Resea ch A icle
P e alence and Fac o s Associa ed wi h D ooling in Pa kinson’s
Disease: Resul s om a Longi udinal P ospec i e Coho and
Compa ison wi h a Con ol G oup
Diego San os-Ga c´
ıa ,
1
Te esa de Deus Fon icoba,
2
Ca los Co es Ba olom´
e,
1
Ma ia J. Feal Paincei as,
1
Ma ia C is ina ´
Iñiguez-Al a ado,
1
Sil ia Jes´
us,
3
,
4
Ma ia Te esa Buongio no,
5
Llu´
ıs Planellas,
6
Ma ina Cosgaya,
7
Juan Ga c´
ıa Calden ey,
8
Nu ia Caballol,
9
Ines Lega da,
10
Jo ge He n´
andez Va a,
11,
4
I ia Cabo,
12
Lydia L´
opez Manzana es,
13
Isabel Gonz´
alez A ambu u,
14,
4
Ma ia A. ´
A ila Ri e a,
15
V´
ıc o G´
omez Mayo domo,
16
V´
ıc o Noguei a,
17
V´
ıc o Puen e,
18
Julio Do o Ga c´
ıa-So o,
19
Ca men Bo u´
e,
20
Be a Solano Vila,
21
Ma ´
ıa´
Al a ez Sauco,
22
Lydia Vela,
23
Sonia Escalan e,
24
Es he Cubo,
25
F ancisco Ca illo Padilla,
26
Juan C. Ma ´
ınez Cas illo ,
27
Pila S´
anchez Alonso,
28
Ma ia G. Alonso Losada,
29
Nu iaL´
opezA iz egui ,
30
I zia Gas ´
on,
31
JaimeKulise sky,
32,
4
Ma aBl´
azquezEs ada,
33
Manuel Seijo,
12
Ja ie R´
uiz Ma ´
ınez,
34
Ca idad Vale o,
35
M´
onica Ku is,
36
O iol de F´
ab egues ,
11
Jessica Gonz´
alez A du a,
37
Ruben Alonso Redondo,
38
Ca los O d´
as,
39
Luis M. L. L´
opez D´
ıaz,
40
Da ian McA ee,
41
Pablo Ma inez-Ma in ,
4
Pablo Mi ,
3
,
4
and S udy G oup COPPADIS
42
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 olog´
ıa y Neu o siolog´
ıa Cl´
ınica, Ins i u o de Biomedicina 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
4
CIBERNED (Cen o de In es igaci´
on Biom´
edica en Red En e medades Neu odegene a i as), Mad id, Spain
5
Hospi al Uni e si a i Mu ua de Te assa, Te assa, Ba celona, Spain
6
Cl´ınica del Pila , Ba celona, Spain
7
Hospi al Cl´
ınic de Ba celona, Ba celona, Spain
8
Cen o Neu ol´
ogico Oms 42, Palma de Mallo ca, Spain
9
Conso ci Sani a i In eg al, Hospi al Mois´es B oggi, San Joan Desp´ı, 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 qu´
es 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 Cl´ınico 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 ´
ıa, Mad id, Spain
21
Ins i u d’Assis `
encia Sani `
a ia (IAS), Ins i u Ca al`
ade La Salu , Gi ona, Spain
22
Hospi al Gene al Uni e si a io de Elche, Elche, Spain
23
Fundaci´
on Hospi al de Alco c´
on, 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
Hindawi
Pa kinson’s Disease
Volume 2023, A icle ID 3104425, 18 pages
h ps://doi.o g/10.1155/2023/3104425
26
Hospi 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
27
Hospi al Uni e si a io Ram´
on 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 ´
Al 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 i´
an, Spain
35
Hospi al A nau de Vilano a, Valencia, Spain
36
Hospi al Rube In e nacional, Mad id, Spain
37
Hospi al de Cabueñes, Gij´
on, Spain
38
Uni e si a io Lucus Augus i (HULA), Lugo, Spain
39
Hospi al Rey Juan Ca los, Mad id, Spain
40
Complejo Hospi ala io Uni e si a io de O ense (CHUO), O ense, Spain
41
Uni e si y o Ma yland School o Medicine, Bal imo e, MD, USA
42
Fundaci´on Degen, C/Juana de Vega 23 2°, A Co uña 15004, Spain
Co espondence should be add essed o Diego San os-Ga c´
ıa; [email p o ec ed]
Recei ed 2 No embe 2022; Re ised 8 Decembe 2022; Accep ed 20 Decembe 2022; Published 6 Ap il 2023
Academic Edi o : Ca lo Colosimo
Copy igh ©2023 Diego San os-Ga c´
ıa e al. Tis is an open access a icle dis ibu ed unde he C ea i e Commons A ibu ion
License, which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly
ci ed.
In oduc ion. D ooling in Pa kinson’s disease (PD) is equen bu o en goes unde ecognized. Ou aim was o examine he
p e alence o d ooling in a PD coho and compa e i wi h a con ol g oup. Speci cally, we iden i ed ac o s associa ed wi h
d ooling and conduc ed subanalyses in a subg oup o e y ea ly PD pa ien s. Pa ien s and Me hods. PD pa ien s who we e
ec ui ed om Janua y 2016 o No embe 2017 (baseline isi ; V0) and e alua ed again a a 2-yea ±30-day ollow-up (V2) om
35 cen e s in Spain om he COPPADIS coho we e included in his longi udinal p ospec i e s udy. Subjec s we e classi ed as
wi h o wi hou d ooling acco ding o i em 19 o he NMSS (Nonmo o Symp oms Scale) a V0, V1 (1-yea ±15 days), and V2 o
pa ien s and a V0 and V2 o con ols. Resul s. Te equency o d ooling in PD pa ien s was 40.1% (277/691) a V0 (2.4% (5/201)
in con ols; p<0.0001), 43.7% (264/604) a V1, and 48.2% (242/502) a V2 (3.2% (4/124) in con ols; p<0.0001), wi h a pe iod
p e alence o 63.6% (306/481). Being olde (OR �1.032; p�0.012), being male (OR �2.333; p<0.0001), ha ing g ea e nonmo o
symp om (NMS) bu den a he baseline (NMSS o al sco e a V0; OR �1.020; p<0.0001), and ha ing a g ea e inc ease in he
NMS bu den om V0 o V2 (change in he NMSS o al sco e om V0 o V2; OR �1.012; p<0.0001) we e iden i ed as in-
dependen p edic o s o d ooling a e he 2-yea ollow-up. Simila esul s we e obse ed in he g oup o pa ien s wi h ≤2 yea s
since symp om onse , wi h a cumula i e p e alence o 64.6% and a highe sco e on he UPDRS-III a V0 (OR �1.121; p�0.007) as
a p edic o o d ooling a V2. Conclusion. D ooling is equen in PD pa ien s e en a he ini ial onse o he disease and is
associa ed wi h a g ea e mo o se e i y and NMS bu den.
1. In oduc ion
Sialo hea, commonly e e ed o as d ooling, is de ned as
excessi e sali a beyond he ma gin o he lip. D ooling can
be a complica ion o Pa kinson’s disease (PD) and is one o
he mos p e alen complain s o pa ien s, bu i is o en
unde ecognized and unde ea ed [1]. A wide p e alence
ange has been epo ed in he li e a u e, anging om 10 o
84%, wi h no signi can a ia ion ac oss e hnic g oups
[2–15]. Howe e , when s udies compa ed PD pa ien s wi h
con ols, d ooling only occu ed in 6–15% o people wi hou
PD [5, 6, 15, 16]. Te b oad ange in PD pa ien s is likely due
o he lack o a s anda d de ni ion o and diagnos ic c i e ia
o sialo hea and he di e ences in he PD popula ion
s udied and he me hods used. Despi e hese obs acles,
d ooling has s ill been ound o nega i ely impac he
quali y o li e (QoL) o bo h pa ien s and ca egi e s
[5, 12, 13, 17–19]. Sialo hea may b ing epe cussions o he
psychosocial heal h o he pe son who d ools and added
bu den o he ca egi e as well (e.g., odo , s ained clo hes,
cons an wiping, es ic ed social li e, e c.) [1]. Mo eo e ,
d ooling is associa ed wi h an inc eased isk o d y mou h,
impac on bolus o ma ion, loss o an ibac e ial e ec s o
sali a, pe io al de ma ological changes, ulce a ion, oo h
decay, gingi i is, dehyd a ion, candidiasis, hali osis, and
inc eased speech di cul ies [20–22]. D ooling in PD pa-
ien s appea s o be p ima ily ela ed o educed swallowing
e ciency and no o an inc ease in sali a p oduc ion
[20, 23], as dysphagia is he s onges ac o associa ed wi h
d ooling [7, 12, 23]. O he epo ed ac o s associa ed wi h
d ooling a e o o acial igidi y/hypomimia, lingual b ady-
kinesia, aging, male gende , cogni i e impai men ,
2Pa kinson’s Disease
hallucina ions, non emo dominan PD pheno ype, longe
disease du a ion, and mo e ad anced disease s age
[3–8, 11–14, 23–26].
