ARTICLE OPEN
P edic o s o clinically significan quali y o li e impai men in
Pa kinson’s disease
Diego San os Ga cía
1
✉, Te esa de Deus Fon icoba
2
, Ca los Co es
1
, Guille mo Muñoz
1
, Jose M. Paz González
1
,
C is ina Ma ínez Mi ó
1
, Es e Suá ez
2
, Sil ia Jesús
3,4
, Miquel Aguila
5
, Pau Pas o
5
, Lluis Planellas
6
, Ma ina Cosgaya
7
,
Juan Ga cía Calden ey
8
, Nu ia Caballol
9
, Inés Lega da
10
, Jo ge He nández Va a
11
, I ia Cabo
12
, Luis López Manzana es
13
,
Isabel González A ambu u
4,14
, Ma ía A. Á ila Ri e a
15
, Ma ia J. Ca alán
16
, Víc o Noguei a
17
, Víc o Puen e
18
, Ma ía Ruíz de A cos
19
,
Ca men Bo ué
20
, Be a Solano Vila
21
, Ma ía Ál a ez Sauco
22
, Lydia Vela
23
, Sonia Escalan e
24
, Es he Cubo
25
,
F ancisco Ca illo Padilla
26
, Juan C. Ma ínez Cas illo
27
, Pila Sánchez Alonso
28
, Ma ia G. Alonso Losada
29
, Nu ia López A iz egui
30
,
I zia Gas ón
31
, Ped o Cla e o
31
, Jaime Kulise sky
4,32
, Ma a Blázquez Es ada
33
, Manuel Seijo
12
, Ja ie Rúiz Ma ínez
34
,
Ca idad Vale o
35
, Mónica Ku is
36
, O iol de Fáb egues
11
, Jessica González A du a
37
, Ca los O dás
38
, Luis M. López Díaz
39
,
Da ian McA ee
40
, Pablo Ma inez-Ma in
4
, Pablo Mi
3,4
and COPPADIS S udy G oup*
Quali y o li e (QOL) plays an impo an ole in independen li ing in Pa kinson’s disease (PD) pa ien s, being c ucial o know wha
ac o s impac QoL h oughou he cou se o he disease. He e we iden ified p edic o s o QoL impai men in PD pa ien s om a
Spanish coho . PD pa ien s ec ui ed om 35 cen e s o Spain om he COPPADIS coho om Janua y 2016, o No embe 2017,
we e ollowed up du ing 2 yea s. Heal h- ela ed QoL (HRQoL) and global QoL (GQoL) we e assessed wi h he 39-i em Pa kinson’s
disease Ques ionnai e (PDQ-39) and he EUROHIS-QOL 8-i em index (EUROHIS-QOL8), espec i ely, a baseline (V0) and a
24 mon hs ± 1 mon h (V2). Clinically significan QoL impai men was defined as p esen ing an inc ease (PDQ-39SI) o dec emen
(EUROHIS-QOL8) a V2 ≥10% o he sco e a baseline (V0). A compa ison wi h a con ol g oup was conduc ed o GQoL. GQoL did
no change significan ly in PD pa ien s (N=507; p=0.686) o in he con ol g oup (N=119; p=0.192). The mean PDQ-39SI was
significan ly inc eased in PD pa ien s (62.7 ± 8.5 yea s old; 58.8% males; N=500) by 21.6% ( om 16.7 ± 13 o 20.3 ± 16.4; p< 0.0001)
a V2. Nine y- h ee pa ien s (18.6%) p esen ed a clinically significan HRQoL impai men a V2. To be younge (OR =0.896; 95% CI
0.829–0.968; p=0.006), o be a emale (OR =4.181; 95% CI 1.422–12.290; p=0.009), and o ha e a g ea e inc ease in BDI-II (Beck
Dep ession In en o y-II) (OR =1.139; 95% CI 1.053–1.231; p=0.001) and NMSS (Non-Mo o Symp oms Scale) (OR =1.052; 95% CI
1.027–1.113; p< 0.0001) o al sco es om V0 o V2 we e associa ed wi h clinically significan HRQoL impai men a he 2-yea
ollow-up (Hosme –Lemeshow es , p=0.665; R
2
=0.655). An inc ease in ≥5 and ≥10 poin s o BDI-II and NMSS o al sco e a V2
mul iplied he p obabili y o p esen ing clinically significan HRQoL impai men by 5 (OR =5.453; 95% CI 1.663–17.876; p=0.005)
and 8 (OR =8.217; 95% CI, 2.975–22.696; p=0.002), espec i ely. In conclusion, age, gende , mood, and non-mo o impai men
we e associa ed wi h clinically significan HRQoL impai men a e he 2-yea ollow-up in PD pa ien s.
npj Pa kinson’s Disease (2021) 7:118 ; h ps://doi.o g/10.1038/s41531-021-00256-w
INTRODUCTION
Pa kinson’s disease (PD) is a complex diso de in which di e en
mo o and non-mo o symp oms (NMS) can be p esen wi h a
equency and se e i y ha a ies among pa ien s o e ime
1
.
Bo h mo o and NMS a e impo an because hey nega i ely
impac he pa ien ’s quali y o li e (QoL). Di e en s udies ha e
analyzed wha ac o s con ibu e o a poo QoL in PD pa ien s
2–13
.
Recen ly, we obse ed ha NMS bu den, mood, and gai p oblems
we e he mos ele an ac o s a ec ing heal h- ela ed (HRQoL)
and global pe cei ed QoL (GQoL) in non-demen ed PD pa ien s
om he Spanish coho COPPADIS
14
. These esul s aligned wi h
o he c oss-sec ional s udies obse a ions
15–17
. Howe e , wi h
1
CHUAC, Complejo Hospi ala io Uni e si a io de A Co uña, A Co uña, Spain.
2
CHUF, Complejo Hospi ala io Uni e si a io de Fe ol, A Co uña, Spain.
3
Unidad de T as o nos del
Mo imien o, Se icio de Neu ología y Neu ofisiología Clínica, Ins i u o de Biomedicina de Se illa, Hospi al Uni e si a io Vi gen del Rocío/CSIC/Uni e sidad de Se illa, Se ille, Spain.
4
CIBERNED (Cen o de In es igación Biomédica en Red sob e En e medades Neu odegene a i as), Ála a, Spain.
5
Hospi al Uni e si a i Mu ua de Te assa, Te assa, Ba celona, Spain.
6
Neu ología, Clínica del Pila , Ba celona, Spain.
7
Hospi al Clínic de Ba celona, Ba celona, Spain.
8
Cen o Neu ológico Oms 42, Palma de Mallo ca, Spain.
9
Conso ci Sani a i In eg al,
Hospi al Moisés B oggi, San Joan Despí, Ba celona, Spain.
10
Hospi al Uni e si a io Son Espases, Palma de Mallo ca, Spain.
11
Hospi al Uni e si a io Vall d´Heb on, Ba celona, Spain.
12
Complejo Hospi ala io Uni e si a io de Pon e ed a (CHOP), Pon e ed a, Spain.
13
Hospi al Uni e si a io La P incesa, Mad id, Spain.
14
Hospi al Uni e si a io Ma qués de
Valdecilla, San ande , Spain.
15
Conso ci Sani a i In eg al, Hospi al Gene al de L´Hospi ale , L´Hospi ale de Llob ega , Ba celona, Spain.
16
Hospi al Uni e si a io Clínico San
Ca los, Mad id, Spain.
17
Hospi al Da Cos a, Bu ela, Lugo, Spain.
18
Hospi al del Ma , Ba celona, Spain.
19
Hospi al Uni e si a io Vi gen Maca ena, Se illa, Spain.
20
Hospi al In an a
So ía, Mad id, Spain.
21
Ins i u d’Assis ència Sani à ia (IAS) - Ins i u Ca alà de la Salu , Gi ona, Spain.
22
Hospi al Gene al Uni e si a io de Elche, Elche, Spain.
23
Fundación Hospi al de
Alco cón, Mad id, Spain.
24
Hospi al de To osa Ve ge de la Cin a (HTVC), To osa, Ta agona, Spain.
25
Complejo Asis encial Uni e si a io de Bu gos, Bu gos, Spain.
26
Hospi al
Uni e si a io de Cana ias, San C is óbal de la Laguna, San a C uz de Tene i e, Spain.
27
Hospi al Uni e si a io Ramón y Cajal, IRYCIS, Mad id, Spain.
28
Hospi al Uni e si a io Pue a de
Hie o, Mad id, Spain.
29
Hospi al Ál a o Cunquei o, Complejo Hospi ala io Uni e si a io de Vigo (CHUVI), Vigo, Spain.
30
Complejo Hospi ala io de Toledo, Toledo, Spain.
31
Complejo
Hospi ala io de Na a a, Pamplona, Spain.
32
Hospi al de San Pau, Ba celona, Spain.
33
Hospi al Uni e si a io Cen al de As u ias, O iedo, Spain.
34
Hospi al Uni e si a io
Donos ia, San Sebas ián, Spain.
35
Hospi al A nau de Vilano a, Valencia, Spain.
36
Hospi al Rube In e nacional, Mad id, Spain.
37
Hospi al Uni e si a io de Cabueñes, Gijón, Spain.
38
Hospi al Rey Juan Ca los, Mad id, Spain, Mad id, Spain.
39
Complejo Hospi ala io Uni e si a io de O ense (CHUO), O ense, Spain.
40
Uni e is y o Pennsyl ania, Pennsyl ania, USA.
*A lis o au ho s and hei a filia ions appea s a he end o he pape . ✉email: diegosan[email p o ec ed]s
www.na u e.com/npjpa kd
Published in pa ne ship wi h he Pa kinson’s Founda ion
1234567890():,;
ega d o how he QoL o PD changes h oughou he cou se o
he disease, he e is much less in o ma ion
18–23
and p ospec i e
longi udinal s udies a e needed. In clinical p ac ice, i is impo an
o know wha ac o s wo sen PD pa ien s’QoL wi h he in en ion
o ca y ou e ec i e in e en ions. Known in o ma ion limi ed by
ac o s om he s udies such as he sample size, he di e ences
be ween scales used o assessing QoL, he di e en ypes o QoL
assessed, being a non-mul icen e s udy, he absence o a con ol
g oup, and/o he lack o a global e alua ion including di e en
aspec s ha could impac on QoL
18–23
. In addi ion, he impac o
some complica ions on QoL in ad anced PD has been analyzed
be o e
24,25
. Howe e , i is no clea wha he significance o sho -
e m changes in QoL is in ea ly PD pa ien s o wha ac o s
con ibu e o i when an ex ensi e assessmen conside ing
mo o and NMS is pe o med
26
. I is ema kable ha NMS occu
no only in ad anced bu also in he ea ly s ages o PD. Some
symp oms, o example, ol ac o y defici , cons ipa ion, apid-eye-
mo emen sleep beha io diso de , and dep ession, can e en
p ecede he appea ance o mo o symp oms by many yea s
1
.By
he con a y, o he s such as psychosis o demen ia a e no
p esen . The fi s yea s a e condi ioned by he accep ance o he
diagnosis, bu in gene al, he pa ien has g ea e au onomy. In his
con ex , i is essen ial o know wha influences he changes in he
PD pa ien QoL pe cep ion wi h he in en ion o being able o ac
as soon as possible.
