Staging Parkinson’s disease according to the MNCD classification correlates with caregiver burden

Received: 25 September 2023 Revised: 8 October 2023 Accepted: 12 October 2023 DOI: 10.1002/brb3.3295 ORIGINAL ARTICLE Staging Parkinson’s disease according to the MNCD classification correlates with caregiver burden Diego Santos-García1Teresa de Deus Fonticoba2Carlos Cores Bartolomé1 María J. Feal Painceiras1Iago García Díaz1María Cristina Íñiguez Alvarado1 Jose Manuel Paz1Silvia Jesús3,4Marina Cosgaya5Juan García Caldentey6 Nuria Caballol7Ines Legarda8Jorge Hernández Vara4,9Iria Cabo10 Lydia López Manzanares11 Isabel González Aramburu4,12 Maria A. Ávila Rivera13 Víctor Gómez Mayordomo14 Víctor Nogueira15 Julio Dotor García-Soto16 Carmen Borrué17 Berta Solano Vila18 María Álvarez Sauco19 Lydia Vela20 Sonia Escalante21 Esther Cubo22 Zebenzui Mendoza23 Juan C. Martínez Castrillo24 Pilar Sánchez Alonso25 Maria G. Alonso Losada26 Nuria López Ariztegui27 Itziar Gastón28 Jaime Kulisevsky4,29 Manuel Seijo10 Caridad Valero30 Ruben Alonso Redondo15 Maria Teresa Buongiorno31 Carlos Ordás32 Manuel Menéndez-González33 Darrian McAfee34 Pablo Martinez-Martin4Pablo Mir4,3COPPADIS Study Group 1Department of Neurology, CHUAC, Complejo Hospitalario Universitario de A Coruña, A Coruña, Spain 2Department of Neurology, CHUF, Complejo Hospitalario Universitario de Ferrol, A Coruña, Spain 3Department of Neurology, Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain 4CIBERNED (Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas), Madrid, Spain 5Department of Neurology, Hospital Clínic de Barcelona, Barcelona, Spain 6Department of Neurology, Centro Neurológico Oms 42, Palma de Mallorca, Spain 7Department of Neurology, Consorci Sanitari Integral, Hospital Moisés Broggi, Sant Joan Despí, Barcelona, Spain 8Department of Neurology, Hospital Universitario Son Espases, Palma de Mallorca, Spain 9Department of Neurology, Hospital Universitario Vall dt’Hebron, Barcelona, Spain 10Department of Neurology, Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain 11Department of Neurology, Hospital Universitario La Princesa, Madrid, Spain 12Department of Neurology, Hospital Universitario Marqués de Valdecilla – IDIVAL, Santander, Spain 13Department of Neurology, Consorci Sanitari Integral, Hospital General de Lt’Hospitalet, Lt’Hospitalet de Llobregat, Barcelona, Spain 14Department of Neurology, Institute of Neuroscience, Vithas Madrid La Milagrosa University Hospital, Vithas Hospital Group, Madrid, Spain 15Department of Neurology, Hospital Universitario Lucus Augusti, Lugo, Spain 16Department of Neurology, Hospital Universitario Virgen Macarena, Sevilla, Spain 17Department of Neurology, Hospital Infanta Sofía, Madrid, Spain 18Department of Neurology, Institut d’Assistència Sanitària (IAS) – Institut Català de la Salut, Girona, Spain This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC. Brain Behav. 2023;13:e3295. wileyonlinelibrary.com/journal/brb3 1of23 https://doi.org/10.1002/brb3.3295 SANTOS-GARCÍA ET AL.2of23 19Department of Neurology, Hospital General Universitario de Elche, Elche, Spain 20Department of Neurology, Fundación Hospital de Alcorcón, Madrid, Spain 21Department of Neurology, Hospital de Tortosa Verge de la Cinta (HTVC), Tortosa, Tarragona, Spain 22Department of Neurology, Complejo Asistencial Universitario de Burgos, Burgos, Spain 23Department of Neurology, Hospital Universitario de Canarias, San Cristóbal de la Laguna, Santa Cruz de Tenerife, Spain 24Department of Neurology, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain 25Department of Neurology, Hospital Universitario Puerta de Hierro, Madrid, Spain 26Department of Neurology, Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo (CHUVI), Vigo, Spain 27Department of Neurology, Complejo Hospitalario de Toledo, Toledo, Spain 28Department of Neurology, Complejo Hospitalario de Navarra, Pamplona, Spain 29Department of Neurology, Hospital de Sant Pau, Barcelona, Spain 30Department of Neurology, Hospital Arnau de Vilanova, Valencia, Spain 31Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain 32Department of Neurology, Hospital Rey Juan Carlos, Madrid, Spain 33Department of Neurology, Hospital Universitario Central de Asturias, Oviedo, Spain 34University of Maryland School of Medicine, Baltimore, Maryland, USA Correspondence Diego Santos-García, Department of Neurology, Hospital Universitario de A Coruña (HUAC), Complejo Hospitalario Universitario de A Coruña (CHUAC), C/ As Xubias 84, 15006 A Coruña, Spain. Email: [email protected] Funding information Fundación Española de Ayuda a la Investigación en Enfermedades Neurodegenerativas y/o de