Related Experiment Video
Updated: May 28, 2026
A High Throughput, Multiplexed and Targeted Proteomic CSF Assay to Quantify Neurodegenerative Biomarkers and Apolipoprotein E Isoforms Status
Published on: October 20, 2016
Longitudinal CSF and Serum Biomarker Dynamics in Tofersen-Treated SOD1-ALS: A Real-World Multicentre Cohort Study
Andrea Giordano1,2, Jessica Mandrioli3,4, Federica Cerri5
1Neurology 3-Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133 Milan, Italy.
Abstract:
Tofersen is a gene-targeted therapy for superoxide dismutase 1 (SOD1)-associated amyotrophic lateral sclerosis (ALS), but neurofilament light chain (NfL) may not fully capture the biological response to treatment. We performed a multicentre retrospective longitudinal study including 24 patients with SOD1-ALS treated with intrathecal tofersen at four Italian referral centres between 2022 and 2025. Cerebrospinal fluid (CSF) and serum biomarkers were assessed at baseline, month 3, month 6, and last available administration using single-molecule array assays to quantify NfL, glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCHL-1), and total Tau. NfL decreased after treatment initiation in both CSF and serum, providing the clearest pharmacodynamic signal. In contrast, CSF GFAP increased progressively over follow-up, while CSF total Tau and UCHL-1 rose mainly at later timepoints; serum GFAP, total Tau, and UCHL-1 also showed increases during follow-up. ALS Functional Rating Scale-Revised trajectories were broadly stable, whereas disease progression rate was lower at last follow-up than at baseline. Greater reductions in CSF NfL were observed in pathogenic versus uncertain SOD1 variants, and early serum NfL and UCHL-1 changes were associated with longer-term changes in disease progression. These findings suggest that longitudinal multi-analyte profiling may refine biological response stratification beyond NfL alone in tofersen-treated SOD1-ALS.
Insights
Tofersen treatment for SOD1-ALS shows decreased neurofilament light chain (NfL). Other biomarkers like GFAP, Tau, and UCHL-1 increased, suggesting multi-analyte profiling refines treatment response assessment beyond NfL alone.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Tofersen is a gene-targeted therapy for SOD1-ALS.
- Neurofilament light chain (NfL) is a biomarker for neurodegeneration, but may not fully reflect treatment response.
Purpose of the Study:
- To evaluate the longitudinal changes of multiple biomarkers in cerebrospinal fluid (CSF) and serum following tofersen treatment in SOD1-ALS patients.
- To assess if multi-analyte profiling offers a more comprehensive understanding of tofersen's biological effects compared to NfL alone.
Main Methods:
- Retrospective longitudinal study of 24 SOD1-ALS patients treated with intrathecal tofersen.
- CSF and serum biomarkers (NfL, GFAP, UCHL-1, Tau) were measured at baseline and follow-up visits using single-molecule array assays.
Main Results:
- CSF and serum NfL decreased after tofersen initiation, showing the clearest pharmacodynamic effect.
- CSF GFAP, Tau, and UCHL-1 increased progressively over time, as did serum GFAP, Tau, and UCHL-1.
- ALS Functional Rating Scale-Revised scores remained stable, and disease progression rate decreased.
- Greater NfL reduction was seen with pathogenic SOD1 variants; early NfL and UCHL-1 changes correlated with long-term disease progression.
Conclusions:
- Longitudinal multi-analyte biomarker profiling provides a more nuanced view of tofersen's biological response in SOD1-ALS.
- Combining NfL with GFAP, Tau, and UCHL-1 may improve the stratification of treatment response.
- These findings support the use of comprehensive biomarker panels in clinical trials and practice for SOD1-ALS.
