Predictors of clinically significant quality of life impairment in Parkinson’s disease

ARTICLE OPEN P edic o s o clinically significan quali y o li e impai men in Pa kinson’s disease Diego San os Ga cía 1 ✉, Te esa de Deus Fon icoba 2 , Ca los Co es 1 , Guille mo Muñoz 1 , Jose M. Paz González 1 , C is ina Ma ínez Mi ó 1 , Es e Suá ez 2 , Sil ia Jesús 3,4 , Miquel Aguila 5 , Pau Pas o 5 , Lluis Planellas 6 , Ma ina Cosgaya 7 , Juan Ga cía Calden ey 8 , Nu ia Caballol 9 , Inés Lega da 10 , Jo ge He nández Va a 11 , I ia Cabo 12 , Luis López Manzana es 13 , Isabel González A ambu u 4,14 , Ma ía A. Á ila Ri e a 15 , Ma ia J. Ca alán 16 , Víc o Noguei a 17 , Víc o Puen e 18 , Ma ía Ruíz de A cos 19 , Ca men Bo ué 20 , Be a Solano Vila 21 , Ma ía Ál a ez Sauco 22 , Lydia Vela 23 , Sonia Escalan e 24 , Es he Cubo 25 , F ancisco Ca illo Padilla 26 , Juan C. Ma ínez Cas illo 27 , Pila Sánchez Alonso 28 , Ma ia G. Alonso Losada 29 , Nu ia López A iz egui 30 , I zia Gas ón 31 , Ped o Cla e o 31 , Jaime Kulise sky 4,32 , Ma a Blázquez Es ada 33 , Manuel Seijo 12 , Ja ie Rúiz Ma ínez 34 , Ca idad Vale o 35 , Mónica Ku is 36 , O iol de Fáb egues 11 , Jessica González A du a 37 , Ca los O dás 38 , Luis M. López Díaz 39 , Da ian McA ee 40 , Pablo Ma inez-Ma in 4 , Pablo Mi 3,4 and COPPADIS S udy G oup* Quali y o li e (QOL) plays an impo an ole in independen li ing in Pa kinson’s disease (PD) pa ien s, being c ucial o know wha ac o s impac QoL h oughou he cou se o he disease. He e we iden ified p edic o s o QoL impai men in PD pa ien s om a Spanish coho . PD pa ien s ec ui ed om 35 cen e s o Spain om he COPPADIS coho om Janua y 2016, o No embe 2017, we e ollowed up du ing 2 yea s. Heal h- ela ed QoL (HRQoL) and global QoL (GQoL) we e assessed wi h he 39-i em Pa kinson’s disease Ques ionnai e (PDQ-39) and he EUROHIS-QOL 8-i em index (EUROHIS-QOL8), espec i ely, a baseline (V0) and a 24 mon hs ± 1 mon h (V2). Clinically significan QoL impai men was defined as p esen ing an inc ease (PDQ-39SI) o dec emen (EUROHIS-QOL8) a V2 ≥10% o he sco e a baseline (V0). A compa ison wi h a con ol g oup was conduc ed o GQoL. GQoL did no change significan ly in PD pa ien s (N=507; p=0.686) o in he con ol g oup (N=119; p=0.192). The mean PDQ-39SI was significan ly inc eased in PD pa ien s (62.7 ± 8.5 yea s old; 58.8% males; N=500) by 21.6% ( om 16.7 ± 13 o 20.3 ± 16.4; p< 0.0001) a V2. Nine y- h ee pa ien s (18.6%) p esen ed a clinically significan HRQoL impai men a V2. To be younge (OR =0.896; 95% CI 0.829–0.968; p=0.006), o be a emale (OR =4.181; 95% CI 1.422–12.290; p=0.009), and o ha e a g ea e inc ease in BDI-II (Beck Dep ession In en o y-II) (OR =1.139; 95% CI 1.053–1.231; p=0.001) and NMSS (Non-Mo o Symp oms Scale) (OR =1.052; 95% CI 1.027–1.113; p< 0.0001) o al sco es om V0 o V2 we e associa ed wi h clinically significan HRQoL impai men a he 2-yea ollow-up (Hosme –Lemeshow es , p=0.665; R 2 =0.655). An inc ease in ≥5 and ≥10 poin s o BDI-II and NMSS o al sco e a V2 mul iplied he p obabili y o p esen ing clinically significan HRQoL impai men by 5 (OR =5.453; 95% CI 1.663–17.876; p=0.005) and 8 (OR =8.217; 95% CI, 2.975–22.696; p=0.002), espec i ely. In conclusion, age, gende , mood, and non-mo o impai men we e associa ed wi h clinically significan HRQoL impai men a e he 2-yea ollow-up in PD pa ien s. npj Pa kinson’s Disease (2021) 7:118 ; h ps://doi.o g/10.1038/s41531-021-00256-w INTRODUCTION Pa kinson’s disease (PD) is a complex diso de in which di e en mo o and non-mo o symp oms (NMS) can be p esen wi h a equency and se e i y ha a ies among pa ien s o e ime 1 . Bo h mo o and NMS a e impo an because hey nega i ely impac he pa ien ’s quali y o li e (QoL). Di e en s udies ha e analyzed wha ac o s con ibu e o a poo QoL in PD pa ien s 2–13 . Recen ly, we obse ed ha NMS bu den, mood, and gai p oblems we e he mos ele an ac o s a ec ing heal h- ela ed (HRQoL) and global pe cei ed QoL (GQoL) in non-demen ed PD pa ien s om he Spanish coho COPPADIS 14 . These esul s aligned wi h o he c oss-sec ional s udies obse a ions 15–17 . Howe e , wi h 1 CHUAC, Complejo Hospi ala io Uni e si a io de A Co uña, A Co uña, Spain. 2 CHUF, Complejo Hospi ala io Uni e si a io de Fe ol, A Co uña, Spain. 3 Unidad de T as o nos del Mo imien o, Se icio de Neu ología y Neu ofisiología Clínica, Ins i u o de Biomedicina de Se illa, Hospi al Uni e si a io Vi gen del Rocío/CSIC/Uni e sidad de Se illa, Se ille, Spain. 4 CIBERNED (Cen o de In es igación Biomédica en Red sob e En e medades Neu odegene a i as), Ála a, Spain. 5 Hospi al Uni e si a i Mu ua de Te assa, Te assa, Ba celona, Spain. 6 Neu ología, Clínica del Pila , Ba celona, Spain. 7 Hospi al Clínic de Ba celona, Ba celona, Spain. 8 Cen o Neu ológico Oms 42, Palma de Mallo ca, Spain. 9 Conso ci Sani a i In eg al, Hospi al Moisés B oggi, San Joan Despí, Ba celona, Spain. 10 Hospi al Uni e si a io Son Espases, Palma de Mallo ca, Spain. 11 Hospi al Uni e si a io Vall d´Heb on, Ba celona, Spain. 12 Complejo Hospi ala io Uni e si a io de Pon e ed a (CHOP), Pon e ed a, Spain. 13 Hospi al Uni e si a io La P incesa, Mad id, Spain. 14 Hospi al Uni e si a io Ma qués de Valdecilla, San ande , Spain. 15 Conso ci Sani a i In eg al, Hospi al Gene al de L´Hospi ale , L´Hospi ale de Llob ega , Ba celona, Spain. 16 Hospi al Uni e si a io Clínico San Ca los, Mad id, Spain. 17 Hospi al Da Cos a, Bu ela, Lugo, Spain. 18 Hospi al del Ma , Ba celona, Spain. 19 Hospi al Uni e si a io Vi gen Maca ena, Se illa, Spain. 20 Hospi al In an a So ía, Mad id, Spain. 21 Ins i u d’Assis ència Sani à ia (IAS) - Ins i u Ca alà de la Salu , Gi ona, Spain. 22 Hospi al Gene al Uni e si a io de Elche, Elche, Spain. 23 Fundación Hospi al de Alco cón, Mad id, Spain. 24 Hospi al de To osa Ve ge de la Cin a (HTVC), To osa, Ta agona, Spain. 25 Complejo Asis encial Uni e si a io de Bu gos, Bu gos, Spain. 26 Hospi al Uni e si a io de Cana ias, San C is óbal de la Laguna, San a C uz de Tene i e, Spain. 27 Hospi al Uni e si a io Ramón y Cajal, IRYCIS, Mad id, Spain. 28 Hospi al Uni e si a io Pue a de Hie o, Mad id, Spain. 29 Hospi al Ál a o Cunquei o, Complejo Hospi ala io Uni e si a io de Vigo (CHUVI), Vigo, Spain. 30 Complejo Hospi ala io de Toledo, Toledo, Spain. 31 Complejo Hospi ala io de Na a a, Pamplona, Spain. 32 Hospi al de San Pau, Ba celona, Spain. 33 Hospi al Uni e si a io Cen al de As u ias, O iedo, Spain. 34 Hospi al Uni e si a io Donos ia, San Sebas ián, Spain. 