Origen Genético; Alpha Bioresearch; Spanish Ministry of Economy and Competitiveness, Grant/Award Number: PI16/01575 Abstract Background and objective: Recently, we demonstrated that staging Parkinson’s disease (PD) with a novel simple classification called MNCD, based on four axes (motor, non-motor, cognition, and dependency) and five stages, correlated with disease severityandpatients’quality oflife. Here,we analyzedthe correlationof MNCDstaging with PD caregiver’s status. Patients and methods: Data from the baseline visit of PD patients and their principal caregiver recruited from 35 centers in Spain from the COPPADIS cohort from January 2016 to November 2017 were used to apply the MNCD total score (from 0 to 12) and MNCD stages (from 1 to 5) in this cross-sectional analysis. Caregivers completed the Zarit Caregiver Burden Inventory (ZCBI), Caregiver Strain Index (CSI), Beck Depression Inventory-II (BDI-II), PQ-10, and EUROHIS-QOL 8-item index (EUROHIS-QOL8). Results: Two hundred and twenty-four PD patients (63 ±9.6 years old; 61.2% males) and their caregivers (58.5 ±12.1 years old; 67.9% females) were included. The frequency of MNCD stages was 1, 7.6%; 2, 58.9%; 3, 31.3%; and 4–5, 2.2%. A more advanced MNCD stage was associated with a higher score on the ZCBI (p<.0001) and CSI (p<.0001), and a lower score on the PQ-10 (p=.001), but no significant differences were observed in the BDI-II (p=.310) and EUROHIS-QOL8 (p=.133). Moderate correlations were observed between the MNCD total score and the ZCBI (r=.496; p<.0001), CSI (r=.433; p<.0001), and BDI-II (r=.306; p<.0001) in caregivers. Conclusion: Staging PD according to the MNCD classification is correlated with caregivers’ strain and burden. KEYWORDS burden, caregiver, non-motor symptoms, Parkinson’s disease, stage 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 3of23 SANTOS-GARCÍA ET AL. 1INTRODUCTION Parkinson’s disease (PD) is a complex and very heterogeneous progressive neurodegenerative disorder causing not only motor but also non-motor symptoms (NMSs) that result in loss of patient autonomy for activities of daily living (ADL) and worse quality of life (QoL) impairment, but second, caregiver’s strain and burden as well (Greenland et al., 2019; Mosley et al., 2017;Zhaoetal.,2021). Moreover, caregiver’s status impacts on patient’s status as well, which has been named the “vicious circle of illness” (Santos-García et al., 2023b). From a clinical point of view and with the aim of defining exhaustively the status of a patient with PD at each moment, a novel simple classification called “MNCD” has been proposed (Santos-García et al., 2021a). The MNCD is based on four major axes (M, motor; N, non-motor; C, cognition; D, dependency) and proposes five stages, from MNCD stage 1, no relevant symptoms, to MNCD stage 5, dementia and dependency for basic ADL, and a total score from 0 (0 +0+0+0=0; the best possible status) to 12 (4 +4+2+2=12; the worst possible status). Recently, we demonstrated using data from the COPPADIS cohort (Santos-García et al., 2016,2019) that staging PD with the MNCD classification correlated with disease severity and patients’ QoL (Santos-García et al., 2023a). Based on these findings and awaiting the results of an ongoing validation study of the MNCD classification and of its application in a prospective follow-up cohort, early observations suggest that the MNCD classification could be a useful tool to apply in PD patients to identify the main symptoms of the disease andtomonitortheprogression ofthedisorder.Neuropsychiatricsymptoms, such as visual hallucinations, depression, cognitive impairment and/or dementia, falls, disability, and a more advanced stage disease, have been identified as patient factors associated with caregiver burden in PD (Aamodt et al., 2023). All these data are collected in the MNCDclassification with also a proposedstaging andscoring that indicates the degree of severity, from least to most. That is why we think that the MNCD classification can quickly provide us with information about the patient’s condition that affects his/her QoL as well as the status of his/her principal caregiver. Importantly, with the aim to stop the vicious circle of illness in PD (Santos-García et al., 2023b), the detection of burden in the principal caregiver of the patient is important and should be acted on as earlier as possible. The aim of this new analysis was to study the correlation of the MNCD staging with PD caregiver’s status. Data from the COPPADIS cohort (Santos-García et al., 2021a) used in the previous publication (Santos-García et al., 2023a) were used in this analysis. Our hypothesis was that caregivers’ status would be different between the different PD stages according to the MNCD classification, with a better QoL and mood when the patient has a low stage with a low score and vice versa, a worse mood and QoL with greater burden and stress when the patient has a higher stage and score (i.e., a more advanced MNCD stage, a worse caregiver’s status). 