Predictors of global non-motor symptoms burden progression in Parkinson’s disease. Results from the COPPADIS cohort at 2-year follow-up

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-García1,* , Teresa de Deus 2, Carlos Cores 1, Hector Canfield 2, Jose M Paz González 1, Cristina Martínez Miró1, Lorena Valdés Aymerich 1, Ester Suárez 2, Silvia Jesús3,4, 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 Catalán15, Victor Nogueira 16, Victor Puente 17, Julio Dotor 18, Carmen Borrué19, 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 Gastón30, 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 Ordás38, Luis M López Díaz 39, Darrian McAfee 40, Pablo Martinez-Martin 4, Pablo Mir 3,4 and COPPADIS Study Group †   Citation: Santos-García, D.; de Deus, T.; Cores, C.; Canfield, H.; Paz González, J.M.; Martínez Miró, C.; Valdés Aymerich, L.; Suárez, E.; Jesús, S.; Aguilar, M.; et al. Predictors of Global Non-Motor Symptoms Burden Progression in Parkinson’s Disease. Results from the COPPADIS Cohort at 2-Year Follow-Up. J. Pers. Med. 2021,11, 626. https://doi.org/ 10.3390/jpm11070626 Academic Editor: Felix Javier Jiménez Jiménez Received: 10 May 2021 Accepted: 28 June 2021 Published: 30 June 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1CHUAC, Complejo Hospitalario Universitario de A Coruña, 15006 A Coruña, Spain; [email protected] (C.C.); [email protected] (J.M.P.G.); [email protected] (C.M.M.); lor[email protected] (L.V.A.) 2CHUF, Complejo Hospitalario Universitario de Ferrol, 15405 A Coruña, Spain; terecorr[email protected] (T.d.D.); [email protected] (H.C.); [email protected] (E.S.) 3Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41009 Seville, Spain; [email protected] (S.J.); [email protected] (P.M.) 4CIBERNED (Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas), 28031 Madrid, Spain; [email protected] (I.G.A.); [email protected] (J.K.); [email protected] (P.M.-M.) 5Hospital Universitari Mutua de Terrassa, 08221 Barcelona, Spain; [email protected] (M.A.); [email protected] (P.P.) 6Hospital Clínic de Barcelona, 08036 Barcelona, Spain; [email protected] (L.P.); [email protected] (M.C.) 7Centro Neurológico Oms 42, 07003 Palma de Mallorca, Spain; [email protected] 8Consorci Sanitari Integral, Hospital Moisés Broggi, 08970 Barcelona, Spain; [email protected] 9Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain; ines.legar[email protected] 10 Hospital Universitario Vall d’Hebron, 08035 Barcelona, Spain; [email protected] (J.H.-V.); [email protected] (O.d.F.) 11 Complejo Hospitalario Universitario de Pontevedra (CHOP), 36071 Pontevedra, Spain; [email protected] (I.C.); [email protected] (M.S.) 12 Hospital Universitario La Princesa, 28006 Madrid, Spain; [email protected] 13 Hospital Universitario Marqués de Valdecilla, 39011 Santander, Spain 14 Consorci Sanitari Integral, Hospital General de L’Hospitalet, 08906 Barcelona, Spain; [email protected] 15 Hospital Universitario Clínico San Carlos, 28040 Madrid, Spain; [email protected] 16 Hospital Da Costa, 27880 Burela, Spain; victor[email protected] 17 Hospital del Mar, 08003 Barcelona, Spain; [email protected] 18 Hospital Universitario Virgen Macarena, 41009 Sevilla, Spain; [email protected] 19 Hospital Infanta Sofía, 28702 Madrid, Spain; [email protected] 20 Institut d’Assistència Sanitària (IAS)—Institut Catalàde la Salut, 17190 Girona, Spain; [email protected] 21 Hospital General Universitario de Elche, 03203 Elche, Spain; [email protected] 22 Fundación Hospital de Alcorcón, 28922 Madrid, Spain; [email protected] 23 Hospital de Tortosa Verge de la Cinta (HTVC), 43500 Tarragona, Spain; [email protected] 24 Complejo Asistencial Universitario de Burgos, 09006 Burgos, Spain; esther[email protected] 25 Hospital Universitario de Canarias, 38320 San Cristóbal de la Laguna, Spain; [email protected] 26 Hospital Universitario Ramón y Cajal, IRYCIS, 28034 Madrid, Spain; [email protected] 27 Hospital Universitario Puerta de Hierro, 28222 Madrid, Spain; [email protected] 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; [email protected] 29 Complejo Hospitalario de Toledo, 45071 Toledo, Spain; [email protected] 30 Complejo Hospitalario de Navarra, 31008 Pamplona, Spain; itziar[email protected] 31 Hospital de Sant Pau, 