35 Hospi al A nau de Vilano a, Valencia, Spain. 36 Hospi al Rube In e nacional, Mad id, Spain. 37 Hospi al Uni e si a io de Cabueñes, Gijón, Spain. 38 Hospi al Rey Juan Ca los, Mad id, Spain, Mad id, Spain. 39 Complejo Hospi ala io Uni e si a io de O ense (CHUO), O ense, Spain. 40 Uni e is y o Pennsyl ania, Pennsyl ania, USA. *A lis o au ho s and hei a filia ions appea s a he end o he pape . ✉email: diegosan[email p o ec ed]s www.na u e.com/npjpa kd Published in pa ne ship wi h he Pa kinson’s Founda ion 1234567890():,; ega d o how he QoL o PD changes h oughou he cou se o he disease, he e is much less in o ma ion 18–23 and p ospec i e longi udinal s udies a e needed. In clinical p ac ice, i is impo an o know wha ac o s wo sen PD pa ien s’QoL wi h he in en ion o ca y ou e ec i e in e en ions. Known in o ma ion limi ed by ac o s om he s udies such as he sample size, he di e ences be ween scales used o assessing QoL, he di e en ypes o QoL assessed, being a non-mul icen e s udy, he absence o a con ol g oup, and/o he lack o a global e alua ion including di e en aspec s ha could impac on QoL 18–23 . In addi ion, he impac o some complica ions on QoL in ad anced PD has been analyzed be o e 24,25 . Howe e , i is no clea wha he significance o sho - e m changes in QoL is in ea ly PD pa ien s o wha ac o s con ibu e o i when an ex ensi e assessmen conside ing mo o and NMS is pe o med 26 . I is ema kable ha NMS occu no only in ad anced bu also in he ea ly s ages o PD. Some symp oms, o example, ol ac o y defici , cons ipa ion, apid-eye- mo emen sleep beha io diso de , and dep ession, can e en p ecede he appea ance o mo o symp oms by many yea s 1 .By he con a y, o he s such as psychosis o demen ia a e no p esen . The fi s yea s a e condi ioned by he accep ance o he diagnosis, bu in gene al, he pa ien has g ea e au onomy. In his con ex , i is essen ial o know wha influences he changes in he PD pa ien QoL pe cep ion wi h he in en ion o being able o ac as soon as possible. The aim o he p esen s udy was o (1) analyze he change in HRQoL and GQoL in PD pa ien s om he COPPADIS coho a e he 2-yea ollow-up, (2) o compa e wi h a con ol g oup, and (3) o iden i y p edic o s o clinically significan QoL impai men in he PD g oup. Finally, a subanalysis was conduc ed in a subg oup o pa ien s wi h ea ly PD (≤5 yea s o disease du a ion). RESULTS Changes in assessmen s om V0 o V2 A e he 2-yea ollow-up, GQoL did no change significan ly in PD pa ien s ( om PQ-10 V0 o 7.28 ± 1.55 o PQ-10 V2 o 7.14 ± 1.54 [N=503; p=0.070]; om EUROHIS-QOL8 V0 o 3.77 ± 0.54 o EUROHIS-QOL8 V2 o 3.75 ± 0.58 [N=507; p=0.686]) o in he con ol g oup ( om PQ-10 V0 o 8.07 ± 1.22 o PQ-10 V2 o 7.86 ± 1.65 [N=122; p=0.361]; om EUROHIS-QOL8 V0 o 4.18 ± 0.5 o EUROHIS-QOL8 V2 o 4.12 ± 0.51 [N=119; p=0.192] (Fig. 1). The mean PDQ-39SI was significan ly inc eased in PD pa ien s (62.7 ± 8.5 yea s old; 58.8% males; N=500) by 21.6% ( om 16.72 ± 13.02 o 20.3 ± 16.41; p< 0.0001) a V2 (Table 1and Fig. 1). By domains, he sco e o all domains o he PDQ-39SI a V2 was significan ly highe han a V0 excep o domain 4 (s igma iza ion) (Table 1). The change in he sco e o o he scales om V0 o V2 in PD pa ien s and con ols is shown in Table 1. Pa ien s wi h s wi hou clinically HRQoL impai men Al hough 291 PD pa ien s (58.2%) p esen ed an inc ease in he PDQ-39SI sco e a e he 2-yea ollow-up, only 93 (18.6%) p esen ed a clinically significan HRQoL impai men a V2. Di e ences in change om V0 o V2 o UPDRS-III, UPDRS-IV, FOGQ, NMSS, BDI-II, PDSS, NPI, VAS-PAIN, VASF-physical, VASF- men al, and ADLS sco es be ween pa ien s wi h and wi hou clinically significan HRQoL impai men we e obse ed (Table 2). Specifically, PD pa ien s who p esen ed a he 2-yea ollow-up a clinically significan HRQoL impai men p esen ed a 97.3% inc ease o he NMS bu den (NMSS o al sco e om 29.2 ± 25.87 o 57.84 ± 46.73 [p< 0.0001]) compa ed o 8.6% in hose pa ien s who did no (NMSS o al sco e om 48.38 ± 38.59 o 52.53 ± 41.35 [p=0.003]) (Fig. 2A). By domains, he mos significan di e ences we e obse ed o sleep/ a igue (p< 0.0001) and mood/apa hy (p< 0.0001) (Table 2and Fig. 2B). Mode a e co ela ions we e obse ed be ween he change om V0 o V2 in he PDQ-39SI sco e and he sco e in FOGQ ( =0.34; p< 0.0001), NMSS ( =0.41; p< 0.0001), BDI-II ( =0.33; p< 0.0001) and ADLS ( =−0.40; p< 0.0001) (Supplemen a y Table 1). P edic o s o clinically HRQoL impai men To be younge (OR =0.896; 95% CI 0.829–0.968; p=0.006), o be a emale (OR =4.181; 95% CI 1.422–12.290; p=0.009), and o ha e a g ea e inc ease in BDI-II (OR =1.139; 95% CI 1.053–1.231; p=0.001) and NMSS (OR =1.052; 95% CI 1.027–1.113; p< 0.0001) o al sco es om V0 o V2 we e associa ed wi h clinically significan HRQoL impai men a he 2-yea ollow-up, a e adjus men o many co a ia es (Hosme –Lemeshow es , p= 0.665; R 2 =0.655) (Table 3). Specifically, an inc ease in ≥5 and ≥10 poin s o BDI-II and NMSS o al sco e a V2 mul iplied he p obabili y o p esen ing a clinically significan HRQoL impai men by 5 (OR =5.453; 95% CI 1.663–17.876; p=0.005) and 8 (OR = 8.217; 95% CI 2.975–22.696; p=0.002), espec i ely. When ADLS was included in he model (ADLS a V0 and he change in ADLS sco e om V0 o V2), only a g ea e inc ease in BDI-II (OR =1.148; 95% CI 1.057–1.258; p=0.001), NMSS (Non-Mo o Symp oms Scale) (OR =1.056; 95% CI 1.029–1.083; p< 0.0001) and NPI (OR = 1.072; 95% CI, 1.001–1.147; p=0.046) o al sco es and a dec ease in ADLS sco e (OR =0.884; 95% CI 0.820–0.954; p< 0.0001) om V0 o V2 we e associa ed wi h clinically significan HRQoL impai men a he 2-yea ollow-up (Hosme –Lemeshow es , p=0.621; R 2 =0.718). Fig. 1 Change in PDQ-39SI, PQ-10, and EUROHIS-QOL8 sco es om V0 (baseline) o V2 (2 yea ± 1 mon h) in PD pa ien s and/o con ols. Da a a e p esen ed as box plo s, wi h he box ep esen ing he median and he wo middle qua iles (25–75%). p- alues we e compu ed using he Wilcoxon-signed ank es . Mild ou lie s (O) a e da a poin s ha a e mo e ex eme han Q1 −1.5 * IQR o Q3 +1.5 * IQR. EUROHIS-QOL8, Eu opean Heal h In e iew Su ey-Quali y o Li e 8-I em Index; PDQ-39SI, 39-i em Pa kinson’s Disease Quali y o Li e Ques ionnai e Summa y Index. D.S. Ga cía e al. 2 npj Pa kinson’s Disease (2021) 118 Published in pa ne ship wi h he Pa kinson’s Founda ion 1234567890():,; In he subg oup o ea ly PD (N=277), qui e simila esul s, an inc ease in mean PDQ-39SI om V0 o V2 o 23.4% ( om 14.22 ± 11.29 o 17.62 ± 15.36; p< 0.0001), we e obse ed. Fi y-six pa ien s (20.2%) p esen ed a clinically significan HRQoL