Journal of Personalized Medicine Article Predictors of Global Non-Motor Symptoms Burden Progression in Parkinson’s Disease. Results from the COPPADIS Cohort at 2-Year Follow-Up Diego Santos-García 1, * , Teresa de Deus 2 , Carlos Cores 1 , Hector Canfield 2 , Jose M Paz González 1 , Cristina Martínez Miró 1 , Lorena Valdés Aymerich 1 , Ester Suárez 2 , Silvia Jesús 3,4 , Miquel Aguilar 5 , Pau Pastor 5 , Lluis Planellas 6 , Marina Cosgaya 6 , Juan García Caldentey 7 , Nuria Caballol 8 , Ines Legarda 9 , Jorge Hernández-Vara 10 , Iria Cabo 11 , Lydia López Manzanares 12 , Isabel González Aramburu 4,13 , Maria A Ávila Rivera 14 , Maria J Catalán 15 , Victor Nogueira 16 , Victor Puente 17 , Julio Dotor 18 , Carmen Borrué 19 , Berta Solano 20 , Maria Álvarez Sauco 21 , Lydia Vela 22 , Sonia Escalante 23 , Esther Cubo 24 , Francisco Carrillo 25 , Juan C Martínez Castrillo 26 , Pilar Sánchez Alonso 27 , Gemma Alonso 28 , Nuria López Ariztegui 29 , Itziar Gastón 30 , Jaime Kulisevsky 4,31 , Marta Blázquez 32 , Manuel Seijo 11 , Javier Rúiz Martínez 33 , Caridad Valero 34 , Monica Kurtis 35 , Oriol de Fábregues 10 , Jessica Ardura 36 , Ruben Alonso 37 , Carlos Ordás 38 , Luis M López Díaz 39 , Darrian McAfee 40 , Pablo Martinez-Martin 4 , Pablo Mir 3,4 and COPPADIS Study Group † 1 CHUAC, Complejo Hospitalario Universitario de A Coruña, 15006 A Coruña, Spain;  Carlos.Cores.Bartolome@sergas.es (C.C.); jpazg1@hotmail.com (J.M.P.G.);  Cristina.Martinez.Miro@sergas.es (C.M.M.); lorena.aymerich@gamil.com (L.V.A.) 2 CHUF, Complejo Hospitalario Universitario de Ferrol, 15405 A Coruña, Spain; Citation: Santos-García, D.; de Deus, T.; Cores, C.; Canfield, H.; Paz terecorreomovil@gmail.com (T.d.D.); canfield.hector@gmail.com (H.C.); str_sc@hotmail.com (E.S.) 3 Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de González, J.M.; Martínez Miró, C.; Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Valdés Aymerich, L.; Suárez, E.; Jesús, 41009 Seville, Spain; smaestre-ibis@us.es (S.J.); pmir@us.es (P.M.) S.; Aguilar, M.; et al. Predictors of 4 CIBERNED (Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas), Global Non-Motor Symptoms Burden 28031 Madrid, Spain; isagaramburu@gmail.com (I.G.A.); Jkulisevsky@santpau.cat (J.K.); Progression in Parkinson’s Disease. pmm650@hotmail.com (P.M.-M.) Results from the COPPADIS Cohort 5 Hospital Universitari Mutua de Terrassa, 08221 Barcelona, Spain; miquelaguilar@gmail.com (M.A.); at 2-Year Follow-Up. J. Pers. Med. paupastor@mutuaterrassa.es (P.P.) 6 Hospital Clínic de Barcelona, 08036 Barcelona, Spain; lplanellas@hotmail.com (L.P.); 2021, 11, 626. https://doi.org/ 10.3390/jpm11070626 marinacosgaya@gmail.com (M.C.) 7 Centro Neurológico Oms 42, 07003 Palma de Mallorca, Spain; juangcaldentey@hotmail.com 8 Consorci Sanitari Integral, Hospital Moisés Broggi, 08970 Barcelona, Spain; nuriacaballol@hotmail.com Academic Editor: Felix Javier Jiménez 9 Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain; ines.legarda@ssib.es Jiménez 10 Hospital Universitario Vall d’Hebron, 08035 Barcelona, Spain; hernandezvarajorge76@gmail.com (J.H.-V.); odefabregues@gmail.com (O.d.F.) Received: 10 May 2021 11 Complejo Hospitalario Universitario de Pontevedra (CHOP), 36071 Pontevedra, Spain; icabol@yahoo.es (I.C.); Accepted: 28 June 2021 manuel.seijo.martinez@sergas.es (M.S.) Published: 30 June 2021 12 Hospital Universitario La Princesa, 28006 Madrid, Spain; lydialopez@hotmail.com 13 Hospital Universitario Marqués de Valdecilla, 39011 Santander, Spain 14 Consorci Sanitari Integral, Hospital General de L’Hospitalet, 08906 Barcelona, Spain; Publisher’s Note: MDPI stays neutral asuncion.avila@sanitatintegral.org with regard to jurisdictional claims in 15 Hospital Universitario Clínico San Carlos, 28040 Madrid, Spain; mariajose.catalan@salud.madrid.org published maps and institutional affil- 16 Hospital Da Costa, 27880 Burela, Spain; victor.nogueira.fernandez@sergas.es iations. 17 Hospital del Mar, 08003 Barcelona, Spain; Vpuente@parcdesalutmar.cat 18 Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain; juliodotor@gmail.com 19 Hospital Infanta Sofía, 28702 Madrid, Spain; carmenborrue@hotmail.com 20 Institut d’Assistència Sanitària (IAS)—Institut Català de la Salut, 17190 Girona, Spain; berta_solano@hotmail.com Copyright: © 2021 by the authors. 21 Hospital General Universitario de Elche, 03203 Elche, Spain; mariaalsa@hotmail.com Licensee MDPI, Basel, Switzerland. 22 Fundación Hospital de Alcorcón, 28922 Madrid, Spain; lvela@fhalcorcon.es This article is an open access article 23 Hospital de Tortosa Verge de la Cinta (HTVC), 43500 Tarragona, Spain; sescalant@yahoo.es distributed under the terms and 24 Complejo Asistencial Universitario de Burgos, 09006 Burgos, Spain; esthercubo@gmail.com conditions of the Creative Commons 25 Hospital Universitario de Canarias, 38320 San Cristóbal de la Laguna, Spain; fcarpad@gobiernodecanarias.org 26 Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain; jcmcastrillo@gmail.com Attribution (CC BY) license (https:// 27 Hospital Universitario Puerta de Hierro, 28222 Madrid, Spain; PISANCHEZAL@GMAIL.COM creativecommons.org/licenses/by/ 4.0/). J. Pers. Med. 2021, 11, 626. https://doi.org/10.3390/jpm11070626 https://www.mdpi.com/journal/jpm J. Pers. Med. 2021, 11, 626 2 of 25 28 Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo (CHUVI), 36213 Vigo, Spain; gemavarita@gmail.com 29 Complejo Hospitalario de Toledo, 45071 Toledo, Spain; nlariztegui@gmail.com 30 Complejo Hospitalario de Navarra, 31008 Pamplona, Spain; itziar.gaston.zubimendi@cfnavarra.es 31 Hospital de Sant Pau, 08041 Barcelona, Spain 32 Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; marta.blazquez.estrada@gmail.com 33 Hospital Universitario Donostia, 20009 San Sebastián, Spain; JAVIER.RUIZMARTINEZ@osakidetza.eus 34 Hospital Arnau de Vilanova, 46015 Valencia, Spain; carivalero@icloud.com 35 Hospital Ruber Internacional, 28034 Madrid, Spain; mkurtis@ruberinternacional.es 36 Hospital de Cabueñes, 33394 Gijón, Spain; jessardura@yahoo.es 37 Hospital Universitario Lucus Augusti (HULA), 27002 Lugo, Spain; r.alonso1408@gmail.com 38 Hospital Rey Juan Carlos, 28933 Madrid, Spain; carlos.ordas@quironsalud.es 39 Complejo Hospitalario Universitario de Orense (CHUO), 32005 Orense, Spain; Luis.Manuel.Lopez.Diaz@sergas.es 40 Laboratory for Cognition and Neural Stimulation, Univeristy of Pennsylvania, Philadelphia, PA 19104, USA; mcafeed@sas.upenn.edu * Correspondence: diegosangar@yahoo.es; Tel.: +34-64617-3341 † The full list of the Study Group COPPADIS is provided in the Appendix A. Abstract: 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. Keywords: mood; non-motor symptoms; Parkinson’s disease; progression; quality of life 1. Introduction Parkinson’s disease (PD), the second most common neurodegenerative disease after Alzheimer’s disease, is a progressive neurodegenerative disorder causing motor and non- motor symptoms (NMS) that result in disability, loss of patient autonomy, and caregiver burden [1]. Some NMS (e.g., olfactory disorders, constipation, or sleep disturbances) may precede motor symptoms and could be useful as prodromal/preclinical markers of PD [2]. Other symptoms, such as dementia and psychosis, more frequently develop during the late stages of the disease and are sometimes difficult to manage [3]. Early identification and proper management of NMS is important because NMS are common and negatively impact a patient’s quality of life (QoL) [4]. Many cross-sectional studies have analyzed the impact of NMS burden on QoL in PD patients [5–8]. However, there is a lack of knowledge about how NMS burden progresses over time and how its progression impacts on QoL [9–12]. Thus, there are limited data from large, controlled, prospective studies on the evolution of NMS in PD [12]. Very recently, we observed that NMS progression is an important factor J. Pers. Med. 2021, 11, 626 3 of 25 which impacts the change in a patient’s QoL in PD patients from the COPPADIS cohort after a 2-year follow-up [13]. However, not all PD patients progress in the same way with regard to NMS. Identification of predictive factors for global NMS burden progression is necessary to be able to propose specific interventions (e.g., medication, other therapy, preventive action, etc.). In other words, avoiding or at least reducing the progression of NMS perceived by the patient could help avoid a deterioration in his/her QoL perception. The aim of the present study was to (1) analyze the change in global NMS burden, and in some NMS in particular, in PD patients from the COPPADIS 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. 2. Methods PD patients and controls, who were recruited from January 2016 to November 2017 from 35 centers of Spain from the COPPADIS cohort [14] and were evaluated again at 2-year follow-up, were included in the study. Methodology about COPPADIS-2015 study can be consulted at https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-016-0548-9 (25 February 2016) [15]. This is a multi-center, observational, longitudinal-prospective, 5-year follow-up study designed to analyze disease progression in a Spanish population of PD patients. All patients included were diagnosed according to UK PD Brain Bank criteria. Exclusion criteria were: atypical parkinsonism, dementia (Mini Mental State Examination (MMSE) <26), age <18 or >75 years, inability to read or understand the questionnaires, to receive any advanced therapy (continuous infusion of levodopa or apomorphine, and/or with deep brain stimulation at baseline), and the presence of comorbidity, sequelae, or any disorder that could interfere with the assessment. Information on sociodemographic aspects, factors related to PD, comorbidity, and treatment was collected. V0 (baseline visit) and V2 (2 years ± 1 month) evaluations included motor assessment (Hoenh & Yahr [H&Y], Unified Parkinson’s Disease Rating Scale (UPDRS) part III and part IV, Freezing of Gait Questionnaire (FOGQ)), non-motor symptoms (Non-Motor Symptoms Scale (NMSS), Parkinson’s Disease Sleep Scale (PDSS), Visual Analog Scale-Pain (VAS-Pain), Visual Analog Fatigue Scale (VAFS)), cognition (MMSE, Parkinson’s Disease Cognitive Rating Scale (PD-CRS), completing a simple 16- piece puzzle), mood and neuropsychiatric symptoms (Beck Depression Inventory-II (BDI- II), Neuropsychiatric Inventory (NPI), Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale (QUIP-RS)), disability (Schwab & England Activities of Daily Living Scale (ADLS)), and QoL (the 39-item Parkinson’s disease Questionnaire (PDQ-39), PQ-10, the EUROHIS-QOL 8-item index (EUROHIS-QOL8)) [15]. 