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Diagnostic and Prognostic Value of Blood and Cerebrospinal Fluid Biomarkers in Amyotrophic Lateral Sclerosis : A Systematic Review and Meta-Analysis

Obara, Kazuki LU orcid ; Ito, Daisuke LU ; Nilsson, Christer ; Janelidze, Shorena LU ; Santillo, Alexander LU orcid ; Katsuno, Masahisa LU and Mattsson-Carlgren, Niklas LU orcid (2025) In European Journal of Neurology 32(10). p.1-17
Abstract

BACKGROUND: Reliable biomarkers for amyotrophic lateral sclerosis (ALS) are urgently needed due to diagnostic and prognostic challenges. This systematic review and meta-analysis aimed to synthesize recent evidence on the utility of blood and cerebrospinal fluid (CSF) biomarkers for ALS.

METHODS: We systematically reviewed studies published from January 1, 2019 to March 25, 2025, that evaluated blood or CSF biomarkers for ALS. Eligible studies reported diagnostic performance, group-level biomarker values, hazard ratios (HRs) for survival, or correlations with functional rating scales or disease progression rates. Study quality was assessed using the QUADAS-2 and QUIPS frameworks. Random-effects models were employed to pool summary... (More)

BACKGROUND: Reliable biomarkers for amyotrophic lateral sclerosis (ALS) are urgently needed due to diagnostic and prognostic challenges. This systematic review and meta-analysis aimed to synthesize recent evidence on the utility of blood and cerebrospinal fluid (CSF) biomarkers for ALS.

METHODS: We systematically reviewed studies published from January 1, 2019 to March 25, 2025, that evaluated blood or CSF biomarkers for ALS. Eligible studies reported diagnostic performance, group-level biomarker values, hazard ratios (HRs) for survival, or correlations with functional rating scales or disease progression rates. Study quality was assessed using the QUADAS-2 and QUIPS frameworks. Random-effects models were employed to pool summary receiver operating characteristic (SROC) curves, HRs, standardized mean differences, and correlation coefficients.

RESULTS: We included 47 studies in the SROC analysis and 27 in the HR analysis, covering 9078 participants (5556 ALS and 3522 controls). Neurofilament light chain (NfL) consistently demonstrated the highest diagnostic accuracy (sensitivity/specificity: 0.81-0.87 vs. ALS mimics) and high prognostic value (pooled HRs: 2.8-4.3) in both blood and CSF. CSF chitinases and the p-tau/t-tau ratio showed moderate utility. Other biomarkers, including interleukins, had limited clinical relevance. Most studies showed moderate to high risk of bias, with methodological heterogeneity and limited transparency.

CONCLUSIONS: NfL is the most validated biomarker for ALS diagnosis and prognosis, in both blood and CSF. However, its limited accuracy when used alone carries a considerable risk of misclassification. Future studies should adopt prevalence-specific strategies and integrate biomarkers within multimodal frameworks to enhance diagnostic and prognostic precision.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Amyotrophic Lateral Sclerosis/cerebrospinal fluid, Biomarkers/cerebrospinal fluid, Prognosis, Neurofilament Proteins/cerebrospinal fluid
in
European Journal of Neurology
volume
32
issue
10
article number
e70382
pages
1 - 17
publisher
Wiley-Blackwell
external identifiers
  • pmid:41140053
ISSN
1351-5101
DOI
10.1111/ene.70382
project
Fluid biomarkers for Diagnosis, Prognosis and Monitoring of Amyotrophic Lateral Sclerosis
language
English
LU publication?
yes
additional info
© 2025 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
id
9595327e-d77c-4790-9694-2128af120009
date added to LUP
2025-10-27 21:37:01
date last changed
2025-10-28 07:21:35
@article{9595327e-d77c-4790-9694-2128af120009,
  abstract     = {{<p>BACKGROUND: Reliable biomarkers for amyotrophic lateral sclerosis (ALS) are urgently needed due to diagnostic and prognostic challenges. This systematic review and meta-analysis aimed to synthesize recent evidence on the utility of blood and cerebrospinal fluid (CSF) biomarkers for ALS.</p><p>METHODS: We systematically reviewed studies published from January 1, 2019 to March 25, 2025, that evaluated blood or CSF biomarkers for ALS. Eligible studies reported diagnostic performance, group-level biomarker values, hazard ratios (HRs) for survival, or correlations with functional rating scales or disease progression rates. Study quality was assessed using the QUADAS-2 and QUIPS frameworks. Random-effects models were employed to pool summary receiver operating characteristic (SROC) curves, HRs, standardized mean differences, and correlation coefficients.</p><p>RESULTS: We included 47 studies in the SROC analysis and 27 in the HR analysis, covering 9078 participants (5556 ALS and 3522 controls). Neurofilament light chain (NfL) consistently demonstrated the highest diagnostic accuracy (sensitivity/specificity: 0.81-0.87 vs. ALS mimics) and high prognostic value (pooled HRs: 2.8-4.3) in both blood and CSF. CSF chitinases and the p-tau/t-tau ratio showed moderate utility. Other biomarkers, including interleukins, had limited clinical relevance. Most studies showed moderate to high risk of bias, with methodological heterogeneity and limited transparency.</p><p>CONCLUSIONS: NfL is the most validated biomarker for ALS diagnosis and prognosis, in both blood and CSF. However, its limited accuracy when used alone carries a considerable risk of misclassification. Future studies should adopt prevalence-specific strategies and integrate biomarkers within multimodal frameworks to enhance diagnostic and prognostic precision.</p>}},
  author       = {{Obara, Kazuki and Ito, Daisuke and Nilsson, Christer and Janelidze, Shorena and Santillo, Alexander and Katsuno, Masahisa and Mattsson-Carlgren, Niklas}},
  issn         = {{1351-5101}},
  keywords     = {{Humans; Amyotrophic Lateral Sclerosis/cerebrospinal fluid; Biomarkers/cerebrospinal fluid; Prognosis; Neurofilament Proteins/cerebrospinal fluid}},
  language     = {{eng}},
  month        = {{10}},
  number       = {{10}},
  pages        = {{1--17}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{European Journal of Neurology}},
  title        = {{Diagnostic and Prognostic Value of Blood and Cerebrospinal Fluid Biomarkers in Amyotrophic Lateral Sclerosis : A Systematic Review and Meta-Analysis}},
  url          = {{http://dx.doi.org/10.1111/ene.70382}},
  doi          = {{10.1111/ene.70382}},
  volume       = {{32}},
  year         = {{2025}},
}