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

ARTICLE OPEN Predictors of clinically significant quality of life impairment in Parkinson’s disease Diego Santos García 1 ✉, Teresa de Deus Fonticoba 2 , Carlos Cores 1 , Guillermo Muñoz 1 , Jose M. Paz González 1 , Cristina Martínez Miró 1 , Ester Suárez 2 , Silvia Jesús 3,4 , Miquel Aguilar 5 , Pau Pastor 5 , Lluis Planellas 6 , Marina Cosgaya 7 , Juan García Caldentey 8 , Nuria Caballol 9 , Inés Legarda 10 , Jorge Hernández Vara 11 , Iria Cabo 12 , Luis López Manzanares 13 , Isabel González Aramburu 4,14 , María A. Ávila Rivera 15 , Maria J. Catalán 16 , Víctor Nogueira 17 , Víctor Puente 18 , María Ruíz de Arcos 19 , Carmen Borrué 20 , Berta Solano Vila 21 , María Álvarez Sauco 22 , Lydia Vela 23 , Sonia Escalante 24 , Esther Cubo 25 , Francisco Carrillo Padilla 26 , Juan C. Martínez Castrillo 27 , Pilar Sánchez Alonso 28 , Maria G. Alonso Losada 29 , Nuria López Ariztegui 30 , Itziar Gastón 31 , Pedro Clavero 31 , Jaime Kulisevsky 4,32 , Marta Blázquez Estrada 33 , Manuel Seijo 12 , Javier Rúiz Martínez 34 , Caridad Valero 35 , Mónica Kurtis 36 , Oriol de Fábregues 11 , Jessica González Ardura 37 , Carlos Ordás 38 , Luis M. López Díaz 39 , Darrian McAfee 40 , Pablo Martinez-Martin 4 , 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, 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; R 2 =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 Parkinson’s disease (PD) is a complex disorder in which different motor and non-motor symptoms (NMS) can be present with a frequency and severity that varies among patients over time 1 . Both motor and NMS are important because they negatively impact the patient’s quality of life (QoL). Different studies have analyzed what factors contribute to a poor QoL in PD patients 2–13 . Recently, we observed that NMS burden, mood, and gait problems were the most relevant factors affecting health-related (HRQoL) and global perceived QoL (GQoL) in non-demented PD patients from the Spanish cohort COPPADIS 14 . These results aligned with other cross-sectional studies observations 15–17 . However, with 1 CHUAC, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain. 2 CHUF, Complejo Hospitalario Universitario de Ferrol, A Coruña, Spain. 3 Unidad 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. 5 Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain. 6 Neurología, Clínica del Pilar, Barcelona, Spain. 7 Hospital Clínic de Barcelona, Barcelona, Spain. 8 Centro Neurológico Oms 42, Palma de Mallorca, Spain. 9 Consorci Sanitari Integral, Hospital Moisés Broggi, Sant Joan Despí, Barcelona, Spain. 10 Hospital Universitario Son Espases, Palma de Mallorca, Spain. 11 Hospital Universitario Vall d´Hebron, Barcelona, Spain. 12 Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain. 13 Hospital Universitario La Princesa, Madrid, Spain. 14 Hospital Universitario Marqués de Valdecilla, Santander, Spain. 15 Consorci Sanitari Integral, Hospital General de L´Hospitalet, L´Hospitalet de Llobregat, Barcelona, Spain. 16 Hospital Universitario Clínico San Carlos, Madrid, Spain. 17 Hospital Da Costa, Burela, Lugo, Spain. 18 Hospital del Mar, Barcelona, Spain. 19 Hospital Universitario Virgen Macarena, Sevilla, Spain. 20 Hospital Infanta Sofía, Madrid, Spain. 21 Institut d’Assistència Sanitària (IAS) - Institut Català de la Salut, Girona, Spain. 22 Hospital General Universitario de Elche, Elche, Spain. 23 Fundación Hospital de Alcorcón, Madrid, Spain. 24 Hospital de Tortosa Verge de la Cinta (HTVC), Tortosa, Tarragona, Spain. 25 Complejo Asistencial Universitario de Burgos, Burgos, Spain. 26 Hospital Universitario de Canarias, San Cristóbal de la Laguna, Santa Cruz de Tenerife, Spain. 27 Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain. 28 Hospital Universitario Puerta de Hierro, Madrid, Spain. 29 Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo (CHUVI), Vigo, Spain. 30 Complejo Hospitalario de Toledo, Toledo, Spain. 31 Complejo Hospitalario de Navarra, Pamplona, Spain. 32 Hospital de Sant Pau, Barcelona, Spain. 33 Hospital Universitario Central de Asturias, Oviedo, Spain. 34 Hospital Universitario Donostia, San Sebastián, Spain. 35 Hospital Arnau de Vilanova, Valencia, Spain. 36 Hospital Ruber Internacional, Madrid, Spain. 37 Hospital Universitario de Cabueñes, Gijón, Spain. 38 Hospital Rey Juan Carlos, Madrid, Spain, Madrid, Spain. 39 Complejo Hospitalario Universitario de Orense (CHUO), Orense, Spain. 40 Univeristy of Pennsylvania, Pennsylvania, USA. *A list of authors and their affiliations appears at the end of the paper. ✉email: diegosan[email protected]s www.nature.com/npjparkd Published in partnership with the Parkinson’s Foundation 1234567890():,; regard to how the QoL of PD changes throughout the course of the disease, there is much less information 18–23 and prospective longitudinal studies are needed. In clinical practice, it is important to know what factors worsen PD patients’QoL with the intention to carry out effective interventions. Known information limited by factors from the studies such as the sample size, the differences between scales used for assessing QoL, the different types of QoL assessed, being a non-multicenter study, the absence of a control group, and/or the lack of a global evaluation including different aspects that could impact on QoL 18–23 . In addition, the impact of some complications on QoL in advanced PD has been analyzed before 24,25 . However, it is not clear what the significance of shortterm changes in QoL is in early PD patients or what factors contribute to it when an extensive assessment considering motor and NMS is performed 26 . It is remarkable that NMS occur not only in advanced but also in the early stages of PD. Some symptoms, for example, olfactory deficit, constipation, rapid-eyemovement sleep behavior disorder, and depression, can even precede the appearance of motor symptoms by many years 1 .By the contrary, others such as psychosis or dementia are not present. The first years are conditioned by the acceptance of the diagnosis, but in general, the patient has greater autonomy. In this context, it is essential to know what influences the changes in the PD patient QoL perception with the intention of being able to act as soon as possible. The aim of the present study was to (1) analyze the change in HRQoL and GQoL in PD patients from the COPPADIS cohort after the 2-year follow-up, (2) to compare with a control group, and (3) to identify predictors of clinically significant QoL impairment in the PD group. Finally, a subanalysis was conducted in a subgroup of patients with early PD (≤5 years of disease duration). RESULTS Changes in assessments from V0 to V2 After the 2-year follow-up, GQoL did not change significantly in PD patients (from PQ-10 V0 of 7.28 ± 1.55 to PQ-10 V2 of 7.14 ± 1.54 [N=503; p=0.070]; from EUROHIS-QOL8 V0 of 3.77 ± 0.54 to EUROHIS-QOL8 V2 of 3.75 ± 0.58 [N=507; p=0.686]) or in the control group (from PQ-10 V0 of 8.07 ± 1.22 to PQ-10 V2 of 7.86 ± 1.65 [N=122; p=0.361]; from EUROHIS-QOL8 V0 of 4.18 ± 0.5 to EUROHIS-QOL8 V2 of 4.12 ± 0.51 [N=119; p=0.192] (Fig. 1). 