COPPADIS-2015 (COhort of Patients with PArkinson's DIsease in Spain, 2015), a global -clinical evaluations, serum biomarkers, genetic studies and ...
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Santos-García et al. BMC Neurology (2016) 16:26
DOI 10.1186/s12883-016-0548-9
STUDY PROTOCOL Open Access
COPPADIS-2015 (COhort of Patients with
PArkinson’s DIsease in Spain, 2015), a
global –clinical evaluations, serum
biomarkers, genetic studies and
neuroimaging– prospective, multicenter,
non-interventional, long-term study on
Parkinson’s disease progression
Diego Santos-García1*, Pablo Mir2,3, Esther Cubo4, Lydia Vela5, Mari Cruz Rodríguez-Oroz6, Maria José Martí7,
José Matías Arbelo8, Jon Infante9, Jaime Kulisevsky10, Pablo Martínez-Martín3,11 and COPPADIS Study Group
Abstract
Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder causing motor and non-motor
symptoms that can affect independence, social adjustment and the quality of life (QoL) of both patients and caregivers.
Studies designed to find diagnostic and/or progression biomarkers of PD are needed. We describe here the study
protocol of COPPADIS-2015 (COhort of Patients with PArkinson’s DIsease in Spain, 2015), an integral PD project based
on four aspects/concepts: 1) PD as a global disease (motor and non-motor symptoms); 2) QoL and caregiver issues; 3)
Biomarkers; 4) Disease progression.
(Continued on next page)
* Correspondence: diegosangar@yahoo.es
1
Sección de Neurología, Complejo Hospitalario Universitario de Ferrol (CHUF),
Hospital Arquitecto Marcide, c/Avenida La Residencia, s/n, 15405 Ferrol, Spain
Full list of author information is available at the end of the article
© 2016 Santos-García et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Santos-García et al. BMC Neurology (2016) 16:26 Page 2 of 14 (Continued from previous page) Methods/design: Observational, descriptive, non-interventional, 5-year follow-up, national (Spain), multicenter (45 centers from 15 autonomous communities), evaluation study. Specific goals: (1) detailed study (clinical evaluations, serum biomarkers, genetic studies and neuroimaging) of a population of PD patients from different areas of Spain, (2) comparison with a control group and (3) follow-up for 5 years. COPPADIS-2015 has been specifically designed to assess 17 proposed objectives. Study population: approximately 800 non-dementia PD patients, 600 principal caregivers and 400 control subjects. Study evaluations: (1) baseline includes motor assessment (e.g., Unified Parkinson’s Disease Rating Scale part III), non-motor symptoms (e.g., Non-Motor Symptoms Scale), cognition (e.g., Parkinson’s Disease Cognitive Rating Scale), mood and neuropsychiatric symptoms (e.g., Neuropsychiatric Inventory), disability, QoL (e.g., 39-item Parkinson’s disease Quality of Life Questionnaire Summary-Index) and caregiver status (e.g., Zarit Caregiver Burden Inventory); (2) follow-up includes annual (patients) or biannual (caregivers and controls) evaluations. Serum biomarkers (S-100b protein, TNF-α, IL-1, IL-2, IL-6, vitamin B12, methylmalonic acid, homocysteine, uric acid, C-reactive protein, ferritin, iron) and brain MRI (volumetry, tractography and MTAi [Medial Temporal Atrophy Index]), at baseline and at the end of follow-up, and genetic studies (DNA and RNA) at baseline will be performed in a subgroup of subjects (300 PD patients and 100 control subjects). Study periods: (1) recruitment period, from November, 2015 to February, 2017 (basal assessment); (2) follow-up period, 5 years; (3) closing date of clinical follow-up, May, 2022. Funding: Public/Private. Discussion: COPPADIS-2015 is a challenging initiative. This project will provide important information on the natural history of PD and the value of various biomarkers. Keywords: Biomarkers, Caregiver, Genetic studies, Magnetic resonance imaging, Non-motor symptoms, Parkinson’s disease, Progression, Quality of life Background Although the identification of a marker for diagnosis Parkinson’s disease (PD), the second most common neu- and for disease progression (preferably one that is non- rodegenerative disease after Alzheimer’s disease, is a pro- invasive, affordable and accessible) is of utmost import- gressive neurodegenerative disorder causing motor and ance, concepts like quality of life (QoL) are also very non-motor symptoms that result in disability, loss of pa- important in chronic diseases, such as PD, for which a tient autonomy and caregiver burden [1]. Understanding cure does not exist [6]. Improving patient QoL and iden- of PD has changed over recent years, with the disease tifying factors that lead to caregiver burden are very im- currently considered to be a neurodegenerative disease portant aspects of the management of PD. In particular, involving a diversity of pathways and neurotransmitters the role of the principal caregiver in PD is very import- that may explain, in part, the large range of symptoms ant because caregiver burden generates poor care and, in that patients may have [2]. PD is not only a motor dis- the long term, leads to patient institutionalization [7]. ease, as it also involves various non-motor symptoms Specifically, identifying the changes experienced by PD that are important for different reasons. Non-motor patients and their caregivers in their QoL and degree of symptoms are frequent and disabling, therefore, early burden, respectively, over time, as well as factors that identification and proper management of these symp- may predict these changes, in order to carry out a toms is important [3]. Some non-motor symptoms (e.g., proper intervention, should be a priority. Well-designed, olfactory disorders, constipation or sleep disturbances) longitudinal prospective studies are key. Access to a may precede motor symptoms, and could be useful as population with a high proportion of patients who have prodromal/preclinical markers of PD [4]. Others, such been assessed comprehensively and rigorously, without as dementia and psychosis, are more frequently develop screening bias, is highly valuable for both cross-sectional during the late stages of the disease and sometimes dif- analysis and prospective follow-up. This is especially ficult to manage. We need to know, in detail, the pro- relevant for studying populations affected by a neurode- gression of non-motor symptoms and their relationship generative disease, given that these patients are expected with motor changes over time. Reliable and well- to develop different complications that we could identify validated biomarkers for PD to identify individuals “at and analyze. risk” before motor symptoms develop, to accurately Studies designed to identify PD diagnostic and/or pro- diagnose individuals at the threshold of clinical PD, and gression biomarkers and to elucidate the natural pro- to monitor PD progression (motor and non-motor gression of the disease are needed. We describe here the symptoms) throughout the course of the disease would COPPADIS-2015 (COhort of Patients with PArkinson’s dramatically accelerate research into both the cause DIsease in Spain, 2015) study protocol, an integral PD and treatment of PD [5]. project based on four aspects/concepts: 1) PD as a global
Santos-García et al. BMC Neurology (2016) 16:26 Page 3 of 14
disease (motor and non-motor symptoms); 2) QoL and More than one hundred researchers from 48 centers in
caregiver issues; 3) Biomarkers; 4) Disease progression. Spain, from 15 autonomous communities, will partici-
pate in this project.
