Jou nal o Pa kinson’s Disease 13 (2023) 219–231
DOI 10.3233/JPD-225014
IOS P ess
219
Resea ch Repo
Changes in P incipal Ca egi e Mood
A ec s he Mood o he Pa kinson’s Disease
Pa ien : The Vicious Cycle o Illness
Diego San os-Ga c´
ıaa,∗, Te esa de Deus Fon icobab, Ca los Co es Ba olom´
ea, Ma ia J. Feal
Paincei asa, Ma ia C is ina ´
I˜
niguez-Al a adoa, Iago Ga c´
ıa D´
ıaza, Sil ia Jes´
usc,d, Ma ia Te esa
Buongio noe, Llu´
ıs Planellas , Ma ina Cosgayag, Juan Ga c´
ıa Calden eyh, Nu ia Caballoli, Ines
Lega daj, Jo ge He n´
andez Va ad,k, I ia Cabol, Lydia L´
opez Manzana esm, Isabel Gonz´
alez
A ambu ud,n, Ma ia A. ´
A ila Ri e ao,V
´
ıc o G´
omez Mayo domop,V
´
ıc o Noguei aq,V
´
ıc o
Puen e , Julio Do o Ga c´
ıa-So os, Ca men Bo u´
e , Be a Solano Vilau, Ma ´
ıa ´
Al a ez Sauco , Lydia
Velaw, Sonia Escalan ex, Es he Cuboy, F ancisco Ca illo Padillaz, Juan C. Ma ´
ınez Cas illoaa,
Pila S´
anchez Alonsobb, Ma ia G. Alonso Losadacc, Nu ia L´
opez A iz eguidd, I zia Gas ´
onee, Jaime
Kulise skyd, , Manuel Men´
endez Gonz´
alezgg, Manuel Seijol, Ja ie R´
uiz Ma ´
ınezhh, Ca idad
Vale oii,M
´
onica Ku isjj, Jessica Gonz´
alez A du akk, Ruben Alonso Redondoll, Ca los O d´
asmm,
Luis M. L´
opez D´
ıazcc, Da ian McA eenn, Pablo Ma inez-Ma ind, Pablo Mi d,cand COPPADIS
S udy G oup1
aCHUAC, Complejo Hospi ala io Uni e si a io de A Co u˜na, A Co u˜na, Spain
bCHUF, Complejo Hospi ala io Uni e si a io de Fe ol, A Co u˜na, Spain
cUnidad de T as o nos del Mo imien o, Se icio de Neu olog´ıa y Neu ofisiolog´ıa Cl´ınica, Ins i u o de Biomedic-
ina de Se illa, Hospi al Uni e si a io Vi gen del Roc´ıo/CSIC/Uni e sidad de Se illa, Se ille, Spain
dCIBERNED (Cen o de In es igaci´on Biom´edica en Red En e medades Neu odegene a i as), Spain
eHospi al Uni e si a i Mu ua de Te assa, Te assa, Ba celona, Spain
Cl´ınica del Pila , Ba celona, Spain
gHospi al Cl´ınic de Ba celona, Ba celona, Spain
hCen o Neu ol´ogico Oms 42, Palma de Mallo ca, Spain
iConso ci Sani a i In eg al, Hospi al Mois´es B oggi, San Joan Desp´ı, Ba celona, Spain
jHospi al Uni e si a io Son Espases, Palma de Mallo ca, Spain
kHospi al Uni e si a io Vall d´Heb on, Ba celona, Spain
lComplejo Hospi ala io Uni e si a io de Pon e ed a (CHOP), Pon e ed a, Spain
mHospi al Uni e si a io La P incesa, Mad id, Spain
nHospi al Uni e si a io Ma qu´es de Valdecilla, San ande , Spain
oConso ci Sani a i In eg al, Hospi al Gene al de L´Hospi ale , L´Hospi ale de Llob ega , Ba celona, Spain
1See he Supplemen a y Ma e ial o ull de ails.
∗Co espondence o: D . Diego San os Ga c´
ıa, Depa men o
Neu ology, Hospi al Uni e si a io de A Co u˜
na (HUAC), Com-
plejo Hospi ala io Uni e si a io de A Co u˜
na (CHUAC), C/ As
Xubias 84, 15006, A Co u˜
na, Spain. Tel.: +34 646173341; E-mail:
[email p o ec ed].
ISSN 1877-7171 © 2023 – The au ho s. Published by IOS P ess. This is an Open Access a icle dis ibu ed unde he e ms
o he C ea i e Commons A ibu ion-NonComme cial License (CC BY-NC 4.0).