2MATERIALS AND METHODS Data collected at the baseline visit from PD patients and their principal caregiver recruited from 35 hospitals in Spain from the COPPADIS cohort (Santos-García et al., 2016) from January 2016 to November 2017 were used in this cross-sectional transversal study. Methodology about COPPADIS-2015 study has been published and can be consulted (Santos-García et al., 2019). All patients included were diagnosed according to UK PD Brain Bank criteria (Hughes et al., 1992). Exclusion criteria were: non-PD parkinsonism; a mini-mental state examination<26; age <18 or >75years;inability toreadorunderstand the questionnaires; to be receiving any advanced therapy (continuous infusion of levodopa or apomorphine, and/or with deep brain stimulation); and the presence of comorbidity, sequelae, or any disorder that could interfere with the assessment. 2.1 PD patient assessment Information on sociodemographic aspects, factors related to PD, comorbidity, and treatment, including levodopa equivalent daily dose (Schade et al., 2020), were collected at baseline. As this analysis was focused on the caregiver status and the results about the relationship between the MNCD staging and patients’ symptoms have been already published (Santos-García et al., 2023a), all the information collected about motor, NMS, QoL, and autonomy for ADL in PD patients (Santos-García et al., 2019) were not provided on this occasion. 2.2 Caregiver assessment A person who, without being a professional and/or receiving money in exchange for services, lived with the patient and was responsible for his/her was included as a primary caregiver (Santos-García et al., 2016). His/her participation was voluntary, and a written informed consent was collected for all participants. In caregivers, four aspects were analyzed using validated specific scales: burden (Zarit Caregiver Burden Inventory [ZCBI]), strain (Caregiver Strain Index [CSI]), mood (Beck Depression Inventory-II [BDI-II]), and global QoL (PQ-10 and EUROHIS-QOL 8-item index [EUROHIS-QOL8]). The ZCBI (Novak & Guest, 1989) contains 22 items that rate the impact of the disease on the caregiver’s physical, emotional, and socioeconomic status. Responses are scored on a scale from 0 (never) to 4 (nearly always). The maximum total score, indicative of the highest burden, is 88. The CSI (Robinson, 1983) is a 13-item questionnaire designed to assess the level of stress experienced by caregivers. There are two possible responses for each item: “yes” or “no”. The total score is the result of adding all positive responses (from 0, no stress, to 13, maximum level of stress). Mood was assessed with the BDI-II (Beck et al., 1996). This is a self-administered, 21-item instrument. It has been designed to assess the severity of depression symptoms in adults and adolescents with a minimum age of 13 years. The evaluated subject must choose one of four alternatives (ordered from lesser to greater severity), in each item, which best describes his/her status over the previous 2 weeks. The score ranges from 0 (minimum) to 63 (maximum). Higher scores will reflect, a priori, a worse mood. Finally, global QoL was measured with the PQ-10 and the EUROHIS-QOL8. The PQ-10 (Santos-García et al., 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SANTOS-GARCÍA ET AL.4of23 2019)is a ratingof globalperceivedQoLbasedona scale from0(worst) to 10 (best). The EUROHIS-QOL8 (Da Rocha et al., 2012) is an 8-item QoL questionnaire (QoL; health status; energy; autonomy in ADL; selfesteem; social relationships; economic capacity; habitat) derived from the WHOQOL-100 and the WHOQOL-BREF. For each item, the score ranges from 0 (not at all) to 5 (completely). The total score is expressed as the mean of the individual scores. A higher score indicates a higher QoL. Sociodemographic data about the principal caregiver of the PD patient was also collected. 