Methods/design
Type of study Specific goals
COPPADIS-2015 is a national, multicenter, epidemio- The aim COPPADIS-2015 is to: (1) study in detail
logical, descriptive, observational, non-interventional, (clinical evaluations, serum biomarkers, genetic studies
longitudinal-prospective, 5-year follow-up study. COPP and neuroimaging) a population of patients with PD
ADIS-2015 has been classified by the AEMPS (Agencia representative of different areas of Spain; (2) compare it
Española del Medicamento y Productos Sanitarios) as a with a control group and (3) follow-up for 5 years.
Post-authorization Prospective Follow-Up study. COPPADIS-2015 has been specifically designed to assess
The study will be conducted at different hospital sites 17 proposed objectives (Table 1).
in Spain. The essential requirement will be that the
Principal Investigator participating at each site has ex- Study population
perience and skills in the diagnosis and standard man- Non-dementia patients with idiopathic PD, caregivers
agement of patients with PD in their daily clinical (patient’s primary caregiver, if applicable) and controls
practice. As such, the participating site could be any es- will be assessed. We plan to include:
tablishment from a highly-specialized Movement Disor- 1) Approximately 800 patients with PD. Patients will
ders Unit of a tertiary hospital to a general neurologist be included if they have idiopathic PD according to the
from a regional hospital with the aforementioned skills. United Kingdom Parkinson’s Disease Society Brain Bank
Table 1 Specific objectives of the COPPADIS-2015 project
1) To study what variables (non-motor symptoms, cognition, neuropsychiatric symptoms, falls, disability, etc.) impact negatively on both overall and
health-related QoL of patients with PD.
2) To study what variables contribute to a worse QoL, mood and the burden of the primary caregiver for the patient with PD, as well as if the
latter have repercussions on the mood and QoL of the patient him/herself.
3) To study the frequency of impulse control disorders and their types in patients with PD, as well as what variables are associated with them and
to compare it against a control group.
4) To study the frequency of different non-motor symptoms in patients with PD and to compare it against a control group.
5) To study the frequency of pain (and its types) [90] in patients with PD, its relationship to the disease and different variables and to compare it
against a control group.
6) To study the frequency of different types of mood disorders (major depression, minor depression, subclinical depression) [91, 92] in patients
with PD, its relationship with other disease variables and to compare it against a control group.
7) To study the different types of parkinsonian phenotypes [93, 94] and their relationship with other variables (clinical, molecular, genetic and
neuroimaging).
8) To study the relationship between different variables (clinical, molecular, genetic and neuroimaging) and motor laterality asymmetry [95].
9) To study the relationship between the serum levels of S-100b protein, TNF-ɑ, IL-1, IL-2, IL-6, vitamin B12, methylmalonic acid, homocysteine, uric
acid, C-reactive protein, ferritin and iron and other disease variables in patients with PD and to compare it against a control group.
10) To perform genetic studies on DNA and RNA extracted from the lymphocytes of peripheral blood samples.
11) To study the possible value of a recently proposed imaging marker (MTAi) [30] to detect cognitive alterations in patients with PD and to
compare it against a control group.
12) To perform volumetric imaging and tractography studies to find correlations, under plausible hypotheses, between the neuroimaging
parameters and the clinical or neuropsychiatric variables and/or other variables covered in this study [59–61].
13) To study the incidence of acute hospitalization throughout the 12 months following the baseline assessment (for each patient), their causes, and
predictive factors in patients with PD and to compare it against a control group.
14) To study what percentage of patients with PD develop motor complications (in the subgroup of those who do not present them at the
baseline assessment) throughout the 48 months following the baseline assessment (for each patient) and to identify predictive factors.
15) To study what percentage of patients with PD develop significant cognitive impairment and/or dementia over the course of the 24, 48 and
60 months following the baseline assessment (for each patient), to compare it against a control group and to identify predictive factors (clinical,
molecular, genetic, imaging).
16) To study the morbidity and mortality of patients with PD throughout the 24 and 60 months following the baseline assessment (for each
patient), to compare it against a control group and to identify predictive factors (clinical, molecular, genetic, imaging).
17) At the end of follow-up, to compare the course of the different clinical (motor and no-motor features) and paraclinical variables (molecular and
imaging markers).
IL interleukin, PD parkinson’s disease, MTAi, medial temporal atrophy index, QoL quality of life, TNF tumor necrosis factorSantos-García et al. BMC Neurology (2016) 16:26 Page 4 of 14
criteria [8], have no dementia criteria (Mini Mental State [NMSS] [14], Parkinson’s Disease Sleep Scale [PDSS]
Examination [MMSE] ≥ 26) [9], are aged between 30 and [15], Visual Analog Scale-Pain [VAS-Pain] [16], Visual
75 years, are participating voluntarily and have provided Analog Fatigue Scale [VAFS] [17]), cognition (MMSE
written informed consent. Patients will be excluded from [18], Parkinson’s Disease Cognitive Rating Scale [PD-
the study if they: (1) are not capable of completing the CRS] [19], completing a simple 16-piece puzzle [20]),
questionnaires adequately; (2) have other disabling con- mood and neuropsychiatric symptoms (Beck Depression
comitant neurological disease (stroke, severe head Inventory-II [BDI-II] [21], Neuropsychiatric Inventory
trauma, neurodegenerative disease, etc.); (3) have other [NPI] [22], Questionnaire for Impulsive-Compulsive
severe and disabling concomitant non-neurological dis- Disorders in Parkinson’s Disease-Rating Scale [QUIP-RS]
ease (oncological, autoimmune, etc.); (4) have known [23]), disability (Schwab & England Activities of Daily
chronic anemia and/or hyperuricemia; (5) are receiving Living Scale [ADLS] [24]) and QoL (39-item Parkinson’s
active treatment with continuous infusion of levodopa disease Quality of Life Questionnaire Summary Index
and/or apomorphine and/or with deep brain stimulation; [PDQ-39SI] [25], PQ-10 [26], European Health Interview
(6) they are participating in a clinical trial and/or other Survey-Quality of Life 8 item index [EUROHIS-QOL 8
type of study that does not permit concomitant partici- item-index] [27]). Caregiver baseline evaluation includes
pation in another or (7) if long-term follow-up is not the degree of burden (Zarit Caregiver Burden Inventory
expected to be possible. [ZCBI] [28], Caregiver Strain Index [CSI] [29]), mood
2) Approximately 600 caregivers (patient’s primary (BDI-II) and QoL (PQ-10, EUROHIS-QOL 8 item-
caregiver). A person who, without being a professional index). The same evaluation as for the patients, except
and/or receiving money in exchange for services, lives for the motor assessment, will be performed in control
with the patient and is responsible for his/her care will subjects at baseline.
