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

Research Article Prevalence and Factors Associated with Drooling in Parkinson’s Disease: Results from a Longitudinal Prospective Cohort and Comparison with a Control Group Diego Santos-Garc´ ıa , 1 Teresa de Deus Fonticoba, 2 Carlos Cores Bartolom´ e, 1 Maria J. Feal Painceiras, 1 Maria Cristina ´ Iñiguez-Alvarado, 1 Silvia Jes´ us, 3 , 4 Maria Teresa Buongiorno, 5 Llu´ ıs Planellas, 6 Marina Cosgaya, 7 Juan Garc´ ıa Caldentey, 8 Nuria Caballol, 9 Ines Legarda, 10 Jorge Hern´ andez Vara, 11, 4 Iria Cabo, 12 Lydia L´ opez Manzanares, 13 Isabel Gonz´ alez Aramburu, 14, 4 Maria A. ´ Avila Rivera, 15 V´ ıctor G´ omez Mayordomo, 16 V´ ıctor Nogueira, 17 V´ ıctor Puente, 18 Julio Dotor Garc´ ıa-Soto, 19 Carmen Borru´ e, 20 Berta Solano Vila, 21 Mar´ ıa´ Alvarez Sauco, 22 Lydia Vela, 23 Sonia Escalante, 24 Esther Cubo, 25 Francisco Carrillo Padilla, 26 Juan C. Mart´ ınez Castrillo , 27 Pilar S´ anchez Alonso, 28 Maria G. Alonso Losada, 29 NuriaL´ opezAriztegui , 30 ItziarGast´ on, 31 JaimeKulisevsky, 32, 4 MartaBl´ azquezEstrada, 33 Manuel Seijo, 12 Javier R´ uiz Mart´ ınez, 34 Caridad Valero, 35 M´ onica Kurtis, 36 Oriol de F´ abregues , 11 Jessica Gonz´ alez Ardura, 37 Ruben Alonso Redondo, 38 Carlos Ord´ as, 39 Luis M. L. L´ opez D´ ıaz, 40 Darrian McAfee, 41 Pablo Martinez-Martin , 4 Pablo Mir , 3 , 4 and Study Group COPPADIS 42 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 Neurolog´ ıa y Neurofsiolog´ ıa Cl´ ınica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Roc´ ıo, CSIC, Universidad de Sevilla, Seville, Spain 4 CIBERNED (Centro de Investigaci´ on Biom´ edica en Red Enfermedades Neurodegenerativas), Madrid, Spain 5 Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain 6 Cl´ınica del Pilar, Barcelona, Spain 7 Hospital Cl´ ınic de Barcelona, Barcelona, Spain 8 Centro Neurol´ ogico Oms 42, Palma de Mallorca, Spain 9 Consorci Sanitari Integral, Hospital Mois´es Broggi, Sant Joan Desp´ı, 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 Marqu´ es de Valdecilla, Santander, Spain 15 Consorci Sanitari Integral, Hospital General de L´Hospitalet, L´Hospitalet de Llobregat, Barcelona, Spain 16 Hospital Universitario Cl´ınico 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 Sof´ ıa, Madrid, Spain 21 Institut d’Assist` encia Sanit` aria (IAS), Institut Catal` ade La Salut, Girona, Spain 22 Hospital General Universitario de Elche, Elche, Spain 23 Fundaci´ on Hospital de Alcorc´ on, Madrid, Spain 24 Hospital de Tortosa Verge de La Cinta (HTVC), Tortosa, Tarragona, Spain 25 Complejo Asistencial Universitario de Burgos, Burgos, Spain Hindawi Parkinson’s Disease Volume 2023, Article ID 3104425, 18 pages https://doi.org/10.1155/2023/3104425 26 Hospital Universitario de Canarias, San Crist´ obal de La Laguna, Santa Cruz de Tenerife, Spain 27 Hospital Universitario Ram´ on y Cajal, IRYCIS, Madrid, Spain 28 Hospital Universitario Puerta de Hierro, Madrid, Spain 29 Hospital ´ Alvaro 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 Sebasti´ an, Spain 35 Hospital Arnau de Vilanova, Valencia, Spain 36 Hospital Ruber Internacional, Madrid, Spain 37 Hospital de Cabueñes, Gij´ on, Spain 38 Universitario Lucus Augusti (HULA), Lugo, Spain 39 Hospital Rey Juan Carlos, Madrid, Spain 40 Complejo Hospitalario Universitario de Orense (CHUO), Orense, Spain 41 University of Maryland School of Medicine, Baltimore, MD, USA 42 Fundaci´on Degen, C/Juana de Vega 23 2°, A Coruña 15004, Spain Correspondence should be addressed to Diego Santos-Garc´ ıa; [email protected] Received 2 November 2022; Revised 8 December 2022; Accepted 20 December 2022; Published 6 April 2023 Academic Editor: Carlo Colosimo Copyright ©2023 Diego Santos-Garc´ ıa et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction. Drooling in Parkinson’s disease (PD) is frequent but often goes underrecognized. Our aim was to examine the prevalence of drooling in a PD cohort and compare it with a control group. Specifcally, we identifed factors associated with drooling and conducted subanalyses in a subgroup of very early PD patients. Patients and Methods. PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ±30-day follow-up (V2) from 35 centers in Spain from the COPPADIS cohort were included in this longitudinal prospective study. Subjects were classifed as with or without drooling according to item 19 of the NMSS (Nonmotor Symptoms Scale) at V0, V1 (1-year ±15 days), and V2 for patients and at V0 and V2 for controls. Results. Te frequency of drooling in PD patients was 40.1% (277/691) at V0 (2.4% (5/201) in controls; p<0.0001), 43.7% (264/604) at V1, and 48.2% (242/502) at V2 (3.2% (4/124) in controls; p<0.0001), with a period prevalence of 63.6% (306/481). Being older (OR �1.032; p�0.012), being male (OR �2.333; p<0.0001), having greater nonmotor symptom (NMS) burden at the baseline (NMSS total score at V0; OR �1.020; p<0.0001), and having a greater increase in the NMS burden from V0 to V2 (change in the NMSS total score from V0 to V2; OR �1.012; p<0.0001) were identifed as independent predictors of drooling after the 2-year follow-up. Similar results were observed in the group of patients with ≤2 years since symptom onset, with a cumulative prevalence of 64.6% and a higher score on the UPDRS-III at V0 (OR �1.121; p�0.007) as a predictor of drooling at V2. Conclusion. Drooling is frequent in PD patients even at the initial onset of the disease and is associated with a greater motor severity and NMS burden. 