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Background and Objective: Recently, we demonstrated that staging Parkinson's disease (PD) with a novel simple classification called MNCD, based on four axes (motor, non-motor, cognition, and dependency) and five stages, correlated with disease severity and patients' quality of life. Here, we analyzed the correlation of MNCD staging with PD caregiver's status., Patients and Methods: Data from the baseline visit of PD patients and their principal caregiver recruited from 35 centers in Spain from the COPPADIS cohort from January 2016 to November 2017 were used to apply the MNCD total score (from 0 to 12) and MNCD stages (from 1 to 5) in this cross-sectional analysis. Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory-II (BDI-II), PQ-10, and EUROHIS-QOL 8-item index (EUROHIS-QOL8)., Results: Two hundred and twenty-four PD patients (63 ± 9.6 years old; 61.2% males) and their caregivers (58.5 ± 12.1 years old; 67.9% females) were included. The frequency of MNCD stages was 1, 7.6%; 2, 58.9%; 3, 31.3%; and 4-5, 2.2%. A more advanced MNCD stage was associated with a higher score on the ZCBI (p < .0001) and CSI (p < .0001), and a lower score on the PQ-10 (p = .001), but no significant differences were observed in the BDI-II (p = .310) and EUROHIS-QOL8 (p = .133). Moderate correlations were observed between the MNCD total score and the ZCBI (r = .496; p < .0001), CSI (r = .433; p < .0001), and BDI-II (r = .306; p < .0001) in caregivers., Conclusion: Staging PD according to the MNCD classification is correlated with caregivers' strain and burden., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background and Purpose: Visual hallucinations (VH) and subjective cognitive complaints (SCC) are associated with cognitive impairment (CI) in Parkinson's disease. Our aims were to determine the association between VH and SCC and the risk of CI development in a cohort of patients with Parkinson's disease and normal cognition (PD-NC)., Methods: Patients with PD-NC (total score of >80 on the Parkinson's Disease Cognitive Rating Scale [PD-CRS]) recruited from the Spanish COPPADIS cohort from January 2016 to November 2017 were followed up after 2 years. Subjects with a score of ≥1 on domain 5 and item 13 of the Non-Motor Symptoms Scale at baseline (V0) were considered as "with SCC" and "with VH," respectively. CI at the 2-year follow-up (plus or minus 1 month) (V2) was defined as a PD-CRS total score of <81., Results: At V0 ( n =376, 58.2% males, age 61.14±8.73 years [mean±SD]), the frequencies of VH and SCC were 13.6% and 62.2%, respectively. VH were more frequent in patients with SCC than in those without: 18.8% (44/234) vs 4.9% (7/142), p <0.0001. At V2, 15.2% (57/376) of the patients had developed CI. VH presenting at V0 was associated with a higher risk of CI at V2 (odds ratio [OR]=2.68, 95% confidence interval=1.05-6.83, p =0.0.039) after controlling for the effects of age, disease duration, education, medication, motor and nonmotor status, mood, and PD-CRS total score at V0. Although SCC were not associated with CI at V2, presenting both VH and SCC at V0 increased the probability of having CI at V2 (OR=3.71, 95% confidence interval=1.36-10.17, p =0.011)., Conclusions: VH were associated with the development of SCC and CI at the 2-year follow-up in patients with PD-NC., 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., (Copyright © 2023 Korean Neurological Association.)