08041 Barcelona, Spain 32 Hospital Universitario Central de Asturias, 33011 Oviedo, Spain; [email protected] 33 Hospital Universitario Donostia, 20009 San Sebastián, Spain; JAVIER.RUIZMAR[email protected] 34 Hospital Arnau de Vilanova, 46015 Valencia, Spain; carivaler[email protected] 35 Hospital Ruber Internacional, 28034 Madrid, Spain; [email protected] 36 Hospital de Cabueñes, 33394 Gijón, Spain; [email protected] 37 Hospital Universitario Lucus Augusti (HULA), 27002 Lugo, Spain; r[email protected] 38 Hospital Rey Juan Carlos, 28933 Madrid, Spain; [email protected] 39 Complejo Hospitalario Universitario de Orense (CHUO), 32005 Orense, Spain; [email protected] 40 Laboratory for Cognition and Neural Stimulation, Univeristy of Pennsylvania, Philadelphia, PA 19104, USA; [email protected] *Correspondence: [email protected]; 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 shortterm 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 nonmotor 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 (BDIII), 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 Comitéde 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) 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; 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 V0 PD Patients V2 Cohen’s Test paControls V0 Controls V2 pbpcpd 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 pvalues 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) 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 = 0.944; V2 vs. V0 in PD patients, p < 0.0001; difference in the change from V0 to V2 between PD patients and controls, p = 0.002. (C) Mean score on each domain of the NMSS scale at V0, V1, and V2 in PD patients (blue) and controls (red). Data (A and B) are presented as box plots, with the box representing the median and the two middle quartiles (25–75%). P values were computed using general linear models (GLM) repeated measures. Mild outliers (O) are data points that are more extreme than Q1 − 1.5 × IQR or Q3 + 1.5 × IQR. NMSS, Non-Motor Symptoms Scale. 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 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= 0.944; V2 vs. V0 in PD patients, p< 0.0001; difference in the change from V0 to V2 between PD patients and controls, p= 0.002. ( C ) Mean score on each domain of the NMSS scale at V0, V1, and V2 in PD patients (blue) and controls (red). Data (A and B) are presented as box plots, with the box representing the median and the two middle quartiles (25–75%). Pvalues were computed using general linear models (GLM) repeated measures. Mild outliers (O) are data points that are more extreme than Q1 −1.5 ×IQR or Q3 + 1.5 ×IQR. NMSS, Non-Motor Symptoms Scale. 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 TS NMSS D1 NMSS D2 NMSS D3 NMSS D4 NMSS D5 NMSS D6 NMSS D7 NMSS D8 NMSS 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 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 Name) Location Role Contribution Astrid Adarmes, Daniela Hospital Universitario Virgen del Rocío, Sevilla, Spain Site investigator Evaluation of participants and/or data management Almeria, Marta Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Neuropsychologist; evaluation of participants Alonso Losada, Maria Gema Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo (CHUVI), Vigo, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Alonso Cánovas, Araceli Hospital Universitario Ramón y Cajal, Madrid, Spain Site investigator Evaluation of participants and/or data management Alonso Frech, Fernando Hospital Universitario Clínico San Carlos, Madrid, Spain Site investigator Evaluation of participants and/or data management Alonso Redondo, Ruben Hospital Universitario Lucus Augusti (HULA), Lugo, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Aneiros Díaz, Ángel Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Álvarez, Ignacio Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Evaluation of participants and/or data management Álvarez Sauco, María Hospital General Universitario de Elche, Elche, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Arnáiz, Sandra Complejo Asistencial Universitario de Burgos, Burgos, Spain Site investigator Evaluation of participants and/or data management