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March 2023; 10 (2) Research ArticleOpen Access

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

Noemí de Luna, Álvaro Carbayo, Oriol Dols-Icardo, Janina Turon-Sans, David Reyes-Leiva, Ignacio Illan-Gala, Ivonne Jericó, Inma Pagola-Lorz, Cinta Lleixà, Luis Querol, Sara Rubio-Guerra, Daniel Alcolea, Juan Fortea, Alberto Lleó, Elena Cortés-Vicente, Ricardo Rojas-Garcia
First published December 2, 2022, DOI: https://doi.org/10.1212/NXI.0000000000200072
Noemí de Luna
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.).
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Álvaro Carbayo
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.).
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Oriol Dols-Icardo
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.).
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Janina Turon-Sans
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.).
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David Reyes-Leiva
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.).
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Ignacio Illan-Gala
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.).
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Ivonne Jericó
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.).
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Inma Pagola-Lorz
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.).
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Cinta Lleixà
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.).
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Luis Querol
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.).
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Sara Rubio-Guerra
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.).
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Daniel Alcolea
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.).
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Juan Fortea
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.).
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Alberto Lleó
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.).
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Elena Cortés-Vicente
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.).
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Ricardo Rojas-Garcia
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.).
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Full PDF
Citation
Neuroinflammation-Related Proteins NOD2 and Spp1 Are Abnormally Upregulated in Amyotrophic Lateral Sclerosis
Noemí de Luna, Álvaro Carbayo, Oriol Dols-Icardo, Janina Turon-Sans, David Reyes-Leiva, Ignacio Illan-Gala, Ivonne Jericó, Inma Pagola-Lorz, Cinta Lleixà, Luis Querol, Sara Rubio-Guerra, Daniel Alcolea, Juan Fortea, Alberto Lleó, Elena Cortés-Vicente, Ricardo Rojas-Garcia
Neurol Neuroimmunol Neuroinflamm Mar 2023, 10 (2) e200072; DOI: 10.1212/NXI.0000000000200072

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Abstract

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 (p < 0.05). NOD2 and Spp1 levels were significantly higher in sera from patients with ALS than in HCs (p < 0.001). Receiver operating characteristic analysis showed an area under the curve of 0.63 for NOD2 and 0.81 for Spp1. NOD2 levels were significantly lower in patients with AD and FTD than in patients with ALS (p < 0.0001), but we found no significant differences in Spp1 levels between patients with ALS, AD (p = 0.51), and FTD (p = 0.42). We found a negative correlation between Spp1 levels and ALS functional rating scale (r = −0.24, p = 0.009).

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.

Glossary

AD=
Alzheimer disease;
ALS=
amyotrophic lateral sclerosis;
ALSFRS-R=
ALS functional rating scale;
AUC=
area under the curve;
bvFTD=
behavioral variant of frontotemporal dementia;
DAMPs=
danger-associated molecular patterns;
ELISA=
Enzyme-Linked Immunosorbent Assays;
FTD=
frontotemporal dementia;
FUS=
fused in sarcoma;
HCs=
healthy controls;
IFN=
interferon;
MAVS=
mitochondrial antiviral signaling;
MNDs=
motor neuron diseases;
NLRs=
nucleotide-binding domain leucine-rich repeat-containing receptors;
NOD2=
nucleotide-binding oligomerization domain–containing protein 2;
PAMPs=
pathogen-associated molecular patterns;
RIG-I=
retinoic acid–inducible gene I;
ROC=
receiver operating characteristic;
SPIN=
Sant Pau Initiative on Neurodegeneration;
TAR=
transactivating response;
TDP-43=
TAR DNA binding protein–43

Footnotes

  • ↵* These authors contributed equally to this work.

  • Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by Fondo de Investigación Sanitaria (FIS), ISCIII (PI15/01618 and PI 19/01543).

  • Submitted and externally peer reviewed. The handling editor was Josep O. Dalmau, MD, PhD, FAAN.

  • Received July 12, 2022.
  • Accepted in final form October 13, 2022.
  • Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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