220 D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness
pHospi al Uni e si a io Cl´ınico San Ca los, Mad id, Spain
qHospi al Da Cos a, Bu ela, Lugo, Spain
Hospi al del Ma , Ba celona, Spain
sHospi al Uni e si a io Vi gen Maca ena, Se illa, Spain
Hospi al In an a So ´ıa, Mad id, Spain
uIns i u d’Assis `encia Sani `a ia (IAS) - Ins i u Ca al`a de la Salu , Gi ona, Spain
Hospi al Gene al Uni e si a io de Elche, Elche, Spain
wFundaci´on Hospi al de Alco c´on, Mad id, Spain
xHospi al de To osa Ve ge de la Cin a (HTVC), To osa, Ta agona, Spain
yComplejo Asis encial Uni e si a io de Bu gos, Bu gos, Spain
zHospi al Uni e si a io de Cana ias, San C is ´obal de la Laguna, San a C uz de Tene i e, Spain
aaHospi al Uni e si a io Ram´on y Cajal, IRYCIS, Mad id, Spain
bbHospi al Uni e si a io Pue a de Hie o, Mad id, Spain
ccHospi al ´
Al a o Cunquei o, Complejo Hospi ala io Uni e si a io de Vigo (CHUVI), Vigo, Spain
ddComplejo Hospi ala io de Toledo, Toledo, Spain
eeComplejo Hospi ala io de Na a a, Pamplona, Spain
Hospi al de San Pau, Ba celona, Spain
ggHospi al Uni e si a io Cen al de As u ias, O iedo, Spain
hhHospi al Uni e si a io Donos ia, San Sebas i´an, Spain
iiHospi al A nau de Vilano a, Valencia, Spain
jjHospi al Rube In e nacional, Mad id, Spain
kkHospi al de Cabue˜nes, Gij´on, Spain
llUni e si a io Lucus Augus i (HULA), Lugo, Spain
mmHospi al Rey Juan Ca los, Mad id, Spain, Mad id, Spain
nnUni e si y o Ma yland School o Medicine, Bal imo e, MD, USA
Accep ed 19 Decembe 2022
P e-p ess 14 Janua y 2023
Published 14 Ma ch 2023
Abs ac .
Backg ound: Al hough many s udies ha e analyzed wha ac o s con ibu e o ca egi e bu den in Pa kinson’s disease (PD),
he e is cu en ly no knowledge abou how he s a us o he ca egi e could impac he pa ien .
Objec i e: The aim o his s udy was o analyze how he change in he ca egi e ’s s a us in luences PD pa ien s.
Me hods: PD pa ien s and hei ca egi e s who we e ec ui ed om Janua y/2016 o No embe /2017 om 35 cen e s
in Spain om he COPPADIS coho we e included in he s udy (V0). They we e e alua ed again a 2-yea ollow-up
(V2). Ca egi e s comple ed he Za i Ca egi e Bu den In en o y (ZCBI), Ca egi e S ain Index (CSI), Beck Dep es-
sion In en o y-II (BDI-II), and EUROHIS-QOL 8-i em index (EUROHIS-QOL8) a V0 and V2. Mul i a ia e models we e
used o analyze he impac o he change om V0 o V2 () on he ca egi e ’s s a us o e he change in he pa ien ’s
s a us.
Resul s: BDI-II and EUROHIS-QOL8 in he ca egi e p edic ed BDI-II (␤= 0.32; p< 0.0001; R2= 0.71) and
EUROHIS-QOL8 (␤= 0.39; p< 0.0001; R2= 0.68) in he pa ien , espec i ely. Va iables ela ed o he ca egi e we e
no associa ed wi h changes in he pa ien ´s heal h- ela ed QoL (PDQ-39 [39-i em Pa kinson’s disease Ques ionnai e]) o
au onomy o ac i i ies o daily-li ing (ADLS [Schwab & England Ac i i ies o Daily Li ing Scale]).
Conclusion: The change in he ca egi e ’s mood and global QoL was associa ed wi h he change in he pa ien ’s mood and
global QoL, espec i ely, independen ly o o he a iables o he disease in luencing bo h pa ien ´s aspec s. Based on his
inding, i could be o g ea impo ance o de ec dep ession in he p incipal ca egi e o a pa ien and ac on i as ea lie as
possible.
Keywo ds: Ca egi e , longi udinal, mood, Pa kinson’s disease, quali y o li e
D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness 221
INTRODUCTION
Pa kinson’s disease (PD) is a p og essi e neu ode-
gene a i e diso de causing mo o and non-mo o
symp oms (NMS) ha esul in loss o pa ien au on-
omy o ac i i ies o daily-li ing (ADL) and quali y
o li e (QoL) [1]. Gi en ha symp oms p og es-
sion wi h longe disease du a ion leads o a loss o
independence, he majo i y o pa ien s ha e a p in-
cipal ca egi e esponsible o ca e h oughou he
cou se o he disease. Howe e , PD symp oms impac
no only he pa ien bu on he p incipal ca egi e
oo and can cause s ess, bu den, dep ession, and
a wo se QoL [2]. Pe sis en ca egi e bu den may
lead o s ain, an endu ing change in he ca egi e ’s
sense o well-being ha p edisposes o bu nou [3].
Symp oms associa ed wi h ca egi e bu den ha e
been iden i ied in di e en s udies, such as cogni i e
impai men , apa hy, i i abili y, sleep diso de s, alls,
disabili y, and mo e ad anced s age disease, among
o he s [2–15]. S ill, he e is no knowledge abou how
he s a us o he ca egi e impac s on he pa ien .
This is an impo an associa ion because an o e -
wo ked ca egi e migh ake wo se ca e o he pa ien
o ha e beha io changes (e.g., dep ession, i i abil-
i y, e c.) ha could nega i ely in luence he pa ien
di ec ly, es ablishing a icious cycle; he wo se he
pa ien ’s condi ion, he wo se he ca egi e ’s con-
di ion, and ice e sa. In his con ex , i would be
especially use ul o analyze how he longi udinally
changes expe ienced by he ca egi e can impac on
he PD pa ien .