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 performed without medication in patients without motor fluctuations. The 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 and non-motor assessment (NMSS and ADLS) was conducted in PD patients at 1 year ± 1 month [15]. The NMSS [16] was used for assessing the NMS and defining the global NMS burden at V0 and at V2 in both groups, PD patients and controls. It was applied in PD patients at V1 as well. The NMSS includes 30 items, each with a different non-motor symptom. The symptoms refer to the 4 weeks prior to assessment. The total score for each item is the result of multiplying the frequency (0, never; 1, rarely; 2, often; 3, frequent; 4, very often) x severity (1, mild; 2, moderate; 3, severe) and will vary from 0 to 12 points. The scale score ranges from 0 to 360 points (NMSS total score). The items are grouped into nine different domains: (1) Cardiovascular (items 1 and 2; score, 0 to 24); (2) Sleep/fatigue (items 3, 4, 5, and 6; score, 0 to 48); (3) Depression/apathy (items 7, 8, 9, 10, 11, and 12; score, 0 to 72); (4) Perceptual problems/hallucinations (items 13, 14, and 15; score, 0 to 36); (5) Attention/memory (items 16, 17, and 18; score, 0 to 36); (6) Gastrointestinal tract (items 19, 20, and 21; score 0 to 36); (7) Urinary symptoms (items 22, 23, and 24; score, 0 to 36); J. Pers. Med. 2021, 11, 626 4 of 25 (8) Sexual dysfunction (items 25 and 26; score 0 to 24); and (9) Miscellaneous (items 27, 28, 29, and 30; score, 0 to 48). Each domain of the NMSS was expressed as a percentage: (score/total score) × 100. The global NMS burden was defined as the NMS total score and it was categorized in four groups: mild (NMSS 1–20); moderate (NMSS 21–40); severe (NMSS 41–70); very severe (NMSS >70) [17]. 2.1. Data Analysis Data were processed using SPSS 20.0 (IBM, Armonk, NY, USA) for Windows. For comparisons between groups, the Student’s t-test, Mann–Whitney U test, Chi-square test, or Fisher test was used as appropriate (distribution for variables was verified by one-sample Kolmogorov–Smirnov test). General linear model (GLM) repeated measure was used to test whether the mean differences of the NMSS total score and the NMSS domain scores between the two visits (V0 and V2) were significant in both PD patients and controls. In PD patients, it was analyzed the change between V1 and V0, V2 and V1 and between all groups as well. Age, gender and LEDD (levodopa equivalent daily dose) at V0 and at V2 were included as covariates. This test was also applied for testing the difference between V2 and V0 in other variables. Cohen’s d formula was applied for measuring the effect size (in PD patients). It was considered: small effect = 0.2; medium effect = 0.5; large effect = 0.8. The Bonferroni method was used was used as a post-hoc test after ANOVA. Spearman’s or Pearson’s correlation coefficient, as appropriate, was used for analyzing the relationship between the change from V0 to V2 in 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. The p-value was considered significant when it was <0.05. 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). Any variable with univariate associations with p-values <0.20 were included in a multivariable model, and a backwards selection process was used to remove variables individually until all remaining variables were significant at the 0.10 level [12]. The variables considered for the analysis were: (1) at baseline (V0): age, gender, disease duration, total number of non-antiparkinsonian drugs, LEDD, daily dose of levodopa, daily dose of dopamine agonist, motor phenotype [18], UPDRS-III (OFF), UPDRS-IV, FOGQ, PD-CRS, NMSS, PDSS, NPI, QUIP-RS, VAS-PAIN, VASF-Physical, and VASF-Mental; (2) at 2-year follow-up (V2): to be receiving L-dopa, a MAO-B (monoamine oxidase type B) inhibitor, a COMT (catechol-o-methyl transferase) inhibitor, a dopamine agonist, and to practice regular exercise; (3) at the end of the follow-up (V2): change from V0 to V2 in total number of non-antiparkinsonian drugs, LEDD, daily dose of levodopa, daily dose of dopamine agonist, UPDRS-III, UPDRS-IV, FOGQ, PD-CRS, PDSS, NPI, QUIP-RS, VAS-PAIN, VASF- Physical, and VASF-Mental. Tolerance and variance inflation factor (VIF) were used to detect multicollinearity (multicollinearity was considered problematic when tolerance was less than 0.2 and, simultaneously, the value of VIF 10 and above). Finally, according to the change in the NMSS total score, patients were classified as “NMS—improver” (NMSS total score at V2 < NMSS total score at V0) or “non NMS improver” (NMSS total score at V2 ≥ NMSS total score at V0) and predictors of NMS improvement were identified. A level of p = 0.01 was considered for determining significant variables in the model. 2.2. Standard Protocol Approvals, Registrations, and Patient Consents For this study, we received approval from the Comité de Ética de la Investigación Clínica de Galicia from Spain (2014/534; 2/12/2014). Written informed consent from all participants in this study were obtained before the start of the study. COPPADIS-2015 was classified by the AEMPS (Agencia Española del Medicamento y Productos Sanitarios) as a Post-authorization Prospective Follow-up study with the code COH-PAK-2014-01. J. Pers. Med. 2021, 11, 626 5 of 25 3. Results After the 2-year follow-up, the mean global NMS burden (NMSS total score) signifi- cantly 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; mean disease duration 5.5 ± 4.37 years) compared to no change observed in controls (from 14.74 ± 18.72 to 14.65 ± 21.82; p = 0.944; N = 122; 49.5% males, mean age 60.99 ± 8.32) (difference between groups, p = 0.002) (Table 1 and Figure 1B). Moreover, the increase in the mean NMSS total score from V0 to V1 and from V1 to V2 was significant as well (p < 0.0001; Figure 1A). By domains, the score of all the NMSS domains at V2 was significantly higher than at V0 in PD patients except domain 9 (Miscellaneous) but none in the control group (Table 1). In PD patients, the highest increase from V0 to V2 was for domain 1 (cardiovascular symptoms) with a 117.7% (Cohen’s effect size = 0.644), and the lowest was for domain 9 (miscellaneous) with a 10.7% (Figure 1C). With regard to other NMS, a significant change in the score of the PD-CRS (from 92 ± 15.65 to 90.26 ± 18.07; p < 0.0001; N = 500), VAS-Pain (from 2.61 ± 2.92 to 2.96 ± 2.88; p = 0.037; N = 501), and VAFS-Physical (from 2.86 ± 2.67 to 3.17 ± 2.8; p = 0.025; N = 501) was also observed in the PD group but not in controls (Table 1). In 201/501 patients (40.1%) a score at V2 equal to or less than the baseline NMSS total score was observed compared to in 73/122 controls (59.8%) (p < 0.0001). Specifically, 38.5%, 1.6%, and 59.9% of the patients presented improvement (NMSS at V2 < NMSS at V0), no change (NMSS at V2 = NMSS at V0), and impairment (NMSS at V2 > NMSS at V0), respectively, with regard to the change in the NMSB from V0 to V2 (Figure 2B). A significant change in the percentage of patients with mild, moderate, severe, or very severe burden from V0 to V1 (p = 0.016; N = 600) and from V1 to V2 (p = 0.007; N = 482) was observed in the PD group (when all groups were considered, p < 0.0001 [N = 482]) (Figure 2A). J. Pers. Med. 2021, 11, 626 6 of 25 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 PD Patients Controls Controls Cohen’s Test pa pb pc pd V0 V2 V0 V2 Hoehn & Yahr (OFF) (%) 0.422 <0.0001 N.A. N.A. 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 0.452 <0.0001 N.A. N.A. N.A. N.A. N.A. UPDRS-IV 1.99 ± 2.41 2.65 ± 2.75 0.371 <0.0001 N.A. N.A. N.A. N.A. N.A. FOGQ 3.76 ± 4.69 4.94 ± 5.18 0.4 <0.0001 N.A. N.A. N.A. N.A. N.A. Daily dose L-dopa (mg) 577.48 ± 412.09 767.56 ± 307.1 0.812 <0.0001 N.A. N.A. N.A. N.A. N.A. Number of non-antipark. drugs 2.35 ± 2.38 3.08 ± 2.65 0.507 <0.0001 2.04 ± 2.16 2.76 ± 2.35 0.005 PD-CRS 92 ± 15.65 90.26 ± 18.07 −0.207 <0.0001 99.65 ± 13.56 99.68 ± 13.73 0.368 0.517 0.018 NMSS 45.08 ± 37.62 53.55 ± 42.28 0.343 <0.0001 14.74 ± 18.72 14.65 ± 21.82 0.944 0.784 0.002 Cardiovascular 5.45 ± 9.79 11.87 ± 14.21 0.644 <0.0001 1.78 ± 3.6 1.99 ± 3.91 0.929 0.151 0.004 Sleep/fatigue 16.28 ± 15.91 19.2 ± 17.52 0.241 <0.0001 5.91 ± 7.98 5.32 ± 9.87 0.813 0.243 0.018 Mood/apathy 11.32 ± 16.07 13.21 ± 17.98 0.173 0.007 3.8 ± 8.85 3.93 ± 11.53 0.219 0.438 0.249 Perceptual symptoms 3.24 ± 9.24 5.51 ± 12.71 0.286 <0.0001 0.13 ± 1.12 0.39 ± 2.41 0.352 0.643 0.316 Attention/memory 10.01 ± 14.5 12.69 ± 17.08 0.249 <0.0001 5.13 ± 10.85 5.18 ± 11.25 0.567 0.747 0.321 Gastrointestinal symptoms 9.59 ± 13.1 12.28 ± 14.35 0.3 <0.0001 1.58 ± 5.23 1.53 ± 4.39 0.385 0.414 0.001 Urinary symptos 21.47 ± 22.21 24.09 ± 23.14 0.181 0.013 7.63 ±12.57 7.71 ±11.74 0.851 0.982 0.012 Sexual dysfunction 18.83 ± 25.53 22.67 ± 27.84 1.182 0.005 7.43 ± 16.54 7.5 ± 14.68 0.903 0.714 0.002 Miscellaneous 14.98 ± 15.41 16.59 ± 15.69 0.149 0.054 3.73 ± 8.75 3.54 ± 8.31 0.633 0.698 0.004 BDI-II 8.28 ± 6.9 8.54 ± 7.48 0.048 0.369 4.56 ± 5.46 4.31 ± 5.5 0.484 0.541 0.043 PDSS 117.13 ± 24.48 117.85 ± 24.98 0.038 0.452 131.26 ± 17.41 126.67 ± 26.46 0.796 0.737 0.677 QUIP-RS 4.6 ± 8.8 4.66 ± 9.22 0.007 0.798 1.51 ± 3.73 1.32 ± 3.37 0.284 0.334 0.222 NPI 5.82 ± 7.88 6.17 ± 9.39 0.056 0.491 3.31 ± 7.15 2.64 ± 7.67 0.786 0.714 0.486 VAS-PAIN 2.61 ± 2.92 2.96 ± 2.88 0.147 0.037 1.49 ± 2.41 1.70 ± 2.32 0.272 0.661 0.177 VASF-physical 2.86 ± 2.67 3.17 ± 2.8 0.147 0.025 1.52 ± 2.35 1.29 ± 2.12 0.78 0.488 0.198 VASF-mental 2.09 ± 2.51 2.20 ± 2.61 0.056 0.545 1.29 ± 2.09 1.03 ± 1.97 0.699 0.96 0.254 ADLSL 88.58 ± 10.19 84.26 ± 13.38 −0.519 <0.0001 98.87 ± 6.65 99.52 ± 2.15 0.227 0.069 <0.0001 PDQ-39SI 16.72 ± 13.02 20.3 ± 16.41 0.413 <0.0001 N.A. N.A. N.A. N.A. N.A. PQ-10 3.77 ± 0.54 3.75 ± 0.58 −0.114 0.063 8.07 ± 1.22 7.86 ± 1.65 0.06 0.486 0.831 EUROHIS-QOL8 3.8 ± 0.7 3.68 ± 0.67 0.048 0.4 4.18 ± 0.5 4.12 ± 0.51 0.066 0.852 0.074 p values were computed using general linear models (GLM) repeated measures. The results represent mean ± SD or %; p a , change over time (V2 vs. V0) in PD patients; p b , change over time (V2 vs. V0) in controls. Age, gender and LEDD (levodopa equivalent