be included as a primary caregiver [10]. He or she must In a subgroup of 400 consecutive non-selected sub-
voluntarily agree to participate and provide written in- jects (300 PD patients and 100 controls) willing to par-
formed consent. ticipate voluntarily and without any contraindications
3) Approximately 400 control subjects matched by (e.g., magnetic resonance imaging [MRI]), complemen-
age, sex and educational level. The control subject tary tests will be performed as follows:
could be a family member (not the patient’s caregiver)
or friend of the patient who would like to participate 1) Blood sample collection for the determination of
voluntarily. The same inclusion criteria (except PD different molecular biomarkers: S-100b protein,
diagnosis) and exclusion criteria as those for the pa- tumor necrosis factor (TNF)-ɑ, interleukin (IL)-1,
tients will be applied. IL-2, IL-6, vitamin B12, methylmalonic acid, homo-
cysteine, uric acid, C-reactive protein, ferritin and
Study design iron. The analysis will be conducted at a common
The study will be carried out in two phases: laboratory: REFERENCE LABORATORY (www.re-
ference-laboratory.es). The extraction of the sample
1) Cross-sectional assessment (recruitment of patients will be carried out no longer than 3 months after
with a baseline assessment over a period of the first clinical assessment.
16 months, from November 2015 to February 2017). 2) Blood sample collection for genetic studies on
We have also considered the possibility, if necessary, lymphocyte DNA and RNA with 4 fundamental
of extending the recruitment period up to a objectives: (1) expression profile studies; (2) exome
maximum of 24 months in order to achieve the sequencing (SNCA, LRRK2, FBXO7, PINKI, PRKN,
proposed target sample size. DJ1, HTRA2, UCHLI, ATPI3A2, VPS35, PLA2G6,
2) Prospective follow-up of the defined cohort of PD GIGYF2, EIF4G1, GBA); (3) analysis of genes
patients (COPPADIS) over 5 years. considered relevant according to the state of the art;
(4) candidate gene association studies in order to
Study assessments determine if the pathological variations are present
The Principal Investigator will make the decision on the more frequently in subjects with PD (with respect to
patient’s inclusion. Extensive information on sociodemo- the control group).
graphic aspects, factors related to PD, comorbidity and 3) Neuroimaging study: T1 3D MRI of the head using
treatment will be collected. Patient baseline evaluations standardized protocols that include frontal and/or
will include motor assessment (Hoenh & Yahr [11], Uni- coronal slices in T1 sequence at 1.5 T or above
fied Parkinson’s Disease Rating Scale [UPDRS] part III without intravenous contrast. Volumetric (spoiled
and part IV [12], Freezing of Gait Questionnaire [FOGQ] gradient recalled sequence; TR 8,5 ms, TE 4 ms,
[13]), non-motor symptoms (Non-Motor Symptoms Scale flip angle 8°, FOV 240 × 240 mm2, thicknessSantos-García et al. BMC Neurology (2016) 16:26 Page 5 of 14
1 mm, matrix 288 × 288, voxel size 0.84 mm3) the same site and with the same machine) and determin-
and tractography (echo-planar imaging; TR ation of molecular markers (S-100b, TNF-ɑ, IL-1, IL-2,
9.500 ms, TE 73 ms, FOV 224, thickness 2 mm, IL-6, vitamin B12, methylmalonic acid, homocysteine,
matrix 128 × 128, b-factors of zero and 700 s/ uric acid, C-reactive protein, ferritin and iron; same la-
mm2) studies will be performed. Also, the Medial boratory, REFERENCE LABORATORY) at 60 months.
Temporal Atrophy Index (MTAi) [30] will be Table 3 shows the working plan summary.
calculated. The MRI study will be performed no
longer than 6 months after the first clinical Data collection and statistical analysis
assessment. Data will be collected using an electronic Case Report
Form (e-CRF) and will be transferred to a statistical
Figure 1 shows baseline study assessments. Table 2 package for subsequent analysis. The company re-
shows data regarding centers, number of patients that sponsible for study monitoring is Alphabioresearch
they have estimated to recruit and distribution of pa- (www.alphabioresearch.com).
tients selected for the complementary studies according We calculated the sample size, taking into account a
to the different centers. maximum estimated loss to follow-up of 10 % of pa-
During the 5 years of follow-up, annual evaluations tients per year, and that between 15 % and 20 % of the
(PD patients) or evaluations at 24, 48 and 60 months sites involved in a multicenter study are estimated to
(caregivers and controls) will be performed. Figure 2 leave the study for different reasons [31]. A minimum of
shows assessments during the follow-up phase in each 280 patients at the end of follow-up would be sufficient
group. The subjects who undergo complementary tests to include up to 27 predictive variables in the multiple
at baseline will repeat the head MRI study (preferably at regression analyses with a power of 0.8 and a confidence
a b c
Fig. 1 Recruitment period, from November 2015 to February 2017 (baseline assessment of each participating subject). 1, patient inclusion process
and motor assessment by the Principal Investigator (neurologist who is an expert in movement disorders and Parkinson’s disease); 2a, non-motor
assessment by the Principal Investigator, specialized nurse, psychologist or fellow with adequate training; 2b, caregiver assessment; 2c, control
assessment. *Only patients with motor fluctuations (UPDRS-IV) will be assessed during the OFF-medication (first thing in the morning
without taking medication in the 12 previous hours) and during the ON-medication state; the rest will only be assessed during the OFF-
medication state. Blood samples from the baseline assessment will be stored for the purpose of being able to test other future markers
not currently included in the projectSantos-García et al. BMC Neurology (2016) 16:26 Page 6 of 14
Table 2 Centers, number of patients that they have estimated to recruit and distribution of patients selected for the complementary
studies according to the different centers
Principal Investigator; PI’s participating site City Patients Controls Complementary
(n) (n) studies (PDP/CS)
1. Diego Santos García; Neurology Section, Hospital Arquitecto Marcide, Complejo Ferrol 60 10 45/10
Hospitalario Universitario de Ferrol (CHUF). (A Coruña)
2. (1) Oriol de Fábregues-Boixar Nebot and (2) Jorge Hernández Vara; Movement Barcelona 60 20 40/20
Disorders Unit, Neurology Service, Hospital Universitario Vall d’Hebron. (40/20) (10/10)
3. Carmen Borrue Fernández; Movement Disorders Unit, Neurology Service, Hospital Madrid 50 10 NO
Infanta Sofía.