Recen ly, we published he la ges (N = 192) and
longes (2-yea ollow-up) p ospec i e s udy in which
p edic o s o a change in bu den, s ain, mood, and
QoL in he p incipal ca egi e o PD pa ien s we e
iden i ied [16]. Mood changes in he pa ien we e
he main ac o s a ec ing mood in he ca egi e
and mood changes in he ca egi e was iden i ied
as he main ac o impac ing on s ain, bu den and
QoL o he ca egi e . We hypo hesized ha changes
in he s a us o he ca egi e migh in luence he
pa ien (Fig. 1). Unde his app oach, he aim o he
p esen s udy was o analyze i a change in mood
(BDI-II [Beck Dep ession In en o y-II]), bu den
(ZCBI [Za i Ca egi e Bu den In en o y]), s ain
(CSI [Ca egi e S ain Index]), and/o global QoL
(EUROHIS-QOL8 [EUROHIS-QOL 8-i em index])
o he p incipal ca egi e o a pa ien wi h PD a e
a 2-yea ollow-up was associa ed wi h changes in
he pa ien ’s mood (BDI-II), au onomy o ADL
(ADLS [Schwab & England Ac i i ies o Daily
Li ing Scale]), heal h- ela ed QoL (PDQ-39 [39-
i em Pa kinson’s disease Ques ionnai e], and global
QoL (EUROHIS-QOL8), independen ly o o he PD
ela ed ac o s. In o he wo ds, he goal was o de e -
mine i a wo se s a us o he ca egi e impac s on
he pa ien . Mo e impo an ly, his would jus i y he
necessi y o iden i y and ea o e wo ked ca egi e s
as soon as possible, as has been p e iously sugges ed
[3].
MATERIALS AND METHODS
PD pa ien s and hei ca egi e s, who we e
ec ui ed om 35 cen e s in Spain om he COP-
PADIS coho [17] om Janua y 2016 o No embe
2017 and e alua ed again a 2-yea ollow-up,
we e included in he s udy. Me hodology abou
COPPADIS-2015 s udy can be consul ed a h ps://
bmcneu ol.biomedcen al.com/a icles/10.1186/s128
83-016-0548-9 [18]. This is a mul i-cen e , obse -
a ional, longi udinal-p ospec i e, 5-yea ollow-up
s udy designed o analyze disease p og ession in a
Spanish popula ion o PD pa ien s. All he pa ien s
included we e diagnosed acco ding o UK PD B ain
Bank c i e ia [19]. The p incipal ca egi e [20] o
he pa ien was included i he pa ien had a ca egi e
who olun a ily ag eed o pa icipa e and sign an
in o med consen . Pa ien s had o ha e e ained he
same p ima y ca egi e a bo h ime poin s o be
included in his analysis.
PD pa ien assessmen
In PD subjec s, in o ma ion on sociodemog aphic
aspec s, ac o s ela ed o PD, como bidi y, and ea -
men was collec ed a baseline ( isi V0) and a
2 yea s ±1 mon h ( isi V2). V0 and V2 e alu-
a ions included mo o assessmen (Hoenh & Yah
[H&Y], Uni ied Pa kinson’s Disease Ra ing Scale
[UPDRS] pa III and pa IV, F eezing o Gai
Ques ionnai e [FOGQ]), NMS (Non-Mo o Symp-
oms Scale [NMSS], Pa kinson’s Disease Sleep
Scale [PDSS], Visual Analog Scale-Pain [VAS-Pain],
Visual Analog Fa igue Scale [VAFS]), cogni ion
(PD-CRS), mood and neu opsychia ic symp oms
(BDI-II, Neu opsychia ic In en o y [NPI], Ques-
ionnai e o Impulsi e-Compulsi e Diso de s in
Pa kinson’s Disease-Ra ing Scale [QUIP-RS]), dis-
abili y (ADLS), and heal h- ela ed (PDQ-39) and
global QoL (EUROHIS-QOL8) [18]. In all he
scales/ques ionnai es a highe sco e indica es a mo e
222 D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness
Fig. 1. Hypo hesis p oposed in his s udy. Rega ding p e ious da a published om he COPPADIS coho [16], pa ien ’s mood is he main
ac o in luencing ca egi e ’s mood and ca egi e ’s mood he main ac o in luencing ca egi e ’s bu den, s ain and QoL. The ques ion
(ques ion ma k) is i he change in he long- e m o hese ca egi e ’s a iables can impac o e he change in pa ien ’s a iables (mood, QoL
and au onomy o ADL). ADL, ac i i ies o daily li ing; ADLS, Schwab & England Ac i i ies o Daily Li ing Scale; CSI, Ca egi e S ain
Index; EUROHIS-QOL8, EUROHIS-QOL 8-i em index; PD, Pa kinson’s disease; PDQ-39, 39-i em Pa kinson’s disease Ques ionnai e;
QoL, quali y o li e; ZCBI, Za i Ca egi e Bu den In en o y.
se e e a ec a ion apa om PD-CRS, PDSS, ADLS,
and EUROHIS-QOL8, which we e he opposi e. In
pa ien s wi h mo o luc ua ions, he mo o assess-
men was made du ing he OFF s a e (wi hou
medica ion in he las 12 hou s) and du ing he ON
s a e. The assessmen was only pe o med wi hou
medica ion in pa ien s wi hou mo o luc ua ions.
Ca egi e assessmen
In ca egi e s, sociodemog aphic da a we e col-
lec ed a baseline [16]. Fou aspec s we e analyzed in
he ca egi e a V0 and a V2: mood (BDI-II); bu den
(ZCBI); s ain (CSI); and global QoL (EUROHIS-
QOL8). ZCBI [21] con ains 22 i ems ha a e he
impac o he disease on he ca egi e ’s physical,
emo ional, and socioeconomic s a us. Responses a e
sco ed on a scale om 0 (ne e ) o 4 (nea ly always).
