a 20-i em “ag ee/ disag ee”ques ionnai e measu ing dimensional anxie y, wi h highe o al sco es associa ed wi h anxie y symp oms. Pa icipan s wi h high GDS sco e (≥5) and/o high GAI sco e (≥10) will be clinically assessed using he S uc u ed Clinical In e iew o DSM Diso de (SCID) o ule ou majo psychia ic diso de s (e.g. gene alized anxie y diso de o majo dep essi e diso de ). Neu oimaging assessmen o unc ional connec i i y and s uc u e o he b ain Func ional magne ic esonance imaging ( MRI) will be employed o examine changes in unc ional connec i i y. Images will be acqui ed on a 3 T Siemens scanne using a s anda d Siemens whole head coil. Twen y-eigh axial slices (4-mm hick, 1-mm skip) pa allel o he plane connec ing he an e io and pos e io commissu es and co e ing he whole b ain will be imaged using a T2*- weigh ed g adien echo spi al pulse sequence ( epe i ion ime/echo ime = 2000/30 ms; lip angle = 80°; and in e - lea e = 1). The ield o iew will be 200 × 200 mm 2 and he ma ix size 64 × 64, yielding an in-plane iso opic spa ial esolu ion o 3.125 mm. An au oma ed high- o de shimming me hod based on spi al acquisi ions will be used be o e acqui ing MRI scans. All pa icipan s will unde go he ask- ee MRI scan a e being ins uc ed only o emain awake wi h hei eyes closed. Whi e ma e di usion ac og aphy imaging (DTI) will be u ilized o iden i y ana omical connec ions be- ween unc ionally co ela ed egions. Ana omic T1- weigh ed scans will be ob ained on a 3 T Siemens scan- ne wi h he ollowing pa ame e s: epe i ion ime = 2100 ms; lip angle = 12°; slice hickness = 1.5 mm; in e - sion ime = 1100 ms; ma ix = 192 × 256; ield o iew = 172.5 mm; echo ime = 3.87 ms. The DTI will be ac- qui ed in one non-weigh ed and six di usion-weigh ed non-collinea di ec ions wi h an echo-planne sequence wi h di usion weigh ing 9b alue o 1000 smm −1 . A dual spin echo will be used o minimize dis o ion due o eddy cu en s. Imaging pa ame e s a e: epe i ion ime = 6100 ms; lip angle = 90°; ield o iew = 178 × 219; ma ix = 104 × 128; oxel size = 1.71 × 1.71. × 4 mm; numbe o a e ages = 4; echo ime = 92 ms. The con ol g oup will do baseline ques ionnai es and in es iga ions simila o pa icipan s in he wo in e en- ion a ms. They will do he neu oimaging a baseline and h ee mon hs as well as he o he in es iga ions, simila o hose in he wo in e en ion a ms. The only di e ence is he con ol g oup will no ha e blood sam- ples aken a h ee mon hs. The MRI scanning will be ask- ee. I is non-in asi e and does no in ol e any injec ion o ace dyes. Ca egi e s will be asked o comple e he Za i Bu den Scale a baseline, h ee mon hs, and nine mon hs. This is op ional and ca egi e s can choose no o comple e his scale and his will ha e no impac on subjec pa ici- pa ion. Ca egi e s will be asked o comple e a po ion o he Clinical Demen ia Ra ing a baseline (i hey a e p esen o a ailable) (Fig. 2). Rec ui men Pa icipan s will be ec ui ed om amongs elde ly indi- iduals li ing a ound TaRA@JP and known o he esea ch Mahend an e al. T ials (2017) 18:324 Page 6 o 10 cen e . Only pa icipan s who ag eed o be con ac ed o u u e esea ch and known o ha e ea ly cogni i e impai - men will be con ac ed by phone and in i ed o pa icipa e in he cu en s udy. O he s who ha e hea d abou he s udy will be e- c ui ed i hey mee inclusion c i e ia and eside wi hin close p oximi y o he esea ch si e (TaRA@JP) o a el a angemen s. They will be in o med o he s udy and p o ided wi h a copy o he in i a ion le e and pa icipan in o ma ion shee –bo h English and Manda in e sions will be made a ailable o hem. They will be gi en ime o ead he documen in a p i a e a ea a TaRA@JP and gi en ime o conside whe he o ag ee o pa icipa e in he s udy. Nu ses will