Al hough many s udies ha e analyzed he equency o
d ooling in PD, he e is less in o ma ion abou i s p e alence
and associa ed ac o s in ea ly PD pa ien s and how i
impac s QoL and change o e ime. Some s udies ha e
epo ed a p e alence o abou 20% in de no o and un ea ed
PD pa ien s and ha p e alence inc eases in he long e m
[27, 28]. Ou hypo hesis was ha he p e alence o d ooling
in ea ly PD pa ien s would be high and would nega i ely
impac QoL. Te aim o he cu en s udy was o examine he
p e alence o d ooling, and i s p og ession, in a PD coho
and assess i s impac on QoL. Fu he mo e, we compa ed
he equency o d ooling in PD pa ien s wi h a con ol
g oup and analyzed all hese aspec s in a subg oup o pa-
ien s om he coho wi h a sho disease du a ion o
≤2 yea s since he onse o he symp oms. Mo eo e , we
iden i ed in bo h g oups, he en i e coho and he subg oup
wi h ea ly PD, ac o s associa ed wi h no only d ooling bu
also d ooling se e i y as well.
2. Ma e ials and Me hods
PD pa ien s who we e ec ui ed om Janua y 2016 o
No embe 2017 (baseline isi ; V0) and e alua ed again a
a 2-yea ±30-day ollow-up (V2) om 35 cen e s in Spain
om he COPPADIS coho [29] we e included in his
s udy. Te me hodology o he COPPADIS-2015 s udy can
be consul ed in h ps://bmcneu ol.biomedcen al.com/
a icles/10.1186/s12883-016-0548-9 [30]. Tis is a mul i-
cen e , obse a ional, longi udinal p ospec i e, and 5-yea
ollow-up s udy designed o analyze disease p og ession in
a Spanish popula ion o PD pa ien s. All pa ien s included
we e diagnosed acco ding o he UK PD B ain Bank
c i e ia [31].
In o ma ion on sociodemog aphic aspec s, ac o s e-
la ed o PD, como bidi y, and ea men we e collec ed.
Mo o s a us, nonmo o symp oms (NMS), QoL, and dis-
abili y we e assessed a V0 and a V2 using di e en ali-
da ed scales: Hoehn and Yah (H&Y), UPDRS-III and
UPDRS-IV, F eezing o Gai Ques ionnai e (FOGQ)),
Pa kinson’s Disease Cogni i e Ra ing Scale (PD-CRS),
Nonmo o Symp oms Scale (NMSS), Beck Dep ession
In en o y-II (BDI-II), Pa kinson’s disease sleep scale
(PDSS), 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), isual analog scale-pain (VAS-
Pain), Visual Analog Fa igue Scale (VAFS)), he 39-i em
Pa kinson’s Disease Ques ionnai e (PDQ-39), he EURO-
HIS-QOL 8-i em index (EUROHIS-QOL8), and ADLS
(Schwab and England Ac i i ies o Daily Li ing Scale) [30].
In pa ien s wi h mo o uc ua ions, he mo o assessmen
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. Te assessmen was
only pe o med wi hou medica ion in pa ien s wi hou
mo o uc ua ions. Te same e alua ion as o he pa ien s,
excep o he mo o assessmen , was pe o med in con ol
subjec s a V0 and a V2 (2 yea s ±1 mon h). Fu he mo e,
mo o (H&Y, UPDRS-III, and UPDRS-IV) and nonmo o
assessmen (NMSS and ADLS) was conduc ed in PD pa-
ien s a 1 yea ±1 mon h (V1) [30]. LEED was calcula ed
based on he li e a u e [32].
Subjec s we e classi ed as wi h o wi hou d ooling
acco ding o i em 19 o he NMSS [33]. Tis i em is one o
he 30 i ems on his scale and is included in domain 6
(gas oin es inal ac ). Tis ques ion asks abou d ooling:
“Does he pa ien d ibble sali a du ing he day?.” Te sco e
ange is om 0 (wi hou he symp om) o 12 ( he mos
equen and se e e). Subjec s wi h an NMSS-i em 19
sco e �0 we e conside ed “wi hou d ooling,” whe eas
subjec s wi h an NMSS-i em 19 sco e ≥1 ( om 1 o 12) we e
conside ed “wi h d ooling.” D ooling was iden i ed a V0,
V1, and V2 in pa ien s and a V0 and V2 in con ols. Te
d ooling bu den was also calcula ed o PD pa ien s. Te
sco e a V0, V1, and V2 and he sum o he sco e om he
h ee isi s (NMSS-D ooling
V0+V1+V2
, om 0 o 36) we e
calcula ed. Pa ien s epo ing d ooling du ing he h ee isi s
we e de ned as pa ien s wi h “pe sis en d ooling.” Te same
me hod was used o de ne dysphagia (i em 20 o he NMSS)
[34] and hypomimia (i em 19 o he UPDRS-III du ing he
OFF s a e) [35].
2.1.S a is icalAnalysis. Da a we e p ocessed using SPSS 20.0
o Windows. Fo compa isons be ween PD pa ien s in he
con ol g oup and PD pa ien s wi h and wi hou d ooling,
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 i ed by one-sample Kolmogo o –Smi no
es ).
Bina y and linea eg ession models we e used o de-
e mining independen ac o s associa ed wi h d ooling
(d ooling as he dependen a iable) and d ooling se e i y
(NMSS-D ooling
V0+V1+V2
sco e as he dependen a iable),
espec i ely. Va iables wi h uni a ia e associa ions wi h p
alues <0.20 we e included in a mul i a iable model, and
a backwa d selec ion p ocess was used o emo e a iables
indi idually un il all emaining a iables we e signi can a
he 0.10 le el. Fo explo ing he associa ion be ween
d ooling and QoL, linea eg ession models we e used wi h
PDQ-39SI (heal h- ela ed QoL) and EUROHIS-QOL8
(global QoL) as dependen a iables. Te o al domain sco es
o he PDQ-39 we e exp essed as a pe cen age o he co -
esponding maximum possible sco e, and a summa y index
was ob ained as an a e age o he domain sco es (PDQ-
39SI). Te e ec was con olled by age, gende , disease
du a ion, LEDD, como bidi ies ( o al numbe o non-an i-
Pa kinsonian d ugs [36]), mo o (H&Y, UPDRS-III,
UPDRS-IV, and FOGQ) and nonmo o (NMSS) s a us,
cogni i e unc ion (PC-CRS o al sco e), dysphagia, hypo-
mimia, and au onomy o ADL (ADLS), which we e in-
cluded as co a ia es in he model [36].
Fo PD pa ien s, analyses we e conduc ed in he en i e
coho and in he subg oup o pa ien s wi h ≤2 yea s o
disease du a ion since symp oms’ onse (PD ≤2 y) a he
baseline. Te p alue was conside ed signi can o all
analyses when i was <0.05.
Pa kinson’s Disease 3
2.2. S anda d P o ocol App o als, Regis a ions, and Pa ien
Consen s. Fo his s udy, we ecei ed app o al om he
Comi ´
e de ´
E ica de la In es igaci´
on Cl´
ınica de Galicia in
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. COP-
PADIS-2015 was classi ed by he AEMPS (Agencia Española
del Medicamen o y P oduc os Sani a ios) as a pos -
au ho iza ion p ospec i e ollow-up s udy wi h he code
COH-PAK-2014-01.