The maximum o al sco e, indica i e o he highes
bu den, is 88. CSI [22] is a 13-i em ques ionnai e
designed o assess he le el o s ess expe ienced by
ca egi e s. The e a e wo possible esponses o each
i em: “yes” o “no”. The o al sco e is he esul o
adding all posi i e esponses ( om 0, no s ess, o
13, maximum le el o s ess). Mood was assessed
wi h he BDI-II [23]. This is a sel -adminis e ed,
21 i em ins umen . I has been designed o assess
he se e i y o dep ession symp oms in adul s and
adolescen s wi h a minimum age o 13 yea s. The
e alua ed subjec mus choose one o ou al e na-
i es (o de ed om lesse o g ea e se e i y), in each
i em, ha bes desc ibes his/he s a us o e he p e i-
ous wo weeks. The sco e anges om 0 (minimum)
o 63 (maximum). Highe sco es will e lec , a p io i,
a wo se mood. Finally, global QoL was measu ed
wi h he EUROHIS-QOL8 [24]. This is an 8-i em
QoL ques ionnai e (QoL, heal h s a us, ene gy, au on-
omy in ac i i ies o daily li ing [ADL], sel -es eem,
social ela ionships, economic capaci y, and habi a )
de i ed om he WHOQOL-100 and he WHOQOL-
BREF. Fo each i em, he sco e anges om 0 (no a
all) o 5 (comple ely). The o al sco e is exp essed
as he mean o he indi idual sco es. A highe sco e
indica es a highe QoL.
D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness 223
Table 1
Co ela ion be ween he change in he s age o he p incipal ca egi e (mood, bu den, s ain and QoL) and he change in he s age o he
pa ien (mood, au onomy o ADL, and QoL) om baseline isi (V0) o 2-yea ollow-up isi (V2)
V2 – V0 BDI-IIcZCBIcCSIcEUROSHIS-QOL8c
BDI-IIcN. A 0.42 (p< 0.0001) 0.39 (p< 0.0001) –0.35 (p< 0.0001)
ZCBIc0.42 (p< 0.0001) N. A. 0.55 (p< 0.0001) –0.34 (p< 0.0001)
CSIc0.39 (p< 0.0001) 0.55 (p< 0.0001) N. A. –0.31 (p< 0.0001)
EUROHIS-QOL8c–0.35 (p< 0.0001) –0.34 (p< 0.0001) –0.31 (p< 0.0001) N. A.
BDIp0.39 (p< 0.0001) 0.19 (p= 0.007) 0.18 (p= 0.010) –0.23 (p= 0.001)
ADLSp–0.08 (p= 0.271) –0.18 (p= 0.012) –0.14 (p= 0.042) 0.09 (p= 0.184)
PDQ-39p0.15 (p= 0.037) 0.13 (p= 0.065) 0.10 (p= 0.163) 0.02 (p= 0.740)
EUROHIS-QOL8p–0.08 (p= 0.231) –0.03 (p= 0.629) –0.10 (p= 0.156) 0.39 (p< 0.0001)
Spea man co ela ion coe icien was applied ( and p alue a e shown). ADLS, Schwab & England Ac i i ies o Daily Li ing Scale; BDI-II,
Beck Dep ession In en o y-II; CSI, Ca egi e S ain Index; PDQ-39, he ZCBI, Za i Ca egi e Bu den In en o y; QoL, quali y o li e. C in
subsc ip , ca egi e (i.e., BDI-IIc, change om V0 o V2 in he BDI-II sco e, e c.); P in subsc ip , pa ien .
Da a analysis
Da a we e p ocessed using SPSS 20.0 o Win-
dows. Only PD pa ien s and hei ca egi e s ( he same
ca egi e a e he 2-yea ollow-up) om he COP-
PADIS coho wi h da a o he BDI-II, ZCBI, CSI, and
EUROHIS-QOL8 collec ed a bo h isi s, V0 and V2,
we e included in he analysis [16].
Wi h he aim o know he in luence o he change
om V0 o V2 o ca egi e ’s a iables o e he
change in mood, QoL, and au onomy o ADL in he
PD pa ien , linea eg ession models we e conduc ed.
The change in each a iable om he pa ien and he
ca egi e was calcula ed as he di e ence be ween
he alue a V2 and a V0 (i.e., BDI-II = BDI-IIV2
– BDI-IIV0). In all he models, he ou ca egi e ’s
a iables we e included (BDI-II; ZCBI; CSI;
EUROHIS-QOL8). Fou models we e de ined as
ha ing an aspec o he pa ien o analyze as a
dependen a iable: 1) Model 1, change in mood
(BDI-II); 2) Model 2, change in heal h- ela ed
QoL (PDQ-39); 3) Model 3, change in global QoL
(EUROHIS-QOL8); 4) Model 4, change in au on-
omy o ADL (ADLS). Co a ia es om he pa ien
included in he models we e he change om V0 o
V2 () in LEDD [25], UPDRS-III-OFF, UPDRS-IV,
FOGQ, PD-CRS, NMSS, BDI-II (excep in Model 1
o being he dependen a iable), PDSS, QUIP-RS,
NPI, VAS-PAIN, VAFS, ADLS (excep in Model 4
o being he dependen a iable), PDQ-39 (excep
in Model 2 o being he dependen a iable), and
EUROHIS-QOL8 (excep in Model 3 o being he
dependen a iable). Each model was adjus ed o he
alue o he dependen a iable a baseline oo. Tol-
e ance and a iance in la ion ac o (VIF) we e used
o de ec mul icollinea i y. Mul icollinea i y was con-
side ed p oblema ic when ole ance was less han 0.2
and, simul aneously, he alue o VIF was 10 and
abo e. Spea man’s o Pea son’s co ela ion coe i-
cien we e also used as app op ia e (dis ibu ion o
a iables was e i ied by a one-sample Kolmogo o -
Smi no es ). Co ela ions we e conside ed weak
o coe icien alues ≤0.29, mode a e o alues
be ween 0.30 and 0.59, and s ong o alues ≥0.60.
