diagnostics Article Predictors of Loss of Functional Independence in Parkinson’s Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up and Comparison with a Control Group Diego Santos García 1, * , Teresa de Deus Fonticoba 2 , Carlos Cores Bartolomé 1 , Lucía Naya Ríos 1 , Lucía García Roca 1 , Cristina Martínez Miró 1 , Hector Canfield 1 , Silvia Jesús 3,4 , Miquel Aguilar 5 , Pau Pastor 5 , Marina Cosgaya 6 , Juan García Caldentey 7 , Nuria Caballol 8 , Inés Legarda 9 , Jorge Hernández Vara 10 , Iria Cabo 11 , Lydia López Manzanares 12 , Isabel González Aramburu 4,13 , María A. Ávila Rivera 14 , Víctor Gómez Mayordomo 15 , Víctor Nogueira 16 , Víctor Puente 17 , Julio Dotor 18 , Carmen Borrué 19 , Berta Solano Vila 20 , María Álvarez Sauco 21 , Lydia Vela 22 , Sonia Escalante 23 , Esther Cubo 24 , Francisco Carrillo Padilla 25 , Juan C. Martínez Castrillo 26 , Pilar Sánchez Alonso 27 , Maria G. Alonso Losada 28 , Nuria López Ariztegui 29 , Itziar Gastón 30 , Jaime Kulisevsky 4,31 , Marta Blázquez Estrada 32 , Manuel Seijo 11 , Javier Rúiz Martínez 33 , Caridad Valero 34 , Mónica Kurtis 35 , Oriol de Fábregues 10 , Jessica González Ardura 36 , Ruben Alonso Redondo 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.B.); lucia.naya.rios@gmail.com (L.N.R.); Citation: Santos García, D.; de Deus lucia.garcia.toca@gmail.com (L.G.R.); Cristina.Martinez.Miro@sergas.es (C.M.M.); Fonticoba, T.; Cores Bartolomé, C.; canfield.hector@gmail.com (H.C.) 2 CHUF, Complejo Hospitalario Universitario de Ferrol, 15405 A Coruña, Spain; terecorreomovil@gmail.com Naya Ríos, L.; García Roca, L.; 3 Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Martínez Miró, C.; Canfield, H.; Jesús, Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, S.; Aguilar, M.; Pastor, P.; et al. 41009 Seville, Spain; smaestre-ibis@us.es (S.J.); pmir@us.es (P.M.) Predictors of Loss of Functional 4 CIBERNED (Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas), Independence in Parkinson’s Disease: 28031 Madrid, Spain; isagaramburu@gmail.com (I.G.A.); jkulisevsky@santpau.cat (J.K.); Results from the COPPADIS Cohort pmm650@hotmail.com (P.M.-M.) at 2-Year Follow-Up and Comparison 5 Hospital Universitari Mutua de Terrassa, Terrassa, 08221 Barcelona, Spain; miquelaguilar@gmail.com (M.A.); with a Control Group. Diagnostics paupastor@mutuaterrassa.es (P.P.) 6 Hospital Clínic de Barcelona, 08036 Barcelona, Spain; marinacosgaya@gmail.com 2021, 11, 1801. https://doi.org/ 7 Centro Neurológico Oms 42, 07003 Palma de Mallorca, Spain; juangcaldentey@hotmail.com 10.3390/diagnostics11101801 8 Consorci Sanitari Integral, Hospital Moisés Broggi, Sant Joan Despí, 08970 Barcelona, Spain; nuriacaballol@hotmail.com Academic Editor: Aldo Quattrone 9 Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain; ines.legarda@ssib.es 10 Hospital Universitario Vall d’Hebron, 08035 Barcelona, Spain; hernandezvarajorge76@gmail.com (J.H.V.); Received: 21 August 2021 odefabregues@gmail.com (O.d.F.) Accepted: 26 September 2021 11 Complejo Hospitalario Universitario de Pontevedra (CHOP), 36071 Pontevedra, Spain; icabol@yahoo.es (I.C.); Published: 29 September 2021 manuel.seijo.martinez@sergas.es (M.S.) 12 Hospital Universitario La Princesa, 28006 Madrid, Spain; lydialopez@hotmail.com 13 Hospital Universitario Marqués de Valdecilla, 39011 Santander, Spain Publisher’s Note: MDPI stays neutral 14 Consorci Sanitari Integral, Hospital General de L’Hospitalet, L’Hospitalet de Llobregat, with regard to jurisdictional claims in published maps and institutional affil- 08906 Barcelona, Spain; asuncion.avila@sanitatintegral.org 15 Hospital Universitario Clínico San Carlos, 28040 Madrid, Spain; vicmayordomo@gmail.com iations. 16 Hospital Da Costa, Burela, 27880 Lugo, Spain; victor.nogueira.fernandez@sergas.es 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; Copyright: © 2021 by the authors. berta_solano@hotmail.com Licensee MDPI, Basel, Switzerland. 21 Hospital General Universitario de Elche, 03203 Elche, Spain; mariaalsa@hotmail.com This article is an open access article 22 Fundación Hospital de Alcorcón, 28922 Madrid, Spain; lvela@fhalcorcon.es distributed under the terms and 23 Hospital de Tortosa Verge de la Cinta (HTVC), 43500 Tarragona, Spain; sescalant@yahoo.es conditions of the Creative Commons 24 Complejo Asistencial Universitario de Burgos, 09006 Burgos, Spain; esthercubo@gmail.com Attribution (CC BY) license (https:// 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 creativecommons.org/licenses/by/ 27 Hospital Universitario Puerta de Hierro, 28222 Madrid, Spain; PISANCHEZAL@GMAIL.COM 4.0/). Diagnostics 2021, 11, 1801. https://doi.org/10.3390/diagnostics11101801 https://www.mdpi.com/journal/diagnostics Diagnostics 2021, 11, 1801 2 of 26 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 Universitario Lucus Augusti (HULA), 27002 Lugo, Spain; alonso_1408@hotmail.es 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.: +34-646173341 † The full list of the Study Group COPPADIS is provided in the Appendix A. Abstract: Background and objective: The aim of this study was to compare the progression of independence in activities of daily living (ADL) in Parkinson’s disease (PD) patients versus a control group, as well as to identify predictors of disability progression and functional dependency (FD). Patients and Methods: PD patients and control subjects, who were recruited from 35 centers of Spain from the COPPADIS cohort between January 2016 and November 2017 (V0), were included. Patients and subjects were then evaluated again at the 2-year follow-up (V2). Disability was assessed with the Schwab & England Activities of Daily Living Scale (S&E-ADLS) at V0 and V2. FD was defined as an S&E-ADLS score less than 80%. Results: In the PD group, a significant decrease in the S&E-ADLS score from V0 to V2 (N = 507; from 88.58 ± 10.19 to 84.26 ± 13.38; p < 0.0001; Cohen’s effect size = −0.519) was observed but not in controls (N = 124; from 98.87 ± 6.52 to 99.52 ± 2.15; p = 0.238). When only patients considered functional independent at baseline were included, 55 out of 463 (11.9%) converted to functional dependent at V2. To be a female (OR = 2.908; p = 0.009), have longer disease duration (OR = 1.152; p = 0.002), have a non-tremoric motor phenotype at baseline (OR = 3.574; p = 0.004), have a higher score at baseline in FOGQ (OR = 1.244; p < 0.0001) and BDI-II (OR = 1.080; p = 0.008), have a lower score at baseline in PD-CRS (OR = 0.963; p = 0.008), and have a greater increase in the score from V0 to V2 in UPDRS-IV (OR = 1.168; p = 0.0.29), FOGQ (OR = 1.348; p < 0.0001) and VAFS-Mental (OR = 1.177; p = 0.013) (adjusted R-squared 0.52; Hosmer and Lemeshow test = 0.94) were all found to be independent predictors of FD at V2. Conclusions: In conclusion, autonomy for ADL worsens in PD patients compared to controls. Cognitive impairment, gait problems, fatigue, depressive symptoms, more advanced disease, and a non-tremor phenotype are independent predictors of FD in the short-term. Keywords: activities of daily living; dependency; disability; gait; Parkinson’s disease 1. Introduction Parkinson’s disease (PD) is a neurodegenerative disorder in which the symptoms will progress and generate a disability for the patient to carry out his/her activities of daily living (ADL). Loss of functional independence leads to caregiver burden, high resource use, institutionalization, increased risk of death and comorbid complications, worse quality of life (QoL) [1,2], and it is also considered an important outcome of progression [3]. Since there is currently no cure for PD, the goal of treatment in PD is to improve the patient’s symptoms with the intention