1. Introduction Sialorrhea, commonly referred to as drooling, is defned as excessive saliva beyond the margin of the lip. Drooling can be a complication of Parkinson’s disease (PD) and is one of the most prevalent complaints of patients, but it is often underrecognized and undertreated [1]. A wide prevalence range has been reported in the literature, ranging from 10 to 84%, with no signifcant variation across ethnic groups [2–15]. However, when studies compared PD patients with controls, drooling only occurred in 6–15% of people without PD [5, 6, 15, 16]. Te broad range in PD patients is likely due to the lack of a standard defnition of and diagnostic criteria for sialorrhea and the diferences in the PD population studied and the methods used. Despite these obstacles, drooling has still been found to negatively impact the quality of life (QoL) of both patients and caregivers [5, 12, 13, 17–19]. Sialorrhea may bring repercussions for the psychosocial health of the person who drools and added burden for the caregiver as well (e.g., odor, stained clothes, constant wiping, restricted social life, etc.) [1]. Moreover, drooling is associated with an increased risk of dry mouth, impact on bolus formation, loss of antibacterial efects of saliva, perioral dermatological changes, ulceration, tooth decay, gingivitis, dehydration, candidiasis, halitosis, and increased speech difculties [20–22]. Drooling in PD patients appears to be primarily related to reduced swallowing efciency and not to an increase in saliva production [20, 23], as dysphagia is the strongest factor associated with drooling [7, 12, 23]. Other reported factors associated with drooling are orofacial rigidity/hypomimia, lingual bradykinesia, aging, male gender, cognitive impairment, 2Parkinson’s Disease hallucinations, nontremor dominant PD phenotype, longer disease duration, and more advanced disease stage [3–8, 11–14, 23–26]. Although many studies have analyzed the frequency of drooling in PD, there is less information about its prevalence and associated factors in early PD patients and how it impacts QoL and change over time. Some studies have reported a prevalence of about 20% in de novo and untreated PD patients and that prevalence increases in the long term [27, 28]. Our hypothesis was that the prevalence of drooling in early PD patients would be high and would negatively impact QoL. Te aim of the current study was to examine the prevalence of drooling, and its progression, in a PD cohort and assess its impact on QoL. Furthermore, we compared the frequency of drooling in PD patients with a control group and analyzed all these aspects in a subgroup of patients from the cohort with a short disease duration of ≤2 years since the onset of the symptoms. Moreover, we identifed in both groups, the entire cohort and the subgroup with early PD, factors associated with not only drooling but also drooling severity as well. 2. Materials and Methods PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ±30-day follow-up (V2) from 35 centers in Spain from the COPPADIS cohort [29] were included in this study. Te methodology of the COPPADIS-2015 study can be consulted in https://bmcneurol.biomedcentral.com/ articles/10.1186/s12883-016-0548-9 [30]. Tis is a multicenter, observational, longitudinal prospective, and 5-year follow-up study designed to analyze disease progression in a Spanish population of PD patients. All patients included were diagnosed according to the UK PD Brain Bank criteria [31]. Information on sociodemographic aspects, factors related to PD, comorbidity, and treatment were collected. Motor status, nonmotor symptoms (NMS), QoL, and disability were assessed at V0 and at V2 using diferent validated scales: Hoehn and Yahr (H&Y), UPDRS-III and UPDRS-IV, Freezing of Gait Questionnaire (FOGQ)), Parkinson’s Disease Cognitive Rating Scale (PD-CRS), Nonmotor Symptoms Scale (NMSS), Beck Depression Inventory-II (BDI-II), Parkinson’s disease sleep scale (PDSS), Neuropsychiatric Inventory (NPI), Questionnaire for impulsive-compulsive disorders in Parkinson’s DiseaseRating Scale (QUIP-RS), visual analog scale-pain (VASPain), Visual Analog Fatigue Scale (VAFS)), the 39-item Parkinson’s Disease Questionnaire (PDQ-39), the EUROHIS-QOL 8-item index (EUROHIS-QOL8), and ADLS (Schwab and England Activities of Daily Living Scale) [30]. In patients with motor fuctuations, the motor assessment was made during the OFF state (without medication in the last 12 hours) and during the ON state. Te assessment was only performed without medication in patients without motor fuctuations. Te same evaluation as for the patients, except for the motor assessment, was performed in control subjects at V0 and at V2 (2 years ±1 month). Furthermore, motor (H&Y, UPDRS-III, and UPDRS-IV) and nonmotor assessment (NMSS and ADLS) was conducted in PD patients at 1 year ±1 month (V1) [30]. LEED was calculated based on the literature [32]. Subjects were classifed as with or without drooling according to item 19 of the NMSS [33]. Tis item is one of the 30 items on this scale and is included in domain 6 (gastrointestinal tract). Tis question asks about drooling: “Does the patient dribble saliva during the day?.” Te score range is from 0 (without the symptom) to 12 (the most frequent and severe). Subjects with an NMSS-item 19 score �0 were considered “without drooling,” whereas subjects with an NMSS-item 19 score ≥1 (from 1 to 12) were considered “with drooling.” Drooling was identifed at V0, V1, and V2 in patients and at V0 and V2 in controls. Te drooling burden was also calculated for PD patients. Te score at V0, V1, and V2 and the sum of the score from the three visits (NMSS-Drooling V0+V1+V2 , from 0 to 36) were calculated. Patients reporting drooling during the three visits were defned as patients with “persistent drooling.” Te same method was used to defne dysphagia (item 20 of the NMSS) [34] and hypomimia (item 19 of the UPDRS-III during the OFF state) [35]. 2.1.StatisticalAnalysis. Data were processed using SPSS 20.0 for Windows. For comparisons between PD patients in the control group and PD patients with and without drooling, the Student’s t-test, Mann–Whitney Utest, chi-square test, or Fisher test were used as appropriate (distribution for variables was verifed by one-sample Kolmogorov–Smirnov test). Binary and linear regression models were used for determining independent factors associated with drooling (drooling as the dependent variable) and drooling severity (NMSS-Drooling V0+V1+V2 score as the dependent variable), respectively. Variables with univariate associations with p values <0.20 were included in a multivariable model, and a backward selection process was used to remove variables individually until all remaining variables were signifcant at the 0.10 level. For exploring the association between drooling and QoL, linear regression models were used with PDQ-39SI (health-related QoL) and EUROHIS-QOL8 (global QoL) as dependent variables. Te total domain scores of the PDQ-39 were expressed as a percentage of the corresponding maximum possible score, and a summary index was obtained as an average of the domain scores (PDQ39SI). Te efect was controlled by age, gender, disease duration, LEDD, comorbidities (total number of