impai - men a he 2-yea ollow-up. Howe e , as in he whole coho , GQoL did no change significan ly (PQ-10, p=0.111; EUROHIS- QOL8, p=0.756). In he bina y eg ession model, as in he all coho , o be younge (OR =0.813; 95% CI 0.709–0.933; p=0.003), o be a emale (OR =35.847; 95% CI 3.452–372.204; p=0.003), and o ha e a g ea e inc ease in BDI-II (OR =1.400; 95% CI 1.149–1.705; p=0.001) and NMSS (OR =1.069; 95% CI 1.007–1.043; p=0.001) o al sco es om V0 o V2 we e associa ed wi h clinically significan HRQoL impai men a he 2-yea ollow- up, a e adjus men o many co a ia es (Hosme –Lemeshow es , p=0.998; R 2 =0.745) (Table 3). When ADLS was included in he model, o be younge (OR =0.769; 95% CI 0.624–0.946; p=0.013), Table 1. Changes in mo o and non-mo o symp oms, disabili y, and quali y o li e in PD pa ien s and/o con ols om V0 (baseline) o V2 (2 yea s ± 1 mon h). PD pa ien s V0 PD pa ien s V2 p a Con ols V0 Con ols V2 p b Hoehn & Yah (OFF) (%) <0.0001 N. A. N. A. N. A. S age 1 22.7 13.3 S age 2 68 77 S age 3–5 9.3 9.7 UPDRS-III (OFF) 21.92 ± 10.53 25.26 ± 12.19 <0.0001 N. A. N. A. N. A. UPDRS-IV 1.99 ± 2.41 2.65 ± 2.75 <0.0001 N. A. N. A. N. A. FOGQ 3.76 ± 4.69 4.94 ± 5.18 <0.0001 N. A. N. A. N. A. LEDD 577.48 ± 412.09 767.56 ± 307.1 <0.0001 N. A. N. A. Numbe o non-an ipa k. d ugs 2.35 ± 2.38 3.08 ± 2.65 <0.0001 2.04 ± .2.16 2.76 ± 2.35 0.001 PD-CRS 92 ± 15.65 90.26 ± 18.07 <0.0001 99.65 ± 13.56 99.68 ± 13.73 0.744 NMSS 45.08 ± 37.62 53.55 ± 42.28 <0.0001 14.74 ± 18.72 14.65 ± 21.82 0.428 BDI-II 8.28 ± 6.9 8.54 ± 7.48 0.472 4.56 ± 5.46 4.31 ± 5.5 0.776 PDSS 117.13 ± 24.48 117.85 ± 24.98 0.797 131.26 ± 17.41 126.67 ± 26.46 0.947 QUIP-RS 4.6 ± 8.8 4.66 ± 9.22 0.937 1.51 ± 3.73 1.32 ± 3.37 0.498 NPI 5.82 ± 7.88 6.17 ± 9.39 0.671 3.31 ± 7.15 2.64 ± 7.67 0.120 VAS-PAIN 2.61 ± 2.92 2.96 ± 2.88 0.013 1.49 ± 2.41 1.70 ± 2.32 0.319 VASF −physical 2.86 ± 2.67 3.17 ± 2.8 0.010 1.52 ± 2.35 1.29 ± 2.12 0.103 VASF −men al 2.09 ± 2.51 2.20 ± 2.61 0.538 1.29 ± 2.09 1.03 ± 1.97 0.273 ADLSL 88.58 ± 10.19 84.26 ± 13.38 <0.0001 98.87 ± 6.65 99.52 ± 2.15 0.285 PDQ-39SI 16.72 ± 13.02 20.3 ± 16.41 <0.0001 N. A. N. A. N. A. Mobili y 16.28 ± 19.2 21.31 ± 22.5 <0.0001 Ac i i ies o daily li ing 17.83 ± 18.83 21.82 ± 21.37 <0.0001 Emo ional well-being 20.92 ± 19.52 23.53 ± 23.45 <0.0001 S igma iza ion 12.81 ± 19.24 14.14 ± 21.09 0.069 Social suppo 7.29 ± 15.43 10.01 ± 19.09 <0.0001 Cogni ion 18.51 ± 17.38 23.17 ± 20.16 <0.0001 Communica ion 9.68 ± 14.44 13.55 ± 18.88 <0.0001 Pain and discom o 26.75 ± 22.33 28.67 ± 23.37 0.009 PQ-10 7.28 ± 1.55 7.14 ± 1.54 0.070 8.07 ± 1.22 7.86 ± 1.65 0.361 EUROHIS-QOL8 3.77 ± 0.54 3.75 ± 0.58 0.686 4.18 ± 0.5 4.12 ± 0.51 0.192 Quali y o li e 3.8 ± 0.7 3.68 ± 0.67 0.003 4.14 ± 0.65 4.2 ± 0.63 0.298 Heal h s a us 3.18 ± 0.87 3.32 ± 0.93 0.004 3.97 ± 0.75 3.87 ± 0.82 0.148 Ene gy 3.76 ± 0.79 3.72 ± 0.86 0.266 4.15 ± 0.68 4.11 ± 0.69 0.531 Au onomy o ADL 3.61 ± 0.86 3.63 ± 0.88 0.852 4.24 ± 0.75 4.19 ± 0.61 0.983 Sel -es eem 3.83 ± 0.76 3.82 ± 0.81 0.866 4.18 ± 0.68 4.00 ± 0.66 0.124 Social ela ionships 4.04 ± 0.67 3.94 ± 0.75 0.004 4.29 ± 0.65 4.19 ± 0.61 0.071 Economic capaci y 3.84 ± 0.78 3.77 ± 0.8 0.091 4.07 ± 0.74 3.97 ± 0.81 0.078 Habi a 4.22 ± 0.67 4.21 ± 0.67 0.904 4.43 ± 0.63 4.29 ± 0.66 0.016 p- alues we e compu ed using he Wilcoxon-signed ank es o ma ginal homogenei y es . The esul s ep esen mean ± SD o %; p a , V2 s V0 in PD pa ien s; p b , V2 s V0 in con ols. ADLS Schwab & England Ac i i ies o Daily Li ing Scale, BDI-II Beck Dep ession In en o y-II, FOGQ F eezing O Gai Ques ionnai e, LEDD le odopa equi alen daily dose (mg), NMSS Non-Mo o Symp oms Scale, NPI Neu opsychia ic In en o y, PD-CRS Pa kinson’s Disease Cogni i e Ra ing Scale, PDSS Pa kinson’s Disease Sleep Scale, QUIP-RS Ques ionnai e o Impulsi e-Compulsi e Diso de s in Pa kinson’s Disease-Ra ing Scale, UPDRS Unified Pa kinson’s Disease Ra ing Scale, VAFS Visual Analog Fa igue Scale, VAS-Pain Visual Analog Scale-Pain. The bold alues indica es s a is ically significan p alues. D.S. Ga cía e al. 3 Published in pa ne ship wi h he Pa kinson’s Founda ion npj Pa kinson’s Disease (2021) 118 o be a emale (OR =31.982; 95% CI 1.678–609.587; p =0.021), and o ha e a g ea e inc ease in BDI-II (OR =1.197; 95% CI 1.126–1.990; p=0.006), NMSS (Non-Mo o Symp oms Scale) (OR =1.108; 95% CI 1.033–1.188; p=0.004) and NPI (OR =1.323; 95% CI 1.041–1.681; p=0.022) o al sco es om V0 o V2 we e associa ed wi h clinically significan HRQoL impai men a he 2-yea ollow-up (Hosme –Lemeshow es , p=0.217; R 2 =0.816), bu no he change in he ADLS sco e (OR =0.889; 95% CI 0.786–1.1006; p=0.062). Mode a e co ela ions we e obse ed be ween he change om V0 o V2 in he PDQ-39SI sco e and he sco e in FOGQ ( =0.39; p< 0.0001), NMSS ( =0.41; p< 0.0001), NPI ( =0.35; p< 0.0001) and ADLS ( =−0.41; p< 0.0001) (Supplemen a y Table 2). P edic o s o he change in he PDQ-39SI om V0 o V2 Finally, simila esul s we e obse ed in bo h g oups, he whole coho and he ea ly PD subg oup, when a linea eg ession model was conside ed (PDQ-39SI change om V0 o V2 as dependen a iable) (Supplemen a y Table 2). To be a emale (β=0.17; p< 0.0001) and change in UPDRS-III (β=0.23; p< 0.0001), FOGQ (β= 0.20; p< 0.0001), and NMSS (β=0.37; p< 0.0001) sco es p o ided he highes con ibu ion o he model (adjus ed R-squa ed 0.45) in he whole coho . In ea ly PD pa ien s, he a iables associa ed wi h HRQoL change a he 2-yea ollow-up we e he same (Supplemen a y Table 2). When he ADLS sco e was included in he model, he esul s we e simila bu wi h he ADLS as an independen a iable associa ed wi h HRQoL change oo (β= −0.21; 95% CI −0.353, −0.107; p< 0.0001; adjus ed R-squa ed 0.45 [N=500; all coho ]; β=−0.23; 95% CI −0.433, −0.076; p=0.005; adjus ed R-squa ed 0.431 [N=277; ea ly PD subg oup]). DISCUSSION In his longi udinal ollow-up s udy, we epo ha he e is a significan HRQoL impai men in PD pa ien s in he sho - e m and ha impai men in he mo o s a us du ing he OFF s a e (UPDRS-III), inc eased gai p oblems (FOGQ), and inc eased NMS bu den con ibu e o i . Specifically, mood impai men and NMS bu den inc ease we e independen ac o s associa ed wi h clinically significan HRQoL impai men a he 2-yea ollow-up, which one was p esen in abou e e y 5 pa ien s. Mo eo e , he esul s indica e ha i will be especially impo an o be igilan abou clinically significan HRQoL impai men in women and younge pa ien s. A e a 2-yea ollow-up, PD pa ien s om he COPPADIS coho demons a ed impai men in mo o unc