of increasing his/her autonomy for ADL and achieving a better QoL perception. Knowing what factors will predict when a patient could become functionally dependent is important, since pharmacological and non-pharmacological strategies could be established with the intention of delaying the appearance of functional Diagnostics 2021, 11, 1801 3 of 26 dependence [4]. In addition, it can also be useful when foreseeing needs such as certain socio-health care and estimating costs both at a particular and global level for a health sys- tem [5]. Suggested predictors of functional dependency in PD are older age, higher severity of rigidity and bradykinesia, more severe axial symptoms, dyskinesia, cognitive impair- ment, and more advanced disease [6–9]. However, there is a lack of evidence about the progression of disability in PD and the identification of functional dependency predictors in prospective studies. A systematic review about loss of independence in PD published in 2015 included only 14 studies of 15,145 unique references identified [10]. It is noteworthy that many of the studies were carried out many years ago. The authors concluded that little high-quality data on dependency were available and there was heterogeneity in study populations and methodology, showing the necessity for well-conducted studies to better understand the progression of dependency in PD [10]. Specific limitations are the small sample size and the absence of a control group in the majority of the studies. Although many of them have a long-term follow-up, it is key to identify what factors can predict a deterioration in autonomy for ADL in the short-term with the intention to intervene as early as possible. The aim of this study was to compare the progression of independence in ADL in PD patients vs. a control group from the Spanish cohort COPPADIS (COhort of Patients with PArkinson’s DIsease in Spain), as well as to identify predictors of disability progression and functional dependency in the PD group. 2. Methods PD patients and control subjects, who were recruited from January 2016 to November 2017 and evaluated again at a 2-year follow-up from 35 centers of Spain from the COPPADIS cohort [11], were included in this study. Methodology about COPPADIS-2015 study can be consulted in https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-016-0548-9 (accessed on 22 February 2016) [12]. This is a longitudinal-prospective, 5-year follow-up study designed to analyze natural progression of PD in which patients diagnosed with PD according to UK PD Brain Bank criteria without dementia were included [11]. Data from two visits were obtained in this study: (1) at baseline (V0); (2) at 2-year ± 30 days follow-up (V2). Disability was assessed with the Schwab & England Activities of Daily Living Scale (S&E-ADLS) [13]. This scale is a method of assessing the capabilities of people suffering from impaired mobility. Originally presented in 1968 at Third Symposium on Parkinson’s Disease, Royal College of Surgeons in Edinburgh, the scale assesses the difficulties patients have completing daily activities or chores. It uses percentages to represent how much effort and dependence on others patients need to complete daily chores. S&E-ADLS is a recommended scale for assessing disability in PD patients by the MDS Task Force [14]. The patient must indicate the degree of autonomy for carrying out ADL (the higher the score, the less disability), being from 0% (bed-ridden, vegetative functions such as swallowing, bladder and bowel functions are not functioning) to 100% (completely independent, essentially normal). Functional dependency was defined as an S&E-ADLS score less than 80% (80% = completely independent; 70% = not completely independent) [2,8,15]. Information on sociodemographic aspects, factors related to PD, comorbidity, and treatment was collected. Moreover, motor status, non-motor symptoms (NMS), and QoL was assessed at V0 and at V2 using different validated scales: Hoenh & Yahr (H&Y); Unified Parkinson’s Disease Rating Scale [UPDRS] part III and part IV; Freezing of Gait Questionnaire [FOGQ]); Parkinson’s Disease Cognitive Rating Scale (PD-CRS); Non-Motor Symptoms Scale (NMSS); Beck Depression Inventory-II (BDI-II); Parkinson’s Disease Sleep Scale (PDSS); Neuropsychiatric Inventory (NPI); Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale (QUIP-RS); Visual Analog Scale-Pain (VAS- Pain); Visual Analog Fatigue Scale (VAFS]); the 39-item Parkinson’s disease Questionnaire (PDQ-39); PQ-10; and the European Health Interview Survey-Quality of Life 8 item index (EUROHIS-QOL8) [12]. In patients with motor fluctuations, the motor assessment was Diagnostics 2021, 11, 1801 4 of 26 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 conducted in control subjects at V0 and at V2. 2.1. Data Analysis Data were processed using SPSS 20.0 for Windows. For comparisons between groups, the Student’s t-test, Mann–Whitney–Wilcoxon test, Chi-square test, or Fisher test were 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 S&E-ADLS score between the two visits (V0 and V2) were significant in both PD patients and controls. Age, gender, and LEDD (levodopa equivalent daily dose) [16] at V0 and at V2 were included as covariates. This test was also applied for testing the difference between V0 and V2 in other variables, being furthermore the S&E-ADLS score at baseline and the change in the S&E-ADLS score from V0 to V2 included as covariates. 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; and large effect = 0.8. The Bonferroni method was used as a post-hoc test after ANOVA. Spearman’s or Pearson’s correlation coefficient, as appropriate, were used for ana- lyzing the relationship between the change from V0 to V2 in the S&E-ADLS score and the change from V0 to V2 in the score of other scales. 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 increase disability (i.e., S&E-ADLS score from V0 to V2 decrease; S&E-ADLS 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 0.05 level [17]. The variables considered for the analysis were: (1) at V0: age, gender, dis- ease duration, total number of non-antiparkinsonian drugs, LEDD, motor phenotype [18], UPDRS-III-OFF, UPDRS-IV, FOGQ, PD-CRS, NMSS, BDI-II, PDSS, NPI, QUIP-RS, VAS- PAIN, VASF-Physical, and VASF-Mental; (2) at V2: to be receiving L-dopa, a MAO-B (monoamine oxidase type B) inhibitor, a COMT (catechol-o-methyl transferase) inhibitor, a dopamine agonist, to practice regular exercise, and to assist regularly to a PD Asso- ciation; (3) from V0 to V2: the change in total number of non-antiparkinsonian drugs, LEDD, UPDRS-III-OFF, UPDRS-IV, FOGQ, PD-CRS, BDI-II, PDSS, NPI, QUIP-RS, VAS- PAIN, VASF-Physical, and VASF-Mental. All models were adjusted by S&E-ADLS score at V0. Tolerance and variance inflation factor (VIF) were used to detect multicollinearity (multicollinearity was considered problematic when tolerance was less than 0.2 and, simul- taneously, the value of VIF 10 and above). By the other hand, binary regression models were used for determining predictive factors of functional dependency at V2 (S&E-ADLS score at V2 < 80% as dependent variable). The variables considered for the analysis were the same as in previous linear models. 