daily dose) (except for assessing changes in this variable) at V0 and at V2 were included as covariates; p c , group visit interaction; p d , PD vs. controls. PD vs. controls is not applicable if test of interaction was significant (a significant test of interaction means the rates of changes over time are different between the two groups). All patients with the data at V0 and V2 were included for each comparative analysis. For NMSS and its domains, N = 501 in PD patients and N = 122 in the control group. ADLS, Schwab & England Activities of Daily Living Scale; BDI-II, Beck Depression Inventory-II; FOGQ, Freezing Of Gait Questionnaire; 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. J. Pers. Med. 2021, 11, 626 7 of 25 J. Pers. Med. 2021, 11, x FOR PEER REVIEW 6 of 23 A B C Figure 1. (A) Mean NMSS total score at V0 (baseline), V1 (1 year follow-up ± 1 month), and V2 (2-year follow-up ± 1 month) Figure 1. (A) Mean NMSS total score at V0 (baseline), V1 (1 year follow-up ± 1 month), and V2 (2-year follow-up ± 1 month) in PD patients (N = 481). V1 vs. V0, p < 0.0001; V2 vs. V1, p < 0.0001; V2 vs. V0, p < 0.0001; All groups; p < 0.0001. (B) Change in PD patients (N = 481). V1 vs. V0, p < 0.0001; V2 vs. V1, p < 0.0001; V2 vs. V0, p < 0.0001; All groups; p < 0.0001. (B) Change from V0 to V2 in the mean NMSS total score in PD patients (N = 501) and controls (N = 122). V2 vs. V0 in controls, p = from V0 0.944; V2tovs. V2V0in in thePD mean NMSSptotal patients, scoredifference < 0.0001; in PD patients (Nchange in the = 501) and fromcontrols V0 to V2(Nbetween = 122). V2 PDvs. V0 in controls, patients p = 0.944; and controls, p= V2 vs. V0 in PD patients, p < 0.0001; difference in the change from V0 to V2 between PD patients and 0.002. (C) Mean score on each domain of the NMSS scale at V0, V1, and V2 in PD patients (blue) and controls (red). controls, p = 0.002. Data (C) and (A Mean B)score on each domain are presented as boxofplots, the NMSS scalebox with the at V0, V1, and V2the representing in PD patients median and(blue) andmiddle the two controlsquartiles (red). Data (A and B) (25–75%). P are presented values as box plots, were computed usingwith the box general representing linear models (GLM)the median andmeasures. repeated the two middle quartiles Mild outliers (O)(25–75%). P values are data points were that are more extreme computed than using Q1 − 1.5 general × IQR linear or Q3(GLM) models + 1.5 ×repeated IQR. NMSS, Non-Motor measures. Symptoms Mild outliers (O) Scale. are data points that are more extreme than Q1 − 1.5 × IQR or Q3 + 1.5 × IQR. NMSS, Non-Motor Symptoms Scale. J. Pers. Med. 2021, 11, 626 8 of 25 Figure 2. (A) Percentage of PD patients with mild (NMSS 1–20), moderate (NMSS 21–40), severe (NMSS 41–70), and very severe (NMSS >70) NMS burden at V0 (baseline), V1 (1 year follow-up ± 1 month), and V2 (2-year follow-up ± 1 month). V1 vs. V0, p < 0.016 (N = 600); V2 vs. V1, p = 0.007 (N = 482), All groups; p < 0.0001 (N = 481). (B) Percentage of patients with a greater NMS burden (NMS burden impairment; in red), no change (No changes in the NMSS total score), and a lower NMS burden (NMS burden improvement; in green) at V1 compared to V0, V2 compared to V1, and V2 compared to V0. NMSS, Non-Motor Symptoms Scale. A moderate correlation was observed between the change in the NMSS total score from V0 to V2 and the change in the BDI-II (r = 0.35; p < 0.0001), PDSS (r = −0.34; p < 0.0001), NPI (r = 0.31; p < 0.0001), and PDQ-39SI (r = 0.42; p < 0.0001) scores over the same period (Table 2). When the change in the score of the domains of the NMSS was considered, moderate correlations were observed between the changes from V0 to V2 in domain 1 (cardiovascular symptoms) and ADLS (r = −0.35; p < 0.0001), domain 2 and PDSS (r = −0.34; p < 0.0001) and PDQ-39SI (r = 0.33; p < 0.0001), and domain 3 and BDI-II (r = 0.33; p < 0.0001), VAS-PAIN (r = 0.41; p < 0.0001), and PDQ-39SI (r = 0.35; p < 0.0001) (Table 2). Correlation between the change from V0 to V2 in NMS (NMSS total score and score domains) and LEDD, daily dose of levodopa, and daily dose of dopamine agonist was negligible. In the multivariate analysis, a greater increase in the NMSS total score from V0 to V2 was associated with longer disease duration (p = 0.006), a higher NPI total score (indicative of more severe neuropsychiatric symptoms) (p < 0.0001) and a lower total score on the NMSS (p < 0.0001) and PDSS (indicative of a worse sleep quality) (p = 0.001) at baseline, a greater decrease in the PDSS total score from V0 to V2 (indicative of a greater sleep quality impairment) (p < 0.0001), a greater increase in the FOGQ from V0 to V2 (indicative of a more worsening in gait problems) (p = 0.001) and in the NPI total score from V0 to V2 (indicative of a more impairment in neuropsychiatric symptoms) (p < 0.0001), and to be taking an antipsychotic agent at V2 (p = 0.003) (Table 3). NMSS total score at baseline (β = −0.52), change from V0 to V2 in PDSS (β = −0.34), and change from V0 to V2 in NPI (β = 0.25) provided the highest contributions to the model (adjusted R-squared 0.41; Durbin-Watson test = 1.865) (Table 3). In the final model, tolerance was from 0.61 to 0.94 and VIF from 1.05 to 1.72. J. Pers. Med. 2021, 11, 626 9 of 25 Table 2. Correlations between the changes in non-motor symptoms (NMSS total score and NMSS domains) and other disease-related variables in PD patients from V0 (baseline) to V2 (2 years ± 1 month). NMSS NMSS NMSS NMSS NMSS NMSS NMSS NMSS NMSS NMSS TS D1 D2 D3 D4 D5 D6 D7 D8 D9 Age at baseline −0.06 0.12 *** −0.03 −0.01 0.04 0.04 −0.04 −0.08 −0.03 −0.04 Disease duration (at V0) 0.10 *** 0.11 *** 0.02 0.07 0.06 0.04 0.02 0.06 0.12 *** 0.05 N. of non-antipark. drugs (at V0) −0.05 0.12 *** −0.03 −0.03 0 −0.02 −0.03 −0.06 −0.02 −0.07 Change at V2 (from V0 to V2) LEDD 0.02 −0.02 0.03 0.02 0.02 0.01 0.08 0.04 −0.01 0 Daily dose L-dopa (mg) 0.01 −0.05 0.01 0.03 −0.02 0.02 0.05 0.01 −0.03 0.04 Equivalent daily dose of DA (mg) −0.04 0.02 0.02 −0.1 0.02 −0.09 *** 0.05 −0.04 −0.06 −0.05 Number of non-antipark. drugs 0.06 0.07 −0.02 0 0.09 *** 0.08 0.03 0.07 0 0.04 UPDRS-III (OFF) 0.16 * 0.07 0.12 *** 0.16 ** 0.07 0.11 *** 0.07 0.14 *** 0 0.15 *** UPDRS-IV 0.10 *** 0.02 0.12 *** 0.09 0.06 0 0.06 0.11 *** 0 0.04 FOGQ 0.21 * 0.11 *** 0.19 * 0.13 ** 0.09 *** 0.13 *** 0.12 *** 0.14 *** 0.10 *** 0.11 *** PD-CRS 0.01 −0.05 −0.04 −0.01 −0.05 −0.11 *** 0.02 −0.03 0.15 0.03 BDI-II 0.35 * 0.17 * 0.29 * 0.33 * 0.19 * 0.22 * 0.09 *** 0.15 ** 0.13 *** 0.14 *** PDSS −0.34 * −0.04 −0.34 * −0.23 −014 ** −0.15 ** −0.17* −0.24 * −0.12 *** −0.17 * QUIP-RS 0.10 *** 0 0.06 −0.03 0.17 * 0.05 −0.02 0.11 *** 0.03 0.05 NPI 0.31 * 0.12 *** 0.19 * −0.03 0.21 * 0.18 * 0.12 *** 0.12 *** 0.14 *** 0.06 VAS-PAIN 0.12 *** 0.09 *** 0.09 *** 0.41 * 0.06 0.01 0.07 0.02 0.11 *** 0.12 *** VASF-physical 0.21 * 0.01 0.10 *** 0.11 *** 0.07 0.08 0.13 *** 0.08 0.09 0.14 *** VASF-mental 0.21 * 0 0.15 * 0.18 * 0.07 0.11 0.18 * 0.09 0.07 0.10 *** PDQ-39SI 0.42 * 0.09 *** 0.33 * 0.35 * 0.15 ** 0.23 * 0.20 * 0.19 *** 0.12 *** 0.17 * PQ-10 −0.17 * −0.06 −0.15 ** −0.17 * −0.11 *** −0.11 *** −0.07 −0.07 −0.01 −0.08 EUROHIS-QOL8 −0.20 * −0.03 −0.25 * −0.09 *** −0.11 *** −0.12 *** −0.05 −013 *** −0.04 −0.09 ADLS −0.24 * −0.35 * −0.19 * −0.19 −0.15 ** −0.18 * −0.17 −0.15 ** −0.17 * −0.10 *** Spearman correlation test was applied. *, p < 0.0001; **, p < 0.001; ***, p < 0.05. In bold are expressed significant values. NMSS: TS, total score. D1, Cardiovascular (items 1 and 2; score, 0 to 24); D2, Sleep/fatigue (items 3, 4, 5, and 6; score, 0 to 48); D3, Depression/apathy (items 7, 8, 9, 10, 11, and 12; score, 0 to 72); D4, Perceptual problems/hallucinations (items 13, 14, and 15; score, 0 to 36); D5, Attention/memory (items 16, 17, and 18; score, 0 to 36); D6, Gastrointestinal tract (items 19, 20, and 21; score 0 to 36); D7, Urinary symptoms (items 22, 23, and 24; score, 0 to 36); D8, Sexual dysfunction (items 25 and 26; score 0 to 24); D9, Miscellaneous (items 27, 28, 29, and 30; score, 0 to 48). ADLS, Schwab & England Activities of Daily Living Scale; BDI-II, Beck Depression Inventory-II; DA, dopamine agonist; FOGQ, Freezing Of Gait Questionnaire; LEDD, levodopa equivalent dauly dose; N, number; 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; TS, total score; UPDRS, Unified Parkinson’s Disease Rating Scale; VAFS, Visual Analog Fatigue Scale; VAS-Pain, Visual Analog Scale-Pain. J. Pers. Med. 2021, 11, 626 10 of 25 Table 3. Linear regression model about factors associated with global burden progression after 2-year follow-up (change in the NMSS total score from V0 to V2). βa βb 95% IC a 95% IC b pa pb At V0 (baseline) Age at baseline −0.036 N.A. −0.501–0.211 N.A. 0.423 N.A. Gender −0.045 N.A. −9.419–3.024 N.A. 0.313 N.A. Disease duration 0.092 0.118 0.019–1.499 0.261–1.591 0.044 0.006 Number of non-antipark. drugs −0.041 N.A. −1.862–0.683 N.A. 0.363 N.A. LEDD 0.062 N.A. −0.002–0.012 N.A. 0.17 N.A. Daily dose L-dopa (mg) 0.077 0.152 −0.001–0.019 N.A. 0.085 N.A. Equivalent Daily dose of DA (mg) 0.08 N.A. −0.002–0.038 N.A. 0.075 N.A. No-tremoric motor phenotype 0.062 0.094 −1.788–10.373 0.675–12.195 0.166 0.029 UPDRS-III 0.026 N.A. −0.217–0.387 N.A. 0.58 N.A. UPDRS-IV 0.015 N.A. −1.047–1.473 N.A. 0.74 N.A. FOGQ −0.023 N.A. −0.823–0.482 N.A. 0.608 N.A. PD-CRS −0.03 N.A. −0.262–0.129 N.A. 0.504 N.A. NMSS −0.317 −0.52 −0.369–0.215 −0.557–−0.370 <0.0001 <0.0001 BDI-II −0.174 N.A. −0.872 N.A. <0.0001 N.A. PDSS 0.077 −0.186 −0.015–0.234 −0.397–−0.106 0.085 0.001 NPI −0.12 0.208 −0.912–0.107 0.441–1.353 0.013 <0.0001 QUIP-RS −0.005 N.A. −0.310–0.271 N.A. 0.896 N.A. VAS-PAIN 0.032 N.A. −0.62–0.148 N.A. 0.032 N.A. VASF-Physical −0.021 N.A. −1.181– -0.684 N.A. 0.601 N.A. VASF-Mental −0.015 N.A. −1.206–0.832 N.A. 0.719 N.A. Change at V2 (from V0 to V2) Number of non-antipark. drugs 0.087 N.A. −0.040–3.925 N.A. 0.055 N.A. LEDD 0.072 N.A. −0.002–0.017 N.A. 0.115 N.A. Daily dose L-dopa (mg) 0.044 N.A. −0.007–0.019 N.A. 0.339 N.A. Equivalent daily dose of DA (mg) 0.009 N.A. −0.013–0.016 N.A. 0.843 N.A. UPDRS-III (OFF) 0.178 N.A. 0.296–0.938 N.A. <0.0001 N.A. UPDRS-IV 0.086 N.A. −0.041–2.434 N.A. 0.058 N.A. FOGQ 0.284 0.149 1.658–3.074 0.522–1.922 <0.0001 0.001 PD-CRS −0.026 N.A −0.339–0.186 N.A. 0.567 N.A. BDI-II 0.334 N.A. 1.120–1.862 N.A. <0.0001 N.A. PDSS −0.303 −0.339 −0.222 −0.543–−0.292 <0.0001 <0.0001 NPI 0.307 