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 16.72 ± 13.02 to 20.3 ± 16.41; p< 0.0001) at V2 (Table 1and Fig. 1). By domains, the score of all domains of the PDQ-39SI at V2 was significantly higher than at V0 except for domain 4 (stigmatization) (Table 1). The change in the score of other scales from V0 to V2 in PD patients and controls is shown in Table 1. Patients with vs without clinically HRQoL impairment Although 291 PD patients (58.2%) presented an increase in the PDQ-39SI score after the 2-year follow-up, only 93 (18.6%) presented a clinically significant HRQoL impairment at V2. Differences in change from V0 to V2 of UPDRS-III, UPDRS-IV, FOGQ, NMSS, BDI-II, PDSS, NPI, VAS-PAIN, VASF-physical, VASFmental, and ADLS scores between patients with and without clinically significant HRQoL impairment were observed (Table 2). Specifically, PD patients who presented at the 2-year follow-up a clinically significant HRQoL impairment presented a 97.3% increase of the NMS burden (NMSS total score from 29.2 ± 25.87 to 57.84 ± 46.73 [p< 0.0001]) compared to 8.6% in those patients who did not (NMSS total score from 48.38 ± 38.59 to 52.53 ± 41.35 [p=0.003]) (Fig. 2A). By domains, the most significant differences were observed for sleep/fatigue (p< 0.0001) and mood/apathy (p< 0.0001) (Table 2and Fig. 2B). Moderate correlations were observed between the change from V0 to V2 in the PDQ-39SI score and the score in FOGQ (r=0.34; p< 0.0001), NMSS (r=0.41; p< 0.0001), BDI-II (r=0.33; p< 0.0001) and ADLS (r=−0.40; p< 0.0001) (Supplementary Table 1). Predictors of clinically HRQoL impairment 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 (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) 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= 0.665; R 2 =0.655) (Table 3). Specifically, an increase in ≥5 and ≥10 points of BDI-II and NMSS total score at V2 multiplied the probability of presenting a 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. When ADLS was included in the model (ADLS at V0 and the change in ADLS score from V0 to V2), only a greater increase in BDI-II (OR =1.148; 95% CI 1.057–1.258; p=0.001), NMSS (Non-Motor Symptoms 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) total scores and a decrease in ADLS score (OR =0.884; 95% CI 0.820–0.954; p< 0.0001) from V0 to V2 were associated with clinically significant HRQoL impairment at the 2-year follow-up (Hosmer–Lemeshow test, p=0.621; R 2 =0.718). 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. D.S. García et al. 2 npj Parkinson’s Disease (2021) 118 Published in partnership with the Parkinson’s Foundation 1234567890():,; In the subgroup of early PD (N=277), quite similar results, an increase in mean PDQ-39SI from V0 to V2 of 23.4% (from 14.22 ± 11.29 to 17.62 ± 15.36; p< 0.0001), were observed. Fifty-six patients (20.2%) presented a clinically significant HRQoL impairment at the 2-year follow-up. However, as in the whole cohort, GQoL did not change significantly (PQ-10, p=0.111; EUROHISQOL8, p=0.756). In the binary regression model, as in the all cohort, to be younger (OR =0.813; 95% CI 0.709–0.933; p=0.003), to be a female (OR =35.847; 95% CI 3.452–372.204; p=0.003), and to have a greater increase 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) total scores from V0 to V2 were associated with clinically significant HRQoL impairment at the 2-year followup, after adjustment to many covariates (Hosmer–Lemeshow test, p=0.998; R 2 =0.745) (Table 3). When ADLS was included in the model, to be younger (OR =0.769; 95% CI 0.624–0.946; p=0.013), 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 p a Controls V0 Controls V2 p b 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 %; p a , V2 vs V0 in PD patients; p b , 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 pvalues. D.S. García et al. 3 Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2021) 118 to be a female (OR =31.982; 95% CI 1.678–609.587; p =0.021), and to have a greater increase in BDI-II (OR =1.197; 95% CI 1.126–1.990; p=0.006), NMSS (Non-Motor Symptoms 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) total scores from V0 to V2 were associated with clinically significant HRQoL impairment at the 2-year follow-up (Hosmer–Lemeshow test, p=0.217; R 2 =0.816), but not the change in the ADLS score (OR =0.889; 95% CI 0.786–1.1006; p=0.062). Moderate correlations were observed between the change from V0 to V2 in the PDQ-39SI score and the score in FOGQ (r=0.39; p< 0.0001), NMSS (r=0.41; p< 0.0001), NPI (r=0.35; p< 0.0001) and ADLS (r=−0.41; p< 0.0001) (Supplementary Table 2). Predictors of the change in the PDQ-39SI from V0 to V2 Finally, similar results were observed in both groups, the whole cohort and the early PD subgroup, when a linear regression model was considered (PDQ-39SI change from V0 to V2 as dependent 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= 0.20; p< 0.0001), and NMSS (β=0.37; p< 0.0001) scores provided the highest contribution to the model (adjusted R-squared 0.45) in the whole cohort. In early PD patients, the variables associated with HRQoL change at the 2-year follow-up were the same (Supplementary Table 2). When the ADLS score was included in the model, the results were similar but with the ADLS as an independent variable associated with HRQoL change too (β= −0.21; 95% CI −0.353, −0.107; p< 0.0001; adjusted R-squared 0.45 [N=500; all cohort]; β=−0.23; 95% CI −0.433, −0.076; p=0.005; adjusted R-squared 0.431 [N=277; early PD subgroup]). DISCUSSION In this longitudinal follow-up study, we report that there is a significant HRQoL impairment in PD patients in the short-term and that impairment in the motor status during the OFF state (UPDRS-III), increased gait problems (FOGQ), and increased NMS burden contribute to it. Specifically, mood impairment and NMS burden increase were independent factors associated with clinically significant HRQoL impairment at the 2-year follow-up, which one was present in about every 5 patients. Moreover, the results indicate that it will be especially important to be vigilant about clinically significant HRQoL impairment in women and younger patients. After a 2-year follow-up, PD patients from the COPPADIS cohort demonstrated impairment in motor function (H&Y, UPDRS-III, UPDRSIV, FOGQ). The increase of motor impairments measured with the UPDRS were in agreement with other studies 27,28 .Also,significant changes in NMS were observed in the NMS burden as a whole, pain, fatigue, and cognition, but not in controls. These results aligned with previous longitudinal studies indicating that the severity of NMS in PD tends to become progressively worse with the course of the disease and also indicate that non-motor evaluation is complementary to measuring PD progression 19,26,29–32 .WithrespecttotheQoL, although more than a half of PD patients presented a PDQ-39SI score at the 2-year follow-up higher than at baseline, only 18.6% presented HRQoL impairment as clinically significant. In a previous study with 707 PD patients followed prospectively for the 2-year