Arribas, Sonia Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Neuropsychologist; evaluation of participants Ascunce Vidondo, Arancha Complejo Hospitalario de Navarra, Pamplona, Spain Site investigator Evaluation of participants and/or data management Aguilar, Miquel Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Evaluation of participants and/or data management Ávila Rivera, Maria Asunción Consorci Sanitari Integral, Hospital General de L’Hospitalet, L’Hospitalet de Llobregat, Barcelona, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Bernardo Lambrich, Noemí Hospital de Tortosa Verge de la Cinta (HTVC), Tortosa, Tarragona, Spain Site investigator Evaluation of participants and/or data management Bejr-Kasem, Helena Hospital de Sant Pau, Barcelona, Spain Site investigator Evaluation of participants and/or data management J. Pers. Med. 2021,11, 626 17 of 25 Name (Last Name, First Name) Location Role Contribution Blázquez Estrada, Marta Hospital Universitario Central de Asturias, Oviedo, Spain Site investigator Evaluation of participants and/or data management BotíGonzález, Maria Ángeles Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Neuropsychologist; evaluation of participants Borrué, Carmen Hospital Infanta Sofía, Madrid, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Buongiorno, Maria Teresa Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Nurse study coordinator Cabello González, Carolina Complejo Hospitalario de Navarra, Pamplona, Spain Site investigator Scheduling of evaluations Cabo López, Iria Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Caballol, Nuria Consorci Sanitari Integral, Hospital Moisés Broggi, Sant Joan Despí, Barcelona, Spain. Site investigator/PI Coordination at the center Evaluation of participants and/or data management Cámara Lorenzo, Ana Hospital Clínic de Barcelona, Barcelona, Spain Site investigator Nurse study coordinator Canfield Medina, Héctor Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Evaluation of participants and/or data management Carrillo, Fátima Hospital Universitario Virgen del Rocío, Sevilla, Spain Site investigator Evaluation of participants and/or data management Carrillo Padilla, Francisco José Hospital Universitario de Canarias, San Cristóbal de la Laguna, Santa Cruz de Tenerife, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Casas, Elena Complejo Asistencial Universitario de Burgos, Burgos, Spain Site investigator Evaluation of participants and/or data management Catalán, Maria José Hospital Universitario Clínico San Carlos, Madrid, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Clavero, Pedro Complejo Hospitalario de Navarra, Pamplona, Spain Site investigator Evaluation of participants and/or data management Cortina Fernández, A Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Coordination of blood extractions Cosgaya, Marina Hospital Clínic de Barcelona, Barcelona, Spain Site investigator Evaluation of participants and/or data management Cots Foraster, Anna Institut d’Assistència Sanitària (IAS) - InstituíCátala de la Salud. Girona, Spain Site investigator Evaluation of participants and/or data management J. Pers. Med. 2021,11, 626 18 of 25 Name (Last Name, First Name) Location Role Contribution Crespo Cuevas, Ane Hospital del Mar, Barcelona, Spain. Site investigator Evaluation of participants and/or data management Cubo, Esther Complejo Asistencial Universitario de Burgos, Burgos, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management De Deus Fonticoba, Teresa Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Nurse study coordinator Evaluation of participants and/or data management De Fábregues-Boixar, Oriol Hospital Universitario Vall d’Hebron, Barcelona, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Díez Fairen, M Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Evaluation of participants and/or data management Dotor García-Soto, Julio Hospital Universitario Virgen Macarena, Sevilla, Spain Site investigator/PI Evaluation of participants and/or data management Erro, Elena Complejo Hospitalario de Navarra, Pamplona, Spain Site investigator Evaluation of participants and/or data management Escalante, Sonia Hospital de Tortosa Verge de la Cinta (HTVC), Tortosa, Tarragona, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Estelrich Peyret, Elena Institut d’Assistència Sanitària (IAS) - InstituíCátala de la Salud. Girona, Spain Site investigator Evaluation of participants and/or data management Fernández Guillán, Noelia Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Neuroimaging studies Gámez, Pedro Complejo Asistencial Universitario de Burgos, Burgos, Spain Site investigator Evaluation of participants and/or data management Gallego, Mercedes Hospital La Princesa, Madrid, Spain Site investigator Evaluation of participants and/or data management García Caldentey, Juan Centro Neurológico Oms 42, Palma de Mallorca, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management García Campos, Cristina Hospital Universitario Virgen Macarena, Sevilla, Spain Site investigator Evaluation of participants and/or data management García Moreno, Jose Manuel Hospital Universitario Virgen Macarena, Sevilla, Spain Site investigator/PI (until MAR/21) Coordination at the center Evaluation of participants and/or data management Gastón, Itziar Complejo Hospitalario de Navarra, Pamplona, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Gómez Garre, María del Pilar Hospital Universitario Virgen del Rocío, Sevilla, Spain Site investigator Genetic studies coordination Gómez Mayordomo, Víctor Hospital Clínico San Carlos, Madrid, Spain Site investigator Evaluation of participants and/or data management J. Pers. Med. 2021,11, 626 19 of 25 Name (Last Name, First Name) Location Role Contribution González Aloy, Javier Institut d’Assistència Sanitària (IAS) - InstituíCátala de la Salud. Girona, Spain Site investigator Evaluation of participants and/or data management González Aramburu, Isabel Hospital Universitario Marqués de Valdecilla, Santander, Spain Site investigator Evaluation of participants and/or data management González Ardura, Jessica Hospital Universitario Lucus Augusti (HULA), Lugo, Spain Site investigator/PI (until FEB/21) Evaluation of participants and/or data management González García, Beatriz Hospital La Princesa, Madrid, Spain Site investigator Nurse study coordinator González Palmás, Maria Josefa Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain Site investigator Evaluation of participants and/or data management González Toledo, Gabriel Ricardo Hospital Universitario de Canarias, San Cristóbal de la Laguna, Santa Cruz de Tenerife, Spain Site investigator Evaluation of participants and/or data management Golpe Díaz, Ana Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Laboratory analysis coordination Grau Solá, Mireia Consorci Sanitari Integral, Hospital Moisés Broggi, Sant Joan Despí, Barcelona, Spain Site investigator Evaluation of participants and/or data management Guardia, Gemma Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Evaluation of participants and/or data management Hernández Vara, Jorge Hospital Universitario Vall d’Hebron, Barcelona, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Horta Barba, Andrea Hospital de Sant Pau, Barcelona, Spain Site investigator Neuropsychologist; evaluation of participants Idoate Calderón, Daniel Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain Site investigaor Neuropsychologist; evaluation of participants Infante, Jon Hospital Universitario Marqués de Valdecilla, Santander, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Jesús, Silvia Hospital Universitario Virgen del Rocío, Sevilla, Spain Site investigator Evaluation of participants and/or data management Kulisevsky, Jaime Hospital de Sant Pau, Barcelona, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Kurtis, Mónica Hospital Ruber Internacional, Madrid, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Labandeira, Carmen Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo (CHUVI), Vigo, Spain Site investigator Evaluation of participants and/or data management J. Pers. Med. 2021,11, 626 20 of 25 Name (Last Name, First Name) Location Role Contribution Labrador Espinosa, Miguel Ángel Hospital Universitario Virgen del Rocío, Sevilla, Spain Site investigator Neuroimaging data analysis Lacruz, Francisco Complejo Hospitalario de Navarra, Pamplona, Spain Site investigator Evaluation of participants and/or data management Lage