The aim o he p esen s udy was o (1) analyze he change in
HRQoL and GQoL in PD pa ien s om he COPPADIS coho a e
he 2-yea ollow-up, (2) o compa e wi h a con ol g oup, and (3)
o iden i y p edic o s o clinically significan QoL impai men in
he PD g oup. Finally, a subanalysis was conduc ed in a subg oup
o pa ien s wi h ea ly PD (≤5 yea s o disease du a ion).
RESULTS
Changes in assessmen s om V0 o V2
A e he 2-yea ollow-up, GQoL did no change significan ly in PD
pa ien s ( om PQ-10
V0
o 7.28 ± 1.55 o PQ-10
V2
o 7.14 ± 1.54
[N=503; p=0.070]; om EUROHIS-QOL8
V0
o 3.77 ± 0.54 o
EUROHIS-QOL8
V2
o 3.75 ± 0.58 [N=507; p=0.686]) o in he
con ol g oup ( om PQ-10
V0
o 8.07 ± 1.22 o PQ-10
V2
o 7.86 ±
1.65 [N=122; p=0.361]; om EUROHIS-QOL8
V0
o 4.18 ± 0.5 o
EUROHIS-QOL8
V2
o 4.12 ± 0.51 [N=119; p=0.192] (Fig. 1). The
mean PDQ-39SI was significan ly inc eased in PD pa ien s (62.7 ±
8.5 yea s old; 58.8% males; N=500) by 21.6% ( om 16.72 ± 13.02
o 20.3 ± 16.41; p< 0.0001) a V2 (Table 1and Fig. 1). By domains,
he sco e o all domains o he PDQ-39SI a V2 was significan ly
highe han a V0 excep o domain 4 (s igma iza ion) (Table 1).
The change in he sco e o o he scales om V0 o V2 in PD
pa ien s and con ols is shown in Table 1.
Pa ien s wi h s wi hou clinically HRQoL impai men
Al hough 291 PD pa ien s (58.2%) p esen ed an inc ease in he
PDQ-39SI sco e a e he 2-yea ollow-up, only 93 (18.6%)
p esen ed a clinically significan HRQoL impai men a V2.
Di e ences in change om V0 o V2 o UPDRS-III, UPDRS-IV,
FOGQ, NMSS, BDI-II, PDSS, NPI, VAS-PAIN, VASF-physical, VASF-
men al, and ADLS sco es be ween pa ien s wi h and wi hou
clinically significan HRQoL impai men we e obse ed (Table 2).
Specifically, PD pa ien s who p esen ed a he 2-yea ollow-up a
clinically significan HRQoL impai men p esen ed a 97.3%
inc ease o he NMS bu den (NMSS o al sco e om 29.2 ± 25.87
o 57.84 ± 46.73 [p< 0.0001]) compa ed o 8.6% in hose pa ien s
who did no (NMSS o al sco e om 48.38 ± 38.59 o 52.53 ± 41.35
[p=0.003]) (Fig. 2A). By domains, he mos significan di e ences
we e obse ed o sleep/ a igue (p< 0.0001) and mood/apa hy
(p< 0.0001) (Table 2and Fig. 2B). Mode a e co ela ions we e
obse ed be ween he change om V0 o V2 in he PDQ-39SI
sco e and he sco e in FOGQ ( =0.34; p< 0.0001), NMSS ( =0.41;
p< 0.0001), BDI-II ( =0.33; p< 0.0001) and ADLS ( =−0.40; p<
0.0001) (Supplemen a y Table 1).
P edic o s o clinically HRQoL impai men
To be younge (OR =0.896; 95% CI 0.829–0.968; p=0.006), o be
a emale (OR =4.181; 95% CI 1.422–12.290; p=0.009), and o
ha e a g ea e inc ease in BDI-II (OR =1.139; 95% CI 1.053–1.231;
p=0.001) and NMSS (OR =1.052; 95% CI 1.027–1.113; p< 0.0001)
o al sco es om V0 o V2 we e associa ed wi h clinically
significan HRQoL impai men a he 2-yea ollow-up, a e
adjus men o many co a ia es (Hosme –Lemeshow es , p=
0.665; R
2
=0.655) (Table 3). Specifically, an inc ease in ≥5 and ≥10
poin s o BDI-II and NMSS o al sco e a V2 mul iplied he
p obabili y o p esen ing a clinically significan HRQoL impai men
by 5 (OR =5.453; 95% CI 1.663–17.876; p=0.005) and 8 (OR =
8.217; 95% CI 2.975–22.696; p=0.002), espec i ely. When ADLS
was included in he model (ADLS a V0 and he change in ADLS
sco e om V0 o V2), only a g ea e inc ease in BDI-II (OR =1.148;
95% CI 1.057–1.258; p=0.001), NMSS (Non-Mo o Symp oms
Scale) (OR =1.056; 95% CI 1.029–1.083; p< 0.0001) and NPI (OR =
1.072; 95% CI, 1.001–1.147; p=0.046) o al sco es and a dec ease
in ADLS sco e (OR =0.884; 95% CI 0.820–0.954; p< 0.0001) om
V0 o V2 we e associa ed wi h clinically significan HRQoL
impai men a he 2-yea ollow-up (Hosme –Lemeshow es ,
p=0.621; R
2
=0.718).
Fig. 1 Change in PDQ-39SI, PQ-10, and EUROHIS-QOL8 sco es om V0 (baseline) o V2 (2 yea ± 1 mon h) in PD pa ien s and/o con ols.
Da a a e p esen ed as box plo s, wi h he box ep esen ing he median and he wo middle qua iles (25–75%). p- alues we e compu ed using
he Wilcoxon-signed ank es . Mild ou lie s (O) a e da a poin s ha a e mo e ex eme han Q1 −1.5 * IQR o Q3 +1.5 * IQR. EUROHIS-QOL8,
Eu opean Heal h In e iew Su ey-Quali y o Li e 8-I em Index; PDQ-39SI, 39-i em Pa kinson’s Disease Quali y o Li e Ques ionnai e
Summa y Index.
D.S. Ga cía e al.
2
npj Pa kinson’s Disease (2021) 118 Published in pa ne ship wi h he Pa kinson’s Founda ion
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In he subg oup o ea ly PD (N=277), qui e simila esul s, an
inc ease in mean PDQ-39SI om V0 o V2 o 23.4% ( om 14.22 ±
11.29 o 17.62 ± 15.36; p< 0.0001), we e obse ed. Fi y-six
pa ien s (20.2%) p esen ed a clinically significan HRQoL impai -
men a he 2-yea ollow-up. Howe e , as in he whole coho ,
GQoL did no change significan ly (PQ-10, p=0.111; EUROHIS-
QOL8, p=0.756). In he bina y eg ession model, as in he all
coho , o be younge (OR =0.813; 95% CI 0.709–0.933; p=0.003),
o be a emale (OR =35.847; 95% CI 3.452–372.204; p=0.003),
and o ha e a g ea e inc ease in BDI-II (OR =1.400; 95% CI
1.149–1.705; p=0.001) and NMSS (OR =1.069; 95% CI
1.007–1.043; p=0.001) o al sco es om V0 o V2 we e associa ed
wi h clinically significan HRQoL impai men a he 2-yea ollow-
up, a e adjus men o many co a ia es (Hosme –Lemeshow es ,
p=0.998; R
2
=0.745) (Table 3). When ADLS was included in he
model, o be younge (OR =0.769; 95% CI 0.624–0.946; p=0.013),
Table 1. Changes in mo o and non-mo o symp oms, disabili y, and quali y o li e in PD pa ien s and/o con ols om V0 (baseline) o V2 (2 yea s ±
1 mon h).
PD pa ien s V0 PD pa ien s V2 p
a
Con ols V0 Con ols V2 p
b
Hoehn & Yah (OFF) (%) <0.0001 N. A. N. A. N. A.
S age 1 22.7 13.3
S age 2 68 77
S age 3–5 9.3 9.7
UPDRS-III (OFF) 21.92 ± 10.53 25.26 ± 12.19 <0.0001 N. A. N. A. N. A.
UPDRS-IV 1.99 ± 2.41 2.65 ± 2.75 <0.0001 N. A. N. A. N. A.
FOGQ 3.76 ± 4.69 4.94 ± 5.18 <0.0001 N. A. N. A. N. A.
LEDD 577.48 ± 412.09 767.56 ± 307.1 <0.0001 N. A. N. A.
Numbe o non-an ipa k. d ugs 2.35 ± 2.38 3.08 ± 2.65 <0.0001 2.04 ± .2.16 2.76 ± 2.35 0.001
PD-CRS 92 ± 15.65 90.26 ± 18.07 <0.0001 99.65 ± 13.56 99.68 ± 13.73 0.744
NMSS 45.08 ± 37.62 53.55 ± 42.28 <0.0001 14.74 ± 18.72 14.65 ± 21.82 0.428
BDI-II 8.28 ± 6.9 8.54 ± 7.48 0.472 4.56 ± 5.46 4.31 ± 5.5 0.776
PDSS 117.13 ± 24.48 117.85 ± 24.98 0.797 131.26 ± 17.41 126.67 ± 26.46 0.947
QUIP-RS 4.6 ± 8.8 4.66 ± 9.22 0.937 1.51 ± 3.73 1.32 ± 3.37 0.498
NPI 5.82 ± 7.88 6.17 ± 9.39 0.671 3.31 ± 7.15 2.64 ± 7.67 0.120
VAS-PAIN 2.61 ± 2.92 2.96 ± 2.88 0.013 1.49 ± 2.41 1.70 ± 2.32 0.319
VASF −physical 2.86 ± 2.67 3.17 ± 2.8 0.010 1.52 ± 2.35 1.29 ± 2.12 0.103
VASF −men al 2.09 ± 2.51 2.20 ± 2.61 0.538 1.29 ± 2.09 1.03 ± 1.97 0.273
ADLSL 88.58 ± 10.19 84.26 ± 13.38 <0.0001 98.87 ± 6.65 99.52 ± 2.15 0.285
PDQ-39SI 16.72 ± 13.02 20.3 ± 16.41 <0.0001 N. A. N. A. N. A.
