학술논문
Phosphorylated neurofilament heavy chain in cerebrospinal fluid and plasma as a Nusinersen treatment response marker in childhood-onset SMA individuals from Serbia.
Document Type
Academic Journal
Author
Brkušanin M; Faculty of Biology, Centre for Human Molecular Genetics, University of Belgrade, Belgrade, Serbia.; Kosać A; Clinic for Neurology and Psychiatry for Children and Youth, Belgrade, Serbia.; Branković-Srećković V; Clinic for Neurology and Psychiatry for Children and Youth, Belgrade, Serbia.; Jovanović K; University Children's Hospital Tirsova, University Clinical Centre of Serbia, Belgrade, Serbia.; Perić S; Neurology Clinic, University Clinical Centre of Serbia, Belgrade, Serbia.; Karanović J; Faculty of Biology, Centre for Human Molecular Genetics, University of Belgrade, Belgrade, Serbia.; Matijašević Joković S; Faculty of Biology, Centre for Human Molecular Genetics, University of Belgrade, Belgrade, Serbia.; Garai N; Faculty of Biology, Centre for Human Molecular Genetics, University of Belgrade, Belgrade, Serbia.; Pešović J; Faculty of Biology, Centre for Human Molecular Genetics, University of Belgrade, Belgrade, Serbia.; Nikolić D; University Children's Hospital Tirsova, University Clinical Centre of Serbia, Belgrade, Serbia.; School of Medicine, University of Belgrade, Belgrade, Serbia.; Stević Z; Neurology Clinic, University Clinical Centre of Serbia, Belgrade, Serbia.; School of Medicine, University of Belgrade, Belgrade, Serbia.; Brajušković G; Faculty of Biology, Centre for Human Molecular Genetics, University of Belgrade, Belgrade, Serbia.; Milić-Rašić V; Clinic for Neurology and Psychiatry for Children and Youth, Belgrade, Serbia.; School of Medicine, University of Belgrade, Belgrade, Serbia.; Savić-Pavićević D; Faculty of Biology, Centre for Human Molecular Genetics, University of Belgrade, Belgrade, Serbia.
Source
Publisher: Frontiers Research Foundation Country of Publication: Switzerland NLM ID: 101546899 Publication Model: eCollection Cited Medium: Print ISSN: 1664-2295 (Print) Linking ISSN: 16642295 NLM ISO Abbreviation: Front Neurol Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
1664-2295
Abstract
Introduction: Biomarkers capable of reflecting disease onset and short- and long-term therapeutic effects in individuals with spinal muscular atrophy (SMA) are still an unmet need and phosphorylated neurofilament heavy chain (pNF-H) holds significant promise.
Methods: We conducted a longitudinal prospective study to evaluate pNF-H levels in the cerebrospinal fluid (CSF) and plasma of 29 individuals with childhood-onset SMA treated with Nuinersen (SMA type 1: n = 6, 2: n = 17, 3: n = 6). pNF-H levels before and during treatment were compared with the levels of controls ( n = 22), patients with Duchenne muscular dystrophy ( n = 17), myotonic dystrophy type 1 ( n = 11), untreated SMA individuals with chronic type 3 disease ( n = 8), and children with presymptomatic SMA ( n = 3).
Results: SMA type 1 showed the highest mean CSF pNF-H levels before treatment initiation. All Nusinersen-treated individuals (types 1, 2, and 3) showed significantly elevated mean baseline CSF pNF-H compared to controls, which inversely correlated with age at disease onset, age at first dose, disease duration and the initial CHOP INTEND result (SMA type 1 and 2). During 22 months of treatment, CSF pNF-H levels declined during loading doses, stabilizing at reduced levels from the initial maintenance dose in all individuals. Baseline plasma pNF-H levels in type 1 and 2 SMA were significantly increased compared to other cohorts and decreased notably in type 1 after 2 months of treatment and type 2 after 14 months. Conversely, SMA type 3, characterized by lower baseline pNF-H levels, did not show significant fluctuations in plasma pNF-H levels after 14 months of treatment.
Conclusion: Our findings suggest that CSF pNF-H levels in untreated SMA individuals are significantly higher than in controls and that monitoring of CSF pNF-H levels may serve as an indicator of rapid short-term treatment response in childhood-onset SMA individuals, irrespective of the subtype of the disease, while also suggesting its potential for assessing long-term suppression of neurodegeneration. Plasma pNF-H may serve as an appropriate outcome measure for disease progression and/or response to treatment in types 1 and 2 but not in type 3. Presymptomatic infants with SMA may show elevated pNF-H levels, confirming early neuronal degeneration.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Brkušanin, Kosać, Branković-Srećković, Jovanović, Perić, Karanović, Matijašević Joković, Garai, Pešović, Nikolić, Stević, Brajušković, Milić-Rašić and Savić-Pavićević.)
Methods: We conducted a longitudinal prospective study to evaluate pNF-H levels in the cerebrospinal fluid (CSF) and plasma of 29 individuals with childhood-onset SMA treated with Nuinersen (SMA type 1: n = 6, 2: n = 17, 3: n = 6). pNF-H levels before and during treatment were compared with the levels of controls ( n = 22), patients with Duchenne muscular dystrophy ( n = 17), myotonic dystrophy type 1 ( n = 11), untreated SMA individuals with chronic type 3 disease ( n = 8), and children with presymptomatic SMA ( n = 3).
Results: SMA type 1 showed the highest mean CSF pNF-H levels before treatment initiation. All Nusinersen-treated individuals (types 1, 2, and 3) showed significantly elevated mean baseline CSF pNF-H compared to controls, which inversely correlated with age at disease onset, age at first dose, disease duration and the initial CHOP INTEND result (SMA type 1 and 2). During 22 months of treatment, CSF pNF-H levels declined during loading doses, stabilizing at reduced levels from the initial maintenance dose in all individuals. Baseline plasma pNF-H levels in type 1 and 2 SMA were significantly increased compared to other cohorts and decreased notably in type 1 after 2 months of treatment and type 2 after 14 months. Conversely, SMA type 3, characterized by lower baseline pNF-H levels, did not show significant fluctuations in plasma pNF-H levels after 14 months of treatment.
Conclusion: Our findings suggest that CSF pNF-H levels in untreated SMA individuals are significantly higher than in controls and that monitoring of CSF pNF-H levels may serve as an indicator of rapid short-term treatment response in childhood-onset SMA individuals, irrespective of the subtype of the disease, while also suggesting its potential for assessing long-term suppression of neurodegeneration. Plasma pNF-H may serve as an appropriate outcome measure for disease progression and/or response to treatment in types 1 and 2 but not in type 3. Presymptomatic infants with SMA may show elevated pNF-H levels, confirming early neuronal degeneration.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2024 Brkušanin, Kosać, Branković-Srećković, Jovanović, Perić, Karanović, Matijašević Joković, Garai, Pešović, Nikolić, Stević, Brajušković, Milić-Rašić and Savić-Pavićević.)