in e p e o ally o hose who a e illi e a e and o hose who do no unde s and English. A Sho Consen Fo m (Manda in) will be used o he pa ici- pan ’s signa u e (o humb p in ) and an impa ial wi - ness will be p esen and sign he documen as well. I a ansla o is in ol ed in he consen aking, he/she will also sign he consen o m. Ou comes P ima y ou come measu es: 1. Imp o emen s in neu opsychological es sco es a h ee mon hs and nine mon hs; 2. Posi i e changes in ce eb al unc ioning a h ee mon hs. Seconda y ou come measu es: 1. Imp o emen in GDS and GAI sco es a h ee mon hs and nine mon hs; 2. Inc ease in elome e leng hs a h ee mon hs and nine mon hs. Sample size jus i ica ion To ob ain he con idence in e al wi h he wid h o 1 s anda d de ia ion (SD), which has a 90% chance o include he ue di e ence o mean change in neu o- psychological es sco e a h ee mon hs be ween he in e en ion and con ol g oups, equi es 22 pa icipan s in each g oup. By conside ing he 25% d op-ou a e, 30 pa icipan s will be equi ed in each g oup. Thus, he o al sample size will be 90 pa icipan s (30 in he AT in e en- ion g oup, 30 in MRA, and 30 in he con ol g oup). Assessmen s and isi schedule P e-baseline Sc eening, consen aking, and eligibili y c i e ia a e checked. Those wi h high GDS/GAI sco es will go h ough a SCID examina ion o e alua e he p esence o a majo psychia ic diso de . This willbedonebypsychia is sin he s udy eam who ha e been ained o do his examin- a ion. Any pa icipan s ound o ha e a psychia ic diso de h ough he SCID examina ion will be e e ed o ollow- up by a medical p o essional. A s anda d e e al le e has been p epa ed. Baseline Demog aphy ques ionnai e, basic heal h sc een, unc- ional assessmen , neu opsychological es s, neu oimag- ing, and blood in es iga ions a e ca ied ou . Th ee mon hs Basic heal h sc een (excluding heigh ), unc ional assess- men , neu opsychological es s, neu oimaging, and blood in es iga ions a e epea ed. Nine mon hs (s udy end) Basic heal h sc een (excluding heigh ), unc ional assess- men , neu opsychological es s, and blood in es iga ions a e epea ed. The ime aken o he heal h sc eening, comple ion o he demog aphic da a, main ques ionnai e, and blood sample collec ion will ake abou 1 h. The neu opsychological es s will ake abou 1 h 45 min. The baseline isi o TaRA@JP will ake abou 3 h. Subse- quen isi s a h ee mon hs and nine mon hs will ake 2 h. The MRI scans will be conduc ed a CIRC in NUS and he appoin men will be on ano he day. The im- aging sessions will ake 1 h. Howe e , he ime wi hin he scanne is abou 45 min. See Tables 1 and 2 o he isi schedules o he in e - en ions and con ol g oups, espec i ely. Blood samples (3 mL) will be collec ed a h ee ime- poin s o hose in he AT and MRA a ms (baseline, h ee mon hs, nine mon hs) o elome e leng hs. Fo he con ol g oup, i will be done wice, a baseline and a nine mon hs. Samples will be s o ed immedia ely in a mini- idge (4 °C) a TaRA@JP and anspo ed wi hin 12 h o col- lec ion o he labs. Risks and sa e y moni o ing Risks include some pain and b uising du ing blood sam- pling. To minimize isks associa ed wi h he blood, sam- pling only one enipunc u e will be pe o med a each o he h ee ime-poin s and blood will be collec ed using acu aine s. T ained nu ses will pe o m he p ocedu e. Some may expe ience some discom o om he noise and he enclosed space wi hin he scanne . Pa icipan s will be in o med abou he noise and ea plugs will be p o ided. I he noise is in ole able and he pa icipan wishes o discon inue wi h he scanning, he scanning will be s opped. Mahend an e al. T ials (2017) 18:324 Page 7 o 10 Da a managemen Da a o ms will be coded wi h a s udy numbe (s a ing wi h 001). Da a will be en e ed and s