4. Pablo Mir Rivera; Movement Disorders Unit, Neurology and Clinical Neurophysiology Seville 40 10 40/0
Service, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío,
CSIC and Universidad de Sevilla.
5. Maria José Martí Domenech; Parkinson’s and Movement Disorders Unit, Neurology Barcelona 40 10 NO
Service, Instituto Clínico de Neurociencias, Hospital Clínic.
6. Miquel Aguilar Barberá; Movement Disorders Unit, Hospital Universitario Mutua de Barcelona 40 10 30/10
Terrassa.
7. Beatriz Tijero Merino; Functional Neurology and Parkinson’s Disease Unit, Hospital de Bilbao 35-40 10 NO
Cruces.
8. José Chacón Peña; Neurology Unit, Hospital Infanta Luisa. Seville 30-35 10 NO
9. (1) Manuel Seijo Martínez and (2) Iria Cabo López; Neurology Section, Hospital de Pontevedra 30 20 NO
Pontevedra. (15/15) (10/10)
10. Víctor Puente Périz; Movement Disorders Unit, Neurology Service, Hospital del Mar. Barcelona 25-30 10 20/10
11. Inés Legarda Ramiréz; Neurology Service, Hospital Universitario Son Espases. Palma de 25 10 NO
Mallorca
12. Francisco Carrillo Padilla; Neurology Service, Hospital Universitario de Canarias, San Santa Cruz de 25 10 20/0
Cristóbal de la Laguna. Tenerife
13. Lydia López Manzanares; Movement Disorders Unit, Neurology Service, Hospital La Madrid 25 10 NO
Princesa.
14. Caridad Valero Merino; Neurology Unit, Hospital Arnau de Vilanova. Valencia 20-25 10 NO
15. Jaime Kulisevsky Bojarski; Movement Disorders Unit, Neurology Service, Hospital de Barcelona 20 10 NO
Sant Pau.
16. José Manuel García Moreno; Movement Disorders Unit, Hospital Universitario Virgen Seville 20 10 20/10
Macarena.
17. Benito Galeano Bilbao; Neurology Section, Hospital Universitario de Ceuta. Ceuta 20-25 10 20/0
18. Nuria Caballol Pons; Movement Disorders Unit, Consorci Sanitari Integral, Hospital Sant Joan 20 10 NO
Moisés Broggi. Despí
19. Mari Cruz Rodríguez Oroz; Hospital Universitario Donostia, Instituto de Investigación San Sebastián 20 10 20/10
Biodonostia.
20. María Iciar Gastón Zubimendi; Movement Disorders Unit, Neurology Service, Pamplona 20 10 NO
Complejo Hospitalario de Navarra.
21. Pilar Sánchez Alonso; Neurology Service, Hospital Puerta de Hierro. Madrid 15-25 10 NO
22. Esther Cubo Delgado; Neurology Service, Complejo Asistencial Universitario de Burgos 15 10 NO
Burgos.
23. Lydia Vela Desojo; Neurology Unit, Fundación Hospital de Alcorcón. Alcorcón 15 10 NO
(Madrid)
24. Maria José Catalán Alonso; Movement Disorders Unit, Neurology Service, Hospital Madrid 15 10 NO
Clínico San Carlos.
25. Luis Manuel López Díaz; Neurology Section, Hospital de Burela. Burela (Lugo) 15 10 NO
26. Maria Gema Alonso Losada; Neurology Service, Hospital Meixoeiro, Complejo Vigo 15 10 NO
Hospitalario Universitario de Vigo (CHUVI). (Pontevedra)
27. Nuria López Ariztegui; Movement Disorders Unit, Complejo Hospitalario de Toledo. Toledo 15 10 NO
28. Mónica Kurtis Urra; Movement Disorders Unit, Neurology Service, Hospital Ruber Madrid 15 10 NO
Internacional.Santos-García et al. BMC Neurology (2016) 16:26 Page 7 of 14
Table 2 Centers, number of patients that they have estimated to recruit and distribution of patients selected for the complementary
studies according to the different centers (Continued)
29. Jon Infante Ceberio; Movement Disorders Unit, Neurology Service, Hospital Santander 15 10 15/10
Universitario Marqués de Valdecilla.
30. Sonia Escalante Arroyo; Neurology Service, Hospital de Tortosa Verge de la Cinta Tortosa 15 10 15/10
(HTVC). (Tarragona)
31. Juan Carlos Martínez Castrillo; Movement Disorders Unit, Neurology Service, Hospital Madrid 15 10 NO
Ramón y Cajal.
32. José Matías Arbelo González; Movement Disorders and Parkinson’s Disease Unit, Las Palmas de 15 10 NO
Neurology Service, Hospital Universitario Insular de Gran Canaria. Gran Canaria
33. René Ribacoba Montero; Movement Disorders Unit, Neurology Service, Hospital Oviedo 15 10 15/10
Central de Asturias.
34. Jessica González Ardura; Neurology Service, Hospital Universitario Lucus Augusti Lugo 15 10 NO
(HULA).
35. Javier López del Val; Movement Disorders Unit, Neurology Service, Hospital Clínico Zaragoza 15 10 NO
Universitario Lozano Blesa.