2.3 MNCD classification The MNCD classification was applied using the same criteria recently reported in the COPPADIS cohort (Santos-García et al., 2023). This new classification (Santos-García et al., 2021a) is based on four axes: (1) motor symptoms, (2) NMSs, (3) cognition, and (4) dependency for ADL. The first axis (motor symptoms) is subdivided into four defined sub-axes: (1) motor fluctuations, (2) dyskinesia, (3) axial symptoms, and (4) tremor. The second axis (NMSs) is subdivided into four defined sub-axes: (1) neuropsychiatric symptoms, (2) autonomic dysfunction, (3) sleep disturbances and fatigue, and (4) pain and sensory disorders. Regarding the third axis (cognition), patients are classified as having normal cognition, with mild cognitive impairment or dementia. Finally, patients are classified according to the fourth axis (dependency) as having independency for ADL, with dependency for instrumental or with dependency for basic activities. Patients were classified in four groups according to the MNCD stage: stage 1 (the patient has no relevant symptoms); stage 2 (there is at least one motor symptom or one NMS scoring in the MNCD classification); stage 3 (there is mild cognitive impairment and/or dependency for instrumental ADL); stages 4–5 (there is dementia and/or dependency for basic ADL). Moreover, the MNCD total score (from 0 to 12) was calculated according to the sum of the score of all axes of the MNCD classification: M (from 0 to 4) +N (from 0 to 4) +C (from 0 to 2) +D (from 0 to 2). 2.4 Data analysis Data were processed using SPSS 20.0 for Windows. Only PD patients and their caregivers from the COPPADIS cohort with data collected about the MNCD classification and the ZCBI, CSI, BDI-II, PQ-10, and EUROHIS-QOL8, respectively, were included in the analysis. ZCBI and CSI scores were expressed as quantitative and qualitative variables. Relative to the ZCBI score (from 0 to 88), four groups were defined (Santos-García & Añón, 2012; Santos-García & de la Fuente- Fernández, 2015): little or no burden (0–20); mild-to-moderate burden (21–40); moderate-to-severe burden (41–60); severe burden (61– 88). Two groups were considered according to CSI score (from 0 to 13) (Santos-García & Añón, 2012; Santos-García & de la Fuente- Fernández, 2015): no high level of stress (0–6); high level of stress (7–13). With regard to mood (assessed by BDI-II]), caregivers were classified as with major depression, minor depression, subthreshold depression, or non-depression (Santos-García et al., 2019). Specifically, regarding items 1, 4, 5, 9, 13, 15, 16, 17, and 18 of the BDI-II, depression was defined: major depression, ≥5 symptoms with the presence of item 1 (feeling of sadness) and/or item 4 (anhedonia) (DSM-IV criteria); minor depression, from 2 to 4 symptoms with the presence of item 1 and/or item 4 (DSM-IV criteria); subthreshold depression, from 2 to 4 symptoms without the presence of item 1 and item 4 (Judd criteria) (American Psychiatric Association, 1994; Judd et al., 1994). For comparison of caregivers’ burden (ZCBI), strain (CSI), mood (BDI-II), and QoL (PQ-10 and EUROHIS-QOL8) between patients with a different MNCD stage (all stages together or two consecutive stages), the Student t-test, the Mann–Whitney Utest, Chi-square test, Fisher test, ANOVA test, or the Kruskal–Wallis test were used as appropriate (distribution for variables was verified by one-sample Kolmogorov–Smirnov test). Spearman’s or Pearson’s correlation coefficient,as appropriate, was used for analyzingthe relationship between the MNCD total score (from 0 to 12) and the total score on ZCBI, CSI, BDI-II, PQ-10, and EUROHIS-QOL8 on caregivers. Correlations were considered weak for coefficient values ≤.29, moderate for values between .30 and .59, and strong for values ≥.60. Linear regression models were used to determine in what grade the MNCD stage and the MNCD total score were associated with caregivers’ burden (ZCBI), strain (CSI), mood (BDI-II), and QoL (PQ-10 and EUROHIS-QOL8). Age, gender, disease duration (years from symptoms onset), and caregiver’s sociodemographic variables (age, gender, relationship with the patient, civil status, habitat, time as a caregiver, living with the patient or not, full-time care or not and care of others or not) were included as covariates. With the aim of having a very strong evidence against the null hypothesis, the p-value was considered significant (highly significant) when it was ≤.001 (Krikwood & Sterne, 2003). 2.5 Standard protocol approvals, registrations, and patient consents Approval from the Comité de Ética de la Investigación Clínica de Galicia (2014/534; 02/DEC/2014) and a written informed consent from all participants in this study were obtained. 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. 2.5.1 Data availability The protocol and the statistical analysis plan are available on request. Deidentified participant data are not available for legal and ethical reasons. 