www.nature.com/npjparkd ARTICLE OPEN Predictors of clinically significant quality of life impairment in Parkinson’s disease Diego Santos García 1 ✉, Teresa de Deus Fonticoba2, Carlos Cores 1, Guillermo Muñoz1, Jose M. Paz González1, Cristina Martínez Miró1, Ester Suárez2, Silvia Jesús3,4, Miquel Aguilar5, Pau Pastor5, Lluis Planellas6, Marina Cosgaya7, Juan García Caldentey8, Nuria Caballol9, Inés Legarda10, Jorge Hernández Vara 11, Iria Cabo12, Luis López Manzanares13, Isabel González Aramburu4,14, María A. Ávila Rivera15, Maria J. Catalán16, Víctor Nogueira17, Víctor Puente18, María Ruíz de Arcos19, Carmen Borrué20, Berta Solano Vila21, María Álvarez Sauco22, Lydia Vela 23, Sonia Escalante 24, Esther Cubo25, Francisco Carrillo Padilla26, Juan C. Martínez Castrillo 27, Pilar Sánchez Alonso28, Maria G. Alonso Losada29, Nuria López Ariztegui 30, Itziar Gastón31, Pedro Clavero31, Jaime Kulisevsky 4,32, Marta Blázquez Estrada33, Manuel Seijo12, Javier Rúiz Martínez34, Caridad Valero35, Mónica Kurtis36, Oriol de Fábregues 11, Jessica González Ardura37, Carlos Ordás38, Luis M. López Díaz39, Darrian McAfee40, Pablo Martinez-Martin4, Pablo Mir 3,4 and COPPADIS Study Group* Quality of life (QOL) plays an important role in independent living in Parkinson’s disease (PD) patients, being crucial to know what factors impact QoL throughout the course of the disease. Here we identified predictors of QoL impairment in PD patients from a Spanish cohort. PD patients recruited from 35 centers of Spain from the COPPADIS cohort from January 2016, to November 2017, 1234567890():,; were followed up during 2 years. Health-related QoL (HRQoL) and global QoL (GQoL) were assessed with the 39-item Parkinson’s disease Questionnaire (PDQ-39) and the EUROHIS-QOL 8-item index (EUROHIS-QOL8), respectively, at baseline (V0) and at 24 months ± 1 month (V2). Clinically significant QoL impairment was defined as presenting an increase (PDQ-39SI) or decrement (EUROHIS-QOL8) at V2 ≥ 10% of the score at baseline (V0). A comparison with a control group was conducted for GQoL. GQoL did not change significantly in PD patients (N = 507; p = 0.686) or in the control group (N = 119; p = 0.192). The mean PDQ-39SI was significantly increased in PD patients (62.7 ± 8.5 years old; 58.8% males; N = 500) by 21.6% (from 16.7 ± 13 to 20.3 ± 16.4; p < 0.0001) at V2. Ninety-three patients (18.6%) presented a clinically significant HRQoL impairment at V2. To be younger (OR = 0.896; 95% CI 0.829–0.968; p = 0.006), to be a female (OR = 4.181; 95% CI 1.422–12.290; p = 0.009), and to have a greater increase in BDI-II (Beck Depression Inventory-II) (OR = 1.139; 95% CI 1.053–1.231; p = 0.001) and NMSS (Non-Motor Symptoms Scale) (OR = 1.052; 95% CI 1.027–1.113; p < 0.0001) total scores from V0 to V2 were associated with clinically significant HRQoL impairment at the 2-year follow-up (Hosmer–Lemeshow test, p = 0.665; R2 = 0.655). An increase in ≥5 and ≥10 points of BDI-II and NMSS total score at V2 multiplied the probability of presenting clinically significant HRQoL impairment 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), respectively. In conclusion, age, gender, mood, and non-motor impairment were associated with clinically significant HRQoL impairment after the 2-year follow-up in PD patients. npj Parkinson’s Disease (2021) 7:118 ; https://doi.org/10.1038/s41531-021-00256-w INTRODUCTION analyzed what factors contribute to a poor QoL in PD patients2–13. Parkinson’s disease (PD) is a complex disorder in which different Recently, we observed that NMS burden, mood, and gait problems motor and non-motor symptoms (NMS) can be present with a were the most relevant factors affecting health-related (HRQoL) frequency and severity that varies among patients over time1. and global perceived QoL (GQoL) in non-demented PD patients Both motor and NMS are important because they negatively from the Spanish cohort COPPADIS14. These results aligned with impact the patient’s quality of life (QoL). Different studies have other cross-sectional studies observations15–17. However, with 1 CHUAC, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain. 2CHUF, Complejo Hospitalario Universitario de Ferrol, A Coruña, Spain. 3Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. 4 CIBERNED (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas), Álava, Spain. 5Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain. 6 Neurología, Clínica del Pilar, Barcelona, Spain. 7Hospital Clínic de Barcelona, Barcelona, Spain. 8Centro Neurológico Oms 42, Palma de Mallorca, Spain. 9Consorci Sanitari Integral, Hospital Moisés Broggi, Sant Joan Despí, Barcelona, Spain. 10Hospital Universitario Son Espases, Palma de Mallorca, Spain. 11Hospital Universitario Vall d´Hebron, Barcelona, Spain. 12 Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain. 13Hospital Universitario La Princesa, Madrid, Spain. 14Hospital Universitario Marqués de Valdecilla, Santander, Spain. 15Consorci Sanitari Integral, Hospital General de L´Hospitalet, L´Hospitalet de Llobregat, Barcelona, Spain. 16Hospital Universitario Clínico San Carlos, Madrid, Spain. 17Hospital Da Costa, Burela, Lugo, Spain. 18Hospital del Mar, Barcelona, Spain. 19Hospital Universitario Virgen Macarena, Sevilla, Spain. 20Hospital Infanta Sofía, Madrid, Spain. 21Institut d’Assistència Sanitària (IAS) - Institut Català de la Salut, Girona, Spain. 22Hospital General Universitario de Elche, Elche, Spain. 23Fundación Hospital de Alcorcón, Madrid, Spain. 24Hospital de Tortosa Verge de la Cinta (HTVC), Tortosa, Tarragona, Spain. 25Complejo Asistencial Universitario de Burgos, Burgos, Spain. 26Hospital Universitario de Canarias, San Cristóbal de la Laguna, Santa Cruz de Tenerife, Spain. 27Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain. 28Hospital Universitario Puerta de Hierro, Madrid, Spain. 29Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo (CHUVI), Vigo, Spain. 30Complejo Hospitalario de Toledo, Toledo, Spain. 31Complejo Hospitalario de Navarra, Pamplona, Spain. 32Hospital de Sant Pau, Barcelona, Spain. 33Hospital Universitario Central de Asturias, Oviedo, Spain. 34Hospital Universitario Donostia, San Sebastián, Spain. 35Hospital Arnau de Vilanova, Valencia, Spain. 36Hospital Ruber Internacional, Madrid, Spain. 37Hospital Universitario de Cabueñes, Gijón, Spain. 38 Hospital Rey Juan Carlos, Madrid, Spain, Madrid, Spain. 39Complejo Hospitalario Universitario de Orense (CHUO), Orense, Spain. 