Mobili y 16.28 ± 19.2 21.31 ± 22.5 <0.0001
Ac i i ies o daily li ing 17.83 ± 18.83 21.82 ± 21.37 <0.0001
Emo ional well-being 20.92 ± 19.52 23.53 ± 23.45 <0.0001
S igma iza ion 12.81 ± 19.24 14.14 ± 21.09 0.069
Social suppo 7.29 ± 15.43 10.01 ± 19.09 <0.0001
Cogni ion 18.51 ± 17.38 23.17 ± 20.16 <0.0001
Communica ion 9.68 ± 14.44 13.55 ± 18.88 <0.0001
Pain and discom o 26.75 ± 22.33 28.67 ± 23.37 0.009
PQ-10 7.28 ± 1.55 7.14 ± 1.54 0.070 8.07 ± 1.22 7.86 ± 1.65 0.361
EUROHIS-QOL8 3.77 ± 0.54 3.75 ± 0.58 0.686 4.18 ± 0.5 4.12 ± 0.51 0.192
Quali y o li e 3.8 ± 0.7 3.68 ± 0.67 0.003 4.14 ± 0.65 4.2 ± 0.63 0.298
Heal h s a us 3.18 ± 0.87 3.32 ± 0.93 0.004 3.97 ± 0.75 3.87 ± 0.82 0.148
Ene gy 3.76 ± 0.79 3.72 ± 0.86 0.266 4.15 ± 0.68 4.11 ± 0.69 0.531
Au onomy o ADL 3.61 ± 0.86 3.63 ± 0.88 0.852 4.24 ± 0.75 4.19 ± 0.61 0.983
Sel -es eem 3.83 ± 0.76 3.82 ± 0.81 0.866 4.18 ± 0.68 4.00 ± 0.66 0.124
Social ela ionships 4.04 ± 0.67 3.94 ± 0.75 0.004 4.29 ± 0.65 4.19 ± 0.61 0.071
Economic capaci y 3.84 ± 0.78 3.77 ± 0.8 0.091 4.07 ± 0.74 3.97 ± 0.81 0.078
Habi a 4.22 ± 0.67 4.21 ± 0.67 0.904 4.43 ± 0.63 4.29 ± 0.66 0.016
p- alues we e compu ed using he Wilcoxon-signed ank es o ma ginal homogenei y es . The esul s ep esen mean ± SD o %; p
a
, V2 s V0 in PD pa ien s;
p
b
, V2 s V0 in con ols.
ADLS Schwab & England Ac i i ies o Daily Li ing Scale, BDI-II Beck Dep ession In en o y-II, FOGQ F eezing O Gai Ques ionnai e, LEDD le odopa equi alen
daily dose (mg), NMSS 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, 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 Unified Pa kinson’s Disease Ra ing Scale,
VAFS Visual Analog Fa igue Scale, VAS-Pain Visual Analog Scale-Pain.
The bold alues indica es s a is ically significan p alues.
D.S. Ga cía e al.
3
Published in pa ne ship wi h he Pa kinson’s Founda ion npj Pa kinson’s Disease (2021) 118
o be a emale (OR =31.982; 95% CI 1.678–609.587; p =0.021),
and o ha e a g ea e inc ease in BDI-II (OR =1.197; 95% CI
1.126–1.990; p=0.006), NMSS (Non-Mo o Symp oms Scale)
(OR =1.108; 95% CI 1.033–1.188; p=0.004) and NPI (OR =1.323;
95% CI 1.041–1.681; p=0.022) o al sco es om V0 o V2 we e
associa ed wi h clinically significan HRQoL impai men a he
2-yea ollow-up (Hosme –Lemeshow es , p=0.217; R
2
=0.816),
bu no he change in he ADLS sco e (OR =0.889; 95% CI
0.786–1.1006; p=0.062). Mode a e co ela ions we e obse ed
be ween he change om V0 o V2 in he PDQ-39SI sco e and he
sco e in FOGQ ( =0.39; p< 0.0001), NMSS ( =0.41; p< 0.0001),
NPI ( =0.35; p< 0.0001) and ADLS ( =−0.41; p< 0.0001)
(Supplemen a y Table 2).
P edic o s o he change in he PDQ-39SI om V0 o V2
Finally, simila esul s we e obse ed in bo h g oups, he whole
coho and he ea ly PD subg oup, when a linea eg ession model
was conside ed (PDQ-39SI change om V0 o V2 as dependen
a iable) (Supplemen a y Table 2). To be a emale (β=0.17; p<
0.0001) and change in UPDRS-III (β=0.23; p< 0.0001), FOGQ (β=
0.20; p< 0.0001), and NMSS (β=0.37; p< 0.0001) sco es p o ided
he highes con ibu ion o he model (adjus ed R-squa ed 0.45) in
he whole coho . In ea ly PD pa ien s, he a iables associa ed
wi h HRQoL change a he 2-yea ollow-up we e he same
(Supplemen a y Table 2). When he ADLS sco e was included in
he model, he esul s we e simila bu wi h he ADLS as an
independen a iable associa ed wi h HRQoL change oo (β=
−0.21; 95% CI −0.353, −0.107; p< 0.0001; adjus ed R-squa ed 0.45
[N=500; all coho ]; β=−0.23; 95% CI −0.433, −0.076; p=0.005;
adjus ed R-squa ed 0.431 [N=277; ea ly PD subg oup]).
DISCUSSION
In his longi udinal ollow-up s udy, we epo ha he e is a
significan HRQoL impai men in PD pa ien s in he sho - e m
and ha impai men in he mo o s a us du ing he OFF s a e
(UPDRS-III), inc eased gai p oblems (FOGQ), and inc eased NMS
bu den con ibu e o i . Specifically, mood impai men and NMS
bu den inc ease we e independen ac o s associa ed wi h
clinically significan HRQoL impai men a he 2-yea ollow-up,
which one was p esen in abou e e y 5 pa ien s. Mo eo e , he
esul s indica e ha i will be especially impo an o be igilan
abou clinically significan HRQoL impai men in women and
younge pa ien s.
A e a 2-yea ollow-up, PD pa ien s om he COPPADIS coho
demons a ed impai men in mo o unc ion (H&Y, UPDRS-III, UPDRS-
IV, FOGQ). The inc ease o mo o impai men s measu ed wi h he
UPDRS we e in ag eemen wi h o he s udies
27,28
.Also,significan
changes in NMS we e obse ed in he NMS bu den as a whole, pain,
a igue, and cogni ion, bu no in con ols. These esul s aligned wi h
p e ious longi udinal s udies indica ing ha he se e i y o NMS in
PD ends o become p og essi ely wo se wi h he cou se o he
disease and also indica e ha non-mo o e alua ion is complemen-
a y o measu ing PD p og ession
19,26,29–32
.Wi h espec o heQoL,
al hough mo e han a hal o PD pa ien s p esen ed a PDQ-39SI sco e
a he 2-yea ollow-up highe han a baseline, only 18.6% p esen ed
HRQoL impai men as clinically significan . In a p e ious s udy wi h
707 PD pa ien s ollowed p ospec i ely o he 2-yea as well, 17%
wo sened clinically while 584 we e a ed as s able
29
.The esul scan
be a y due o he defini ion o QoL impai men as clinically
significan
31,33,34
. Based on he pos al eply o 728 PD pa ien s, Pe o
e al.
34
de e mined ha 1.6 poin s wo sening on a PDQ-39SI is he
minimal clinically impo an di e ence h eshold. Mo e ecen ly,
Ho á h e al.
31
conside ed he mos op imal es ima es h eshold o
PDQ-39-SI in +4.22 poin s o de ec ing minimal clinically impo an
wo sening. Howe e , he e is no “gold s anda d”me hodology o
es ima ing he minimal impo an di e ence and as he deg ee o
imp o emen is condi ioned by he baseline sco e; he e o e, he use
o a pe cen age migh be mo e app op ia e
35,36
. Pa ien s appea o
be able o de ec changes o 7–10% on QoL ins umen s o pain
scales
36
. In ou case, he minimal impo an di e ence was conside ed
Table 2. Changes in mo o and non-mo o symp oms and disabili y in
PD pa ien s om V0 (baseline) o V2 (2 yea s ± 1 mon h) wi h ega ds
o p esen ing o no clinically significan HRQoL impai men .
Non clinically
significan HRQoL
impai men
N=407
Clinically
significan HRQoL
impai men
N=93
p
Age a baseline 63.04 ± 7.99 61.32 ± 10.17 0.354
Gende (males) (%) 60 57 0.341
Disease du a ion
(a V0)
5.65 ± 4.36 4.91 ± 3.55 0.247
Numbe o non-
an ipa k. d ugs
(a V0)
2.56 ± 2.36 2.33 ± 2.49 0.220
Change a V2 ( om V0 o V2)
LEDD +177.15 ± 330.2 +228.75 ± 318.27 0.174
Numbe o non-
an ipa k. d ugs
+0.55 ± 1.56 +0.65 ± 1.45 0.685
UPDRS-III (OFF) +2.25 ± 9.77 +7.76 ± 11.2 <0.0001
UPDRS-IV +0.47 ± 2.47 +1.47 ± 2.55 0.002
FOGQ +0.68 ± 3.85 +3.32 ± 4.71 <0.0001
PD-CRS −2.17 ± 12.18 −0.67 ± 10.12 0.293
NMSS +4.15 ± 32.03 +28.64 ± 35.65 <0.0001
Ca dio ascula +6.21 ± 14.41 +8.11 ± 12.83 0.310
Sleep/ a igue +0.7 ± 15.96 +12.98 ± 18.42 <0.0001
Mood/apa hy +0.5 ± 14.57 +8.62 ± 15.19 <0.0001
Pe cep ual
symp oms
+1.89 ± 10.61 +4.35 ± 12.56 0.141
A en ion/memo y +1.74 ± 14.16 +7.28 ± 17.30 0.07
Gas oin es inal
symp oms
+2.19 ± 12.64 +4.9 ± 12.8 0.020
U ina y symp oms +1.29 ± 20.22 +9.28 ± 21.56 0.001
Sexual dys unc ion +2.63 ± 30.71 +10.51 ± 23.43 0.007
Miscellaneous +0.72 ± 14.88 +6.19 ± 14.89 0.011
BDI-II −0.63 ± 7.75 +4.51 ± 6.13 <0.0001
PDSS +2.82 ± 25.80 −9.04 ± 24.96 <0.0001
QUIP-RS −0.02 ± 9.25 +0.34 ± 8.06 0.736
NPI −0.43 ± 4.28 +4.28 ± 8.06 <0.0001
VAS-PAIN +0.18 ± 3.21 +1.01 ± 3.74 0.023
VASF −physical +0.09 ± 2.97 +1.1 ± 2.92 0.004
VASF-men al −0.12 ± 2.76 +1.05 ± 2.95 0.002
ADLS −2.84 ± 11.08 −10.97 ± 12.42 <0.0001
Chi-squa ed and Mann–Whi ney–Wilcoxon es we e applied. The esul s
ep esen pe cen ages o mean ± SD. The symbol “+”indica es an inc ease
in he sco e o he scale a V2 compa ed o V0 while he symbol “–”
indica es a dec ease. Da a abou UPDRS-III a e du ing he OFF s a e (fi s
hou in he mo ning wi hou aking medica ion in he p e ious 12 h).