as well, 17% worsened clinically while 584 were rated as stable 29 .Theresultscan be vary due to the definition of QoL impairment as clinically significant 31,33,34 . Based on the postal reply of 728 PD patients, Peto et al. 34 determined that 1.6 points worsening on a PDQ-39SI is the minimal clinically important difference threshold. More recently, Horváth et al. 31 considered the most optimal estimates threshold for 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 improvement is conditioned by the baseline score; therefore, the use of a percentage might be more appropriate 35,36 . Patients appear to be able to detect changes of 7–10% on QoL instruments or pain scales 36 . In our case, the minimal important difference was considered Table 2. Changes in motor and non-motor symptoms and disability in PD patients from V0 (baseline) to V2 (2 years ± 1 month) with regards to presenting or not clinically significant HRQoL impairment. Non clinically significant HRQoL impairment N=407 Clinically significant HRQoL impairment N=93 p Age at baseline 63.04 ± 7.99 61.32 ± 10.17 0.354 Gender (males) (%) 60 57 0.341 Disease duration (at V0) 5.65 ± 4.36 4.91 ± 3.55 0.247 Number of nonantipark. drugs (at V0) 2.56 ± 2.36 2.33 ± 2.49 0.220 Change at V2 (from V0 to V2) LEDD +177.15 ± 330.2 +228.75 ± 318.27 0.174 Number of nonantipark. drugs +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 Cardiovascular +6.21 ± 14.41 +8.11 ± 12.83 0.310 Sleep/fatigue +0.7 ± 15.96 +12.98 ± 18.42 <0.0001 Mood/apathy +0.5 ± 14.57 +8.62 ± 15.19 <0.0001 Perceptual symptoms +1.89 ± 10.61 +4.35 ± 12.56 0.141 Attention/memory +1.74 ± 14.16 +7.28 ± 17.30 0.07 Gastrointestinal symptoms +2.19 ± 12.64 +4.9 ± 12.8 0.020 Urinary symptoms +1.29 ± 20.22 +9.28 ± 21.56 0.001 Sexual dysfunction +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-mental −0.12 ± 2.76 +1.05 ± 2.95 0.002 ADLS −2.84 ± 11.08 −10.97 ± 12.42 <0.0001 Chi-squared and Mann–Whitney–Wilcoxon test were applied. The results represent percentages or mean ± SD. The symbol “+”indicates an increase in the score of the scale at V2 compared to V0 while the symbol “–” indicates a decrease. Data about UPDRS-III are during the OFF state (first hour in the morning without taking medication in the previous 12 h). 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 pvalues. D.S. García et al. 4 npj Parkinson’s Disease (2021) 118 Published in partnership with the Parkinson’s Foundation as an increase of 10% or more in the PDQ-39SI score 33,35–37 .Ten percent of the mean score of the PDQ-39SI in our study represents 1.6 points; therefore, similar to the proposal of Peto et al. 34 .However, in a patient with a higher baseline PDQ-39SI score, for example, 50 points, the minimal clinically significant worsening change should be 5 points. Hence, in less than 1 in 3 patients who had an increase in the PDQ-39 score, this was considered clinically significant. In any case,itseemsclearthateveninarelativelyshortfollow-upperiod, patients with PD experience a significant decrease in HRQoL 21,29 . However, as Reuther et al. 22 reported in 145 PD patients after a 12month follow-up, there doesn’t seem to be a significant change in QoL generic scales. For assessing the NMS as a whole, we used the NMSS. To date, this scale has been used in more than 100 clinical studies and trials and it has shown to be capable of detecting longitudinal changes in NMS, where studies have shown differential changes over time of several of the NMSS domains 32,38,39 . Moreover, it has been demonstrated a consistent and strong correlations between NMSS burden and HRQoL measures 32,40–42 . In our study, a very clear difference in the change of NMS burden was observed between patients with and without clinically significant HRQoL impairment. Changes in all domains of the NMSS scale correlated with QoL changes. Similarly, previous studies observed a correlation between NMS burden assessed with the NMSS and QoL changes over time 19 . Moreover, in our analysis, NMS burden progression was an independent factor related to HRQoL impairment. Prakash et al. observed for the first time that nonmotor problems provided a better prediction of the change of QoL in 227 PD patients over a 2-year follow-up period 19 . However, they did not provide the variance value of the model, many factors potentially affecting QoL were not included, and what they considered was the baseline NMSS score. On the contrary, in this study we wanted to analyze in detail what changes in many aspects of the disease observed after the 2-year follow-up contributed to a worsening in the patients´ QoL. So, several variables were included, the results of the model represented ~70% of the variance when HRQoL changes were considered, and the changes in all variables were adjusted to the scores at baseline. To our best knowledge, this is the first longitudinalprospective study analyzing in such detail which are the predictors of QoL impairment in a large sample of PD patients. Reinforcing the idea that the progression of NMS is pivotal to the worsening of the QoL throughout the evolution of the disease, improvements of NMS were associated with improved QoL in advanced parkinsonian patients during 2‐year treatment with levodopa‐carbidopa intestinal gel infusion therapy 43 . In line with this, Erro et al. observed that NMS significantly affected QoL in PD, demonstrating that this was especially the case when patients were in their honeymoon period (during which time the side effects of the disease aren’t too disabling and there is a response to medications) 44 . In the subgroup of early PD patients from our study, the change in the NMSS total score at 2-years was one of the most significant contributors to HRQoL impairment. Another important factor is mood. Like in other studies, the mean score of BDI didn’t change over time 18,22 , suggesting that depression-type frequency does not appear to change over time in PD 45 . Cross-sectional studies have reported the clear contribution of depression or a worse mood to a poorer QoL in PD patients 3,12,13 . In fact, it was observed in the COPPADIS baseline cross-sectional analysis 14 . However, to our knowledge, this is the first time that mood worsening is identified as an independent factor associated with clinically significant HRQoL impairment in PD patients. This subgroup of patients (N=93) presented a mean increase in the BDI-II score of 4.5 points at the 2-year follow-up and specifically, an increase in ≥5 points multiplied by 5 the probability of presenting a clinically significant HRQoL impairment, independent of other factors. Reuther et al. 22 identified depression as the strongest predictor for reduced HRQoL in 145 PD patients after 1-year follow-up. However, we identified the change in the score of the BDI-II as a predictor of clinically significant HRQoL impairment after adjustment to BDI-II score at baseline. From a practical point of view, our findings suggest an important role of the neurologist being alert to a possible worsening of mood, as well as greater NMS burden, in patients with PD throughout