Falls Predict Acute Hospitalization in Parkinson’s Disease

Journal of Parkinson’s Disease 13 (2023) 105–124 DOI 10.3233/JPD-212539 IOS Press 105 Research Report Falls Predict Acute Hospitalization in Parkinson’s Disease Diego Santos Garc´ ıaa,1,∗, Teresa de Deus Fonticobab, Carlos Coresa, Ester Su´ arez Castrob, Jorge Hern´ andez Varac, Silvia Jes´ usd,e, Pablo Mird,e, Marina Cosgayaf, Maria Jos´ e Mart´ ıf, Pau Pastorg, Iria Caboh, Manuel Seijoh,In ´ es Legardai,B ´ arbara Vivesi, Nuria Caballolj, Javier R´ uiz Mart´ ınezk, Ioana Croitoruk, Esther Cubol, Javier Mirandal, Maria Gema Alonso Losadam, Carmen Labandeiram, Nuria L´ opez Arizteguin, Mabel Morales-Casadon, Isabel Gonz´ alez Aramburuo, Jon Infanteo, Sonia Escalantep, Noem´ ı Bernardop, Marta Bl´ azquez Estradaq, Manuel Men´ endez Gonz´ alezg, Juan Garc´ ıa Caldenteyr, Carmen Borru´ es, Lydia Velat, Maria Jos´ e Catal´ anu, V´ ıctor G´ omez Mayordomou,M ´ onica Kurtisv, Cristina Prietow, Carlos Ord´ asw,V ´ ıctor Nogueirax, Lydia L´ opez Manzanaresy, Maria Asunci´ on ´ Avila Riveraz, Victor Puenteaa, Jose Manuel Garc´ ıa Morenobb, Berta Solano Vilacc, Mar´ ıa ´ Alvarez Saucodd, Francisco Carrillo Padillaee, Juan Carlos Mart´ ınez Castrilloff , Pilar S´ anchez Alonsogg, Itziar Gast´ onhh, Jaime Kulisevskye,ii, Caridad Valerojj, Oriol de F´ abreguesc, Jessica Gonz´ alez Ardurakk, Luis Manuel L´ opez D´ ıazll, Pablo Martinez-Martineand COPPADIS Study Group aCHUAC, Complejo Hospitalario Universitario de A Coru˜na, A Coru˜na, Spain bCHUF, Complejo Hospitalario Universitario de Ferrol, A Coru˜na, Spain cNeurology Department and Neurodegenerative Diseases Research. Vall D’Hebron Universitary Campus, Barcelona, Spain dUnidad de Trastornos del Movimiento, Servicio de Neurolog´ıa y Neurofisiolog´ıa Cl´ınica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Roc´ıo/CSIC/Universidad de Sevilla, Seville, Spain eCIBERNED (Centro de Investigaci´on Biom´edica en Red Enfermedades Neurodegenerativas), Spain fHospital Cl´ınic de Barcelona, Barcelona, Spain gMovement disorders Unit, University Hospital Mutua de Terrassa, Barcelona, Spain hComplejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain iHospital Universitario Son Espases, Palma de Mallorca, Spain jConsorci Sanitari Integral, Hospital Mois´es Broggi, Sant Joan Desp´ı, Barcelona, Spain kHospital Universitario Donostia, San Sebasti´an, Spain lComplejo Asistencial Universitario de Burgos, Burgos, Spain mHospital ´ Alvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo (CHUVI), Vigo, Spain nComplejo Hospitalario de Toledo, Toledo, Spain oHospital Universitario Marqu´es de Valdecilla, Santander, Spain pHospital de Tortosa Verge de la Cinta (HTVC), Tortosa, Tarragona, Spain qHospital Universitario Central de Asturias, Oviedo, Spain rCentro Neurol´ogico Oms, Palma de Mallorca, Spain 1ORCID ID: 0000-0002-3126-5111. ∗Correspondence to: Dr. Diego Santos Garc´ ıa, Department of Neurology, Hospital Universitario de A Coru˜ na (HUAC), Complejo Hospitalario Universitario de A Coru˜ na (CHUAC), C/ As Xubias 84, 15006, A Coru˜ na, Spain. Tel.: +34 646173341; E-mail: [email protected]. ISSN 1877-7171 © 2023 – The authors. Published by IOS Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 4.0). 106 D. Santos Garc´ıa et al. / Acute Hospitalization in PD sHospital Infanta Sof´ıa, Madrid, Spain tFundaci´on Hospital de Alcorc´on, Madrid, Spain uHospital Universitario Cl´ınico San Carlos, Madrid, Spain vHospital Ruber Internacional, Madrid, Spain wHospital Rey Juan Carlos, Madrid, Spain xHospital Da Costa, Burela, Lugo, Spain yHospital Universitario La Princesa, Madrid, Spain zConsorci Sanitari Integral, Hospital General de L’Hospitalet, L’Hospitalet de Llobregat, Barcelona, Spain aaHospital del Mar, Barcelona, Spain bbHospital Universitario Virgen Macarena, Sevilla, Spain ccInstitut d’Assist`encia Sanit`aria (IAS) - Institut Catal`a de la Salut. Girona, Spain ddHospital General Universitario de Elche, Elche, Spain eeHospital Universitario de Canarias, San Crist´obal de la Laguna, Santa Cruz de Tenerife, Spain ff Hospital Universitario Ram´on y Cajal, Madrid, Spain ggHospital Universitario Puerta de Hierro, Madrid, Spain hhComplejo Hospitalario de Navarra, Pamplona, Spain iiHospital de Sant Pau, Barcelona, Spain jjHospital Arnau de Vilanova, Valencia, Spain kkHospital Universitario Lucus Augusti (HULA), Lugo, Spain llComplejo Hospitalario Universitario de Orense (CHUO), Orense, Spain Accepted 14 March 2021 Pre-press 7 April 2021 Published 31 January 2023 Abstract. Background: There is a need for identifying risk factors for hospitalization in Parkinson’s disease (PD) and also interventions to reduce acute hospital admission. Objective: To analyze the frequency, causes, and predictors of acute hospitalization (AH) in PD patients from a Spanish cohort. Methods: PD patients recruited from 35 centers of Spain from the COPPADIS-2015 (COhort of Patients with PArkinson’s DIsease in Spain, 2015) cohort from January 2016 to November 2017, were included in the study. In order to identify predictors of AH, Kaplan-Meier estimates of factors considered as potential predictors were obtained and Cox regression performed on time to hospital encounter 1-year after the baseline visit. Results: Thirty-five out of 605 (5.8%) PD patients (62.5 ±8.9 years old; 59.8% males) presented an AH during the 1-year follow-up after the baseline visit. Traumatic falls represented the most frequent cause of admission, being 23.7% of all acute hospitalizations. To suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065–5.678; p= 0.035), a very severe non-motor symptoms burden (HR [hazard ratio] 2.828; 95% CI, 1.319–6.063; p= 0.008), falls (HR 3.966; 95% CI 1.757–8.470; p= 0.001), and dysphagia (HR 2.356; 95% CI 1.124–4.941; p= 0.023) was associated with AH after adjustment to age, gender, disease duration, levodopa equivalent daily dose, total number of non-antiparkinsonian drugs, and UPDRS-IIIOFF. Of the previous variables, only falls (HR 2.998; 95% CI 1.080–8.322; p= 0.035) was an independent predictor of AH. Conclusion: Falls is an independent