ADLS Schwab & England Ac i i ies o Daily Li ing Scale, BDI-II Beck
Dep ession In en o y-II, FOGQ, F eezing O Gai Ques ionnai e, LEDD
le odopa equi alen daily dose (mg), NMSS 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, 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 Unified Pa kinson’s Disease Ra ing Scale, VAFS Visual Analog Fa igue
Scale, VAS-Pain Visual Analog Scale-Pain.
The bold alues indica es s a is ically significan p alues.
D.S. Ga cía e al.
4
npj Pa kinson’s Disease (2021) 118 Published in pa ne ship wi h he Pa kinson’s Founda ion
as an inc ease o 10% o mo e in he PDQ-39SI sco e
33,35–37
.Ten
pe cen o he mean sco e o he PDQ-39SI in ou s udy ep esen s
1.6 poin s; he e o e, simila o he p oposal o Pe o e al.
34
.Howe e ,
in a pa ien wi h a highe baseline PDQ-39SI sco e, o example, 50
poin s, he minimal clinically significan wo sening change should be
5 poin s. Hence, in less han 1 in 3 pa ien s who had an inc ease in
he PDQ-39 sco e, his was conside ed clinically significan . In any
case,i seemsclea ha e enina ela i elysho ollow-uppe iod,
pa ien s wi h PD expe ience a significan dec ease in HRQoL
21,29
.
Howe e , as Reu he e al.
22
epo ed in 145 PD pa ien s a e a 12-
mon h ollow-up, he e doesn’ seem o be a significan change in
QoL gene ic scales.
Fo assessing he NMS as a whole, we used he NMSS. To da e,
his scale has been used in mo e han 100 clinical s udies and
ials and i has shown o be capable o de ec ing longi udinal
changes in NMS, whe e s udies ha e shown di e en ial changes
o e ime o se e al o he NMSS domains
32,38,39
. Mo eo e , i has
been demons a ed a consis en and s ong co ela ions be ween
NMSS bu den and HRQoL measu es
32,40–42
. In ou s udy, a e y
clea di e ence in he change o NMS bu den was obse ed
be ween pa ien s wi h and wi hou clinically significan HRQoL
impai men . Changes in all domains o he NMSS scale co ela ed
wi h QoL changes. Simila ly, p e ious s udies obse ed a
co ela ion be ween NMS bu den assessed wi h he NMSS and
QoL changes o e ime
19
. Mo eo e , in ou analysis, NMS bu den
p og ession was an independen ac o ela ed o HRQoL
impai men . P akash e al. obse ed o he fi s ime ha non-
mo o p oblems p o ided a be e p edic ion o he change o
QoL in 227 PD pa ien s o e a 2-yea ollow-up pe iod
19
. Howe e ,
hey did no p o ide he a iance alue o he model, many
ac o s po en ially a ec ing QoL we e no included, and wha hey
conside ed was he baseline NMSS sco e. On he con a y, in his
s udy we wan ed o analyze in de ail wha changes in many
aspec s o he disease obse ed a e he 2-yea ollow-up
con ibu ed o a wo sening in he pa ien s´ QoL. So, se e al
a iables we e included, he esul s o he model ep esen ed
~70% o he a iance when HRQoL changes we e conside ed, and
he changes in all a iables we e adjus ed o he sco es a
baseline. To ou bes knowledge, his is he fi s longi udinal-
p ospec i e s udy analyzing in such de ail which a e he p edic o s
o QoL impai men in a la ge sample o PD pa ien s. Rein o cing
he idea ha he p og ession o NMS is pi o al o he wo sening o
he QoL h oughou he e olu ion o he disease, imp o emen s o
NMS we e associa ed wi h imp o ed QoL in ad anced pa kinso-
nian pa ien s du ing 2‐yea ea men wi h le odopa‐ca bidopa
in es inal gel in usion he apy
43
. In line wi h his, E o e al.
obse ed ha NMS significan ly a ec ed QoL in PD, demons a -
ing ha his was especially he case when pa ien s we e in hei
honeymoon pe iod (du ing which ime he side e ec s o he
disease a en’ oo disabling and he e is a esponse o
medica ions)
44
. In he subg oup o ea ly PD pa ien s om ou
s udy, he change in he NMSS o al sco e a 2-yea s was one o
he mos significan con ibu o s o HRQoL impai men .
Ano he impo an ac o is mood. Like in o he s udies, he
mean sco e o BDI didn’ change o e ime
18,22
, sugges ing ha
dep ession- ype equency does no appea o change o e ime
in PD
45
. C oss-sec ional s udies ha e epo ed he clea con ibu-
ion o dep ession o a wo se mood o a poo e QoL in PD
pa ien s
3,12,13
. In ac , i was obse ed in he COPPADIS baseline
c oss-sec ional analysis
14
. Howe e , o ou knowledge, his is he
fi s ime ha mood wo sening is iden ified as an independen
ac o associa ed wi h clinically significan HRQoL impai men in
PD pa ien s. This subg oup o pa ien s (N=93) p esen ed a mean
inc ease in he BDI-II sco e o 4.5 poin s a he 2-yea ollow-up
and specifically, an inc ease in ≥5 poin s mul iplied by 5 he
p obabili y o p esen ing a clinically significan HRQoL impai -
men , independen o o he ac o s. Reu he e al.
22
iden ified
dep ession as he s onges p edic o o educed HRQoL in 145
PD pa ien s a e 1-yea ollow-up. Howe e , we iden ified he
change in he sco e o he BDI-II as a p edic o o clinically
significan HRQoL impai men a e adjus men o BDI-II sco e a
baseline. F om a p ac ical poin o iew, ou findings sugges an
impo an ole o he neu ologis being ale o a possible
wo sening o mood, as well as g ea e NMS bu den, in pa ien s
wi h PD h oughou he e olu ion o he disease since his is wha
impac s on he pa ien ’s QoL. Knowing wha impac s on he QoL
and con ibu es o i s wo sening, depending on he a iable,
in e en ion measu es wi h he in en ion o co ec ing hem can
be p oposed
46
. S udies demons a ing a QoL imp o emen
co ela ed wi h mood and NMS bu den imp o emen ha e been
published
47
. Wi h ega ds o he esul s obse ed he e, i should
be necessa y o be ale abou mood and NMS bu den changes
o e ime, especially in younge pa ien s and emales. A mildly
significan gende di e ence in disabili y and QoL epo ing has
been no ed, wi h women ci ing g ea e disabili y and educed
QoL
48,49
. Dep ession and a igue we e he majo causes o low
Fig. 2 E olu ion o NMS a e 2-yea ollow up. A Change in he NMSS o al sco e om V0 (baseline) o V2 (2 yea ± 1 mon h) in PD pa ien s
wi hou s wi h clinically significan HRQoL impai men . BMean sco e on each domain o he ESS scale a V0 and V2 in PD pa ien s wi hou s
wi h clinically significan HRQoL impai men . Da a a e p esen ed as box plo s, wi h he box ep esen ing he median and he wo middle
qua iles (25–75%). p- alues we e compu ed using he Wilcoxon-signed ank es . Mild ou lie s (O) a e da a poin s ha a e mo e ex eme han
Q1 −1.5 * IQR o Q3 +1.5 * IQR. NMSS, Non-Mo o Symp oms Scale.
D.S. Ga cía e al.
5
Published in pa ne ship wi h he Pa kinson’s Founda ion npj Pa kinson’s Disease (2021) 118

HRQoL in women e en in he ea ly phases o PD
50
. To a enua e
his sex di e ence in disease expe ience, psychological dis ess
sc eening and managemen (pa icula ly a ge ing emales)
should be conside ed as pa o PD clinical ca e
23
. Mo eo e ,
QoL, as measu ed on he PDQ-39, is significan ly wo se in young-
onse PD pa ien s han in olde -onse PD pa ien s, and young-
onse PD pa ien s also expe ience loss o employmen , dis up ion
o amily li e, g ea e pe cei ed s igma iza ion, and dep ession
han do olde -onse PD pa ien s
51,52
.
The mos impo an limi a ion o his s udy is he ac ha
in o ma ion abou ollow-up was eco ded only in 524 pa ien s o
695 ini ially included in he s udy (75.5%). O hem, da a o he
PDQ-39, PQ-10, and EUROHIS-QOL8 a baseline and a V2 was
a ailable in 500, 503, and 507 PD pa ien s, espec i ely. Thi y-eigh
pa ien s (5.5%) d opped ou o he s udy (1 dea h; 2 wi h change in
diagnosis; 35 o he easons) a he 2-yea ollow-up and 132 (19%)
we e no assessed. Howe e , his is a limi a ion obse ed in o he
p ospec i e s udies. O 7507 PD pa ien s, ollow-up da a was
a ailable only o 4680 pa icipan s (62.3%)
53
. In he s udy o
An onini e al.
29
, 707 PD pa ien s om 1142 ini ially included (61.9%)
we e e aluable a 24 mon hs. An impo an second limi a ion is ha
PD pa ien s olde han 75 yea s old we e excluded om
pa icipa ion by COPPADIS s udy p o ocol
14
, which leads o an ea ly
PD bias in his coho . Fo some a iables, he in o ma ion was no
collec ed in all cases. Mo eo e , his is a mul icen e mono-coun y
s udy, being he ideal o his ype o s udies he pa icipa ion o
pa ien s om di e en pa s o he wo ld, so he esul s should be
conside ed wi h cau ion when ex apola ing hem o he gene al PD
popula ion (i.e., ace, coun y heal hca e, e c.). By he con a y,
s eng hs o ou s udy include a e y comple e assessmen , he la ge
sample size, a p ospec i e longi udinal ollow-up design, he ac
ha his analysis was “a p io i”planned as one objec i e o he
mul icen e COPPADIS p ojec
16
, and he ex ensi e clinical and
demog aphic in o ma ion eco ded.
The findings o his s udy ha e impo an implica ions in daily
clinical p ac ice. In a diso de like PD in which one he e is no a
cu e, ea men is symp oma ic and he aim is o imp o e he
pa ien ’s QoL. This is complex because many ac o s influence
QoL in PD. Fu he mo e, PD is a complex diso de wi h many
mani es a ions and wi h a g ea a iabili y in i s p og ession
among pa ien s. Rega ding his s udy obse a ions, some
impo an poin s should be conside ed in daily clinical p ac ice.