The p- alue was conside ed signi ican (highly sig-
ni ican ) when i was <0.001.
S anda d p o ocol app o als, egis a ions, and
pa ien consen s
Fo his s udy, we ecei ed app o al om he
Comi ´ede ´
E ica de la In es igaci´on Cl´ınica de
Galicia om Spain (2014/534; 02/DEC/2014). W i -
en in o med consen s om all pa icipan s in his
s udy we e ob ained. COPPADIS-2015 was classi ied
by he AEMPS (Agencia Espa˜
nola del Medica-
men o y P oduc os Sani a ios) as a Pos -au ho iza ion
P ospec i e Follow-up s udy wi h he code COH-
PAK-2014-01.
Da a a ailabili y
The p o ocol and he s a is ical analysis plan a e
a ailable on eques . Deiden i ied pa icipan da a a e
no a ailable o legal and e hical easons.
RESULTS
The s udy included one hund ed and nine y- wo
PD pa ien s (63.96 ±8.74 yea s old; 63% males) and
hei p incipal ca egi e . The mean age o he ca e-
gi e s was 58.82 ±11.71 yea s old, and 69.3% we e
emales. Clinical and sociodemog aphic de ails o
pa ien s and ca egi e s ha e been ecen ly published
[16] and a e shown in Supplemen a y Table 1.

224 D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness
Table 2
E ec o changes in he ca egi e o e he change in mood in PD pa ien s om he COPPADIS
coho a e 2-yea ollow-up (N = 192)
Uni a ia e analysis Mul i a ia e analysis
␤95% CI p␤95% CI p
Ca egi e
BDI-II 0.42 0.40 – 0.77 <0.0001 0.32 0.27 – 0.67 <0.0001
ZCBI 0.19 0.05 – 0.28 0.006 0.10 –0.02–0.22 0.125
CSI 0.14 0.03 – 1.33 0.039 –0.03 –0.89–0.50 0.576
EUROHIS-QOL8 –0.21 –7.97––1.67 0.003 0.20 1.74–8.13 0.003
Pa ien
EUROHIS-QOL8 0.22 0.07–0.40 0.006 –0.56 –9.34––5.95 <0.0001
BDI-II a baseline 0.19 –0.14––0.01 0.035 –0.36 –0.64––0.32 <0.0001
Dependen a iable: change in he PD pa ien om V0 o V2 () in he BDI-II o al sco e. ␤s anda dized coe icien
and 95% IC a e shown. a, uni a ia e analysis; b, mul i a ia e analysis (Du bin-Wa son es = 2.11; R2= 0.71). Only
signi ican a iables (p< 0.01) om he pa ien in he mul i a ia e analysis a e shown. Co a ia es om he pa ien
included we e he change om V0 o V2 () in LEDD, UPDRS-III-OFF, UPDRS-IV, FOGQ, PD-CRS, NMSS,
PDSS, QUIP-RS, NPI, VAS-PAIN, VAFS, ADLS, PDQ-39SI, EUROHIS-QOL8, and he sco e on he BDI-II
a baseline. ADLS, Schwab & England Ac i i ies o Daily Li ing Scale; BDI-II, Beck Dep ession In en o y-II;
CSI, Ca egi e S ain Index; FOGQ, F eezing O Gai Ques ionnai e; LEDD, le odopa equi alen daily dose;
Non-Mo o Symp oms Scale; NPI, Neu opsychia ic In en o y; PD-CRS, Pa kinson’s Disease Cogni i e Ra ing
Scale; PDQ-39, he 39-i em Pa kinson’s disease Ques ionnai e Summa y Index; PDSS, Pa kinson’s Disease Sleep
Scale; QUIP-RS, Ques ionnai e o Impulsi e-Compulsi e Diso de s in Pa kinson’s Disease-Ra ing Scale; UPDRS,
Uni ied Pa kinson’s Disease Ra ing Scale; VAS, Visual Analogue Scale; ZCBI, Za i Ca egi e Bu den In en o y.
A signi ican mode a e co ela ion was obse ed
be ween he ou ca egi e ’s a iables (p< 0.0001 in
all analyses): BDI-II and ZCBI, = 0.42; BDI-
II and CSI, = 0.39; BDI-II and EUROHIS-
QOL8, = –0.35; ZCBI and CSI, = 0.55;
ZCBI and EUROHIS-QOL8, = –0.34; CSI
and EUROHIS-QOL8, = –0.31. Rega ding PD-
ela ed a iables, he s onges co ela ion was
obse ed o he change om V0 o V2 in mood
(BDI-II) in he pa ien and he ca egi e ( = 0.39;
p< 0.0001) and in he global QoL (EUROSHIS-
QOL8) in he pa ien and he ca egi e ( = 0.39;
p< 0.0001) (Table 1).