2.2. Standard Protocol Approvals, Registrations, and Patient Consents Approval from the Comité de Ética de la Investigación Clínica de Galicia from Spain (2014/534; 02/DEC/2014) was obtained. A written informed consent from all participants was signed. COPPADIS-2015 was classified by the AEMPS (Agencia Española del Medica- mento y Productos Sanitarios) as a Post-authorization Prospective Follow-up study with the code COH-PAK-2014-01. Diagnostics 2021, 11, x FOR PEER REVIEW 5 of 25 Diagnostics 2021, 11, 1801 5 of 26 2.3. Data Availability The 2.3. Data data that support the findings of this study are available from the corresponding Availability author upon The data reasonable that request. support the No of findings computer coding this study was used are available in the from the completion of the corresponding current manuscript. author upon reasonable request. No computer coding was used in the completion of the current manuscript. 3. Results 3. Results A total of 507 PD patients (62.63 ± 8.52 years old; 58.8% males; mean disease duration 5.5A±total 4.37 of years) andpatients 507 PD 124 controls (62.63(62.59 ± 8.52±years 7.22 years old; 50% old; 58.8% males) males; meanfrom the COPPADIS disease duration cohort were considered valid for analysis in this study. At V0, the ADLS 5.5 ± 4.37 years) and 124 controls (62.59 ± 7.22 years old; 50% males) from the COPPADIS score was lower in the cohort PD considered were group compared to the valid for control analysis in group (88.58 this study. At±V0, 10.19 thevs. 98.87score ADLS ± 6.52; wasp 5, OR = 5.495 (95%CI, 2.300–13.126; p < 0.0001); PD-CRS total score at V0 ≤ 81: score duration = 0.004); FOGQ total OR = at V0 (95%CI, 3.788 > 5, OR = 5.495 1.590–9.026; 95%CI p = 0.003);p BDI-II (95%CI, 2.300–13.126; < 0.0001); totalPD-CRS score attotal V0 score > 15: at ORV0 =≤ 81: 2.995 OR = 3.788 (95%CI, 95%CI 1.590–9.026; p = 0.003); BDI-II total score at V0 (95%CI, 1.168–7.681; p = 0.022); FOGQ total score increase from V0 to V2 > 3: OR = 5.913 > 15: OR = 2.995 (95%CI, 1.168–7.681; pp=<0.022); (95%CI, 2.471–14.147; 0.0001);FOGQ total score increase and VAFS-Mental fromincrease total score V0 to V2 > 3:V0 from ORto=V25.913 > 3: (95%CI, 2.471–14.147; p < 0.0001); and VAFS-Mental total score increase OR = 3.560 (95%CI, 1.207–10.504; p = 0.021) (Figure 3). Significant OR for UPDRS-IV totalfrom V0 to V2 > 3: OR = 3.560 (95%CI, 1.207–10.504; p = 0.021) (Figure 3). Significant OR score increase from V0 to V2 was not observed when cut-points were defined (increase infor UPDRS-IV total >score 2, 3, increase from V0 4 or 5 points). to V2when Finally, was notthe observed presence of when FOGcut-points at baselinewere (scoredefined (increase ≥1 in the item 3 in > 2, 3, 4 or 5 points). Finally, when the presence of FOG at of the FOGQ [19,20]) was considered, experiencing FOG at V0 was an independent baseline (score ≥ 1 inpre- the item 3 of the FOGQ [19,20]) was considered, experiencing FOG at V0 was an independent dictor of functional dependency at the 2-year follow-up: univariate analysis, OR = 2.945 predictor of functional dependency at the 2-year follow-up: univariate analysis, OR = 2.945 (95%CI, 1.660–5.223; p < 0.0001); multivariate analysis, OR = 2.936 (95%CI, 1.300–6.633; p = (95%CI, 1.660–5.223; p < 0.0001); multivariate analysis, OR = 2.936 (95%CI, 1.300–6.633; 0.010; adjusted R-squared 0.47; Hosmer and Lemeshow test = 0.79). p = 0.010; adjusted R-squared 0.47; Hosmer and Lemeshow test = 0.79). Figure 3. Predictors Figure 3. Predictorsofoffunctional functionaldisability (S&E-ADLS disability (S&E-ADLS score < 80%) score at V2. < 80%) Light at V2. greygrey Light arrows showshow arrows the OR theofOR variables from of variables baseline visit (V0). from baseline Dark Dark visit (V0). grey arrows showshow grey arrows the ORtheofOR change of variables of change fromfrom of variables V0 toV0V2.toRed arrows V2. Red withwith arrows discontinue line discontinue line represent the 95%CI. BDI-II, Beck Depression Inventory-II; DD, disease duration; FOGQ, Freezing Of represent the 95%CI. BDI-II, Beck Depression Inventory-II; DD, disease duration; FOGQ, Freezing Of Gait Questionnaire; Gait Question- naire; PD-CRS, PD-CRS, Parkinson’s Parkinson’s DiseaseDisease Cognitive Cognitive RatingRating Scale; VAFS, Scale; VAFS, Visual Analog Visual Analog FatigueFatigue Scale. Scale. Table 4. Factors associated with functional dependency at V2 (S&E-ADLS score < 80%). ORa ORb 95% ICa 95% ICb pa pb At V0 (baseline) Age 1.013 N. A. 0.985–1.042 N. A. 0.354 N. A. Gender (female) 1.602 2.334 1.003–2.559 1.127–4.833 0.049 0.022 Diagnostics 2021, 11, 1801 12 of 26 Table 4. Cont. ORa ORb 95% ICa 95% ICb pa pb Disease duration (at V0) 1.163 1.098 1.001–1.227 1.008–1.195 <0.0001 0.031 At V0 Number of non-antipark. drugs 1.19 N. A. 1.088–1.302 N. A. <0.0001 N. A. LEDD 1.001 N. A. 1.001–1.002 N. A. <0.0001 N. A. UPDRS-III (OFF) 1.063 N. A. 1.040–1.087 N. A. <0.0001 N. A. UPDRS-IV 1.377 N. A. 1.255–1.511 N. A. <0.0001 N. A. FOGQ 1.208 1.199 1.152–1.267 1.092–1.317 <0.0001 <0.0001 Non-tremoric motor 3.119 N. A. 1.851–5.254 N. A. <0.0001 N. A. phenotype (%) PD-CRS 0.959 0.964 0.944–0.975 0.942–0.987 <0.0001 <0.0001 NMSS 1.016 N. A. 1.010–1.022 N. A. <0.0001 N. A. BDI-II 1.101 N. A. 1.066–1.137 N. A. <0.0001 N. A. PDSS 0.985 N. A. 0.997–0.993 N. A. 0.001 N. A. QUIP-RS 1.011 N. A. 0.985–1.037 N. A. 0.409 N. A. NPI 1.088 1.048 1.057–1.120 1.007–1.091 <0.0001 0.02 VAS-PAIN 1.162 N. A. 1.076–1.254 N. A. <0.0001 N. A. VASF–physical 1.268 N. A. 1.162–1.384 N. A. <0.0001 N. A. VASF–mental 1.133 N. A. 1.038–1.236 N. A. 0.005 N. A. S&E-ADLS 0.895 0.926 0.872–0.920 0.889–0.965 <0.0001 <0.0001 At V2 To be receiving levodopa 5.77 N. A. 1.377–24.175 N. A. 0.016 N. A. To be receiving a 0.808 N. A. 0.533–1.515 N. A. 0.687 N. A. dopamine agonist To be receiving a MAO-B inhibitor 0.749 N. A. 0.439–1.276 N. A. 0.288 N. A. To be receiving a COMT inhibitor 2.764 N. A. 1.704–4.485 N. A. <0.0001 N. A. To practice regular exercise 0.488 N. A. 0.173–4.908 N. A. 0.005 N. A. To assist regularly to a 1.024 N. A. 0.545–1.922 N. A. 0.942 N. A. PD association Change at V2 (V2 vs. V0) LEDD 1.001 N. A. 1.000–1.001 N. A. 0.093 N. A. Number of non-antipark. drugs 1.141 N. A. 0.985–1.322 N. A. 0.079 N. A. UPDRS-III (OFF) 1.03 N. A. 1.006–1.054 N. A. 0.014 N. A. UPDRS-IV 1.109 N. A. 1.012–1.216 N. A. 0.027 N. A. FOGQ 1.137 1.305 1.075–1.201 1.195–1.424 <0.0001 <0.0001 PD-CRS 0.974 N. A. 0.954–0.994 N. A. 0.011 N. A. NMSS 1.009 N. A. 1.002–1.015 N. A. 0.011 N. A. BDI-II 0.993 N. A. 0.963–1.024 N. A. 0.662 N. A. PDSS 0.999 N. A. 0.090–1.008 N. A. 0.853 N. A. QUIP-RS 0.991 N. A. 0.964–1.018 N. A. 0.494 N. A. NPI 1.006 N. A. 0.978–1.035 N. A. 0.677 N. A. Diagnostics 2021, 11, 1801 13 of 26 Table 4. Cont. ORa ORb 95% ICa 95% ICb pa pb VAS-PAIN 1.023 N. A. 0.953–1.098 N. A. 0.533 N. A. VASF–physical 1.025 N. A. 0.947–1.109 N. A. 0.548 N. A. VASF–mental 1.106 1.236 1.019–1.200 1.093–1.379 0.016 0.001 Dependent variable: Functional dependency (S&E-ADLS < 80% at V2). OR and 95% IC are shown. a, univariate analysis; b, multivariate analysis (Hosmer and Lemeshow test = 0.27; R2 = 0.57). 