Fi s , a comple e assessmen o he pa ien wi h PD pe iodically
including mo o s a us, NMS, QoL and disabili y should be he
ideal p ac ice. Second, NMS p og ession con ibu es significan ly
o a QoL wo sening and i is c ucial i s e alua ion. Ve y
in e es ingly, we epo ed e y ecen ly ha PD pa ien s om
he COPPADIS coho wi h a lowe H&Y s age bu a g ea e global
NMS bu den may ha e a wo se QoL han pa ien s wi h a highe
H&Y s age bu lowe global NMS
54
. Thi d, mood is ano he key
ac o o conside whene e we e alua e he pa ien in clinical
p ac ice. Fou h, we ha e o keep in mind ha mood impai men
and global NMS p og ession p edic a pa ien ´s QoL wo sening.
Finally, we should be especially ca e ul in all o he abo e in he
case o a emale pa ien and in young pa ien s.
A p oblem in clinical p ac ice is he lack o ime o e alua e he
pa ien . Fo he PD pa ien , o b ing adequa ely co e ed ques-
ionnai es o he consul a ion, o example wi h he help o nu sing
s a , o e en in he u u e wi h mobile applica ions ha ans e he
da a o he pa ien ’s medical eco d, i could be a possibili y ha
acili a es he comple e and comp ehensi e assessmen . In gene al, i
is some hing ha is no done oday, and p oo o his is he ala ming
lack o li e a u e abou he global p og ession o he disease including
NMS in la ge coho s o pa ien s. Mo e s udies wi h la ge PD coho s
and long- e m ollow-up a e equi ed. Ou aim wi h he COPPADIS
coho is o ollow o 5 yea s
55
. Collec ing da a om di e en coho s
and making compa isons would also be o g ea in e es .
In conclusion, he p esen s udy obse es HRQoL impai men
in PD pa ien s in a sho 2-yea ollow-up, e en in ea ly PD
pa ien s, bu no he GQoL. A younge age, o be a emale, and
mood and NMS bu den impai men we e associa ed wi h
clinically significan HRQoL impai men a e he 2-yea ollow-
up. The p og ession o NMS is pi o al in he wo sening o he QoL
h oughou he e olu ion o he disease in PD, and i is necessa y
o keep in mind o ask o mood o NMS changes, especially in
emales and young pa ien s.
Table 3. Bina y logis ic eg ession model abou ac o s associa ed wi h clinically significan HRQoL impai men a V2 (2 yea s ollow-up).
OR
a
OR
b
95% CI
a
95% CI
b
p
a
p
b
Age 0.896 0.813 0.829–0.968 0.709–0.933 0.006 0.003
Gende ( emale) 4.181 35.847 3.452–372.204 1.378–8.424 0.009 0.003
Disease du a ion 1.040 0.734 0.388–1.389 0.763–1.360 0.673 0.342
No. o non-an ipa kinsonian d ugs/day 0.922 1.005 0.728–1.167 0.697–1.449 0.499 0.979
Change a 2 yea s ollow-up
LEDD (mg) 1.000 1.002 0.998–1.005 0.998–1.002 0.860 0.385
UPDRS-III 1.056 1.088 0.995–1.120 0.978–1.211 0.071 0.121
UPDRS-IV 0.959 0.756 0.417–1.372 0.650–1.137 0.785 0.358
FOGQ 1.143 1.160 0.906–1.485 1.108–1.559 0.088 0.239
NMSS 1.052 1.069 1.027–1.113 1.007–1.043 <0.0001 0.001
PD-CRS 0.995 0.972 0.900–1.050 0.963–1.045 0.837 0.473
BDI-II 1.139 1.400 1.053–1.231 1.149–1.705 0.001 0.001
NPI 1.037 1.158 0.976–1.103 0.995–1.348 0.238 0.058
Dependen a iable: Clinically significan HRQoL impai men (defined as PDQ-39SI
V2
≥10% PDQ-39SI
V0
). OR and 95% CI a e shown. Hosme –Lemeshow es ,
p
a
=0.665; p
b
=0.998; R
2a
=0.655; R
2b
=745. The model was adjus ed o a iables a baseline: LEDD (mg), UPDRS-III, UPDRS-IV, FOGQ, NMSS, PD-CRS, BDI-II,
NPI, PDQ-39SI.
BDI-II Beck Dep ession In en o y-II, FOGQ F eezing O Gai Ques ionnai e, LEDD le odopa equi alen daily dose (mg), NMSS 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-39SI 39-i em Pa kinson’s Disease Quali y o Li e Ques ionnai e Summa y
Index, QUIP-RS, Ques ionnai e o Impulsi e-Compulsi e Diso de s in Pa kinson’s Disease-Ra ing Scale, UPDRS Unified Pa kinson’s Disease Ra ing Scale.
a
All coho (n=500).
b
Ea ly PD pa ien s (n=277).
The bold alues indica es s a is ically significan p alues.
D.S. Ga cía e al.
6
npj Pa kinson’s Disease (2021) 118 Published in pa ne ship wi h he Pa kinson’s Founda ion
METHODS
PD pa ien s and con ols who we e ec ui ed om Janua y 2016 o
No embe 2017 (baseline isi ; V0) and e alua ed again a he 2-yea
ollow-up (V2) om 35 cen e s o Spain om he COPPADIS coho
56
, we e
included in he s udy. Me hodology abou COPPADIS-2015 has been
p e iously published
57
. This is a mul icen e , obse a ional, longi udinal-
p ospec i e, 5-yea ollow-up s udy designed o analyzing disease
p og ession in a Spanish popula ion o PD pa ien s. Specifically, 17
objec i es we e p oposed in he p o ocol
55
. E en hough he ec ui men
pe iod ended in Oc obe 2017, he p ospec i e ollow-up phase is ongoing.
Pa ien s, ca egi e s (pa ien ´s p ima y ca egi e ), and con ols (subjec s
wi hou PD and any o he se e e and disabling concomi an diso de ) we e
included
55
. Annual isi s om V0 (baseline) o V5 (60 mo hs ± 3 mon hs) a e
conduc ed o he pa ien s and a V0, V2, V4, and V5 o he con ols and
ca egi e s. All pa ien s included we e diagnosed acco ding o UK PD B ain
Bank c i e ia
57
. Exclusion c i e ia
55
we e: non-PD pa kinsonism, demen ia
c i e ia (Mini Men al S a e Examina ion [MMSE] ≥26), age < 18 o >75 yea s,
inabili y o ead o unde s and he ques ionnai es, o be ecei ing any
ad anced he apy (con inuous in usion o le odopa o apomo phine, and/
o wi h deep b ain s imula ion), and p esence o como bidi y, sequelae, o
any diso de ha could in e e e wi h he assessmen .
In o ma ion on sociodemog aphic aspec s, ac o s ela ed o PD,
como bidi y, and ea men we e collec ed. V0 and V2 e alua ions
included
55
: (1) mo o assessmen (Hoenh & Yah [H&Y]
58
, Unified
Pa kinson’s Disease Ra ing Scale [UPDRS] pa III and pa IV
59
, F eezing
o Gai Ques ionnai e [FOGQ]
60
; (2) NMS (Non-Mo o Symp oms Scale
[NMSS]
61
, Pa kinson’s Disease Sleep Scale [PDSS]
62
, Visual Analog Scale-
Pain [VAS-Pain]
63
, Visual Analog Fa igue Scale [VAFS]
64
, cogni ion (MMSE
65
,
Pa kinson’s Disease Cogni i e Ra ing Scale [PD-CRS]
66
, comple ing a simple
16-piece puzzle); (3) mood and neu opsychia ic symp oms (Beck
Dep ession In en o y-II [BDI-II]
67
, Neu opsychia ic In en o y [NPI]
68
,
Ques ionnai e o Impulsi e-Compulsi e Diso de s in Pa kinson’s Disease-
Ra ing Scale [QUIP-RS]
69
; (4) and disabili y (Schwab & England Ac i i ies o
Daily Li ing Scale [ADLS]
70
. In pa ien s wi h mo o fluc ua ions, he mo o
assessmen was made du ing he OFF s a e (wi hou medica ion in he las
12 h) and du ing he ON s a e. On he o he hand, he assessmen was only
conduc ed wi hou medica ion in pa ien s wi hou mo o fluc ua ions. The
same e alua ion as o he pa ien s, excep o he mo o assessmen , was
conduc ed in con ol subjec s a V0 and a V2 (2 yea s ± 1 mon h). Th ee
scales we e used o assess QoL a V0 and a V2
28
: (1) he 39-i em
Pa kinson’s disease Ques ionnai e (PDQ-39)
71
, (2) a a ing o global
pe cei ed QoL (PQ-10) on a scale om 0 (wo s ) o 10 (bes )
13
, and (3)
he EUROHIS-QOL 8-i em index (EUROHIS-QOL8)
72
. The PDQ-39 is a PD-
specific ques ionnai e ha assesses he pa ien s’HRQoL. The e a e 39
i ems g ouped in o 8 domains: (1) Mobili y (i ems 1 o 10); (2) Ac i i ies o
daily li ing (i ems 11 o 16); (3) Emo ional well-being (i ems 17 o 22); (4)
S igma (i ems 23 o 26); (5) Social suppo (i ems 27 o 29); (6) Cogni ion
(i ems 30 o 33); (7) Communica ion (i ems 34 o 36); (8) Pain and
discom o (i ems 37 o 39). Fo each i em, he sco e may ange om 0
(ne e ) o 4 (always). The symp oms e e o he 4 weeks p io o
assessmen . Domain o al sco es a e exp essed as a pe cen age o he
co esponding maximum possible sco e and a Summa y Index is ob ained
as a e age o he domain sco es. The EUROHIS-QOL8 is an 8-i em GQoL
ques ionnai e (quali y o li e, heal h s a us, ene gy, au onomy o ac i i ies
o daily li ing, sel -es eem, social ela ionships, economic capaci y, and
habi a ) de i ed om 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 be e QoL. In
con ols, only he PQ-10 and he EUROHIS-QOL8 we e assessed.
Clinically significan HRQoL impai men was defined as p esen ing an
inc ease in PDQ-39SI sco e a V2 ≥10% o sco e a baseline (V0) whe eas
GQoL impai men as p esen ing a dec emen in PQ-10 and/o EUROHIS-
QOL8 sco e a V2 ≤10% o sco e a baseline (V0)
33
. Taking in o accoun
ha in he COPPADIS coho he ange o disease du a ion a ies om <1
yea o 30 yea s and based on he gene al esponse o ea men and
p og ession o symp oms in PD and conside ing a ecen publica ion o
his same coho
73
, pa ien s wi h ≤5 yea s o disease du a ion we e
conside ed as ea ly PD pa ien s.