non-antiParkinsonian drugs [36]), motor (H&Y, UPDRS-III, UPDRS-IV, and FOGQ) and nonmotor (NMSS) status, cognitive function (PC-CRS total score), dysphagia, hypomimia, and autonomy for ADL (ADLS), which were included as covariates in the model [36]. For PD patients, analyses were conducted in the entire cohort and in the subgroup of patients with ≤2 years of disease duration since symptoms’ onset (PD ≤2 y) at the baseline. Te pvalue was considered signifcant for all analyses when it was <0.05. Parkinson’s Disease 3 2.2. Standard Protocol Approvals, Registrations, and Patient Consents. For this study, we received approval from the Comit´ e de ´ Etica de la Investigaci´ on Cl´ ınica de Galicia in Spain (2014/534; 02/DEC/2014). Written informed consents from all participants in this study were obtained. COPPADIS-2015 was classifed by the AEMPS (Agencia Española del Medicamento y Productos Sanitarios) as a postauthorization prospective follow-up study with the code COH-PAK-2014-01. 3. Results At the baseline, 691 PD patients (62.59 ±8.92 years old; 60.2% males; mean disease duration 5.5 ±4.37 years) and 206 patients in the control group (60.98 ±8.34 years old; 50% males) were considered valid for the analysis. Te frequency of drooling in PD patients was 40.1% (277/691) at V0; 43.7% (264/604) at V1; 48.2% (242/502) at V2 (Figure 1(a)). At V0 and V2, drooling was signifcantly less frequent (p<0.0001) in the control group than in PD patients (2.4% at V0 and 3.2% at V2 in controls). In the patients (N�481; 62.62 ±8.54 years old, from 35 to 75; 59.2% males) with assessments carried out during all visits (V0, V1, and V2), 63.6% (306/481) of them reported drooling at least once during the study (period prevalence). Specifcally, 18.9% (91/ 481) in only one visit, 19.1% (92/481) in two out of the three visits, and 25.6% (123/481) in all three visits (i.e., persistent drooling) (Figure 1(b)). In the PD ≤2 y group (62.22 ±8.33 years old; 57.3% males; mean disease duration 1.29 ±0.37 years), the frequency of drooling was 34.8% (64/ 184) at V0, 37.5% at V1 (60/160), and 50.4% (66/131) at V2. After the 2-year follow-up, the cumulative prevalence of drooling in this group was 64.6% (21.3% in 1 visit, 23.6% in 2 visits, and 19.7% in all visits) (Figure 1(b)). Regarding drooling burden in PD patients, as expected, the NMSS-Drooling V0+V1+V2 score was higher in patients with persistent drooling (p<0.0001): drooling in one visit, 1.95 ±1.67 (N�91); drooling in two out of the three visits, 4.22 ±2.95 (N�92); persistent drooling, 10.36 ±6.12 (N�123). Drooling was more frequent in patients with dysphagia than in those without dysphagia: 60% (96/160) vs. 34.1% (181/531) (p<0.0001) at V0; 57.9% (99/171) vs. 38.1% (165/433) (p<0.0001) at V1; 55.9% (76/136) vs. 45.4% (60/ 166/366) (p�0.023) at V2 (Figure 2(a)). Drooling burden (NMSS-item 19 total score) correlated with dysphagia burden (NMSS-item 20 total score) at V0 (N�691; r�0.322; p<0.0001), at V1 (N�604; r�0.344; p<0.0001), at V2 (N�502; r�0.198; p<0.0001), and after considering all visits together (N�481; r�0.292; p<0.0001). Drooling was also more frequent in patients with hypomimia than in those without hypomimia at V0 (43% vs. 31%; p�0.011), at V1 (48.4% vs. 30.9%; p�0.001), and at V2 (51.9% vs. 33.8%; p �0.002) (Figure 2(a)). A signifcant correlation was observed between drooling burden and hypomimia burden at V0 (r�0.197; p<0.0001), at V1 (r�0.149; p<0.0001), at V2 (r�0.189; p<0.0001), and after considering all visits (r�0.213; p<0.0001). Similar results were observed in the PD ≤2 y group, with signifcant correlations between drooling burden and dysphagia burden (r�565; p<0.0001) and between drooling burden and hypomimia burden (r�0.360; p<0.00001) after considering the sum of the burden of all visits during the follow-up. Drooling was more frequent in patients with dysphagia at V0 and at V1 and with hypomimia at V2 than in those patients with these symptoms in the PD ≤2 y group (Figure 2(b)). Regarding the treatment, none of the patients were receiving botulinum toxin at any of the 3 visits (V0, V1, and V2). At the baseline, drooling was associated with gender (males, 69% vs. 54.3%; p<0.0001), older age (63.79 ±8.21 vs. 61.8 ±9.29; p�0.008), and a higher LEDD (646.01 ±410.21 vs. 512.73 ±409.22; p<0.0001) (Table 1). Patients with drooling were worse in terms of motor (UPDRS-III; UPDRS-IV; FOGQ) and nonmotor (PD-CRS; NMSS; BDIII; NPI; PDSS; VAS-PAIN; VASF-physical; VASF-mental) status, QoL (PDQ-39SI; EUROHIS-QOL8; Figure 3), and autonomy for activities of daily living (ADLS) when compared to those without drooling (Table 1). In the PD ≤2 y group, drooling was associated with gait problems (FOGQ), a greater motor severity (UPDRS-III) and NMS burden (NMSS) including mood and other neuropsychiatric symptoms (BDI-II; NPI), pain (VAS-PAIN) and mental fatigue (VASF-mental), and a worse QoL (PDQ-39SI; EUROHIS-QOL8) (Table 1). Compared to patients without drooling, the frequency of major depression, freezing of gait, and falls in the subgroup of PD ≤2 y patients with drooling was roughly double (Table 1). To be older (OR �1.025; 95% CI, 1.004–1.046; p�0.019), to be male (OR �2.165; 95% CI, 1.486–3.153; p<0.0001), to have a higher score on the UPDRS-III (OR �1.018; 95% CI, 1.001–1.037; p�0.047) and the NMSS (OR �1.011; 95% CI, 1.005–1.016; p<0.0001), and to have dysphagia (OR �2.274; 95% CI, 1.476–3.505; p<0.0001) were independent factors associated with drooling at the baseline (Table 2). In the PD ≤2 y group, a higher NMSS total score was the only independent factor associated with drooling at the baseline (OR �1.017; 95% CI, 1.005–1.029; p�0.001). Like as seen with baseline predictions, being older (OR �1.032; 95% CI, 1.007–1.057; p�0.012), being male (OR �2.333; 95% CI, 1.540–3.536; p<0.0001), having a greater NMS burden at the baseline (NMSS total score at V0; OR �1.020; 95% CI, 1.011–1.030; p<0.0001), and having a greater increase in the NMS burden from V0 to V2 (change in the NMSS total score from V0 to V2; OR �1.012; 95% CI, 1.006–1.019; p<0.0001) were identifed as independent predictors of drooling after the 2-year follow-up (Table 3). When NMS burden at the baseline was considered as a categorical variable in the model, to have a very severe NMS burden at V0 (NMSS total score >70) increased the probability of drooling at V2 more than double (OR �2.696; 95% CI, 