the evolution of the disease since this is what impacts on the patient’s QoL. Knowing what impacts on the QoL and contributes to its worsening, depending on the variable, intervention measures with the intention of correcting them can be proposed 46 . Studies demonstrating a QoL improvement correlated with mood and NMS burden improvement have been published 47 . With regards of the results observed here, it should be necessary to be alert about mood and NMS burden changes over time, especially in younger patients and females. A mildly significant gender difference in disability and QoL reporting has been noted, with women citing greater disability and reduced QoL 48,49 . Depression and fatigue were the major causes of low 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. BMean 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. D.S. García et al. 5 Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2021) 118 HRQoL in women even in the early phases of PD 50 . To attenuate this sex difference in disease experience, psychological distress screening and management (particularly targeting females) should be considered as part of PD clinical care 23 . Moreover, QoL, as measured on the PDQ-39, is significantly worse in youngonset PD patients than in older-onset PD patients, and youngonset PD patients also experience loss of employment, disruption of family life, greater perceived stigmatization, and depression than do older-onset PD patients 51,52 . The most important limitation of this study is the fact that information about follow-up was recorded only in 524 patients of 695 initially included in the study (75.5%). Of them, data for the PDQ-39, PQ-10, and EUROHIS-QOL8 at baseline and at V2 was available in 500, 503, and 507 PD patients, respectively. Thirty-eight patients (5.5%) dropped out of the study (1 death; 2 with change in diagnosis; 35 other reasons) at the 2-year follow-up and 132 (19%) were not assessed. However, this is a limitation observed in other prospective studies. Of 7507 PD patients, follow-up data was available only for 4680 participants (62.3%) 53 . In the study of Antonini et al. 29 , 707 PD patients from 1142 initially included (61.9%) were evaluable at 24 months. An important second limitation is that PD patients older than 75 years old were excluded from participation by COPPADIS study protocol 14 , which leads to an early PD bias in this cohort. For some variables, the information was not collected in all cases. Moreover, this is a multicenter mono-country study, being the ideal for this type of studies the participation of patients from different parts of the world, so the results should be considered with caution when extrapolating them to the general PD population (i.e., race, country healthcare, etc.). By the contrary, strengths of our study include a very complete assessment, the large sample size, a prospective longitudinal follow-up design, the fact that this analysis was “a priori”planned as one objective of the multicenter COPPADIS project 16 , and the extensive clinical and demographic information recorded. The findings of this study have important implications in daily clinical practice. In a disorder like PD in which one there is no a cure, treatment is symptomatic and the aim is to improve the patient’s QoL. This is complex because many factors influence QoL in PD. Furthermore, PD is a complex disorder with many manifestations and with a great variability in its progression among patients. Regarding this study observations, some important points should be considered in daily clinical practice. First, a complete assessment of the patient with PD periodically including motor status, NMS, QoL and disability should be the ideal practice. Second, NMS progression contributes significantly to a QoL worsening and it is crucial its evaluation. Very interestingly, we reported very recently that PD patients from the COPPADIS cohort with a lower H&Y stage but a greater global NMS burden may have a worse QoL than patients with a higher H&Y stage but lower global NMS 54 . Third, mood is another key factor to consider whenever we evaluate the patient in clinical practice. Fourth, we have to keep in mind that mood impairment and global NMS progression predict a patient´s QoL worsening. Finally, we should be especially careful in all of the above in the case of a female patient and in young patients. A problem in clinical practice is the lack of time to evaluate the patient. For the PD patient, to bring adequately covered questionnaires to the consultation, for example with the help of nursing staff, or even in the future with mobile applications that transfer the data to the patient’s medical record, it could be a possibility that facilitates the complete and comprehensive assessment. In general, it is something that is not done today, and proof of this is the alarming lack of literature about the global progression of the disease including NMS in large cohorts of patients. More studies with large PD cohorts and long-term follow-up are required. Our aim with the COPPADIS cohort is to follow for 5 years 55 . Collecting data from different cohorts and making comparisons would also be of great interest. In conclusion, the present study observes HRQoL impairment in PD patients in a short 2-year follow-up, even in early PD patients, but not the GQoL. A younger age, to be a female, and mood and NMS burden impairment were associated with clinically significant HRQoL impairment after the 2-year followup. The progression of NMS is pivotal in the worsening of the QoL throughout the evolution of the disease in PD, and it is necessary to keep in mind to ask for mood or NMS changes, especially in females and young patients. Table 3. Binary logistic regression model about factors associated with clinically significant HRQoL impairment at V2 (2 years follow-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 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-39SI V2 ≥10% PDQ-39SI V0 ). OR and 95% CI are shown. Hosmer–Lemeshow test, p a =0.665; p b =0.998; R 2a =0.655; R 2b =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 pvalues. D.S. García et al. 6 npj Parkinson’s Disease (2021) 118 Published in partnership with the Parkinson’s Foundation METHODS PD patients and controls who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at the 2-year follow-up (V2) from 35 centers of Spain from the COPPADIS cohort 56 , were included in the study. Methodology about COPPADIS-2015 has been previously published 57 . This is a multicenter, observational, longitudinalprospective, 5-year follow-up study designed for analyzing disease progression in a Spanish population of PD patients. Specifically, 17 objectives were proposed in the protocol 55 . Even though the recruitment period ended in October 2017, the prospective follow-up phase is ongoing. Patients, caregivers (patient´s primary caregiver), and controls (subjects without PD and any other severe and disabling concomitant disorder) were included 55 . Annual visits from V0 (baseline) to V5 (60 moths ± 3 months) are conducted to