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; S&E-ADLS, Schwab & England Activities of Daily Living Scale; UPDRS, Unified Parkinson’s Disease Rating Scale; VAFS, Visual Analog Fatigue Scale; VAS-Pain, Visual Analog Scale-Pain. 4. Discussion In this study, we observed a worsening in functional independence for ADL in a cohort of 507 PD patients compared to a control group after a 2-year follow-up, being double those PD patients with functional dependency after follow-up compared to at baseline (17% vs. 9%). Moreover, longer disease duration, gender (female), non-tremoric motor phenotype, a worse motor and non-motor status at baseline related to cognitive impairment (PD-CRS), neuropsychiatric symptoms (NPI, BDI-II) and gait problems and motor complications (FOGQ, UPDRS-IV), and a greater impairment in gait problems (FOGQ) and fatigue (VAFS) after 2-year follow-up were identified as predictors of disability/functional dependency in this cohort. The frequency of patients with functional dependency in our cohort seems to be in line with other studies. The proportion of patients with dependency in inception studies varies between 10–25% at 5 years and 20–50% at 10 years [10]. However, some cohorts reported “dependency or mortality”, being about 15–40% at 5 years and 35–70% at 10 years [10,21–25]. We used the S&E-ADLS for assessing disability and defining functional dependency [13]. Many disability measures are available for application in PD, and the S&E-ADLS is one of the nine recommended scales by the International Parkinson and Movement Disorder Society Task Force [14]. The definition of functional dependency as a S&E-ADLS score <80% was considered according to previous studies [2,8,10]. In a prospective, community-based incident cohort of PD from the Parkinsonism Incidence in North-East Scotland (PINE) study, Macleod et al. observed in 198 patients with PD a rate of development of functional dependency (S&E-ADLS score < 80%) of 14 per 100 person years of follow-up [8]. We observed functional dependency in 9% of 507 PD patients with a mean disease duration of 5 years and a half, being double after a 2-year follow-up. Only one PD patient from our cohort was dead. However, from the initial cohort (N = 689) [11,15], the ADLS score was not recorded for 144 patients (21%). Compared to other studies, mean age and mean disease duration in our cohort were lower and the follow-up period was shorter [8,10,26,27]. It is likely that selection biases and methodological differences between studies can explain the variation in the rates of functional dependency rather than true population differences in dependency risk. Despite the limitations, our study shows that, in a short time (2 years), there is a global worsening in the autonomy of the patients to carry out their ADL, being 12% of functional independent patients at V0 dependent at V2. This does not happen in controls. A few previous studies included a control group [28,29], showing that PD constitutes a significant factor of dependency even in newly diagnosed subjects and also in elderly subjects living at home, as well as that institutionalization occurs more frequently in PD patients than in the general population. Remarkably, motor and NMS in our cohort progressed after the 2-year follow-up, but GLM repeated measures adjusted to disability at baseline and change in disability after the follow-up period showed not significant differences between patients and controls in any variable (but it was observed without this adjustment in many of them [30]), indicating the important influence of motor and NMS progression over functional capacity for ADL. In Diagnostics 2021, 11, 1801 14 of 26 this context, it is crucial to identify predictive factors of functional dependence in the short term in PD patients because some early interventions could be applied. Some studies have identified different predictors for increased dependency in PD: older age, age > 60 years old at initiation of levodopa therapy, male sex, greater smok- ing story, PIGD (postural instability gait difficulty) motor phenotype, more severe ax- ial symptoms, higher severity of rigidity and bradykinesia rather than tremor, no re- sponse to levodopa at one year, dyskinesia, cognitive impairment, and more advanced disease [6–10,15,24–29,31,32]. To our knowledge, our study is the largest study in which more variables were included in the analysis, both at the baseline level and considering their change over time, and which takes into account the degree of autonomy at baseline. Recently, it has been reported that de novo PD patients with PIGD phenotype have greater disability for ADL [33]. Our findings about age, motor phenotype, motor complications, and cognitive impairment as independent predictors of functional dependency are in line with the literature [6–10,15,24–32]. With regard to gender and contrary to Guillard et al. study [32], to be a female increased the probability of functional dependency at 2-year follow-up three-fold, but gender was not a predictor when disability (S&E-ADLS score as continuous variable) was considered as the dependent variable. Recently, Sperens et al. [34] reported that 9 of the 12 domains in the ADL taxonomy showed a change over time (up to 8-year follow-up) in 129 PD patients, with worse scores (N = 53) in women in some scores (shopping and cleaning). In general, it seems that, as PD progresses, gender differences emerge, with men exhibiting more severe Parkinsonian motor features and women experi- encing more levodopa-induced dyskinesia, fatigue, feelings of nervousness and sadness, constipation, restless legs, and pain [35,36]. Importantly, in our cohort, a greater global NMS burden was an independent predictor of QoL worsening at 2-year follow-up [37] but not of functional dependency or increased disability for ADL. However, mood and fatigue were factors increasing the probability of functional dependency in the short-term. Higher UPDRS-ADL and PDQ-39 mobility scores have been associated with fatigue [38]. Further- more, depression impacts QoL and contributes to greater disability in PD, so treatment of depression may in fact improve function [39]. Finally, gait problems were a predictor of disability in our cohort. To score >5 points in the FOGQ and to increase >3 points on the score after 2-year follow-up increased the probability of functional dependency five times. In particular, freezing of gait (FOG) was an independent factor associated with functional dependency in the COPPADIS study baseline cross-sectional analysis (N = 689; adjusted R-squared 0.513; p = 0.007) [15]. Again, in this 2-year longitudinal follow-up analysis, FOG was a predictor of functional dependency, so suffering from FOG increased the risk of being functional dependent threefold after 2 years. Balance confidence and FOG are associated with the mobility aspect of health-related QoL [40] and therapies and/or strategies designed to improve gait problems and FOG can benefit QoL and autonomy for ADL [41,42]. For example, compensation strategies seem to be an effective and simple treatment for gait impairment in PD patients [43]. Importantly, other strategies for delaying mobility disability is to practice regular physical exercise [44], as our results suggest. The present study has some limitations. The most important is that information about ADLS after 2-year follow-up was recorded in 507 out of 689 PD patients (74%) and in 124 out of 207 controls (60%). Thirty-eight patients dropped out of the study (1 death; 2 with change in diagnosis; 35 other reasons) at V2 and for 132 a follow-up was not obtained. In 12 patients evaluated at V2, the ADLS was not assessed. However, this is a limitation observed in other prospective studies, with maintenance rates of 89.8% (380/423) [16], 83.6% (117/140) [45], 73.9% (147/199) [46], and 61.9% (707/1142) [47]. Although a bias regarding the underestimation of functional dependency due to the withdrawal of the most affected patients from the study cannot be ruled out, significant differences between both groups, continuing vs. not continuing in the study at 2-year follow-up, in terms of disability and functional dependency at baseline, were not observed (data not shown). Second, for some variables, the information was not collected in all cases. Third, instead of a specific tool for assessing comorbidity, like Charlson Index or others, the total number of Diagnostics 2021, 11, 1801 15 of 26 non-antiparkinsonian medications was used as a surrogated marker of comorbidity [48]. Fourth, the diagnosis of FOG was subjective, and an insufficient or