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. Specifically, we identified 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 classified 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: The 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 identified 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., Competing Interests: Santos García D. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, Italfarmaco, Teva, Archímedes, Esteve, Stada, and grants from the Spanish Ministry of Economy and Competitiveness [PI16/01575] co-founded by ISCIII (Concesión de subvenciones de Proyectos de Investigación en Salud de la convocatoria 2020 de la Acción Estratégica en Salud 2017–2020 por el proyecto “PROGRESIÓN NO MOTORA E IMPACTO EN LA CALIDAD DE VIDA EN LA ENFERMEDAD DE PARKINSON”). De Deus Fonticoba T.: None. Cores Bartolomé C. has received honoraria for educational presentations and advice service by Lundbeck and UCB Pharma. Feal Painceiras M. J.: None. Íñiguez Alvarado MC: None. Jesús S. 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). Buongiorno M. T.: Planellas LL.: None. 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, Italfarmaco, 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. Gómez Mayordomo V.: None. Nogueira V.: None. Puente V. has served as consultant for Abbvie and Zambon; has received grant/research from Abbvie. Dotor García-Soto J.: Compensated advisory services, consulting, research grant support, or speaker honoraria: Merck, Sanofi-Genzyme, Allergan, Biogen, Roche, UCB, and Novartis. Borrué C.: None. Solano Vila B. has received honoraria for educational presentations and advice service by UCB, Zambon, Teva, Abbvie, and 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, and Merz. Sánchez Alonso P. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Alonso Losada M. G. 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. 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 corporation: No; (8) Corporate laboratory funding: No; (9) Others (e.g. trips, travel, or gifts): No. Blázquez 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 Martínez 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 Fábregues O. has received honoraria for educational presentations and advice service by Bial, Zambon, Abbvie, KRKA, and Teva. González 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. Ordás C.: None. López Díaz L. M. has received honoraria from UCB, Lundbeck, and KRKA. McAfee D.: None. Martínez-Martin P. has received honoraria from National School of Public Health (ISCIII), Editori-al 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 (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [PI-0437-2012, PI-0471-2013], the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña., (Copyright © 2023 Diego Santos-García et al.)

Background and Objective: Sex plays a role in Parkinson's disease (PD) mechanisms. We analyzed sex difference manifestations among Spanish patients with PD., Patients and Methods: PD patients who were recruited from the Spanish cohort COPPADIS from January 2016 to November 2017 were included. A cross-sectional and a two-year follow-up analysis were conducted. Univariate analyses and general linear model repeated measure were used., Results: At baseline, data from 681 PD patients (mean age 62.54 ± 8.93) fit the criteria for analysis. Of them, 410 (60.2%) were males and 271 (39.8%) females. There were no differences between the groups in mean age (62.36 ± 8.73 vs. 62.8 ± 9.24; p = 0.297) or in the time from symptoms onset (5.66 ± 4.65 vs. 5.21 ± 4.11; p = 0.259). Symptoms such as depression ( p < 0.0001), fatigue ( p < 0.0001), and pain ( p < 0.00001) were more frequent and/or severe in females, whereas other symptoms such as hypomimia ( p < 0.0001), speech problems ( p < 0.0001), rigidity ( p < 0.0001), and hypersexuality ( p < 0.0001) were more noted in males. Women received a lower levodopa equivalent daily dose ( p = 0.002). Perception of quality of life was generally worse in females (PDQ-39, p = 0.002; EUROHIS-QOL8, p = 0.009). After the two-year follow-up, the NMS burden (Non-Motor Symptoms Scale total score) increased more significantly in males ( p = 0.012) but the functional capacity (Schwab and England Activities of Daily Living Scale) was more impaired in females ( p = 0.001)., Conclusion: The present study demonstrates that there are important sex differences in PD. Long-term prospective comparative studies are needed.

Background: There is a need for identifying risk factors for hospitalization in Parkinson's disease (PD) and also interventions to reduce acute hospital admission., Objective: To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort., Methods: PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson's DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study. In order to identify predictors of AH, Kaplan-Meier estimates of factors considered as potential predictors were obtained and Cox regression performed on time to hospital encounter 1-year after the baseline visit., Results: Thirty-five out of 605 (5.8%) PD patients (62.5±8.9 years old; 59.8% males) presented an AH during the 1-year follow-up after the baseline visit. Traumatic falls represented the most frequent cause of admission, being 23.7% of all acute hospitalizations. To suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065-5.678; p = 0.035), a very severe non-motor symptoms burden (HR [hazard ratio] 2.828; 95% CI, 1.319-6.063; p = 0.008), falls (HR 3.966; 95% CI 1.757-8.470; p = 0.001), and dysphagia (HR 2.356; 95% CI 1.124-4.941; p = 0.023) was associated with AH after adjustment to age, gender, disease duration, levodopa equivalent daily dose, total number of non-antiparkinsonian drugs, and UPDRS-IIIOFF. Of the previous variables, only falls (HR 2.998; 95% CI 1.080-8.322; p = 0.035) was an independent predictor of AH., Conclusion: Falls is an independent predictor of AH in PD patients.