36. María Asunción Ávila Rivera; Movement Disorders Unit, Consorci Sanitari Integral, L’Hospitalet de 15 10 NO
Hospital General de L’Hospitalet. Llobregat
37. Hortensia Alonso Navarro; Neurology Section, Hospital Universitario del Sureste, Madrid 15 10 NO
Madrid.
38. Berta Solano Vila; Neurology Service, Hospital Josep Trueta and Parc Martí i Juliá, Girona 15 10 NO
Girona.
39. Juan García Caldentey; Neurology Unit, Hospital Quirón Palmaplanas. Palma de 15 10 NO
Mallorca
40. Ana Rojo Sebastián; Parkinson’s and Abnormal Movement Unit, Neurology Service, Alcalá de 15 10 NO
Hospital Universitario Príncipe de Asturias. Henares
(Madrid)
41. Silvia Martí Martínez; Neurology Service, Hospital General de Alicante. Alicante 15 10 NO
42. José Andrés Domínguez Morán; Neurology Unit, Hospital de la Rivera. Alcira (Valencia) 15 10 NO
43. Irene Martínez Torres; Movement Disorders Unit, Neurology Service, Hospital La Fe. Valencia 15 10 NO
44. María Álvarez Sauco; Neurology Service, Hospital General Universitario de Elche. Elche (Alicante) 15 10 NO
45. Cristina Prieto Jurczynska; Movement Disorders Unit, Hospital Infanta Elena-Hospital Madrid 15 10 NO
Rey Juan Carlos-Hospital Collado Villalba, Madrid.
1.000 470 300/100
PDP parkinson’s disease patient, CS control subject
interval of 95 % [32]. The pertinent analysis (descriptive Study timetable
studies, univariate studies, binary logistic regression,
multiple linear regression, etc.) will be performed based 1) Pre-start-up procedures: until October 2015.
on the type of objective. In addition, given de complexity 2) First assessment (cross-sectional assessment):
of potential analysis including a diversity of variables November 2015 to February 2017.
from different origin and measurement properties, ad- 3) Database review: March–June 2017.
vanced statistical methodology (data mining, artificial 4) Statistical analysis: second half of 2017.
intelligence techniques, etc.) will be applied as needed. 5) Reporting and publication of papers (objectives 1 to
One of the authors (PMM) will coordinate these aspects. 12 of the cross-sectional assessment and other suba-
nalyses): years 2017 to 2019.
Ethical considerations 6) Objectives of the prospective follow-up of the co-
The project will be conducted in accordance with the hort: from 2018 onwards.
standards for Good Clinical Practice, the fundamental
ethical principles established in the Declaration of Future possibilities of the project
Helsinki and the Oviedo Convention, as well as the re-
quirements established in Spanish legislation in the re- 1) To perform other evaluations and/or
search field. Approval of the Ethics Committee at each complementary studies during follow-up; for ex-
center was obtained. ample, electromyographic studies to determine theSantos-García et al. BMC Neurology (2016) 16:26 Page 8 of 14
a
b
c
Fig. 2 Follow-up of the cohort of patients (a), caregivers (b) and controls (c). At the end of follow-up, the patients (n = 300) and controls (n = 100) who
underwent complementary tests at baseline will undergo repeat testing (molecular markers and imaging study). ADLS, Schwab & England Activities of Daily
Living Scale; BDI, Beck Depression Inventory; CSI, Caregiver Strain Index; FOGQ, Freezing of Gait Questionnaire; HY, Hoenh & Yahr; NMSS, Non-Motor
Symptoms Scale; NPI, Neuropsychiatric Inventory; PD-CRS, Parkinson’s Disease Cognitive Rating Scale; PDQ-39SI, 39-item Parkinson’s disease
Quality of Life Questionnaire Summary Index; QUIP-RS, Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease-Rating Scale;
PDSS, Parkinson’s Disease Sleep Scale; UPDRS, Unified Parkinson’s Disease Rating Scale; VAFS, Visual Analog Fatigue Scale; VAS-Pain, Visual
Analog Scale-Pain; ZCBI, Zarit Caregiver Burden Inventory
frequency of polyneuropathy in PD patients com- participation, with more than 40 Spanish centers in-
pared with controls and also to identify related risk volved, exhaustive clinic evaluations, including motor
factors (clinical, biomarkers, etc.); other studies (op- and non-motor features (more than 500 variables col-
tical coherence tomography, electroencephalogram, lected from the baseline assessment), biomarkers, study
salivary secretion and/or cerebrospinal fluid analysis, design and interesting future possibilities are strong
skin biopsy, etc.). points of this project. COPPADIS-2015 will enable us to
2) To continue follow-up of the subjects (patients, identify different complications that develop over time
caregivers and controls) over time (10, 15, in a very large population of patients with PD. There-
20 years, etc.). fore, we expect to be able to identify the incidence of
3) To create a COPPADIS Brain Bank. We have different problems, their impact on QoL and predictive
designed a working group with the participation of factors that will allow us to identify these problems early
members of different biobanks in Spain with the aim in order to act.
