Brkušanin, Miloš (55659956500)Miloš (55659956500)BrkušaninKosać, Ana (55786067800)Ana (55786067800)KosaćBranković-Srećković, Vesna (6505942755)Vesna (6505942755)Branković-SrećkovićJovanović, Kristina (57201635836)Kristina (57201635836)JovanovićPerić, Stojan (35750481700)Stojan (35750481700)PerićKaranović, Jelena (56055635600)Jelena (56055635600)KaranovićMatijašević Joković, Suzana (58962228300)Suzana (58962228300)Matijašević JokovićGarai, Nemanja (58998128000)Nemanja (58998128000)GaraiPešović, Jovan (15725996300)Jovan (15725996300)PešovićNikolić, Dimitrije (8279362600)Dimitrije (8279362600)NikolićStević, Zorica (57204495472)Zorica (57204495472)StevićBrajušković, Goran (55508235500)Goran (55508235500)BrajuškovićMilić-Rašić, Vedrana (6507653181)Vedrana (6507653181)Milić-RašićSavić-Pavićević, Dušanka (18435454500)Dušanka (18435454500)Savić-Pavićević2025-07-022025-07-022024https://doi.org/10.3389/fneur.2024.1394001https://www.scopus.com/inward/record.uri?eid=2-s2.0-85193506851&doi=10.3389%2ffneur.2024.1394001&partnerID=40&md5=3daa3f29010c0b61f88c2ee98ec4e33bhttps://remedy.med.bg.ac.rs/handle/123456789/11672Introduction: 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. Copyright © 2024 Brkušanin, Kosać, Branković-Srećković, Jovanović, Perić, Karanović, Matijašević Joković, Garai, Pešović, Nikolić, Stević, Brajušković, Milić-Rašić and Savić-Pavićević.antisense oligonucleotidebiomarkercerebrospinal fluidNusinersenphosphorylated neurofilament heavy chain (pNFH)spinal muscular atrophy