predictor of AH in PD patients. Keywords: Falls, hospitalization, non-motor symptoms, Parkinson’s disease, predictors INTRODUCTION Motor and non-motor symptoms (NMS) in Parkinson’s disease (PD) progress as the disease advances, which leads to complications such as falls, fractures, or infections. As a consequence, PD patients are reported to have 1.44 times more hospital admissions when compared to age and sex-matched peers [1, 2]. These admissions are associated with prolonged length-of-stay and increased morbidity and mortality [3–5]. Once PD patients are admitted to hospital, they have prolonged inpatient stays [6], poor motor outcomes, infections, prescription errors, and increased postoperative mortality [7–10]. Moreover, following a first hospital encounter, the rate of a second encounter increased to approximately 50% when D. Santos Garc´ıa et al. / Acute Hospitalization in PD 107 patients were followed into a second year [11]. Previous studies reported a significant economic burden from PD hospitalization as well [12, 13]. There is a need for identifying risk factors for hospitalization in PD and also interventions to reduce acute PD hospital admission [14]. The aim of the present study was (1) to analyze the frequency and causes of acute hospitalization in PD patients from a Spanish cohort followed for 1-year and (2) to identify predictors of acute hospitalization. MATERIAL AND METHODS PD patients recruited from 35 centers of Spain from the COPPADIS cohort [15], from January 2016 to November 2017, were included in the study. Methodology about COPPADIS-2015 study can be consulted in https://bmcneurol.biomedcentral.com/ articles/10.1186/s12883-016-0548-9. This is a multicenter, observational, longitudinal-prospective, 5year follow-up study designed to analyze disease progression in a Spanish population of PD patients. All patients included were diagnosed according to UK PD Brain Bank criteria. Exclusion criteria were: atypical parkinsonism, dementia (Mini-Mental State Examination [MMSE] < 26), age < 18 or > 75 years, inability to read or understand the questionnaires, to be receiving any advanced therapy (continuous infusion of levodopa or apomorphine, and/or with deep brain stimulation at baseline), and the presence of comorbidity, sequelae, or any disorder that could interfere with the assessment. The data for the present study was obtained from the baseline evaluation [15]. Patient baseline evaluation included staging of severity of disease (modified Hoehn &Yah [H&Y] scale), motor assessment (Unified Parkinson’s Disease Rating Scale [UPDRS] part III and part IV, Freezing of Gait Questionnaire [FOG-Q]), non-motor symptoms (Non-Motor Symptoms Scale [NMSS], Parkinson’s Disease Sleep Scale [PDSS], Visual Analog ScalePain [VAS-Pain], Visual Analog Fatigue Scale [VAFS]), cognition (MMSE, Parkinson’s Disease Cognitive Rating Scale [PD-CRS], completing a simple 16-piece puzzle), mood and neuropsychiatric symptoms (Beck Depression Inventory-II [BDI-II], Neuropsychiatric Inventory [NPI], Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale [QUIP-RS]), disability (Schwab &England Activities of Daily Living Scale [S&E]), health related quality of life (QoL) (the 39-item Parkinson’s disease Questionnaire [PDQ39SI]), and global QoL (PQ-10, EUROHIS-QOL 8-item index [EUROHIS-QOL8]) [16]. Interviews were conducted to determine the presence of falls according to the definition for falls proposed by the Kellogg International Work Group on the prevention of falls by the elderly [17]: a fall is an unintentional or unexpected event, results in the person coming to rest on the ground or another lower level and is not the result of a major intrinsic event (such as a loss of consciousness) or an overwhelming external force. The event was considered when it was not something that happened for a specific reason some time ago but was a repeated abnormal phenomenon. A time frame was not defined but it was specifically asked about the presence and number of falls in the last month. Moreover, falls diary, calendar, or postcard were not used. In patients with motor fluctuations, the motor assessment was conducted during the OFF state (without medication in the last 12 hours) and during the ON state. However, in patients without motor fluctuations, the assessment was only performed without medication (first hour in the morning without taking medication in the previous 12 hours). The patients were followed for 1-year after the baseline visit and information about hospital admission was collected. Specifically, the following hospitalization-related data were recorded: number of hospitalizations, hospital stay days, and reasons for hospital admission. Those patients with at least one acute hospitalization during the follow-up were defined as Patients with acute hospitalization, whereas those with non-acute hospitalization during the follow-up was defined as Patients without acute hospitalization. Therefore, those patients with one or more programmed admission but without any acute hospitalization were considered as Patients without acute hospitalization. Rehospitalization was not considered for the analysis. The reasons for hospital admissions were divides in three groups [18]: 1) Direct PD-related morbidity: motor complications, psychiatric symptoms, autonomic dysfunction, sensory symptoms, sleep disorders, and side effects of anti-parkinsonian drugs; 2) Indirect PD-related morbidity: traumas, pneumonia, and intestinal obstruction / gastroparesis; 3) Non-PD related causes. Data analysis Data were processed using SPSS 20.0 for Windows. For comparisons between patients with and 108 D. Santos Garc´ıa et al. / Acute Hospitalization in PD Fig. 1. Flowchart about PD patients from the COPPADIS cohort participating in the present study. Of 594 patients, 1 patient was excluded due to change in the diagnosis (from PD to MSA) and 88 for other reasons. Of 605 patients included in the analysis, 41 (6.8%) presented at least one hospitalization (35 acute and 6 planned hospitalization). MSA, multiple system atrophy; PD, Parkinson’s disease. without