The change in he ca egi e om V0 o V2 in mood
was associa ed wi h he change in he pa ien om
V0 o V2 in mood (BDI-II) a e he adjus men o
co a ia es (Model 1; R2= 0.71): ␤= 0.32; p< 0.0001
(Table 2). The o he ac o associa ed wi h BDI-II in
he pa ien was he change in global QoL in he pa ien
(␤= –0.56; p< 0.0001). No ca egi e ’s a iables we e
associa ed wi h he change in he pa ien om V0
o V2 in his/he heal h- ela ed QoL (Table 3A), as
he change in he pa ien om V0 o V2 in he
NMSS o al sco e he ac o signi ican ly associ-
a ed wi h PDQ-39 (␤= 0.29; p< 0.0001) (Model 2;
R2= 0.51). Howe e , ega ding he pa ien ’s change
in global QoL, he change in he ca egi e om V0 o
V2 in he global QoL was iden i ied as an associa ed
ac o (␤= 0.39; p< 0.0001) oge he wi h he change
in he own ca egi e in mood (␤= 0.55; p< 0.0001)
(Model 3; R2= 0.68; Table 3B). Finally, and again,
no ca egi e ’s a iables we e associa ed wi h he
change in he pa ien om V0 o V2 in he au on-
omy o ADL, being he change in he own pa ien
in he heal h- ela ed QoL he ac o associa ed wi h
ADLS (␤= –0.42; p< 0.0001) (Model 4; R2= 0.33;
Table 4). Figu e 2 shows he in luence o ca egi e ’s
a iables (BDI-II; ZCBI; CSI; EUROHIS-
QOL8) o e pa ien ’s a iables (BDI-II; PDQ-39;
EUROHIS-QOL8; ADLS) and he associa ions
be ween pa ien ’s a iables. In all models, ole ance
was less han 0.2 o all a iables included.
DISCUSSION
Unlike p e iously published s udies [2–15] ha
analyze which ac o s o PD in luence he s a us
o he p incipal ca egi e , he p esen s udy ana-
lyzes whe he he p og essi e changes in he s a us
o he ca egi e ha e epe cussions on he s a us o
he pa ien . We ound ha he change in he ca e-
gi e ’s mood p edic ed he change in he pa ien ’s
mood independen ly o o he a iables o he dis-
ease in luencing he pa ien ’s mood. We also ound
an associa ion be ween he change in he global QoL
in bo h he pa ien and he ca egi e . This inding is
no el and ag ees wi h he idea o he icious cycle o
illness. Dep essi e symp oms in he pa ien impac
he ca egi e ’s mood, and dep essi e symp oms in
D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness 225
Table 3
E ec o changes in he ca egi e o e he change in heal h- ela ed and global QoL in PD pa ien s om
he COPPADIS coho a e 2-yea ollow-up (N = 192)
Uni a ia e analysis Mul i a ia e analysis
␤95% CI p␤95% CI p
A) PDQ-39SI
Ca egi e
BDI-II 0.19 0.10–0.62 0.006 0.16 0.01–0.54 0.047
ZCBI 0.28 0.16–0.46 <0.0001 0.03 –0.13–0.20 0.671
CSI 0.20 0.41–2.15 0.004 0.04 –0.72–1.20 0.818
EUROHIS-QOL8 0.01 –3.89–4.64 0.863 0.13 –0.33–7.74 0.072
Pa ien
UPDRS-III 0.41 0.37–0.73 <0.0001 0.20 0.06–0.43 0.008
NMSS 0.57 0.16–0.25 <0.0001 0.29 0.05–0.15 <0.0001
ADLS –0.48 –0.62––0.36 <0.0001 –0.25 –0.39––0.10 0.001
PDQ-39 a baseline –0.20 –0.32––0.05 0.005 –0.20 –0.29––0.06 0.002
B) EUROSHIS-QOL8
Ca egi e
BDI-II –0.14 –0.029––0.001 0.039 0.24 0.01–0.04 0.001
ZCBI –0.04 –0.011–0.006 0.530 0.02 -0.00–0.01 0.679
CSI –0.09 –0.078–0.016 0.201 –0.03 –0.06–0.03 0.604
EUROHIS-QOL8 0.41 0.454–0.878 <0.0001 0.39 0.49–0.89 <0.0001
Pa ien
BDI-II –0.63 –0.053––0.037 <0.0001 –0.55 –0.03––0.66 <0.0001
EUROHIS-QOL8 a baseline 0.39 0.024–0.049 <0.0001 –0.37 –0.65––0.36 <0.0001
Dependen a iable: change in he PD pa ien om V0 o V2 () in he PDQ-39 (A) and EROHIS-QOL8 (B). ␤
s anda dized coe icien and 95% IC a e shown. a, uni a ia e analysis; b, mul i a ia e analysis: A) Du bin-Wa son
es = 2.07; R2= 0.51; B) Du bin-Wa son es = 2.02; R2= 0.68. Only signi ican a iables (p< 0.01) om he pa ien
in he mul i a ia e analysis a e shown. Co a ia es om he pa ien included we e he change om V0 o V2 ()in
LEDD, UPDRS-III-OFF, UPDRS-IV, FOGQ, PD-CRS, NMSS, PDSS, QUIP-RS, NPI, VAS-PAIN, VAFS, ADLS,
and he sco e on he PDQ-39SI (A) and EUROHIS-QOL8 (B) a baseline. ADLS, Schwab & England Ac i i-
ies o Daily Li ing Scale; BDI-II, Beck Dep ession In en o y-II; CSI, Ca egi e S ain Index; FOGQ, F eezing
O Gai Ques ionnai e; LEDD, le odopa equi alen daily dose; Non-Mo o Symp oms Scale; NPI, Neu opsychi-
a ic In en o y; PD-CRS, Pa kinson’s Disease Cogni i e Ra ing Scale; PDQ-39, he 39-i em Pa kinson’s disease
Ques ionnai e Summa y Index; PDSS, Pa kinson’s Disease Sleep Scale; QUIP-RS, Ques ionnai e o Impulsi e-
Compulsi e Diso de s in Pa kinson’s Disease-Ra ing Scale; UPDRS, Uni ied Pa kinson’s Disease Ra ing Scale;
VAS, Visual Analogue Scale; ZCBI, Za i Ca egi e Bu den In en o y.