excessive diagnosis cannot be ruled out [49]. Fifth, our sample was not fully representative of the PD population due to inclusion and exclusion criteria at baseline (i.e., age limit, no dementia, no severe comorbidities, no second line therapies, etc.) [11,12], which leads to an early PD bias in this cohort. Sixth, all scales or questionnaires used for assessing motor and NMS are validated except PQ-10. This is a very simple question about global QoL perception from 0 (worst) to 10 (best) used in previous studies [46]. To use the PQ-10 takes very little time and provides information similar to the EUROHIS-QOL8 total score [48]. Finally, the sample size of the control group was clearly smaller than in patients. On the contrary, the strengths of our study include the large sample size and the extensive clinical and demographic information recorded with many justified variables included in the models. In conclusion, our study observes that autonomy for ADLS worsens in patients with PD compared to control subjects and identifies different predictors of functional dependency. The neurologist should be alert and think that those patients with PD with cognitive impairment, non-tremor phenotype, gait problems, fatigue, depressive symptoms, and more advanced disease are more likely to be dependent in the short term. Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/diagnostics11101801/s1. Author Contributions: D.S.G.: conception, organization, and execution of the project; statistical analysis; writing of the first draft of the manuscript; recruitment and/or evaluation of participants. T.d.D.F.: review and critique; recruitment and/or evaluation of participants. C.C.B.: Collaboration in the preparation of the manuscript. Review and critique. L.G.R.: Collaboration in the preparation of the manuscript; review and critique. L.N.R.: Collaboration in the preparation of the manuscript. Review and critique. H.C.: review and critique; recruitment and/or evaluation of participants. C.M.M.: review and critique. S.J.: review and critique; recruitment and/or evaluation of participants. M.A.: review and critique; recruitment and/or evaluation of participants. P.P.: review and critique; recruitment and/or evaluation of participants. M.C.: review and critique; recruitment and/or evaluation of participants. J.G.C.: review and critique; recruitment and/or evaluation of participants. N.C.: review and critique; recruitment and/or evaluation of participants. I.L.: review and critique; recruitment and/or evaluation of participants. J.H.V.: review and critique; recruitment and/or evaluation of participants. I.C.: review and critique; recruitment and/or evaluation of participants. L.L.M.: review and critique; recruitment and/or evaluation of participants. I.G.A.: review and critique; recruitment and/or evaluation of participants. M.A.Á.R.: review and critique; recruitment and/or evaluation of participants. V.G.M.: review and critique; recruitment and/or evaluation of participants. V.N.: review and critique; recruitment and/or evaluation of participants. V.P.: review and critique; recruitment and/or evaluation of participants. J.D.: review and critique; recruitment and/or evaluation of participants. C.B.: review and critique; recruitment and/or evaluation of participants. B.S.V.: review and critique; recruitment and/or evaluation of participants. M.Á.S.: review and critique; recruitment and/or evaluation of participants. L.V.: review and critique; recruitment and/or evaluation of participants. S.E.: review and critique; recruitment and/or evaluation of participants. E.C.: review and critique; recruitment and/or evaluation of participants. F.C.P.: review and critique; recruitment and/or evaluation of participants. J.C.M.C.: review and critique; recruitment and/or evaluation of participants. P.S.A.: review and critique; recruitment and/or evaluation of participants. M.G.A.L.: review and critique; recruitment and/or evaluation of participants. N.L.A.: review and critique; recruitment and/or evaluation of participants. I.G.: review and critique; recruitment and/or evaluation of participants. J.K.: review and critique; recruitment and/or evaluation of participants. M.B.E.: review and critique; recruitment and/or evaluation of participants. M.S.: review and critique; recruitment and/or evaluation of participants. J.R.M.: review and critique; recruitment and/or evaluation of participants. C.V.: review and critique; recruitment and/or evaluation of participants. M.K.: review and critique; recruitment and/or evaluation of participants. O.d.F.: review and critique; recruitment and/or evaluation of participants. J.G.A.: review and critique; recruitment and/or evaluation of participants. R.A.R.: review and critique; recruitment and/or evaluation of participants. C.O.: review and critique; recruitment and/or evaluation of participants. L.M.L.D.: review and critique; recruitment and/or evaluation of participants. D.M.: review and critique; review of english style. P.M.-M.: review and critique; Diagnostics 2021, 11, 1801 16 of 26 supervision. P.M.: review and critique; recruitment and/or evaluation of participants. All authors have read and agreed to the published version of the manuscript. Funding: Fundación 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. 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. Financial Disclosures: Santos García D. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, Italfarmaco, and Teva. De Deus Fonticoba T: None. Cores Bartolomé C. has received honoraria for educational presentations and advice service by Lundbeck and UCB Pharma. García Roca L: None. Naya Ríos L: None. Canfield H: None. Martínez Miró C: None. Jesús S. has received honoraria from AbbVie, Bial, Merz, UCB, and Zambon and holds the competitive contract “Juan Rodés” supported by the Instituto de Salud Carlos III. She has received grants from the Spanish Ministry of Economy and Competitiveness (PI18/01898) and the Consejería de Salud de la Junta de Andalucía (PI-0459-2018). Aguilar M: UCB and Schwabe with assistance to a Congress; Nutricia with assistance to a Congress and payment of lecture. Pastor p: None. Cosgaya M: None. García Caldentey J. has received honoraria for educational presentations and advice service by Qualigen, Nutricia, Abbvie, Italfarmaco, UCB Pharma, Lundbeck, Zambon, Bial, and Teva. Caballol N. has received honoraria from Bial, Italfármaco, Qualigen, Zambon, UCB, Teva and KRKA and sponsorship from Zambon, TEVA and Abbvie for attending medical conferences. Legarda I. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Zambon, Bial, and Teva. Hernández Vara J. has received travel bursaries and educational grants from Abbvie and has received honoraria for educational presentations from Abbvie, Teva, Bial, Zambon, Italfarmaco, and Sanofi-Genzyme. Cabo I. has received honoraria for educational presentations and advice service by Abbvie, Zambon, and Bial. López Manzanares L: Compensated advisory services, consulting, research grant support, or speaker honoraria: AbbVie, Acorda, Bial, Intec Pharma, Italfarmaco, Pfizer, Roche, Teva, UCB, and Zambon. González Aramburu I: None. Ávila Rivera MA has received honoraria from Zambon, UCB Pharma, Qualigen, Bial, and Teva, and sponsorship from Zambon and Teva for attending conferences. Gómez Mayordomo: Nogueira V: None. Puente V. has served as consultant for Abbvie and Zambon; has received grant/research from Abbvie. Dotor García-Soto J: Compensated advisory services, consulting, research grant support, or speaker honoraria: Merck, Sanofi-Genzyme, Allergan, Biogen, Roche, UCB and Novartis. Borrué C: None. Solano Vila B. has received honoraria for educational presentations and advice service by UCB, Zambon, Teva, Abbvie, Bial. Álvarez Sauco M. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Zambon, Bial, and Teva. Vela L. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Escalante S. has received honoraria for educational presentations and advice service by Abbvie, Zambon, and Bial. Cubo E: Travel grants: Abbvie, Allergan, Boston; Lecturing honoraria: Abbvie, International Parkinson’s disease Movement Disorder Society. Carrillo Padilla F. has received honoraria from Zambon (SEN Congress assistance). Martínez Castrillo JC. has received research support from Lundbeck, Italfarmaco, Allergan, Zambon, Merz, and Abbvie. He has received speaking honoraria from AbbVie, Bial, Italfarmaco, Lundbeck, Krka, TEVA, UCB, Zambon, Allergan, Ipsen, and Merz. Sánchez Alonso p. has received honoraria for educational presentations and advice service by Abbvie, UCB Pharma, Lundbeck, KRKA, Zambon, Bial, and Teva. Alonso Losada MG. has received honoraria for educational presentations and advice service by Zambon and Bial. López Ariztegui N. has received honoraria for educational presentations and advice service by Abbvie, Italfarmaco, Zambon, and Bial. Gastón I. has received research support from Abbvie and Zambon and has served as a consultant for Abbvie, Exelts, and Zambon. Kulisevsky J: (1) Consulting fees: Roche, Zambon; (2) Stock/allotment: No; (3) Patent royalties/licensing fees: No; (4) Honoraria (e.g., Diagnostics 2021, 11, 1801 17 of 26 lecture fees): Zambon, Teva, Bial, UCB; (5) Fees for promotional materials: No; (6) Research funding: Roche, Zambon, Ciberned; Instituto de SaludCarlos III; FundacióLa Maratóde TV3; (7) Scholarship from corporation: No; (8) Corporate laboratory funding: No; (9) Others (e.g., trips, travel, or gifts): No. Blázquez Estrada M. has received honoraria for educational presentations and advice service by Abbvie, Abbott, UCB Pharma, Allergan, Zambon, Bial, and Qualigen. Seijo M. has received honoraria for educational services from KRKA, UCB, Zambon, Bial; travel grants from Daiichi and Roche. Ruiz Martínez J. has received honoraria for educational presentations, attending medical conferences, and advice service by Abbvie, UCB Pharma, Zambon, Italfarmaco, Bial, and Teva. Valero C. has received honoraria for educational services from Zambon, Abbvie and UCB. Kurtis M. has received honoraria from Bial, the Spanish Neurology Society, and the International and Movement Disorders Society. de Fábregues O. has received honoraria for educational presentations and advice service by Bial, Zambon, Abbvie, KRKA, and Teva. González Ardura J. has recieved honoraria for speaking from italofarma, Krka, Genzyme, UCB, Esteve, Psyma iberica marketing research SL and Ferrer, course grant from Teva and travel grant from Merck. Alonso Redondo R: None. Ordás C: None. López Díaz L. has received honoraria from UCB, Lundbeck, and KRKA. McAfee D: None. Martínez-Martin p. has received honoraria from National School of Public Health (ISCIII), Editori-al Viguera and Takeda Pharmaceuticals for lecturing in courses, and from the International Parkinson and Movement Disorder Society (MDS) for management of the Program on Rating Scales. Mir p. has received honoraria from AbbVie, Abbott, Allergan, Bial, Merz, UCB, and Zambon and have received grants from the Spanish Ministry of Economy and Competitiveness [ PI16/01575] co-founded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Salud y Bienestar Social de la Junta de Andalucía [ PI-0437-2012, PI-0471-2013], the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña. 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, Puig Daví A, 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, Solano Vila B, Suárez Castro E, Tartari JP, Valero C, Vargas L, Vela L, Villanueva C, Vives B, Villar MD. Diagnostics 2021, 11, 1801 18 of 26 Name (Last Name, First Name) Location Role Contribution Hospital Universitario Virgen del Rocío, Evaluation of participants Astrid Adarmes, Daniela Site investigator Sevilla, Spain and/or data management Hospital Universitari Mutua de Neuropsychologist; Almeria, Marta Site investigator Terrassa, Terrassa, Barcelona, Spain evaluation of participants Hospital Álvaro Cunqueiro, Complejo Coordination at the center Site Alonso Losada, Maria Gema Hospitalario Universitario de Vigo Evaluation of participants investigator/PI (CHUVI), Vigo, Spain and/or data management Hospital Universitario Ramón y Cajal, Evaluation of participants Alonso Cánovas, Araceli Site investigator Madrid, Spain 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 Augusti Site Alonso Redondo, Ruben Evaluation of participants (HULA), Lugo, Spain investigator/PI and/or data management Coordination at the center Complejo Hospitalario Universitario de Site Aneiros Díaz, Ángel Evaluation of participants Ferrol (CHUF), Ferrol, A Coruña, Spain investigator/PI and/or data management Hospital Universitari Mutua de Evaluation of participants Álvarez, Ignacio Site investigator Terrassa, Terrassa, Barcelona, Spain and/or data management Coordination at the center Hospital General Universitario de Site Álvarez Sauco, María Evaluation of participants Elche, Elche, Spain investigator/PI and/or data management Complejo Asistencial Universitario de Evaluation of participants Arnáiz, Sandra Site investigator Burgos, Burgos, Spain and/or data management Hospital Universitari Mutua de Neuropsychologist; Arribas, Sonia Site investigator Terrassa, Terrassa, Barcelona, Spain evaluation of participants Complejo Hospitalario de Navarra, Evaluation of participants Ascunce Vidondo, Arancha Site investigator Pamplona, Spain and/or data management Hospital Universitari Mutua de Evaluation of participants Aguilar, Miquel Site investigator Terrassa, Terrassa, Barcelona, Spain and/or data management Consorci Sanitari Integral, Hospital Coordination at the center Site Ávila Rivera, Maria Asunción General de L’Hospitalet, L’Hospitalet Evaluation of participants investigator/PI de Llobregat, Barcelona, Spain and/or data management Hospital de Tortosa Verge de la Cinta Evaluation of participants Bernardo Lambrich, Noemí Site investigator (HTVC), Tortosa, Tarragona, Spain and/or data management Evaluation of participants Bejr-Kasem, Helena Hospital de Sant Pau, Barcelona, Spain Site investigator and/or data management 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 Site investigator Terrassa, Terrassa, Barcelona, Spain evaluation of participants Coordination at the center Site Borrué, Carmen Hospital Infanta Sofía, Madrid, Spain Evaluation of participants investigator/PI and/or data management Hospital Universitari Mutua de Buongiorno, Maria Teresa Site investigator Nurse study coordinator Terrassa, Terrassa, Barcelona, Spain Complejo Hospitalario de Navarra, Cabello González, Carolina Site investigator Scheduling of evaluations Pamplona, Spain Diagnostics 2021, 11, 1801 19 of 26 Name (Last Name, First Name) Location Role Contribution Coordination at the center Complejo Hospitalario Universitario de Site Cabo López, Iria Evaluation of participants Pontevedra (CHOP), Pontevedra, Spain investigator/PI and/or data management Consorci Sanitari Integral, Hospital Coordination at the center Site Caballol, Nuria Moisés Broggi, Sant Joan Despí, Evaluation of participants investigator/PI Barcelona, Spain. and/or data management Hospital Clínic de Barcelona, Cámara Lorenzo, Ana Site investigator Nurse study coordinator Barcelona, Spain Complejo Hospitalario Universitario de Evaluation of participants Canfield Medina, Héctor Site investigator Ferrol (CHUF), Ferrol, A Coruña, Spain and/or data management Hospital