an acute hospitalization, the Student’s t-test, Mann-Whitney-Wilcoxon test, Chi-square test, or Fisher test, as appropriate, were used (distribution for variables was verified by one-sample KolmogorovSmirnov test). Kaplan-Meier estimates were obtained to determine the risk of acute hospitalization with regards to the presence of different PD symptoms and/or complications: motor fluctuations; dyskinesia; very severe NMS (NMSS total score > 70) [19]; major depression [16]; cognitive impairment [20]; freezing of gait (FOG); falls; dysphagia. Selfreported FOG was defined regarding the FOG-Q as presenting with a FOG-Q item-3 score > 0. Functional dependency was defined as a S&E score less than 80% (80% = completely independent; 70% = not completely independent) [21]. Patients with a NMSS item-19 score > 0 were considered as suffering from dysphagia. Cox proportional hazards models were applied to identify independent predictors of acute hospitalization during the 1-year follow-up. Factors included as potential predictors were motor severity, motor complications, axial symptoms and related complications (FOG; falls; dysphagia), NMS burden, mood, cognition, neuropsychiatric symptoms, and disability for activities of daily living (Supplementary Table 1). Age, gender, disease duration, LEDD (levodopa equivalent daily dose [22]), and total number of non-antiparkinsonian drugs (as a marker of comorbidity [23]) were included as covariates (Supplementary Table 1). Values of p< 0.05 were considered significant. Standard protocol approvals, registrations, and patient consents For this study, we received approval from the Comit´ ede ´ Etica de la Investigaci´ onCl ´ ınica de Galicia from Spain (2014/534; 02/DEC/2014). Written informed consents from all participants in this study were obtained before the start of the study. COPPADIS-2015 was classified by the AEMPS (Agencia Espa˜ nola del Medicamento y Productos Sanitarios) as a Post-authorization Prospective Follow-up study with the code COH-PAK-2014-01. Data availability The protocol and the statistical analysis plan are available on request. De-identified participant data are not available for legal and ethical reasons. RESULTS A total of 605 (62.5 ±8.9 years old; 59.8% males) from the 694 patients diagnosed with PD at baseline from the COPPADIS cohort were included in the analysis (87.2%). Figure 1 shows the reasons for the lack of follow-up of 89 patients. In 64 cases (9.2%) no data was recorded. The mean disease duration (N = 605) at baseline was 5.5 ±4.4 years. Forty-one out of 605 PD patients (6.8%) presented at least one hospitalization during the 1-year follow-up after the baseline visit, being 35 of them (85.4%) with at least D. Santos Garc´ıa et al. / Acute Hospitalization in PD 109 one acute hospitalization. From the initial PD cohort (N = 693; 1 case excluded due to change in diagnosis), 5% of the patients presented an acute hospitalization (Fig. 2A). In 35 out of 41 patients (85.4%) hospital admission was reported once, twice in 4 patients (9.8%), and three times in 2 patients (4.8%). The mean hospital stay days was 8.4 ±8.3 (range 1–39). A total of 49 admissions were reported, being 38 acute and 11 programmed hospitalizations (Table 1). With regards to the acute admissions, 3 patients out of 35 (8.6%) were hospitalized due to a direct PD-related morbidity, 15 (42.9%) due to an indirect PD-related morbidity, and 14 (40%) due to non-PD related causes (Fig. 2B). Traumatic falls (9 events) represented the most frequent cause of admission, being 56.3% of all indirect PD-related morbidity causes, 23.7% all acute hospitilizations (38 events), and 18.4% of all hospitalizations (49 events) (Table 1 and Fig. 2C). No deaths were reported, neither in patients who presented a hospitalization nor in those who did not. There were no differences between patients who presented an acute hospitalization compared to those who did not in terms of age, gender, disease duration, motor phenotype, and H&Y motor stage (Table 2). However, patients who suffered from an acute hospitalization presented a worse motor (UPDRS-III-OFF and UPDRS-IV) and non-motor status (PD-CRS, NMSS, BDI-II, NPI, and PDSS) at baseline (Table 2). Motor fluctuations, dyskinesia, falls, dysphagia, Table 1 Causes of hospitalization during the 1 year follow-up after the baseline visit: 49events in 41 PD patients Acute unplanned hospitalizations (38 events) Direct disease related morbidity (4 events) -DBS PD system infection (2 events) -Motor impairment(1 event) -Orthostatic hypotension (1 event) Indirect disease related morbidity (16 events) -Traumatic falls (9 events) -Pneumonia and/or respiratory infection (4 events) -Intestinal obstruction and/orgastroparesia (3 events) Non-PD related causes (16 events) -Other infections (6 events) -Cardiac ischemic attack (3 events) -Urinary system complications (3 events) -Cardiac insufficiency (1 event) -Syncope secondary to a orticstenosis (1 event) -Stroke (1 event) -Esophagitis (1 event) Unclear diagnosis (2 events) Programmed hospitalizations (11 events) -Lumbar canal stenosis surgery (2 events) -Deep brain stimulation surgery (2 events) -Carotid bypass surgery (1 event) -Aortic valve replacement (1 event) -knee replacement surgery (1 event) -Transurethral resection of the prostate (1 event) -Urinary incontinence surgery (1 event) -Carcinoma pulmonary resection (1 event) -Apomorphine test (1 event) Fig. 2. A) Percentage of PD patients from the COPPADIS cohort (N = 693; 1 excluded due to change in the diagnosis) without follow-up data (N = 88; 12.7%), without hospitalization (N = 564; 81.4%), with planned hospitalization (N = 6; 1%), and with acute hospitalization (N = 35; 5%) during the 1-year follow-up after the baseline visit. B) Percentage of patients with at least one acute hospitalization (N = 35) regarding the reason of admission: Direct PD-related morbidity (N = 3; 8.6%); Indirect PD-related morbidity (N = 15; 42.9%); Non-PD related causes (N = 40; 40%); More than 1 hospitalization with both reasons (N = 1; 2.8%); Unclear diagnosis (N = 2; 5.7%). C) Reasons for hospital admissions (38 events) in the subgroup of patients with acute hospitalization: 1) Direct PD-related morbidity (4 events; 10.5%); 2) Indirect PD-related morbidity: traumas, pneumonia, and intestinal obstruction / gastroparesis (16 events; 42.1%); 3. Non-PD related causes (16 events; 42.1%). PD, Parkinson’s disease. 