o ed on a s anda- lone compu e and he in o ma ion will be passwo d p o ec ed. Only he p incipal in es iga o , in es iga o s, and s udy coo dina o in he p ojec will ha e access o he da a o analysis. In acco dance wi h NUS da a man- agemen policy (DPRT-2011-04), da a will be kep o en yea s a e he esea ch is comple ed and all da a (elec onic and ha d copy) will be des oyed a e he s o age pe iod. The in es iga o s and he ial coo dina o s will moni o ha he in o med consen p ocess is conduc ed app op i- a ely and ha in o med consen was ob ained p io o p oceeding wi h any s udy p ocedu es. Only pa icipan s who mee s udy eligibili y c i e ia will be en olled. Pa icipan s’da a will be iden i ied only by a s udy num- be . Only he p incipal in es iga o will ha e access o iden i ie s ha can link he da a o he indi idual pa ici- pan . De-iden i ied da a will be collec ed and analyzed as speci ied in he p o ocol. Pa icipan s who d op ou will be no ed and hei easons documen ed. P ima y and seconda y end-poin s will be e iewed o ensu e da a a e co ec ly en e ed and mee p o ocol equi emen s. S a is ical analyses All e icacy analyses will be ca ied ou on an in en ion- o- ea (ITT) basis. Tha is, all andomized pa icipan s will be included in he analysis and he in e en ion g oup o pa icipan s will be acco ding o he andomiza ion lis planned p io o he in e en ion commencemen . The p ima y ou comes –neu opsychological es sco es –a baseline, h ee mon hs, and nine mon hs will be modeled using he linea mixed model o epea ed measu emen s. Di e ences in he es ima ed means o he changes a h ee and nine mon hs om baseline be ween he in e en ion and con ol g oups and hei associa ed 90% and 95% con idence in e als will be calcula ed. Fu he , analysis may be pe o med o adjus he model o po en ial con ounde s, such as age, gende , and educa ion le el. Seconda y ou comes (ce eb al unc ioning, he GDS and GAI sco es, and elome e leng hs) will be analyzed simila o he p i- ma y ou comes. Demog aphic and o he baseline cha ac e is ics and epo ed ad e se e en s and se ious ad e se e en s will be summa ized using desc ip i e s a is ics. Discussion A and music ac i i ies ha e been desc ibed as “empow- e ing ools ha can assis in he aging p ocess”[29]. E i- dence sugges s ha aining in hese a eas s eng hen a en ion sys ems and imp o e cogni ion. Howe e , he esea ch o da e is s ill limi ed on he e ec i eness o inco po a ing hese ac i i ies as pa o ca e plans o he elde ly wi h cogni i e impai men . Fu he mo e, i is unlikely ha hese ac i i ies will “always imp o e gene al cogni ion”[30]. This s udy will mo e sys ema ically de- e mine whe he bo h hese ac i i ies will be o bene i o elde ly wi h mild cogni i e impai men and will p o ide addi ional psychosocial in e en ions ha will be o use o his g oup. T ial s a us a he ime o manusc ip submission The ec ui men commenced in 13 June 2016 and he ial will end in Ap il 2017. Addi ional ile Addi ional ile 1: SPIRIT Checklis . Recommended i ems o add ess in a clinical ial p o ocol and ela ed documen s. (PDF 122 kb) Table 1 Visi schedule o in e en ion a ms P e-baseline/Baseline Th ee mon hs Nine mon hs (s udy end) In o med consen p ocess Main ques ionnai e Main ques ionnai e Eligibili y sc eening Neu opsychological es s Neu opsychological es s Demog aphic da a MRI scan Clinical Demen ia Ra ing Main ques ionnai e Weigh , i al Signs Weigh , i al signs Neu opsychological es s Blood sample collec ion Blood sample collec ion Clinical Demen ia Ra ing MRI scan Basic heal h sc een Blood sample collec ion Table 2 Visi schedule o con ols P e-baseline/Baseline Th ee mon hs Nine mon hs (s udy end) In o med consen p ocess Main ques ionnai e Main ques ionnai e Eligibili y