Background: Recently, a novel simple classification called MNCD, based on 4 axes (Motor; Non-motor; Cognition; Dependency) and 5 stages, has been proposed to classify Parkinson's disease (PD)., Objective: Our aim was to apply the MNCD classification in a cohort of PD patients for the first time and also to analyze the correlation with quality of life (QoL) and disease severity., Methods: Data from the baseline visit of PD patients recruited from 35 centers in Spain from the COPPADIS cohort fromJanuary 2016 to November 2017 were used to apply the MNCD classification. Three instruments were used to assess QoL:1) the 39-item Parkinson's disease Questionnaire [PDQ-39]); PQ-10; the EUROHIS-QOL 8-item index (EUROHIS-QOL8)., Results: Four hundred and thirty-nine PD patients (62.05±7.84 years old; 59% males) were included. MNCD stage was:stage 1, 8.4% (N = 37); stage 2, 62% (N = 272); stage 3, 28.2% (N = 124); stage 4-5, 1.4% (N = 6). A more advancedMNCD stage was associated with a higher score on the PDQ39SI (p < 0.0001) and a lower score on the PQ-10 (p< 0.0001) and EUROHIS-QOL8 (p< 0.0001). In many other aspects of the disease, such as disease duration, levodopa equivalent daily dose, motor symptoms, non-motor symptoms, and autonomy for activities of daily living, an association between the stage and severity was observed, with data indicating a progressive worsening related to disease progression throughout the proposed stages., Conclusion: Staging PD according to the MNCD classification correlated with QoL and disease severity. The MNCD could be a proper tool to monitor the progression of PD.

Objective: The aim of the present study was to analyze the progression of non-motor symptoms (NMS) burden in Parkinson's disease (PD) patients regarding the development of motor fluctuations (MF). Methods: PD patients without MF at baseline, who were recruited from January 2016 to November 2017 (V0) and evaluated again at a 2-year follow-up (V2) from 35 centers of Spain from the COPPADIS cohort, were included in this analysis. MF development at V2 was defined as a score ≥ 1 in the item-39 of the UPDRS-Part IV, whereas NMS burden was defined according to the Non-motor Symptoms Scale (NMSS) total score. Results: Three hundred and thirty PD patients (62.67 ± 8.7 years old; 58.8% males) were included. From V0 to V2, 27.6% of the patients developed MF. The mean NMSS total score at baseline was higher in those patients who developed MF after the 2-year follow-up (46.34 ± 36.48 vs. 34.3 ± 29.07; p = 0.001). A greater increase in the NMSS total score from V0 to V2 was observed in patients who developed MF (+16.07 ± 37.37) compared to those who did not develop MF (+6.2 ± 25.8) ( p = 0.021). Development of MF after a 2-year follow-up was associated with an increase in the NMSS total score (β = 0.128; p = 0.046) after adjustment to age, gender, years from symptoms onset, levodopa equivalent daily dose (LEDD) and the NMSS total score at baseline, and the change in LEDD from V0 to V2. Conclusions: In PD patients, the development of MF is associated with a greater increase in the NMS burden after a 2-year follow-up.

Background and Objective: Diplopia is relatively common in Parkinson's disease (PD) but is still understudied. Our aim was to analyze the frequency of diplopia in PD patients from a multicenter Spanish cohort, to compare the frequency with a control group, and to identify factors associated with it., 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 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort were included in this longitudinal prospective study. The patients and controls were classified as "with diplopia" or "without diplopia" according to item 15 of the Non-Motor Symptoms Scale (NMSS) at V0, V1 (1-year ± 15 days), and V2 for the patients and at V0 and V2 for the controls., Results: The frequency of diplopia in the PD patients was 13.6% (94/691) at V0 (1.9% in controls [4/206]; p < 0.0001), 14.2% (86/604) at V1, and 17.1% (86/502) at V2 (0.8% in controls [1/124]; p < 0.0001), with a period prevalence of 24.9% (120/481). Visual hallucinations at any visit from V0 to V2 (OR = 2.264; 95%CI, 1.269-4.039; p = 0.006), a higher score on the NMSS at V0 (OR = 1.009; 95%CI, 1.012-1.024; p = 0.015), and a greater increase from V0 to V2 on the Unified Parkinson's Disease Rating Scale-III (OR = 1.039; 95%CI, 1.023-1.083; p < 0.0001) and Neuropsychiatric Inventory (OR = 1.028; 95%CI, 1.001-1.057; p = 0.049) scores were independent factors associated with diplopia (R 2 = 0.25; Hosmer and Lemeshow test, p = 0.716)., Conclusions: Diplopia represents a frequent symptom in PD patients and is associated with motor and non-motor severity.