Castro, Melva Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain Site investigator Evaluation of participants and/or data management Lastres Gómez, Sonia Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain Site investigator Neuropsychologist; evaluation of participants Legarda, Inés Hospital Universitario Son Espases, Palma de Mallorca, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management López Ariztegui, Nuria Complejo Hospitalario de Toledo, Toledo, Spain Site investigator/PI Evaluation of participants and/or data management López Díaz, Luis Manuel Hospital Da Costa de Burela, Lugo, Spain Site investigator/PI (until SEP/16) Evaluation of participants and/or data management López Manzanares, Lydia Hospital La Princesa, Madrid, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management López Seoane, Balbino Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Neuroimaging studies Lucas del Pozo, Sara Hospital Universitario Vall d’Hebron, Barcelona, Spain Site investigator Evaluation of participants and/or data management Macías, Yolanda Fundación Hospital de Alcorcón, Madrid, Spain Site investigator Evaluation of participants and/or data management Mata, Marina Hospital Infanta Sofía, Madrid, Spain Site investigator Evaluation of participants and/or data management MartíAndres, Gloria Hospital Universitario Vall d’Hebron, Barcelona, Spain Site investigator Evaluation of participants and/or data management Martí, Maria JoséHospital Clínic de Barcelona, Barcelona, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Martínez Castrillo, Juan Carlos Hospital Universitario Ramón y Cajal, Madrid, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Martinez-Martin, Pablo Centro Nacional de Epidemiología y CIBERNED, Instituto de Salud Carlos III. Madrid Collaborator in statistical and methods analysis Methods and statistical reviewer McAfee, Darrian University of Pennsylvania, Philadelphia Collaborator in english style English style reviewer Meitín, Maria Teresa Hospital Da Costa de Burela, Lugo, Spain Site investigator Evaluation of participants and/or data management J. Pers. Med. 2021,11, 626 21 of 25 Name (Last Name, First Name) Location Role Contribution Menéndez González, Manuel Hospital Universitario Central de Asturias, Oviedo, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Méndez del Barrio, Carlota Hospital Universitario Virgen del Rocío, Sevilla, Spain Site investigator Evaluation of participants and/or data management Mir, Pablo Hospital Universitario Virgen del Rocío, Sevilla, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Miranda Santiago, Javier Complejo Asistencial Universitario de Burgos, Burgos, Spain Site investigator Evaluation of participants and/or data management Morales Casado, Maria Isabel Complejo Hospitalario de Toledo, Toledo, Spain. Site investigator Evaluation of participants and/or data management Moreno Diéguez, Antonio Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Neuroimaging studies Nogueira, Víctor Hospital Da Costa de Burela, Lugo, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Novo Amado, Alba Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Neuroimaging studies Novo Ponte, Sabela Hospital Universitario Puerta de Hierro, Madrid, Spain. Site investigator Evaluation of participants and/or data management Ordás, Carlos Hospital Rey Juan Carlos, Madrid, Spain, Madrid, Spain. Site Investigator Evaluation of participants and/or data management Pagonabarraga, Javier Hospital de Sant Pau, Barcelona, Spain Site investigator Evaluation of participants and/or data management Isabel PareésHospital Ruber Internacional, Madrid, Spain Site investigator Evaluation of participants and/or data management Pascual-Sedano, Berta Hospital de Sant Pau, Barcelona, Spain Site Investigator Evaluation of participants and/or data management Pastor, Pau Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Evaluation of participants and/or data management Pérez Fuertes, Aída Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Blood analysis Pérez Noguera, Rafael Hospital Universitario Virgen Macarena, Sevilla, Spain Site investigator Evaluation of participants and/or data management Planas-Ballvé, Ana Consorci Sanitari Integral, Hospital Moisés Broggi, Sant Joan