3RESULTS Two hundred and twenty-four PD patients (63 ±9.6 years old; 61.2% males) and their caregivers (58.5 ±12.1 years old; 67.9% females) were 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 5of23 SANTOS-GARCÍA ET AL. FIGURE 1 (a) Zarit Caregiver Burden Inventory (ZCBI) total score (on the left) and frequency of caregivers with different burden degree (on the right) regarding to the motor, non-motor, cognition, and dependency (MNCD) stage, from stage 0 to stages 4–5. (b) Caregiver Strain Index (CSI) total score (on the left) and frequency of caregivers with high level (CSI >6) versus no high level of stress (on the left) regarding to the MNCD stage, from stage 0 to stages 4–5. included. The mean disease duration was 5.6 ±4.1 years. Regarding MNCD stages, the distribution was stage 1, 7.6% (N=17); stage 2, 58.9% (N=132); stage 3, 31.3% (N=70); stages 4–5, 2.2% (N=5; four patients in stage 4 and only one patient in stage 5 from the MNCD classification according to the original description [Santos-García et al., 2021a]). Nearly 70% of the caregivers were females (67.9%) and up to 92.4% were living with the patient and 21.9% taking care of the patient full time (33.5% of the patients had cognitive impairment and/or needed some help for some ADL). No significant differences were observed in sociodemographic aspects between caregivers of PD patients in the different stages except in age (p=.002), being younger the caregivers of those patients in stages 4–5 (in this group, 40% of the caregivers were the son or the daughter) (Table 1). A more advanced MNCD stage was associated with a higher score on the ZCBI (from 7.4 ±7.7 at stage 1 to 33.6 ±14.5 at stages 4–5; p<.0001) and CSI (from 1.1 ±1.5 at stage 1 to 5.8 ±2.3 at stages 4–5; p<.0001) (Table 1). One out of four caregivers (24.6%) had burden(mild-to-moderate,20.1%; moderate-to-severe,4%; severeburden 0.4%) and 5.8% high level of stress (CSI >6). At stage 1, only 11.8% of the caregivers had burden (mild-to-severe; ZCBI 21-88) compared to 18.2% at stage 2, 34.3% at stage 3, and 100% at stages 4–5 (p=.001) (Figure 1). The frequency of the high level of stress in the different groups was 0% at stage 1; 0% at stage 2; 8.6% at stage 3; 40% at stages 4–5 (p=.022) (Figure 1). Moderate correlations were observed between the MNCD total score and the ZCBI (r=.496; p<.0001) and between the MNCD total score and the CSI (r=.433; p<.0001). Regarding mood, no significant differences were detected between different stages neither in the BDI-II total score (p=.310) nor groups according to depressive symptoms (p=.330) (Table 1and Figure 2). However, the correlation between the MNCD stage and the BDI-II total score was moderate (r=.306; p<.0001). Moderate correlations were observed between the BDI-II and the ZCBI (r=.541; p<.0001) and the BDI-II and the CSI (r=.599; p<.0001). Global QoL was related to MNCD stage when the PQ-10 was used, with a lower score at a higher stage (from 8.4 ±1.4atstage1to5.6±2.5 at stage 4; p=.001) (Table 1and Figure 2). However, no significance was detected when the EUROHIS-QOL8 was used (p=.133) (Table 1). By domains, significant differences were observed in “quality of life” and “economic capacity” between groups (from MNCD stage 1 to stages 4–5), with a lower score at a higher stage (Table 1and Figure 2). Correlations between the MNCD total score and the PQ-10 and between the MNCD total score and the EUROHIS-QOL8 were weak (Table 2). As the proof of the utility of the PQ-10, the correlation between the PQ-10 and the EUROHIS-QOL8 was strong (r=.735; p<.0001). After controlling for covariates mentioned in methods (age; gender; disease duration; caregiver’s sociodemographic variables), the MNCD 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SANTOS-GARCÍA ET AL.6of23 TABLE 1 Sociodemographic details and data about the status of the principal caregiver of patients with Parkinson’s disease (PD) according to the motor, non-motor, cognition, and dependency (MNCD) stage (N=224). Stage 1 (N=17; 7.6%) Stage 2 (N=132; 58.9%) Stage 3 (N=70; 31.3%) Stages 4–5 (N=5; 2.2%) Total (N=224) p Patients Age 63.2 ±8.3 60.2 ±10.2 68.3 ±6.6 63.8 ±8.3 63 ±9.6 <.0001 Males (%) 64.7 61.4 58.6 80 61.2 .855 Disease duration (years) 3.4 ±1.9 5.4 ±4.1 6.3 ±4.4 7.5 ±1.9 5.6 ±4.2 .062 L-Dopa eq. daily dose (mg) 303.4 ±255.1 541.9 ±391.9 666.2 ±427.9 1218 ±775.9 574.8 ±420.9 <.0001 Number of non antip. drugs 3 [0, 4] 2 [1, 4] 3 [2, 6.25] 5.5 [1.25, 6] 2 [1, 5] <.0001 Hoehn & Yahr 2 [1.5, 2] 2 [1.5, 2] 2 [2, 2.5] 3.5 [2.25, 4] 2 [2, 2] <.0001 MNCD—total score 02.6 ±1.5 4.5 ±1.9 7.6 ±1.3 3.1 ±2.1 <.0001 Caregivers Age 60.7 ±10.1 56.4 ±11.5 62.5 ±11.6 49.8 ±9.1 58.5 ±12.1 .002 Females (%) 76.5 68.2 64.3 80 67.9 .761 Relationship (%): .191 Spouse 94.1 87.1 