Universitario Virgen del Rocío, Evaluation of participants Carrillo, Fátima Site investigator Sevilla, Spain and/or data management Hospital Universitario de Canarias, San Coordination at the center Site Carrillo Padilla, Francisco José Cristóbal de la Laguna, Santa Cruz de Evaluation of participants investigator/PI Tenerife, Spain and/or data management Complejo Asistencial Universitario de Evaluation of participants Casas, Elena Site investigator Burgos, Burgos, Spain and/or data management Coordination at the center Hospital Universitario Clínico San Site Catalán, Maria José Evaluation of participants Carlos, Madrid, Spain investigator/PI and/or data management Complejo Hospitalario de Navarra, Evaluation of participants Clavero, Pedro Site investigator Pamplona, Spain and/or data management Complejo Hospitalario Universitario de Coordination of Cortina Fernández, A Site investigator Ferrol (CHUF), Ferrol, A Coruña, Spain blood extractions 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 Evaluation of participants Crespo Cuevas, Ane Hospital del Mar, Barcelona, Spain. Site investigator and/or data management Coordination at the center Complejo Asistencial Universitario de Site Cubo, Esther Evaluation of participants Burgos, Burgos, Spain investigator/PI and/or data management Nurse study Complejo Hospitalario Universitario de coordinatorEvaluation of De Deus Fonticoba, Teresa Site investigator Ferrol (CHUF), Ferrol, A Coruña, Spain participants and/or data management Coordination at the center Hospital Universitario Vall d’Hebron, Site De Fábregues-Boixar, Oriol Evaluation of participants Barcelona, Spain investigator/PI and/or data management Hospital Universitari Mutua de Evaluation of participants Díez Fairen, M Site investigator Terrassa, Terrassa, Barcelona, Spain and/or data management Hospital Universitario Virgen Site Evaluation of participants Dotor García-Soto, Julio Macarena, Sevilla, Spain investigator/PI and/or data management Complejo Hospitalario de Navarra, Evaluation of participants Erro, Elena Site investigator Pamplona, Spain and/or data management Diagnostics 2021, 11, 1801 20 of 26 Name (Last Name, First Name) Location Role Contribution Coordination at the center Hospital de Tortosa Verge de la Cinta Site Escalante, Sonia Evaluation of participants (HTVC), Tortosa, Tarragona, Spain investigator/PI 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 Universitario de Fernández Guillán, Noelia Site investigator Neuroimaging studies Ferrol (CHUF), Ferrol, A Coruña, Spain Complejo Asistencial Universitario de Evaluation of participants Gámez, Pedro Site investigator Burgos, Burgos, Spain and/or data management Evaluation of participants Gallego, Mercedes Hospital La Princesa, Madrid, Spain Site investigator and/or data management Coordination at the center Centro Neurológico Oms 42, Palma de Site García Caldentey, Juan Evaluation of participants Mallorca, Spain investigator/PI and/or data management Hospital Universitario Virgen Evaluation of participants García Campos, Cristina Site investigator Macarena, Sevilla, Spain and/or data management Site Coordination at the center Hospital Universitario Virgen García Moreno, Jose Manuel investigator/PI Evaluation of participants Macarena, Sevilla, Spain (until MAR/21) and/or data management Coordination at the center Complejo Hospitalario de Navarra, Site Gastón, Itziar Evaluation of participants Pamplona, Spain investigator/PI and/or data management Hospital Universitario Virgen del Rocío, Gómez Garre, María del Pilar Site investigator Genetic studies coordination Sevilla, Spain Hospital Clínico San Carlos, Evaluation of participants Gómez Mayordomo, Víctor Site investigator Madrid, Spain and/or data management 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 de Evaluation of participants González Aramburu, Isabel Site investigator Valdecilla, Santander, Spain and/or data management Site Hospital Universitario Lucus Augusti Evaluation of participants González Ardura, Jessica investigator/PI (HULA), Lugo, Spain and/or data management (until FEB/21) González García, Beatriz Hospital La Princesa, Madrid, Spain Site investigator Nurse study coordinator Complejo Hospitalario Universitario de Evaluation of participants González Palmás, Maria Josefa Site investigator Pontevedra (CHOP), Pontevedra, Spain and/or data management Hospital Universitario de Canarias, San González Toledo, Evaluation of participants Cristóbal de la Laguna, Santa Cruz de Site investigator Gabriel Ricardo and/or data management Tenerife, Spain Complejo Hospitalario Universitario de Laboratory analysis Golpe Díaz, Ana Site investigator Ferrol (CHUF), Ferrol, A Coruña, Spain coordination Consorci Sanitari Integral, Hospital Evaluation of participants Grau Solá, Mireia Moisés Broggi, Sant Joan Despí, Site investigator and/or data management Barcelona, Spain Hospital Universitari Mutua de Evaluation of participants Guardia, Gemma Site investigator Terrassa, Terrassa, Barcelona, Spain and/or data management Diagnostics 2021, 11, 1801 21 of 26 Name (Last Name, First Name) Location Role Contribution Coordination at the center Hospital Universitario Vall d’Hebron, Site Hernández Vara, Jorge Evaluation of participants Barcelona, Spain investigator/PI and/or data management Neuropsychologist; Horta Barba, Andrea Hospital de Sant Pau, Barcelona, Spain Site investigator evaluation of participants Complejo Hospitalario Universitario de Neuropsychologist; Idoate Calderón, Daniel Site investigaor Pontevedra (CHOP), Pontevedra, Spain evaluation of participants Coordination at the center Hospital Universitario Marqués de Site Infante, Jon Evaluation of participants Valdecilla, Santander, Spain investigator/PI and/or data management Hospital Universitario Virgen del Rocío, Evaluation of participants Jesús, Silvia Site investigator Sevilla, Spain and/or data management Coordination at the center Site Kulisevsky, Jaime Hospital de Sant Pau, Barcelona, Spain Evaluation of participants investigator/PI and/or data management Coordination at the center Hospital Ruber Internacional, Site Kurtis, Mónica Evaluation of participants Madrid, Spain investigator/PI and/or data management Hospital Álvaro Cunqueiro, Complejo Evaluation of participants Labandeira, Carmen Hospitalario Universitario de Vigo Site investigator and/or data management (CHUVI), Vigo, Spain Labrador Espinosa, Hospital Universitario Virgen del Rocío, Site investigator Neuroimaging data analysis Miguel Ángel Sevilla, Spain Complejo Hospitalario de Navarra, Evaluation of participants Lacruz, Francisco Site investigator Pamplona, Spain and/or data management Complejo Hospitalario Universitario de Evaluation of participants Lage Castro, Melva Site investigator Pontevedra (CHOP), Pontevedra, Spain and/or data management Complejo Hospitalario Universitario de Neuropsychologist; Lastres Gómez, Sonia Site investigator Pontevedra (CHOP), Pontevedra, Spain evaluation of participants Coordination at the center Hospital Universitario Son Espases, Site Legarda, Inés Evaluation of participants Palma de Mallorca, Spain investigator/PI and/or data management Complejo Hospitalario de Toledo, Site Evaluation of participants López Ariztegui, Nuria Toledo, Spain investigator/PI and/or data management Hospital Da Costa de Burela, Evaluation of participants López Díaz, Luis Manuel Site investigator Lugo, Spain and/or data management Coordination at the center Site López Manzanares, Lydia Hospital La Princesa, Madrid, Spain Evaluation of participants investigator/PI and/or data management Complejo Hospitalario Universitario de López Seoane, Balbino Site investigator Neuroimaging studies Ferrol (CHUF), Ferrol, A Coruña, Spain Hospital Universitario Vall d’Hebron, Evaluation of participants Lucas del Pozo, Sara Site investigator Barcelona, Spain and/or data management Fundación Hospital de Alcorcón, Evaluation of participants Macías, Yolanda Site investigator Madrid, Spain and/or data management Evaluation of participants Mata, Marina Hospital Infanta Sofía, Madrid, Spain Site investigator and/or data management Hospital Universitario Vall d’Hebron, Evaluation of participants Martí Andres, Gloria Site investigator Barcelona, Spain and/or data management Diagnostics 2021, 11, 1801 22 of 26 Name (Last Name, First Name) Location Role Contribution Coordination at the center Hospital Clínic de Barcelona, Site Martí, Maria José Evaluation of participants Barcelona, Spain investigator/PI and/or data management Coordination at the center Hospital Universitario Ramón y Cajal, Site Martínez Castrillo, Juan Carlos Evaluation of participants Madrid, Spain investigator/PI and/or data management Centro Nacional de Epidemiología y Collaborator in Methods and Martinez-Martin, Pablo CIBERNED, Instituto de Salud Carlos statistical and statistical reviewer III. Madrid methods analysis University of Maryland School Collaborator in McAfee, Darrian English style reviewer of Medicine English style Hospital Da Costa de Burela, Evaluation of participants Meitín, Maria Teresa Site investigator Lugo, Spain and/or data management Coordination at the center Hospital Universitario Central de Site Menéndez González, Manuel Evaluation of participants Asturias, Oviedo, Spain investigator/PI and/or data management Hospital Universitario Virgen del Rocío, Evaluation of participants Méndez del Barrio, Carlota Site investigator Sevilla, Spain and/or data management Coordination at the center Hospital Universitario Virgen del Rocío, Site Mir, Pablo Evaluation of participants Sevilla, Spain investigator/PI and/or data management Complejo Asistencial Universitario de Evaluation of participants Miranda Santiago, Javier Site investigator Burgos, Burgos, Spain and/or data management Complejo Hospitalario de Toledo, Evaluation of participants Morales Casado, Maria Isabel Site investigator Toledo, Spain. and/or data management Complejo Hospitalario Universitario de Moreno Diéguez, Antonio Site investigator Neuroimaging studies Ferrol (CHUF), Ferrol, A Coruña, Spain Coordination at the center Hospital Da Costa de Burela, Site Nogueira, Víctor Evaluation of participants Lugo, Spain investigator/PI and/or data management Complejo Hospitalario Universitario de Novo Amado, Alba Site investigator Neuroimaging studies Ferrol (CHUF), 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 Evaluation of participants Pagonabarraga, Javier Hospital de Sant Pau, Barcelona, Spain Site investigator and/or data management Hospital Ruber Internacional, Evaluation of participants Pareés, Isabel Site investigator Madrid, Spain and/or data management Evaluation of participants Pascual-Sedano, Berta Hospital de Sant Pau, Barcelona, Spain Site Investigator and/or data management Hospital Universitari Mutua de Evaluation of participants Pastor, Pau Site investigator Terrassa, Terrassa, Barcelona, Spain and/or data management Complejo Hospitalario Universitario de Pérez Fuertes, Aída Site investigator Blood analysis Ferrol (CHUF), Ferrol, A Coruña, Spain Hospital Universitario Virgen Evaluation of participants Pérez Noguera, Rafael Site investigator Macarena, Sevilla, Spain and/or data management Diagnostics 2021, 11, 1801 23 of 26 Name (Last Name, First Name) Location Role Contribution Consorci Sanitari Integral, Hospital Evaluation of participants Planas-Ballvé, Ana Moisés Broggi, Sant Joan Despí, Site investigator and/or data management 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 Coordination at the center Hospital Rey Juan Carlos, Madrid, Site Prieto Jurczynska, Cristina Evaluation of participants Spain, Madrid, Spain investigator/PI and/or data management Coordination at the center Site Puente, Víctor Hospital del Mar, Barcelona, Spain Evaluation of participants investigator/PI and/or data management Hospital Universitario de Canarias, San Evaluation of participants Pueyo Morlans, Mercedes Cristóbal de la Laguna, Santa Cruz de Site investigator and/or data management Tenerife, Spain Evaluation of participants Puig Daví, Arnau Hospital de Sant Pau, Barcelona, Spain Site investigator and/or data management Evaluation of participants Redondo, Nuria Hospital La Princesa, Madrid, Spain Site Investigator and/or data management Complejo Hospitalario Universitario de Rodríguez Méndez, Luisa Site investigator Blood analysis Ferrol (CHUF), Ferrol, A Coruña, Spain Hospital General Universitario de Evaluation of participants Rodríguez Pérez, Amparo Belén Site investigator Elche, Elche, Spain and/or data management Hospital Universitario Virgen del Rocío, Roldán, Florinda Site investigator Neuroimaging studies Sevilla, Spain Hospital Universitario Virgen Evaluation of participants Ruíz de Arcos, María Site investigator Macarena, Sevilla, Spain. and/or data management Hospital Universitario Donostia, San Evaluation of participants Ruíz Martínez, Javier Site investigator 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 Universitario de Sánchez-Carpintero, Macarena Site investigator Neuroimaging studies Ferrol (CHUF), Ferrol, A Coruña, Spain Hospital Universitario Ramón y Cajal, Evaluation of participants Sánchez Díez, Gema Site investigator Madrid, Spain and/or data management Hospital Universitario Marqués de Evaluation of participants Sánchez Rodríguez, Antonio Site investigator 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 Coordinator of the Coordination of the Santos García, Diego Universitario de A Coruña Project COPPADIS-2015 Segundo Rodríguez, Complejo Hospitalario de Toledo, Evaluation of participants Site investigator José Clemente Toledo, Spain and/or data management Coordination at the center Complejo Hospitalario Universitario de Site Seijo, Manuel Evaluation of participants Pontevedra (CHOP), Pontevedra, Spain investigator/PI and/or data management Diagnostics 2021, 11, 1801 24 of 26 Name (Last Name, First Name) Location Role Contribution Hospital Universitario Marqués de Evaluation of participants Sierra, María Site investigator Valdecilla, Santander, Spain and/or data management Institut d’Assistència Sanitària Coordination at the center Site Solano, Berta (IAS)—Instituí Cátala de la Salud. Evaluation of participants investigator/PI Girona, Spain and/or data management Complejo Hospitalario Universitario de Evaluation of participants Suárez Castro, Ester Site investigator Ferrol (CHUF), Ferrol, A Coruña, Spain and/or data management Hospital Universitari Mutua de Evaluation of participants Tartari, Juan Pablo Site investigator Terrassa, Terrassa, Barcelona, Spain and/or data management Hospital Arnau de Vilanova, Evaluation of participants Valero, Caridad Site investigator Valencia, Spain and/or data management Hospital Universitario Virgen del Rocío, Evaluation of participants Vargas, Laura Site investigator Sevilla, Spain and/or data management Coordination at the center Fundación Hospital de Alcorcón, Site Vela, Lydia Evaluation of participants Madrid, Spain investigator/PI 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 Espases, Evaluation of participants Vives, Bárbara Site investigator Palma de Mallorca, Spain and/or data management Hospital Universitario de Canarias, San Evaluation of participants Villar, Maria Dolores Cristóbal de la Laguna, Santa Cruz de Site investigator and/or data management Tenerife, Spain References 1. 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