ion (H&Y, UPDRS-III, UPDRS- IV, FOGQ). The inc ease o mo o impai men s measu ed wi h he UPDRS we e in ag eemen wi h o he s udies 27,28 .Also,significan changes in NMS we e obse ed in he NMS bu den as a whole, pain, a igue, and cogni ion, bu no in con ols. These esul s aligned wi h p e ious longi udinal s udies indica ing ha he se e i y o NMS in PD ends o become p og essi ely wo se wi h he cou se o he disease and also indica e ha non-mo o e alua ion is complemen- a y o measu ing PD p og ession 19,26,29–32 .Wi h espec o heQoL, al hough mo e han a hal o PD pa ien s p esen ed a PDQ-39SI sco e a he 2-yea ollow-up highe han a baseline, only 18.6% p esen ed HRQoL impai men as clinically significan . In a p e ious s udy wi h 707 PD pa ien s ollowed p ospec i ely o he 2-yea as well, 17% wo sened clinically while 584 we e a ed as s able 29 .The esul scan be a y due o he defini ion o QoL impai men as clinically significan 31,33,34 . Based on he pos al eply o 728 PD pa ien s, Pe o e al. 34 de e mined ha 1.6 poin s wo sening on a PDQ-39SI is he minimal clinically impo an di e ence h eshold. Mo e ecen ly, Ho á h e al. 31 conside ed he mos op imal es ima es h eshold o PDQ-39-SI in +4.22 poin s o de ec ing minimal clinically impo an wo sening. Howe e , he e is no “gold s anda d”me hodology o es ima ing he minimal impo an di e ence and as he deg ee o imp o emen is condi ioned by he baseline sco e; he e o e, he use o a pe cen age migh be mo e app op ia e 35,36 . Pa ien s appea o be able o de ec changes o 7–10% on QoL ins umen s o pain scales 36 . In ou case, he minimal impo an di e ence was conside ed Table 2. Changes in mo o and non-mo o symp oms and disabili y in PD pa ien s om V0 (baseline) o V2 (2 yea s ± 1 mon h) wi h ega ds o p esen ing o no clinically significan HRQoL impai men . Non clinically significan HRQoL impai men N=407 Clinically significan HRQoL impai men N=93 p Age a baseline 63.04 ± 7.99 61.32 ± 10.17 0.354 Gende (males) (%) 60 57 0.341 Disease du a ion (a V0) 5.65 ± 4.36 4.91 ± 3.55 0.247 Numbe o non- an ipa k. d ugs (a V0) 2.56 ± 2.36 2.33 ± 2.49 0.220 Change a V2 ( om V0 o V2) LEDD +177.15 ± 330.2 +228.75 ± 318.27 0.174 Numbe o non- an ipa k. d ugs +0.55 ± 1.56 +0.65 ± 1.45 0.685 UPDRS-III (OFF) +2.25 ± 9.77 +7.76 ± 11.2 <0.0001 UPDRS-IV +0.47 ± 2.47 +1.47 ± 2.55 0.002 FOGQ +0.68 ± 3.85 +3.32 ± 4.71 <0.0001 PD-CRS −2.17 ± 12.18 −0.67 ± 10.12 0.293 NMSS +4.15 ± 32.03 +28.64 ± 35.65 <0.0001 Ca dio ascula +6.21 ± 14.41 +8.11 ± 12.83 0.310 Sleep/ a igue +0.7 ± 15.96 +12.98 ± 18.42 <0.0001 Mood/apa hy +0.5 ± 14.57 +8.62 ± 15.19 <0.0001 Pe cep ual symp oms +1.89 ± 10.61 +4.35 ± 12.56 0.141 A en ion/memo y +1.74 ± 14.16 +7.28 ± 17.30 0.07 Gas oin es inal symp oms +2.19 ± 12.64 +4.9 ± 12.8 0.020 U ina y symp oms +1.29 ± 20.22 +9.28 ± 21.56 0.001 Sexual dys unc ion +2.63 ± 30.71 +10.51 ± 23.43 0.007 Miscellaneous +0.72 ± 14.88 +6.19 ± 14.89 0.011 BDI-II −0.63 ± 7.75 +4.51 ± 6.13 <0.0001 PDSS +2.82 ± 25.80 −9.04 ± 24.96 <0.0001 QUIP-RS −0.02 ± 9.25 +0.34 ± 8.06 0.736 NPI −0.43 ± 4.28 +4.28 ± 8.06 <0.0001 VAS-PAIN +0.18 ± 3.21 +1.01 ± 3.74 0.023 VASF −physical +0.09 ± 2.97 +1.1 ± 2.92 0.004 VASF-men al −0.12 ± 2.76 +1.05 ± 2.95 0.002 ADLS −2.84 ± 11.08 −10.97 ± 12.42 <0.0001 Chi-squa ed and Mann–Whi ney–Wilcoxon es we e applied. The esul s ep esen pe cen ages o mean ± SD. The symbol “+”indica es an inc ease in he sco e o he scale a V2 compa ed o V0 while he symbol “–” indica es a dec ease. Da a abou UPDRS-III a e du ing he OFF s a e (fi s hou in he mo ning wi hou aking medica ion in he p e ious 12 h). ADLS Schwab & England Ac i i ies o Daily Li ing Scale, BDI-II Beck Dep ession In en o y-II, FOGQ, F eezing O Gai Ques ionnai e, LEDD le odopa equi alen daily dose (mg), NMSS Non-Mo o Symp oms Scale, NPI Neu opsychia ic In en o y, PD-CRS Pa kinson’s Disease Cogni i e Ra ing Scale, PDSS Pa kinson’s Disease Sleep Scale, QUIP-RS Ques ionnai e o Impulsi e-Compulsi e Diso de s in Pa kinson’s Disease-Ra ing Scale, UPDRS Unified Pa kinson’s Disease Ra ing Scale, VAFS Visual Analog Fa igue Scale, VAS-Pain Visual Analog Scale-Pain. The bold alues indica es s a is ically significan p alues. D.S. Ga cía e al. 4 npj Pa kinson’s Disease (2021) 118 Published in pa ne ship wi h he Pa kinson’s Founda ion as an inc ease o 10% o mo e in he PDQ-39SI sco e 33,35–37 .Ten pe cen o he mean sco e o he PDQ-39SI in ou s udy ep esen s 1.6 poin s; he e o e, simila o he p oposal o Pe o e al. 34 .Howe e , in a pa ien wi h a highe baseline PDQ-39SI sco e, o example, 50 poin s, he minimal clinically significan wo sening change should be 5 poin s. Hence, in less han 1 in 3 pa ien s who had an inc ease in he PDQ-39 sco e, his was conside ed clinically significan . In any case,i seemsclea ha e enina ela i elysho ollow-uppe iod, pa ien s wi h PD expe ience a significan dec ease in HRQoL 21,29 . Howe e , as Reu he e al. 22 epo ed in 145 PD pa ien s a e a 12- mon h ollow-up, he e doesn’ seem o be a significan change in QoL gene ic scales. Fo assessing he NMS as a whole, we used he NMSS. To da e, his scale has been used in mo e han 100 clinical s udies and ials and i has shown o be capable o de ec ing longi udinal changes in NMS, whe e s udies ha e shown di e en ial changes o e ime o se e al o he NMSS domains 32,38,39 . Mo eo e , i has been demons a ed a consis en and s ong co ela ions be ween NMSS bu den and HRQoL measu es 32,40–42 . In ou s udy, a e y clea di e ence in he change o NMS bu den was obse ed be ween pa ien s wi h and wi hou clinically significan HRQoL impai men . Changes in all domains o he NMSS scale co ela ed wi h QoL changes. Simila ly, p e ious s udies obse ed a co ela ion be ween NMS bu den assessed wi h he NMSS and QoL changes o e ime 19 . Mo eo e , in ou analysis, NMS bu den p og ession was an independen ac o ela ed o HRQoL impai men . P akash e al. obse ed o he fi s ime ha non- mo o p oblems p o ided a be e p edic ion o he change o QoL in 227 PD pa ien s o e a 2-yea ollow-up pe iod 19 . Howe e , hey did no p o ide he a iance alue o he model, many ac o s po en ially a ec ing QoL we e no included, and wha hey conside ed was he baseline NMSS sco e. On he con a y, in his s udy we wan ed o analyze in de ail wha changes in many aspec s o he disease obse ed a e he 2-yea ollow-up con ibu ed o a wo sening in he pa ien s´ QoL. So, se e al a iables we e included, he esul s o he model ep esen ed ~70% o he a iance when HRQoL changes we e conside ed, and he changes in all a iables we e