3. Resul s
A he baseline, 691 PD pa ien s (62.59 ±8.92 yea s old;
60.2% males; mean disease du a ion 5.5 ±4.37 yea s) and 206
pa ien s in he con ol g oup (60.98 ±8.34 yea s old; 50%
males) we e conside ed alid o he analysis. Te equency
o d ooling in PD pa ien s was 40.1% (277/691) a V0; 43.7%
(264/604) a V1; 48.2% (242/502) a V2 (Figu e 1(a)). A V0
and V2, d ooling was signi can ly less equen (p<0.0001)
in he con ol g oup han in PD pa ien s (2.4% a V0 and
3.2% a V2 in con ols). In he pa ien s (N�481;
62.62 ±8.54 yea s old, om 35 o 75; 59.2% males) wi h
assessmen s ca ied ou du ing all isi s (V0, V1, and V2),
63.6% (306/481) o hem epo ed d ooling a leas once
du ing he s udy (pe iod p e alence). Speci cally, 18.9% (91/
481) in only one isi , 19.1% (92/481) in wo ou o he h ee
isi s, and 25.6% (123/481) in all h ee isi s (i.e., pe sis en
d ooling) (Figu e 1(b)). In he PD ≤2 y g oup
(62.22 ±8.33 yea s old; 57.3% males; mean disease du a ion
1.29 ±0.37 yea s), he equency o d ooling was 34.8% (64/
184) a V0, 37.5% a V1 (60/160), and 50.4% (66/131) a V2.
A e he 2-yea ollow-up, he cumula i e p e alence o
d ooling in his g oup was 64.6% (21.3% in 1 isi , 23.6% in 2
isi s, and 19.7% in all isi s) (Figu e 1(b)).
Rega ding d ooling bu den in PD pa ien s, as expec ed,
he NMSS-D ooling
V0+V1+V2
sco e was highe in pa ien s
wi h pe sis en d ooling (p<0.0001): d ooling in one isi ,
1.95 ±1.67 (N�91); d ooling in wo ou o he h ee isi s,
4.22 ±2.95 (N�92); pe sis en d ooling, 10.36 ±6.12
(N�123). D ooling was mo e equen in pa ien s wi h
dysphagia han in hose wi hou dysphagia: 60% (96/160) s.
34.1% (181/531) (p<0.0001) a V0; 57.9% (99/171) s. 38.1%
(165/433) (p<0.0001) a V1; 55.9% (76/136) s. 45.4% (60/
166/366) (p�0.023) a V2 (Figu e 2(a)). D ooling bu den
(NMSS-i em 19 o al sco e) co ela ed wi h dysphagia
bu den (NMSS-i em 20 o al sco e) a V0 (N�691; �0.322;
p<0.0001), a V1 (N�604; �0.344; p<0.0001), a V2
(N�502; �0.198; p<0.0001), and a e conside ing all
isi s oge he (N�481; �0.292; p<0.0001). D ooling was
also mo e equen in pa ien s wi h hypomimia han in hose
wi hou hypomimia a V0 (43% s. 31%; p�0.011), a V1
(48.4% s. 30.9%; p�0.001), and a V2 (51.9% s. 33.8%; p
�0.002) (Figu e 2(a)). A signi can co ela ion was ob-
se ed be ween d ooling bu den and hypomimia bu den a
V0 ( �0.197; p<0.0001), a V1 ( �0.149; p<0.0001), a V2
( �0.189; p<0.0001), and a e conside ing all isi s
( �0.213; p<0.0001). Simila esul s we e obse ed in he
PD ≤2 y g oup, wi h signi can co ela ions be ween
d ooling bu den and dysphagia bu den ( �565; p<0.0001)
and be ween d ooling bu den and hypomimia bu den
( �0.360; p<0.00001) a e conside ing he sum o he
bu den o all isi s du ing he ollow-up. D ooling was mo e
equen in pa ien s wi h dysphagia a V0 and a V1 and wi h
hypomimia a V2 han in hose pa ien s wi h hese symp-
oms in he PD ≤2 y g oup (Figu e 2(b)). Rega ding he
ea men , none o he pa ien s we e ecei ing bo ulinum
oxin a any o he 3 isi s (V0, V1, and V2).
A he baseline, d ooling was associa ed wi h gende
(males, 69% s. 54.3%; p<0.0001), olde age (63.79 ±8.21 s.
61.8 ±9.29; p�0.008), and a highe LEDD (646.01 ±410.21
s. 512.73 ±409.22; p<0.0001) (Table 1). Pa ien s wi h
d ooling we e wo se in e ms o mo o (UPDRS-III;
UPDRS-IV; FOGQ) and nonmo o (PD-CRS; NMSS; BDI-
II; NPI; PDSS; VAS-PAIN; VASF-physical; VASF-men al)
s a us, QoL (PDQ-39SI; EUROHIS-QOL8; Figu e 3), and
au onomy o ac i i ies o daily li ing (ADLS) when com-
pa ed o hose wi hou d ooling (Table 1). In he PD ≤2 y
g oup, d ooling was associa ed wi h gai p oblems (FOGQ),
a g ea e mo o se e i y (UPDRS-III) and NMS bu den
(NMSS) including mood and o he neu opsychia ic
symp oms (BDI-II; NPI), pain (VAS-PAIN) and men al
a igue (VASF-men al), and a wo se QoL (PDQ-39SI;
EUROHIS-QOL8) (Table 1). Compa ed o pa ien s wi hou
d ooling, he equency o majo dep ession, eezing o gai ,
and alls in he subg oup o PD ≤2 y pa ien s wi h d ooling
was oughly double (Table 1).
To be olde (OR �1.025; 95% CI, 1.004–1.046; p�0.019),
o be male (OR �2.165; 95% CI, 1.486–3.153; p<0.0001), o
ha e a highe sco e on he UPDRS-III (OR �1.018; 95% CI,
1.001–1.037; p�0.047) and he NMSS (OR �1.011; 95% CI,
1.005–1.016; p<0.0001), and o ha e dysphagia (OR �2.274;
95% CI, 1.476–3.505; p<0.0001) we e independen ac o s
associa ed wi h d ooling a he baseline (Table 2). In he
PD ≤2 y g oup, a highe NMSS o al sco e was he only
independen ac o associa ed wi h d ooling a he baseline
(OR �1.017; 95% CI, 1.005–1.029; p�0.001). Like as seen
wi h baseline p edic ions, being olde (OR �1.032; 95% CI,
1.007–1.057; p�0.012), being male (OR �2.333; 95% CI,
1.540–3.536; p<0.0001), ha ing a g ea e NMS bu den a
he baseline (NMSS o al sco e a V0; OR �1.020; 95% CI,
1.011–1.030; p<0.0001), and ha ing a g ea e inc ease in he
NMS bu den om V0 o V2 (change in he NMSS o al sco e
om V0 o V2; OR �1.012; 95% CI, 1.006–1.019; p<0.0001)
we e iden i ed as independen p edic o s o d ooling a e
he 2-yea ollow-up (Table 3). When NMS bu den a he
baseline was conside ed as a ca ego ical a iable in he
model, o ha e a e y se e e NMS bu den a V0 (NMSS o al
sco e >70) inc eased he p obabili y o d ooling a V2 mo e
han double (OR �2.696; 95% CI, 4.248–10.729; p<0.0001).
Mo eo e , o ha e d ooling a he baseline mul iplied by 6
(OR �6.751; 95% CI, 1.011–1.030; p<0.0001), he p oba-
bili y o d ooling a V2 a e adjus men mus be ecei ing
an icholine gic d ugs and he o he co a ia es o he model.
