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
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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.
Recei ed: 1 Decembe 2016 Accep ed: 3 July 2017
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