0.249 0.798–1.521 0.595–1.296 <0.0001 <0.0001 QUIP-RS 0.095 N.A. 0.038–0.612 N.A. 0.027 N.A. VAS-PAIN 0.156 N.A. 0.761–2.302 N.A. <0.0001 N.A. VASF-Physical 0.192 0.101 1.258–2.973 0.179–2.061 <0.0001 0.02 VASF-Mental 0.194 N.A. 1.282–3.010 N.A. <0.0001 N.A. J. Pers. Med. 2021, 11, 626 11 of 25 Table 3. Cont. βa βb 95% IC a 95% IC b pa pb At V2 To be taking L-dopa 0.025 N.A. −7.129–12.723 N.A. 0.58 N.A. To be taking a MAO-B inhibitor 0.03 N.A. −4.722–9.684 N.A. 0.499 N.A. To be taking a COMT inhibitor 0.003 N.A. −6.564–6.987 N.A. 0.951 N.A. To be receiving a DA 0.067 N.A. −1.651–12.057 N.A. 0.136 N.A. To be taking an analgecic −0.074 N.A. −11.116–0.388 N.A. 0.068 N.A. To be taking a benzodiazepin 0.025 N.A. −4.350–8.277 N.A. 0.542 N.A. To be taking an antidepressive agent 0.051 N.A. −2.049–9.514 N.A. 0.205 N.A. To be taking an antipsychotic agent 0.067 0.129 6.067–29.381 −3.084–22.227 0.138 0.003 To practice regular exercise 0.011 N.A. −6.668–8.440 N.A. 0.818 N.A. Cognitive stimulation therapy −0.017 N.A. −7.935–5.396 N.A. 0.708 N.A. Physiotherapy 0.016 N.A. −5.661–8.179 N.A. 0.721 N.A. Speech therapy −0.008 N.A. −10.296–8.548 N.A. 0.885 N.A. Dependent variable: change from V0 to V2 in the NMSS total score. β standardized coefficient and 95% IC are shown. a , univariate analysis; b , multivariate analysis (Durbin-Watson test = 1.865; R2 = 0.41). BDI-II, Beck Depression Inventory-II; COMT, catechol-o-methyl transferase; DA, dopamine agonist; FOG, freezing of gait; FOGQ, Freezing Of Gait Questionnaire; LEDD, levodopa equivalent daily dose (mg); MAO-B, monoamine oxidase type B; N.A., not applicable; NMS, non-motor symptoms; NMSS, Non-Motor Symptoms Scale; NPI, Neuropsychiatric Inventory; PD, Parkinson’s disease; PD-CRS, Parkinson’s Disease Cognitive Rating Scale; PDQ-39SI, 39-item Parkinson’s Disease Quality of Life Questionnaire Summary Index; PDSS, Parkinson’s Disease Sleep Scale; QoL, Quality of life; 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. J. Pers. Med. 2021, 11, 626 12 of 25 When change from V0 to V2 in the NMSS total score was considered as a binary variable (to be an NMS—improver as dependent variable), a lower dopamine agonist equivalent dose (OR = 0.998; 95%CI, 0.996–0.999; p = 0.013) and NPI total score (OR = 0.926; 95%CI, 0.884–0.970; p = 0.001) at V0, a higher NMSS total score (OR = 1.028; 95%CI, 1.018–1.039; p < 0.0001) at V0, and a greater decrease in the NPI total score (OR = 0.902; 95%CI, 0.864–0.943; p < 0.0001) and VASF-Physical (OR = 0.901; 95%CI, 0.831–0.977; p < 0.0001) from V0 to V2 were independent predictors of NMS improvement at 2-year follow-up (adjusted R-squared 0.27; Hosmer–Lemeshow test = 0.160). In NMS—improvers, the mean NPI and VASF-Physical total scores decreased from V0 to V2 in 2.34 ± 8.55 and of 0.39 ± 3.03 points, respectively, compared to an increase in 2.17 ± 8.57 and 0.74 ± 2.88 in non NMS improvers, respectively (p < 0.0001 for both analysis). The motor phenotype was not associated with NMS outcome, being NMS—improvers 104 out of 262 (39.7%) PD patients with a tremor-dominant motor phenotype vs. 89 out of 230 (37.2%) patients with a PIGD/indeterminate motor phenotype (p = 0.573). 4. Discussion The present study observes that global NMS burden (defined as NMSS total score) demonstrates short-term progression in PD patients and identifies some factors associated with this progression. Specifically, worsening gait problems (FOGQ), sleep symptoms (PDSS), and neuropsychiatric symptoms (NPI) was associated with an increase in global NMS burden at 2-year follow-up after adjustment to baseline status. On the contrary, a progression in NMS burden in the control group was not observed. Awareness of the progression of these symptoms in clinical practice, with the aim to introduce interventions to reduce NMS burden progression when possible, could be important. As example, bilateral subthalamic stimulation (STN-DBS) improved significantly the global SNMS burden and QoL in advanced PD patients after 36 months but not in patients who received the standard-of-care medical therapy [19]. Since global NMS burden impacts the patient’s QoL [8] and its progression worsens QoL [13], understanding the role global NMS plays in PD is very relevant. Although NMS are common and their importance has been increasing during the last years in PD [20], very little is known about the progression of NMS in PD patients, partially because there is a lack of longitudinal studies [12]. To our knowledge, our study represents the largest observational study about the longitudinal evolution of NMS in PD patients compared with non-PD controls in which a very extensive assessment and analysis have been conducted. Aligning with previous studies, we observed a significant increase in NMS burden over 2 years in PD patients compared with controls [9–12]. Erro et al. reported 2- year and 4-year longitudinal data about the baseline prevalence and longitudinal evolution of NMS in a cohort of PD patients, but the sample was small (N = 91 for 2-year and N = 61 for 4-year follow-up), a control group was not included, and a qualitative scale (NMSQ (Non-Motor Symptoms Questionnaire)) was used instead of a quantitative one [9,10]. As we observed, they found no association between NMS progression and motor disability as measured by the UPDRS-III and either drug class (i.e., L-dopa, DA, etc.) or total LEDD. In our study, the only motor feature related with NMS burden progression was gait problems. Previous studies have reported that gait problems including freezing of gait (FOG) are associated with higher NMSS total score and some NMS in particular such as cognitive impairment or anxiety [21–23]. Further, discrete gait impairment progresses in PD over time [24], as we noted here. In practice, it is important to keep in mind that patients with PD who develop an impairment in gait could progress more in their global NMS burden. Using gait impairment as a simple clinical biomarker of NMS progression could be helpful. More recently, Simuni et al. [12], identified clinical and biological variables associated with NMS progression in 380 PD patients from the PPMI (Parkinson’s Progression Mark- ers Initiative) and compared them with a control group (174 health control subjects) [12]. Although they used the MDS-UPDRS (Movement Disorder Society-Unified Parkinson’s Dis- ease Rating Scale) Part I [25], a strong convergent validity was shown with the NMSS [26]. J. Pers. Med. 2021, 11, 626 13 of 25 They observed a significant worsening in global cognition, depression, autonomic dys- function, and impulse control disorders in PD subjects, while controls worsened only in cognition and trait anxiety. In our cohort, the mean score of all domains of the NMSS except domain 9 (miscellaneous) increased significantly in patients but not in controls, although a significant change from baseline to 2-year assessment was not observed in the rest of scales except for the PD-CRS and VAS for pain and physical fatigue. In general, these results align with a majority of previous reports [27–29] but contrary to others [30]. An- tonini et al. [27] observed in 707 PD patients that sleep, gastrointestinal, attention/memory, and skin disturbances became more prevalent during a 24-month follow-up while psychi- atric, cardiovascular, and respiratory disorders became less prevalent. In another study, Vu et al. [28] reported that anxiety and depression were significantly less frequent in 795 de novo PD patients, while pain, sexual difficulties, and weight change were more frequent at 2-year follow-up period. In another study, NMS severity in 117 PD patients increased after a mean follow-up visit of 21.6 ± 5.6 months [29]. Unlike the above, Prakash et al. [30] noted in 147 PD patients a small but significant median reduction of total NMS burden over a 12–18-month study period, postulating that the improvement in total NMS burden with various therapies may be attributed to the early stages of PD in a majority (more than 80%) of their study patients. The early stages of PD are known to have the best therapeutic window response to symptomatic therapy for motor symptoms and it could be the best window for NMS as well [30,31]. However, in the COPPADIS cohort more than 90% of the patients included at baseline were in stage 1 or 2 of H&Y and a progression of some symptoms impacting on NMS burden progression was still observed even after considering different treatments in the model (dopaminergic and non-dopaminergic therapies). In spite of a lack of longitudinal studies about cognitive changes in the short-term in PD patients, there seems to be a slow and heterogenic progression of cognitive function in PD [32]. A very recent study observed that PD patients had significantly more fatigue than the control group from baseline and throughout 9 years of follow-up [33]. Although there is no clear evidence about the progression of pain in PD and again, more longitudinal studies are needed, some reports suggest a higher frequency of pain after long-term progres- sion [34]. Another study demonstrated that autonomic dysfunction is not only common in early-stage PD, but it increases in severity with increasing disease stage [35]. In addition, orthostatic hypotension has been associated with impaired daily living activities even in the asymptomatic stage [36]. In the COPPADIS cohort, cardiovascular symptoms was the domain of the NMSS with the greatest impairment, and a moderate correlation between the changes in cardiovascular symptoms and the changes in the ADLS at 2-year follow-up was observed. All these findings suggest that, despite symptomatic treatment, there is a lot of variability between patients with different non-motor phenotypes proposed [37] and that, globally, there is a slow progression of motor symptoms and NMS in PD. Results about the effect of size in this cohort suggest that the progression of NMS could be slower than motor symptoms. Simuni et al. [12] identified only two predictors of the longitudinal change of NMS, age at the time of analysis and lower CSF Aβ1-42. In our analysis, as in some other reports [29,38,39] but unlike some cross-sectional and case–control studies [40,41], age was not related with the severity evolution of NMS in PD. The large heterogeneity of PD patients in terms of treatments and age (in our study patients older than 75 years old