110 D. Santos Garc´ıa et al. / Acute Hospitalization in PD Table 2 Disease related characteristics, motor and non-motor symptoms, autonomy for activities of daily living and quality of life in PD patients with and without acute hospitalization during the year after the baseline visit (n= 605) All sample Without acute With acute p (N = 605) hospitalization hospitalization (N = 570) (N = 35) Age 62.5 ±8.9 62.5 ±8.9 63.5 ±7.9 0.646 Males (%) 59.8 71.4 59.3 0.106 Disease duration (years) 5.5 ±4.4 5.5 ±4.3 5.8 ±4.4 0.656 Number of non anti parkinsonian drugs 2.6 ±2.4 2.6 ±2.4 2.6 ±2.5 0.980 L-dopa eq. daily dose (mg) 563.9 ±420.5 555.8 ±416.6 703.7 ±468.4 0.063 Motor phenotype (%) 0.621 - Tremoricdominant 47.3 48.4 40 - PIGD 38.8 37.8 45.7 - Indeterminate 13.9 13.8 14.3 Hoehn&Yahr 2 [2, 2] 2 [2, 2] 2 [2, 2] 0.720 - Stage from 3 to 5(%) 10.3 9.9 13.3 0.373 UPDRS-III 21.6 ±10.4 20.7 ±9.9 27.8 ±11.8 0.001 UPDRS-IV 2 ±2.4 1.8 ±3.3 3.3 ±30.001 - Motor fluctuations (%) 32.7 29.3 57.1 0.001 - Dyskinesia (%) 18.1 15.6 36.4 0.006 FOG-Q 3.5 ±4.6 3.4 ±4.5 4.7 ±4.7 0.006 - Patients with FOG (%) 33.8 32.5 42.9 0.154 - Patients with falls (%) 17.5 15.5 31.4 0.020 PD-CRS 91.6 ±15.3 92.2 ±15.3 86.8 ±13.9 0.049 - Cognitive impairment (PD-CRS ≤84) (%) 28 26.6 38.2 0.114 NMSS 44.8 ±36.7 41.9 ±35 66.1 ±42.8 < 0.0001 - Severe and/or NMS burden (NMSS > 40) (%) 40.7 37 67.6 0.001 - Very severe NMS burden (NMSS > 70) (%) 21.1 18.3 41.2 0.004 - Dysphagia 21.1 17.5 47.1 < 0.0001 BDI-II 8.9 ±7.7 8.4 ±7.5 12.1 ±8.5 0.007 - Major depression (%) 17.1 15.4 28.6 0.051 NPI 6.7 ±8.4 6.2 ±8.1 10.1 ±9.4 0.005 QUIP-RS 4.3 ±8.1 3.4 ±7.1 4.5 ±8 0.227 PDSS 118.1 ±23.9 119.2 ±23.7 110.9 ±24.3 0.014 VAS-PAIN 2.8 ±3 2.8 ±3.1 3.4 ±2.4 0.133 - Patients with pain (%) 61.2 58.9 77.1 0.027 VASF – physical 2.9 ±2.8 2.9 ±2.8 3.3 ±2.8 0.342 VASF – mental 2.1 ±2.6 2.1 ±2.5 2.3 ±2.9 0.668 ADLS 87.5 ±10.9 87.9 ±10.7 84.3 ±11.4 0.048 - Patients with functional dependency (%) 12.1 11.4 17.1 0.233 PDQ-39SI 17.2 ±14.1 15.9 ±13.3 26.6 ±16 < 0.0001 PQ-10 7.2 ±1.6 7.3 ±1.6 6.8 ±1.7 0.119 EUROHIS-QOL8 3.8 ±0.5 3.8 ±0.5 3.6 ±0.6 0.038 The results represent percentages, mean ±SD or median [p25, p75].Chi-squared and Mann-Whitney-Wilcoxon test were applied for comparisons between Non acute hospitalization (N = 570) and Acute unplanned hospitalization (N = 35) patients. Data about H&Y and UPDRS-III are during the OFF state (first thing in the morning without taking medication in the previous 12 hours). ADLS, Schwab and England Activities of daily living Scale); BDI, Beck Depression Inventory-II; NMSS, Non-Motor Symptoms Scale; NPI, Neuropsychiatric Inventory; PD, Parkinson’s disease; PD-CRS, Parkinson’s Disease Cognitive Rating Scale; PDSS, Parkinson’s Disease Sleep Scale; PIGD, Postural Inestability Gait Difficulty; QUIP-RS, Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale; UPDRS, Unified Parkinson’s Disease Rating Scale; VAFS, Visual Analog Fatigue Scale; VAS-Pain, Visual Analog Scale-Pain. a severe and/or very severe NMS burden, and pain were more frequent in patients who presented an acute hospitalization compared to those who did not (Table 2). Specifically, the NMSS total score (66.1 ±42.8 vs 41.9 ±35; p< 0.0001) and the score on domains 2 (sleep/fatigue), 3 (mood/apathy), 4 (perceptual problems/hallucinations), 5 (attention/memory), 6 (gastrointestinal symptoms), and 7 (urinary symptoms) of the NMSS indicating a greater severe burden were higher in patients with acute hospitalization (Fig. 3A and Supplementary Table 2). Moreover, QoL and disability were worse in this group of patients with acute hospitalization, presenting a higher score at baseline on the PDQ39SI (26.6 ±16 vs 15.9 ±13.3; p< 0.0001) and a lower score on the EUROHIS-QOL8 (3.6 ±0.6 vs 3.8 ±0.5; p= 0.038) and S&E score (83.4 ±11.4 vs 87.9 ±10.7; p= 0.048) when compared with patients D. Santos Garc´ıa et al. / Acute Hospitalization in PD 111 Fig. 3. A) Comparison in PD patients with vs without acute hospitalization of mean NMSS score on each domain of the scale at baseline; NMSS-1, Cardiovascular (p= 0.892); 2) NMSS-2, Sleep/fatigue (p= 0.003); NMSS-3, Depression/apathy (p= 0.003); NMSS-4, Perceptual problems/hallucinations (p= 0.001); NMSS-5, Attention/memory (p= 0.001); NMSS-6, Gastrointestinal tract (p= 0.041); NMSS-7, Urinary symptoms (p= 0.040); NMSS-8, Sexual dysfunction (p= 0.152); NMSS-9, Miscellaneous (p= 0.106). B) Comparison in PD patients with vs without acute hospitalization of mean PDQ-39SI score on each domain of the scale: PDQ-39SI-1, Mobility (p= 0.001); PDQ-39SI-2, Activities of daily living (p= 0.002); PDQ-39SI-3, Emotional well-being (p= 0.002); PDQ-39SI-4, Stigma (p= 0.153); PDQ-39S-5, Social support (p= 0.259); PDQ-39SI-6, Cognition (p= 0.001); PDQ-39SI-7, Communication (p< 0.0001); PDQ-39SI-8, Pain and discomfort (p= 0.133). NMS, Non-motor symptoms; PD, Parkinson’s disease. without acute hospitalization (Table 2). With regards to the domains of the PDQ-39SI, patients with acute hospitalizations presented significantly higher scores in all domains indicating a worse QoL except on domains 4 (stigma), 5 (social support), and 8 (pain/ discomfort) (Fig. 3B and Supplementary Table 2). In Kaplan-Meier analysis, the presence at baseline of motor fluctuations (p= 0.004), dyskinesia (p= 0.003), very severe NMS burden (p= 0.001), major depression (p= 0.037), falls (p= 0.001), and dysphagia (p= 0.001) was related to a higher risk of acute hospitalization (Fig. 4). Specifically, to suffer from motor fluctuations (HR [hazard ratio] 2.461; 95% CI, 1.065–5.678; p= 0.035), a very severe NMS burden (HR [hazard ratio] 2.828; 95% CI, 1.319–6.063; p= 0.008), falls (HR 3.966; 95% CI 1.757–8.470; p= 0.001), and dysphagia (HR 2.356; 95% CI 1.124–4.941; p= 0.023) was associated with acute