the patients and at V0, V2, V4, and V5 to the controls and caregivers. All patients included were diagnosed according to UK PD Brain Bank criteria 57 . Exclusion criteria 55 were: non-PD parkinsonism, dementia criteria (Mini Mental State Examination [MMSE] ≥26), age < 18 or >75 years, inability to read or understand the questionnaires, to be receiving any advanced therapy (continuous infusion of levodopa or apomorphine, and/ or with deep brain stimulation), and presence of comorbidity, sequelae, or any disorder that could interfere with the assessment. Information on sociodemographic aspects, factors related to PD, comorbidity, and treatment were collected. V0 and V2 evaluations included 55 : (1) motor assessment (Hoenh & Yahr [H&Y] 58 , Unified Parkinson’s Disease Rating Scale [UPDRS] part III and part IV 59 , Freezing of Gait Questionnaire [FOGQ] 60 ; (2) NMS (Non-Motor Symptoms Scale [NMSS] 61 , Parkinson’s Disease Sleep Scale [PDSS] 62 , Visual Analog ScalePain [VAS-Pain] 63 , Visual Analog Fatigue Scale [VAFS] 64 , cognition (MMSE 65 , Parkinson’s Disease Cognitive Rating Scale [PD-CRS] 66 , completing a simple 16-piece puzzle); (3) mood and neuropsychiatric symptoms (Beck Depression Inventory-II [BDI-II] 67 , Neuropsychiatric Inventory [NPI] 68 , Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s DiseaseRating Scale [QUIP-RS] 69 ; (4) and disability (Schwab & England Activities of Daily Living Scale [ADLS] 70 . In patients with motor fluctuations, the motor assessment was made during the OFF state (without medication in the last 12 h) and during the ON state. On the other hand, the assessment was only conducted without medication in patients without motor fluctuations. The same evaluation as for the patients, except for the motor assessment, was conducted in control subjects at V0 and at V2 (2 years ± 1 month). Three scales were used to assess QoL at V0 and at V2 28 : (1) the 39-item 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 PDspecific questionnaire that assesses the patients’HRQoL. There are 39 items grouped into 8 domains: (1) Mobility (items 1 to 10); (2) Activities of 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 discomfort (items 37 to 39). For each item, the score may range from 0 (never) to 4 (always). The symptoms refer to the 4 weeks prior to 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 of daily living, self-esteem, social relationships, economic capacity, and 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 mean of the individual scores. A higher score indicates a better QoL. In controls, only the PQ-10 and the EUROHIS-QOL8 were assessed. Clinically significant HRQoL impairment was defined as presenting an increase in PDQ-39SI score at V2 ≥10% of score at baseline (V0) whereas GQoL impairment as presenting a decrement in PQ-10 and/or EUROHISQOL8 score at V2 ≤10% of score at baseline (V0) 33 . Taking into account that in the COPPADIS cohort the range of disease duration varies from <1 year to 30 years and based on the general response to treatment and progression of symptoms in PD and considering a recent publication of this same cohort 73 , patients with ≤5 years of disease duration were considered as early PD patients. Data analysis Data were processed using SPSS 20.0 for Windows. For comparisons between patients and controls, the Student’st-test, Mann–Whitney Utest, Chi-square test, or Fisher test were used as appropriate (distribution for variables was verified by one-sample Kolmogorov–Smirnov test). The Wilcoxon-signed rank test was performed to test whether the mean differences of the PDQ-39SI, PQ-10, and EUROHIS-QOL8 scores and the individual PDQ-39SI and EUROHISQOL8 domain scores between the two visits (V0 and V2) were significant. This test and/or the marginal homogeneity test were applied for other scales for analyzing the change from V0 to V2. Spearman’sorPearson’s correlation coefficient, as appropriate, were used for analyzing the relationship between continuous variables. Correlations were considered weak for coefficient values ≤0.29, moderate for values between 0.30 and 0.59, and strong for values ≥0.60. Clinically significant QoL impairment was expressed as a percentage and it was only calculated if the change between scores (PDQ-39SI; PQ-10; EUROHIS-QOL8) from V0 to V2 was significant. For determining predictive factors of QoL impairment, a logistic regression model (QoL impairment as dependent variable) was performed. The model was well-planned, as recommended by best-practice methods 74 , in which known and presumably predictor variables affecting QoL changes (dependent variable) were included: change from V0 to V2 in levodopa equivalent daily dose (LEDD) 75 , UPDRS-III-OFF (motor severity), UPDRS-IV (motor complications), FOGQ, NMSS (NMS burden), PD-CRS (cognition), BDI-II (mood), and NPI (neuropsychiatric symptoms). The model was adjusted to baseline QoL and age, gender, disease duration, comorbidity (total number of nonantiparkinsonian medications as surrogate marker 14 ), and the score of the rest of the variables at baseline (LEDD, UPDRS-III-OFF, UPDRS-IV, FOGQ, NMSS, PD-CRS, and NPI). Disability (ADLS) was not included in the model because this is consequence of symptoms, but since it is related to QoL, in a second model ADLS at baseline and change in ADLS from V0 to V2 were included. Hosmer–Lemeshow test was applied and adjusted R-squared was calculated for all analyses. Finally, multiple linear regressions were performed with “change in QoL”as dependent variable but only for variables (PDQ-39SI; PQ-10; EUROHIS-QOL8) changing significantly from V0 to V2. The independent variables included were the same as in the binary model. The p-value was considered significant when it was <0.05. Standard protocol approvals, registrations, and patient consents The Comité de Ética de la Investigación Clínica de Galicia from Spain (2014/ 534; 02/DEC/2014) approval was obtained. Written informed consents from all participants in this study were obtained before the start of the study. COPPADIS-2015 was classified by the AEMPS as a Post-authorization Prospective Follow-up study with the code COH-PAK-2014-01. Reporting summary Further information on research design is available in the Nature Research Reporting Summary linked to this article. DATA AVAILABILITY The data that support the findings of this study are available from the corresponding author upon reasonable request. CODE AVAILABILITY No computer coding was used in the completion of the current manuscript. Received: 25 March 2021; Accepted: 27 July 2021; Published online: 16 December 2021 REFERENCES 1. Chaudhuri, K. R. et al. The nondeclaration of nonmotor symptoms of Parkinson’s disease to health care professionals: an international study using the nonmotor symptoms questionnaire. Mov. Disord. 25, 704–709 (2010). 2. Hinnell, C. et al. Nonmotor versus motor symptoms: how much do they matter to health status in Parkinson’s disease? Mov. Disord. 27, 236–241 (2012). 3. Schrag, A., Jahanshahi, M. & Quinn, N. What contributes to quality of life in patients with Parkinson’s disease? J. Neurol. Neurosurg. Psychiatry 69, 308–312 (2000). 