4.248–10.729; p<0.0001). Moreover, to have drooling at the baseline multiplied by 6 (OR �6.751; 95% CI, 1.011–1.030; p<0.0001), the probability of drooling at V2 after adjustment must be receiving anticholinergic drugs and the other covariates of the model. In the PD ≤2 y group, a higher UPDRS-III score at V0 was the only predictor of drooling at V2 identifed (OR �1.093; 95% CI, 1.025–1.166; p�0.007) (Table 3). Specifcally, to have at V0 a score on the UPDRS-III higher than 20 points increased the probability of drooling at V2 by 3-fold 4Parkinson’s Disease 0 100 200 300 400 500 600 With dysphagia Without dysphagia With hypomimia Without hypomimia With dysphagia Without dysphagia With hypomimia Without hypomimia With dysphagia Without dysphagia With hypomimia Without hypomimia With drooling Without drooling 48.4% 30.9% p=0.001 308 V0 V1 V2 96 64 60% 34.1% p<0.0001 181 350 43% 31% p=0.011 57.9% 38.1% p<0.0001 55.9% 45.4% p=0.023 51.9% 33.8% p=0.002 232 78 35 99 165 72 268 243 65 228 29 76 166 203 27 60 200 188 53 (a) 0 20 40 60 80 100 120 140 160 With dysphagia Without dysphagia With hypomimia Without hypomimia With dysphagia Without dysphagia With hypomimia Without hypomimia With dysphagia Without dysphagia With hypomimia Without hypomimia With drooling Without drooling 20 55.6% 29.7% p=0.004 16 44 51 12 104 85 29 37.5% 29.3% p=0.219 54.3% 30.7% p=0.005 42.9% 31.1% p=0.121 45 14 60 31 21 79 25 35 55.6% 48.4% p=0.297 55.3% 30% p=0.013 20 46 52 9 16 49 42 21 (b) Figure 2: (a) Number of patients reporting drooling at V0, V1, and V2 when they were divided in patients with vs. without dysphagia and with vs. without hypomimia (the whole cohort). A comparison between the percentage is shown for each analysis. (b) Number of patients from the PD ≤2 y group reporting drooling at V0, V1, and V2 when they were divided in patients with vs. without dysphagia and with vs. without hypomimia. A comparison between the percentage is shown for each analysis. PD: Parkinson’s disease. PD ≤2 y group: patients with ≤2 years since symptom onset. 0 100 200 300 400 500 600 700 PD cohort PD≤2y Controls PD cohort PD≤2y PD cohort PD≤2y Controls With drooling Without drooling 40.1% 277/691 34.8% 64/184 2.4% 5/201 48.2% 242/502 50.4% 66/131 3.2% 4/124 43.7% 264/604 37.5% 60/160 (a) 1 visit 2 visits 3 visits None 1 visit 2 visits 3 visits None PD cohort (N=481) V0 → V1 → V2 PD≤2y (N=127) V0 → V1 → V2 63.6% 64.6% 35.4% 21.3% 23.6% 19.7% 36.4% 35.4% 36.4% 18.9% 19.1% 25.6% (b) Figure 1: (a) Percentage of patients (the whole cohort and the group with no more than 2 years since symptom onset (PD ≤2 y) and controls reporting drooling at diferent visits: V0, V1, and V2. (b) Prevalence of drooling during the follow-up period in all patients and in the PD ≤2 y group who completed the three visits (V1, V2, and V3) and percentage of cases presenting drooling in only 1 visit, 2 visits, and all visits. PD cohort vs. controls at V0, p<0.0001; PD cohort vs. controls at V2, p<0.0001; PD ≤2 y group vs. controls at V0, p<0.0001; PD ≤2 y group vs. controls at V2, p<0.0001. PD: Parkinson’s disease. PD ≤2 y group: patients with ≤2 years since symptom onset. Parkinson’s Disease 5 (OR �3.671; 95% CI, 1.350–9.986; p�0.011). Finally, to have a greater NMS burden at the baseline (β�0.492; 95% CI, 0.052–0.089; p<0.0001) and a greater increase in the NMS burden from V0 to V2 (β�0.221; 95% CI, 0.020–0.048; p <0.0001) were the most signifcant factors associated with drooling severely at V2 in the entire cohort, whereas to have at the baseline, a greater score on the UPDRS-III (β�0.272; 95% CI, 0.038–0.204; p�0.005) and the NMSS (β�0.272; 95% CI, 0.009–0.049; p�0.005) were in the PD ≤2 y group (Table 4). Similar results were observed when the item-19 score was excluded from the NMSS total score. With regard to QoL, drooling was associated with a worse health-related QoL (PDQ-39SI as the dependent variable) at V0 (β�0.180; 95% CI, 2.928–6.992; p<0.0001) and at V2 (β�0.131; 95% CI, 1.409–7.115; p�0.003) and also with a worse global QoL (EUROHIS-QOL8 as dependent variable) at V0 (β� −0.118; 95% CI, −0.218 to −0.050; p�0.002) and at V2 (β� −0.128; 95% CI, −0.251 to −0.047; p�0.004). In the PD ≤2 y group, drooling was associated with a worse health-related QoL at V0 (β�0.249; 95% CI, 2.855–10.362; p�0.001) and at V2 (β�0.306; 95% CI, 4.193–14.327; p<0.0001) and with a worse global QoL at V0 (β� −0.238; 95% CI, −0.438 to −0.110; p�0.001) as well. However, after adjustment to covariates defned in the methods, the association between drooling and both healthrelated and global QoL at V0 and at V2 was not signifcant, Table 1: Disease-related characteristics, motor and nonmotor symptoms, and autonomy for activities of daily living and quality of life in patients with and without drooling at the baseline in the entire cohort (n�691) and in PD ≤2 y (N�184). Without drooling entire cohort (N�414) With drooling entire cohort (N�277) p Without drooling PD ≤2 y (N�120) With drooling PD ≤2 y (N�64) p Age 61.8 ±9.29 63.79 ±8.21 0.008 61.68 ±8.54 63.39 ±7.84 0.252 Males (%) 54.3 69 <0.0001 55 60.9 0.269 Weight (kgs) 75.37 ±13.83 76.56 ±13.34 0.341 75.84 ±14.75 75.75 ±11 0.755 Disease duration (years) 5.31 ±4.24 5.8 ±4.55 0.136 1.33 ±0.73 1.22 ±0.75 0.332 L-dopa eq. daily dose (mg) 512.73 ±409.22 646.01 ±410.21 <0.0001 303.51 ±242.63 343.11 ±256.34 0.296 Number of non antip. drugs 2.45 ±2.43 2.79 ±2.62 0.106 2.72 ±2.44 2.94 ±2.66 0.680 Motor phenotype (%) 0.899 0.995 Tremoric dominant 45.6 44.9 58.8 57.8 PIGD 39.1 38.4 27.7 29.7 Indeterminate 15.3 16.7 13.4 12.5 Hoehn and Yahr-OFF 2 [1.5, 2] 2 [2, 2] 0.031 2 [1.5, 2] 2 [1.5, 2] 0.186 Stage from 3 to 5 (%) 8.6 10.5 0.257 2.9 1.7 0.526 UPDRS-III-OFF 20.97 ±10.56 25.17 ±11.59 <0.0001 17.56 ±8.46 21.69 ±9.68 0.005 Hypomimia (%) 79.8 86.9 0.011 74.6 81 0.219 UPDRS-IV 1.79 ±2.34 2.33 ±2.48 <0.0001 0.86 ±1.38 1.16 ±1.54 0.136 Motor fuctuations (%) 29.1 38.3 0.008 6.7 12.5 0.148 Dyskinesia (%) 17.5 21.2 0.137 2.6 6.6 0.190 FOGQ 3.3 ±4.36 4.53 ±4.78 <0.0001 1.75 ±2.81 3.05 ±3.66 0.031 Patients with FOG (%) 30.1 42 0.001 16.7 31.2 0.019 Patients with falls (%) 10.8 17.2 0.011 6.6 15.6 0.034 PD-CRS total score 92.52 ±15.97 89.36 ±15.25 0.006 92.18 ±15.44 88.09 ±13.73 0.077 NMSS 37.69 ±32.09 57.28 ±42.55 <0.0001 32.85 ±28.08 56.4 ±37.17 <0.0001 Dysphagia (%) 15.5 34.7 <0.0001 13.3 31.2 0.004 BDI-II 8.12 ±7.18 9.64 ±7.43 0.002 7.15 ±6.98 10.81 ±7.51 <0.0001 Major depression (%) 13.3 20.2 0.010 11.7 25 0.018 NPI 5.12 ±6.99 7.58 ±9.36 0.001 4.2 ±6.52 7.34 ±6.95 <0.0001 QUIP-RS 3.96 ±7.63 4.97 ±9.07 0.254 3.42 ±7.66 2.93 ±7.46 0.312 PDSS 116.83 ±25.32 111.98 ±28.8 0.027 119.45 ±25.19 111.22 ±32.04 0.110 VAS-PAIN 2.51 ±2.94 2.9 ±2.93 0.046 2.37 ±2.9 3.18 ±2.79 0.046 VASF −physical 2.83 ±2.79 3.2 ±2.68 0.038 2.55 ±2.9 2.78 ±2.43 0.211 VASF – mental 1.93 ±2.5 2.47 ±2.58 0.002 1.85 ±2.51 2.56 ±2.51 0.035 ADLS 89.49 ±10.64 86.85 ±10.15 <0.0001 92.08 ±8.39 89.22 ±10.12 0.053 Functional dependency (%) 8.2 10.5 0.186 4.2 7.8 0.238 PDQ-39SI 15.15 ±12.6 20.11 ±14.33 <0.0001 12.4 ±11.33 19.01 ±13.91 <0.0001 EUROHIS-QOL8 3.83 ±0.54 2.71 ±0.56 0.005 3.91 ±0.56 3.64 ±0.48 0.001 Te results represent percentages, mean ±SD, or median (p25, p75). Te chi-squared and Mann-Whitney-Wilcoxon tests were applied for comparisons between patients with and without drooling at the baseline. Data about H&Y and UPDRS-III are during the OFF state (frst thing in the morning without taking medication in the previous 12 hours). ADLS: Schwab and England Activities of Daily Living Scale); antip.: antiparkinsonian; BDI: Beck Depression Inventory-II; NMSS: Nonmotor Symptoms Scale; NPI: Neuropsychiatric Inventory; PD: Parkinson’s disease; PD ≤2 y: PD with ≤2 years from symptom onset; PD-CRS: Parkinson’s Disease Cognitive Rating Scale; PDSS: Parkinson’s Disease Sleep Scale; PIGD: Postural Instability Gait Difculty; QUIP-RS: Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale; UPDRS: Unifed Parkinson’s Disease Rating Scale; VAFS: Visual Analog Fatigue Scale; VAS-Pain: Visual Analog Scale-Pain. 6Parkinson’s Disease 0 5 10 15 20 25 30 Mobility* ADL* Emotional wellbeing* Stigmatization Social support* Cognition* Communication* Pain and discomfort Without drooling With drooling (a) Without drooling With drooling 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Quality of life* Health status Energy Autonomy for ADL* Self-esteem* Social relationships* Economic capacity* Habitat* (b) Figure 3: (a) Mean score on each domain of the PDQ-39 at the baseline in PD patients from the entire cohort with vs. without drooling; p <0.0001 for all analysis except for “emotional well-being” (p�0.001), “stigmatization” (p�0.129), and “pain and discomfort” (p�0.063). (b) Mean score on each domain of the EUROHIS-QOL8 at the baseline in PD patients from the entire cohort with vs. without drooling; “quality of life,” p�0.005; “health status,” p�0.178; “energy,” p�0.183; “autonomy for ADL,” p�0.011; “self-esteem,” p�0.033; “social relationships,” p�0.032; “economic capacity,” p�0.020; “habitat,” p�0.046. EUROHIS-QOL8, EUROHIS-QOL 8-item index; PD, Parkinson’s disease; PDQ-39, 39-item Parkinson’s disease quality of life questionnaire. Table 3: Predictors of drooling after the 2-year follow-up in the entire cohort (N�481) and in the PD ≤2 y group (N�127). OR a OR b 95% CI a 95% CI b p a p b Entire cohort Age 1.033 1.032 1.011–1.056 1.007–1.057 0.003 0.012 Male 2.023 2.333 1.396–2.932 1.540–3.536 <0.0001 <0.0001 UPDRS-III at V0 1.028 1.016 1.010–1.047 0.995–1.038 0.002 0.097 NMSS at V0 1.010 1.020 1.005–1.016 1.011–1.030 <0.0001 <0.0001 PDQ-39SI at V0 1.016 0.978 1.002–1.031 0.955–1.002 0.024 0.069 Change from V0 to V2 in NMSS 1.006 1.012 1.001–1.011 1.006–1.019 0.042 <0.0001 PD ≤2 y group Age 1.037 1.037 0.994–1.082 0.984–1.092 0.096 0.098 Male 1.707 2.064 0.845–3.450 0.886–4.810 0.136 0.093 UPDRS-III at V0 1.121 1.093 1.056–1.191 1.025–1.166 <0.0001 0.007 NMSS at V0 1.019 1.013 1.007–1.032 0.998–1.032 0.128 0.082 Dependent variable: drooling at V2 (NMSS-item 19 ≥1). OR (odds ratio) and 95% IC are shown. a univariate analysis; b multivariate analysis; entire cohort, R 2 �0.33; Hosmer and Lemeshow test, p�0.163; PD ≤2 y, R 2 �26; Hosmer and Lemeshow test, p�0.788. LEED: levodopa equivalent daily dose (mg/day); NMSS: Nonmotor Symptoms Scale; PD ≤2 y: PD with ≤2 years from symptom onset; PDQ-39SI: 39-item Parkinson’s disease Questionnaire Summary Index; UPDRS: Unifed Parkinson’s Disease Rating Scale. Table 2: Factors associated with drooling at the baseline in the entire cohort (n�691) and in the PD ≤2 y group (N�184). OR a OR b 95% CI a 95% CI b p a p b Entire cohort Age 1.026 1.025 1.008–1.044 1.004–1.046 0.004 0.019 Male 1.806 2.165 1.308–2.493 1.486–3.153 <0.0001 <0.0001 LEDD 1.001 1.000 1.001–1.002 1.000–1.001 <0.0001 0.172 UPDRS-III 1.035 1.018 1.020–1.050 1.001–1.037 <0.0001 0.047 NMSS 1.015 1.011 1.010–1.019 1.005–1.016 <0.0001 <0.0001 Dysphagia 2.901 2.274 2.016–4.173 1.476–3.505 <0.0001 <0.0001 PD ≤2 y group UPDRS-III 1.052 1.034 1.014–1.090 0.994–1.076 0.006 0.096 NMSS 1.022 1.017 1.012–1.033 1.005–1.029 <0.0001 0.004 Dysphagia 2.995 2.002 1.401–6.229 0.858–4.672 0.004 0.108 Dependent variable: drooling at V0 (NMSS-item 19 ≥1). OR (odds ratio) and 95% ICare shown. a univariate analysis; b multivariate analysis; entire cohort, R 2 �0.19; Hosmer and Lemeshow test, p�0.226; PD ≤2 y, R 2 �0.19; Hosmer and Lemeshow test, p�0.774. LEED: levodopa equivalent daily dose (mg/day); NMSS: Nonmotor Symptoms Scale; PD ≤2 y: PD with ≤2 years from symptom onset; UPDRS: Unifed Parkinson’s Disease Rating Scale. Parkinson’s Disease 7 not even when persisting drooling or the NMSSDrooling V0+V1+V2 score was considered in the model. A correlation was observed between the NMSSDrooling V0+V1+V2 score and the score on both PDQ-39SI and EUROHIS-QOL8 at V2 in the entire cohort (PDQ-39SI, r�0.234 (p<0.0001); EUROHIS-QOL8, r� −0.222 (p <0.0001)) and in the PD ≤2 y group (PDQ-39SI, r�0.483 (p <0.0001); EUROHIS-QOL8, r� −0.304 (p�0.001)). QoL at V2 was worse in patients with persistent drooling in both the entire cohort (PDQ-39SI, 25.18 ±19.14 vs. 18.4 ±14.81 (p <0.0001); EUROHIS-QOL8, 3.64 ±0.51 vs. 3.8 ±0.59 (p <0.005)) and in the PD ≤2 y group (PDQ-39SI, 28.58 ±22.71 vs. 14.03 ±11.35 (p�0.001); EUROHIS-QOL8, 3.54 ±0.53 vs. 3.88 ±0.57 (p�0.006)). Finally, by domains, drooling was an independent factor associated with a worse “Activities of daily living” (β�0.086; 95% CI, 0.654–5.925; p �0.015; R 2 �0.43) and “Communication” (β�0.088; 95% CI, 0.297–5.075; p�0.028; R 2 �0.28) at V0 in the entire cohort. 