Blood and CSF Biomarkers in Amyotrophic Lateral Sclerosis: Diagnostic and Prognostic Insights from a Systematic Review and Meta-analysis

Aims: Identifying reliable biomarkers is crucial for addressing diagnostic uncertainty and prognostic stratification in amyotrophic lateral sclerosis (ALS). This systematic review and meta-analysis aimed to integrate recent evidence on blood and cerebrospinal fluid (CSF) biomarkers.

Methods: We searched studies published between January 1, 2019, and March 25, 2025, investigating blood or CSF biomarkers in ALS. Eligible studies reported diagnostic accuracy, biomarker concentrations, hazard ratios (HRs) for survival, or correlations with functional rating scales or progression rate. Random-effects models pooled summary ROC curves, HRs, standardized mean differences, and correlation coefficients. Simulation analyses illustrated predictive values under varying prevalence scenarios.

Results: Forty-seven studies contributed to the diagnostic meta-analysis and 27 to the prognostic analysis, including 5,556 ALS and 3,522 controls. Neurofilament light chain (NfL) consistently showed the highest diagnostic performance. NfL yielded ≈90% pooled sensitivity and specificity against neurologically healthy controls; 81–87% against ALS mimics. Simulations highlighted prevalence-dependent predictive values: assuming 90% sensitivity and specificity, the NPV was 99% at a 5% simulated prevalence in primary care, whereas the PPV was only 32%. Even at 25–50% simulated prevalence in secondary care, PPV remained moderate. For prognosis, elevated NfL was associated with poorer survival (pooled HRs 2.7–4.3 across blood and CSF). CSF chitinases and the p-tau/t-tau ratio showed moderate diagnostic and prognostic utility, whereas most other biomarkers showed heterogeneity.

Conclusions: Among fluid biomarkers, NfL demonstrated the highest diagnostic and prognostic value, but its accuracy is limited when used alone, particularly in low-prevalence contexts. Prospective studies with external validation and harmonized methodologies are needed to establish whether additional biomarkers can complement NfL and to support biomarker-guided clinical practice and trials.