In he PD ≤2 y g oup, a highe UPDRS-III sco e a V0 was
he only p edic o o d ooling a V2 iden i ed (OR �1.093;
95% CI, 1.025–1.166; p�0.007) (Table 3). Speci cally, o
ha e a V0 a sco e on he UPDRS-III highe han 20 poin s
inc eased he p obabili y o d ooling a V2 by 3- old
4Pa kinson’s Disease
0
100
200
300
400
500
600
Wi h
dysphagia
Wi hou
dysphagia
Wi h
hypomimia
Wi hou
hypomimia
Wi h
dysphagia
Wi hou
dysphagia
Wi h
hypomimia
Wi hou
hypomimia
Wi h
dysphagia
Wi hou
dysphagia
Wi h
hypomimia
Wi hou
hypomimia
Wi h d ooling
Wi hou d ooling
48.4% 30.9%
p=0.001
308
V0 V1 V2
96
64
60% 34.1%
p<0.0001
181
350
43% 31%
p=0.011
57.9% 38.1%
p<0.0001
55.9% 45.4%
p=0.023
51.9% 33.8%
p=0.002
232
78
35
99 165
72
268
243
65
228
29 76
166 203
27
60
200 188
53
(a)
0
20
40
60
80
100
120
140
160
Wi h
dysphagia
Wi hou
dysphagia
Wi h
hypomimia
Wi hou
hypomimia
Wi h
dysphagia
Wi hou
dysphagia
Wi h
hypomimia
Wi hou
hypomimia
Wi h
dysphagia
Wi hou
dysphagia
Wi h
hypomimia
Wi hou
hypomimia
Wi h d ooling
Wi hou d ooling
20
55.6% 29.7%
p=0.004
16 44 51
12
104 85
29
37.5% 29.3%
p=0.219
54.3% 30.7%
p=0.005
42.9% 31.1%
p=0.121
45
14
60
31
21
79
25 35
55.6% 48.4%
p=0.297
55.3% 30%
p=0.013
20
46 52
9
16
49 42
21
(b)
Figu e 2: (a) Numbe o pa ien s epo ing d ooling a V0, V1, and V2 when hey we e di ided in pa ien s wi h s. wi hou dysphagia and wi h s.
wi hou hypomimia ( he whole coho ). A compa ison be ween he pe cen age is shown o each analysis. (b) Numbe o pa ien s om he PD ≤2 y
g oup epo ing d ooling a V0, V1, and V2 when hey we e di ided in pa ien s wi h s. wi hou dysphagia and wi h s. wi hou hypomimia. A
compa ison be ween he pe cen age is shown o each analysis. PD: Pa kinson’s disease. PD ≤2 y g oup: pa ien s wi h ≤2 yea s since symp om onse .
0
100
200
300
400
500
600
700
PD coho PD≤2y Con ols PD coho PD≤2y PD coho PD≤2y Con ols
Wi h d ooling
Wi hou d ooling
40.1%
277/691
34.8%
64/184
2.4%
5/201
48.2%
242/502
50.4%
66/131
3.2%
4/124
43.7%
264/604
37.5%
60/160
(a)
1 isi
2 isi s
3 isi s
None
1 isi
2 isi s
3 isi s
None
PD coho (N=481)
V0 → V1 → V2
PD≤2y (N=127)
V0 → V1 → V2
63.6% 64.6%
35.4%
21.3%
23.6%
19.7%
36.4% 35.4%
36.4%
18.9%
19.1%
25.6%
(b)
Figu e 1: (a) Pe cen age o pa ien s ( he whole coho and he g oup wi h no mo e han 2 yea s since symp om onse (PD ≤2 y) and con ols
epo ing d ooling a di e en isi s: V0, V1, and V2. (b) P e alence o d ooling du ing he ollow-up pe iod in all pa ien s and in he
PD ≤2 y g oup who comple ed he h ee isi s (V1, V2, and V3) and pe cen age o cases p esen ing d ooling in only 1 isi , 2 isi s, and all
isi s. PD coho s. con ols a V0, p<0.0001; PD coho s. con ols a V2, p<0.0001; PD ≤2 y g oup s. con ols a V0, p<0.0001;
PD ≤2 y g oup s. con ols a V2, p<0.0001. PD: Pa kinson’s disease. PD ≤2 y g oup: pa ien s wi h ≤2 yea s since symp om onse .
Pa kinson’s Disease 5

(OR �3.671; 95% CI, 1.350–9.986; p�0.011). Finally, o ha e
a g ea e NMS bu den a he baseline (β�0.492; 95% CI,
0.052–0.089; p<0.0001) and a g ea e inc ease in he NMS
bu den om V0 o V2 (β�0.221; 95% CI, 0.020–0.048; p
<0.0001) we e he mos signi can ac o s associa ed wi h
d ooling se e ely a V2 in he en i e coho , whe eas o ha e
a he baseline, a g ea e sco e on he UPDRS-III (β�0.272;
95% CI, 0.038–0.204; p�0.005) and he NMSS (β�0.272;
95% CI, 0.009–0.049; p�0.005) we e in he PD ≤2 y g oup
(Table 4). Simila esul s we e obse ed when he i em-19
sco e was excluded om he NMSS o al sco e.
Wi h ega d o QoL, d ooling was associa ed wi h
a wo se heal h- ela ed QoL (PDQ-39SI as he dependen
a iable) a V0 (β�0.180; 95% CI, 2.928–6.992; p<0.0001)
and a V2 (β�0.131; 95% CI, 1.409–7.115; p�0.003) and
also wi h a wo se global QoL (EUROHIS-QOL8 as de-
penden a iable) a V0 (β� −0.118; 95% CI, −0.218 o
−0.050; p�0.002) and a V2 (β� −0.128; 95% CI, −0.251 o
−0.047; p�0.004). In he PD ≤2 y g oup, d ooling was as-
socia ed wi h a wo se heal h- ela ed QoL a V0 (β�0.249;
95% CI, 2.855–10.362; p�0.001) and a V2 (β�0.306; 95%
CI, 4.193–14.327; p<0.0001) and wi h a wo se global QoL a
V0 (β� −0.238; 95% CI, −0.438 o −0.110; p�0.001) as well.
Howe e , a e adjus men o co a ia es de ned in he
me hods, he associa ion be ween d ooling and bo h heal h-
ela ed and global QoL a V0 and a V2 was no signi can ,
Table 1: Disease- ela ed cha ac e is ics, mo o and nonmo o symp oms, and au onomy o ac i i ies o daily li ing and quali y o li e in
pa ien s wi h and wi hou d ooling a he baseline in he en i e coho (n�691) and in PD ≤2 y (N�184).
Wi hou d ooling
en i e
coho
(N�414)
Wi h d ooling
en i e
coho
(N�277)
p
Wi hou
d ooling
PD ≤2 y
(N�120)
Wi h
d ooling
PD ≤2 y
(N�64)
p
Age 61.8 ±9.29 63.79 ±8.21 0.008 61.68 ±8.54 63.39 ±7.84 0.252
Males (%) 54.3 69 <0.0001 55 60.9 0.269
Weigh (kgs) 75.37 ±13.83 76.56 ±13.34 0.341 75.84 ±14.75 75.75 ±11 0.755
Disease du a ion (yea s) 5.31 ±4.24 5.8 ±4.55 0.136 1.33 ±0.73 1.22 ±0.75 0.332
L-dopa eq. daily dose (mg) 512.73 ±409.22 646.01 ±410.21 <0.0001 303.51 ±242.63 343.11 ±256.34 0.296
Numbe o non an ip. d ugs 2.45 ±2.43 2.79 ±2.62 0.106 2.72 ±2.44 2.94 ±2.66 0.680
Mo o pheno ype (%) 0.899 0.995
T emo ic dominan 45.6 44.9 58.8 57.8
PIGD 39.1 38.4 27.7 29.7
Inde e mina e 15.3 16.7 13.4 12.5
Hoehn and Yah -OFF 2 [1.5, 2] 2 [2, 2] 0.031 2 [1.5, 2] 2 [1.5, 2] 0.186
S age om 3 o 5 (%) 8.6 10.5 0.257 2.9 1.7 0.526
UPDRS-III-OFF 20.97 ±10.56 25.17 ±11.59 <0.0001 17.56 ±8.46 21.69 ±9.68 0.005
Hypomimia (%) 79.8 86.9 0.011 74.6 81 0.219
UPDRS-IV 1.79 ±2.34 2.33 ±2.48 <0.0001 0.86 ±1.38 1.16 ±1.54 0.136
Mo o uc ua ions (%) 29.1 38.3 0.008 6.7 12.5 0.148
Dyskinesia (%) 17.5 21.2 0.137 2.6 6.6 0.190