were not included) may account for this discrepancy; therefore, longer periods of follow-up studies are needed. On the contrary, a longer disease duration was related to a greater global NMS burden impairment, aligning with the observation that NMS become more prevalent and severe in advanced PD patients throughout the course of the disease [42]. We did not introduce MRI and CSF biomarkers. Mollenhauer et al., did it and did not identify an association of NMS with the CSF measures [43]. Unlike Simuni et al., information about the variance and β regression coefficients were provided in our analysis. A novel aspect to be highlighted of the present study is the fact that greater sleep symptoms (PDSS) and neuropsychiatric symptoms (NPI) impairment predicted a greater global NMS J. Pers. Med. 2021, 11, 626 14 of 25 burden increase. The NMSS includes questions about these symptoms, but it has not been previously reported and this relationship was not observed for example with mood, a factor impacting very importantly in the perception of the patients about NMS [44]. As neuropsychiatric symptoms impact on QoL and several of these symptoms have a presumed effective treatment [45,46], doctors should be encouraged to assess the presence of these symptoms for the purpose of applying the proper treatment to improve the patients’ health-related QoL [46,47]. Remarkably, a reduction in the NPI score in this study from baseline visit to 2-year follow-up visit was a predictor of being an NMS—improver (i.e., to have a lower global NMS burden after 2 years of follow-up). With regard to sleep problems, there is a progressive increase in the frequency of sleep disturbances in PD, with the number of subjects reporting multiple sleep disturbances increasing over time [48]. Recently, we observed in the baseline analysis of the COPPADIS cohort that NMS burden was associated with sleep problems after adjustment for age, gender, disease duration, LEDD, H&Y, UPDRS-III, UPDRS-IV, PD-CRS, BDI-II, NPI, VAS-Pain, VAFS, FOGQ, and total number of non-antiparkinsonian treatments [49]. Here, after a 2-year follow-up we observed that changes in sleep predict changes in the global NMS burden. A large number of patients are not treated for their sleep disturbances [48] and these findings call for an increased awareness of sleep problems in PD patients. Finally, the most significant predictor of global NMS burden progression was the NMSS total score at baseline. The risk is higher when the score is lower, signifying that even in early PD patients it is necessary to be alert when the patient has a low global NMS burden because it is liable to increase. Again, it is logical to consider and on the contrary, a greater improvement in NMS after an intervention has been observed in patients with a greater NMS burden [50], so changes are related to the score at baseline. The present study has some limitations. First, the information about NMS burden follow-up was recorded in 501 patients of 677 (74%). Thirty-eight patients dropped out of the study (1 death; 2 with change in diagnosis; 35 other reasons) at the 2-year follow-up and 132 were not evaluated. In six patients, NMSS was not assessed. However, this is a limitation observed in other prospective studies. In the study of Antonini et al. [27], 707 PD patients from 1142 initially included (61.9%) were evaluable at 24 months. The percentage in other studies was 89.8% (380/423) [12], 83.6% (117/140) [29], and 73.9% (147/199) [30]. Second, 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.) [15], which leads to an early PD bias in this cohort. Third, for some variables, the information was not collected in all cases. Fourth, a specific tool for assessing comorbidity, like Charlson Index or others, has not been used. However, the total number of non-antiparkinsonian medications has been suggested as a useful marker of comorbidity in PD [8]. Fifth, the smaller sample size of the control group. On the contrary, the strengths of our study include the large sample size of the PD group, a very thorough assessment, a prospective longitudinal follow-up design, the fact that this analysis was “a priori” planned as one objective of the multicenter COPPADIS project [15], and the extensive clinical and demographic information recorded. In conclusion, the present study observes that 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. Strategies designed to act over these symptoms and to analyze the short-term and long-term progression of NMS burden could be of interest. J. Pers. Med. 2021, 11, 626 15 of 25 Author Contributions: Conception, D.S.-G.; Organization, D.S.-G.; Execution of the project, D.S.-G.; statistical analysis, D.S.-G.; writing of the first draft of the manuscript, D.S.-G.; Recruitment, D.S.-G., T.d.D., E.S., S.J., M.A., P.P., L.P., M.C., J.G.C., N.C., I.L., J.H.-V., I.C., L.L.M., I.G.A., M.A.Á.R., M.J.C., V.N., V.P., J.D., C.B., B.S., M.Á.S., L.V., S.E., E.C., F.C., J.C.M.C., P.S.A., G.A., N.L.A., I.G., J.K., M.B., M.S., J.R.M., C.V., M.K., O.d.F., J.A., R.A., C.O., L.M.L.D. and P.M.; Review and critique: T.d.D., C.C., L.V.A., H.C., J.M.P.G., C.M.M., E.S., S.J., M.A., P.P., L.P., M.C., J.G.C., N.C., I.L., J.H.-V., I.C., L.L.M., I.G.A., M.A.Á.R., M.J.C., V.N., V.P., J.D., C.B., B.S., M.Á.S., L.V., S.E., E.C., F.C., J.C.M.C., P.S.A., G.A., N.L.A., I.G., J.K., M.B., M.S., J.R.M., C.V., M.K., O.d.F., J.A., R.A., C.O., L.M.L.D., D.M., P.M.-M. and P.M.; Evaluation of participants: D.S.-G., T.d.D., E.S., S.J., M.A., P.P., L.P., M.C., J.G.C., N.C., I.L., J.H.-V., I.C., L.L.M., I.G.A., M.A.Á.R., M.J.C., V.N., V.P., J.D., C.B., B.S., M.Á.S., L.V., S.E., E.C., F.C., J.C.M.C., P.S.A., G.A., N.L.A., I.G., J.K., M.B., M.S., J.R.M., C.V., M.K., O.d.F., J.A., R.A., C.O., L.M.L.D. and P.M.; Collaboration in the preparation of the manuscript: C.C. and L.V.A.; Review of english style: D.M.; Supervision: P.M.-M. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Fundación Española de Ayuda a la Investigación en Parkinson y otras Enfermedades Neuro-degenerativas (Curemos el Parkinson; www.curemoselparkinson.org). Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki, and ap-proved by Comité de Ética de la Investigación Clínica de Galicia from Spain (2014/534; 2/DEC/2014). Informed Consent Statement: Written informed consent from all participants in this study were obtained before the start of the study. Data Availability Statement: The protocol and the statistical analysis plan are available on request. Deidentified participant data are not available for legal and ethical reasons. Acknowledgments: 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. Conflicts of Interest: The authors declare no conflict of interest. Appendix A COPPADIS STUDY GROUP Adarmes AD, Almeria M, Alonso Losada MG, Alonso Cánovas A, Alonso Frech F, Alonso Redondo R, Álvarez I, Álvarez Sauco M, Aneiros Díaz A, Arnáiz S, Arribas S, Ascunce Vidondo A, Aguilar M, Ávila MA, Bernardo Lambrich N, Bejr-Kasem H, Blázquez Estrada M, Botí M, Borrue C, Buongiorno MT, Cabello González C, Cabo López I, Caballol N, Cámara Lorenzo A, Canfield Medina H, Carrillo F, Carrillo Padilla FJ, Casas E, Catalán MJ, Clavero P, Cortina Fernández A, Cosgaya M, Cots Foraster A, Crespo Cuevas A, Cubo E, de Deus Fonticoba T, de Fábregues-Boixar O, Díez-Fairen M, Dotor García-Soto J, Erro E, Escalante S, Estelrich Peyret E, Fernández Guillán N, Gámez P, Gallego M, García Caldentey J, García Campos C, García Moreno JM, Gastón I, Gómez Garre MP, Gómez Mayordomo V, González Aloy J, González-Aramburu I, González Ardura J, González García B, González Palmás MJ, González Toledo GR, Golpe Díaz A, Grau Solá M, Guardia G, Hernández Vara J, Horta-Barba A, Idoate Calderón D, Infante J, Jesús S, Kulisevsky J, Kurtis M, Labandeira C, Labrador MA, Lacruz F, Lage Castro M, Lastres Gómez S, Legarda I, López Ariztegui N, López Díaz LM, López Manzanares L, López Seoane B, Lucas del Pozo S, Macías Y, Mata M, Martí Andres G, Martí MJ, Martínez Castrillo JC, Martinez-Martin P, McAfee D, Meitín MT, Menéndez González M, Méndez del Barrio C, Mir P, Miranda Santiago J, Morales Casado MI, Moreno Diéguez A, Nogueira V, Novo Amado A, Novo Ponte S, Ordás C, Pagonabarraga J, Pareés I, Pascual-Sedano B, Pastor P, Pérez Fuertes A, Pérez Noguera R, Planas-Ballvé A, Planellas L, Prats MA, Prieto Jurczynska C, Puente V, Pueyo Morlans M, Redondo Rafales N, Rodríguez Méndez L, Rodríguez Pérez AB, Roldán F, Ruíz De Arcos M, Ruíz Martínez J, Sánchez Alonso P, Sánchez-Carpintero M, Sánchez Díez G, Sánchez Rodríguez A, Santacruz P, Santos García D, Segundo Rodríguez JC, Seijo M, Sierra Peña M, J. Pers. Med. 2021, 11, 626 16 of 25 Solano Vila B, Suárez Castro E, Tartari JP, Valero C, Vargas L, Vela L, Villanueva C, Vives B, Villar MD. Name (Last Name, First Location Role Contribution Name) Hospital Universitario Virgen del Evaluation of participants Astrid Adarmes, Daniela Site investigator Rocío, Sevilla, Spain and/or data management Hospital Universitari Mutua de Neuropsychologist; Almeria, Marta Terrassa, Terrassa, Barcelona, Site investigator evaluation of participants Spain Hospital Álvaro Cunqueiro, Coordination at the center Complejo Hospitalario Alonso Losada, Maria Gema Site investigator/PI Evaluation of participants Universitario de Vigo (CHUVI), and/or data management Vigo, Spain Hospital Universitario Ramón y Evaluation of participants Alonso Cánovas, Araceli Cajal, Madrid, Spain Site investigator and/or data management Hospital Universitario Clínico San Evaluation of participants Alonso Frech, Fernando Site investigator Carlos, Madrid, Spain and/or data management Coordination at the center Hospital Universitario Lucus Alonso Redondo, Ruben Site investigator/PI Evaluation of participants Augusti (HULA), Lugo, Spain and/or data management Complejo Hospitalario Coordination at the center Aneiros Díaz, Ángel Universitario de Ferrol (CHUF), Site investigator/PI Evaluation of participants Ferrol, A Coruña, Spain and/or data management Hospital Universitari Mutua de Evaluation of participants Álvarez, Ignacio Terrassa, Terrassa, Barcelona, Site investigator and/or data management Spain Coordination at the center Hospital General Universitario de Álvarez Sauco, María Site investigator/PI Evaluation of participants Elche, Elche, Spain and/or data management Complejo Asistencial Evaluation of participants Arnáiz, Sandra