Da a analysis
Da a we e p ocessed using SPSS 20.0 o Windows. Fo compa isons be ween
pa ien s and con ols, he S uden ’s - es , Mann–Whi ney U es , Chi-squa e
es , o Fishe es we e used as app op ia e (dis ibu ion o a iables was
e ified by one-sample Kolmogo o –Smi no es ). The Wilcoxon-signed ank
es was pe o med o es whe he he mean di e ences o he PDQ-39SI,
PQ-10, and EUROHIS-QOL8 sco es and he indi idual PDQ-39SI and EUROHIS-
QOL8 domain sco es be ween he wo isi s (V0 and V2) we e significan . This
es and/o he ma ginal homogenei y es we e applied o o he scales o
analyzing he change om V0 o V2. Spea man’so Pea son’s co ela ion
coe ficien , as app op ia e, we e used o analyzing he ela ionship be ween
con inuous a iables. Co ela ions we e conside ed weak o coe ficien
alues ≤0.29, mode a e o alues be ween 0.30 and 0.59, and s ong o
alues ≥0.60.
Clinically significan QoL impai men was exp essed as a pe cen age and
i was only calcula ed i he change be ween sco es (PDQ-39SI; PQ-10;
EUROHIS-QOL8) om V0 o V2 was significan . Fo de e mining p edic i e
ac o s o QoL impai men , a logis ic eg ession model (QoL impai men as
dependen a iable) was pe o med. The model was well-planned, as
ecommended by bes -p ac ice me hods
74
, in which known and p e-
sumably p edic o a iables a ec ing QoL changes (dependen a iable)
we e included: change om V0 o V2 in le odopa equi alen daily dose
(LEDD)
75
, UPDRS-III-OFF (mo o se e i y), UPDRS-IV (mo o complica ions),
FOGQ, NMSS (NMS bu den), PD-CRS (cogni ion), BDI-II (mood), and NPI
(neu opsychia ic symp oms). The model was adjus ed o baseline QoL and
age, gende , disease du a ion, como bidi y ( o al numbe o non-
an ipa kinsonian medica ions as su oga e ma ke
14
), and he sco e o
he es o he a iables a baseline (LEDD, UPDRS-III-OFF, UPDRS-IV, FOGQ,
NMSS, PD-CRS, and NPI). Disabili y (ADLS) was no included in he model
because his is consequence o symp oms, bu since i is ela ed o QoL, in
a second model ADLS a baseline and change in ADLS om V0 o V2 we e
included. Hosme –Lemeshow es was applied and adjus ed R-squa ed
was calcula ed o all analyses. Finally, mul iple linea eg essions we e
pe o med wi h “change in QoL”as dependen a iable bu only o
a iables (PDQ-39SI; PQ-10; EUROHIS-QOL8) changing significan ly om V0
o V2. The independen a iables included we e he same as in he bina y
model. The p- alue was conside ed significan when i was <0.05.
S anda d p o ocol app o als, egis a ions, and pa ien
consen s
The Comi é de É ica de la In es igación Clínica de Galicia om Spain (2014/
534; 02/DEC/2014) app o al was ob ained. W i en in o med consen s om
all pa icipan s in his s udy we e ob ained be o e he s a o he s udy.
COPPADIS-2015 was classified by he AEMPS as a Pos -au ho iza ion
P ospec i e Follow-up s udy wi h he code COH-PAK-2014-01.
Repo ing summa y
Fu he in o ma ion on esea ch design is a ailable in he Na u e Resea ch
Repo ing Summa y linked o his a icle.
DATA AVAILABILITY
The da a ha suppo he findings o his s udy a e a ailable om he co esponding
au ho upon easonable eques .
CODE AVAILABILITY
No compu e coding was used in he comple ion o he cu en manusc ip .
Recei ed: 25 Ma ch 2021; Accep ed: 27 July 2021;
Published online: 16 Decembe 2021
REFERENCES
1. Chaudhu i, K. R. e al. The nondecla a ion o nonmo o symp oms o Pa kinson’s
disease o heal h ca e p o essionals: an in e na ional s udy using he nonmo o
symp oms ques ionnai e. Mo . Diso d. 25, 704–709 (2010).
2. Hinnell, C. e al. Nonmo o e sus mo o symp oms: how much do hey ma e o
heal h s a us in Pa kinson’s disease? Mo . Diso d. 27, 236–241 (2012).
3. Sch ag, A., Jahanshahi, M. & Quinn, N. Wha con ibu es o quali y o li e in
pa ien s wi h Pa kinson’s disease? J. Neu ol. Neu osu g. Psychia y 69, 308–312
(2000).
4. Kuopio, A. M., Ma ila, R. J., Helenius, H., Toi onen, M. & Rinne, U. K. The quali y o
li e in Pa kinson’s disease. Mo . Diso d. 15, 216–223 (2000).
5. Muslimo ic, D., Pos , B., Speelman, J. D., Schmand, B. & de Haan, R. J. De e mi-
nan s o disabili y and quali y o li e in mild o mode a e Pa kinson disease.
Neu ology 70, 2241–2247 (2008).
D.S. Ga cía e al.
7
Published in pa ne ship wi h he Pa kinson’s Founda ion npj Pa kinson’s Disease (2021) 118
6. Beha i, M., S i as a a, A. K. & Pandey, R. M. Quali y o li e in pa ien s wi h Pa -
kinson’s disease. Pa kinsonism Rela . Diso d. 11, 221–226 (2005).
7. Ka lsen, K. H., La sen, J. P., Tandbe g, E. & Maland, J. G. Quali y o li e measu e-
men s in pa ien s wi h Pa kinson’s disease: a communi ybased s udy. Eu . J.
Neu ol. 5, 443–450 (1998).
8. Rahman, S., G i fin, H. J., Quinn, N. P. & Jahanshahi, M. Quali y o li e in Pa kinson’s
disease: he ela i e impo ance o he symp oms. Mo . Diso d. 23, 1428–1434
(2008).
9. Slawek, J., De ejko, M. & Lass, P. Fac o s a ec ing he quali y o li e o pa ien s
wi h idiopa hic Pa kinson’s disease-a c oss-sec ional s udy in an ou pa ien clinic
a endees. Pa kinsonism Rela . Diso d. 11, 465–468 (2005).
10. Chapuis, S., Ouchchane, L., Me z, O., Ge baud, L. & Du i , F. Impac o he mo o
complica ions o Pa kinson’s disease on he quali y o li e. Mo . Diso d. 20,
224–230 (2005).
11. Ka lsen, K. H., La sen, J. P., Tandbe g, E. & Maeland, J. G. Influence o clinical and
demog aphic a iables on quali y o li e in pa ien s wi h Pa kinson’s disease.
J. Neu ol. Neu osu g. Psychia y 66, 431–435 (1999).
12. Ma inez-Ma in, P. e al. The impac o non-mo o symp oms on heal h- ela ed
quali y o li e o pa ien s wi h Pa kinson’sdisease.Mo . Diso d. 26,399–406 (2011).
13. San os Ga cía, D. & de la Fuen e-Fe nández, R. Impac o non-mo o symp oms on
heal h- ela ed and pe cei ed quali y o li e in Pa kinson’s disease. J. Neu ol. Sci.
332, 136–140 (2013).
14. San os Ga cía, D. e al. Non-mo o symp oms bu den, mood, and gai p oblems
a e he mos significan ac o s con ibu ing o a poo quali y o li e in non-
demen ed Pa kinson’s disease pa ien s: esul s om he COPPADIS S udy Coho .
Pa kinsonism Rela . Diso d. 66, 151–157 (2019).
15. Ma inez-Ma in, P. Wha is quali y o li e and how do we measu e i ? Rele-
ance o Pa kinson’s disease and mo emen diso de s. Mo . Diso d. 32,
382–392 (2017).
16. Ma inez-Ma in, P. & Ku is, M. M. Heal h- ela ed quali y o li e as an ou come
a iable in Pa kinson’s disease. The . Ad . Neu ol. Diso d. 5, 105–117 (2012).
17. Soh, S. E., Mo is, M. E. & McGinley, J. L. De e minan s o heal h- ela ed quali y o li e in
Pa kinson’s disease: a sys ema ic e iew. Pa kinsonism Rela . Diso d. 17,1–9 (2011).
18. Ka lsen, K. H., Tandbe g, E., A sland, D. & La sen, J. P. Heal h ela ed quali y o li e
in Pa kinson’s disease: a p ospec i e longi udinal s udy. J. Neu ol. Neu osu g.
Psychia y 69, 584–589 (2000).
19. P akash, K. M., Nadka ni, N. V., Lye, W. K., Yong, M. H. & Tan, E. K. The impac o
non-mo o symp oms on he quali y o li e o Pa kinson’s disease pa ien s: a
longi udinal s udy. Eu . J. Neu ol. 23, 854–860 (2016).
20. Higginson, I. J. e al. Symp oms and quali y o li e in la e s age Pa kinson syn-
d omes: a longi udinal communi y s udy o p edic i e ac o s. PLoS ONE 7,
e46327 (2012).
21. Visse , M., Ve baan, D., an Rooden, S., Ma inus, J., an Hil en, J. & S iggelbou , A.
A longi udinal e alua ion o heal h- ela ed quali y o li e o pa ien s wi h Pa -
kinson’s disease. Value Heal h 12, 392–396 (2009).
22. Reu he , M. e al. Assessing heal h- ela ed quali y o li e in pa ien s wi h Pa -
kinson’s disease in a p ospec i e longi udinal s udy. Pa kinsonism Rela . Diso d.
13, 108–114 (2007).
23. Ab aham, D. S. e al. Sex di e ences in Pa kinson’s disease p esen a ion and
p og ession. Pa kinsonism Rela . Diso d. 69,48–54 (2019).
24. Klie z, M. e al. Impai ed quali y o li e and need o pallia i e ca e in a Ge man
Coho o ad anced Pa kinson’s disease pa ien s. F on . Neu ol. 9, 120 (2018).
25. Fasano, A. e al. Cha ac e izing ad anced Pa kinson’s disease: OBSERVE-PD
obse a ional s udy esul s o 2615 pa ien s. BMC Neu ol. 19, 50 (2019).
26. Valko ic, P., Ha sany, J., Hanako a, M., Ma inko a, J. & Bene in, J. Nonmo o
symp oms in ea ly- and ad anced-s age Pa kinson’s disease pa ien s on dopa-
mine gic he apy: how do hey co ela e wi h quali y o li e? ISRN Neu ol. 2014,
587302 (2014).