adjus ed o he sco es a baseline. To ou bes knowledge, his is he fi s longi udinal- p ospec i e s udy analyzing in such de ail which a e he p edic o s o QoL impai men in a la ge sample o PD pa ien s. Rein o cing he idea ha he p og ession o NMS is pi o al o he wo sening o he QoL h oughou he e olu ion o he disease, imp o emen s o NMS we e associa ed wi h imp o ed QoL in ad anced pa kinso- nian pa ien s du ing 2‐yea ea men wi h le odopa‐ca bidopa in es inal gel in usion he apy 43 . In line wi h his, E o e al. obse ed ha NMS significan ly a ec ed QoL in PD, demons a - ing ha his was especially he case when pa ien s we e in hei honeymoon pe iod (du ing which ime he side e ec s o he disease a en’ oo disabling and he e is a esponse o medica ions) 44 . In he subg oup o ea ly PD pa ien s om ou s udy, he change in he NMSS o al sco e a 2-yea s was one o he mos significan con ibu o s o HRQoL impai men . Ano he impo an ac o is mood. Like in o he s udies, he mean sco e o BDI didn’ change o e ime 18,22 , sugges ing ha dep ession- ype equency does no appea o change o e ime in PD 45 . C oss-sec ional s udies ha e epo ed he clea con ibu- ion o dep ession o a wo se mood o a poo e QoL in PD pa ien s 3,12,13 . In ac , i was obse ed in he COPPADIS baseline c oss-sec ional analysis 14 . Howe e , o ou knowledge, his is he fi s ime ha mood wo sening is iden ified as an independen ac o associa ed wi h clinically significan HRQoL impai men in PD pa ien s. This subg oup o pa ien s (N=93) p esen ed a mean inc ease in he BDI-II sco e o 4.5 poin s a he 2-yea ollow-up and specifically, an inc ease in ≥5 poin s mul iplied by 5 he p obabili y o p esen ing a clinically significan HRQoL impai - men , independen o o he ac o s. Reu he e al. 22 iden ified dep ession as he s onges p edic o o educed HRQoL in 145 PD pa ien s a e 1-yea ollow-up. Howe e , we iden ified he change in he sco e o he BDI-II as a p edic o o clinically significan HRQoL impai men a e adjus men o BDI-II sco e a baseline. F om a p ac ical poin o iew, ou findings sugges an impo an ole o he neu ologis being ale o a possible wo sening o mood, as well as g ea e NMS bu den, in pa ien s wi h PD h oughou he e olu ion o he disease since his is wha impac s on he pa ien ’s QoL. Knowing wha impac s on he QoL and con ibu es o i s wo sening, depending on he a iable, in e en ion measu es wi h he in en ion o co ec ing hem can be p oposed 46 . S udies demons a ing a QoL imp o emen co ela ed wi h mood and NMS bu den imp o emen ha e been published 47 . Wi h ega ds o he esul s obse ed he e, i should be necessa y o be ale abou mood and NMS bu den changes o e ime, especially in younge pa ien s and emales. A mildly significan gende di e ence in disabili y and QoL epo ing has been no ed, wi h women ci ing g ea e disabili y and educed QoL 48,49 . Dep ession and a igue we e he majo causes o low Fig. 2 E olu ion o NMS a e 2-yea ollow up. A Change in he NMSS o al sco e om V0 (baseline) o V2 (2 yea ± 1 mon h) in PD pa ien s wi hou s wi h clinically significan HRQoL impai men . BMean sco e on each domain o he ESS scale a V0 and V2 in PD pa ien s wi hou s wi h clinically significan HRQoL impai men . Da a a e p esen ed as box plo s, wi h he box ep esen ing he median and he wo middle qua iles (25–75%). p- alues we e compu ed using he Wilcoxon-signed ank es . Mild ou lie s (O) a e da a poin s ha a e mo e ex eme han Q1 −1.5 * IQR o Q3 +1.5 * IQR. NMSS, Non-Mo o Symp oms Scale. D.S. Ga cía e al. 5 Published in pa ne ship wi h he Pa kinson’s Founda ion npj Pa kinson’s Disease (2021) 118 HRQoL in women e en in he ea ly phases o PD 50 . To a enua e his sex di e ence in disease expe ience, psychological dis ess sc eening and managemen (pa icula ly a ge ing emales) should be conside ed as pa o PD clinical ca e 23 . Mo eo e , QoL, as measu ed on he PDQ-39, is significan ly wo se in young- onse PD pa ien s han in olde -onse PD pa ien s, and young- onse PD pa ien s also expe ience loss o employmen , dis up ion o amily li e, g ea e pe cei ed s igma iza ion, and dep ession han do olde -onse PD pa ien s 51,52 . The mos impo an limi a ion o his s udy is he ac ha in o ma ion abou ollow-up was eco ded only in 524 pa ien s o 695 ini ially included in he s udy (75.5%). O hem, da a o he PDQ-39, PQ-10, and EUROHIS-QOL8 a baseline and a V2 was a ailable in 500, 503, and 507 PD pa ien s, espec i ely. Thi y-eigh pa ien s (5.5%) d opped ou o he s udy (1 dea h; 2 wi h change in diagnosis; 35 o he easons) a he 2-yea ollow-up and 132 (19%) we e no assessed. Howe e , his is a limi a ion obse ed in o he p ospec i e s udies. O 7507 PD pa ien s, ollow-up da a was a ailable only o 4680 pa icipan s (62.3%) 53 . In he s udy o An onini e al. 29 , 707 PD pa ien s om 1142 ini ially included (61.9%) we e e aluable a 24 mon hs. An impo an second limi a ion is ha PD pa ien s olde han 75 yea s old we e excluded om pa icipa ion by COPPADIS s udy p o ocol 14 , which leads o an ea ly PD bias in his coho . Fo some a iables, he in o ma ion was no collec ed in all cases. Mo eo e , his is a mul icen e mono-coun y s udy, being he ideal o his ype o s udies he pa icipa ion o pa ien s om di e en pa s o he wo ld, so he esul s should be conside ed wi h cau ion when ex apola ing hem o he gene al PD popula ion (i.e., ace, coun y heal hca e, e c.). By he con a y, s eng hs o ou s udy include a e y comple e assessmen , he la ge sample size, a p ospec i e longi udinal ollow-up design, he ac ha his analysis was “a p io i”planned as one objec i e o he mul icen e COPPADIS p ojec 16 , and he ex ensi e clinical and demog aphic in o ma ion eco ded. The findings o his s udy ha e impo an implica ions in daily clinical p ac ice. In a diso de like PD in which one he e is no a cu e, ea men is symp oma ic and he aim is o imp o e he pa ien ’s QoL. This is complex because many ac o s influence QoL in PD. Fu he mo e, PD is a complex diso de wi h many mani es a ions and wi h a g ea a iabili y in i s p og ession among pa ien s. Rega ding his s udy obse a ions, some impo an poin s should be conside ed in daily clinical p ac ice. Fi s , a comple e assessmen o he pa ien wi h PD pe iodically including mo o s a us, NMS, QoL and disabili y should be he ideal p ac ice. Second, NMS p og ession con ibu es significan ly o a QoL wo sening and i is c ucial i s e alua ion. Ve y in e es ingly, we epo ed e y ecen ly ha PD pa ien s om he COPPADIS coho wi h a lowe H&Y s age bu a g ea e global NMS bu den may ha e a wo se QoL han pa ien s wi