Universitario de Burgos, Burgos, Site investigator and/or data management Spain Hospital Universitari Mutua de Neuropsychologist; Arribas, Sonia Terrassa, Terrassa, Barcelona, Site investigator evaluation of participants Spain Complejo Hospitalario de Evaluation of participants Ascunce Vidondo, Arancha Site investigator Navarra, Pamplona, Spain and/or data management Hospital Universitari Mutua de Evaluation of participants Aguilar, Miquel Terrassa, Terrassa, Barcelona, Site investigator and/or data management Spain Consorci Sanitari Integral, Coordination at the center Hospital General de L’Hospitalet, Ávila Rivera, Maria Asunción Site investigator/PI Evaluation of participants L’Hospitalet de Llobregat, and/or data management Barcelona, Spain Hospital de Tortosa Verge de la Evaluation of participants Bernardo Lambrich, Noemí Cinta (HTVC), Tortosa, Tarragona, Site investigator and/or data management Spain Hospital de Sant Pau, Barcelona, Evaluation of participants Bejr-Kasem, Helena Site investigator Spain and/or data management J. Pers. Med. 2021, 11, 626 17 of 25 Name (Last Name, First Location Role Contribution Name) Hospital Universitario Central de Evaluation of participants Blázquez Estrada, Marta Site investigator Asturias, Oviedo, Spain and/or data management Hospital Universitari Mutua de Neuropsychologist; Botí González, Maria Ángeles Terrassa, Terrassa, Barcelona, Site investigator evaluation of participants Spain Coordination at the center Hospital Infanta Sofía, Madrid, Borrué, Carmen Site investigator/PI Evaluation of participants Spain and/or data management Hospital Universitari Mutua de Buongiorno, Maria Teresa Terrassa, Terrassa, Barcelona, Site investigator Nurse study coordinator Spain Complejo Hospitalario de Cabello González, Carolina Site investigator Scheduling of evaluations Navarra, Pamplona, Spain Complejo Hospitalario Coordination at the center Cabo López, Iria Universitario de Pontevedra Site investigator/PI Evaluation of participants (CHOP), Pontevedra, Spain and/or data management Consorci Sanitari Integral, Coordination at the center Caballol, Nuria Hospital Moisés Broggi, Sant Joan Site investigator/PI Evaluation of participants Despí, Barcelona, Spain. and/or data management Hospital Clínic de Barcelona, Cámara Lorenzo, Ana Site investigator Nurse study coordinator Barcelona, Spain Complejo Hospitalario Evaluation of participants Canfield Medina, Héctor Universitario de Ferrol (CHUF), Site investigator and/or data management Ferrol, A Coruña, Spain Hospital Universitario Virgen del Evaluation of participants Carrillo, Fátima Site investigator Rocío, Sevilla, Spain and/or data management Hospital Universitario de Coordination at the center Canarias, San Cristóbal de la Carrillo Padilla, Francisco José Site investigator/PI Evaluation of participants Laguna, Santa Cruz de Tenerife, and/or data management Spain Complejo Asistencial Evaluation of participants Casas, Elena Universitario de Burgos, Burgos, Site investigator and/or data management Spain Coordination at the center Hospital Universitario Clínico San Catalán, Maria José Site investigator/PI Evaluation of participants Carlos, Madrid, Spain and/or data management Complejo Hospitalario de Evaluation of participants Clavero, Pedro Site investigator Navarra, Pamplona, Spain and/or data management Complejo Hospitalario Coordination of blood Cortina Fernández, A Universitario de Ferrol (CHUF), Site investigator extractions Ferrol, A Coruña, Spain Hospital Clínic de Barcelona, Evaluation of participants Cosgaya, Marina Site investigator Barcelona, Spain and/or data management Institut d’Assistència Sanitària Evaluation of participants Cots Foraster, Anna (IAS) - Instituí Cátala de la Salud. Site investigator and/or data management Girona, Spain J. Pers. Med. 2021, 11, 626 18 of 25 Name (Last Name, First Location Role Contribution Name) Hospital del Mar, Barcelona, Evaluation of participants Crespo Cuevas, Ane Site investigator Spain. and/or data management Complejo Asistencial Coordination at the center Cubo, Esther Universitario de Burgos, Burgos, Site investigator/PI Evaluation of participants Spain and/or data management Complejo Hospitalario Nurse study coordinator De Deus Fonticoba, Teresa Universitario de Ferrol (CHUF), Site investigator Evaluation of participants Ferrol, A Coruña, Spain and/or data management Coordination at the center Hospital Universitario Vall De Fábregues-Boixar, Oriol Site investigator/PI Evaluation of participants d’Hebron, Barcelona, Spain and/or data management Hospital Universitari Mutua de Evaluation of participants Díez Fairen, M Terrassa, Terrassa, Barcelona, Site investigator and/or data management Spain Hospital Universitario Virgen Evaluation of participants Dotor García-Soto, Julio Site investigator/PI Macarena, Sevilla, Spain and/or data management Complejo Hospitalario de Evaluation of participants Erro, Elena Site investigator Navarra, Pamplona, Spain and/or data management Hospital de Tortosa Verge de la Coordination at the center Escalante, Sonia Cinta (HTVC), Tortosa, Tarragona, Site investigator/PI Evaluation of participants Spain and/or data management Institut d’Assistència Sanitària Evaluation of participants Estelrich Peyret, Elena (IAS) - Instituí Cátala de la Salud. Site investigator and/or data management Girona, Spain Complejo Hospitalario Fernández Guillán, Noelia Universitario de Ferrol (CHUF), Site investigator Neuroimaging studies Ferrol, A Coruña, Spain Complejo Asistencial Evaluation of participants Gámez, Pedro Universitario de Burgos, Burgos, Site investigator and/or data management Spain Hospital La Princesa, Madrid, Evaluation of participants Gallego, Mercedes Site investigator Spain and/or data management Coordination at the center Centro Neurológico Oms 42, García Caldentey, Juan Site investigator/PI Evaluation of participants Palma de Mallorca, Spain and/or data management Hospital Universitario Virgen Evaluation of participants García Campos, Cristina Site investigator Macarena, Sevilla, Spain and/or data management Coordination at the center Hospital Universitario Virgen Site investigator/PI (until García Moreno, Jose Manuel Evaluation of participants Macarena, Sevilla, Spain MAR/21) and/or data management Coordination at the center Complejo Hospitalario de Gastón, Itziar Site investigator/PI Evaluation of participants Navarra, Pamplona, Spain and/or data management Hospital Universitario Virgen del Gómez Garre, María del Pilar Site investigator Genetic studies coordination Rocío, Sevilla, Spain Hospital Clínico San Carlos, Evaluation of participants Gómez Mayordomo, Víctor Site investigator Madrid, Spain and/or data management J. Pers. Med. 2021, 11, 626 19 of 25 Name (Last Name, First Location Role Contribution Name) Institut d’Assistència Sanitària Evaluation of participants González Aloy, Javier (IAS) - Instituí Cátala de la Salud. Site investigator and/or data management Girona, Spain Hospital Universitario Marqués Evaluation of participants González Aramburu, Isabel Site investigator de Valdecilla, Santander, Spain and/or data management Hospital Universitario Lucus Site investigator/PI (until Evaluation of participants González Ardura, Jessica Augusti (HULA), Lugo, Spain FEB/21) and/or data management Hospital La Princesa, Madrid, González García, Beatriz Site investigator Nurse study coordinator Spain Complejo Hospitalario González Palmás, Maria Evaluation of participants Universitario de Pontevedra Site investigator Josefa and/or data management (CHOP), Pontevedra, Spain Hospital Universitario de González Toledo, Gabriel Canarias, San Cristóbal de la Evaluation of participants Site investigator Ricardo Laguna, Santa Cruz de Tenerife, and/or data management Spain Complejo Hospitalario Laboratory analysis Golpe Díaz, Ana Universitario de Ferrol (CHUF), Site investigator coordination Ferrol, A Coruña, Spain Consorci Sanitari Integral, Evaluation of participants Grau Solá, Mireia Hospital Moisés Broggi, Sant Joan Site investigator and/or data management Despí, Barcelona, Spain Hospital Universitari Mutua de Evaluation of participants Guardia, Gemma Terrassa, Terrassa, Barcelona, Site investigator and/or data management Spain Coordination at the center Hospital Universitario Vall Hernández Vara, Jorge Site investigator/PI Evaluation of participants d’Hebron, Barcelona, Spain and/or data management Hospital de Sant Pau, Barcelona, Neuropsychologist; Horta Barba, Andrea Site investigator Spain evaluation of participants Complejo Hospitalario Neuropsychologist; Idoate Calderón, Daniel Universitario de Pontevedra Site investigaor evaluation of participants (CHOP), Pontevedra, Spain Coordination at the center Hospital Universitario Marqués Infante, Jon Site investigator/PI Evaluation of participants de Valdecilla, Santander, Spain and/or data management Hospital Universitario Virgen del Evaluation of participants Jesús, Silvia Site investigator Rocío, Sevilla, Spain and/or data management Coordination at the center Hospital de Sant Pau, Barcelona, Kulisevsky, Jaime Site investigator/PI Evaluation of participants Spain and/or data management Coordination at the center Hospital Ruber Internacional, Kurtis, Mónica Site investigator/PI Evaluation of participants Madrid, Spain and/or data management Hospital Álvaro Cunqueiro, Complejo Hospitalario Evaluation of participants Labandeira, Carmen Site investigator Universitario de Vigo (CHUVI), and/or data management Vigo, Spain J. Pers. Med. 2021, 11, 626 20 of 25 Name (Last Name, First Location Role Contribution Name) Labrador Espinosa, Miguel Hospital Universitario Virgen del Site investigator Neuroimaging data analysis Ángel Rocío, Sevilla, Spain Complejo Hospitalario de Evaluation of participants Lacruz, Francisco Site investigator Navarra, Pamplona, Spain and/or data management Complejo Hospitalario Evaluation of participants Lage Castro, Melva Universitario de Pontevedra Site investigator and/or data management (CHOP), Pontevedra, Spain Complejo Hospitalario Neuropsychologist; Lastres Gómez, Sonia Universitario de Pontevedra Site investigator evaluation of participants (CHOP), Pontevedra, Spain Hospital Universitario Son Coordination at the center Legarda, Inés Espases, Palma de Mallorca, Site investigator/PI Evaluation of participants Spain and/or data management Complejo Hospitalario de Toledo, Evaluation of