FOGQ 3.3 ±4.36 4.53 ±4.78 <0.0001 1.75 ±2.81 3.05 ±3.66 0.031
Pa ien s wi h FOG (%) 30.1 42 0.001 16.7 31.2 0.019
Pa ien s wi h alls (%) 10.8 17.2 0.011 6.6 15.6 0.034
PD-CRS o al sco e 92.52 ±15.97 89.36 ±15.25 0.006 92.18 ±15.44 88.09 ±13.73 0.077
NMSS 37.69 ±32.09 57.28 ±42.55 <0.0001 32.85 ±28.08 56.4 ±37.17 <0.0001
Dysphagia (%) 15.5 34.7 <0.0001 13.3 31.2 0.004
BDI-II 8.12 ±7.18 9.64 ±7.43 0.002 7.15 ±6.98 10.81 ±7.51 <0.0001
Majo dep ession (%) 13.3 20.2 0.010 11.7 25 0.018
NPI 5.12 ±6.99 7.58 ±9.36 0.001 4.2 ±6.52 7.34 ±6.95 <0.0001
QUIP-RS 3.96 ±7.63 4.97 ±9.07 0.254 3.42 ±7.66 2.93 ±7.46 0.312
PDSS 116.83 ±25.32 111.98 ±28.8 0.027 119.45 ±25.19 111.22 ±32.04 0.110
VAS-PAIN 2.51 ±2.94 2.9 ±2.93 0.046 2.37 ±2.9 3.18 ±2.79 0.046
VASF −physical 2.83 ±2.79 3.2 ±2.68 0.038 2.55 ±2.9 2.78 ±2.43 0.211
VASF – men al 1.93 ±2.5 2.47 ±2.58 0.002 1.85 ±2.51 2.56 ±2.51 0.035
ADLS 89.49 ±10.64 86.85 ±10.15 <0.0001 92.08 ±8.39 89.22 ±10.12 0.053
Func ional dependency (%) 8.2 10.5 0.186 4.2 7.8 0.238
PDQ-39SI 15.15 ±12.6 20.11 ±14.33 <0.0001 12.4 ±11.33 19.01 ±13.91 <0.0001
EUROHIS-QOL8 3.83 ±0.54 2.71 ±0.56 0.005 3.91 ±0.56 3.64 ±0.48 0.001
Te esul s ep esen pe cen ages, mean ±SD, o median (p25, p75). Te chi-squa ed and Mann-Whi ney-Wilcoxon es s we e applied o compa isons
be ween pa ien s wi h and wi hou d ooling a he baseline. Da a abou H&Y and UPDRS-III a e du ing he OFF s a e ( s hing in he mo ning wi hou
aking medica ion in he p e ious 12 hou s). ADLS: Schwab and England Ac i i ies o Daily Li ing Scale); an ip.: an ipa kinsonian; BDI: Beck Dep ession
In en o y-II; NMSS: Nonmo o Symp oms Scale; NPI: Neu opsychia ic In en o y; PD: Pa kinson’s disease; PD ≤2 y: PD wi h ≤2 yea s om symp om onse ;
PD-CRS: Pa kinson’s Disease Cogni i e Ra ing Scale; PDSS: Pa kinson’s Disease Sleep Scale; PIGD: Pos u al Ins abili y Gai Di cul y; QUIP-RS:
Ques ionnai e o Impulsi e-Compulsi e Diso de s in Pa kinson’s Disease-Ra ing Scale; UPDRS: Uni ed Pa kinson’s Disease Ra ing Scale; VAFS: Visual
Analog Fa igue Scale; VAS-Pain: Visual Analog Scale-Pain.
6Pa kinson’s Disease
0
5
10
15
20
25
30
Mobili y*
ADL*
Emo ional well-
being*
S igma iza ion
Social suppo *
Cogni ion*
Communica ion*
Pain and discom o
Wi hou d ooling
Wi h d ooling
(a)
Wi hou d ooling
Wi h d ooling
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Quali y o li e*
Heal h s a us
Ene gy
Au onomy o ADL*
Sel -es eem*
Social ela ionships*
Economic capaci y*
Habi a *
(b)
Figu e 3: (a) Mean sco e on each domain o he PDQ-39 a he baseline in PD pa ien s om he en i e coho wi h s. wi hou d ooling; p
<0.0001 o all analysis excep o “emo ional well-being” (p�0.001), “s igma iza ion” (p�0.129), and “pain and discom o ” (p�0.063).
(b) Mean sco e on each domain o he EUROHIS-QOL8 a he baseline in PD pa ien s om he en i e coho wi h s. wi hou d ooling;
“quali y o li e,” p�0.005; “heal h s a us,” p�0.178; “ene gy,” p�0.183; “au onomy o ADL,” p�0.011; “sel -es eem,” p�0.033; “social
ela ionships,” p�0.032; “economic capaci y,” p�0.020; “habi a ,” p�0.046. EUROHIS-QOL8, EUROHIS-QOL 8-i em index; PD,
Pa kinson’s disease; PDQ-39, 39-i em Pa kinson’s disease quali y o li e ques ionnai e.
Table 3: P edic o s o d ooling a e he 2-yea ollow-up in he en i e coho (N�481) and in he PD ≤2 y g oup (N�127).
OR
a
OR
b
95% CI
a
95% CI
b
p
a
p
b
En i e coho
Age 1.033 1.032 1.011–1.056 1.007–1.057 0.003 0.012
Male 2.023 2.333 1.396–2.932 1.540–3.536 <0.0001 <0.0001
UPDRS-III a V0 1.028 1.016 1.010–1.047 0.995–1.038 0.002 0.097
NMSS a V0 1.010 1.020 1.005–1.016 1.011–1.030 <0.0001 <0.0001
PDQ-39SI a V0 1.016 0.978 1.002–1.031 0.955–1.002 0.024 0.069
Change om V0 o V2 in NMSS 1.006 1.012 1.001–1.011 1.006–1.019 0.042 <0.0001
PD ≤2 y g oup
Age 1.037 1.037 0.994–1.082 0.984–1.092 0.096 0.098
Male 1.707 2.064 0.845–3.450 0.886–4.810 0.136 0.093
UPDRS-III a V0 1.121 1.093 1.056–1.191 1.025–1.166 <0.0001 0.007
NMSS a V0 1.019 1.013 1.007–1.032 0.998–1.032 0.128 0.082
Dependen a iable: d ooling a V2 (NMSS-i em 19 ≥1). OR (odds a io) and 95% IC a e shown.
a
uni a ia e analysis;
b
mul i a ia e analysis; en i e coho ,
R
2
�0.33; Hosme and Lemeshow es , p�0.163; PD ≤2 y, R
2
�26; Hosme and Lemeshow es , p�0.788. LEED: le odopa equi alen daily dose (mg/day);
NMSS: Nonmo o Symp oms Scale; PD ≤2 y: PD wi h ≤2 yea s om symp om onse ; PDQ-39SI: 39-i em Pa kinson’s disease Ques ionnai e Summa y Index;
UPDRS: Uni ed Pa kinson’s Disease Ra ing Scale.
Table 2: Fac o s associa ed wi h d ooling a he baseline in he en i e coho (n�691) and in he PD ≤2 y g oup (N�184).
OR
a
OR
b
95% CI
a
95% CI
b
p
a
p
b
En i e coho
Age 1.026 1.025 1.008–1.044 1.004–1.046 0.004 0.019
Male 1.806 2.165 1.308–2.493 1.486–3.153 <0.0001 <0.0001
LEDD 1.001 1.000 1.001–1.002 1.000–1.001 <0.0001 0.172
UPDRS-III 1.035 1.018 1.020–1.050 1.001–1.037 <0.0001 0.047
NMSS 1.015 1.011 1.010–1.019 1.005–1.016 <0.0001 <0.0001
Dysphagia 2.901 2.274 2.016–4.173 1.476–3.505 <0.0001 <0.0001
PD ≤2 y g oup
UPDRS-III 1.052 1.034 1.014–1.090 0.994–1.076 0.006 0.096
NMSS 1.022 1.017 1.012–1.033 1.005–1.029 <0.0001 0.004
Dysphagia 2.995 2.002 1.401–6.229 0.858–4.672 0.004 0.108
Dependen a iable: d ooling a V0 (NMSS-i em 19 ≥1). OR (odds a io) and 95% ICa e shown.
a
uni a ia e analysis;
b
mul i a ia e analysis; en i e coho ,
R
2
�0.19; Hosme and Lemeshow es , p�0.226; PD ≤2 y, R
2
�0.19; Hosme and Lemeshow es , p�0.774. LEED: le odopa equi alen daily dose (mg/day);
NMSS: Nonmo o Symp oms Scale; PD ≤2 y: PD wi h ≤2 yea s om symp om onse ; UPDRS: Uni ed Pa kinson’s Disease Ra ing Scale.