of create a Brain Donation Program for COPPADIS This project is based on four aspects/concepts: 1) PD
PD patients. as a global disease (motor and non-motor symptoms); 2)
QoL and caregiver issues; 3) Biomarkers; 4) Disease
Discussion progression. For years, PD management was focused on
The described project, COPPADIS-2015 (COhort of motor symptoms. However, more recently, non-motor
Patients with PArkinson’s DIsease in Spain, 2015), is an features have been gaining in importance. Non-motor
ambitious initiative that will provide important informa- symptoms are important for different reasons [33]: they
tion regarding the natural history of PD and the value of are frequent and disabling; some non-motor symptoms
various biomarkers. The large sample size, high level of such as hyposmia, constipation, depression or REMSantos-García et al. BMC Neurology (2016) 16:26 Page 9 of 14 Table 3 Working Plan Summary Assessments Baseline 12 m 24 m 36 m 48 m 60 m Inclusion/exclusion criteria P; C Hoehn & Yahr P P P P P P UPDRS-III and UPDRS-IV P P P P P P MMSE P; C P; C P; C P; C PD-CRS P; C P; C P; C P; C Puzzle test P; C P; C P; C P; C NMSS P; C P P; C P P; C P; C BDI-II P; pC; C P; pC; C P; pC; C P; pC; C QUIP-RS P; C P; C P; C P; C PDSS P; C P; C P; C P; C NPI P; C P; C P; C P; C VAS-Pain and VAFS P; C P; C P; C P; C FOGQ P; C P; C P; C P; C ADLS P; C P P; C P P; C P; C PDQ-39SI P; C P; C P; C P; C PQ-10 P; pC; C P; pC; C P; pC; C P; pC; C EUROHIS-QOL 8 item index P; pC; C P; pC; C P; pC; C P; pC; C ZCBI pC pC pC pC CSI pC pC pC pC Samples-serum markers P; C P; C Samples-genetic studies P; C Head MRI P; C P; C ADLS Schwab & England activities of daily living scale, BDI beck depression inventory, C control, CSI caregiver strain index, EUROHIS-QOL European health interview survey-quality of life, FOGQ freezing of gait questionnaire, m month, MMSE mini mental state examination, MRI magnetic resonance imaging, NMSS non-motor symptoms scale, NPI neuropsychiatric inventory, P patient, pC primary caregiver, PD-CRS parkinson’s disease cognitive rating scale, PDQ-39SI 39-item parkinson’s disease quality of life questionnaire summary index, PDSS parkinson’s disease sleep scale, 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, ZCBI zarit caregiver burden inventory sleep behavior disorders can precede motor symptoms assessment) and predictive (prospective follow-up) fac- and, in the future, such symptoms could be used to es- tors for the development of different non-motor symp- tablish an earlier diagnosis of premotor PD; non-motor toms. For example, factors related to mild cognitive symptoms can sometimes be difficult to manage (ortho- impairment at baseline and risk factors that could static hypotension, behavioral disorders, etc.); some non- predict the chance of mild cognitive impairment pro- motor symptoms (dementia, psychosis, etc.) increase the gressing to dementia will be identified [36]. We will also risk of institutionalization and generate a high economic compare non-motor symptoms (and other features of cost; and they are not always sufficiently recognized by the disease) and disease progression in patients with the neurologist. Additionally, various studies have dem- different phenotypes and motor laterality asymmetry. onstrated that non-motor symptoms impact negatively Moreover, we will try to determine if non-motor on patient QoL, and that by improving these symptoms, symptoms (NMSS) predict acute hospitalization in PD we help improve QoL [34, 35]. Early identification and patients [37]. proper management should currently be a priority in At present we have no cure for PD. We use different daily clinical practice [4], but for many reasons, this is therapies to improve patient symptoms, health status, not always the case. In COPPADIS-2015, we will degree of autonomy and QoL. The key is to understand exhaustively evaluate different non-motor features what factors affect QoL (depression, pain, motor compli- (NMSS, PDSS, VAS-Pain, VAFS, MMSE, PD-CRS, BDI-II, cations, etc.), given that interventions will be based on NPI, QUIP-RS) in a large population of PD patients. We these factors. Moreover, the role of the patient’s primary will also compare these features with a control group caregiver is also very important because PD is a neuro- and analyze their evolution with disease progression. degenerative disorder and the patient will become Finally, we will try to identify related (cross-sectional increasingly dependent. We will need to determine
Santos-García et al. BMC Neurology (2016) 16:26 Page 10 of 14 which factors cause caregivers’ stress and increase their relationship with the type of symptomatic therapy burden in order to carry out an early intervention, since initially used [68–70], cognitive impairment and/or caregiver burden generates poor care and, in the long dementia [71–74], the course following a given inter- term, often leads to the patient’s institutionalization [7]. vention (e.g., deep brain stimulation) [75, 76] or other In this regard, it has been observed that patient QoL is data on the course of the disease [77–86]. There are correlated with the caregiver’s status, and interventions other promising studies currently underway with a targeted at improving caregiver burden to also improve fundamental objective of identifying a disease progres- the patient’s QoL have been suggested [38]. Although sion biomarker [87]. Nevertheless, many of the studies there are several studies focused on factors related to have significant limitations, such as an insufficient caregiver burden [39–41], there is no information about sample size and follow-up, significant losses to follow- caregiver strain changes during disease progression. In up, limitations in the recruitment or origin of the sam- COPPADIS-2015 we will analyze changes in QoL, mood ple and performance of analyses not specifically and burden experimented by principal caregivers and we allowed for in the design. As seen for other neurode- will attempt to correlate these with changes in different generative diseases like Huntington’s disease [88], the aspects of the disease (motor symptoms, mood, cogni- most beneficial study model for achieving relevant tion, behavior, other non-motor symptoms, etc.) ob- advances in the understanding of PD is likely to be a served in patients. study that includes a baseline cross-sectional assess- A top priority at present in PD is to identify a ment of patients (with a control group) with analysis diagnostic and prognostic biomarker [42, 43]. In of multiple variables (clinical and complementary tests; COPPADIS-2015, different molecular markers in for example, serum molecular markers, other biological blood will be evaluated (S-100b protein, TNF-ɑ, IL-1, samples like cerebrospinal fluid, saliva or skin, structural IL-2, IL-6, vitamin B12, methylmalonic acid, homo- neuroimaging, functional neuroimaging, ophthalmological cysteine, uric acid, C-reactive protein, ferritin and studies, neurophysiological tests, etc.) followed by a subse- iron) [44–57], and genetic studies (DNA and RNA) quent prospective follow-up (ideally over a long period of [58], and cranial MRI (MTAi, volumetry and tracto- follow-up and without losses of cases) of the population graphy) [30, 59–65] will be performed in a subgroup studied with multiple periodic analyses that would make it of patients and controls. We will try to identify possible to compare the course of the different variables markers with diagnostic and/or prognostic value, analyzed. These features are all covered by the described either alone or in combination (clinical and/or para- project, COPPADIS-2015. Unlike the PPMI Study, PD clinical). For example, we will analyze the role of patients at all Hoenh & Yahr stages who meet the selection serum S-100b protein and uric acid as possible prog- criteria and not only early patients will be included in the nostic biomarkers [44–46, 56], the relationship COPPADIS Study. That’s because we focused firstly on between serum levels of TNF-ɑ, IL-1, IL-2, IL-6 and studying very exhaustively a large population of PD C-reactive protein and different non-motor symptoms patients from different areas of Spain analyzing the [47–51], or the sensitivity and specificity of a simple relationship between different variables according to puzzle test as a cognitive impairment screening test. cross-sectional study methodology. Changes observed in Moreover, biomarkers included in this project have different variables during the follow-up will be ad- some of the characteristics needed in an ideal marker: justed and interestingly, different groups of subjects fast and affordable to obtain; available; repeatable; and according to disease duration, motor stage or to have safe [66, 67]. Finally, in the future, other molecular motor complications at baseline could be defined to biomarkers could be analyzed from stored blood sam- compare evolution. Some original aspects in COPPA- ples and other complementary studies could be done. DIS are to include the caregivers (the principal Moreover, creation of a brain bank (COPPADIS Brain caregiver of the patient was also included in a previous Donation Program) from patients included in this pro- Spanish Study, the ELEP Study –Estudio Longitudinal ject is being developed. de pacientes con Enfermedad de Parkinson/Longitu- Therefore, well-designed, longitudinal prospective dinal Parkinson’s Disease Patient Study [89] –), to studies must be conducted to identify a biomarker of study the incidence and predictors of acute linear progression and also to understand the natural hospitalization and to analyze the value of the MTAi. progression of PD. Today, we still do not know what Furthermore, as it was mentioned, we are working to relationship exists between the progression of motor develop a COPPADIS Donation Brain Program. In- symptoms and non-motor symptoms in the long term. deed, the long-term goal is to design a Spanish PD Different longitudinal studies with prospective follow- patients clinical-pathological registry (with the inclu- up of patients have provided an understanding of the sion of early new patients) with long-term monitoring development of motor complications and their and implementation of many additional tests.