82.9 60 85.7 Son or daughter 5.9 7.6 14.3 40 10.3 Other 0 5.3 2.6 0 4 Civil status (%): .938 Married 88.2 86.4 88.6 100 87.5 Single 5.9 6.8 8.6 07.1 Other 5.9 6.8 2.8 0 5.6 Habitat (%): .911 Rural 17.6 13.6 12.9 20 13.8 Semiurban 29.4 22 20 20 21.9 Urban 52.9 64.4 67.1 60 64.3 (Continues) 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 7of23 SANTOS-GARCÍA ET AL. TABLE 1 (Continued) Stage 1 (N=17; 7.6%) Stage 2 (N=132; 58.9%) Stage 3 (N=70; 31.3%) Stages 4–5 (N=5; 2.2%) Total (N=224) p Time as a caregiver (%): .135 <1year 29.4 12.1 8.6 012.1 1–5 years 35.3 44.7 30 20 38.8 >5, <10 years 17.6 19.7 24.3 20 21.9 ≥10 years 17.6 23.5 37.1 60 27.2 Living with the patient (%) 100 93.2 90 80 92.4 .283 Full time care (%) 11.8 20 25.7 40 21.9 .411 Care of others (%) 52.9 34.8 27.1 60 34.4 .111 ZCBI 7.4 ±7.7 11.7 ±10.6 18.1 ±14.2 33.6 ±14.5 13.9 ±12.6 <.0001 Moderate-to-severe burden (%) 0 3 7.1 20 4.4 .001 CSI 1.1 ±1.5 1.6 ±2.1 2.8 ±2.8 5.8 ±2.3 2 ±2.5 <.0001 High level of stress (%) 03.8 8.6 40 5.8 .022 BDI-II 4.4 ±3.7 7.1 ±8.5 8.2 ±8.1 9.8 ±5.7 7.3 ±8.1 .31 Depressive symptoms (%): 35.3 40.8 47.1 60 .344 Major depression 5.9 13.6 18.6 20 Minor depression 23.5 13.6 21.4 40 Subthreshold depression 5.9 13.6 7.1 0 EUROHIS-QOL8 4.1 ±0.5 3.9 ±0.6 3.8 ±0.5 3.6 ±0.6 3.9 ±0.6 .133 Quality of life 4.2 ±0.8 3.9 ±0.8 3.6 ±0.8 2.8 ±1.3 3.8 ±0.8 .001 Health status 3.7 ±0.9 3.7 ±0.9 3.7 ±0.8 3.6 ±1.1 3.7 ±0.9 .968 Energy 4 ±0.9 3.9 ±0.9 3.8 ±0.8 3.4 ±1.1 3.9 ±0.9 .357 Autonomy for ADL 4.1 ±0.8 4±0.8 4±0.9 3.8 ±0.8 4±0.8 .917 Self-esteem 4.2 ±0.4 3.9 ±0.7 3.9 ±0.6 3.4 ±0.5 3.9 ±0.7 .064 Social relationships 4.2 ±0.5 4±0.7 4±0.7 3.9 ±0.7 4±0.7 .529 Economic capacity 4.2 ±0.7 3.9 ±0.8 3.6 ±0.8 3.4 ±0.9 3.8 ±08 .016 Habitat 4.4 ±0.7 4.3 ±0.8 4.3 ±0.5 4.2 ±0.4 4.3 ±0.7 .959 PQ-10 8.4 ±1.4 7.4 ±1.4 7 ±1.6 5.6 ±2.5 7.3 ±1.6 .001 Note: The results represent percentages, mean ±SD, or median [p25, p75]. Fisher exact test and ANOVA test were applied. Data about H&Y are during the OFF state (first thing in the morning without taking medication in the previous 12 h). Abbreviations: ADL, activities of daily living scale; BDI-II, Beck Depression Inventory-II; EUROHIS-QOL8, EUROHIS-QOL 8-item index; PD, Parkinson’s disease. 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SANTOS-GARCÍA ET AL.8of23 FIGURE 2 (a) EUROHIS-QOL 8-item index (EUROHIS-QOL8) total score (on the left) and mean value of each domain of the scale (on the right) regarding to the motor, non-motor, cognition, and dependency (MNCD) stage, from stage 0 to stages 4–5. (b) PQ-10 score regarding to the MNCD stage, from stage 0 to stages 4–5. (c) Beck Depression Inventory II (BDI-II) total score regarding to the MNCD stage, from stage 0 to stages 4–5. stage was significantly associated to ZCBI (β=.36; 95%CI 4.42–10.25; R2=0.34; p<.0001), CSI (β=.27; 95%CI .44–1.59; R2=.31; p=.001), and PQ-10 (β=−.32; 95%CI −1.27 to −.39; R2=.12; p<.0001). Regarding the MNCD total score, the significance was observed to ZCBI (β=.36; 95%CI 1.14–2.98; R2=.32; p<.0001) and CSI (β=.3; 95%CI.15–0.51; R2=.25; p<.0001), with a trend of significance to BDI-II (β=.23; 95%CI .25–1.6; R2=.17; p=.007), EUROHIS-QOL8 (β=−.21; 95%CI −.11 to −.09; R2=.03; p=.024) and PQ-10 (β=−.32; 95%CI −.37 – −.1; R2=.03; p=.01). 4DISCUSSION The present study observed that a more advanced stage in PD patients according to the MNCD classification was associated with greater strain and burden (ZCBI; CSI) and a worse QoL (PQ-10) in the principal caregiver. This finding, combined with previous reports (Santos-García et al., 2023), supports that the MNCD classification could be a useful tool to monitor the progression of PD. PD is a complex and very heterogeneous disorder with a variable prognosis between patients. From a clinical point of view and looking at the disease as a whole, four cardinal aspects in the patient linked to outcome are motor symptoms, NMS, cognition, and the ability to perform day-to-day activities. Throughout the evolution of the disease, motor and NMS burden increase, and progressive cognitive impairment and dependency for ADL appear. However, many phenotypes in PD have been reported, and disability can appear very early in some patients or late in the disease course in others (Lawton et al., 2018; Fereshtehnejad et al., 2015; De Pablo-Fernández et al., 2019). In this context, a classification to monitor PD is required. Although the Hoehn and Yahr (1967) stage is used very frequently in clinical practice because it is very simple, it provides information only about the motor stage. As NMS or cognitive dysfunction can be present at the first steps of the disease or even before motor