Pa kinson’s Disease 7
no e en when pe sis ing d ooling o he NMSS-
D ooling
V0+V1+V2
sco e was conside ed in he model. A
co ela ion was obse ed be ween he NMSS-
D ooling
V0+V1+V2
sco e and he sco e on bo h PDQ-39SI
and EUROHIS-QOL8 a V2 in he en i e coho (PDQ-39SI,
�0.234 (p<0.0001); EUROHIS-QOL8, � −0.222 (p
<0.0001)) and in he PD ≤2 y g oup (PDQ-39SI, �0.483 (p
<0.0001); EUROHIS-QOL8, � −0.304 (p�0.001)). QoL a
V2 was wo se in pa ien s wi h pe sis en d ooling in bo h he
en i e coho (PDQ-39SI, 25.18 ±19.14 s. 18.4 ±14.81 (p
<0.0001); EUROHIS-QOL8, 3.64 ±0.51 s. 3.8 ±0.59 (p
<0.005)) and in he PD ≤2 y g oup (PDQ-39SI,
28.58 ±22.71 s. 14.03 ±11.35 (p�0.001); EUROHIS-QOL8,
3.54 ±0.53 s. 3.88 ±0.57 (p�0.006)). Finally, by domains,
d ooling was an independen ac o associa ed wi h a wo se
“Ac i i ies o daily li ing” (β�0.086; 95% CI, 0.654–5.925; p
�0.015; R
2
�0.43) and “Communica ion” (β�0.088; 95%
CI, 0.297–5.075; p�0.028; R
2
�0.28) a V0 in he en i e
coho .
4. Discussion
Te p esen s udy ep esen s one o he la ges coho s o PD
pa ien s in whom he p e alence o d ooling was epo ed
using a alida ed global NMS scale. We obse ed ha
d ooling was common in PD pa ien s, clea ly much mo e
equen han in he con ol g oup, and was associa ed wi h
he male gende , olde age, and a g ea e mo o and non-
mo o se e i y. In addi ion, pa ien s wi h d ooling had
a wo se global and heal h- ela ed QoL, al hough he e ec o
d ooling on QoL was no signi can a e adjus ing o o he
co a ia es. Impo an ly, we obse ed ha d ooling was also
a e y equen symp om a he beginning o he disease, as
seen in he e y ea ly PD pa ien s, sugges ing he clinical
impo ance o asking o he p esence o d ooling a he
beginning o he pa ien ’s ollow-up.
Abou 2 ou o e e y 3 pa ien s om he Spanish coho
COPPADIS epo ed d ooling o e a 2-yea ollow-up. Tis
cumula i e p e alence is in line wi h he p e iously pub-
lished da a [11]. Howe e , due o he lack o a s anda d
de ni ion and c i e ia o diagnosing d ooling in PD pa-
ien s, es ima es o i s p e alence a y conside ably wi h
a wide ange om 10% o 84% [2–15]. Tis is pa ly due o
di e en ools such as he UPDRS-II, SCOPA-AUT (Scale
o Ou comes in Pa kinson’s disease o Au onomic
Symp oms), PD-NMSQues (Pa kinson’s Disease Non-
mo o Symp oms Ques ionnai e), NMSS, o di e en ypes
o sc eening ques ionnai es ha e been used o sc een
d ooling in PD coho s wi h di e en cha ac e is ics also
[1, 3, 11]. Some speci c scales o assess d ooling ha e been
designed, bu hey ha e been poo ly used in s udies wi h PD
pa ien s [37]. Using he NMSS-i em 19 o de ec ing
d ooling like us, an Wamelen e al. [23] de ec ed in a coho
o 728 PD pa ien s wi h a mean disease du a ion o 5.6 yea s
a p e alence o 37.2% a he baseline and 40.1% a e a mean
ollow-up o 3.3 yea s ( ange 0.5–7.2 yea s). In many c oss-
sec ional s udies, he p e alence o d ooling in PD is be ween
40% and 50% [2, 6–8, 11, 23, 24, 38, 39], which is in
ag eemen wi h ou ndings. An in e es ing nding is ha
like in o he s udies [5, 13], d ooling was no ela ed o
disease du a ion and in ac , he p e alence a each yea
( om 35% o 50%) and he cumula i e p e alence a e he
2-yea ollow-up (65%) was simila in hose pa ien s wi h no
mo e han 2 yea s since symp om onse compa ed o he
whole coho . D ooling is equen e en in de no o pa ien s.
E o e al. [27] epo ed in 61 de no o PD pa ien s a e-
quency o d ooling o 19.4% a he baseline and 15.3% a e
a 2-yea ollow-up, whe eas Picillo e al. [28] ound in 86
men and 48 women de no o PD pa ien s a equency o
d ooling a he baseline and a e a 2-yea ollow-up o 23.3%
and 25% and 10.4% and 4.1%, espec i ely. Te Picillo s udy,
in addi ion o ou s and o he s udies, sugges s ha d ooling
could be mo e equen in males [3, 11, 28, 40]. Al hough
speci cally well-designed s udies o analyze he p e alence
o d ooling using speci c alida ed scales [37, 41] in la ge
coho s a e equi ed, all hese da a sugges a ecommenda-
ion o ule ou d ooling in PD pa ien s a he beginning and
h oughou ollow-up since i s p esence is associa ed wi h
a wo se QoL and i is po en ially ea able. Conside a ion is
especially alid in elde ly men o which he p e alence o
d ooling is mo e equen . Despi e his, d ooling is an
unde ecognized and unde ea ed symp om in PD [1]. O
no e, no pa ien om ou coho was ecei ing bo ulinum
oxin injec ions.
Table 4: Fac o s associa ed wi h d ooling se e i y a e he 2-yea ollow-up in he en i e coho (N�481) and in he PD ≤2 y g oup
(N�127).
β
a
β
b
95% CI
a
95% CI
b
p
a
p
b
En i e coho
Age 0.114 0.083 0.015–0.127 −0.001–0.109 0.013 0.052
Male 0.112 0.136 0.252–2.199 0.568–2.445 0.014 0.002
UPDRS-III a V0 0.207 0.087 0.060–1.054 −0.003–0.093 <0.0001 0.068
NMSS a V0 0.359 0.492 0.039–0.063 0.052–0.089 <0.0001 <0.0001
PDQ-39SI a V0 0.240 −0.110 0.063–1.135 −0.098–0.007 <0.0001 0.087
Change om V0 o V2 in NMSS 0.073 0.221 −0.003–0.125 0.020–0.048 0.110 <0.0001
PD ≤2 y g oup
UPDRS-III a V0 1.121 0.272 1.056–1.191 0.038–0.204 <0.0001 0.005
NMSS a V0 1.019 0.272 1.007–1.032 0.009–0.049 <0.0001 0.005
Dependen a iable: d ooling
V0+V1+V2
sco e. βs anda dized coe cien and 95% IC a e shown.
a
uni a ia e analysis;
b
mul i a ia e analysis; en i e coho ,
R
2
�0.21; Du bin–Wa son es �1.92; PD ≤2 y, R
2
�22; Du bin–Wa son es �1.94. NMSS: Nonmo o Symp oms Scale; PD ≤2 y: PD wi h ≤2 yea s om
symp om onse ; PDQ-39SI: 39-i em Pa kinson’s disease Ques ionnai e Summa y Index; UPDRS: Uni ed Pa kinson’s Disease Ra ing Scale.
8Pa kinson’s Disease
In addi ion o male gende , many o he a iables ha e
been associa ed wi h d ooling in PD pa ien s such as dys-
phagia [1, 42], dysa h ia [1, 43], hypomimia [14, 17], lingual
b adykinesia [14, 17], cogni i e s a us [15, 24], hallucina-
ions [5], aging [3, 23], mo e ad anced disease s age [16, 24],
o hos a ic hypo ension [1], camp oco mia [44], and a his-
o y o using an idep essan s [6]. D ooling in PD pa ien s
can be in pa due o he inabili y o main ain sali a in he
mou h (i.e., hypomimia, abno mal exed pos u e, e c.) and
impai men o sali a y clea ance (i.e., lingual b adykinesia,
o opha yngeal dysphagia, and uppe esophageal dysmo-
ili y), as dysphagia is he s onges ac o associa ed wi h
d ooling [7, 12, 23]. We iden i ed dysphagia as a ac o ha
doubles he p obabili y o d ooling independen ly o o he
a iables, e en hough i was measu ed h ough pa ien -
epo ed ou comes. Mo eo e , no only dysphagia bu den
bu also hypomimia bu den co ela ed wi h d ooling bu den
in he en i e coho and he e y ea ly PD g oup as well. On
he o he hand, some ecen s udies comp ehensi ely
e alua ing many ea u es o he disease ound an associa ion
be ween d ooling and la e onse o he disease, a highe
LEDD, uc ua ions, dep ession, highe mo o sco es, and
a g ea e NMS bu den [13–15, 23, 45]. In his Spanish co-
ho , we iden i ed a g ea e mo o se e i y (UPDRS-III) and
a g ea e NMS bu den (NMSS) as independen ac o s as-
socia ed wi h d ooling and/o also p edic o s o d ooling
a e a 2-yea ollow-up. Speci cally, a wo se s a us in e ms
o mo o and NMS p edic ed a g ea e d ooling se e i y as
well. Tis could explain why d ooling was associa ed wi h
a wo se QoL bu was no an independen p edic o o i .