h a highe H&Y s age bu lowe global NMS 54 . Thi d, mood is ano he key ac o o conside whene e we e alua e he pa ien in clinical p ac ice. Fou h, we ha e o keep in mind ha mood impai men and global NMS p og ession p edic a pa ien ´s QoL wo sening. Finally, we should be especially ca e ul in all o he abo e in he case o a emale pa ien and in young pa ien s. A p oblem in clinical p ac ice is he lack o ime o e alua e he pa ien . Fo he PD pa ien , o b ing adequa ely co e ed ques- ionnai es o he consul a ion, o example wi h he help o nu sing s a , o e en in he u u e wi h mobile applica ions ha ans e he da a o he pa ien ’s medical eco d, i could be a possibili y ha acili a es he comple e and comp ehensi e assessmen . In gene al, i is some hing ha is no done oday, and p oo o his is he ala ming lack o li e a u e abou he global p og ession o he disease including NMS in la ge coho s o pa ien s. Mo e s udies wi h la ge PD coho s and long- e m ollow-up a e equi ed. Ou aim wi h he COPPADIS coho is o ollow o 5 yea s 55 . Collec ing da a om di e en coho s and making compa isons would also be o g ea in e es . In conclusion, he p esen s udy obse es HRQoL impai men in PD pa ien s in a sho 2-yea ollow-up, e en in ea ly PD pa ien s, bu no he GQoL. A younge age, o be a emale, and mood and NMS bu den impai men we e associa ed wi h clinically significan HRQoL impai men a e he 2-yea ollow- up. The p og ession o NMS is pi o al in he wo sening o he QoL h oughou he e olu ion o he disease in PD, and i is necessa y o keep in mind o ask o mood o NMS changes, especially in emales and young pa ien s. Table 3. Bina y logis ic eg ession model abou ac o s associa ed wi h clinically significan HRQoL impai men a V2 (2 yea s ollow-up). OR a OR b 95% CI a 95% CI b p a p b Age 0.896 0.813 0.829–0.968 0.709–0.933 0.006 0.003 Gende ( emale) 4.181 35.847 3.452–372.204 1.378–8.424 0.009 0.003 Disease du a ion 1.040 0.734 0.388–1.389 0.763–1.360 0.673 0.342 No. o non-an ipa kinsonian d ugs/day 0.922 1.005 0.728–1.167 0.697–1.449 0.499 0.979 Change a 2 yea s ollow-up LEDD (mg) 1.000 1.002 0.998–1.005 0.998–1.002 0.860 0.385 UPDRS-III 1.056 1.088 0.995–1.120 0.978–1.211 0.071 0.121 UPDRS-IV 0.959 0.756 0.417–1.372 0.650–1.137 0.785 0.358 FOGQ 1.143 1.160 0.906–1.485 1.108–1.559 0.088 0.239 NMSS 1.052 1.069 1.027–1.113 1.007–1.043 <0.0001 0.001 PD-CRS 0.995 0.972 0.900–1.050 0.963–1.045 0.837 0.473 BDI-II 1.139 1.400 1.053–1.231 1.149–1.705 0.001 0.001 NPI 1.037 1.158 0.976–1.103 0.995–1.348 0.238 0.058 Dependen a iable: Clinically significan HRQoL impai men (defined as PDQ-39SI V2 ≥10% PDQ-39SI V0 ). OR and 95% CI a e shown. Hosme –Lemeshow es , p a =0.665; p b =0.998; R 2a =0.655; R 2b =745. The model was adjus ed o a iables a baseline: LEDD (mg), UPDRS-III, UPDRS-IV, FOGQ, NMSS, PD-CRS, BDI-II, NPI, PDQ-39SI. BDI-II Beck Dep ession In en o y-II, FOGQ F eezing O Gai Ques ionnai e, LEDD le odopa equi alen daily dose (mg), NMSS Non-Mo o Symp oms Scale, NPI Neu opsychia ic In en o y, PD-CRS Pa kinson’s Disease Cogni i e Ra ing Scale, PDQ-39SI 39-i em Pa kinson’s Disease Quali y o Li e Ques ionnai e Summa y Index, QUIP-RS, Ques ionnai e o Impulsi e-Compulsi e Diso de s in Pa kinson’s Disease-Ra ing Scale, UPDRS Unified Pa kinson’s Disease Ra ing Scale. a All coho (n=500). b Ea ly PD pa ien s (n=277). The bold alues indica es s a is ically significan p alues. D.S. Ga cía e al. 6 npj Pa kinson’s Disease (2021) 118 Published in pa ne ship wi h he Pa kinson’s Founda ion METHODS PD pa ien s and con ols who we e ec ui ed om Janua y 2016 o No embe 2017 (baseline isi ; V0) and e alua ed again a he 2-yea ollow-up (V2) om 35 cen e s o Spain om he COPPADIS coho 56 , we e included in he s udy. Me hodology abou COPPADIS-2015 has been p e iously published 57 . This is a mul icen e , obse a ional, longi udinal- p ospec i e, 5-yea ollow-up s udy designed o analyzing disease p og ession in a Spanish popula ion o PD pa ien s. Specifically, 17 objec i es we e p oposed in he p o ocol 55 . E en hough he ec ui men pe iod ended in Oc obe 2017, he p ospec i e ollow-up phase is ongoing. Pa ien s, ca egi e s (pa ien ´s p ima y ca egi e ), and con ols (subjec s wi hou PD and any o he se e e and disabling concomi an diso de ) we e included 55 . Annual isi s om V0 (baseline) o V5 (60 mo hs ± 3 mon hs) a e conduc ed o he pa ien s and a V0, V2, V4, and V5 o he con ols and ca egi e s. All pa ien s included we e diagnosed acco ding o UK PD B ain Bank c i e ia 57 . Exclusion c i e ia 55 we e: non-PD pa kinsonism, demen ia c i e ia (Mini Men al S a e Examina ion [MMSE] ≥26), age < 18 o >75 yea s, inabili y o ead o unde s and he ques ionnai es, o be ecei ing any ad anced he apy (con inuous in usion o le odopa o apomo phine, and/ o wi h deep b ain s imula ion), and p esence o como bidi y, sequelae, o any diso de ha could in e e e wi h he assessmen . In o ma ion on sociodemog aphic aspec s, ac o s ela ed o PD, como bidi y, and ea men we e collec ed. V0 and V2 e alua ions included 55 : (1) mo o assessmen (Hoenh & Yah [H&Y] 58 , Unified Pa kinson’s Disease Ra ing Scale [UPDRS] pa III and pa IV 59 , F eezing o Gai Ques ionnai e [FOGQ] 60 ; (2) NMS (Non-Mo o Symp oms Scale [NMSS] 61 , Pa kinson’s Disease Sleep Scale [PDSS] 62 , Visual Analog Scale- Pain [VAS-Pain] 63 , Visual Analog Fa igue Scale [VAFS] 64 , cogni ion (MMSE 65 , Pa kinson’s Disease Cogni i e Ra ing Scale [PD-CRS] 66 , comple ing a simple 16-piece puzzle); (3) mood and neu opsychia ic symp oms (Beck Dep ession In en o y-II [BDI-II] 67 , Neu opsychia ic In en o y [NPI] 68 , Ques ionnai e o Impulsi e-Compulsi e Diso de s in Pa kinson’s Disease- Ra ing Scale [QUIP-RS] 69 ; (4) and disabili y (Schwab & England Ac i i ies o Daily Li ing Scale [ADLS] 70 . In pa ien s wi h mo o fluc ua ions, he mo o assessmen was made du ing he OFF s a e (wi hou medica ion in he las 12 h) and du ing he ON s a e. On he o he hand, he assessmen was only conduc ed wi hou medica ion in pa ien s wi hou mo o fluc ua ions. The same e alua ion as o he pa ien s, excep o he mo o assessmen , was conduc ed in con ol subjec s a V0 and a V2 (2 yea s ± 1 mon h). Th ee scales we e used o assess QoL a V0 and a V2 28 : (1) he 39-i em Pa kinson’s disease Ques ionnai e (PDQ-39) 71 , (2) a a ing o global pe cei ed QoL (PQ-10) on a scale om 0 (wo s ) o 10 (bes ) 13 , and (3) he EUROHIS-QOL 8-i em index (EUROHIS-QOL8) 72 . The PDQ-39 is a PD- specific ques ionnai e ha assesses he pa ien s’HRQoL. The e a e 39 i ems g