27. Velseboe , D. C. e al. P ognos ic ac o s o mo o impai men , disabili y, and
quali y o li e in newly diagnosed PD. Neu ology 80, 627–633 (2013).
28. Pos , B. e al. P og ession and p ognos ic ac o s o mo o impai men , disabili y
and quali y o li e in newly diagnosed Pa kinson’s disease. Mo Diso d. 26,
449–456 (2011).
29. An onini, A. e al. The p og ession o non-mo o symp oms in Pa kinson’s disease
and hei con ibu ion o mo o disabili y and quali y o li e. J. Neu ol. 259,
2621–2631 (2012).
30. Simuni, T. e al. Baseline p e alence and longi udinal e olu ion o non-mo o
symp oms in ea ly Pa kinson’s disease: he PPMI coho . J. Neu ol. Neu osu g.
Psychia y. 89,78–88 (2018).
31. Ho á h, K. e al. Changes in quali y o li e in Pa kinson’s disease: how la ge mus
hey be o be ele an ? Neu oepidemiology 48,1–8 (2017).
32. Ou, R. e al. P og ession o non-mo o symp oms in Pa kinson’sdiseaseamong
di e en age popula ions: a wo-yea ollow-up s udy. J. Neu ol. Sci. 360,72–77 (2016).
33. Ringash, J., O’Sulli an, B., Bezjak, A. & Redelmeie , D. A. In e p e ing clinically
significan changes in pa ien - epo ed ou comes. Cance 110, 196–202 (2007).
34. Pe o,V.,Jenkinson,C.&Fi zpa ick,R.De e mining minimally impo an di e ences
o he PDQ-39 Pa kinson’s disease ques ionnai e. Age Ageing 30,299–302 (2001).
35. B ozek, J. L., Guya , G. H. & Schünemann, H. J. How a well-g ounded minimal
impo an di e ence can enhance anspa ency o labelling claims and imp o e
in e p e a ion o a pa ien epo ed ou come measu e. Heal h Qual. Li e Ou comes
27, 69 (2006).
36. Ba e , B., B own, D., Mund , M. & B own, R. Su ficien ly impo an di e ence:
expanding he amewo k o clinical significance. Med. Decis. Making 25, 250–261
(2005).
37. Deng, X. e al. Fou -yea longi udinal s udy o mo o and non-mo o symp oms in
LRRK2- ela ed Pa kinson’s disease. F on . Neu ol. 10, 1379 (2020).
38. an Wamelen, D. J. e al. In e na ional Pa kinson and Mo emen Diso de Socie y
Pa kinson’s Disease Non-Mo o S udy G oup. The Non-Mo o Symp oms Scale in
Pa kinson’s disease: alida ion and use. Ac a Neu ol. Scand. 143,3–12 (2021).
39. Ma inez-Ma in, P. e al. Gende - ela ed di e ences in he bu den o non-mo o
symp oms in Pa kinson’s disease. J. Neu ol. 259, 1639–1647 (2012).
40. Guo, X. e al. Disease du a ion- ela ed di e ences in non-mo o symp oms: a
s udy o 616 Chinese Pa kinson’s disease pa ien s. J. Neu ol. Sci. 330,32–37
(2013).
41. Song, W. e al. The impac o non-mo o symp oms on he heal h- ela ed quali y
o li e o Pa kinson’s disease pa ien s om Sou hwes China. Pa kinsonism Rela .
Diso d. 20, 149–152 (2014).
42. Wu, Y. e al. De e minan s o he quali y o li e in Pa kinson’s disease: esul s o a
coho s udy om Sou hwes China. J. Neu ol. Sci. 340, 144–149 (2014).
43. Ray Chaudhu i, K. e al. Bu den o non-mo o symp oms in Pa kinson’s disease
pa ien s p edic s imp o emen in quali y o li e du ing ea men wi h le odopa-
ca bidopa in es inal gel. Eu . J. Neu ol. 26, 581–e43 (2019).
44. E o, R. e al. The non-mo o side o he honeymoon pe iod o Pa kinson’s disease
and i s ela ionship wi h quali y o li e: a 4-yea longi udinal s udy. Eu . J. Neu ol.
23, 1673–1679 (2016).
45. San os-Ga cía, D. e al. Sleep p oblems a e ela ed o a wo se quali y o li e and a
g ea e non-mo o symp oms bu den in Pa kinson’s disease. In . J. Ge ia . Psy-
chia y 34, 642–658 (2021).
46. Ra e y, M. R. e al. Regula exe cise, quali y o li e, and mobili y in Pa kinson’s
disease: a longi udinal analysis o Na ional Pa kinson Founda ion quali y
imp o emen ini ia i e da a. J. Pa kinsons. Dis. 7, 193–202 (2017).
47. San os Ga cía, D. e al. Safinamide imp o es non-mo o symp oms bu den in
Pa kinson’s disease: an open-label p ospec i e s udy. B ain Sci. 11, 316 (2021).
48. Shulman, L. M. Gende di e ences in Pa kinson’s disease. Gend. Med. 4,8–18
(2007).
49. C ispino, P. e al. Gende di e ences and quali y o li e in Pa kinson’s disease. In .
J. En i on. Res. Public. Heal h 18, 198 (2020).
50. Yoon, J. E. e al. Gende di e ences o nonmo o symp oms a ec ing quali y o
li e in Pa kinson disease. Neu odegene . Dis. 17, 276–280 (2017).
51. Sch ag, A., Ho is, A., Mo ley, A., Quinn, A. & Jahanshahi, M. Young- e sus olde -
onse Pa kinson’s disease: impac o disease and psychosocial consequences.
Mo . Diso d. 18, 1250–1256 (2003).
52. Mehanna, R. & Janko ic, J. Young-onse Pa kinson’s disease: I s unique ea u es
and hei impac on quali y o li e. Pa kinsonism Rela . Diso d. 65,39–48 (2019).
53. Shahgholi, L. e al. Hospi aliza ion and ehospi aliza ion in Pa kinson disease
pa ien s: da a om he Na ional Pa kinson Founda ion Cen e s o Excellence.
PLoS ONE 12, e0180425 (2017).
54. San os Ga cía, D. e al. S aging Pa kinsonas disease combining mo o and non-
mo o symp oms co ela es wi h disabili y and quali y o li e. Pa kinsons Dis.
2021, 8871549 (2021).
55. San os-Ga cía, D. e al. COPPADIS S udy G oup. COPPADIS-2015 (COho o
Pa ien s wi h PA kinson’s DIsease in Spain, 2015), a global-clinical e alua ions,
se um bioma ke s, gene ic s udies and neu oimaging-p ospec i e, mul icen e ,
non-in e en ional, long- e m s udy on Pa kinson’s disease p og ession. BMC
Neu ol. 16, 26 (2016).
56. San os Ga cía, D. e al. COPPADIS S udy G oup. COPPADIS-2015 (COho o
Pa ien s wi h PA kinson’s DIsease in Spain, 2015): an ongoing global Pa kinson’s
disease p ojec abou disease p og ession wi h mo e han 1000 subjec s inclu-
ded. Resul s om he baseline e alua ion. Eu . J. Neu ol. 26, 1399–1407 (2019).
57. Daniel, S. E. & Lees, A. J. Pa kinson’s Disease Socie y B ain Bank, London: o e iew
and esea ch. J. Neu al. T ansm. Suppl. 39, 165–172 (1993).
58. Hoehn, M. M. & Yah , M. D. Pa kinsonism: onse , p og ession and mo ali y.
Neu ology 17, 427–442 (1967).
59. Fanhn, S., El on, R. L. & Membe s o he UPDRS De elopmen Commi ee. in
Recen De elopmen s in Pa kinson’s Disease (eds. Fahn, S., Ma sden, C. D., Calne, D.
B. & Golds ein M.) Vol. 2, 153–164 (Macmillan Heal h Ca e In o ma ion, Flo ham
Pa k, NJ, 1987).
60. Giladi, N., Shab ai, H., Simon, E. S., Bi an, S., Tal, J. & Ko czyn, A. D. Cons uc ion o
eezing o gai ques ionnai e o pa ien s wi h Pa kinsonism. Pa kinsonism Rela .
Diso d. 6, 165–170 (2000).
D.S. Ga cía e al.
8
npj Pa kinson’s Disease (2021) 118 Published in pa ne ship wi h he Pa kinson’s Founda ion
61. Chaudhu i, K. R. e al. The me ic p ope ies o a no el non-mo o symp oms scale
o Pa kinson’s disease: Resul s om an in e na ional pilo s udy. Mo . Diso d. 22,
1901–1911 (2007).
62. Chaudhu i, K. R. e al. The Pa kinson’s disease sleep scale: a new ins umen o
assessing sleep and noc u nal disabili y in Pa kinson’s disease. J. Neu ol. Neu o-
su g. Psychia y 73, 629–635 (2002).
63. Bu ckha d , C. S. & Jones, K. D. Adul measu es o pain: The McGill Pain Ques-
ionnai e (MPQ), Rheuma oid A h i is Pain Scale (RAPS), Sho Fo m McGill Pain
Ques ionnai e (SF-MPQ), Ve bal Desc ip i e Scale (VDS), Visual Analog Scale
(VAS), and Wes Ha en-Yale Mul idisciplina y Pain In en o y (WHYMPI). A h i is.
Rheum. 49,96–104 (2003).
64. Tseng, B. Y., Gajewski, B. J. & Kluding, P. M. Reliabili y, esponsi eness, and alidi y
o he isual analog a igue scale o measu e exe ion a igue in people wi h
ch onic s oke: a p elimina y s udy. S oke. Res. T ea . 2010, 412964 (2010).
65. Fols ein, M. F., Fols ein, S. E. & McHugh, P. R. Mini-men al s a e". A p ac ical
me hod o g ading he cogni i e s a e o pa ien s o he clinician. J. Psychia .
Res. 12, 189–198 (1975).
66. Pagonaba aga, J., Kulise sky, J., Lleba ia, G., Ga cía-Sánchez, C., Pascual-Sedano,
B. & Gi onell, A. Pa kinson’s disease-cogni i e a ing scale: a new cogni i e scale
specific o Pa kinson’s disease. Mo . Diso d. 23, 998–1005 (2008).
67. Beck, A. T., S ee , R. A. & B own, G. K. Beck Dep ession In en o y 2nd ed (The
Psychological Co po a ion, San An onio, 1996).
68. Cummings, J. L., Mega, M., G ay, K., Rosenbe g-Thompson, S., Ca usi, D. A. &
Go nbein, J. The Neu opsychia ic In en o y: comp ehensi e assessmen o
psychopa hology in demen ia. Neu ology 44, 2308–2314 (1994).