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., (© 2021. The Author(s).)

Background and Objective: The aim of this study was to compare the progression of independence in activities of daily living (ADL) in Parkinson's disease (PD) patients versus a control group, as well as to identify predictors of disability progression and functional dependency (FD)., Patients and Methods: PD patients and control subjects, who were recruited from 35 centers of Spain from the COPPADIS cohort between January 2016 and November 2017 (V0), were included. Patients and subjects were then evaluated again at the 2-year follow-up (V2). Disability was assessed with the Schwab & England Activities of Daily Living Scale (S&E-ADLS) at V0 and V2. FD was defined as an S&E-ADLS score less than 80%., Results: In the PD group, a significant decrease in the S&E-ADLS score from V0 to V2 (N = 507; from 88.58 ± 10.19 to 84.26 ± 13.38; p < 0.0001; Cohen's effect size = -0.519) was observed but not in controls (N = 124; from 98.87 ± 6.52 to 99.52 ± 2.15; p = 0.238). When only patients considered functional independent at baseline were included, 55 out of 463 (11.9%) converted to functional dependent at V2. To be a female (OR = 2.908; p = 0.009), have longer disease duration (OR = 1.152; p = 0.002), have a non-tremoric motor phenotype at baseline (OR = 3.574; p = 0.004), have a higher score at baseline in FOGQ (OR = 1.244; p < 0.0001) and BDI-II (OR = 1.080; p = 0.008), have a lower score at baseline in PD-CRS (OR = 0.963; p = 0.008), and have a greater increase in the score from V0 to V2 in UPDRS-IV (OR = 1.168; p = 0.0.29), FOGQ (OR = 1.348; p < 0.0001) and VAFS-Mental (OR = 1.177; p = 0.013) (adjusted R-squared 0.52; Hosmer and Lemeshow test = 0.94) were all found to be independent predictors of FD at V2., Conclusions: In conclusion, autonomy for ADL worsens in PD patients compared to controls. Cognitive impairment, gait problems, fatigue, depressive symptoms, more advanced disease, and a non-tremor phenotype are independent predictors of FD in the short-term.

Background and Objective: Non-motor symptoms (NMS) progress in different ways between Parkinson's disease (PD) patients. The aim of the present study was to (1) analyze the change in global NMS burden in a PD cohort after a 2-year follow-up, (2) to compare the changes with a control group, and (3) to identify predictors of global NMS burden progression in the PD group. Material and Methods: PD patients and controls, recruited from 35 centers of Spain from the COPPADIS cohort from January 2016 to November 2017, were followed-up with after 2 years. The Non-Motor Symptoms Scale (NMSS) was administered at baseline (V0) and at 24 months ± 1 month (V2). Linear regression models were used for determining predictive factors of global NMS burden progression (NMSS total score change from V0 to V2 as dependent variable). Results: After the 2-year follow-up, the mean NMS burden (NMSS total score) significantly increased in PD patients by 18.8% (from 45.08 ± 37.62 to 53.55 ± 42.28; p < 0.0001; N = 501; 60.2% males, mean age 62.59 ± 8.91) compared to no change observed in controls (from 14.74 ± 18.72 to 14.65 ± 21.82; p = 0.428; N = 122; 49.5% males, mean age 60.99 ± 8.32) ( p < 0.0001). NMSS total score at baseline (β = -0.52), change from V0 to V2 in PDSS (Parkinson's Disease Sleep Scale) (β = -0.34), and change from V0 to V2 in NPI (Neuropsychiatric Inventory) (β = 0.25) provided the highest contributions to the model (adjusted R-squared 0.41; Durbin-Watson test = 1.865). Conclusions: Global NMS burden demonstrates short-term progression in PD patients but not in controls and identifies worsening sleep problems and neuropsychiatric symptoms as significant independent predictors of this NMS progression.