participants López Ariztegui, Nuria Site investigator/PI Toledo, Spain and/or data management Hospital Da Costa de Burela, Site investigator/PI (until Evaluation of participants López Díaz, Luis Manuel Lugo, Spain SEP/16) and/or data management Coordination at the center Hospital La Princesa, Madrid, López Manzanares, Lydia Site investigator/PI Evaluation of participants Spain and/or data management Complejo Hospitalario López Seoane, Balbino Universitario de Ferrol (CHUF), Site investigator Neuroimaging studies Ferrol, A Coruña, Spain Hospital Universitario Vall Evaluation of participants Lucas del Pozo, Sara Site investigator d’Hebron, Barcelona, Spain and/or data management Fundación Hospital de Alcorcón, Evaluation of participants Macías, Yolanda Site investigator Madrid, Spain and/or data management Hospital Infanta Sofía, Madrid, Evaluation of participants Mata, Marina Site investigator Spain and/or data management Hospital Universitario Vall Evaluation of participants Martí Andres, Gloria Site investigator d’Hebron, Barcelona, Spain and/or data management Coordination at the center Hospital Clínic de Barcelona, Martí, Maria José Site investigator/PI Evaluation of participants Barcelona, Spain and/or data management Coordination at the center Martínez Castrillo, Juan Hospital Universitario Ramón y Site investigator/PI Evaluation of participants Carlos Cajal, Madrid, Spain and/or data management Centro Nacional de Epidemiología y CIBERNED, Collaborator in statistical Methods and statistical Martinez-Martin, Pablo Instituto de Salud Carlos III. and methods analysis reviewer Madrid University of Pennsylvania, Collaborator in english McAfee, Darrian English style reviewer Philadelphia style Hospital Da Costa de Burela, Evaluation of participants Meitín, Maria Teresa Site investigator Lugo, Spain and/or data management J. Pers. Med. 2021, 11, 626 21 of 25 Name (Last Name, First Location Role Contribution Name) Coordination at the center Hospital Universitario Central de Menéndez González, Manuel Site investigator/PI Evaluation of participants Asturias, Oviedo, Spain and/or data management Hospital Universitario Virgen del Evaluation of participants Méndez del Barrio, Carlota Site investigator Rocío, Sevilla, Spain and/or data management Coordination at the center Hospital Universitario Virgen del Mir, Pablo Site investigator/PI Evaluation of participants Rocío, Sevilla, Spain and/or data management Complejo Asistencial Evaluation of participants Miranda Santiago, Javier Universitario de Burgos, Burgos, Site investigator and/or data management Spain Complejo Hospitalario de Toledo, Evaluation of participants Morales Casado, Maria Isabel Site investigator Toledo, Spain. and/or data management Complejo Hospitalario Moreno Diéguez, Antonio Universitario de Ferrol (CHUF), Site investigator Neuroimaging studies Ferrol, A Coruña, Spain Coordination at the center Hospital Da Costa de Burela, Nogueira, Víctor Site investigator/PI Evaluation of participants Lugo, Spain and/or data management Complejo Hospitalario Novo Amado, Alba Universitario de Ferrol (CHUF), Site investigator Neuroimaging studies Ferrol, A Coruña, Spain Hospital Universitario Puerta de Evaluation of participants Novo Ponte, Sabela Site investigator Hierro, Madrid, Spain. and/or data management Hospital Rey Juan Carlos, Madrid, Evaluation of participants Ordás, Carlos Site Investigator Spain, Madrid, Spain. and/or data management Hospital de Sant Pau, Barcelona, Evaluation of participants Pagonabarraga, Javier Site investigator Spain and/or data management Hospital Ruber Internacional, Evaluation of participants Isabel Pareés Site investigator Madrid, Spain and/or data management Hospital de Sant Pau, Barcelona, Evaluation of participants Pascual-Sedano, Berta Site Investigator Spain and/or data management Hospital Universitari Mutua de Evaluation of participants Pastor, Pau Terrassa, Terrassa, Barcelona, Site investigator and/or data management Spain Complejo Hospitalario Pérez Fuertes, Aída Universitario de Ferrol (CHUF), Site investigator Blood analysis Ferrol, A Coruña, Spain Hospital Universitario Virgen Evaluation of participants Pérez Noguera, Rafael Site investigator Macarena, Sevilla, Spain and/or data management Consorci Sanitari Integral, Evaluation of participants Planas-Ballvé, Ana Hospital Moisés Broggi, Sant Joan Site investigator and/or data management Despí, Barcelona, Spain Hospital Clínic de Barcelona, Evaluation of participants Planellas, Lluís Site investigator Barcelona, Spain and/or data management Institut d’Assistència Sanitària Evaluation of participants Prats, Marian Ángeles (IAS)—Instituí Cátala de la Salud. Site investigator and/or data management Girona, Spain J. Pers. Med. 2021, 11, 626 22 of 25 Name (Last Name, First Location Role Contribution Name) Coordination at the center Hospital Rey Juan Carlos, Madrid, Prieto Jurczynska, Cristina Site investigator/PI Evaluation of participants Spain, Madrid, Spain and/or data management Coordination at the center Hospital del Mar, Barcelona, Puente, Víctor Site investigator/PI Evaluation of participants Spain and/or data management Hospital Universitario de Canarias, San Cristóbal de la Evaluation of participants Pueyo Morlans, Mercedes Site investigator Laguna, Santa Cruz de Tenerife, and/or data management Spain Hospital La Princesa, Madrid, Evaluation of participants Redondo, Nuria Site Investigator Spain and/or data management Complejo Hospitalario Rodríguez Méndez, Luisa Universitario de Ferrol (CHUF), Site investigator Blood analysis Ferrol, A Coruña, Spain Rodríguez Pérez, Amparo Hospital General Universitario de Evaluation of participants Site investigator Belén Elche, Elche, Spain and/or data management Hospital Universitario Virgen del Roldán, Florinda Site investigator Neuroimaging studies Rocío, Sevilla, Spain Hospital Universitario Virgen Evaluation of participants Ruíz de Arcos, María Site investigator Macarena, Sevilla, Spain. and/or data management Hospital Universitario Donostia, Evaluation of participants Ruíz Martínez, Javier Site investigator San Sebastián, Spain and/or data management Hospital Universitario Puerta de Evaluation of participants Sánchez Alonso, Pilar Site investigator Hierro, Madrid, Spain and/or data management Complejo Hospitalario Sánchez-Carpintero, Universitario de Ferrol (CHUF), Site investigator Neuroimaging studies Macarena Ferrol, A Coruña, Spain Hospital Universitario Ramón y Evaluation of participants Sánchez Díez, Gema Site investigator Cajal, Madrid, Spain and/or data management Hospital Universitario Marqués Evaluation of participants Sánchez Rodríguez, Antonio Site investigator de Valdecilla, Santander, Spain and/or data management Hospital Clínic de Barcelona, Evaluation of participants Santacruz, Pilar Site investigator Barcelona, Spain and/or data management CHUAC, Complejo Hospitalario Coordination of the Santos García, Diego Coordinator of the Project Universitario de A Coruña COPPADIS-2015 Segundo Rodríguez, José Complejo Hospitalario de Toledo, Evaluation of participants Site investigator Clemente Toledo, Spain and/or data management Complejo Hospitalario Coordination at the center Seijo, Manuel Universitario de Pontevedra Site investigator/PI Evaluation of participants (CHOP), Pontevedra, Spain and/or data management Hospital Universitario Marqués Evaluation of participants Sierra, María Site investigator de Valdecilla, Santander, Spain and/or data management Institut d’Assistència Sanitària Coordination at the center Solano, Berta (IAS)—Instituí Cátala de la Salud. Site investigator/PI Evaluation of participants Girona, Spain and/or data management J. Pers. Med. 2021, 11, 626 23 of 25 Name (Last Name, First Location Role Contribution Name) Complejo Hospitalario Evaluation of participants Suárez Castro, Ester Universitario de Ferrol (CHUF), Site investigator and/or data management Ferrol, A Coruña, Spain Hospital Universitari Mutua de Evaluation of participants Tartari, Juan Pablo Terrassa, Terrassa, Barcelona, Site investigator and/or data management Spain Hospital Arnau de Vilanova, Evaluation of participants Valero, Caridad Site investigator Valencia, Spain and/or data management Hospital Universitario Virgen del Evaluation of participants Vargas, Laura Site investigator Rocío, Sevilla, Spain and/or data management Coordination at the center Fundación Hospital de Alcorcón, Vela, Lydia Site investigator/PI Evaluation of participants Madrid, Spain and/or data management Hospital Universitario Clínico San Evaluation of participants Villanueva, Clara Site investigator Carlos, Madrid, Spain and/or data management Hospital Universitario Son Evaluation of participants Vives, Bárbara Espases, Palma de Mallorca, Site investigator and/or data management Spain Hospital Universitario de Canarias, San Cristóbal de la Evaluation of participants Villar, Maria Dolores Site investigator Laguna, Santa Cruz de Tenerife, and/or data management Spain References 1. Armstrong, M.J.; Okun, M.S. Diagnosis and Treatment of Parkinson Disease: A Review. JAMA 2020, 323, 548–560. [CrossRef] [PubMed] 2. Tolosa, E.; Gaig, C.; Santamaría, J.; Compta, Y. Diagnosis and the premotor phase of Parkinson disease. Neurology 2009, 72 (Suppl. S7), S12–S20. [CrossRef] 3. Poewe, W.; Mahlknecht, P. The clinical progression of Parkinson’s disease. Parkinsonism Relat. Disord. 2009, 15 (Suppl. S4), S28–S32. [CrossRef] 4. Chaudhuri, K.R.; Healy, D.G.; Schapira, A.H. National Institute for Clinical Excellence. Non-motor symptoms of Parkinson’s disease: Diagnosis and management. Lancet Neurol. 2006, 5, 235–245. [CrossRef] 5. Martinez-Martin, P. What is quality of life and how do we measure it? Relevance to Parkinson’s disease and movement disorders. Mov. Disord. 2017, 32, 382–392. [CrossRef] [PubMed] 6. Martinez-Martin, P.; Kurtis, M.M. Health-related quality of life as an outcome variable in Parkinson’s disease. Ther. Adv. Neurol. Disord. 2012, 5, 105–117. [CrossRef] 7. 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. 2011, 17, 1–9. [CrossRef] [PubMed] 8. Santos García, D.; de Deus Fonticoba, T.; Suárez Castro, E.; Borrué, C.; Mata, M.; Solano Vila, B.; Cots Foraster, A.; Álvarez Sauco, M.; Rodríguez Pérez, A.B.; Vela, L.; et al. Non-motor symptoms burden, mood, and gait problems are the most significant factors contributing to a poor quality of life in non-demented Parkinson’s disease patients: Results from the COPPADIS Study Cohort. Parkinsonism Relat. Disord. 