Table 4
E ec o changes in he ca egi e o e he change in au onomy o ADL in PD pa ien s om he COPPADIS
coho a e 2-yea ollow-up (N = 192)
Uni a ia e analysis Mul i a ia e analysis
␤95% CI p␤95% CI p
Ca egi e
BDI-II –0.05 –0.35–0.16 0.465 0.25 0.07–0.81 0.018
ZCBI -0.23 -0.40––0.10 0.001 –0.14 –0.38–0.04 0.112
CSI –0.18 –1.99––0.28 0.009 –0.05 –1.55–0.79 0.526
EUROHIS-QOL8 0.05 –2.60–5.72 0.461 0.06 –3.62–7.61 0.484
Pa ien
FOGQ –0.38 –1.55––0.75 <0.0001 –0.25 –1.28––0.33 0.001
PDQ39SI –0.48 –0.59––0.34 <0.0001 –0.42 –0.62––0.24 <0.0001
Dependen a iable: change in he PD pa ien om V0 o V2 () in he ADLS sco e. ␤s anda dized coe icien and
95% IC a e shown. a, uni a ia e analysis; b, mul i a ia e analysis (Du bin-Wa son es = 1.956; R2= 0.33). Only
signi ican a iables (p< 0.01) om he pa ien in he mul i a ia e analysis a e shown. Co a ia es om he pa ien
included we e he change om V0 o V2 () in LEDD, UPDRS-III-OFF, UPDRS-IV, FOGQ, PD-CRS, NMSS,
PDSS, QUIP-RS, NPI, VAS-PAIN, VAFS, ADLS, PDQ-39SI, EUROHIS-QOL8, and he sco e on he ADLS
a baseline. ADLS, Schwab & England Ac i i ies o Daily Li ing Scale; BDI-II, Beck Dep ession In en o y-II;
CSI, Ca egi e S ain Index; FOGQ, F eezing O Gai Ques ionnai e; LEDD, le odopa equi alen daily dose;
Non-Mo o Symp oms Scale; NPI, Neu opsychia ic In en o y; PD-CRS, Pa kinson’s Disease Cogni i e Ra ing
Scale; PDQ-39, he 39-i em Pa kinson’s disease Ques ionnai e Summa y Index; PDSS, Pa kinson’s Disease Sleep
Scale; QUIP-RS, Ques ionnai e o Impulsi e-Compulsi e Diso de s in Pa kinson’s Disease-Ra ing Scale; UPDRS,
Uni ied Pa kinson’s Disease Ra ing Scale; VAS, Visual Analogue Scale; ZCBI, Za i Ca egi e Bu den In en o y.
226 D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness
Fig. 2. The associa ions be ween he change om baseline isi (V0) o 2-yea ollow-up isi (V2) in ca egi e ’s and pa ien ’s a iables a e
shown. The change in ca egi e ’s mood in luences he change in pa ien ’s mood (BDI-II; in b igh g een) whe eas he change in ca egi e ’s
global QoL is associa ed o he change in pa ien ’s global QoL (EUROHIS-QOL8; in b igh yellow). Mo eo e , he change in pa ien ’s
mood in luences he change in pa ien ’s global QoL whe eas he change in pa ien ’s global QoL and heal h- ela ed QoL is associa ed wi h
he change in pa ien ’s mood and au onomy o ADL, espec i ely ( ed a ows). ADL, ac i i ies o daily li ing; ADLS, Schwab & England
Ac i i ies o Daily Li ing Scale; CSI, Ca egi e S ain Index; EUROHIS-QOL8, EUROHIS-QOL 8-i em index; PD, Pa kinson’s disease;
PDQ-39, 39-i em Pa kinson’s disease Ques ionnai e; QoL, quali y o li e; ZCBI, Za i Ca egi e Bu den In en o y.
he ca egi e ha e a nega i e impac on he pa ien ’s
mood as well. This could jus i y he necessi y o ea ly
iden i ica ion and p ope managemen o dep ession
and bu den in he p incipal ca egi e o a PD pa ien
[2, 26].
Ca egi ing may ha e ewa ding consequences,
such as s eng hening emo ional ies, imp o ing sel -
es eem, gene a ing al uism, and making inancial
sa ings [27]. Howe e , ca ing o ill amily membe s,
especially wi h a ch onic degene a i e disease in he
long- e m, can ha e nega i e impac s on ca egi e s’
men al heal h [28]. Ca egi ing bu den, in e ms o
physical s ain, has been ound o p edic ca egi e s’
heal h [29]. On he o he hand, men al heal h, in
e ms o dep ession, could p edic bu den [30]. In
ac , dep ession is one o he mos common nega i e
e ec s o ca egi ing [31], being majo dep ession
de ec ed in his coho in 13% and 15.1% o he
ca egi e s a baseline and a e he 2-yea ollow-
up, espec i ely [16]. In his con ex , an impo an
ques ion a ises: does he wo sening o he ca egi e ’s
condi ion wo sen he ca e o he pa ien and sec-
onda ily pe pe ua e he p oblem since bo h ac o s
eed o each o he ? Su p isingly, in PD and o he
pa hologies including cance , he li e a u e ocuses
on iden i ying he causes o ca egi e o e load and
he consequences on he ca egi e bu no on he
pa ien [32, 33]. E en hough he e is li e a u e abou
he apies aimed o ea ca egi e bu den, again he
bene i s o he ca egi e a e analyzed bu no he
posi i e consequences ha hey could ha e on he
pa ien [2, 34, 35]. This is impo an because one o
he consequences o ca egi e bu den is a educ ion
in ca e p o ision and in he quali y o ca e p o ided
[36]. A s udy by Gi en e al. [37] claims ha he
quali y o ca e is educed when a ca egi e expe-
iences bu den, and i may be mani es ed due o a
dec eased coping abili y and lack o emo ional sup-
po o he ca e- ecipien . Ou s udy analyzes o he
i s ime how sho - e m de e io a ion in he s a us
o he ca egi e can nega i ely in luence he pa ien .
