Prevalence and Factors Associated with Drooling in Parkinson’s Disease: Results from a Longitudinal Prospective Cohort and Comparison with a Control Group

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). 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