2019, 66, 151–157. [CrossRef] 9. Erro, R.; Picillo, M.; Vitale, C.; Amboni, M.; Moccia, M.; Longo, K.; Cozzolino, A.; Giordano, F.; De Rosa, A.; De Michele, G.; et al. Non-motor symptoms in early Parkinson’s disease: A 2-year follow-up study on previously untreated patients. J. Neurol. Neurosurg. Psychiatry 2013, 84, 14–17. [CrossRef] 10. Erro, R.; Picillo, M.; Vitale, C.; Amboni, M.; Moccia, M.; Santangelo, G.; Pellecchia, M.T.; Barone, P. 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. 2016, 23, 1673–1679. [CrossRef] 11. 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. 2016, 23, 854–860. [CrossRef] 12. Simuni, T.; Caspell-Garcia, C.; Coffey, C.S.; Weintraub, D.; Mollenhauer, B.; Lasch, S.; Tanner, C.M.; Jennings, D.; Kieburtz, K.; Chahine, L.M.; et al. Baseline prevalence and longitudinal evolution of non-motor symptoms in early Parkinson’s disease: The PPMI cohort. J. Neurol. Neurosurg. Psychiatry 2018, 89, 78–88. [CrossRef] J. Pers. Med. 2021, 11, 626 24 of 25 13. Santos García, D.; de Deus Fonticoba, T.; Cores, C. Predictors of Clinically Significant Quality of Life Impairment in Parkinson’s Disease. Results from the COPPADIS Cohort at 2-Year Follow-up. Unpublished work. 2021. 14. Santos García, D.; Jesús, S.; Aguilar, M.; Planellas, L.L.; García Caldentey, J.; Caballol, N.; Legarda, I.; Hernández Vara, J.; Cabo, I.; López Manzanares, L.; et al. 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. 2019, 26, 1399–1407. [CrossRef] [PubMed] 15. Santos-García, D.; Mir, P.; Cubo, E.; Vela, L.; Rodríguez-Oroz, M.C.; Martí, M.J.; Arbelo, J.M.; Infante, J.; Kulisevsky, J.; Martínez- Martín, P.; et al. 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. 2016, 16, 26. 16. Chaudhuri, K.R.; Martinez-Martin, P.; Brown, R.G.; Sethi, K.; Stocchi, F.; Odin, P.; Ondo, W.; Abe, K.; MacPhee, G.; MacMahon, D.; et al. The metric properties of a novel non-motor symptoms scale for Parkinson’s disease: Results from an international pilot study. Mov. Disord. 2007, 22, 1901–1911. [CrossRef] [PubMed] 17. Ray Chaudhuri, K.; Rojo, J.M.; Schapira, A.H.; Brooks, D.J.; Stocchi, F.; Odin, P.; Antonini, A.; Brown, R.J.; Martinez-Martin, P. A proposal for a comprehensive grading of Parkinson’s disease severity combining motor and non-motor assessments: Meeting an unmet need. PLoS ONE 2013, 8, e57221. [CrossRef] [PubMed] 18. Stebbins, G.T.; Goetz, C.G.; Burn, D.J.; Jankovic, J.; Khoo, T.K.; Tilley, B.C. How to identify tremor dominant and postural instability/gait difficulty groups with the movement disorder society unified Parkinson’s disease rating scale: Comparison with the unified Parkinson’s disease rating scale. Mov. Disord. 2013, 28, 668–670. [CrossRef] 19. Jost, S.T.; Visser-Vandewalle, V.; Rizos, A.; Loehrer, P.A.; Silverdale, M.; Evans, J.; Samuel, M.; Petry-Schmelzer, J.N.; Sauerbier, A.; Gronostay, A.; et al. EUROPAR and the International Parkinson and Movement Disorders Society Non-Motor Parkinson’s Disease Study Group. Non-motor predictors of 36-month quality of life after subthalamic stimulation in Parkinson disease. NPJ Parkinsons Dis. 2021, 7, 48. [CrossRef] 20. Hermanowicz, N.; Jones, S.A.; Hauser, R.A. Impact of non-motor symptoms in Parkinson’s disease: A PMDAlliance survey. Neuropsychiatr. Dis. Treat. 2019, 15, 2205–2212. [CrossRef] 21. Montero-Odasso, M.; Speechley, M.; Muir-Hunter, S.W.; Pieruccini-Faria, F.; Sarquis-Adamson, Y.; Hachinski, V.; Bherer, L.; Borrie, M.; Wells, J.; Garg, A.X.; et al. Canadian Gait and Cognition Network. Dual decline in gait speed and cognition is associated with future dementia: Evidence for a phenotype. Age Ageing 2020, 49, 995–1002. [CrossRef] 22. Ghielen, I.; Koene, P.; Twisk, J.W.; Kwakkel, G.; van den Heuvel, O.A.; van Wegen, E.E. The association between freezing of gait, fear of falling and anxiety in Parkinson’s disease: A longitudinal analysis. Neurodegener Dis. Manag. 2020, 10, 159–168. 23. Choi, S.M.; Jung, H.J.; Yoon, G.J.; Kim, B.C. Factors associated with freezing of gait in patients with Parkinson’s disease. Neurol. Sci. 2019, 40, 293–298. [CrossRef] [PubMed] 24. Wilson, J.; Alcock, L.; Yarnall, A.J.; Lord, S.; Lawson, R.A.; Morris, R.; Taylor, J.-P.; Burn, D.J.; Rochester, L.; Galna, B. Gait Progression Over 6 Years in Parkinson’s Disease: Effects of Age, Medication, and Pathology. Front Aging Neurosci. 2020, 12, 577435. [CrossRef] [PubMed] 25. Goetz, C.G. Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): A new scale for the evaluation of Parkinson’s disease. Rev. Neurol. 2010, 166, 1–4. [CrossRef] [PubMed] 26. Martinez-Martin, P.; Chaudhuri, K.R.; Rojo-Abuin, J.M.; Rodriguez-Blazquez, C.; Alvarez-Sanchez, M.; Arakaki, T.; Bergareche- Yarza, A.; Chade, A.; Garretto, N.; Gershanik, O.; et al. Assessing the non-motor symptoms of Parkinson’s disease: MDS-UPDRS and NMS Scale. Eur. J. Neurol. 2015, 22, 37–43. [CrossRef] 27. Antonini, A.; Barone, P.; Marconi, R.; Morgante, L.; Zappulla, S.; Pontieri, F.E.; Ramat, S.; Ceravolo, M.G.; Meco, G.; Cicarelli, G.; et al. The progression of non-motor symptoms in Parkinson’s disease and their contribution to motor disability and quality of life. J. Neurol. 2012, 259, 2621–2631. [CrossRef] [PubMed] 28. Vu, T.C.; Nutt, J.G.; Holford, N.H. Progression of motor and nonmotor features of Parkinson’s disease and their response to treatment. Br. J. Clin. Pharmacol. 2012, 74, 267–283. [CrossRef] 29. Ou, R.; Yang, J.; Cao, B.; Wei, Q.; Chen, K.; Chen, X.; Zhao, B.; Wu, Y.; Song, W.; Shang, H. Progression of non-motor symptoms in Parkinson’s disease among different age populations: A two-year follow-up study. J. Neurol. Sci. 2016, 360, 72–77. [CrossRef] 30. Prakash, K.M.; Nadkarni, N.V.; Lye, W.K.; Yong, M.H.; Chew, L.M.; Tan, E.K. A longitudinal study of non-motor symptom burden in Parkinson’s disease after a transition to expert care. Parkinsonism Relat. Disord. 2015, 21, 843–847. [CrossRef] 31. Bloem, B.R.; Okun, M.S.; Klein, C. Parkinson’s disease. Lancet 2021. epub ahead of print. [CrossRef] 32. Roheger, M.; Kalbe, E.; Liepelt-Scarfone, I. Progression of Cognitive Decline in Parkinson’s Disease. J. Parkinsons Dis. 2018, 8, 183–193. [CrossRef] 33. Ongre, S.O.; Dalen, I.; Tysnes, O.B.; Alves, G.; Herlofson, K. Progression of fatigue in Parkinson’s disease-a 9-year follow-up. Eur. J. Neurol. 2021, 28, 108–116. [CrossRef] [PubMed] 34. Tai, Y.; Lin, C. An overview of pain in Parkinson’s disease. Clin. Parkinsonism Relat. Disord. 2020, 2, 1–8. [CrossRef] 35. Kim, J.B.; Kim, B.J.; Koh, S.B.; Park, K.W. Autonomic dysfunction according to disease progression in Parkinson’s disease. Parkinsonism Relat. Disord. 2014, 20, 303–307. [CrossRef] 36. Chen, Z.; Li, G.; Liu, J. Autonomic dysfunction in Parkinson’s disease: Implications for pathophysiology, diagnosis, and treatment. Neurobiol. Dis. 2020, 134, 104700. [CrossRef] J. Pers. Med. 2021, 11, 626 25 of 25 37. Marras, C.; Chaudhuri, K.R. Nonmotor features of Parkinson’s disease subtypes. Mov. Disord. 2016, 31, 1095–1102. [CrossRef] 38. Brockmann, K.; Srulijes, K.; Pflederer, S.; Hauser, A.-K.; Schulte, C.; Maetzler, W.; Gasser, T.; Berg, D. GBA-associated Parkinson’s disease: Reduced survival and more rapid progression in a prospective longitudinal study. Mov. Disord. 2015, 30, 407–411. [CrossRef] 39. Krishnan, S.; Sarma, G.; Sarma, S.; Kishore, A. Do nonmotor symptoms in Parkinson’s disease differ from normal aging? Mov. Disord. 2011, 26, 2110–2113. [CrossRef] [PubMed] 40. Guo, X.; Song, W.; Chen, K.; Chen, X.; Zheng, Z.; Cao, B.; Huang, R.; Zhao, B.; Wu, Y.; Shang, H. Gender and onset age-related features of non-motor symptoms of patients with Parkinson’s disease—A study from Southwest China. Parkinsonism Relat. Disord. 2013, 19, 961–965. [CrossRef] 41. Szewczyk-Krolikowski, K.; Tomlinson, P.; Nithi, K.; Wade-Martins, R.; Talbot, K.; Ben-Shlomo, Y.; Hu, M.T.M. The influence of age and gender on motor and non-motor features of early Parkinson’s disease: Initial findings from the Oxford Parkinson Disease Center (OPDC) discovery cohort. Parkinsonism Relat. Disord. 2014, 20, 99–105. [CrossRef] [PubMed] 42. Coelho, M.; Ferreira, J.J. Late-stage Parkinson disease. Nat. Rev. Neurol. 2012, 8, 435–442. [CrossRef] [PubMed] 43. Mollenhauer, B.; Zimmermann, J.; Sixel-Döring, F.; Focke, N.K.; Wicke, T.; Ebentheuer, J.; Schaumburg, M.; Lang, E.; Trautmann, E.; Zetterberg, H.; et al. Monitoring of 30 marker candidates in early Parkinson disease as progression markers. Neurology 2016, 87, 168–177. [CrossRef] [PubMed] 44. 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. 2013, 332, 136–140. [CrossRef] [PubMed] 45. Alvarado-Bolaños, A.; Cervantes-Arriaga, A.; Rodríguez-Violante, M.; Rodrigo, L.-A.; Humberto, C.-F.; Roxanna, M.-C.; Roberto, L.-O.; Ingrid, E.-B.; Carlos, Z.-R. Impact of Neuropsychiatric Symptoms on the Quality of Life of Subjects with Parkinson’s Disease. J. Parkinsons Dis. 2015, 5, 541–548. [CrossRef] [PubMed] 46. Balestrino, R.; Martinez-Martin, P. Neuropsychiatric symptoms, behavioural disorders, and quality of life in Parkinson’s disease. J. Neurol. Sci. 2017, 373, 173–178. [CrossRef] 47. Antonini, A.; Tesei, S.; Zecchinelli, A.; Barone, P.; De Gaspari, D.; Canesi, M.; Sacilotto, G.; Meucci, N.; Mariani, C.; Pezzoli, G. Randomized study of sertraline and low-dose amitriptyline in patients with Parkinson’s disease and depression: Effect on quality of life. Mov. Disord. 2006, 21, 1119–1122. [CrossRef] 48. Xu, Z.; Anderson, K.N.; Saffari, S.E.; Lawson, R.A.; Chaudhuri, K.R.; Brooks, D.; Pavese, N. Progression of sleep disturbances in Parkinson’s disease: A 5-year longitudinal study. J. Neurol. 2021, 268, 312–320. [CrossRef] 49. Santos-García, D.; Castro, E.S.; de Deus Fonticoba, T.; Feal Panceiras, M.J.; Muñoz Enriquez, J.G.; Paz González, J.M.; Cores Bartolomé, C.; Planellas, L.L.; García Caldentey, J.; Caballol, N.; et al. Sleep Problems Are Related to a Worse Quality of Life and a Greater Non-Motor Symptoms Burden in Parkinson’s Disease. J. Geriatr. Psychiatry Neurol. 2020. epub ahead of print. [CrossRef] 50. Santos García, D.; Labandeira Guerra, C.; Yáñez Baña, R.; Hernando, M.I.C.; López, I.C.; Gonález, J.M.P.; Losada, M.G.A.; Palmás, M.J.G.; Miró, C.M. Safinamide Improves Non-Motor Symptoms Burden in Parkinson’s Disease: An Open-Label Prospective Study. Brain Sci. 2021, 11, 316. [CrossRef]