symptoms development and they impact on QoL (Santos-García et al., 2021c; Goldman & Postuma, 2014), they should be identified and monitored from the first moment (i.e., at diagnosis) (Zis et al., 2015). In fact, NMSs have gained in importance in the latest proposed diagnostic criteria of PD (Postuma et al., 2015; Berg et al., 2015; Heinzel et al., 2019). These four capitals’ aspects commented are the basement of a new proposed classification for PD called MNCD (Santos-García et al., 2023). The MNCD classification includes four major axes (M, motor symptoms; N, NMS; C, cognition; D, dependency for ADL) and five stages with the aim to categorize and differentiate patients in a different evolutionary stage, being the first PD classification taking into account key aspects of the disease, such as axial symptoms, 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 9of23 SANTOS-GARCÍA ET AL. TABLE 2 Correlations between the motor, non-motor, cognition, and dependency (MNCD) total score (from 0 to 12) and the other variables about the status of the caregiver (Zarit Caregiver Burden Inventory [ZCBI], Caregiver Strain Index [CSI], Beck Depression Inventory-II [BDI-II], PQ-10, EUROHIS-QOL 8-item index [EUROHIS-QOL8]). MNCD ZCBI CSI BDI-II PQ-10 EUROHIS-QOL8 MNCD N.A. r=.496 p<.0001 r=.433 p<.0001 r=.306 p<.0001 r=−.238 p<.0001 r=−.193 p=.004 ZCBI r=.496 p<.0001 N. A. r=.651 p<.0001 r=.541 p<.0001 r=−.421 p<.0001 r=−.441 p<.0001 CSI r=.433 p<.0001 r=.651 p<.0001 N. A. r=.599 p<.0001 r=−.446 p<.0001 r=−.486 p<.0001 BDI-II r=.306 p<.0001 r=.651 p<.0001 r=.599 p<.0001 N. A. r=−.497 p<.0001 r=−.557 p<.0001 PQ-10 r=−.238 p<.0001 r=−.421 p<.0001 r=−.446 p<.0001 r=−.497 p<.0001 N. A r=.704 p<.0001 EUROHIS-QOL8 r=−.193 p=.004 r=−.441 p<.0001 r=−.486 p<.0001 r=−.557 p<.0001 r=.704 p<.0001 N. A. Note: Spearman correlation test were applied. Correlations between all variables are also shown. motor fluctuations, NMS, cognitive problems, and their impact on disability. Although it is necessary to apply the MNCD in clinical practice and demonstrate good inter- and intra-variability, a very recent application of this tool using retrospectively the database of the baseline visits from the Spanish Cohort COPPADIS found that the MNCD staging was associated with disease severity and patient’s QoL (Santos-García et al., 2023). That is, a more advanced MNCD stage corresponded to a greater disease severity in terms of motor symptoms and NMS and a worse QoL and autonomy for ADL. On the other hand, the MNCD total score (from 0 to 12) correlated strongly with health-related (PDQ-39) and global (EUROHIS-QOL8) QoL in PD patients (Santos-García et al., 2023). In this new analysis using the same database and with the aim of gathering more information about the potential role of the MNCD classification in PD, we wanted to know what the status of the principal caregiver of a PD patient with respect to the MNCD classification was. Many studies have identified symptoms related to caregiver burden, such as depression, visual hallucinations, sleep disturbances, cognitive impairment, falls, a more advanced stage disease, and a greater disability (Santos-García & de la Fuente-Fernández, 2015; Schrag et al., 2006; Martinez-Martin et al., 2007; D’Amelio et al., 2009; Martinez Martinet al., 2012; Smith et al., 2019;Peterset al., 2011; Santos-García et al., 2022). Based on this, our hypothesis was that caregivers’ status would be different between the different MNCD stages, with a better mood and QoL in stage 1 and a worse QoL and mood and a greater strain and burden in caregivers at a more advanced stage (i.e., a more advanced MNCD stage, a worse caregiver’s status). We found differences for caregiver burden (ZCBI), strain (CSI), and QoL (PQ-10) but not for mood (BDI-II). All caregivers of PD patients in stages 4–5 had some degrees of burden compared to only 11.8% at stage 1. Additionally, up to 40% of caregivers of PD patients in stages 4–5 reported a high level of stress compared to none of the caregivers of stage 1 PD patients. However, it is important to be cautious because although the sample size was 224 caregivers, only 5 were of PD patients in the most advancedstage (stages 4 and5).The verysmall sample size ofthegroup with MNCD stages 4–5 (N=5) suggests that these findings need to be replicated and are not entirely reliable. On the other hand, some of the non-statistically significant differences (EUROHIS-QOL8; BDIII) may be due to a small sample size (e.g., 60% of caregivers of patients at stages 4–5 had depressive symptoms compared to 35.3% at stage 1). Of note, a moderate correlation was observed between the caregiver’s BDI-II