69. Wein aub, D. e al. Valida ion o he ques ionnai e o impulsi e-compulsi e
diso de s in Pa kinson’s disease. Mo . Diso d. 24, 1461–1467 (2009).
70. Schwab, R. S. & England, A. C. In Thi d Symposium on Pa kinson’s Disease 152–157
(E. And S. Li ings one, Edinbu gh, 1969).
71. Jenkinson, C., Fi zpa ick, R., Pe o, V., G eenhall, R. & Hyman, N. The Pa kinson’s
Disease Ques ionnai e (PDQ-39): de elopmen and alida ion o a Pa kinson’s
disease summa y index sco e. Age Ageing 26, 353–357 (1997).
72. Da Rocha, N. S., Powe , M. J., Bushnell, D. M. & Fleck, M. P. The EUROHIS-QOL
8-i em index: compa a i e psychome ic p ope ies o i s pa en WHOQOL-BREF.
Value Heal h 15, 449–457 (2012).
73. San os-Ga cía, D. e al. COPPADIS S udy G oup. Non-mo o symp om bu den is
s ongly co ela ed o mo o complica ions in pa ien s wi h Pa kinson’s disease.
Eu . J. Neu ol. 27, 1210–1223 (2020).
74. Cohen, J. & Cohen, P. Applied Mul iple Reg ession/Co ela ion Analysis o he
Beha io al Sciences 2nd ed (Law ence E lbaum, Hillsdale, New Je sey, 1983).
75. Schade, S., Mollenhaue , B. & T enkwalde , C. Le odopa equi alen dose con-
e sion ac o s: an upda ed p oposal including opicapone and safinamide. Mo .
Diso d. Clin. P ac . 2020, 343–345 (2020).
ACKNOWLEDGEMENTS
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 Fundación Española de Ayuda a la In es igación en
Pa kinson y o as En e medades Neu odegene a i as (Cu emos el Pa kinson; www.
cu emoselpa kinson.o g), Alpha Bio esea ch (www.alphabio esea ch.com), and o he
ins i u ions helping us.
AUTHOR CONTRIBUTIONS
S.G.D.: concep ion, o ganiza ion, and execu ion o he p ojec ; s a is ical analysis;
w i ing o he fi s d a o he manusc ip ; ec ui men and/o e alua ion o
pa icipan s. D.D.T.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s.
C.C.: e iew and c i ique. M.G.: e iew and c i ique. P.G.J.M.: e iew and c i ique. M.M.
C.: e iew and c i ique. S.E.: e iew and c i ique; ec ui men and/o e alua ion o
pa icipan s. J.S.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s.
A.M.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. P.P.: e iew
and c i ique; ec ui men and/o e alua ion o pa icipan s. P.L.L.: e iew and c i ique;
ec ui men and/o e alua ion o pa icipan s. C.M.: e iew and c i ique; ec ui men
and/o e alua ion o pa icipan s. G.C.J.: e iew and c i ique; ec ui men and/o
e alua ion o pa icipan s. C.N.: e iew and c i ique; ec ui men and/o e alua ion o
pa icipan s. L.I.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s.
H.V.J.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. C.I.: e iew
and c i ique; ec ui men and/o e alua ion o pa icipan s. L.M.L.: e iew and c i ique;
ec ui men and/o e alua ion o pa icipan s. G.A.I.: e iew and c i ique; ec ui men
and/o e alua ion o pa icipan s. Á.R.M.A.: e iew and c i ique; ec ui men and/o
e alua ion o pa icipan s. C.M.J.: e iew and c i ique; ec ui men and/o e alua ion
o pa icipan s. N.V.: e iew and c i ique; ec ui men and/o e alua ion o
pa icipan s. P.V.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s.
R.d.A.M.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. B.C.:
e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. S.V.B.: e iew and
c i ique; ec ui men and/o e alua ion o pa icipan s. Á.S.M.: e iew and c i ique;
ec ui men and/o e alua ion o pa icipan s. V.L.: e iew and c i ique; ec ui men
and/o e alua ion o pa icipan s. E.S.: e iew and c i ique; ec ui men and/o
e alua ion o pa icipan s. C.E.: e iew and c i ique; ec ui men and/o e alua ion o
pa icipan s. C.P.F.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s.
M.C.J.C.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. S.A.P.:
e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. A.L.M.G.: e iew
and c i ique; ec ui men and/o e alua ion o pa icipan s. L.A.N.: e iew and c i ique;
ec ui men and/o e alua ion o pa icipan s. G.I.: e iew and c i ique; ec ui men
and/o e alua ion o pa icipan s. C.P.: e iew and c i ique; ec ui men and/o
e alua ion o pa icipan s. K.J.: e iew and c i ique; ec ui men and/o e alua ion o
pa icipan s. B.E.M.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s.
S.M.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. R.M.J.: e iew
and c i ique; ec ui men and/o e alua ion o pa icipan s. V.C.: e iew and c i ique;
ec ui men and/o e alua ion o pa icipan s. K.M.: e iew and c i ique; ec ui men
and/o e alua ion o pa icipan s. d.F.O.: e iew and c i ique; ec ui men and/o
e alua ion o pa icipan s. G.A.J.: e iew and c i ique; ec ui men and/o e alua ion
o pa icipan s. O.C.: e iew and c i ique; ec ui men and/o e alua ion o
pa icipan s. L.D.L.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s.
MD: e iew and c i ique; e iew o english s yle. M.-M.P.: e iew and c i ique;
supe ision. M.P.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s.
COMPETING INTERESTS
San os Ga cía D. has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice
by Abb ie, UCB Pha ma, Lundbeck, KRKA, Zambon, Bial, I al a maco, and Te a. De Deus
Fon icoba T: None. Co es C. has ecei ed hono a ia o educa ional p esen a ions and
ad ice se ice by Lundbeck and UCB Pha ma. Muñoz G: None. Paz González JM. has
ecei ed hono a ia o educa ional p esen a ions and/o ad ice se ice by UCB Pha ma,
Lundbeck,KRKA,andZambon.Ma ínezMi óC:None.Suá ezE:None.JesúsS.has
ecei ed hono a ia om AbbVie, Bial, Me z, UCB, and Zambon and holds he compe i i e
con ac “Juan Rodés”suppo ed by he Ins i u o de Salud Ca los III. She has ecei ed
g an s om he Spanish Minis y o Economy and Compe i i eness (PI18/01898) and he
Conseje ía de Salud de la Jun a de Andalucía (PI-0459-2018). Aguila M: UCB and Schwabe
wi h assis ance o a Cong ess; Nu icia wi h assis ance o a Cong ess and paymen o
lec u e. Pas o P: None. Planellas LL. has ecei ed a el bu sa ies g an om Abb ie.
Cosgaya M: None. Ga cía Calden ey J. has ecei ed hono a ia o educa ional
p esen a ions and ad ice se ice by Qualigen, Nu icia, Abb ie, I al a maco, UCB Pha ma,
Lundbeck, Zambon, Bial, and Te a. Caballol N. has ecei ed hono a ia om Bial,
I al á maco, Qualigen, Zambon, UCB, Te a and KRKA and sponso ship om Zambon,
TEVA and Abb ie o a ending medical con e ences. Lega da I. has ecei ed hono a ia o
educa ional p esen a ions and ad ice se ice by Abb ie, UCB Pha ma, Zambon, Bial, and
Te a. He nández Va a J. has ecei ed a el bu sa ies and educa ional g an s om Abb ie
and has ecei ed hono a ia o educa ional p esen a ions om Abb ie, Te a, Bial,
Zambon, I al a maco, and Sanofi-Genzyme. Cabo I. has ecei ed hono a ia o educa ional
p esen a ions and ad ice se ice by Abb ie, Zambon and Bial. López Manzana es L:
Compensa ed ad iso y se ices, consul ing, esea ch g an suppo , o speake hono a ia:
AbbVie, Aco da, Bial, In ec Pha ma, I al a maco, Pfize , Roche, Te a, UCB, and Zambon.
González A ambu u I: None. Á ila Ri e a MA. has ecei ed hono a ia om Zambon, UCB
Pha ma, Qualigen, Bial, and Te a, and sponso ship om Zambon and Te a o a ending
con e ences. Ca alán MJ: None. Noguei a V: None. Puen e V. has se ed as consul an o
Abb ie and Zambon; has ecei ed g an / esea ch om Abb ie. Ruíz de A cos M: None.
Bo ué C: None. Solano Vila B. has ecei ed hono a ia o educa ional p esen a ions and
ad ice se ice by UCB, Zambon, Te a, Abb ie, Bial. Ál a ez Sauco M. has ecei ed
hono a ia o educa ional p esen a ions and ad ice se ice by Abb ie, UCB Pha ma,
Zambon, Bial, and Te a. Vela L. has ecei ed hono a ia o educa ional p esen a ions and
ad ice se ice by Abb ie, UCB Pha ma, Lundbeck, KRKA, Zambon, Bial, and Te a.
Escalan e S. has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by
Abb ie, Zambon, and Bial. Cubo E: T a el g an s: Abb ie, Alle gan,Bos on;Lec u ing
hono a ia: Abb ie, In e na ional Pa kinson´s disease Mo emen Diso de Socie y. Ca illo
Padilla F. has ecei ed hono a ia om Zambon (SEN Cong ess assis ance). Ma ínez
Cas illo JC. has ecei ed esea ch suppo om Lundbeck, I al a maco, Alle gan, Zambon,
Me z, and Abb ie. He has ecei ed speaking hono a ia om AbbVie, Bial, I al a maco,
Lundbeck,K ka,TEVA,UCB,Zambon,Alle gan,Ipsen,andMe z.SánchezAlonsoP.has
ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by Abb ie, UCB
Pha ma, Lundbeck, KRKA, Zambon, Bial, and Te a. Alonso Losada MG. has ecei ed
hono a ia o educa ional p esen a ions and ad ice se ice by Zambon and Bial. López
A iz egui N. has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by
Abb ie, I al a maco, Zambon, and Bial. Gas ón I. has ecei ed esea ch suppo om
Abb ie and Zambon and has se ed as a consul an o Abb ie, Exel s, and Zambon.
Cla e o P: Kulise sky J: (1) Consul ing ees: Roche, Zambon; (2) S ock / allo men : No; (3)
Pa en oyal ies / licensing ees: No; (4) Hono a ia (e.g., lec u e ees): Zambon, Te a, Bial,
UCB; (5) Fees o p omo ional ma e ials: No; (6) Resea ch unding: Roche, Zambon,
Cibe ned; Ins i u o de SaludCa los III; FundacióLa Ma a óde TV3; (7) Schola ship om
D.S. Ga cía e al.
9
Published in pa ne ship wi h he Pa kinson’s Founda ion npj Pa kinson’s Disease (2021) 118