40Univeristy of Pennsylvania, Pennsylvania, USA. *A list of authors and their affiliations appears at the end of the paper. ✉email: diegosangar@yahoo.es Published in partnership with the Parkinson’s Foundation D.S. García et al. 2 Fig. 1 Change in PDQ-39SI, PQ-10, and EUROHIS-QOL8 scores from V0 (baseline) to V2 (2 year ± 1 month) in PD patients and/or controls. Data are presented as box plots, with the box representing the median and the two middle quartiles (25–75%). p-values were computed using the Wilcoxon-signed rank test. Mild outliers (O) are data points that are more extreme than Q1 − 1.5 * IQR or Q3 + 1.5 * IQR. EUROHIS-QOL8, European Health Interview Survey-Quality of Life 8-Item Index; PDQ-39SI, 39-item Parkinson’s Disease Quality of Life Questionnaire Summary Index. regard to how the QoL of PD changes throughout the course of The change in the score of other scales from V0 to V2 in PD the disease, there is much less information18–23 and prospective patients and controls is shown in Table 1. longitudinal studies are needed. In clinical practice, it is important to know what factors worsen PD patients’ QoL with the intention Patients with vs without clinically HRQoL impairment to carry out effective interventions. Known information limited by 1234567890():,; Although 291 PD patients (58.2%) presented an increase in the factors from the studies such as the sample size, the differences PDQ-39SI score after the 2-year follow-up, only 93 (18.6%) between scales used for assessing QoL, the different types of QoL presented a clinically significant HRQoL impairment at V2. assessed, being a non-multicenter study, the absence of a control group, and/or the lack of a global evaluation including different Differences in change from V0 to V2 of UPDRS-III, UPDRS-IV, aspects that could impact on QoL18–23. In addition, the impact of FOGQ, NMSS, BDI-II, PDSS, NPI, VAS-PAIN, VASF-physical, VASF- some complications on QoL in advanced PD has been analyzed mental, and ADLS scores between patients with and without before24,25. However, it is not clear what the significance of short- clinically significant HRQoL impairment were observed (Table 2). term changes in QoL is in early PD patients or what factors Specifically, PD patients who presented at the 2-year follow-up a contribute to it when an extensive assessment considering clinically significant HRQoL impairment presented a 97.3% motor and NMS is performed26. It is remarkable that NMS occur increase of the NMS burden (NMSS total score from 29.2 ± 25.87 not only in advanced but also in the early stages of PD. Some to 57.84 ± 46.73 [p < 0.0001]) compared to 8.6% in those patients symptoms, for example, olfactory deficit, constipation, rapid-eye- who did not (NMSS total score from 48.38 ± 38.59 to 52.53 ± 41.35 movement sleep behavior disorder, and depression, can even [p = 0.003]) (Fig. 2A). By domains, the most significant differences precede the appearance of motor symptoms by many years1. By were observed for sleep/fatigue (p < 0.0001) and mood/apathy the contrary, others such as psychosis or dementia are not (p < 0.0001) (Table 2 and Fig. 2B). Moderate correlations were present. The first years are conditioned by the acceptance of the observed between the change from V0 to V2 in the PDQ-39SI diagnosis, but in general, the patient has greater autonomy. In this score and the score in FOGQ (r = 0.34; p < 0.0001), NMSS (r = 0.41; context, it is essential to know what influences the changes in the p < 0.0001), BDI-II (r = 0.33; p < 0.0001) and ADLS (r = −0.40; p < PD patient QoL perception with the intention of being able to act 0.0001) (Supplementary Table 1). as soon as possible. The aim of the present study was to (1) analyze the change in Predictors of clinically HRQoL impairment HRQoL and GQoL in PD patients from the COPPADIS cohort after To be younger (OR = 0.896; 95% CI 0.829–0.968; p = 0.006), to be the 2-year follow-up, (2) to compare with a control group, and (3) a female (OR = 4.181; 95% CI 1.422–12.290; p = 0.009), and to to identify predictors of clinically significant QoL impairment in have a greater increase in BDI-II (OR = 1.139; 95% CI 1.053–1.231; the PD group. Finally, a subanalysis was conducted in a subgroup p = 0.001) and NMSS (OR = 1.052; 95% CI 1.027–1.113; p < 0.0001) of patients with early PD (≤5 years of disease duration). total scores from V0 to V2 were associated with clinically significant HRQoL impairment at the 2-year follow-up, after adjustment to many covariates (Hosmer–Lemeshow test, p = RESULTS 0.665; R2 = 0.655) (Table 3). Specifically, an increase in ≥5 and ≥10 Changes in assessments from V0 to V2 points of BDI-II and NMSS total score at V2 multiplied the After the 2-year follow-up, GQoL did not change significantly in PD probability of presenting a clinically significant HRQoL impairment patients (from PQ-10V0 of 7.28 ± 1.55 to PQ-10V2 of 7.14 ± 1.54 by 5 (OR = 5.453; 95% CI 1.663–17.876; p = 0.005) and 8 (OR = [N = 503; p = 0.070]; from EUROHIS-QOL8V0 of 3.77 ± 0.54 to 8.217; 95% CI 2.975–22.696; p = 0.002), respectively. When ADLS EUROHIS-QOL8V2 of 3.75 ± 0.58 [N = 507; p = 0.686]) or in the was included in the model (ADLS at V0 and the change in ADLS control group (from PQ-10V0 of 8.07 ± 1.22 to PQ-10V2 of 7.86 ± score from V0 to V2), only a greater increase in BDI-II (OR = 1.148; 1.65 [N = 122; p = 0.361]; from EUROHIS-QOL8V0 of 4.18 ± 0.5 to 95% CI 1.057–1.258; p = 0.001), NMSS (Non-Motor Symptoms EUROHIS-QOL8V2 of 4.12 ± 0.51 [N = 119; p = 0.192] (Fig. 1). The Scale) (OR = 1.056; 95% CI 1.029–1.083; p < 0.0001) and NPI (OR = mean PDQ-39SI was significantly increased in PD patients (62.7 ± 1.072; 95% CI, 1.001–1.147; p = 0.046) total scores and a decrease 8.5 years old; 58.8% males; N = 500) by 21.6% (from 16.72 ± 13.02 in ADLS score (OR = 0.884; 95% CI 0.820–0.954; p < 0.0001) from to 20.3 ± 16.41; p < 0.0001) at V2 (Table 1 and Fig. 1). By domains, V0 to V2 were associated with clinically significant HRQoL the score of all domains of the PDQ-39SI at V2 was significantly impairment at the 2-year follow-up (Hosmer–Lemeshow test, higher than at V0 except for domain 4 (stigmatization) (Table 1). p = 0.621; R2 = 0.718). npj Parkinson’s Disease (2021) 118 Published in partnership with the Parkinson’s Foundation D.S. García et al. 3 Table 1.Changes in motor and non-motor symptoms, disability, and quality of life in PD patients and/or controls from V0 (baseline) to V2 (2 years ± 1 month). PD patients V0 PD patients V2 pa Controls V0 Controls V2 pb Hoehn & Yahr (OFF) (%) <0.0001 N. A. N. A. N. A. Stage 1 22.7 13.3 Stage 2 68 77 Stage 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. Number of non-antipark. drugs 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 − mental 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. Mobility 16.28 ± 19.2 21.31 ± 22.5 <0.0001 Activities of daily living 17.83 ± 18.83 21.82 ± 21.37 <0.0001 Emotional well-being 20.92 ± 19.52 23.53 ± 23.45 <0.0001 Stigmatization 12.81 ± 19.24 14.14 ± 21.09 0.069 Social support 7.29 ± 15.43 10.01 ± 19.09 <0.0001 Cognition 18.51 ± 17.38 23.17 ± 20.16 <0.0001 Communication 9.68 ± 14.44 13.55 ± 18.88 <0.0001 Pain and discomfort 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 Quality of life 3.8 ± 0.7 3.68 ± 0.67 0.003 4.14 ± 0.65 4.2 ± 0.63 0.298 Health status 3.18 ± 0.87 3.32 ± 0.93 0.004 3.97 ± 0.75 3.87 ± 0.82 0.148 Energy 3.76 ± 0.79 3.72 ± 0.86 0.266 4.15 ± 0.68 4.11 ± 0.69 0.531 Autonomy for ADL 3.61 ± 0.86 3.63 ± 0.88 0.852 4.24 ± 0.75 4.19 ± 0.61 0.983 Self-esteem 3.83 ± 0.76 3.82 ± 0.81 0.866 4.18 ± 0.68 4.00 ± 0.66 0.124 Social relationships 4.04 ± 0.67 3.94 ± 0.75 0.004 4.29 ± 0.65 4.19 ± 0.61 0.071 Economic capacity 3.84 ± 0.78 3.77 ± 0.8 0.091 4.07 ± 0.74 3.97 ± 0.81 0.078 Habitat 4.22 ± 0.67 4.21 ± 0.67 0.904 4.43 ± 0.63 4.29 ± 0.66 0.016 p-values were computed using the Wilcoxon-signed rank test or marginal homogeneity test. The results represent mean ± SD or %; pa, V2 vs V0 in PD patients; pb, V2 vs V0 in controls. ADLS Schwab & England Activities of Daily Living Scale, BDI-II Beck Depression Inventory-II, FOGQ Freezing Of Gait Questionnaire, LEDD levodopa equivalent daily dose (mg), NMSS Non-Motor Symptoms Scale, NPI Neuropsychiatric Inventory, PD-CRS Parkinson’s Disease Cognitive Rating Scale, PDSS Parkinson’s Disease Sleep Scale, QUIP-RS Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale, UPDRS Unified Parkinson’s Disease Rating Scale, VAFS Visual Analog Fatigue Scale, VAS-Pain Visual Analog Scale-Pain. The bold values indicates statistically significant p values. In the subgroup of