hospitalization after adjustment to age, gender, disease duration, LEDD, total number of non-antiparkinsonian drugs, and UPDRS-III-OFF (Table 3). Patients who presented a score on the UPDRS-III-OFF > 20 at baseline had a significantly higher risk of acute hospitalization after adjustment to the same covariates as well (HR 3.644; 95% CI 1.430–9.284; p= 0.007). Although unadjusted HR associated with dyskinesia (HR 2.792; 95% CI 1.365–5.711; p= 0.005) and major depression (HR 2.159; 95% CI 1.033–4.515; p= 0.041) were significant (Table 3), the effect was not after adjustment to the previous commented covariates. Of the previous variables, only falls (HR 2.998; 95% CI 1.080–8.322; p= 0.035) was an independent predictor of acute hospitalization when different covariates as potential predictors of hospitalization were included in an “a priori” well-planned model (Table 4). In the model, having falls triples the probability of acute hospital admission regardless of other variables, and the frequency of falls at baseline was double in those patients who were admitted during the 1-year followup compared to those who did not (31.4% vs 15.5%; p= 0.020). Specifically, having falls during the previous month to the baseline visit was associated with acute admission during the 1-year follow-up (Supplementary Figure 1). DISCUSSION In the present study, we observed different important findings: 1) the probability of presenting an acute hospitalization is not infrequent in patients with PD; 2) the QoL and autonomy for activities of daily living is worse and the NMS burden is greater in those PD patients who will have an acute hospitalization; 3) there are certain symptoms associated with a greater risk of acute hospitalization such as motor fluctuations, dyskinesias, severe NMS burden, major depression, falls, and dysphagia; 4) falls is an independent predictor of acute hospitalization that increases the risk by three times. 112 D. Santos Garc´ıa et al. / Acute Hospitalization in PD Fig. 4. Proportion of patients without acute hospitalization with regards to suffering (in blue) or not (in green) from motor fluctuations (p= 0.004), dyskinesia (p= 0.003), very severe NMS burden (p= 0.001), major depression (p= 0.037), falls (p= 0.001), and dysphagia (p= 0.001). Y, survival; X, days of follow-up. NMS, Non-motor symptoms. Table 3 Analysis about the risk of acute hospitalization after 1 year of follow-up with regards to having or not different complications (N = 605) Unadjusted HR (95% CI) pAdjusted HR(95% CI) p Motor fluctuations 2.616 (1.329–5.148) 0.005 2.461 (1.065–5.678) 0.035 Dyskinesia 2.792 (1.365–5.711) 0.005 2.145 (0.905–5.085) 0.083 Severe or very severe NMSB (NMSS > 40) 2.871 (1.400–5.890) 0.004 2.645 (1.154–6.103) 0.022 Very severe NMSB (NMSS > 70) 2.925 (1.477–5.791) 0.002 2.828 (1.319–6.063) 0.008 FOG 1.489 (0.757–2.930) 0.249 1.117 (0.496–2.518) 0.789 Falls 3.262 (1.590–6.696) 0.001 3.966 (1.757–8.470) 0.001 Dysphagia 2.843 (1.450–5.575) 0.002 2.356 (1.124–4.941) 0.023 Major depression 2.159 (1.033–4.515) 0.041 1.934 (0.855–4.377) 0.113 Cognitive impairment (PD-CRS ≤84) 1.493 (0.743–3.002) 0.260 1.160 (0.514–2.615) 0.721 HY-OFF from 3 to 5 1.331 (0.463–3.826) 0.595 0.703 (0.187–1.719) 0.602 UPDRS-III-OFF > 20 2.800 (1.258–6.233) 0.012 3.644 (1.430–9.284) 0.007∗ Functional dependency 2.118 (0.877–5.116) 0.095 1.894 (0.675–5.318) 0.225 Age, gender, disease duration, LEDD (levodopa equivalent daily dose), total number of non-anti parkinsonian drugs (as a marker of comorbidity) and UPDRS-III-OFF were included in the model as covariates. ∗For this analysis the UPDRS-III-OFF was not included in the model. FOG, freezing of gait; HR, Hazard ratio; NMSB, non-motor symptoms burden; NMSS, Non-Motor Symptoms Scale; PD-CRS, Parkinson’s Disease Cognitive Rating Scale; UPDRS, Unified Parkinson’s Disease Rating Scale. About 5% of the patients from the COPPADIS cohort [15, 16] presented an acute hospitalization after 1-year of follow-up. This percentage is low compared to other studies, ranging from 7 to 28% per year [17]. The results between studies vary in part to differences in methodology [1, 2, 24–27]. Moreover, many studies are prospective [6, 26, 28] or, more frequently, retrospective [29–34] analysis conducted only in PD patients admitted with the aim to analyze problems during hospitalization. Moreover, several studies were conducted in small samples and/or without control group: 76 patients [28]; 108 patients [26]; 130 patients [25]; 132 patients [6]; 143 patients [33]; 144 patients [24]; 173 patients [30]; 367 patients [3]. A recent study conducted in a large population from North America, the Netherlands, and Israel showed D. Santos Garc´ıa et al. / Acute Hospitalization in PD 113 Table 4 Cox-regression model about predictors of acute hospitalization in PD patients after 1 year of follow-up (N = 605) HR (95% CI) p Age 1.002 (0.951–1.056) 0.937 Gender 0.627 (0.267–1.469) 0.282 Disease duration 0.838 (0.726–0.968) 0.016 LEDD 1.000 (0.999–1.001) 0.614 Total number of non-anti parkinsonian drugs 0.839 (0.675–1.042) 0.111 UPDRS-III-OFF 1.032 (0.991–1.074) 0.128 UPDRS-IV 1.071 (0.909–1.260) 0.413 NMSS 0.999 (0.989–1.009) 0.823 BDI-II 1.016 (0.955–1.081) 0.613 PD-CRS 0.986 (0.958–1.015) 0.339 NPI 1.021(0.972–1.072) 0.406 Falls 2.998 (1.080–8.322) 0.035 Dysphagia 1.593 (0.645–3.932) 0.313 ADLS 1.004 (0.962–1.048) 0.865 Hazard ratio; LEED, Levodopa equivalent daily dose; NMSS, Non-Motor Symptoms Scale; NPI, Neuropsychiatric Inventory; PD-CRS, Parkinson’s Disease Cognitive Rating Scale; UPDRS, Unified Parkinson’s Disease Rating Scale. The omnibus test indicated an overall significant model χ2= 34,149 (p= 0.001). that of 4,680 PD patients followed during an average of 2 years (median 1.85, maximum 4.85 years), 2,264 patients (48.4%) had a hospital encounter after the baseline visit [35]. Compared with many other studies [6, 29, 30, 33, 34, 36, 37], the mean age of the patients from the COPPADIS cohort is lower, and, as previously reported [23, 38], our sample is 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.) which