4. Kuopio, A. M., Marttila, R. J., Helenius, H., Toivonen, M. & Rinne, U. K. The quality of life in Parkinson’s disease. Mov. Disord. 15, 216–223 (2000). 5. Muslimovic, D., Post, B., Speelman, J. D., Schmand, B. & de Haan, R. J. Determinants of disability and quality of life in mild to moderate Parkinson disease. Neurology 70, 2241–2247 (2008). D.S. García et al. 7 Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2021) 118 6. Behari, M., Srivastava, A. K. & Pandey, R. M. Quality of life in patients with Parkinson’s disease. Parkinsonism Relat. Disord. 11, 221–226 (2005). 7. Karlsen, K. H., Larsen, J. P., Tandberg, E. & Maland, J. G. Quality of life measurements in patients with Parkinson’s disease: a communitybased study. Eur. J. Neurol. 5, 443–450 (1998). 8. Rahman, S., Griffin, H. J., Quinn, N. P. & Jahanshahi, M. Quality of life in Parkinson’s disease: the relative importance of the symptoms. Mov. Disord. 23, 1428–1434 (2008). 9. Slawek, J., Derejko, M. & Lass, P. Factors affecting the quality of life of patients with idiopathic Parkinson’s disease-a cross-sectional study in an outpatient clinic attendees. Parkinsonism Relat. Disord. 11, 465–468 (2005). 10. Chapuis, S., Ouchchane, L., Metz, O., Gerbaud, L. & Durif, F. Impact of the motor complications of Parkinson’s disease on the quality of life. Mov. Disord. 20, 224–230 (2005). 11. Karlsen, K. H., Larsen, J. P., Tandberg, E. & Maeland, J. G. Influence of clinical and demographic variables on quality of life in patients with Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 66, 431–435 (1999). 12. Martinez-Martin, P. et al. The impact of non-motor symptoms on health-related quality of life of patients with Parkinson’sdisease.Mov. Disord. 26,399–406 (2011). 13. Santos García, D. & de la Fuente-Fernández, R. Impact of non-motor symptoms on health-related and perceived quality of life in Parkinson’s disease. J. Neurol. Sci. 332, 136–140 (2013). 14. Santos García, D. et al. Non-motor symptoms burden, mood, and gait problems are the most significant factors contributing to a poor quality of life in nondemented Parkinson’s disease patients: results from the COPPADIS Study Cohort. Parkinsonism Relat. Disord. 66, 151–157 (2019). 15. Martinez-Martin, P. What is quality of life and how do we measure it? Relevance to Parkinson’s disease and movement disorders. Mov. Disord. 32, 382–392 (2017). 16. Martinez-Martin, P. & Kurtis, M. M. Health-related quality of life as an outcome variable in Parkinson’s disease. Ther. Adv. Neurol. Disord. 5, 105–117 (2012). 17. Soh, S. E., Morris, M. E. & McGinley, J. L. Determinants of health-related quality of life in Parkinson’s disease: a systematic review. Parkinsonism Relat. Disord. 17,1–9 (2011). 18. Karlsen, K. H., Tandberg, E., Arsland, D. & Larsen, J. P. Health related quality of life in Parkinson’s disease: a prospective longitudinal study. J. Neurol. Neurosurg. Psychiatry 69, 584–589 (2000). 19. Prakash, K. M., Nadkarni, N. V., Lye, W. K., Yong, M. H. & Tan, E. K. The impact of non-motor symptoms on the quality of life of Parkinson’s disease patients: a longitudinal study. Eur. J. Neurol. 23, 854–860 (2016). 20. Higginson, I. J. et al. Symptoms and quality of life in late stage Parkinson syndromes: a longitudinal community study of predictive factors. PLoS ONE 7, e46327 (2012). 21. Visser, M., Verbaan, D., van Rooden, S., Marinus, J., van Hilten, J. & Stiggelbout, A. A longitudinal evaluation of health-related quality of life of patients with Parkinson’s disease. Value Health 12, 392–396 (2009). 22. Reuther, M. et al. Assessing health-related quality of life in patients with Parkinson’s disease in a prospective longitudinal study. Parkinsonism Relat. Disord. 13, 108–114 (2007). 23. Abraham, D. S. et al. Sex differences in Parkinson’s disease presentation and progression. Parkinsonism Relat. Disord. 69,48–54 (2019). 24. Klietz, M. et al. Impaired quality of life and need for palliative care in a German Cohort of advanced Parkinson’s disease patients. Front. Neurol. 9, 120 (2018). 25. Fasano, A. et al. Characterizing advanced Parkinson’s disease: OBSERVE-PD observational study results of 2615 patients. BMC Neurol. 19, 50 (2019). 26. Valkovic, P., Harsany, J., Hanakova, M., Martinkova, J. & Benetin, J. Nonmotor symptoms in earlyand advanced-stage Parkinson’s disease patients on dopaminergic therapy: how do they correlate with quality of life? ISRN Neurol. 2014, 587302 (2014). 27. Velseboer, D. C. et al. Prognostic factors of motor impairment, disability, and quality of life in newly diagnosed PD. Neurology 80, 627–633 (2013). 28. Post, B. et al. Progression and prognostic factors of motor impairment, disability and quality of life in newly diagnosed Parkinson’s disease. Mov Disord. 26, 449–456 (2011). 29. Antonini, A. et al. The progression of non-motor symptoms in Parkinson’s disease and their contribution to motor disability and quality of life. J. Neurol. 259, 2621–2631 (2012). 30. Simuni, T. et al. Baseline prevalence and longitudinal evolution of non-motor symptoms in early Parkinson’s disease: the PPMI cohort. J. Neurol. Neurosurg. Psychiatry. 89,78–88 (2018). 31. Horváth, K. et al. Changes in quality of life in Parkinson’s disease: how large must they be to be relevant? Neuroepidemiology 48,1–8 (2017). 32. Ou, R. et al. Progression of non-motor symptoms in Parkinson’sdiseaseamong different age populations: a two-year follow-up study. J. Neurol. Sci. 360,72–77 (2016). 33. Ringash, J., O’Sullivan, B., Bezjak, A. & Redelmeier, D. A. Interpreting clinically significant changes in patient-reported outcomes. Cancer 110, 196–202 (2007). 34. Peto,V.,Jenkinson,C.&Fitzpatrick,R.Determining minimally important differences for the PDQ-39 Parkinson’s disease questionnaire. Age Ageing 30,299–302 (2001). 35. Brozek, J. L., Guyatt, G. H. & Schünemann, H. J. How a well-grounded minimal important difference can enhance transparency of labelling claims and improve interpretation of a patient reported outcome measure. Health Qual. Life Outcomes 27, 69 (2006). 36. Barrett, B., Brown, D., Mundt, M. & Brown, R. Sufficiently important difference: expanding the framework of clinical significance. Med. Decis. Making 25, 250–261 (2005). 37. Deng, X. et al. Four-year longitudinal study of motor and non-motor symptoms in LRRK2-related Parkinson’s disease. Front. Neurol. 10, 1379 (2020). 38. van Wamelen, D. J. et al. International Parkinson and Movement Disorder Society Parkinson’s Disease Non-Motor Study Group. The Non-Motor Symptoms Scale in Parkinson’s disease: validation and use. Acta Neurol. Scand. 143,3–12 (2021). 39. Martinez-Martin, P. et al. Gender-related differences in the burden of non-motor symptoms in Parkinson’s disease. J. Neurol. 259, 1639–1647 (2012). 40. Guo, X. et al. Disease duration-related differences in non-motor symptoms: a study of 616 Chinese Parkinson’s disease patients. J. Neurol. Sci. 330,32–37 (2013). 41. Song, W. et al. The impact of non-motor symptoms on the health-related quality of life of Parkinson’s disease patients from Southwest China. Parkinsonism Relat. Disord. 