early PD (N = 277), quite similar results, an to be a female (OR = 35.847; 95% CI 3.452–372.204; p = 0.003), increase in mean PDQ-39SI from V0 to V2 of 23.4% (from 14.22 ± and to have a greater increase in BDI-II (OR = 1.400; 95% CI 11.29 to 17.62 ± 15.36; p < 0.0001), were observed. Fifty-six 1.149–1.705; p = 0.001) and NMSS (OR = 1.069; 95% CI patients (20.2%) presented a clinically significant HRQoL impair- 1.007–1.043; p =0.001) total scores from V0 to V2 were associated ment at the 2-year follow-up. However, as in the whole cohort, with clinically significant HRQoL impairment at the 2-year follow- GQoL did not change significantly (PQ-10, p = 0.111; EUROHIS- up, after adjustment to many covariates (Hosmer–Lemeshow test, QOL8, p = 0.756). In the binary regression model, as in the all p = 0.998; R2 = 0.745) (Table 3). When ADLS was included in the cohort, to be younger (OR = 0.813; 95% CI 0.709–0.933; p = 0.003), model, to be younger (OR = 0.769; 95% CI 0.624–0.946; p = 0.013), Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2021) 118 D.S. García et al. 4 95% CI 1.041–1.681; p = 0.022) total scores from V0 to V2 were Table 2. Changes in motor and non-motor symptoms and disability in associated with clinically significant HRQoL impairment at the PD patients from V0 (baseline) to V2 (2 years ± 1 month) with regards 2-year follow-up (Hosmer–Lemeshow test, p = 0.217; R2 = 0.816), to presenting or not clinically significant HRQoL impairment. but not the change in the ADLS score (OR = 0.889; 95% CI Non clinically Clinically p 0.786–1.1006; p = 0.062). Moderate correlations were observed significant HRQoL significant HRQoL between the change from V0 to V2 in the PDQ-39SI score and the impairment impairment score in FOGQ (r = 0.39; p < 0.0001), NMSS (r = 0.41; p < 0.0001), N = 407 N = 93 NPI (r = 0.35; p < 0.0001) and ADLS (r = −0.41; p < 0.0001) (Supplementary Table 2). Age at baseline 63.04 ± 7.99 61.32 ± 10.17 0.354 Gender (males) (%) 60 57 0.341 Predictors of the change in the PDQ-39SI from V0 to V2 Disease duration 5.65 ± 4.36 4.91 ± 3.55 0.247 (at V0) Finally, similar results were observed in both groups, the whole cohort and the early PD subgroup, when a linear regression model Number of non- 2.56 ± 2.36 2.33 ± 2.49 0.220 was considered (PDQ-39SI change from V0 to V2 as dependent antipark. drugs (at V0) variable) (Supplementary Table 2). To be a female (β = 0.17; p < 0.0001) and change in UPDRS-III (β = 0.23; p < 0.0001), FOGQ (β = Change at V2 (from V0 to V2) 0.20; p < 0.0001), and NMSS (β = 0.37; p < 0.0001) scores provided LEDD +177.15 ± 330.2 +228.75 ± 318.27 0.174 the highest contribution to the model (adjusted R-squared 0.45) in Number of non- +0.55 ± 1.56 +0.65 ± 1.45 0.685 the whole cohort. In early PD patients, the variables associated antipark. drugs with HRQoL change at the 2-year follow-up were the same UPDRS-III (OFF) +2.25 ± 9.77 +7.76 ± 11.2 <0.0001 (Supplementary Table 2). When the ADLS score was included in UPDRS-IV +0.47 ± 2.47 +1.47 ± 2.55 0.002 the model, the results were similar but with the ADLS as an FOGQ +0.68 ± 3.85 +3.32 ± 4.71 <0.0001 independent variable associated with HRQoL change too (β = −0.21; 95% CI −0.353, −0.107; p < 0.0001; adjusted R-squared 0.45 PD-CRS −2.17 ± 12.18 −0.67 ± 10.12 0.293 [N = 500; all cohort]; β = −0.23; 95% CI −0.433, −0.076; p = 0.005; NMSS +4.15 ± 32.03 +28.64 ± 35.65 <0.0001 adjusted R-squared 0.431 [N = 277; early PD subgroup]). Cardiovascular +6.21 ± 14.41 +8.11 ± 12.83 0.310 Sleep/fatigue +0.7 ± 15.96 +12.98 ± 18.42 <0.0001 DISCUSSION Mood/apathy +0.5 ± 14.57 +8.62 ± 15.19 <0.0001 In this longitudinal follow-up study, we report that there is a Perceptual +1.89 ± 10.61 +4.35 ± 12.56 0.141 significant HRQoL impairment in PD patients in the short-term symptoms and that impairment in the motor status during the OFF state Attention/memory +1.74 ± 14.16 +7.28 ± 17.30 0.07 (UPDRS-III), increased gait problems (FOGQ), and increased NMS Gastrointestinal +2.19 ± 12.64 +4.9 ± 12.8 0.020 burden contribute to it. Specifically, mood impairment and NMS symptoms burden increase were independent factors associated with Urinary symptoms +1.29 ± 20.22 +9.28 ± 21.56 0.001 clinically significant HRQoL impairment at the 2-year follow-up, Sexual dysfunction +2.63 ± 30.71 +10.51 ± 23.43 0.007 which one was present in about every 5 patients. Moreover, the Miscellaneous +0.72 ± 14.88 +6.19 ± 14.89 0.011 results indicate that it will be especially important to be vigilant about clinically significant HRQoL impairment in women and BDI-II −0.63 ± 7.75 +4.51 ± 6.13 <0.0001 younger patients. PDSS +2.82 ± 25.80 −9.04 ± 24.96 <0.0001 After a 2-year follow-up, PD patients from the COPPADIS cohort QUIP-RS −0.02 ± 9.25 +0.34 ± 8.06 0.736 demonstrated impairment in motor function (H&Y, UPDRS-III, UPDRS- NPI −0.43 ± 4.28 +4.28 ± 8.06 <0.0001 IV, FOGQ). The increase of motor impairments measured with the VAS-PAIN + 0.18 ± 3.21 +1.01 ± 3.74 0.023 UPDRS were in agreement with other studies27,28. Also, significant changes in NMS were observed in the NMS burden as a whole, pain, VASF − physical + 0.09 ± 2.97 +1.1 ± 2.92 0.004 fatigue, and cognition, but not in controls. These results aligned with VASF-mental −0.12 ± 2.76 +1.05 ± 2.95 0.002 previous longitudinal studies indicating that the severity of NMS in ADLS −2.84 ± 11.08 −10.97 ± 12.42 <0.0001 PD tends to become progressively worse with the course of the Chi-squared and Mann–Whitney–Wilcoxon test were applied. The results disease and also indicate that non-motor evaluation is complemen- represent percentages or mean ± SD. The symbol “+” indicates an increase tary to measuring PD progression19,26,29–32. With respect to the QoL, in the score of the scale at V2 compared to V0 while the symbol “–” although more than a half of PD patients presented a PDQ-39SI score indicates a decrease. Data about UPDRS-III are during the OFF state (first at the 2-year follow-up higher than at baseline, only 18.6% presented hour in the morning without taking medication in the previous 12 h). HRQoL impairment as clinically significant. In a previous study with ADLS Schwab & England Activities of Daily Living Scale, BDI-II Beck 707 PD patients followed prospectively for the 2-year as well, 17% Depression Inventory-II, FOGQ, Freezing Of Gait Questionnaire, LEDD worsened clinically while 584 were rated as stable29. The results can levodopa equivalent daily dose (mg), NMSS Non-Motor Symptoms Scale, be vary due to the definition of QoL impairment as clinically NPI Neuropsychiatric Inventory, PD-CRS Parkinson’s Disease Cognitive Rating Scale, PDSS Parkinson’s Disease Sleep Scale, QUIP-RS Questionnaire significant31,33,34. Based on the postal reply of 728 PD patients, Peto for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale, et al.34 determined that 1.6 points worsening on a PDQ-39SI is the UPDRS Unified Parkinson’s Disease Rating Scale, VAFS Visual Analog Fatigue minimal clinically important difference threshold. More recently, Scale, VAS-Pain Visual Analog Scale-Pain. Horváth et al.31 considered the most optimal estimates threshold for The bold values indicates statistically significant p values. PDQ-39-SI in + 4.22 points for detecting minimal clinically important worsening. However, there is no “gold standard” methodology of estimating the minimal important difference and as the degree of to be a female (OR = 31.982; 95% CI 1.678–609.587; p = 0.021), improvement is conditioned by the baseline score; therefore, the use and to have a greater increase