Neurofilaments in Amyotrophic Lateral Sclerosis: A Systemic Review and Meta-analysis
Pashtun-Poh Shahim1, Gina Norato1, Henrik Zetterberg2, Kaj Blennow3, Leighton Chan1, Christopher Grunseich1
1National Institutes of Health, 2Sahlgrenska University Hospital/Molndal, 3Sahlgrenska Academy at University of Gothenburg
Objective:
The objectives of this study were to assess the diagnostic and prognostic utility of neurofilaments in amyotrophic lateral sclerosis (ALS).
Background:
Neurofilament proteins have been implicated to be altered in ALS.
Design/Methods:
Studies in electronic databases (PubMed/MEDLINE, Embase, Web of Science, and Cochrane CENTRAL) from inception to August 17, 2023 which investigated neurofilament light (NfL) or phosphorylated neurofilament heavy chain (pNfH) in ALS and were assessed by two reviewers. Study design, enrolment criteria, neurofilament concentrations, test accuracy, relationship between neurofilaments in CSF and blood, and clinical outcome were recorded.
Results:
Sixty studies with 8801 participants were included. CSF NfL exhibited AUC of 0.92 and sensitivity of 0.87 (95% CI, 083 to 0.89) and specificity of 0.84 (95% CI, 0.77 to 0.89) in distinguishing ALS from disease mimics. Similarly, CSF pNfH exhibited AUC of 0.91 and sensitivity of 0.84 (95% CI, 0.78 to 0.88) and specificity of 0.86 (95% CI, 0.76 to 0.92) in distinguishing ALS from disease mimics. CSF NfL correlated with corresponding levels in blood (r=0.78 [95% CI, 0.72 to 0.83]), while the correlation between CSF and serum levels of pNfH was lower (r=0.65 [95% CI, 0.54 to 0.74]). Blood NfL exhibited sensitivity of 0.91 (95% CI, 0.88 to 0.93) and specificity of 0.89 (95% CI, 0.81 to 0.94) in distinguishing ALS from controls. Higher blood NfL levels were associated with more severe symptoms assessed by the ALS Functional Rating Scale Revised score (r=-0.31 [95% CI, -0.40 to -0.22]), faster disease progression rate (r=0.46 [95% CI, 0.42 to 0.51]), and shorter survival (HR=3.89 [95% CI, 2.91 to 5.19]).
Conclusions:
Both NfL and pNfH measured in CSF or blood show high diagnostic utility and association with ALS functional scores, while NfL is also associated and measures of disease progression, supporting its use in clinical diagnostics and management.