subsequently entails a bias toward early PD. This aspect may explain the lower frequency of admissions in our analysis after 1-year of follow-up. On the other hand, with regards to the causes of hospitalization, our findings are in line with two recent review studies [26, 39], in which infections, worsening motor features, falls/fractures, cardiovascular co-morbidities, neuropsychiatric, and gastrointestinal complications were the main reasons for hospitalization among people with PD. Specifically, in our study, falls was the most frequent cause despite more than 90% of the patients had a stage 2 of the H&Y. By the contrary, admissions related to a direct PD-related event were infrequent since ambulatory PD symptoms management is often preferred. A worse QoL and a greater disability and NMS burden at baseline was observed in PD patients who presented an acute hospitalization in our study. We observe this finding because, unlike most other studies, the assessment at baseline was exhaustive using different validated scales. Differences were observed between patients who were admitted during the follow-up and those who did not as those who were admitted had a worse motor and nonmotor status and worse autonomy for activities of daily living and QoL. In other words, PD patients more affected by their disease may be more vulnerable and have a higher risk of acute hospitalization. Symptoms such as pain, dysphagia, falls, motor fluctuations, dyskinesia, a worse QoL, and a greater motor disability were more frequent in patients who presented an acute hospitalization, but no differences were observed in fatigue and motor phenotype. Falls, fractures, infections, cognitive, and motor decline have been identified as risk factors for acute hospital admissions in patients with PD [11, 14]. More specifically, longer timed up and go test, higher number of comorbidities, number of medications, the presence of motor fluctuations, having deep brain stimulation, and the degree of caregiver burden have been associated with hospitalization and/or rehospitalization in PD [35]. A higher PDQ-39 total score was observed to be associated with a higher risk of rehospitalization as well [35]. In our study, the factors associated with acute hospitalization are not surprising. However, the only independent predictor of hospitalization was falls. In this context, in a pooled data of 7 studies selected [27], the main causes of general ward admission were falls (30%) and PD-related causes (16%), whereas the main causes of neurological ward were motor (42.3%) and psychiatric complications (21.2%). In any case, our finding of falls as a predictor of acute hospitalization in PD should be interpreted with caution because the rates of admission due to fall (N = 9) were very low. Ideally, these findings should be reproduced over a longer period to capture more admission and arguably with patients with a broader range of severity. A very important point is that some of these symptoms can be treated with the aim of reducing acute PD hospital admission [14]. For example, in our cohort, motor fluctuations were associated with a doubled probability of acute hospitalization, so reducing OFF time could reduce the risk. Many factors are correlated. Falls were associated with motor fluctuations (falls were present in 22.4% of patients with motor fluctuations compared to 8.5% of patients without them; p< 0.0001). One strategy for reducing them could be to increase the ON time in PD patients. However, falls can have different etiology. Optimizing motor symptom control and managing medication side effects may prevent falls and hence 120 D. Santos Garc´ıa et al. / Acute Hospitalization in PD Name (Last Name, First Name) Location Role Contribution Aguilar, Miquel Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Evaluation of participants and/or data management ´ Avila Rivera, Maria Asunci´ on Consorci Sanitari Integral, Hospital General de L’Hospitalet, L’Hospitalet de Llobregat, Barcelona, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Bernardo Lambrich, Noem´ ı Hospital de Tortosa Verge de la Cinta (HTVC), Tortosa, Tarragona, Spain Site investigator Evaluation of participants and/or data management Bejr-Kasem, Helena Hospital de Sant Pau, Barcelona, Spain Site investigator Evaluation of participants and/or data management Bl´ azquez Estrada, Marta Hospital Universitario Central de Asturias, Oviedo, Spain Site investigator Evaluation of participants and/or data management Bot´ ı Gonz´ alez, Maria ´ Angeles Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Neuropsychologist; evaluation of participants Borru´ e, Carmen Hospital Infanta Sof´ ıa, Madrid, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Buongiorno, Maria Teresa Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Nurse study coordinator Cabello Gonz´ alez, Carolina Complejo Hospitalario de Navarra, Pamplona, Spain Site investigator Scheduling of evaluations Cabo L´ opez, Iria Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Caballol, Nuria Consorci Sanitari Integral, Hospital Mois´ es Broggi, Sant Joan Desp´ ı, Barcelona, Spain. Site investigator / PI Coordination at the center Evaluation of participants and/or data management C´ amara Lorenzo, Ana Hospital Cl´ ınic de Barcelona, Barcelona, Spain Site investigator Nurse study coordinator Carrillo, F´ atima Hospital Universitario Virgen del Roc´ ıo, Sevilla, Spain Site investigator Evaluation of participants and/or data management Carrillo Padilla, Francisco Jos´ e Hospital Universitario de Canarias, San Crist´ obal 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 Catal´ an, Maria Jos´ e Hospital Universitario Cl´ ınico 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 Fern´ andez, A Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coru˜ na, Spain Site investigator Coordination of blood extractions Cosgaya, Marina Hospital Cl´ ınic de Barcelona, Barcelona, Spain Site investigator Evaluation of participants and/or data management Cots Foraster, Anna Institut d’Assist` encia Sanit` aria (IAS) - Institu´ ıC ´ atala 