in BDI-II (OR = 1.197; 95% CI of a percentage might be more appropriate35,36. Patients appear to 1.126–1.990; p = 0.006), NMSS (Non-Motor Symptoms Scale) be able to detect changes of 7–10% on QoL instruments or pain (OR = 1.108; 95% CI 1.033–1.188; p = 0.004) and NPI (OR = 1.323; scales36. In our case, the minimal important difference was considered npj Parkinson’s Disease (2021) 118 Published in partnership with the Parkinson’s Foundation D.S. García et al. 5 Fig. 2 Evolution of NMS after 2-year follow up. A Change in the NMSS total score from V0 (baseline) to V2 (2 year ± 1 month) in PD patients without vs with clinically significant HRQoL impairment. B Mean score on each domain of the ESS scale at V0 and V2 in PD patients without vs with clinically significant HRQoL impairment. Data are presented as box plots, with the box representing the median and the two middle quartiles (25–75%). p-values were computed using the Wilcoxon-signed rank test. Mild outliers (O) are data points that are more extreme than Q1 − 1.5 * IQR or Q3 + 1.5 * IQR. NMSS, Non-Motor Symptoms Scale. as an increase of 10% or more in the PDQ-39SI score33,35–37. Ten NMS were associated with improved QoL in advanced parkinso- percent of the mean score of the PDQ-39SI in our study represents nian patients during 2‐year treatment with levodopa‐carbidopa 1.6 points; therefore, similar to the proposal of Peto et al.34. However, intestinal gel infusion therapy43. In line with this, Erro et al. in a patient with a higher baseline PDQ-39SI score, for example, 50 observed that NMS significantly affected QoL in PD, demonstrat- points, the minimal clinically significant worsening change should be ing that this was especially the case when patients were in their 5 points. Hence, in less than 1 in 3 patients who had an increase in honeymoon period (during which time the side effects of the the PDQ-39 score, this was considered clinically significant. In any disease aren’t too disabling and there is a response to case, it seems clear that even in a relatively short follow-up period, medications)44. In the subgroup of early PD patients from our patients with PD experience a significant decrease in HRQoL21,29. study, the change in the NMSS total score at 2-years was one of However, as Reuther et al.22 reported in 145 PD patients after a 12- the most significant contributors to HRQoL impairment. month follow-up, there doesn’t seem to be a significant change in Another important factor is mood. Like in other studies, the QoL generic scales. mean score of BDI didn’t change over time18,22, suggesting that For assessing the NMS as a whole, we used the NMSS. To date, depression-type frequency does not appear to change over time this scale has been used in more than 100 clinical studies and in PD45. Cross-sectional studies have reported the clear contribu- trials and it has shown to be capable of detecting longitudinal tion of depression or a worse mood to a poorer QoL in PD changes in NMS, where studies have shown differential changes patients3,12,13. In fact, it was observed in the COPPADIS baseline over time of several of the NMSS domains32,38,39. Moreover, it has cross-sectional analysis14. However, to our knowledge, this is the been demonstrated a consistent and strong correlations between first time that mood worsening is identified as an independent NMSS burden and HRQoL measures32,40–42. In our study, a very factor associated with clinically significant HRQoL impairment in clear difference in the change of NMS burden was observed PD patients. This subgroup of patients (N=93) presented a mean between patients with and without clinically significant HRQoL increase in the BDI-II score of 4.5 points at the 2-year follow-up impairment. Changes in all domains of the NMSS scale correlated and specifically, an increase in ≥5 points multiplied by 5 the with QoL changes. Similarly, previous studies observed a probability of presenting a clinically significant HRQoL impair- correlation between NMS burden assessed with the NMSS and ment, independent of other factors. Reuther et al.22 identified QoL changes over time19. Moreover, in our analysis, NMS burden depression as the strongest predictor for reduced HRQoL in 145 progression was an independent factor related to HRQoL PD patients after 1-year follow-up. However, we identified the impairment. Prakash et al. observed for the first time that non- change in the score of the BDI-II as a predictor of clinically motor problems provided a better prediction of the change of significant HRQoL impairment after adjustment to BDI-II score at QoL in 227 PD patients over a 2-year follow-up period19. However, baseline. From a practical point of view, our findings suggest an they did not provide the variance value of the model, many important role of the neurologist being alert to a possible factors potentially affecting QoL were not included, and what they worsening of mood, as well as greater NMS burden, in patients considered was the baseline NMSS score. On the contrary, in this with PD throughout the evolution of the disease since this is what study we wanted to analyze in detail what changes in many impacts on the patient’s QoL. Knowing what impacts on the QoL aspects of the disease observed after the 2-year follow-up and contributes to its worsening, depending on the variable, contributed to a worsening in the patients´ QoL. So, several intervention measures with the intention of correcting them can variables were included, the results of the model represented be proposed46. Studies demonstrating a QoL improvement ~70% of the variance when HRQoL changes were considered, and correlated with mood and NMS burden improvement have been the changes in all variables were adjusted to the scores at published47. With regards of the results observed here, it should baseline. To our best knowledge, this is the first longitudinal- be necessary to be alert about mood and NMS burden changes prospective study analyzing in such detail which are the predictors over time, especially in younger patients and females. A mildly of QoL impairment in a large sample of PD patients. Reinforcing significant gender difference in disability and QoL reporting has the idea that the progression of NMS is pivotal to the worsening of been noted, with women citing greater disability and reduced the QoL throughout the evolution of the disease, improvements of QoL48,49. Depression and fatigue were the major causes of low Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2021) 118 D.S. García et al. 6 Table 3. Binary logistic regression model about factors associated with clinically significant HRQoL impairment at V2 (2 years follow-up). ORa ORb 95% CIa 95% CIb pa pb Age 0.896 0.813 0.829–0.968 0.709–0.933 0.006 0.003 Gender (female) 4.181 35.847 3.452–372.204 1.378–8.424 0.009 0.003 Disease duration 1.040 0.734 0.388–1.389 0.763–1.360 0.673 0.342 No. of non-antiparkinsonian drugs/day 0.922 1.005 0.728–1.167 0.697–1.449 0.499 0.979 Change at 2 years follow-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 Dependent variable: Clinically significant HRQoL impairment (defined as PDQ-39SIV2 ≥ 10% PDQ-39SIV0). OR and 95% CI are shown. Hosmer–Lemeshow test, pa = 0.665; pb=0.998; R2a = 0.655; R2b = 745. The model was adjusted to variables at baseline: LEDD (mg), UPDRS-III, UPDRS-IV, FOGQ, NMSS, PD-CRS, BDI-II, NPI, PDQ-39SI. BDI-II Beck Depression Inventory-II, FOGQ Freezing Of Gait Questionnaire, LEDD levodopa equivalent daily dose (mg), NMSS Non-Motor Symptoms