I also de ec s ha he wo sening o he ca egi e ’s
D. San os-Ga c´ıa e al. / Ca egi e and Pa ien , he Vicious Cycle o Illness 227
mood is a key ac o ha impac s on he pa ien ’s
mood a e adjus ing o he changes expe ienced in
many o he a iables o he pa ien ’s disease. Impo -
an ly, he model p o ided abou 70% o he a iance
o he p incipal a iable (pa ien ’s mood change).
This is a c i ical poin gi en ha he change in he
pa ien ’s mood is he mos in luen ial ac o in he
ca egi e ’s mood, and his, a he same ime, gene -
a es o e load, s ess, and a wo se QoL in he ca egi e
him/he sel [16], which is associa ed wi h a wo se
QoL o he pa ien . Howe e , he s a us o he ca e-
gi e did no in luence he pa ien ’s heal h- ela ed
QoL, which is mo e condi ioned (PDQ-39) by he
symp oms o he disease [38, 39], especially NMS
as i has been ound in he model. We also ailed o
demons a e he impac o ca egi e s a us on pa ien
au onomy. Ou indings a e no el, and he nex s ep
should be o demons a e i ea ing ca egi e bu den
and dep ession can imp o e no only he s a us o he
ca egi e bu also he pa ien indi ec ly as well. Di -
e en s a egies could be es ed, such as educa ion
and psycho he apy [40], ehabili a ion [41], o mul-
idisciplina y in e en ions [42]. Again, ea men o
pa ien ’s symp oms o imp o e he ca egi e ’s s a us
has been analyzed [43] bu he opposi e has no .
Ou s udy has some limi a ions, some o hem p e-
iously epo ed in a ecen publica ion [16], such
as a loss o ollow-up o nea ly 30% o he subjec s
(pa ien and his/he ca egi e ) wi h espec o he
baseline sample and he ac ha ca egi e ’s ea men
o o he possible in e en ions we e no collec ed. In
he models, he ela ionship be ween some a iables
changed he sign a e adjus ing o he co a ia es,
such as he ela ion be ween BDI-II in he pa ien
(dependen a iable) and EUROHIS-QOL8 in he
ca egi e in Model 1 ( om nega i e o posi i e) and
EUROHIS-QOL8 in he pa ien (dependen a i-
able) and BDI-II in he ca egi e in Model 3 ( om
nega i e o posi i e), con a y o expec a ion. This
could be explained by he e ec o including many
co a ia es and he in luence o al oge he o e he
dependen a iable. Howe e , in all models he R2
was high, collinea i y was excluded, and only esul s
wi h e y high signi icance (p< 0.001) we e consid-
e ed alid.
In conclusion, his is he i s ime ha he change
in he ca egi e ’s s a us demons a ed an in luence on
he change in pa ien ’s s a us. So, dep essi e symp-
oms in he pa ien a ec he ca egi e bu also ice
e sa. Mo eo e , he change in he ca egi e ’s global
QoL seems o p edic he change in he pa ien ’s
global QoL. Wi h he aim o s op he icious ci cle o
illness in PD, de ec ion o dep ession and bu den in
he p incipal ca egi e o he pa ien is impo an and
should be ac ed on as ea lie as possible. In addi ion,
mo e s udies o eplica e hese indings and es his
hypo hesis a e needed.
ACKNOWLEDGMENTS
We would like o hank all pa ien s and hei
ca egi e s who collabo a ed in his s udy. Many
hanks also o Fundaci´
on Espa˜
nola de Ayuda a la
In es igaci´
on en En e medades Neu odegene a i as
y/o de O igen Gen´
e ico (h ps:// undaciondegen.o g/)
and Alpha Bio esea ch (h ps://www.alphabio esea
ch.com) and o he ins i u ions helping us.
FUNDING
COPPADIS and he p esen s udy we e de el-
oped wi h he help o Fundaci´
on Espa˜
nola de
Ayuda a la In es igaci´
on en En e medades
Neu odegene a i as y/o de O igen Gen´
e ico
(h ps:// undaciondegen.o g/) and Alpha Bio esea ch
(www.alphabio esea ch.com). Also, we ecei ed
g an s om he Spanish Minis y o Economy
and Compe i i eness [PI16/01575] co- ounded by
ISCIII (Concesi´
on de sub enciones de P oyec os
de In es igaci´
on en Salud de la con oca o ia 2020
de la Acci´
on Es a ´
egica en Salud 2017-2020 po
el P oyec o “PROGRESI ´
ON NO MOTORA E
IMPACTO EN LA CALIDAD DE VIDA EN LA
ENFERMEDAD DE PARKINSON”) o de elop a
pa o he COPPADIS p ojec .
CONFLICT OF INTEREST
San os Ga c´
ıa D. has ecei ed hono a ia o edu-
ca ional p esen a ions and ad ice se ice by Abb ie,
UCB Pha ma, Lundbeck, KRKA, Zambon, Bial, I al-
a maco, Te a, A ch´
ımedes, Es e e, S ada, Me z, and
g an s om he Spanish Minis y o Economy and
Compe i i eness [PI16/01575] co- ounded by ISCIII
(Concesi´
on de sub enciones de P oyec os de In es i-
gaci´
on en Salud de la con oca o ia 2020 de la Acci´
on
Es a ´
egica en Salud 2017-2020 po el p oyec o
“PROGRESI ´
ON NO MOTORA E IMPACTO EN LA
CALIDAD DE VIDA EN LA ENFERMEDAD DE
PARKINSON”).