4. Discussion Te present study represents one of the largest cohorts of PD patients in whom the prevalence of drooling was reported using a validated global NMS scale. We observed that drooling was common in PD patients, clearly much more frequent than in the control group, and was associated with the male gender, older age, and a greater motor and nonmotor severity. In addition, patients with drooling had a worse global and health-related QoL, although the efect of drooling on QoL was not signifcant after adjusting to other covariates. Importantly, we observed that drooling was also a very frequent symptom at the beginning of the disease, as seen in the very early PD patients, suggesting the clinical importance of asking for the presence of drooling at the beginning of the patient’s follow-up. About 2 out of every 3 patients from the Spanish cohort COPPADIS reported drooling over a 2-year follow-up. Tis cumulative prevalence is in line with the previously published data [11]. However, due to the lack of a standard defnition and criteria for diagnosing drooling in PD patients, estimates of its prevalence vary considerably with a wide range from 10% to 84% [2–15]. Tis is partly due to diferent tools such as the UPDRS-II, SCOPA-AUT (Scale for Outcomes in Parkinson’s disease for Autonomic Symptoms), PD-NMSQuest (Parkinson’s Disease Nonmotor Symptoms Questionnaire), NMSS, or diferent types of screening questionnaires have been used to screen drooling in PD cohorts with diferent characteristics also [1, 3, 11]. Some specifc scales to assess drooling have been designed, but they have been poorly used in studies with PD patients [37]. Using the NMSS-item 19 for detecting drooling like us, van Wamelen et al. [23] detected in a cohort of 728 PD patients with a mean disease duration of 5.6 years a prevalence of 37.2% at the baseline and 40.1% after a mean follow-up of 3.3 years (range 0.5–7.2 years). In many crosssectional studies, the prevalence of drooling in PD is between 40% and 50% [2, 6–8, 11, 23, 24, 38, 39], which is in agreement with our fndings. An interesting fnding is that like in other studies [5, 13], drooling was not related to disease duration and in fact, the prevalence at each year (from 35% to 50%) and the cumulative prevalence after the 2-year follow-up (65%) was similar in those patients with no more than 2 years since symptom onset compared to the whole cohort. Drooling is frequent even in de novo patients. Erro et al. [27] reported in 61 de novo PD patients a frequency of drooling of 19.4% at the baseline and 15.3% after a 2-year follow-up, whereas Picillo et al. [28] found in 86 men and 48 women de novo PD patients a frequency of drooling at the baseline and after a 2-year follow-up of 23.3% and 25% and 10.4% and 4.1%, respectively. Te Picillo study, in addition to ours and other studies, suggests that drooling could be more frequent in males [3, 11, 28, 40]. Although specifcally well-designed studies to analyze the prevalence of drooling using specifc validated scales [37, 41] in large cohorts are required, all these data suggest a recommendation to rule out drooling in PD patients at the beginning and throughout follow-up since its presence is associated with a worse QoL and it is potentially treatable. Consideration is especially valid in elderly men for which the prevalence of drooling is more frequent. Despite this, drooling is an underrecognized and undertreated symptom in PD [1]. Of note, no patient from our cohort was receiving botulinum toxin injections. Table 4: Factors associated with drooling severity after the 2-year follow-up in the entire cohort (N�481) and in the PD ≤2 y group (N�127). β a β b 95% CI a 95% CI b p a p b Entire cohort Age 0.114 0.083 0.015–0.127 −0.001–0.109 0.013 0.052 Male 0.112 0.136 0.252–2.199 0.568–2.445 0.014 0.002 UPDRS-III at V0 0.207 0.087 0.060–1.054 −0.003–0.093 <0.0001 0.068 NMSS at V0 0.359 0.492 0.039–0.063 0.052–0.089 <0.0001 <0.0001 PDQ-39SI at V0 0.240 −0.110 0.063–1.135 −0.098–0.007 <0.0001 0.087 Change from V0 to V2 in NMSS 0.073 0.221 −0.003–0.125 0.020–0.048 0.110 <0.0001 PD ≤2 y group UPDRS-III at V0 1.121 0.272 1.056–1.191 0.038–0.204 <0.0001 0.005 NMSS at V0 1.019 0.272 1.007–1.032 0.009–0.049 <0.0001 0.005 Dependent variable: drooling V0+V1+V2 score. βstandardized coefcient and 95% IC are shown. a univariate analysis; b multivariate analysis; entire cohort, R 2 �0.21; Durbin–Watson test �1.92; PD ≤2 y, R 2 �22; Durbin–Watson test �1.94. NMSS: Nonmotor Symptoms Scale; PD ≤2 y: PD with ≤2 years from symptom onset; PDQ-39SI: 39-item Parkinson’s disease Questionnaire Summary Index; UPDRS: Unifed Parkinson’s Disease Rating Scale. 8Parkinson’s Disease In addition to male gender, many other variables have been associated with drooling in PD patients such as dysphagia [1, 42], dysarthria [1, 43], hypomimia [14, 17], lingual bradykinesia [14, 17], cognitive status [15, 24], hallucinations [5], aging [3, 23], more advanced disease stage [16, 24], orthostatic hypotension [1], camptocormia [44], and a history of using antidepressants [6]. Drooling in PD patients can be in part due to the inability to maintain saliva in the mouth (i.e., hypomimia, abnormal fexed posture, etc.) and impairment of salivary clearance (i.e., lingual bradykinesia, oropharyngeal dysphagia, and upper esophageal dysmotility), as dysphagia is the strongest factor associated with drooling [7, 12, 23]. We identifed dysphagia as a factor that doubles the probability of drooling independently of other variables, even though it was measured through patientreported outcomes. Moreover, not only dysphagia burden but also hypomimia burden correlated with drooling burden in the entire cohort and the very early PD group as well. On the other hand, some recent studies comprehensively evaluating many features of the disease found an association between drooling and late onset of the disease, a higher LEDD, fuctuations, depression, higher motor scores, and a greater NMS burden [13–15, 23, 45]. In this Spanish cohort, we identifed a greater motor severity (UPDRS-III) and a greater NMS burden (NMSS) as independent factors associated with drooling and/or also predictors of drooling after a 2-year follow-up. Specifcally, a worse status in terms of motor and NMS predicted a greater drooling severity as well. Tis could explain why drooling was associated with a worse QoL but was not an independent predictor of it. Karakoc et al. [46] reported drooling in 65% of 63 people with PD but no independent signifcant correlation of drooling severity with QoL. However, as in our