total score and the MNCD total score (from 0 to 12), and between mood and burden and mood and strain in the caregiver, suggesting the necessity of being alert about depressive symptoms due to its important implications (Santos-García et al., 2023) in the principal caregiver of a patient with a greater disease burden according to the MNCD classification. An ideal scenario could be to apply the MNCD classification in clinical practice to the patient at the first visit (i.e., a naïve patient) and to monitor its changes in each visit in the short-, medium-, and long-term (i.e., >15 years) in a big cohort of PD patients and caregivers (i.e., >500) in a prospective follow-up study. As an alternative, applying the MNCD classification in a big cohort (i.e., >1,000) in onlyone visit(cross-sectionalstudy)with manyPD patientsinall stages 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License SANTOS-GARCÍA ET AL.16 of 23 Name (last Name, first Name) Location Role Contribution 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)—Instituí Cátala de la Salud. Girona, Spain Site investigator Evaluation of participants and/or data management 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 dt’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 (Continues) 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 17 of 23 SANTOS-GARCÍA ET AL. Name (last Name, first Name) Location Role Contribution 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)—Instituí Cátala 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 Díez, Cristina Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain Site investigator (from MAY/22) neuropsychologist; evaluation of participants 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 (Continues) 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. 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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 dt’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 (until MAY/22) 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 (Continues) 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. 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Name (last Name, first Name) Location Role Contribution 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 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 Evaluation of participants and/or data management López Domínguez, Daniel Institut d’Assistència Sanitària (IAS)—Instituí Cátala de la Salud. Girona, Spain Site investigator 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 (Continues) 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. 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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 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 Mendoza Plasencia, Zebenzui Hospital Universitario de Canarias, San Cristóbal de la Laguna, Santa Cruz de Tenerife, 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 (Continues) 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. 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Name (last Name, first Name) Location Role Contribution 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 Pareés, Isabel Hospital 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, Lluís Hospital Clínic de Barcelona, Barcelona, Spain Site investigator (until DEC/19) Evaluation of participants and/or data management (Continues) 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. 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Girona, Spain Site investigator Evaluation of participants and/or data management 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 Puig Daví, Arnau Hospital de Sant Pau, Barcelona, Spain Site einvestigator 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, María Hospital 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 (Continues) 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. 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Name (last Name, first Name) Location Role Contribution 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, María Hospital Universitario Marqués de Valdecilla, Santander, Spain Site investigator Evaluation of participants and/or data management Solano, Berta Institut d’Assistència Sanitària (IAS)—Instituí Cátala de la Salud. Girona, Spain Site investigator/PI Coordination at the center Evaluation of participants and/or data management 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 21579032, 2023, 12, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/brb3.3295 by Readcube (Labtiva Inc.), Wiley Online Library on [26/03/2025]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License