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 Coru˜ na, Spain Site investigator Nurse study coordinator Evaluation of participants and/or data management (Continued) D. Santos Garc´ıa et al. / Acute Hospitalization in PD 121 Name (Last Name, First Name) Location Role Contribution De F´ abregues, Oriol Hospital Universitario Vall d’Hebron, Barcelona, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management D´ ıez Fairen, M Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain Site investigator Evaluation of participants and/or data management Erro, Elena Complejo Hospitalario de Navarra, Pamplona, Spain Site investigator Evaluation of participants and/or data management Escalante, Sonia Hospital de Tortosa Verge de la Cinta (HTVC), Tortosa, Tarragona, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Estelrich Peyret, Elena Institut d’Assist` encia Sanit` aria (IAS) - Institu´ ıC ´ atala de la Salud. Girona, Spain Site investigator Evaluation of participants and/or data management Fern´ andez Guill´ an, Noelia Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coru˜ na, Spain Site investigator Neuroimaging studies G´ amez, 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 Garc´ ıa Caldentey, Juan Centro Neurol´ ogico Oms 42, Palma de Mallorca, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Garc´ ıa Campos, Cristina Hospital Universitario Virgen Macarena, Sevilla, Spain Site investigator Evaluation of participants and/or data management Garc´ ıa Moreno, Jose Manuel Hospital Universitario Virgen Macarena, Sevilla, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Gast´ on, Itziar Complejo Hospitalario de Navarra, Pamplona, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Guill´ en Fopiani, Desir´ e Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain Site investigator Neuropsychologist; evaluation of participants G´ omez Garre, Mar´ ıa del Pilar Hospital Universitario Virgen del Roc´ ıo, Sevilla, Spain Site investigator Genetic studies coordination G´ omez Mayordomo, V´ ıctor Hospital Cl´ ınico San Carlos, Madrid, Spain Site investigator Evaluation of participants and/or data management Gonz´ alez Aloy, Javier Institut d’Assist` encia Sanit` aria (IAS) - Institu´ ıC ´ atala de la Salud. Girona, Spain Site investigator Evaluation of participants and/or data management Gonz´ alez Aramburu, Isabel Hospital Universitario Marqu´ es de Valdecilla, Santander, Spain Site investigator Evaluation of participants and/or data management Gonz´ alez Ardura, Jessica Hospital Universitario Lucus Augusti (HULA), Lugo, Spain Site investigator Evaluation of participants and/or data management Gonz´ alez Garc´ ıa, Beatriz Hospital La Princesa, Madrid, Spain Site investigator Nurse study coordinator Gonz´ alez Palm´ as, Maria Josefa Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain Site investigator Evaluation of participants and/or data management Gonz´ alez Toledo, Gabriel Ricardo Hospital Universitario de Canarias, San Crist´ obal de la Laguna, Santa Cruz de Tenerife, Spain Site investigator Evaluation of participants and/or data management Golpe D´ ıaz, Ana Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coru˜ na, Spain Site investigator Laboratory analysis coordination Grau Sol´ a, Mireia Consorci Sanitari Integral, Hospital Mois´ es Broggi, Sant Joan Desp´ ı, 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 (Continued) 122 D. Santos Garc´ıa et al. / Acute Hospitalization in PD Name (Last Name, First Name) Location Role Contribution Hern´ andez Vara, Jorge Hospital Universitario Vall d’Hebron, Barcelona, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Horta Barba, Andrea Hospital de Sant Pau, Barcelona, Spain Site investigator Neuropsychologist; evaluation of participants Idoate Calder´ on, Daniel Complejo Hospitalario Universitario de Pontevedra (CHOP), Pontevedra, Spain Site investigaor neuropsychologist; evaluation of participants Infante, Jon Hospital Universitario Marqu´ es de Valdecilla, Santander, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Jes´ us, Silvia Hospital Universitario Virgen del Roc´ ıo, Sevilla, Spain Site investigator Evaluation of participants and/or data management Kulisevsky, Jaime Hospital de Sant Pau, Barcelona, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Kurtis, M´ onica Hospital Ruber Internacional, Madrid, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Labandeira, Carmen Hospital ´ Alvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo (CHUVI), Vigo, Spain Site investigator Evaluation of participants and/or data management Labrador Espinosa, Miguel ´ Angel Hospital Universitario Virgen del Roc´ ıo, 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 Legarda, In´ es Hospital Universitario Son Espases, Palma de Mallorca, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management L´ opez Ariztegui, Nuria Complejo Hospitalario de Toledo, Toledo, Spain Site investigator / PI Evaluation of participants and/or data management L´ opez D´ ıaz, Luis Manuel Hospital Da Costa de Burela, Lugo, Spain Site investigator Evaluation of participants and/or data management L´ opez Manzanares, Lydia Hospital La Princesa, Madrid, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management L´ opez Seoane, Balbino Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coru˜ na, Spain Site investigator Neuroimaging studies Lucas del Pozo, Sara Hospital Universitario Vall d’Hebron, Barcelona, Spain Site investigator Evaluation of participants and/or data management Mac´ ıas, Yolanda Fundaci´ on Hospital de Alcorc´ on, Madrid, Spain Site investigator Evaluation of participants and/or data management Mata, Marina Hospital Infanta Sof´ ıa, Madrid, Spain Site investigator Evaluation of participants and/or data management Mart´ ı Andres, Gloria Hospital Universitario Vall d’Hebron, Barcelona, Spain Site investigator Evaluation of participants and/or data management Mart´ ı, Maria Jos´ e Hospital Cl´ ınic de Barcelona, Barcelona, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Mart´ ınez Castrillo, Juan Carlos Hospital Universitario Ram´ on y Cajal, Madrid, Spain