case, they measured the latter from the total PDQ-39 score, rather than with a tool that measures drooling impact. In contrast, when we used the PDQ-39 domains, we identifed drooling as an independent factor associated with a worse autonomy for ADL (PDQ-39 domain 2) and communication (PDQ-39 domain 7). Psychosocially, PD droolers had worse QoL and had more difculty speaking, eating, and socially interacting compared to PD nondroolers [3, 5, 11]. In addition, drooling patients afect their caregivers by increasing their burden, depression, and anxiety and reducing their QoL [47]. For all these reasons, therapeutic options should be evaluated more intensively in patients with PD and drooling [1, 11]. Te present study has some important limitations. Drooling was considered based on an answer to a simple clinical question from the NMSS and not after using a specifc scale [37, 41]. However, this methodology is the most frequent in most studies [2, 3, 6, 7, 11, 24, 40, 47, 48]. Te sample size in the group of PD patients with no more than 2 years since the onset of the symptoms was small and clearly smaller than that of the entire cohort. In the 2-year follow-up group, there was a 30% loss in participants, although this has been observed in other cohorts, with retention rates of 71% [23], 67% [27], or 67% [28]. Te logistic regression models used to identify the independent factors associated with drooling and predictors of drooling only explain 20–30% of the variance in our analysis, but it was either also low or not provided in other studies [6, 7, 13, 23]. For some variables, the information was not collected in all cases. Instead of a specifc tool for assessing comorbidity, like the Charlson index or others, the total number of non-antiParkinsonian medications was used as a surrogate marker of comorbidity [36], and the role of possible comorbidities inducing drooling was not considered. Finally, our sample was not fully representative of the PD population due to inclusion and exclusion criteria (i.e., age limit, no dementia, no severe comorbidities, no second-line therapies, etc.) [49]. Nonetheless, the strengths of our study include a very thorough assessment, a prospective longitudinal follow-up design, and the extensive clinical and demographic information recorded. Data about drooling severity and PDQ-39 domains are novel. In conclusion, this study observes a high prevalence of drooling in PD patients, clearly much more so than in control subjects, and that this feature is frequent even at the frst stages of the disease as well. Dysphagia is associated with drooling, and a higher motor score and a greater NMS burden are predictors of drooling. PD patients with drooling have a worse QoL, and drooling is also an independent factor associated with communication problems. Tus, drooling screening and therapeutic options should be considered in clinical practice. Appendix A. Coppadis Study Group Adarmes AD, Almeria M, Alonso Losada MG, Alonso C´ anovas A, Alonso Frech F, Alonso Redondo R, ´ Alvarez Te authors, ´ Alvarez Sauco M, Aneiros D´ ıaz A, Arn´ aiz S, Arribas S, Ascunce Vidondo A, Aguilar M, ´ Avila MA, Bernardo Lambrich N, Bejr-Kasem H, Bl´ azquez Estrada M, Bot´ ı M, Borrue C, Buongiorno MT, Cabello Gonz´ alez C, Cabo L´ opez Te authors, Caballol N, C´ amara Lorenzo A, Canfeld Medina H, Carrillo F, Carrillo Padilla FJ, Casas E, Catal´ an MJ, Clavero P, Cortina Fern´ andez A, Cosgaya M, Cots Foraster A, Crespo Cuevas A, Cubo E, de Deus Fonticoba T, de F´ abregues-Boixar O, D´ ıez-Fairen M, Dotor Garc´ ıa-Soto J, Erro E, Escalante S, Estelrich Peyret E, Fern´ andez Guill´ an N, G´ amez P, Gallego M, Garc´ ıa Caldentey J, Garc´ ıa Campos C, Garc´ ıa D´ ıez C, Garc´ ıa Moreno JM, Gast´ on Te authors, G´ omez Garre MP, G´ omez Mayordomo V, Gonz´ alez Aloy J, Gonz´ alez-Aramburu Te authors, Gonz´ alez Ardura J, Gonz´ alez Garc´ ıa B, Gonz´ alez Palm´ as MJ, Gonz´ alez Toledo GR, Golpe D´ ıaz A, Grau Sol´ a M, Guardia G, Hern´ andez Vara J, Horta-Barba A, Idoate Calder´ on D, Infante J, Jes´ us S, Kulisevsky J, Kurtis M, Labandeira C, Labrador MA, Lacruz F, Lage Castro M, Lastres G´ omez S, Legarda Te authors, L´ opez Ariztegui N, L´ opez D´ ıaz LM, L´ opez Dom´ ınguez D, L´ opez Manzanares L, L´ opez Seoane B, Lucas del Pozo S, Mac´ ıas Y, Mata M, Mart´ ı Andres G, Mart´ ı MJ, Mart´ ınez Castrillo JC, Martinez-Martin P, McAfee D, Meit´ ın MT, Mendoza Plasencia Z, Men´ endez Gonz´ alez M, M´ endez del Barrio C, Mir P, Miranda Santiago J, Morales Casado MI, Moreno Di´ eguez A, Nogueira V, Novo Amado A, Novo Ponte S, Ord´ as C, Pagonabarraga J, Pare´ es Te authors, Parkinson’s Disease 9 educational presentations and advice service by Abbvie, Italfarmaco, Zambon, and Bial. Gast´ on I. has received research support from Abbvie and Zambon and has served as a consultant for Abbvie, Exelts, and Zambon. 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; Fundaci´ oLa Marat´ ode TV3; (7) Scholarship from corporation: No; (8) Corporate laboratory funding: No; (9) Others (e.g. trips, travel, or gifts): No. Bl´ azquez Estrada M. has received honoraria for educational presentations and advice service by Abbvie, Abbott, UCB Pharma, Allergan, Zambon, Bial, and Qualigen. Seijo M. has received honoraria for educational services from KRKA, UCB, Zambon, Bial; travel grants from Daiichi and Roche. Ruiz Mart´ ınez J. has received honoraria for educational presentations, attending medical conferences, and advice service by Abbvie, UCB Pharma, Zambon, Italfarmaco, Bial, and Teva. Valero C. has received honoraria for educational services from Zambon, Abbvie, and UCB. Kurtis M. has received honoraria from Bial, the Spanish Neurology Society, and the International and Movement Disorders Society. de F´ abregues O. has received honoraria for educational presentations and advice service by Bial, Zambon, Abbvie, KRKA, and Teva. Gonz´ alez Ardura J. has recieved honoraria for speking from italofarma, Krka, Genzyme, UCB, Esteve, Psyma iberica marketing research SL and Ferrer, course grant from Teva and travel grant from Merck. Alonso Redondo R.: None. Ord´ as C.: None. L´ opez D´ ıaz L. M. has received honoraria from UCB, Lundbeck, and KRKA. McAfee D.: None. Mart´ ınez-Martin P. has received honoraria from National School of Public Health (ISCIII), Editori-al Viguera and Takeda Pharmaceuticals for lecturing in courses, and