ouped in o 8 domains: (1) Mobili y (i ems 1 o 10); (2) Ac i i ies o daily li ing (i ems 11 o 16); (3) Emo ional well-being (i ems 17 o 22); (4) S igma (i ems 23 o 26); (5) Social suppo (i ems 27 o 29); (6) Cogni ion (i ems 30 o 33); (7) Communica ion (i ems 34 o 36); (8) Pain and discom o (i ems 37 o 39). Fo each i em, he sco e may ange om 0 (ne e ) o 4 (always). The symp oms e e o he 4 weeks p io o assessmen . Domain o al sco es a e exp essed as a pe cen age o he co esponding maximum possible sco e and a Summa y Index is ob ained as a e age o he domain sco es. The EUROHIS-QOL8 is an 8-i em GQoL ques ionnai e (quali y o li e, heal h s a us, ene gy, au onomy o ac i i ies o daily li ing, sel -es eem, social ela ionships, economic capaci y, and habi a ) de i ed om he WHOQOL-BREF. Fo each i em, he sco e anges om 0 (no a all) o 5 (comple ely). The o al sco e is exp essed as he mean o he indi idual sco es. A highe sco e indica es a be e QoL. In con ols, only he PQ-10 and he EUROHIS-QOL8 we e assessed. Clinically significan HRQoL impai men was defined as p esen ing an inc ease in PDQ-39SI sco e a V2 ≥10% o sco e a baseline (V0) whe eas GQoL impai men as p esen ing a dec emen in PQ-10 and/o EUROHIS- QOL8 sco e a V2 ≤10% o sco e a baseline (V0) 33 . Taking in o accoun ha in he COPPADIS coho he ange o disease du a ion a ies om <1 yea o 30 yea s and based on he gene al esponse o ea men and p og ession o symp oms in PD and conside ing a ecen publica ion o his same coho 73 , pa ien s wi h ≤5 yea s o disease du a ion we e conside ed as ea ly PD pa ien s. Da a analysis Da a we e p ocessed using SPSS 20.0 o Windows. Fo compa isons be ween pa ien s and con ols, he S uden ’s - es , Mann–Whi ney U es , Chi-squa e es , o Fishe es we e used as app op ia e (dis ibu ion o a iables was e ified by one-sample Kolmogo o –Smi no es ). The Wilcoxon-signed ank es was pe o med o es whe he he mean di e ences o he PDQ-39SI, PQ-10, and EUROHIS-QOL8 sco es and he indi idual PDQ-39SI and EUROHIS- QOL8 domain sco es be ween he wo isi s (V0 and V2) we e significan . This es and/o he ma ginal homogenei y es we e applied o o he scales o analyzing he change om V0 o V2. Spea man’so Pea son’s co ela ion coe ficien , as app op ia e, we e used o analyzing he ela ionship be ween con inuous a iables. Co ela ions we e conside ed weak o coe ficien alues ≤0.29, mode a e o alues be ween 0.30 and 0.59, and s ong o alues ≥0.60. Clinically significan QoL impai men was exp essed as a pe cen age and i was only calcula ed i he change be ween sco es (PDQ-39SI; PQ-10; EUROHIS-QOL8) om V0 o V2 was significan . Fo de e mining p edic i e ac o s o QoL impai men , a logis ic eg ession model (QoL impai men as dependen a iable) was pe o med. The model was well-planned, as ecommended by bes -p ac ice me hods 74 , in which known and p e- sumably p edic o a iables a ec ing QoL changes (dependen a iable) we e included: change om V0 o V2 in le odopa equi alen daily dose (LEDD) 75 , UPDRS-III-OFF (mo o se e i y), UPDRS-IV (mo o complica ions), FOGQ, NMSS (NMS bu den), PD-CRS (cogni ion), BDI-II (mood), and NPI (neu opsychia ic symp oms). The model was adjus ed o baseline QoL and age, gende , disease du a ion, como bidi y ( o al numbe o non- an ipa kinsonian medica ions as su oga e ma ke 14 ), and he sco e o he es o he a iables a baseline (LEDD, UPDRS-III-OFF, UPDRS-IV, FOGQ, NMSS, PD-CRS, and NPI). Disabili y (ADLS) was no included in he model because his is consequence o symp oms, bu since i is ela ed o QoL, in a second model ADLS a baseline and change in ADLS om V0 o V2 we e included. Hosme –Lemeshow es was applied and adjus ed R-squa ed was calcula ed o all analyses. Finally, mul iple linea eg essions we e pe o med wi h “change in QoL”as dependen a iable bu only o a iables (PDQ-39SI; PQ-10; EUROHIS-QOL8) changing significan ly om V0 o V2. The independen a iables included we e he same as in he bina y model. The p- alue was conside ed significan when i was <0.05. S anda d p o ocol app o als, egis a ions, and pa ien consen s The Comi é de É ica de la In es igación Clínica de Galicia om Spain (2014/ 534; 02/DEC/2014) app o al was ob ained. W i en in o med consen s om all pa icipan s in his s udy we e ob ained be o e he s a o he s udy. COPPADIS-2015 was classified by he AEMPS as a Pos -au ho iza ion P ospec i e Follow-up s udy wi h he code COH-PAK-2014-01. Repo ing summa y Fu he in o ma ion on esea ch design is a ailable in he Na u e Resea ch Repo ing Summa y linked o his a icle. DATA AVAILABILITY The da a ha suppo he findings o his s udy a e a ailable om he co esponding au ho upon easonable eques . CODE AVAILABILITY No compu e coding was used in he comple ion o he cu en manusc ip . Recei ed: 25 Ma ch 2021; Accep ed: 27 July 2021; Published online: 16 Decembe 2021 REFERENCES 1. Chaudhu i, K. R. e al. 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The EUROHIS-QOL 8-i em index: compa a i e psychome ic p ope ies o i s pa en WHOQOL-BREF. Value Heal h 15, 449–457 (2012). 73. San os-Ga cía, D. e al. COPPADIS S udy G oup. Non-mo o symp om bu den is s ongly co ela ed o mo o complica ions in pa ien s wi h Pa kinson’s disease. Eu . J. Neu ol. 27, 1210–1223 (2020). 74. Cohen, J. & Cohen, P. Applied Mul iple Reg ession/Co ela ion Analysis o he Beha io al Sciences 2nd ed (Law ence E lbaum, Hillsdale, New Je sey, 1983). 75. Schade, S., Mollenhaue , B. & T enkwalde , C. Le odopa equi alen dose con- e sion ac o s: an upda ed p oposal including opicapone and safinamide. Mo . Diso d. Clin. P ac . 2020, 343–345 (2020). ACKNOWLEDGEMENTS We would like o hank all pa ien s and hei ca egi e s who collabo a ed in his s udy. Many hanks also o Fundación Española de Ayuda a la In es igación en Pa kinson y o as En e medades Neu odegene a i as (Cu emos el Pa kinson; www. cu emoselpa kinson.o g), Alpha Bio esea ch (www.alphabio esea ch.com), and o he ins i u ions helping us. AUTHOR CONTRIBUTIONS S.G.D.: concep ion, o ganiza ion, and execu ion o he p ojec ; s a is ical analysis; w i ing o he fi s d a o he manusc ip ; ec ui men and/o e alua ion o pa icipan s. D.D.T.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. C.C.: e iew and c i ique. M.G.: e iew and c i ique. P.G.J.M.: e iew and c i ique. M.M. C.: e iew and c i ique. S.E.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. J.S.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. A.M.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. P.P.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. P.L.L.