Scale, NPI Neuropsychiatric Inventory, PD-CRS Parkinson’s Disease Cognitive Rating Scale, PDQ-39SI 39-item Parkinson’s Disease Quality of Life Questionnaire Summary Index, QUIP-RS, Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale, UPDRS Unified Parkinson’s Disease Rating Scale. a All cohort (n = 500). b Early PD patients (n = 277). The bold values indicates statistically significant p values. HRQoL in women even in the early phases of PD50. To attenuate QoL in PD. Furthermore, PD is a complex disorder with many this sex difference in disease experience, psychological distress manifestations and with a great variability in its progression screening and management (particularly targeting females) among patients. Regarding this study observations, some should be considered as part of PD clinical care23. Moreover, important points should be considered in daily clinical practice. QoL, as measured on the PDQ-39, is significantly worse in young- First, a complete assessment of the patient with PD periodically onset PD patients than in older-onset PD patients, and young- including motor status, NMS, QoL and disability should be the onset PD patients also experience loss of employment, disruption ideal practice. Second, NMS progression contributes significantly of family life, greater perceived stigmatization, and depression to a QoL worsening and it is crucial its evaluation. Very than do older-onset PD patients51,52. interestingly, we reported very recently that PD patients from The most important limitation of this study is the fact that the COPPADIS cohort with a lower H&Y stage but a greater global information about follow-up was recorded only in 524 patients of NMS burden may have a worse QoL than patients with a higher 695 initially included in the study (75.5%). Of them, data for the H&Y stage but lower global NMS54. Third, mood is another key PDQ-39, PQ-10, and EUROHIS-QOL8 at baseline and at V2 was factor to consider whenever we evaluate the patient in clinical available in 500, 503, and 507 PD patients, respectively. Thirty-eight practice. Fourth, we have to keep in mind that mood impairment patients (5.5%) dropped out of the study (1 death; 2 with change in and global NMS progression predict a patient´s QoL worsening. diagnosis; 35 other reasons) at the 2-year follow-up and 132 (19%) Finally, we should be especially careful in all of the above in the were not assessed. However, this is a limitation observed in other case of a female patient and in young patients. prospective studies. Of 7507 PD patients, follow-up data was A problem in clinical practice is the lack of time to evaluate the available only for 4680 participants (62.3%)53. In the study of patient. For the PD patient, to bring adequately covered ques- Antonini et al.29, 707 PD patients from 1142 initially included (61.9%) tionnaires to the consultation, for example with the help of nursing were evaluable at 24 months. An important second limitation is that staff, or even in the future with mobile applications that transfer the PD patients older than 75 years old were excluded from data to the patient’s medical record, it could be a possibility that participation by COPPADIS study protocol14, which leads to an early facilitates the complete and comprehensive assessment. In general, it PD bias in this cohort. For some variables, the information was not is something that is not done today, and proof of this is the alarming collected in all cases. Moreover, this is a multicenter mono-country lack of literature about the global progression of the disease including study, being the ideal for this type of studies the participation of NMS in large cohorts of patients. More studies with large PD cohorts patients from different parts of the world, so the results should be and long-term follow-up are required. Our aim with the COPPADIS considered with caution when extrapolating them to the general PD cohort is to follow for 5 years55. Collecting data from different cohorts population (i.e., race, country healthcare, etc.). By the contrary, and making comparisons would also be of great interest. strengths of our study include a very complete assessment, the large In conclusion, the present study observes HRQoL impairment sample size, a prospective longitudinal follow-up design, the fact in PD patients in a short 2-year follow-up, even in early PD that this analysis was “a priori” planned as one objective of the patients, but not the GQoL. A younger age, to be a female, and multicenter COPPADIS project16, and the extensive clinical and mood and NMS burden impairment were associated with demographic information recorded. clinically significant HRQoL impairment after the 2-year follow- The findings of this study have important implications in daily up. The progression of NMS is pivotal in the worsening of the QoL clinical practice. In a disorder like PD in which one there is no a throughout the evolution of the disease in PD, and it is necessary cure, treatment is symptomatic and the aim is to improve the to keep in mind to ask for mood or NMS changes, especially in patient’s QoL. This is complex because many factors influence females and young patients. npj Parkinson’s Disease (2021) 118 Published in partnership with the Parkinson’s Foundation D.S. García et al. 7 METHODS test was performed to test whether the mean differences of the PDQ-39SI, PD patients and controls who were recruited from January 2016 to PQ-10, and EUROHIS-QOL8 scores and the individual PDQ-39SI and EUROHIS- November 2017 (baseline visit; V0) and evaluated again at the 2-year QOL8 domain scores between the two visits (V0 and V2) were significant. This follow-up (V2) from 35 centers of Spain from the COPPADIS cohort56, were test and/or the marginal homogeneity test were applied for other scales for included in the study. Methodology about COPPADIS-2015 has been analyzing the change from V0 to V2. Spearman’s or Pearson’s correlation previously published57. This is a multicenter, observational, longitudinal- coefficient, as appropriate, were used for analyzing the relationship between prospective, 5-year follow-up study designed for analyzing disease continuous variables. Correlations were considered weak for coefficient progression in a Spanish population of PD patients. Specifically, 17 values ≤0.29, moderate for values between 0.30 and 0.59, and strong for objectives were proposed in the protocol55. Even though the recruitment values ≥0.60. period ended in October 2017, the prospective follow-up phase is ongoing. Clinically significant QoL impairment was expressed as a percentage and Patients, caregivers (patient´s primary caregiver), and controls (subjects it was only calculated if the change between scores (PDQ-39SI; PQ-10; without PD and any other severe and disabling concomitant disorder) were EUROHIS-QOL8) from V0 to V2 was significant. For determining predictive included55. Annual visits from V0 (baseline) to V5 (60 moths ± 3 months) are factors of QoL impairment, a logistic regression model (QoL impairment as conducted to the patients and at V0, V2, V4, and V5 to the controls and dependent variable) was performed. The model was well-planned, as caregivers. All patients included were diagnosed according to UK PD Brain recommended by best-practice methods74, in which known and pre- Bank criteria57. Exclusion criteria55 were: non-PD parkinsonism, dementia sumably predictor variables affecting QoL changes (dependent variable) criteria (Mini Mental State Examination [MMSE] ≥ 26), age < 18 or >75 years, were included: change from V0 to V2 in levodopa equivalent daily dose inability to read or understand the questionnaires, to be receiving any (LEDD)75, UPDRS-III-OFF (motor severity), UPDRS-IV (motor complications), advanced therapy (continuous infusion of levodopa or apomorphine, and/ FOGQ, NMSS (NMS burden), PD-CRS (cognition), BDI-II (mood), and NPI or with deep brain stimulation), and presence of comorbidity, sequelae, or (neuropsychiatric symptoms). The model was adjusted to baseline QoL and any disorder that could interfere with the assessment. age, gender, disease duration, comorbidity (total number of non- Information on sociodemographic aspects, factors related to PD, antiparkinsonian medications as surrogate marker14), and the score of comorbidity, and treatment were collected. V0 and V2 evaluations the rest of the variables at baseline (LEDD, UPDRS-III-OFF, UPDRS-IV, FOGQ, included55: (1) motor assessment (Hoenh & Yahr [H&Y]58, Unified NMSS, PD-CRS, and NPI). Disability (ADLS) was not included in the model Parkinson’s Disease Rating Scale [UPDRS] part III and part IV59, Freezing because this is consequence of symptoms, but since it is related to QoL, in of Gait Questionnaire [FOGQ]60; (2) NMS (Non-Motor Symptoms Scale a second model ADLS at baseline and change in ADLS from V0 to V2 were [NMSS]61, Parkinson’s Disease Sleep Scale [PDSS]62, Visual Analog Scale- included. Hosmer–Lemeshow test was applied and adjusted R-squared Pain [VAS-Pain]63, Visual Analog Fatigue Scale [VAFS]64, cognition (MMSE65, was calculated for all analyses. Finally, multiple linear regressions were Parkinson’s Disease Cognitive Rating Scale [PD-CRS]66, completing a simple performed with “change in QoL” as dependent variable but only for 16-piece puzzle); (3) mood and neuropsychiatric symptoms (Beck variables (PDQ-39SI; PQ-10; EUROHIS-QOL8) changing significantly from V0 Depression Inventory-II [BDI-II]67, Neuropsychiatric Inventory [NPI]68, to V2. The independent variables included were the same as in the binary Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease- model. The p-value was considered significant when it was <0.05. Rating Scale [QUIP-RS]69; (4) and disability (Schwab & England Activities of Daily Living Scale [ADLS]70. In patients with motor fluctuations, the motor Standard protocol approvals, registrations, and patient assessment was made during the OFF state (without medication in the last consents 12 h) and during the ON state. On the other hand, the assessment was only The Comité de Ética de la Investigación Clínica de Galicia from Spain (2014/ conducted without medication in patients without motor fluctuations. The 534; 02/DEC/2014) approval was obtained. Written informed consents from same evaluation as for the patients, except for the motor assessment, was all participants in this study were obtained before the start of the study. conducted in control subjects at V0 and at V2 (2 years ± 1 month). Three COPPADIS-2015 was classified by the AEMPS as a Post-authorization scales were used to assess QoL at V0 and at V228: (1) the 39-item Prospective Follow-up study with the code COH-PAK-2014-01. Parkinson’s disease Questionnaire (PDQ-39)71, (2) a rating of global perceived QoL (PQ-10) on a scale from 0 (worst) to 10 (best)13, and (3) the EUROHIS-QOL 8-item index (EUROHIS-QOL8)72. The PDQ-39 is a PD- Reporting summary specific questionnaire that assesses the patients’ HRQoL. There are 39 Further information on research design is available in the Nature Research items grouped into 8 domains: (1) Mobility (items 1 to 10); (2) Activities of Reporting Summary linked to this article. daily living (items 11 to 16); (3) Emotional well-being (items 17 to 22); (4) Stigma (items 23 to 26); (5) Social support (items 27 to 29); (6) Cognition (items 30 to 33); (7) Communication (items 34 to 36); (8) Pain and DATA AVAILABILITY discomfort (items 37 to 39). For each item, the score may range from 0 The data that support the findings of this study are available from the corresponding (never) to 4 (always). The symptoms refer to the 4 weeks prior to author upon reasonable request. assessment. Domain total scores are expressed as a percentage of the corresponding maximum possible score and a Summary Index is obtained as average of the domain scores. The EUROHIS-QOL8 is an 8-item GQoL questionnaire (quality of life, health status, energy, autonomy for activities CODE AVAILABILITY of daily living, self-esteem, social relationships, economic capacity, and No computer coding was used in the completion of the current manuscript. habitat) derived from the WHOQOL-BREF. For each item, the score ranges from 0 (not at all) to 5 (completely). The total score is expressed as the Received: 25 March 2021; Accepted: 27 July 2021; mean of the individual scores. A higher score indicates a better QoL. In Published online: 16 December 2021 controls, only the PQ-10 and the EUROHIS-QOL8 were assessed. 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B. & Goldstein M.) Vol. 2, 153–164 (Macmillan Health Care Information, Florham 32. Ou, R. et al. Progression of non-motor symptoms in Parkinson’s disease among Park, NJ, 1987). different age populations: a two-year follow-up study. J. Neurol. Sci. 360, 72–77 (2016). 60. Giladi, N., Shabtai, H., Simon, E. S., Biran, S., Tal, J. & Korczyn, A. D. Construction of 33. Ringash, J., O’Sullivan, B., Bezjak, A. & Redelmeier, D. A. Interpreting clinically freezing of gait questionnaire for patients with Parkinsonism. Parkinsonism Relat. significant changes in patient-reported outcomes. Cancer 110, 196–202 (2007). Disord. 6, 165–170 (2000). npj Parkinson’s Disease (2021) 118 Published in partnership with the Parkinson’s Foundation D.S. García et al. 9 61. Chaudhuri, K. R. et al. The metric properties of a novel non-motor symptoms scale review and critique; recruitment and/or evaluation of participants. S.V.B.: review and for Parkinson’s disease: Results from an international pilot study. Mov. Disord. 22, critique; recruitment and/or evaluation of participants. Á.S.M.: review and critique; 1901–1911 (2007). recruitment and/or evaluation of participants. V.L.: review and critique; recruitment 62. Chaudhuri, K. R. et al. The Parkinson’s disease sleep scale: a new instrument for and/or evaluation of participants. E.S.: review and critique; recruitment and/or assessing sleep and nocturnal disability in Parkinson’s disease. J. Neurol. Neuro- evaluation of participants. C.E.: review and critique; recruitment and/or evaluation of surg. Psychiatry 73, 629–635 (2002). participants. C.P.F.: review and critique; recruitment and/or evaluation of participants. 63. Burckhardt, C. S. & Jones, K. D. Adult measures of pain: The McGill Pain Ques- M.C.J.C.: review and critique; recruitment and/or evaluation of participants. S.A.P.: tionnaire (MPQ), Rheumatoid Arthritis Pain Scale (RAPS), Short Form McGill Pain review and critique; recruitment and/or evaluation of participants. A.L.M.G.: review Questionnaire (SF-MPQ), Verbal Descriptive Scale (VDS), Visual Analog Scale and critique; recruitment and/or evaluation of participants. L.A.N.: review and critique; (VAS), and West Haven-Yale Multidisciplinary Pain Inventory (WHYMPI). Arthritis. recruitment and/or evaluation of participants. G.I.: review and critique; recruitment Rheum. 