20, 149–152 (2014). 42. Wu, Y. et al. Determinants of the quality of life in Parkinson’s disease: results of a cohort study from Southwest China. J. Neurol. Sci. 340, 144–149 (2014). 43. Ray Chaudhuri, K. et al. Burden of non-motor symptoms in Parkinson’s disease patients predicts improvement in quality of life during treatment with levodopacarbidopa intestinal gel. Eur. J. Neurol. 26, 581–e43 (2019). 44. Erro, R. et al. The non-motor side of the honeymoon period of Parkinson’s disease and its relationship with quality of life: a 4-year longitudinal study. Eur. J. Neurol. 23, 1673–1679 (2016). 45. Santos-García, D. et al. Sleep problems are related to a worse quality of life and a greater non-motor symptoms burden in Parkinson’s disease. Int. J. Geriatr. Psychiatry 34, 642–658 (2021). 46. Rafferty, M. R. et al. Regular exercise, quality of life, and mobility in Parkinson’s disease: a longitudinal analysis of National Parkinson Foundation quality improvement initiative data. J. Parkinsons. Dis. 7, 193–202 (2017). 47. Santos García, D. et al. Safinamide improves non-motor symptoms burden in Parkinson’s disease: an open-label prospective study. Brain Sci. 11, 316 (2021). 48. Shulman, L. M. Gender differences in Parkinson’s disease. Gend. Med. 4,8–18 (2007). 49. Crispino, P. et al. Gender differences and quality of life in Parkinson’s disease. Int. J. Environ. Res. Public. Health 18, 198 (2020). 50. Yoon, J. E. et al. Gender differences of nonmotor symptoms affecting quality of life in Parkinson disease. Neurodegener. Dis. 17, 276–280 (2017). 51. Schrag, A., Hovris, A., Morley, A., Quinn, A. & Jahanshahi, M. Youngversus olderonset Parkinson’s disease: impact of disease and psychosocial consequences. Mov. Disord. 18, 1250–1256 (2003). 52. Mehanna, R. & Jankovic, J. Young-onset Parkinson’s disease: Its unique features and their impact on quality of life. Parkinsonism Relat. Disord. 65,39–48 (2019). 53. Shahgholi, L. et al. Hospitalization and rehospitalization in Parkinson disease patients: data from the National Parkinson Foundation Centers of Excellence. PLoS ONE 12, e0180425 (2017). 54. Santos García, D. et al. Staging Parkinsonas disease combining motor and nonmotor symptoms correlates with disability and quality of life. Parkinsons Dis. 2021, 8871549 (2021). 55. Santos-García, D. et al. COPPADIS Study Group. COPPADIS-2015 (COhort of Patients with PArkinson’s DIsease in Spain, 2015), a global-clinical evaluations, serum biomarkers, genetic studies and neuroimaging-prospective, multicenter, non-interventional, long-term study on Parkinson’s disease progression. BMC Neurol. 16, 26 (2016). 56. Santos García, D. et al. COPPADIS Study Group. COPPADIS-2015 (COhort of Patients with PArkinson’s DIsease in Spain, 2015): an ongoing global Parkinson’s disease project about disease progression with more than 1000 subjects included. Results from the baseline evaluation. Eur. J. Neurol. 26, 1399–1407 (2019). 57. Daniel, S. E. & Lees, A. J. Parkinson’s Disease Society Brain Bank, London: overview and research. J. Neural. Transm. Suppl. 39, 165–172 (1993). 58. Hoehn, M. M. & Yahr, M. D. Parkinsonism: onset, progression and mortality. Neurology 17, 427–442 (1967). 59. Fanhn, S., Elton, R. L. & Members of the UPDRS Development Committee. in Recent Developments in Parkinson’s Disease (eds. Fahn, S., Marsden, C. D., Calne, D. B. & Goldstein M.) Vol. 2, 153–164 (Macmillan Health Care Information, Florham Park, NJ, 1987). 60. Giladi, N., Shabtai, H., Simon, E. S., Biran, S., Tal, J. & Korczyn, A. D. Construction of freezing of gait questionnaire for patients with Parkinsonism. Parkinsonism Relat. Disord. 6, 165–170 (2000). D.S. García et al. 8 npj Parkinson’s Disease (2021) 118 Published in partnership with the Parkinson’s Foundation 61. Chaudhuri, K. R. et al. The metric properties of a novel non-motor symptoms scale for Parkinson’s disease: Results from an international pilot study. Mov. Disord. 22, 1901–1911 (2007). 62. Chaudhuri, K. R. et al. The Parkinson’s disease sleep scale: a new instrument for assessing sleep and nocturnal disability in Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 73, 629–635 (2002). 63. Burckhardt, C. S. & Jones, K. D. Adult measures of pain: The McGill Pain Questionnaire (MPQ), Rheumatoid Arthritis Pain Scale (RAPS), Short Form McGill Pain Questionnaire (SF-MPQ), Verbal Descriptive Scale (VDS), Visual Analog Scale (VAS), and West Haven-Yale Multidisciplinary Pain Inventory (WHYMPI). Arthritis. Rheum. 49,96–104 (2003). 64. Tseng, B. Y., Gajewski, B. J. & Kluding, P. M. Reliability, responsiveness, and validity of the visual analog fatigue scale to measure exertion fatigue in people with chronic stroke: a preliminary study. Stroke. Res. Treat. 2010, 412964 (2010). 65. Folstein, M. F., Folstein, S. E. & McHugh, P. R. Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J. Psychiatr. Res. 12, 189–198 (1975). 66. Pagonabarraga, J., Kulisevsky, J., Llebaria, G., García-Sánchez, C., Pascual-Sedano, B. & Gironell, A. Parkinson’s disease-cognitive rating scale: a new cognitive scale specific for Parkinson’s disease. Mov. Disord. 23, 998–1005 (2008). 67. Beck, A. T., Steer, R. A. & Brown, G. K. Beck Depression Inventory 2nd ed (The Psychological Corporation, San Antonio, 1996). 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). 69. Weintraub, D. et al. Validation of the questionnaire for impulsive-compulsive disorders in Parkinson’s disease. Mov. Disord. 24, 1461–1467 (2009). 70. Schwab, R. S. & England, A. C. In Third Symposium on Parkinson’s Disease 152–157 (E. And S. Livingstone, Edinburgh, 1969). 71. Jenkinson, C., Fitzpatrick, R., Peto, V., Greenhall, R. & Hyman, N. The Parkinson’s Disease Questionnaire (PDQ-39): development and validation of a Parkinson’s disease summary index score. Age Ageing 26, 353–357 (1997). 72. Da Rocha, N. S., Power, M. J., Bushnell, D. M. & Fleck, M. P. The EUROHIS-QOL 8-item index: comparative psychometric properties to its parent WHOQOL-BREF. Value Health 15, 449–457 (2012). 73. Santos-García, D. et al. COPPADIS Study Group. Non-motor symptom burden is strongly correlated to motor complications in patients with Parkinson’s disease. Eur. J. Neurol. 27, 1210–1223 (2020). 74. Cohen, J. & Cohen, P. Applied Multiple Regression/Correlation Analysis for the Behavioral Sciences 2nd ed (Lawrence Erlbaum, Hillsdale, New Jersey, 1983). 75. Schade, S., Mollenhauer, B. & Trenkwalder, C. Levodopa equivalent dose conversion factors: an updated proposal including opicapone and safinamide. Mov. Disord. Clin. Pract. 