Thrombospondin-4 as potential cerebrospinal fluid biomarker for therapy response in pediatric spinal muscular atrophy.

CSF biomarker Clinical proteomics Spinal muscular atrophy THBS4 TSP4 Thrombospondin-4

Journal

Journal of neurology
ISSN: 1432-1459
Titre abrégé: J Neurol
Pays: Germany
ID NLM: 0423161

Informations de publication

Date de publication:
06 Sep 2024
Historique:
received: 31 05 2024
accepted: 27 08 2024
revised: 26 08 2024
medline: 6 9 2024
pubmed: 6 9 2024
entrez: 6 9 2024
Statut: aheadofprint

Résumé

Spinal muscular atrophy (SMA) as the second most common neurodegenerative disorder in childhood is characterized by the deficiency of survival of motor neuron (SMN) protein leading predominantly to degeneration of alpha motor neurons and consequently to progressive muscle weakness and atrophy. Besides some biomarkers like SMN2 copy number therapeutic biomarkers for SMA with known relevance for neuromuscular transmission are lacking. Here, we examined the potential of Thrombospondin-4 (TSP4) to serve as a cerebrospinal fluid (CSF) biomarker, which may also indicate treatment response. We used untargeted proteomic analyses to determine biomarkers in CSF samples derived from pediatric pre-symptomatic (n = 6) and symptomatic (n = 4) SMA patients. The identified biomarker TSP4 was then validated in additional 68 CSF samples (9 adult and 24 pediatric SMA patients, 5 adult and 13 pediatric non-disease controls in addition to 17 pediatric disease controls) by enzyme-linked immunosorbent assay (ELISA) as an additional analytical approach. Untargeted proteomic analyses of CSF identified a dysregulation of TSP4 and revealed a difference between pre-symptomatic SMA patients and patients identified after the onset of first symptoms. Subsequent ELISA-analyses showed that TSP4 is decreased in pediatric but not adult SMA patients. CSF of pediatric patients with other neurological disorders demonstrated no alteration of TSP4 levels. Furthermore, CSF TSP4 levels of pediatric SMA patients increased after first dose of Nusinersen. We found that TSP4 levels are exclusively reduced in CSF of pediatric SMA patients and increase after treatment, leading us to the hypothesis that TSP4 could serve as a CSF biomarker with the potential to monitor treatment response in pediatric SMA patients. Moreover, TSP4 enable to distinguish pre-symptomatic and symptomatic patients suggesting a potential to serve as a stratification marker.

Sections du résumé

BACKGROUND AND PURPOSE OBJECTIVE
Spinal muscular atrophy (SMA) as the second most common neurodegenerative disorder in childhood is characterized by the deficiency of survival of motor neuron (SMN) protein leading predominantly to degeneration of alpha motor neurons and consequently to progressive muscle weakness and atrophy. Besides some biomarkers like SMN2 copy number therapeutic biomarkers for SMA with known relevance for neuromuscular transmission are lacking. Here, we examined the potential of Thrombospondin-4 (TSP4) to serve as a cerebrospinal fluid (CSF) biomarker, which may also indicate treatment response.
METHODS METHODS
We used untargeted proteomic analyses to determine biomarkers in CSF samples derived from pediatric pre-symptomatic (n = 6) and symptomatic (n = 4) SMA patients. The identified biomarker TSP4 was then validated in additional 68 CSF samples (9 adult and 24 pediatric SMA patients, 5 adult and 13 pediatric non-disease controls in addition to 17 pediatric disease controls) by enzyme-linked immunosorbent assay (ELISA) as an additional analytical approach.
RESULTS RESULTS
Untargeted proteomic analyses of CSF identified a dysregulation of TSP4 and revealed a difference between pre-symptomatic SMA patients and patients identified after the onset of first symptoms. Subsequent ELISA-analyses showed that TSP4 is decreased in pediatric but not adult SMA patients. CSF of pediatric patients with other neurological disorders demonstrated no alteration of TSP4 levels. Furthermore, CSF TSP4 levels of pediatric SMA patients increased after first dose of Nusinersen.
CONCLUSIONS CONCLUSIONS
We found that TSP4 levels are exclusively reduced in CSF of pediatric SMA patients and increase after treatment, leading us to the hypothesis that TSP4 could serve as a CSF biomarker with the potential to monitor treatment response in pediatric SMA patients. Moreover, TSP4 enable to distinguish pre-symptomatic and symptomatic patients suggesting a potential to serve as a stratification marker.

Identifiants

DOI: 10.1007/s00415-024-12670-0 PMID: 39240344
pubmed: 39240344
doi: 10.1007/s00415-024-12670-0
pii: 10.1007/s00415-024-12670-0
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

© 2024. The Author(s).

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Auteurs

Vera Dobelmann (V)

Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany.
ORCID: 0009-0003-9162-2517

Andreas Roos (A)

Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany.
Department of Pediatric Neurology, Developmental Neurology, and Social Pediatrics, Center for Neuromuscular Disorders in Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.
Children's Hospital of Eastern Ontario (CHEO) Research Institute, Ottawa, ON, K1H 5B2, Canada.

Andreas Hentschel (A)

Leibniz Institute of Analytical Sciences, ISAS, Dortmund, Germany.

Adela Della Marina (A)

Department of Pediatric Neurology, Developmental Neurology, and Social Pediatrics, Center for Neuromuscular Disorders in Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.

Markus Leo (M)

Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany.

Linda-Isabell Schmitt (LI)

Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany.

Lorenzo Maggi (L)

Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.

Ulrike Schara-Schmidt (U)

Department of Pediatric Neurology, Developmental Neurology, and Social Pediatrics, Center for Neuromuscular Disorders in Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.

Tim Hagenacker (T)

Department of Neurology, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany.

Tobias Ruck (T)

Department of Neurology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstr. 5, 40225, Duesseldorf, Germany. Tobias.Ruck@med.uni-duesseldorf.de.

Heike Kölbel (H)

Department of Pediatric Neurology, Developmental Neurology, and Social Pediatrics, Center for Neuromuscular Disorders in Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany. Heike.Koelbel@uk-essen.de.

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