Ka akoc e al. [46] epo ed d ooling in 65% o 63 people
wi h PD bu no independen signi can co ela ion o
d ooling se e i y wi h QoL. Howe e , as in ou case, hey
measu ed he la e om he o al PDQ-39 sco e, a he han
wi h a ool ha measu es d ooling impac . In con as , when
we used he PDQ-39 domains, we iden i ed d ooling as an
independen ac o associa ed wi h a wo se au onomy o
ADL (PDQ-39 domain 2) and communica ion (PDQ-39
domain 7). Psychosocially, PD d oole s had wo se QoL and
had mo e di cul y speaking, ea ing, and socially in e ac ing
compa ed o PD nond oole s [3, 5, 11]. In addi ion, d ooling
pa ien s a ec hei ca egi e s by inc easing hei bu den,
dep ession, and anxie y and educing hei QoL [47]. Fo all
hese easons, he apeu ic op ions should be e alua ed mo e
in ensi ely in pa ien s wi h PD and d ooling [1, 11].
Te p esen s udy has some impo an limi a ions.
D ooling was conside ed based on an answe o a simple
clinical ques ion om he NMSS and no a e using
a speci c scale [37, 41]. Howe e , his me hodology is he
mos equen in mos s udies [2, 3, 6, 7, 11, 24, 40, 47, 48].
Te sample size in he g oup o PD pa ien s wi h no mo e
han 2 yea s since he onse o he symp oms was small and
clea ly smalle han ha o he en i e coho . In he 2-yea
ollow-up g oup, he e was a 30% loss in pa icipan s, al-
hough his has been obse ed in o he coho s, wi h e-
en ion a es o 71% [23], 67% [27], o 67% [28]. Te logis ic
eg ession models used o iden i y he independen ac o s
associa ed wi h d ooling and p edic o s o d ooling only
explain 20–30% o he a iance in ou analysis, bu i was
ei he also low o no p o ided in o he s udies [6, 7, 13, 23].
Fo some a iables, he in o ma ion was no collec ed in all
cases. Ins ead o a speci c ool o assessing como bidi y, like
he Cha lson index o o he s, he o al numbe o non-an i-
Pa kinsonian medica ions was used as a su oga e ma ke o
como bidi y [36], and he ole o possible como bidi ies
inducing d ooling was no conside ed. Finally, ou sample
was no ully ep esen a i e o he PD popula ion due o
inclusion and exclusion c i e ia (i.e., age limi , no demen ia,
no se e e como bidi ies, no second-line he apies, e c.) [49].
None heless, he s eng hs o ou s udy include a e y
ho ough assessmen , a p ospec i e longi udinal ollow-up
design, and he ex ensi e clinical and demog aphic in-
o ma ion eco ded. Da a abou d ooling se e i y and
PDQ-39 domains a e no el.
In conclusion, his s udy obse es a high p e alence o
d ooling in PD pa ien s, clea ly much mo e so han in
con ol subjec s, and ha his ea u e is equen e en a he
s s ages o he disease as well. Dysphagia is associa ed wi h
d ooling, and a highe mo o sco e and a g ea e NMS
bu den a e p edic o s o d ooling. PD pa ien s wi h d ooling
ha e a wo se QoL, and d ooling is also an independen ac o
associa ed wi h communica ion p oblems. Tus, d ooling
sc eening and he apeu ic op ions should be conside ed in
clinical p ac ice.
Appendix
A. Coppadis S udy G oup
Ada mes AD, Alme ia M, Alonso Losada MG, Alonso
C´
ano as A, Alonso F ech F, Alonso Redondo R, ´
Al a ez Te
au ho s, ´
Al a ez Sauco M, Anei os D´
ıaz A, A n´
aiz S, A ibas
S, Ascunce Vidondo A, Aguila M, ´
A ila MA, Be na do
Lamb ich N, Bej -Kasem H, Bl´
azquez Es ada M, Bo ´
ı M,
Bo ue C, Buongio no MT, Cabello Gonz´
alez C, Cabo L´
opez
Te au ho s, Caballol N, C´
ama a Lo enzo A, Can eld
Medina H, Ca illo F, Ca illo Padilla FJ, Casas E, Ca al´
an
MJ, Cla e o P, Co ina Fe n´
andez A, Cosgaya M, Co s
Fo as e A, C espo Cue as A, Cubo E, de Deus Fon icoba T,
de F´
ab egues-Boixa O, D´
ıez-Fai en M, Do o Ga c´
ıa-So o J,
E o E, Escalan e S, Es el ich Pey e E, Fe n´
andez Guill´
an N,
G´
amez P, Gallego M, Ga c´
ıa Calden ey J, Ga c´
ıa Campos C,
Ga c´
ıa D´
ıez C, Ga c´
ıa Mo eno JM, Gas ´
on Te au ho s,
G´
omez Ga e MP, G´
omez Mayo domo V, Gonz´
alez Aloy J,
Gonz´
alez-A ambu u Te au ho s, Gonz´
alez A du a J,
Gonz´
alez Ga c´
ıa B, Gonz´
alez Palm´
as MJ, Gonz´
alez Toledo
GR, Golpe D´
ıaz A, G au Sol´
a M, Gua dia G, He n´
andez
Va a J, Ho a-Ba ba A, Idoa e Calde ´
on D, In an e J, Jes´
us S,
Kulise sky J, Ku is M, Labandei a C, Lab ado MA, Lac uz
F, Lage Cas o M, Las es G´
omez S, Lega da Te au ho s,
L´
opez A iz egui N, L´
opez D´
ıaz LM, L´
opez Dom´
ınguez D,
L´
opez Manzana es L, L´
opez Seoane B, Lucas del Pozo S,
Mac´
ıas Y, Ma a M, Ma ´
ı And es G, Ma ´
ı MJ, Ma ´
ınez
Cas illo JC, Ma inez-Ma in P, McA ee D, Mei ´
ın MT,
Mendoza Plasencia Z, Men´
endez Gonz´
alez M, M´
endez del
Ba io C, Mi P, Mi anda San iago J, Mo ales Casado MI,
Mo eno Di´
eguez A, Noguei a V, No o Amado A, No o
Pon e S, O d´
as C, Pagonaba aga J, Pa e´
es Te au ho s,
Pa kinson’s Disease 9
educa ional p esen a ions and ad ice se ice by Abb ie,
I al a maco, Zambon, and Bial. Gas ´
on I. has ecei ed e-
sea ch suppo om Abb ie and Zambon and has se ed as
a consul an o Abb ie, Exel s, and Zambon. 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; Fundaci´
oLa
Ma a ´
ode TV3; (7) Schola ship om co po a ion: No; (8)
Co po a e labo a o y unding: No; (9) O he s (e.g. ips,
a el, o gi s): No. Bl´
azquez Es ada M. has ecei ed
hono a ia o educa ional p esen a ions and ad ice se ice
by Abb ie, Abbo , UCB Pha ma, Alle gan, Zambon, Bial,
and Qualigen. Seijo M. has ecei ed hono a ia o educa-
ional se ices om KRKA, UCB, Zambon, Bial; a el
g an s om Daiichi and Roche. Ruiz Ma ´
ınez J. has ecei ed
hono a ia o educa ional p esen a ions, a ending medical
con e ences, and ad ice se ice by Abb ie, UCB Pha ma,
Zambon, I al a maco, Bial, and Te a. Vale o C. has ecei ed
hono a ia o educa ional se ices om Zambon, Abb ie,
and UCB. Ku is M. has ecei ed hono a ia om Bial, he
Spanish Neu ology Socie y, and he In e na ional and
Mo emen Diso de s Socie y. de F´
ab egues O. has ecei ed
hono a ia o educa ional p esen a ions and ad ice se ice
by Bial, Zambon, Abb ie, KRKA, and Te a. Gonz´
alez A du a
J. has ecie ed hono a ia o speking om i alo a ma, K ka,
Genzyme, UCB, Es e e, Psyma ibe ica ma ke ing esea ch
SL and Fe e , cou se g an om Te a and a el g an om
Me ck. Alonso Redondo R.: None. O d´
as C.: None. L´
opez
D´
ıaz L. M. has ecei ed hono a ia om UCB, Lundbeck, and
KRKA. McA ee D.: None. Ma ´
ınez-Ma in P. has ecei ed
hono a ia om Na ional School o Public Heal h (ISCIII),
Edi o i-al Vigue a and Takeda Pha maceu icals o lec u ing
in cou ses, and om he In e na ional Pa kinson and
Mo emen Diso de Socie y (MDS) o managemen o he
P og am on Ra ing Scales. Mi P. has ecei ed hono a ia
om AbbVie, Abbo , Alle gan, Bial, Me z, UCB, and
Zambon and ha e ecei ed g an s om he Spanish Minis y
o Economy and Compe i i eness [PI16/01575] co- ounded
by ISCIII (Subdi ecci´
on Gene al de E aluaci´
on y Fomen o
de la In es igaci´
on) and by Fondo Eu opeo de Desa ollo
Regional (FEDER), he Conseje ´
ıa de Econom´
ıa,
Inno aci´
on, Ciencia y Empleo de la Jun a de Andaluc´
ıa
[CVI-02526, CTS-7685], he Conseje ´
ıa de Salud y Bienes a
Social de la Jun a de Andaluc´
ıa [PI-0437-2012, PI-0471-
2013], he Sociedad Andaluza de Neu olog´
ıa, he Jacques
and Glo ia Gossweile Founda ion, he Fundaci´
on Alicia
Koplowi z, he Fundaci´
on Mu ua Mad ileña.