2020, 343–345 (2020). ACKNOWLEDGEMENTS We would like to thank all patients and their caregivers who collaborated in this study. Many thanks also to Fundación Española de Ayuda a la Investigación en Parkinson y otras Enfermedades Neurodegenerativas (Curemos el Parkinson; www. curemoselparkinson.org), Alpha Bioresearch (www.alphabioresearch.com), and other institutions helping us. AUTHOR CONTRIBUTIONS S.G.D.: conception, organization, and execution of the project; statistical analysis; writing of the first draft of the manuscript; recruitment and/or evaluation of participants. D.D.T.: review and critique; recruitment and/or evaluation of participants. C.C.: review and critique. M.G.: review and critique. P.G.J.M.: review and critique. M.M. C.: review and critique. S.E.: review and critique; recruitment and/or evaluation of participants. J.S.: review and critique; recruitment and/or evaluation of participants. A.M.: review and critique; recruitment and/or evaluation of participants. P.P.: review and critique; recruitment and/or evaluation of participants. P.L.L.: review and critique; recruitment and/or evaluation of participants. C.M.: review and critique; recruitment and/or evaluation of participants. G.C.J.: review and critique; recruitment and/or evaluation of participants. C.N.: review and critique; recruitment and/or evaluation of participants. L.I.: review and critique; recruitment and/or evaluation of participants. H.V.J.: review and critique; recruitment and/or evaluation of participants. C.I.: review and critique; recruitment and/or evaluation of participants. L.M.L.: review and critique; recruitment and/or evaluation of participants. G.A.I.: review and critique; recruitment and/or evaluation of participants. Á.R.M.A.: review and critique; recruitment and/or evaluation of participants. C.M.J.: review and critique; recruitment and/or evaluation of participants. N.V.: review and critique; recruitment and/or evaluation of participants. P.V.: review and critique; recruitment and/or evaluation of participants. R.d.A.M.: review and critique; recruitment and/or evaluation of participants. B.C.: review and critique; recruitment and/or evaluation of participants. S.V.B.: review and critique; recruitment and/or evaluation of participants. Á.S.M.: review and critique; recruitment and/or evaluation of participants. V.L.: review and critique; recruitment and/or evaluation of participants. E.S.: review and critique; recruitment and/or evaluation of participants. C.E.: review and critique; recruitment and/or evaluation of participants. C.P.F.: review and critique; recruitment and/or evaluation of participants. M.C.J.C.: review and critique; recruitment and/or evaluation of participants. S.A.P.: review and critique; recruitment and/or evaluation of participants. A.L.M.G.: review and critique; recruitment and/or evaluation of participants. L.A.N.: review and critique; recruitment and/or evaluation of participants. G.I.: review and critique; recruitment and/or evaluation of participants. C.P.: review and critique; recruitment and/or evaluation of participants. K.J.: review and critique; recruitment and/or evaluation of participants. B.E.M.: review and critique; recruitment and/or evaluation of participants. S.M.: review and critique; recruitment and/or evaluation of participants. R.M.J.: review and critique; recruitment and/or evaluation of participants. V.C.: review and critique; recruitment and/or evaluation of participants. K.M.: review and critique; recruitment and/or evaluation of participants. d.F.O.: review and critique; recruitment and/or evaluation of participants. G.A.J.: review and critique; recruitment and/or evaluation of participants. O.C.: review and critique; recruitment and/or evaluation of participants. L.D.L.: review and critique; recruitment and/or evaluation of participants. MD: review and critique; review of english style. M.-M.P.: review and critique; supervision. M.P.: review and critique; recruitment and/or evaluation of participants. COMPETING INTERESTS Santos García D. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, Italfarmaco, and Teva. De Deus Fonticoba T: None. Cores C. has received honoraria for educational presentations and advice service by Lundbeck and UCB Pharma. Muñoz G: None. Paz González JM. has received honoraria for educational presentations and/or advice service by UCB Pharma, Lundbeck,KRKA,andZambon.MartínezMiróC:None.SuárezE:None.JesúsS.has received honoraria from AbbVie, Bial, Merz, UCB, and Zambon and holds the competitive contract “Juan Rodés”supported by the Instituto de Salud Carlos III. She has received grants from the Spanish Ministry of Economy and Competitiveness (PI18/01898) and the Consejería de Salud de la Junta de Andalucía (PI-0459-2018). Aguilar M: UCB and Schwabe with assistance to a Congress; Nutricia with assistance to a Congress and payment of lecture. Pastor P: None. Planellas LL. has received travel bursaries grant from Abbvie. Cosgaya M: None. García Caldentey J. has received honoraria for educational presentations and advice service by Qualigen, Nutricia, Abbvie, Italfarmaco, UCB Pharma, Lundbeck, Zambon, Bial, and Teva. Caballol N. has received honoraria from Bial, Italfármaco, Qualigen, Zambon, UCB, Teva and KRKA and sponsorship from Zambon, TEVA and Abbvie for attending medical conferences. Legarda I. has received honoraria for 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, Zambon, Italfarmaco, and Sanofi-Genzyme. Cabo I. has received honoraria for educational presentations and advice service by Abbvie, Zambon and Bial. López Manzanares L: Compensated advisory services, consulting, research grant support, or speaker honoraria: AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. González Aramburu I: None. Ávila Rivera MA. has received honoraria from Zambon, UCB 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. Borrué C: None. Solano Vila B. has received honoraria for educational presentations and advice service by UCB, Zambon, Teva, Abbvie, Bial. Álvarez Sauco M. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Zambon, Bial, and Teva. Vela L. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Escalante S. has received honoraria for educational presentations and advice service by Abbvie, Zambon, and Bial. Cubo E: Travel grants: Abbvie, Allergan,Boston;Lecturing honoraria: Abbvie, International Parkinson´s disease Movement Disorder Society. Carrillo Padilla F. has received honoraria from Zambon (SEN Congress assistance). Martínez Castrillo JC. has received research support from Lundbeck, Italfarmaco, Allergan, Zambon, Merz, and Abbvie. He has received speaking honoraria from AbbVie, Bial, Italfarmaco, Lundbeck,Krka,TEVA,UCB,Zambon,Allergan,Ipsen,andMerz.SánchezAlonsoP.has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Alonso Losada MG. has received honoraria for educational presentations and advice service by Zambon and Bial. López Ariztegui N. has received honoraria for educational presentations and advice service by Abbvie, Italfarmaco, Zambon, and Bial. Gastón I. has received research support from Abbvie and Zambon and has served as a consultant for Abbvie, Exelts, and Zambon. Clavero P: Kulisevsky J: (1) Consulting fees: Roche, Zambon; (2) Stock / allotment: No; (3) Patent royalties / licensing fees: No; (4) Honoraria (e.g., lecture fees): Zambon, Teva, Bial, UCB; (5) Fees for promotional materials: No; (6) Research funding: Roche, Zambon, Ciberned; Instituto de SaludCarlos III; FundacióLa Maratóde TV3; (7) Scholarship from D.S. García et al. 9 Published in partnership with the Parkinson’s Foundation npj Parkinson’s Disease (2021) 118