Santos-García et al. BMC Neurology (2016) 16:26 Page 11 of 14
In conclusion, COPPADIS-2015 is a challenging and Acknowledgments
original initiative. We hope that this project will provide We would like the thank all patients, caregivers and all persons, companies
or institutions collaborating in this project.
important information regarding the natural history of We would also like to thank Marie Cheeseman who provided English editing
PD, including changes in motor and non-motor symp- services on behalf of Springer Healthcare Communications.
toms, QoL and caregiver burden over time, and the
value of various biomarkers. COPPADIS Study group (collaborators)
de Deus Fonticoba T1, de Fábregues-Boixar O2, Hernández Vara J2, Borrue C3,
Abbreviations Aguilar M4, Tijero B5, Chacón J6, Seijo M7, Cabo I7, Puente V8, Legarda I9,
ADLS: Schwab & England activities of daily living scale; AEMPS: Agencia Carrillo Padilla F10, López Manzanares L11, Valero C12, Pagonabarraga J13,
Española del Medicamento y Productos Sanitarios; BDI: beck depression García-Moreno JM14, Galeano B15, Caballol N16, Gastón Zubimendi MI17,
inventory; CSI: caregiver strain index; e-CRF: electronic case report form; Sánchez Alonso P18, Catalán MJ19, López Díaz LM20, Alonso Losada MG21,
EUROHIS-QOL: European health interview survey-quality of life; López Ariztegui N22, Kurtis M23, Sierra M24, Escalante S25, Martínez Castrillo
FOGQ: freezing of gait questionnaire; HY: hoenh & yahr; IL: interleukin; JC26, Ribacoba R27, González Ardura J28, López del Val J29, Ávila MA30, Alonso-
MMSE: mini mental state examination; MRI: magnetic resonance imaging; Navarro H31, Solano B32, García Caldentey J33, Rojo A34, Martí Martínez S35,
MTAi: medial temporal atrophy index; NMSS: non-motor symptoms scale; Domínguez Morán JA36, Martínez Torres I37, Álvarez Sauco MA38, Prieto Jurc-
NPI: neuropsychiatric inventory; PD: parkinson’s disease; PD-CRS: parkinson’s zynska C39, Menéndez González M27,40, Carrillo-García F41, Jesús S41, Cáceres
disease cognitive rating scale; PDQ-39SI: 39-item Parkinson’s disease quality MT41, Oropesa JM41, Gómez-Garre MP41, Huertas I41, Vargas L41, Mariscal N42,
of life questionnaire summary index; PDSS: parkinson’s disease sleep scale; Macías Y43, Ruíz Martínez J44, Delgado M44, Mondragón E44, Barandiarán M44,
QoL: quality of life; QUIP-RS: questionnaire for Impulsive-compulsive Malo R45, Planella L46, Cámara A46, Martí G2, Mata M3, Pastor P4, Quílez P4,
disorders in parkinson’s disease-rating scale; TNF: tumor necrosis factor; Badenes D4, Casas L4, Arribas S4, Romero S4, Tomé G4, Comes L4, Guardia G4,
UPDRS: unified parkinson’s disease rating scale; VAFS: visual analog fatigue López J4, Gómez Esteban JC5, Berganzo K5, González A5, Acera M5, Rodríguez
scale; VAS-Pain: visual analog scale-pain; ZCBI: zarit caregiver burden Bóveda I5, Álvarez López M6, Fernández-Espejo E6,47, Vives B9, Pueyo M10, de
inventory. Toledo M11, Sobrado M11, González García B11, Bosca M12, Salazar C12, Cam-
pos A12, Pascual B13, Damas F14, Pacheco E14, Merino R15, Clavero P17, Erró
Competing interests E17, Lacruz F17, Cabello C17, Díez Álvarez M18, Montero P19, Villanueva C19,
Financial competing interests (for the preceding twelve months) Meitín T20, Murcia S22, Clemente J22, Sánchez P23, González Aramburu I24,
Diego Santos-García has received honoraria for educational presentations by Esteve P25, Reverté S25, Alonso A26, Avilés I26, Suárez E27, Sánchez P27, Guijarro
Abbvie, UCB Pharma and Lundbeck. Pablo Mir has received honoraria for lec- M28, Bellosta E29, López García E29, Jiménez-Jiménez FJ31, Coll C32, Montserrat
turing or advisory boards from AbbVie, UCB, Zambon, Allergan and Merz, M32, Ferriol MM33, Finally, this author will not participate in the study., Leiva
and research grants from the Ministerio de Economía y Competitividad de C35, Hernández L35, López Pesquera P36, Luca L36, Rubio I37, Satre I37, Freire
España [SAF2007-60700], the Instituto de Salud Carlos III [PI10/01674, CP08/ E38, Ordás C39, Torres G39, Cazorla R39, Vengas B39, López Seoane B48, Faraldo
00174, PI13/01461], the Consejería de Economía, Innovación, Ciencia y A48, Fernández Guillán N48, Moreno Diéguez A48, Lage Castro M49, Vázquez
Empleo de la Junta de Andalucía [CVI-02526, CTS-7685], the Consejería de Gómez R49. A48.