Au ho s’ Con ibu ions
San os Ga c´
ıa D. pe o med concep ion, o ganiza ion, and
execu ion o he p ojec , as well as s a is ical analysis, w i ing
o he s d a o he manusc ip , and ec ui men and/o
e alua ion o pa icipan s. De Deus Fon icoba T. conduc ed
e iew and c i ique as well as ec ui men and/o e alua ion
o pa icipan s. Co es Ba olom´
e C. ca ied ou collabo a ion
in he p epa a ion o he manusc ip as well as e iew and
c i ique. Feal Paincei as M. J. conduc ed collabo a ion in he
p epa a ion o he manusc ip alongside e iew and c i ique.
´
Iñiguez Al a ado M. C. pe o med collabo a ion in he
p epa a ion o he manusc ip alongside e iew and c i ique.
Jes´
us S. pe o med e iew and c i ique as well as ec ui men
and/o e alua ion o pa icipan s. Buongio no M. T. ca ied
ou e iew and c i ique and ec ui men and/o e alua ion o
pa icipan s. Planellas LL. execu ed e iew and c i ique as
well as ec ui men and/o e alua ion o pa icipan s.
Cosgaya M. conduc ed e iew and c i ique as well as e-
c ui men and/o e alua ion o pa icipan s. Ga c´
ıa Cal-
den ey J. conduc ed e iew and c i ique as well as
ec ui men and/o e alua ion o pa icipan s. Caballol
N. execu ed e iew and c i ique as well as ec ui men and/
o e alua ion o pa icipan s. Lega da I. execu ed e iew and
c i ique as well as ec ui men and/o e alua ion o pa -
icipan s. He n´
andez Va a J. execu ed e iew and c i ique
and ec ui men and/o e alua ion o pa icipan s. Cabo
I. pe o med e iew and c i ique and ec ui men and/o
e alua ion o pa icipan s. L´
opez Manzana es L. pe o med
e iew and c i ique and ec ui men and/o e alua ion o
pa icipan s. Gonz´
alez A ambu u I. pe o med e iew and
c i ique and ec ui men and/o e alua ion o pa icipan s.
´
A ila Ri e a M. A. pe o med e iew and c i ique and e-
c ui men and/o e alua ion o pa icipan s. G´
omez May-
o domo V. pe o med e iew and c i ique and ec ui men
and/o e alua ion o pa icipan s. Noguei a V. conduc ed
e iew and c i ique and ec ui men and/o e alua ion o
pa icipan s. Puen e V. conduc ed e iew and c i ique and
ec ui men and/o e alua ion o pa icipan s. Do o
Ga c´
ıa-So o J. conduc ed e iew and c i ique and e-
c ui men and/o e alua ion o pa icipan s. Bo u´
e
C. conduc ed e iew and c i ique and ec ui men and/o
e alua ion o pa icipan s. Solano Vila B. conduc ed e iew
and c i ique and ec ui men and/o e alua ion o pa ici-
pan s. ´
Al a ez Sauco M. pe o med e iew and c i ique and
ec ui men and/o e alua ion o pa icipan s. Vela
L. ca ied ou e iew and c i ique and ec ui men and/o
e alua ion o pa icipan s. Escalan e S. execu ed e iew and
c i ique and ec ui men and/o e alua ion o pa icipan s.
Cubo E. execu ed e iew and c i ique and ec ui men and/
o e alua ion o pa icipan s. Ca illo Padilla F. execu ed
e iew and c i ique and ec ui men and/o e alua ion o
pa icipan s. Ma ´
ınez Cas illo J. C. conduc ed e iew and
c i ique and ec ui men and/o e alua ion o pa icipan s.
S´
anchez Alonso P. conduc ed e iew and c i ique and e-
c ui men and/o e alua ion o pa icipan s. Alonso Losada
M. G. execu ed e iew and c i ique and ec ui men and/o
e alua ion o pa icipan s. L´
opez A iz egui N. execu ed
e iew and c i ique and ec ui men and/o e alua ion o
pa icipan s. Gas ´
on I. execu ed e iew and c i ique and
ec ui men and/o e alua ion o pa icipan s. Kulise sky
J. execu ed e iew and c i ique and ec ui men and/o
e alua ion o pa icipan s. Bl´
azquez Es ada M. execu ed
e iew and c i ique and ec ui men and/o e alua ion o
pa icipan s. Seijo M. execu ed e iew and c i ique and
ec ui men and/o e alua ion o pa icipan s. Ruiz
Ma ´
ınez J. execu ed e iew and c i ique and ec ui men
and/o e alua ion o pa icipan s. Vale o C. conduc ed
16 Pa kinson’s Disease

e iew and c i ique and ec ui men and/o e alua ion o
pa icipan s. Ku is M. conduc ed e iew and c i ique and
ec ui men and/o e alua ion o pa icipan s. de F´
ab egues
O. conduc ed e iew and c i ique and ec ui men and/o
e alua ion o pa icipan s. Gonz´
alez A du a J. conduc ed
e iew and c i ique and ec ui men and/o e alua ion o
pa icipan s. Alonso Redondo R. conduc ed e iew and
c i ique and ec ui men and/o e alua ion o pa icipan s.
O d´
as C. conduc ed e iew and c i ique and ec ui men
and/o e alua ion o pa icipan s. L´
opez D´
ıaz L. M. con-
duc ed e iew and c i ique and ec ui men and/o e alu-
a ion o pa icipan s. McA ee D. conduc ed e iew and
c i ique and e iew o English s yle. Ma ´
ınez-Ma in
P. conduc ed e iew and c i ique and supe ision. Mi
P. execu ed e iew and c i ique and ec ui men and/o
e alua ion o pa icipan s.
Acknowledgmen s
COPPADIS and he p esen s udy we e de eloped wi h he
help o Fundaci´
on Española 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). Also, Te au ho s e-
cei 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 . Te au ho s would like o hank all
pa ien s and hei ca egi e s who collabo a ed in his s udy.
Tey would also like o hank Fundaci´
on Española 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 Al-
pha Bio esea ch (h ps://www.alphabio esea ch.com) and
o he ins i u ions o helping hem.
Re e ences
[1] N. Mille , M. Walshe, and R. W. Walke , Resea ch and Re-
iews in Pa kinsonism, ol. 9, pp. 17–28, 2019.
[2] B. Sco , A. Bo gman, H. Engle , B. Johnels, and
S. M. Aquilonius, “Gende di e ences in Pa kinson’s disease
symp om p o le,” Ac a Neu ologica Scandina ica, ol. 102,
no. 1, pp. 37–43, 2000.
[3] J. G. Kal , B. J. M. Swa , G. F. Bo m, B. R. Bloem, and
M. Munneke, “P e alence and de ni ion o d ooling in
Pa kinson’s disease: a sys ema ic e iew,” Jou nal o Neu-
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18 Pa kinson’s Disease