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. C.M.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. G.C.J.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. C.N.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. L.I.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. H.V.J.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. C.I.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. L.M.L.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. G.A.I.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. Á.R.M.A.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. C.M.J.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. N.V.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. P.V.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. R.d.A.M.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. B.C.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. S.V.B.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. Á.S.M.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. V.L.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. E.S.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. C.E.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. C.P.F.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. M.C.J.C.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. S.A.P.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. A.L.M.G.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. L.A.N.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. G.I.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. C.P.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. K.J.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. B.E.M.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. S.M.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. R.M.J.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. V.C.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. K.M.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. d.F.O.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. G.A.J.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. O.C.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. L.D.L.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. MD: e iew and c i ique; e iew o english s yle. M.-M.P.: e iew and c i ique; supe ision. M.P.: e iew and c i ique; ec ui men and/o e alua ion o pa icipan s. COMPETING INTERESTS San os Ga cía D. has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by Abb ie, UCB Pha ma, Lundbeck, KRKA, Zambon, Bial, I al a maco, and Te a. De Deus Fon icoba T: None. Co es C. has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by Lundbeck and UCB Pha ma. Muñoz G: None. Paz González JM. has ecei ed hono a ia o educa ional p esen a ions and/o ad ice se ice by UCB Pha ma, Lundbeck,KRKA,andZambon.Ma ínezMi óC:None.Suá ezE:None.JesúsS.has ecei ed hono a ia om AbbVie, Bial, Me z, UCB, and Zambon and holds he compe i i e con ac “Juan Rodés”suppo ed by he Ins i u o de Salud Ca los III. She has ecei ed g an s om he Spanish Minis y o Economy and Compe i i eness (PI18/01898) and he Conseje ía de Salud de la Jun a de Andalucía (PI-0459-2018). Aguila M: UCB and Schwabe wi h assis ance o a Cong ess; Nu icia wi h assis ance o a Cong ess and paymen o lec u e. Pas o P: None. Planellas LL. has ecei ed a el bu sa ies g an om Abb ie. Cosgaya M: None. Ga cía Calden ey J. has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by Qualigen, Nu icia, Abb ie, I al a maco, UCB Pha ma, Lundbeck, Zambon, Bial, and Te a. Caballol N. has ecei ed hono a ia om Bial, I al á maco, Qualigen, Zambon, UCB, Te a and KRKA and sponso ship om Zambon, TEVA and Abb ie o a ending medical con e ences. Lega da I. has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by Abb ie, UCB Pha ma, Zambon, Bial, and Te a. He nández Va a J. has ecei ed a el bu sa ies and educa ional g an s om Abb ie and has ecei ed hono a ia o educa ional p esen a ions om Abb ie, Te a, Bial, Zambon, I al a maco, and Sanofi-Genzyme. Cabo I. has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by Abb ie, Zambon and Bial. López Manzana es L: Compensa ed ad iso y se ices, consul ing, esea ch g an suppo , o speake hono a ia: AbbVie, Aco da, Bial, In ec Pha ma, I al a maco, Pfize , Roche, Te a, UCB, and Zambon. González A ambu u I: None. Á ila Ri e a MA. has ecei ed hono a ia om Zambon, UCB Pha ma, Qualigen, Bial, and Te a, and sponso ship om Zambon and Te a o a ending con e ences. Ca alán MJ: None. Noguei a V: None. Puen e V. has se ed as consul an o Abb ie and Zambon; has ecei ed g an / esea ch om Abb ie. Ruíz de A cos M: None. Bo ué C: None. Solano Vila B. has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by UCB, Zambon, Te a, Abb ie, Bial. Ál a ez Sauco M. has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by Abb ie, UCB Pha ma, Zambon, Bial, and Te a. Vela L. has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by Abb ie, UCB Pha ma, Lundbeck, KRKA, Zambon, Bial, and Te a. Escalan e S. has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by Abb ie, Zambon, and Bial. Cubo E: T a el g an s: Abb ie, Alle gan,Bos on;Lec u ing hono a ia: Abb ie, In e na ional Pa kinson´s disease Mo emen Diso de Socie y. Ca illo Padilla F. has ecei ed hono a ia om Zambon (SEN Cong ess assis ance). Ma ínez Cas illo JC. has ecei ed esea ch suppo om Lundbeck, I al a maco, Alle gan, Zambon, Me z, and Abb ie. He has ecei ed speaking hono a ia om AbbVie, Bial, I al a maco, Lundbeck,K ka,TEVA,UCB,Zambon,Alle gan,Ipsen,andMe z.SánchezAlonsoP.has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by Abb ie, UCB Pha ma, Lundbeck, KRKA, Zambon, Bial, and Te a. Alonso Losada MG. has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by Zambon and Bial. López A iz egui N. has ecei ed hono a ia o educa ional p esen a ions and ad ice se ice by Abb ie, I al a maco, Zambon, and Bial. Gas ón I. has ecei ed esea ch suppo om Abb ie and Zambon and has se ed as a consul an o Abb ie, Exel s, and Zambon. Cla e o P: Kulise sky J: (1) Consul ing ees: Roche, Zambon; (2) S ock / allo men : No; (3) Pa en oyal ies / licensing ees: No; (4) Hono a ia (e.g., lec u e ees): Zambon, Te a, Bial, UCB; (5) Fees o p omo ional ma e ials: No; (6) Resea ch unding: Roche, Zambon, Cibe ned; Ins i u o de SaludCa los III; FundacióLa Ma a óde TV3; (7) Schola ship om D.S. Ga cía e al. 9 Published in pa ne ship wi h he Pa kinson’s Founda ion npj Pa kinson’s Disease (2021) 118