49, 96–104 (2003). and/or evaluation of participants. C.P.: review and critique; recruitment and/or 64. Tseng, B. Y., Gajewski, B. J. & Kluding, P. M. Reliability, responsiveness, and validity evaluation of participants. K.J.: review and critique; recruitment and/or evaluation of of the visual analog fatigue scale to measure exertion fatigue in people with participants. B.E.M.: review and critique; recruitment and/or evaluation of participants. chronic stroke: a preliminary study. Stroke. Res. Treat. 2010, 412964 (2010). S.M.: review and critique; recruitment and/or evaluation of participants. R.M.J.: review 65. Folstein, M. F., Folstein, S. E. & McHugh, P. R. Mini-mental state". A practical and critique; recruitment and/or evaluation of participants. V.C.: review and critique; method for grading the cognitive state of patients for the clinician. J. Psychiatr. recruitment and/or evaluation of participants. K.M.: review and critique; recruitment Res. 12, 189–198 (1975). and/or evaluation of participants. d.F.O.: review and critique; recruitment and/or 66. Pagonabarraga, J., Kulisevsky, J., Llebaria, G., García-Sánchez, C., Pascual-Sedano, evaluation of participants. G.A.J.: review and critique; recruitment and/or evaluation B. & Gironell, A. Parkinson’s disease-cognitive rating scale: a new cognitive scale of participants. O.C.: review and critique; recruitment and/or evaluation of specific for Parkinson’s disease. Mov. Disord. 23, 998–1005 (2008). participants. L.D.L.: review and critique; recruitment and/or evaluation of participants. 67. Beck, A. T., Steer, R. A. & Brown, G. K. Beck Depression Inventory 2nd ed (The MD: review and critique; review of english style. M.-M.P.: review and critique; Psychological Corporation, San Antonio, 1996). supervision. M.P.: review and critique; recruitment and/or evaluation of participants. 68. Cummings, J. L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D. A. & Gornbein, J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 44, 2308–2314 (1994). COMPETING INTERESTS 69. Weintraub, D. et al. Validation of the questionnaire for impulsive-compulsive Santos García D. has received honoraria for educational presentations and advice service disorders in Parkinson’s disease. Mov. Disord. 24, 1461–1467 (2009). by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, Italfarmaco, and Teva. De Deus 70. Schwab, R. S. & England, A. C. In Third Symposium on Parkinson’s Disease 152–157 Fonticoba T: None. Cores C. has received honoraria for educational presentations and (E. And S. Livingstone, Edinburgh, 1969). advice service by Lundbeck and UCB Pharma. Muñoz G: None. Paz González JM. has 71. Jenkinson, C., Fitzpatrick, R., Peto, V., Greenhall, R. & Hyman, N. The Parkinson’s received honoraria for educational presentations and/or advice service by UCB Pharma, Disease Questionnaire (PDQ-39): development and validation of a Parkinson’s Lundbeck, KRKA, and Zambon. Martínez Miró C: None. Suárez E: None. Jesús S. has disease summary index score. Age Ageing 26, 353–357 (1997). received honoraria from AbbVie, Bial, Merz, UCB, and Zambon and holds the competitive 72. Da Rocha, N. S., Power, M. J., Bushnell, D. M. & Fleck, M. P. The EUROHIS-QOL contract “Juan Rodés” supported by the Instituto de Salud Carlos III. She has received 8-item index: comparative psychometric properties to its parent WHOQOL-BREF. grants from the Spanish Ministry of Economy and Competitiveness (PI18/01898) and the Value Health 15, 449–457 (2012). Consejería de Salud de la Junta de Andalucía (PI-0459-2018). Aguilar M: UCB and Schwabe 73. Santos-García, D. et al. COPPADIS Study Group. Non-motor symptom burden is with assistance to a Congress; Nutricia with assistance to a Congress and payment of strongly correlated to motor complications in patients with Parkinson’s disease. lecture. Pastor P: None. Planellas LL. has received travel bursaries grant from Abbvie. Eur. J. Neurol. 27, 1210–1223 (2020). Cosgaya M: None. García Caldentey J. has received honoraria for educational 74. Cohen, J. & Cohen, P. Applied Multiple Regression/Correlation Analysis for the presentations and advice service by Qualigen, Nutricia, Abbvie, Italfarmaco, UCB Pharma, Behavioral Sciences 2nd ed (Lawrence Erlbaum, Hillsdale, New Jersey, 1983). Lundbeck, Zambon, Bial, and Teva. Caballol N. has received honoraria from Bial, 75. Schade, S., Mollenhauer, B. & Trenkwalder, C. Levodopa equivalent dose con- Italfármaco, Qualigen, Zambon, UCB, Teva and KRKA and sponsorship from Zambon, version factors: an updated proposal including opicapone and safinamide. Mov. TEVA and Abbvie for attending medical conferences. Legarda I. has received honoraria for Disord. Clin. Pract. 2020, 343–345 (2020). educational presentations and advice service by Abbvie, UCB Pharma, Zambon, Bial, and Teva. Hernández Vara J. has received travel bursaries and educational grants from Abbvie and has received honoraria for educational presentations from Abbvie, Teva, Bial, ACKNOWLEDGEMENTS Zambon, Italfarmaco, and Sanofi-Genzyme. Cabo I. has received honoraria for educational We would like to thank all patients and their caregivers who collaborated in this presentations and advice service by Abbvie, Zambon and Bial. López Manzanares L: study. Many thanks also to Fundación Española de Ayuda a la Investigación en Compensated advisory services, consulting, research grant support, or speaker honoraria: Parkinson y otras Enfermedades Neurodegenerativas (Curemos el Parkinson; www. AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. curemoselparkinson.org), Alpha Bioresearch (www.alphabioresearch.com), and other González Aramburu I: None. Ávila Rivera MA. has received honoraria from Zambon, UCB institutions helping us. Pharma, Qualigen, Bial, and Teva, and sponsorship from Zambon and Teva for attending conferences. Catalán MJ: None. Nogueira V: None. Puente V. has served as consultant for Abbvie and Zambon; has received grant/research from Abbvie. Ruíz de Arcos M: None. AUTHOR CONTRIBUTIONS Borrué C: None. Solano Vila B. has received honoraria for educational presentations and S.G.D.: conception, organization, and execution of the project; statistical analysis; advice service by UCB, Zambon, Teva, Abbvie, Bial. Álvarez Sauco M. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, writing of the first draft of the manuscript; recruitment and/or evaluation of Zambon, Bial, and Teva. Vela L. has received honoraria for educational presentations and participants. D.D.T.: review and critique; recruitment and/or evaluation of participants. advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. C.C.: review and critique. M.G.: review and critique. P.G.J.M.: review and critique. M.M. Escalante S. has received honoraria for educational presentations and advice service by C.: review and critique. S.E.: review and critique; recruitment and/or evaluation of Abbvie, Zambon, and Bial. Cubo E: Travel grants: Abbvie, Allergan, Boston; Lecturing participants. J.S.: review and critique; recruitment and/or evaluation of participants. honoraria: Abbvie, International Parkinson´s disease Movement Disorder Society. Carrillo A.M.: review and critique; recruitment and/or evaluation of participants. P.P.: review Padilla F. has received honoraria from Zambon (SEN Congress assistance). Martínez and critique; recruitment and/or evaluation of participants. P.L.L.: review and critique; Castrillo JC. has received research support from Lundbeck, Italfarmaco, Allergan, Zambon, recruitment and/or evaluation of participants. C.M.: review and critique; recruitment Merz, and Abbvie. He has received speaking honoraria from AbbVie, Bial, Italfarmaco, and/or evaluation of participants. G.C.J.: review and critique; recruitment and/or Lundbeck, Krka, TEVA, UCB, Zambon, Allergan, Ipsen, and Merz. Sánchez Alonso P. has evaluation of participants. C.N.: review and critique; recruitment and/or evaluation of received honoraria for educational presentations and advice service by Abbvie, UCB participants. L.I.: review and critique; recruitment and/or evaluation of participants. Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Alonso Losada MG. has received H.V.J.: review and critique; recruitment and/or evaluation of participants. C.I.: review honoraria for educational presentations and advice service by Zambon and Bial. López and critique; recruitment and/or evaluation of participants. L.M.L.: review and critique; Ariztegui N. has received honoraria for educational presentations and advice service by recruitment and/or evaluation of participants. G.A.I.: review and critique; recruitment Abbvie, Italfarmaco, Zambon, and Bial. Gastón I. has received research support from and/or evaluation of participants. Á.R.M.A.: review and critique; recruitment and/or Abbvie and Zambon and has served as a consultant for Abbvie, Exelts, and Zambon. evaluation of participants. C.M.J.: review and critique; recruitment and/or evaluation Clavero P: Kulisevsky J: (1) Consulting fees: Roche, Zambon; (2) Stock / allotment: No; (3) of participants. N.V.: review and critique; recruitment and/or evaluation of Patent royalties / licensing fees: No; (4) Honoraria (e.g., lecture fees): Zambon, Teva, Bial, participants. P.V.: review and critique; recruitment and/or evaluation of participants. UCB; (5) Fees for promotional materials: No; (6) Research funding: Roche, Zambon, R.d.A.M.: review and critique; recruitment and/or evaluation of participants. B.C.: Ciberned; Instituto de SaludCarlos III; FundacióLa Maratóde TV3; (7) Scholarship from Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2021) 118 D.S. García et al. 10 corporation: No; (8) Corporate laboratory funding: No; (9) Others (e.g., trips, travel, or gifts): ADDITIONAL INFORMATION No. Blázquez Estrada M. has received honoraria for educational presentations and advice Supplementary information The online version contains supplementary material service by Abbvie, Abbott, UCB Pharma, Allergan, Zambon, Bial, and Qualigen. Seijo M. available at https://doi.org/10.1038/s41531-021-00256-w. has received honoraria for educational services from KRKA, UCB, Zambon, Bial; travel grants from Daiichi and Roche. Ruiz Martínez J. has received honoraria for educational Correspondence and requests for materials should be addressed to SantosGarcía. D. presentations, attending medical conferences, and advice service by Abbvie, UCB Pharma, Zambon, Italfarmaco, Bial, and Teva. Valero C. has received honoraria for educational Reprints and permission information is available at http://www.nature.com/ services from Zambon, Abbvie and UCB. Kurtis M. has received honoraria from Bial, the reprints Spanish Neurology Society and the International and Movement Disorders Society. de Fábregues O. has received honoraria for educational presentations and advice service by Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims Bial, Zambon, Abbvie, KRKA, and Teva. González Ardura J. has recieved honoraria for in published maps and institutional affiliations. speking from italofarma, Krka, Genzyme, UCB, Esteve, Psyma iberica marketing research SL and Ferrer, course grant from Teva and travel grant from Merck. Ordás C: None. López Díaz L. has received honoraria from UCB, Lundbeck, and KRKA. McAfee D: None. Martínez- Martin P. has received honoraria from National School of Public Health (ISCIII), Editori-al Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, Viguera and Takeda Pharmaceuticals for lecturing in courses; from Britannia for writing an adaptation, distribution and reproduction in any medium or format, as long as you give article in their Parkinson’s Disease Medical Journal-Kinetic; and from the International appropriate credit to the original author(s) and the source, provide a link to the Creative Parkinson and Movement Disorder Society (MDS) for management of the Program on Commons license, and indicate if changes were made. The images or other third party Rating Scales. Grants: from the MDS for development and validation of the MDS-NMS. material in this article are included in the article’s Creative Commons license, unless Mir P. has received honoraria from AbbVie, Abbott, Allergan, Bial, Merz, UCB and Zambon indicated otherwise in a credit line to the material. If material is not included in the and have received grants from the Spanish Ministry of Economy and Competitiveness article’s Creative Commons license and your intended use is not permitted by statutory [PI16/01575] co-founded by ISCIII (Subdirección General de Evaluación y Fomento de la regulation or exceeds the permitted use, you will need to obtain permission directly Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de from the copyright holder. To view a copy of this license, visit http://creativecommons. Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], org/licenses/by/4.0/. the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI-0437-2012, PI-0471- 2013], the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña. © The Author(s) 2021, corrected publication 2022 COPPADIS STUDY GROUP Daniela A. Adarmes3, Marta Almeria5, Araceli Alonso Cánovas27, F. Alonso Frech16, Ruben Alonso Redondo41, Ignacio Álvarez5, Ángel Aneiros Díaz2, Sandra Arnáiz25, Sonia Arribas5, Arancha Ascunce Vidondo31, Noemí Bernardo Lambrich24, Helana Bejr-Kasem32, María A. Botí5, María T. Buongiorno5, Carolina Cabello González31, A. Cámara Lorenzo7, Héctor Canfield Medina2, Fátima Carrillo3, Elena Casas25, Ana Cortina Fernández2, Anna Cots Foraster21, Ane Crespo Cuevas18, Mónica Díez-Fairen5, Julio Dotor García-Soto19, Elena Erro31, Elena Estelrich Peyret21, Noelia Fernández Guillán2, Pedro Gámez25, Mercedes Gallego13, Cristina García Campos19, Jose M. García Moreno19, María P. Gómez Garre3, Vívtor Gómez Mayordomo16, Javier González Aloy21, Beatriz González García13, María J. González Palmás12, González Toledo, R. Gabriel26, Ana Golpe Díaz2, Mireia Grau Solá9, Gemma Guardia5, Andrea Horta-Barba32, Daniel Idoate Calderón12, Jon Infante4,14, Carmen Labandeira29, Miguel A. Labrador3, Francisco Lacruz31, Melva Lage Castro12, Sonia Lastres Gómez12, Balbino López Seoane42, Sara Lucas del Pozo10, Yolanda Macías23, Marina Mata20, Gloria Martí Andres43, María J. Martí7, Maria T. Meitín17, Manuel Menéndez González33, Carlota Méndez del Barrio3, Javier Miranda Santiago25, Morales Casado, I. María30, Antonio Moreno Diéguez2, Alba Novo Amado42, Sabela Novo Ponte28, Javier Pagonabarraga32, Isabel Pareés36, Berta Pascual-Sedano32, Aída Pérez Fuertes2, Rafael Pérez Noguera19, Ana Planas-Ballvé9, Marian A. Prats21, Cristina Prieto Jurczynska38, Mercedes Pueyo Morlans26, Arnayu Puig Daví32, Nuria Redondo Rafales13, Luisa Rodríguez Méndez2, Amparo B. Rodríguez Pérez22, Florinda Roldán3, Macarena Sánchez-Carpintero2, Gemma Sánchez Díez27, Antonio Sánchez Rodríguez14, Pilar Santacruz7, José C. Segundo Rodríguez30, María Sierra Peña14, Juan P. Tartari5, Laura Vargas3, Clara Villanueva16, Bárbara Vives10 and María D. Villar26 41 42 43 Hospital Universitario Lucus Augusti (HULA), Lugo, Spain. Hospital General Juan Cardona, Ferrol, A Coruña, Spain. Clínica Universidad de Navarra, Pamplona, Spain. npj Parkinson’s Disease (2021) 118 Published in partnership with the Parkinson’s Foundation