1
Salud y Bienestar Social de la Junta de Andalucía [PI-0377/2007, PI-0741/ Sección de Neurología, Hospital Arquitecto Marcide, Complexo Hospitalario
2010, PI-0437-2012], the Sociedad Andaluza de Neurología, the Jacques and Universitario de Ferrol (CHUF), Ferrol, A Coruña; 2Unidad de Trastornos del
Gloria Gossweiler Foundation and the Fundación Alicia Koplowitz. Esther Movimiento, Servicio de Neurología, Hospital Universitario Vall d’Hebron,
Cubo has received travel funding from Abbvie, Allergan and UCB Pharma- Barcelona; 3Unidad de Trastornos del Movimiento, Servicio de Neurología,
ceuticals, and received research support from the Movement Disorder Hospital Infanta Sofía, Madrid; 4Unidad de Trastornos del Movimiento,
Society, World Federation of Neurology and Junta de Castilla y León. Lydia Hospital Universitario Mutua de Terrasa, Terrasa, Barcelona; 5Unidad de
Vela has received honoraria for educational presentations by Abbvie, UCB Neurología Funcional y Enfermedad de Parkinson, Hospital de Cruces, Bilbao;
6
Pharma and Lundbeck. Maria C Rodriguez-Oroz has received payment for Unidad de Neurología, Hospital Infanta Luisa, Sevilla; 7Servicio de
lectures, travel and accommodation to attend scientific meetings from UCB, Neurología, Complejo Hospitalario de Pontevedra (CHOP), Pontevedra;
8
Lundbeck, Abbvie and Boston Scientific. She has received grants from Unidad de Trastornos del Movimiento, Servicio de Neurología, Hospital del
CIBERNED, Government of Basque Country and Guipuzcoa, Spanish Health Mar, Barcelona; 9Servicio de Neurología, Hospital Universitario Son Espases,
Institute and Era-net. Maria J Marti has received speaking fees from Ipsen, Palma de Mallorca; 10Servicio de Neurología, Hospital Universitario de
Merz, Allergan and UCB Pharma and research grants from Ministery of Health Canarias, San Cristóbal de la Laguna, Santa Cruz de Tenerife; 11Unidad de
and Social Services, Marató TV3, Centro Investigacion Biomedica en Red and Trastornos del Movimiento, Servicio de Neurología, Hospital La Princesa,
Michael J Fox Foundation for Parkinson’s research. Jose M Arbelo has re- Madrid; 12Unidad de Neurología, Hospital Arnau de Vilanova, Valencia;
13
ceived honoraria for educational presentations or clinical studies participation Unidad de Trastornos del Movimiento, Servicio de Neurología, Hospital de
by Abbvie, UCB Pharma and Italfarmaco. Jon Infante has received honoraria Sant Pau, Barcelona; 14Unidad de Trastornos del Movimiento, Hospital
as a speaker from UCB Pharma and traveling grants from Abbvie. Jaime Universitario Virgen Macarena, Sevilla; 15Sección de Neurología, Hospital
Kulisevsky has received honoraria for lecturing or advisoring from Abbvie, Universitario de Ceuta, Ceuta; 16Unidad de Trastornos del Movimiento,
UCB and Zambon. Pablo Martínez-Martin has received honorarium from Consorci Sanitari Integral, Hospital Moisés Broggi, Sant Joan Despí, Barcelona;
17
Abbvie for a symposium and participation in the Advisory Board for an epi- Unidad de Trastornos del Movimiento, Servicio de Neurología, Complejo
demiological study, Editorial Viguera for a master course, UCB for lecturing in Hospitalario de Navarra; 18Servicio de Neurología, Hospital Puerta de Hierro,
International University Menendez Pelayo summer course. Madrid; 19Unidad de Trastornos del Movimiento, Servicio de Neurología,
Hospital Clínico San Carlos; 20Sección de Neurología, Hospital da Costa
Authors’ contributions Burela, Burela, Lugo; 21Servicio de Neurología, Hospital Meixoeiro, Complejo
DS, MD PhD conception, organization, and execution of the project; writing Hospitalario Universitario de Vigo (CHUVI), Vigo; 22Unidad de Trastornos del
of the first draft of the manuscript. PM, MD PhD participation in the Movimiento, Complejo Hospitalario de Toledo, Toledo; 23Unidad de
consensus protocol; review and critique of this manuscript. EC, MD PhD Trastornos del Movimiento, Servicio de Neurología, Hospital Ruber
participation in the consensus protocol; review and critique of this Internacional, Madrid; 24Unidad de Trastornos del Movimiento, Servicio de
manuscript. LV, MD PhD participation in the consensus protocol; review and Neurología, Hospital Universitario Marqués de Valdecilla, Santander; 25Servicio
critique of this manuscript. MCR, MD PhD participation in the consensus de Neurología, Hospital de Tortosa Verge de la Cinta (HTVC), Tortosa,
protocol; review and critique of this manuscript. MJM, MD PhD participation Tarragona; 26Unidad de Trastornos del Movimiento, Servicio de Neurología,
in the consensus protocol; review and critique of this manuscript. JMA, MD Hospital Ramón y Cajal, Madrid; 27Unidad de Trastornos del Movimiento,
PhD participation in the consensus protocol; review and critique of this Servicio de Neurología, Hospital Central de Asturias; 28Servicio de Neurología,
manuscript. JI, MD PhD review and critique of this manuscript. JK, MD PhD Hospital Universitario Lucus Augusti (HULA), Lugo; 29Unidad de Trastornos
review and critique of this manuscript. PM, MD PhD review and critique of del Movimiento, Servicio de Neurología, Hospital Clínico Universitario Lozano
this manuscript. All authors read and approved the final manuscript. Blesa, Zaragoza; 30Unidad de Trastornos del Movimiento, Consorci SanitariSantos-García et al. BMC Neurology (2016) 16:26 Page 12 of 14
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