from the International Parkinson and Movement Disorder Society (MDS) for management of the Program on Rating Scales. Mir P. has received honoraria from AbbVie, Abbott, Allergan, Bial, Merz, UCB, and Zambon and have received grants from the Spanish Ministry of Economy and Competitiveness [PI16/01575] co-founded by ISCIII (Subdirecci´ on General de Evaluaci´ on y Fomento de la Investigaci´ on) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejer´ ıa de Econom´ ıa, Innovaci´ on, Ciencia y Empleo de la Junta de Andaluc´ ıa [CVI-02526, CTS-7685], the Consejer´ ıa de Salud y Bienestar Social de la Junta de Andaluc´ ıa [PI-0437-2012, PI-04712013], the Sociedad Andaluza de Neurolog´ ıa, the Jacques and Gloria Gossweiler Foundation, the Fundaci´ on Alicia Koplowitz, the Fundaci´ on Mutua Madrileña. Authors’ Contributions Santos Garc´ ıa D. performed conception, organization, and execution of the project, as well as statistical analysis, writing of the frst draft of the manuscript, and recruitment and/or evaluation of participants. De Deus Fonticoba T. conducted review and critique as well as recruitment and/or evaluation of participants. Cores Bartolom´ e C. carried out collaboration in the preparation of the manuscript as well as review and critique. Feal Painceiras M. J. conducted collaboration in the preparation of the manuscript alongside review and critique. ´ Iñiguez Alvarado M. C. performed collaboration in the preparation of the manuscript alongside review and critique. Jes´ us S. performed review and critique as well as recruitment and/or evaluation of participants. Buongiorno M. T. carried out review and critique and recruitment and/or evaluation of participants. Planellas LL. executed review and critique as well as recruitment and/or evaluation of participants. Cosgaya M. conducted review and critique as well as recruitment and/or evaluation of participants. Garc´ ıa Caldentey J. conducted review and critique as well as recruitment and/or evaluation of participants. Caballol N. executed review and critique as well as recruitment and/ or evaluation of participants. Legarda I. executed review and critique as well as recruitment and/or evaluation of participants. Hern´ andez Vara J. executed review and critique and recruitment and/or evaluation of participants. Cabo I. performed review and critique and recruitment and/or evaluation of participants. L´ opez Manzanares L. performed review and critique and recruitment and/or evaluation of participants. Gonz´ alez Aramburu I. performed review and critique and recruitment and/or evaluation of participants. ´ Avila Rivera M. A. performed review and critique and recruitment and/or evaluation of participants. G´ omez Mayordomo V. performed review and critique and recruitment and/or evaluation of participants. Nogueira V. conducted review and critique and recruitment and/or evaluation of participants. Puente V. conducted review and critique and recruitment and/or evaluation of participants. Dotor Garc´ ıa-Soto J. conducted review and critique and recruitment and/or evaluation of participants. Borru´ e C. conducted review and critique and recruitment and/or evaluation of participants. Solano Vila B. conducted review and critique and recruitment and/or evaluation of participants. ´ Alvarez Sauco M. performed review and critique and recruitment and/or evaluation of participants. Vela L. carried out review and critique and recruitment and/or evaluation of participants. Escalante S. executed review and critique and recruitment and/or evaluation of participants. Cubo E. executed review and critique and recruitment and/ or evaluation of participants. Carrillo Padilla F. executed review and critique and recruitment and/or evaluation of participants. Mart´ ınez Castrillo J. C. conducted review and critique and recruitment and/or evaluation of participants. S´ anchez Alonso P. conducted review and critique and recruitment and/or evaluation of participants. Alonso Losada M. G. executed review and critique and recruitment and/or evaluation of participants. L´ opez Ariztegui N. executed review and critique and recruitment and/or evaluation of participants. Gast´ on I. executed review and critique and recruitment and/or evaluation of participants. Kulisevsky J. executed review and critique and recruitment and/or evaluation of participants. Bl´ azquez Estrada M. executed review and critique and recruitment and/or evaluation of participants. Seijo M. executed review and critique and recruitment and/or evaluation of participants. Ruiz Mart´ ınez J. executed review and critique and recruitment and/or evaluation of participants. Valero C. conducted 16 Parkinson’s Disease review and critique and recruitment and/or evaluation of participants. Kurtis M. conducted review and critique and recruitment and/or evaluation of participants. de F´ abregues O. conducted review and critique and recruitment and/or evaluation of participants. Gonz´ alez Ardura J. conducted review and critique and recruitment and/or evaluation of participants. Alonso Redondo R. conducted review and critique and recruitment and/or evaluation of participants. Ord´ as C. conducted review and critique and recruitment and/or evaluation of participants. L´ opez D´ ıaz L. M. conducted review and critique and recruitment and/or evaluation of participants. McAfee D. conducted review and critique and review of English style. Mart´ ınez-Martin P. conducted review and critique and supervision. Mir P. executed review and critique and recruitment and/or evaluation of participants. Acknowledgments COPPADIS and the present study were developed with the help of Fundaci´ on Española de Ayuda a la Investigaci´ on en Enfermedades Neurodegenerativas y/o de Origen Gen´ etico (https://fundaciondegen.org/) and Alpha Bioresearch (https://www.alphabioresearch.com). Also, Te authors received grants from the Spanish Ministry of Economy and Competitiveness [PI16/01575] co-founded by ISCIII (Concesi´ on de subvenciones de Proyectos de Investigaci´ on en Salud de la convocatoria 2020 de la Acci´ on Estrat´ egica en Salud 2017–2020 por el proyecto “PROGRESI ´ ON NO MOTORA E IMPACTO EN LA CALIDAD DE VIDA EN LA ENFERMEDAD DE PARKINSON”) to develop a part of the COPPADIS project. Te authors would like to thank all patients and their caregivers who collaborated in this study. 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