Site investigator /PI Coordination at the center Evaluation of participants and/or data management Martinez-Martin, Pablo Centro Nacional de Epidemiolog´ ıa y CIBERNED, Instituto de Salud Carlos III. Madrid Collaborator in statistical and methods analysis Methods and statistical reviewer McAfee, Darrian University of Pennsylvania, Philadelphia Collaborator in english style English style reviewer (Continued) D. Santos Garc´ıa et al. / Acute Hospitalization in PD 123 Name (Last Name, First Name) Location Role Contribution Meit´ ın, Maria Teresa Hospital Da Costa de Burela, Lugo, Spain Site investigator Evaluation of participants and/or data management Men´ endez Gonz´ alez, Manuel Hospital Universitario Central de Asturias, Oviedo, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management M´ endez del Barrio, Carlota Hospital Universitario Virgen del Roc´ ıo, Sevilla, Spain Site investigator Evaluation of participants and/or data management Mir, Pablo Hospital Universitario Virgen del Roc´ ıo, Sevilla, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Miranda Santiago, Javier Complejo Asistencial Universitario de Burgos, Burgos, Spain Site investigator Evaluation of participants and/or data management Morales Casado, Maria Isabel Complejo Hospitalario de Toledo, Toledo, Spain. Site investigator Evaluation of participants and/or data management Moreno Di´ eguez, Antonio Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coru˜ na, Spain Site investigator Neuroimaging studies Nogueira, V´ ıctor 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 Coru˜ na, Spain Site investigator Neuroimaging studies Novo Ponte, Sabela Hospital Universitario Puerta de Hierro, Madrid, Spain. Site investigator Evaluation of participants and/or data management Ord´ as, Carlos Hospital Rey Juan Carlos, Madrid, Spain, Madrid, Spain. Site Investigator Evaluation of participants and/or data management Pagonabarraga, Javier Hospital de Sant Pau, Barcelona, Spain Site investigator Evaluation of participants and/or data management Isabel Pare´ es 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 P´ erez Fuertes, A´ ıda Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coru˜ na, Spain Site investigator Blood analysis P´ erez Noguera, Rafael Hospital Universitario Virgen Macarena, Sevilla, Spain Site investigator Evaluation of participants and/or data management Planas-Ballv´ e, Ana Consorci Sanitari Integral, Hospital Mois´ es Broggi, Sant Joan Desp´ ı, Barcelona, Spain Site investigator Evaluation of participants and/or data management Planellas, Llu´ ıs Hospital Cl´ ınic de Barcelona, Barcelona, Spain Site investigator Evaluation of participants and/or data management Prats, Marian ´ Angeles Institut d’Assist` encia Sanit` aria (IAS) - Institu´ ıC ´ atala de la Salud. 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, V´ ıctor 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 Crist´ obal de la Laguna, Santa Cruz de Tenerife, Spain Site investigator Evaluation of participants and/or data management Redondo, Nuria Hospital La Princesa, Madrid, Spain Site Investigator Evaluation of participants and/or data management (Continued) 124 D. Santos Garc´ıa et al. / Acute Hospitalization in PD Name (Last Name, First Name) Location Role Contribution Rodr´ ıguez M´ endez, Luisa Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coru˜ na, Spain Site investigator Blood analysis Rodr´ ıguez P´ erez, Amparo Bel´ en Hospital General Universitario de Elche, Elche, Spain Site investigator Evaluation of participants and/or data management Rold´ an, Florinda Hospital Universitario Virgen del Roc´ ıo, Sevilla, Spain Site investigator Neuroimaging studies Ru´ ız de Arcos, Mar´ ıa Hospital Universitario Virgen Macarena, Sevilla, Spain. Site investigator Evaluation of participants and/or data management Ru´ ız Mart´ ınez, Javier Hospital Universitario Donostia, San Sebasti´ an, Spain Site investigator Evaluation of participants and/or data management S´ anchez Alonso, Pilar Hospital Universitario Puerta de Hierro, Madrid, Spain Site investigator Evaluation of participants and/or data management S´ anchez-Carpintero, Macarena Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coru˜ na, Spain Site investigator Neuroimaging studies S´ anchez D´ ıez, Gema Hospital Universitario Ram´ on y Cajal, Madrid, Spain Site investigator Evaluation of participants and/or data management S´ anchez Rodr´ ıguez, Antonio Hospital Universitario Marqu´ es de Valdecilla, Santander, Spain Site investigator Evaluation of participants and/or data management Santacruz, Pilar Hospital Cl´ ınic de Barcelona, Barcelona, Spain Site investigator Evaluation of participants and/or data management Santos Garc´ ıa, Diego CHUAC, Complejo Hospitalario Universitario de A Coru˜ na Coordinator of the Project Coordination of the COPPADIS-2015 Segundo Rodr´ ıguez, Jos´ e 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, Mar´ ıa Hospital Universitario Marqu´ es de Valdecilla, Santander, Spain Site investigator Evaluation of participants and/or data management Solano, Berta Institut d’Assist` encia Sanit` aria (IAS) - Institu´ ıC ´ atala de la Salud. Girona, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Su´ arez Castro, Ester Complejo Hospitalario Universitario de Ferrol (CHUF), Ferrol, A Coru˜ na, 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 Roc´ ıo, Sevilla, Spain Site investigator Evaluation of participants and/or data management Vela, Lydia Fundaci´ on Hospital de Alcorc´ on, Madrid, Spain Site investigator / PI Coordination at the center Evaluation of participants and/or data management Villanueva, Clara Hospital Universitario Cl´ ınico San Carlos, Madrid, Spain Site investigator Evaluation of participants and/or data management Vives, B´ arbara Hospital Universitario Son Espases, Palma de Mallorca, Spain Site investigator Evaluation of participants and/or data management Villar, Maria Dolores Hospital Universitario de Canarias, San Crist´ obal de la Laguna, Santa Cruz de Tenerife, Spain Site investigator Evaluation of participants and/or data management