Neuroinflammation-Related Proteins NOD2 and Spp1 Are Abnormally Upregulated in Amyotrophic Lateral Sclerosis.

Humans Amyotrophic Lateral Sclerosis Osteopontin Frontotemporal Dementia Neurodegenerative Diseases Neuroinflammatory Diseases Alzheimer Disease Nod2 Signaling Adaptor Protein / genetics

Journal

Neurology(R) neuroimmunology & neuroinflammation
ISSN: 2332-7812
Titre abrégé: Neurol Neuroimmunol Neuroinflamm
Pays: United States
ID NLM: 101636388

Informations de publication

Date de publication:
03 2023
Historique:
received: 12 07 2022
accepted: 13 10 2022
entrez: 2 12 2022
pubmed: 3 12 2022
medline: 7 12 2022
Statut: epublish

Résumé

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknown etiology and poorly understood pathophysiology. There is no specific biomarker either for diagnosis or prognosis. The aim of our study was to investigate differentially expressed proteins in the CSF and serum from patients with ALS to determine their role in the disease process and evaluate their utility as diagnostic or prognostic biomarkers. We performed mass spectrometry in the CSF from 3 patients with ALS and 3 healthy controls (HCs). The results were compared with motor cortex dysregulated transcripts obtained from 11patients with sporadic ALS and 8 HCs. Candidate proteins were tested using ELISA in the serum of 123 patients with ALS, 30 patients with Alzheimer disease (AD), 28 patients with frontotemporal dementia (FTD), and 102 HCs. Patients with ALS, AD, and FTD were prospectively recruited from January 2003 to December 2020. A group of age-matched HCs was randomly selected from the Sant Pau Initiative on Neurodegeneration cohort of the Sant Pau Memory Unit. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and osteopontin (Spp1) were differentially expressed in the CSF and the motor cortex transcriptome of patients with ALS compared with that in HCs ( Our discovery-based approach identified NOD2 as a novel biomarker in ALS and adds evidence to the contribution of Spp1 in the disease process. Both proteins are involved in innate immunity and autophagy and are increased in the serum from patients with ALS. Our data support a relevant role of neuroinflammation in the pathophysiology of the disease and may identify targets for disease-modifying treatments in ALS. Further longitudinal studies should investigate the diagnostic and prognostic value of NOD2 and Spp1 in clinical practice.

Sections du résumé

BACKGROUND AND OBJECTIVES
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknown etiology and poorly understood pathophysiology. There is no specific biomarker either for diagnosis or prognosis. The aim of our study was to investigate differentially expressed proteins in the CSF and serum from patients with ALS to determine their role in the disease process and evaluate their utility as diagnostic or prognostic biomarkers.
METHODS
We performed mass spectrometry in the CSF from 3 patients with ALS and 3 healthy controls (HCs). The results were compared with motor cortex dysregulated transcripts obtained from 11patients with sporadic ALS and 8 HCs. Candidate proteins were tested using ELISA in the serum of 123 patients with ALS, 30 patients with Alzheimer disease (AD), 28 patients with frontotemporal dementia (FTD), and 102 HCs. Patients with ALS, AD, and FTD were prospectively recruited from January 2003 to December 2020. A group of age-matched HCs was randomly selected from the Sant Pau Initiative on Neurodegeneration cohort of the Sant Pau Memory Unit.
RESULTS
Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and osteopontin (Spp1) were differentially expressed in the CSF and the motor cortex transcriptome of patients with ALS compared with that in HCs (
DISCUSSION
Our discovery-based approach identified NOD2 as a novel biomarker in ALS and adds evidence to the contribution of Spp1 in the disease process. Both proteins are involved in innate immunity and autophagy and are increased in the serum from patients with ALS. Our data support a relevant role of neuroinflammation in the pathophysiology of the disease and may identify targets for disease-modifying treatments in ALS. Further longitudinal studies should investigate the diagnostic and prognostic value of NOD2 and Spp1 in clinical practice.

Identifiants

DOI: 10.1212/NXI.0000000000200072 PMID: 36460480 PMC: PMC9720732
pubmed: 36460480
pii: 10/2/e200072
doi: 10.1212/NXI.0000000000200072
pmc: PMC9720732
pii:
doi:

Substances chimiques

Osteopontin 106441-73-0
NOD2 protein, human 0
Nod2 Signaling Adaptor Protein 0
SPP1 protein, human 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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Auteurs

Noemí de Luna (N)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

Álvaro Carbayo (Á)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

Oriol Dols-Icardo (O)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

Janina Turon-Sans (J)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

David Reyes-Leiva (D)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

Ignacio Illan-Gala (I)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

Ivonne Jericó (I)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

Inma Pagola-Lorz (I)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

Cinta Lleixà (C)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

Luis Querol (L)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

Sara Rubio-Guerra (S)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

Daniel Alcolea (D)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

Juan Fortea (J)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

Alberto Lleó (A)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

Elena Cortés-Vicente (E)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.).

Ricardo Rojas-Garcia (R)

From the Neuromuscular Diseases Laboratory (N.d.C., A.C., D.R.-L., C.L., L.Q., E.C.-V., R.R.-G.), Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIB Sant-Pau), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (N.d.C., A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Madrid; Motor Neuron Diseases Clinic (A.C., J.T.-S., D.R.-L., L.Q., E.C.-V., R.R.-G.), Neuromuscular Diseases Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Departament de Medicina, Universitat Autònoma de Barcelona; Sant Pau Memory Unit (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Department of Neurology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (O.D.-I., I.I.-G., S.R.-G., D.A., J.F., A.L.), Madrid, Spain; and Neuromuscular and Motor Neuron Diseases Research Group-Health Research Institute of Navarra (IdisNA) (I.J., I.P.-L.). rrojas@santpau.cat.

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