sc eening Neu opsychological es s Neu opsychological es s Main ques ionnai e MRI scan Clinical Demen ia Ra ing Demog aphic da a Weigh , i al signs Weigh , i al signs Neu opsychological es s Blood sample collec ion Clinical Demen ia Ra ing MRI scan Basic heal h sc een Blood sample collec ion Mahend an e al. T ials (2017) 18:324 Page 8 o 10 Abb e ia ions ADL: Ac i i ies o Daily Li ing; CDR: Clinical Demen ia Ra ing; CTT: Colo T ail Tes ; DSB: Digi Span Backwa d; DSF: Digi Span Fo wa d; DTI: Di usion ac og aphy imaging; MRI: Func ional magne ic esonance imaging; GAI: Ge ia ic Anxie y In en o y; GDS: Ge ia ic Dep ession Scale; IADL: Ins umen al Ac i i ies o Daily Li ing; MCI: Mild cogni i e impai men ; MMSE: Mini-Men al S a e Examina ion; PDQ: Pe cei ed De ici s Ques ionnai e; RAVLT: Rey Audi o y Ve bal Lea ning Tes ; SCID: S uc u ed Clinical In e iew o DSM Diso de ; TaRA@JP: T aining and Resea ch Academy a Ju ong Poin Acknowledgemen s No applicable. Funding This ial is unded by a dona ion g an om he Kwan Im Thong Cho Temple (Kwan Im Choo Thong Cho Temple Elde ly Dep ession P e en ion P ojec N-177-000-004-001). The unding o ganiza ion p o ided a lump sum unding o esea ch and does no e iew any esea ch p o ocols. A ailabili y o da a and ma e ials No applicable. Au ho s’con ibu ions RM, IR, JF, LF, and EHK designed he s udy. Funding o he s udy was secu ed by EHK. Telome e labo a o y wo k is supe ised by APK. The neu oimaging pa o he s udy was done by JF. Ad ice on s udy design and s a is ics and andomiza ion was p o ided by MG and JX. The li e a u e sea ch and o ma ing o he manusc ip was done by JW. RM, IR, MG, and JX d a ed he manusc ip . All au ho s commen ed on he inal d a and app o ed he inal manusc ip . Au ho s’in o ma ion No applicable. E hical app o al and consen o pa icipa e This s udy p o ocol was ully e iewed by he E hics Boa d o he Na ional Uni e si y o Singapo e Ins i u ional Re iew Boa d (NUS-IRB Re Code: B-16-095) and he app o al was da ed 6 June 2016. W i en in o med consen is ob ained om e e y pa icipan and con iden iali y s ic ly main ained. All da a will be anonymized and main ained acco ding o E hics Boa d guidelines. Consen o publica ion No applicable. Compe ing in e es s The au ho s decla e ha hey ha e no compe ing in e es s. Publishe ’sNo e Sp inge Na u e emains neu al wi h ega d o ju isdic ional claims in published maps and ins i u ional a ilia ions. Au ho de ails 1 Depa men o Psychological Medicine, Yong Loo Lin School o Medicine, Na ional Uni e si y o Singapo e, Singapo e, Republic o Singapo e. 2 Depa men o Psychological Medicine, Na ional Uni e si y Hospi al, Towe Block, Le el 9, 1E Ken Ridge Road, Singapo e, Republic o Singapo e. 3 Duke-NUS Medical School, Singapo e, Republic o Singapo e. 4 Cance Science Ins i u e o Singapo e, Na ional Uni e si y o Singapo e, 14 Medical D i e, Singapo e, Republic o Singapo e. 5 Depa men o Pha macology, Yong Loo Lin School o Medicine, Na ional Uni e si y o Singapo e, 21 Lowe Ken Ridge Road, Singapo e, Republic o Singapo e. 6 Cu in Heal h Inno a ion Resea ch Ins i u e, Biosciences Resea ch P ecinc , School o Biomedical Sciences, Facul y o Heal h Sciences, Cu in Uni e si y, Ken S ee , Ben ley, Pe h, Wes e n Aus alia, Aus alia. 7 Depa men o Biological Sciences, Uni e si y o No h Texas, 1511 W Sycamo e, Den on, TX, USA. 8 Depa men o Bios a is ics, Singapo e Clinical Resea ch Ins i u e, Singapo e, Republic o Singapo e. 9 Cen e o Quan i a i e Medicine, O ice o Clinical Sciences, Duke-NUS Medical School, Singapo e, Republic o Singapo e. 10 Tampe e Cen e o Child Heal h Resea ch, Uni e si y o Tampe e and Tampe e Uni e si y Hospi al, Tampe e, Finland. 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