Despí, Barcelona, Spain Site investigator Evaluation of participants and/or data management Planellas, LluísHospital Clínic de Barcelona, Barcelona, Spain Site investigator Evaluation of participants and/or data management Prats, Marian Ángeles Institut d’Assistència Sanitària (IAS)—InstituíCátala de la Salud. Girona, Spain Site investigator Evaluation of participants and/or data management J. Pers. Med. 2021,11, 626 22 of 25 Name (Last Name, First Name) Location Role Contribution Prieto Jurczynska, Cristina Hospital Rey Juan Carlos, Madrid, Spain, Madrid, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Puente, Víctor Hospital del Mar, Barcelona, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Pueyo Morlans, Mercedes Hospital Universitario de Canarias, San Cristóbal de la Laguna, Santa Cruz de Tenerife, Spain Site investigator Evaluation of participants and/or data management Redondo, Nuria Hospital La Princesa, Madrid, Spain Site Investigator Evaluation of participants and/or data management Rodríguez Méndez, Luisa Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Blood analysis Rodríguez Pérez, Amparo Belén Hospital General Universitario de Elche, Elche, Spain Site investigator Evaluation of participants and/or data management Roldán, Florinda Hospital Universitario Virgen del Rocío, Sevilla, Spain Site investigator Neuroimaging studies Ruíz de Arcos, MaríaHospital Universitario Virgen Macarena, Sevilla, Spain. Site investigator Evaluation of participants and/or data management Ruíz Martínez, Javier Hospital Universitario Donostia, San Sebastián, Spain Site investigator Evaluation of participants and/or data management Sánchez Alonso, Pilar Hospital Universitario Puerta de Hierro, Madrid, Spain Site investigator Evaluation of participants and/or data management Sánchez-Carpintero, Macarena Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Neuroimaging studies Sánchez Díez, Gema Hospital Universitario Ramón y Cajal, Madrid, Spain Site investigator Evaluation of participants and/or data management Sánchez Rodríguez, Antonio Hospital Universitario Marqués de Valdecilla, Santander, Spain Site investigator Evaluation of participants and/or data management Santacruz, Pilar Hospital Clínic de Barcelona, Barcelona, Spain Site investigator Evaluation of participants and/or data management Santos García, Diego CHUAC, Complejo Hospitalario Universitario de A Coruña Coordinator of the Project Coordination of the COPPADIS-2015 Segundo Rodríguez, José Clemente Complejo Hospitalario de Toledo, Toledo, Spain Site investigator Evaluation of participants and/or data management Seijo, Manuel Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Sierra, MaríaHospital Universitario Marqués de Valdecilla, Santander, Spain Site investigator Evaluation of participants and/or data management Solano, Berta Institut d’Assistència Sanitària (IAS)—InstituíCátala de la Salud. Girona, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management J. Pers. Med. 2021,11, 626 23 of 25 Name (Last Name, First Name) Location Role Contribution Suárez Castro, Ester Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coruña, Spain Site investigator Evaluation of participants and/or data management Tartari, Juan Pablo Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Evaluation of participants and/or data management Valero, Caridad Hospital Arnau de Vilanova, Valencia, Spain Site investigator Evaluation of participants and/or data management Vargas, Laura Hospital Universitario Virgen del Rocío, Sevilla, Spain Site investigator Evaluation of participants and/or data management Vela, Lydia Fundación Hospital de Alcorcón, Madrid, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management Villanueva, Clara Hospital Universitario Clínico San Carlos, Madrid, Spain Site investigator Evaluation of participants and/or data management Vives, Bárbara Hospital Universitario Son Espases, Palma de Mallorca, Spain Site investigator Evaluation of participants and/or data management Villar, Maria Dolores Hospital Universitario de Canarias, San Cristóbal de la Laguna, Santa Cruz de Tenerife, Spain Site investigator Evaluation of participants and/or data management References 1. 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