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Review
. 2024 Apr 16;15(4):496.
doi: 10.3390/genes15040496.

Neurofilaments in Sporadic and Familial Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis

Pashtun Shahim  1   2   3   4   5 , Gina Norato  2 , Ninet Sinaii  6 , Henrik Zetterberg  7   8   9   10   11   12 , Kaj Blennow  7   8 , Leighton Chan  1 , Christopher Grunseich  2
Affiliations
Review

Neurofilaments in Sporadic and Familial Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis

Pashtun Shahim et al. Genes (Basel). .

Abstract

Background: Neurofilament proteins have been implicated to be altered in amyotrophic lateral sclerosis (ALS). The objectives of this study were to assess the diagnostic and prognostic utility of neurofilaments in ALS.

Methods: Studies were conducted in electronic databases (PubMed/MEDLINE, Embase, Web of Science, and Cochrane CENTRAL) from inception to 17 August 2023, and investigated neurofilament light (NfL) or phosphorylated neurofilament heavy chain (pNfH) in ALS. The study design, enrolment criteria, neurofilament concentrations, test accuracy, relationship between neurofilaments in cerebrospinal fluid (CSF) and blood, and clinical outcome were recorded. The protocol was registered with PROSPERO, CRD42022376939.

Results: Sixty studies with 8801 participants were included. Both NfL and pNfH measured in CSF showed high sensitivity and specificity in distinguishing ALS from disease mimics. Both NfL and pNfH measured in CSF correlated with their corresponding levels in blood (plasma or serum); however, there were stronger correlations between CSF NfL and blood NfL. NfL measured in blood exhibited high sensitivity and specificity in distinguishing ALS from controls. Both higher levels of NfL and pNfH either measured in blood or CSF were correlated with more severe symptoms as assessed by the ALS Functional Rating Scale Revised score and with a faster disease progression rate; however, only blood NfL levels were associated with shorter survival.

Discussion: Both NfL and pNfH measured in CSF or blood show high diagnostic utility and association with ALS functional scores and disease progression, while CSF NfL correlates strongly with blood (either plasma or serum) and is also associated with survival, supporting its use in clinical diagnostics and prognosis. Future work must be conducted in a prospective manner with standardized bio-specimen collection methods and analytical platforms, further improvement in immunoassays for quantification of pNfH in blood, and the identification of cut-offs across the ALS spectrum and controls.

Keywords: CSF; amyotrophic lateral sclerosis; blood; neurofilament light; phosphorylated neurofilament heavy chain.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Neurofilament structures and preferred reporting items for systematic reviews and meta-analyses: flow diagram. (A) Structure and assembly of neurofilaments with a length of ~60 nm and a diameter of ~10 nm. Neurofilament light chain (NfL), neurofilament medium chain (NfM), neurofilament heavy chain (NfH), and α internexin are the subunits of neurofilaments. All neurofilament subunits have a conserved α-helical rod domain comprising several coiled coils, and variable amino-terminal globular head regions and carboxy-terminal globular head regions and carboxy-terminal tail domains. NfM and NfH subunits have long carboxy-terminal domains with multiple Lys-Ser-Pro repeats that are heavily phosphorylated. The tail domains of NfM and NfH radiate outward from the filament core because of the negative charges from large numbers of glutamic acid and phosphorylated serine and threonine residues. E segment, glutamic-rich segment; E1, glutamic acid-rich segment 1; E2, glutamic acid-rich segment 2; KSP, lysine–serine–proline; SP, serine–proline; KE, lysine–glutamic acid; KEP, lysine–glutamic acid–proline. (B) Search strategy and records identified, as well as article exclusion following screening for eligibility.
Figure 2
Figure 2
Forest plots and receiver operating characteristic curves for the diagnostic accuracy of CSF neurofilament light chain and phosphorylated neurofilament heavy chain in ALS and controls and disease mimics. Forest plots of sensitivity, specificity, and summary receiver operating characteristics (SROCs) and their confidence intervals for (A) NfL and (B) pNfH distinguishing ALS from controls. Forest plots of sensitivity and SROCs and their confidence intervals for (C) NfL and (D) pNfH distinguishing ALS from mimics are presented. Each individual dot in the SROC represents a unique study. The orange diamond represents the summary estimate of sensitivity and false-positive rate (1-specificity), and the dotted circle represents the 95% confidence region. On top of each SROC, “n” represents the total number of participants in the analyses. Feneberg et al. [17]: early symptomatic ALS vs. controls. Feneberg et al. [17]: late symptomatic ALS vs. controls. Saracino et al. [35]: GRN patients vs. controls. Saracino et al. [35]: C9orf72 patients vs. controls.
Figure 3
Figure 3
Meta-analysis of correlations between CSF and blood neurofilaments. (A) Correlations between cerebrospinal fluid (CSF) and blood neurofilament light (NfL). (B) Correlations between CSF and serum phosphorylated neurofilament heavy chain (pNfH). All correlations were calculated using the Spearman’s rank method. Markers indicate estimates, with the size of the marker indicating weight; horizontal lines represent 95% CIs; diamonds represent summary estimates, with the outer points indicating 95% CIs.
Figure 4
Figure 4
Meta-analysis of CSF and blood neurofilaments and their associations with clinical markers of ALS functional score and disease progression. Correlation of NfL (A) and pNfH (B) measured in blood with ALS Functional Rating Scale (ALSFRS-R). Correlation of NfL (C) and pNfH (D) measured in blood with disease progression. All correlations were calculated using the Spearman’s rank method. Markers indicate estimates, with the size of the marker indicating weight; horizontal lines represent 95% CIs; diamonds represent summary estimates, with the outer points indicating 95% CIs.
Figure 5
Figure 5
Neurofilament and Survival. (A) Higher CSF or blood NfL (B) is associated with shorter survival in patients with ALS. (C) pNfH measured in CSF and survival time. (D) pNfH measured in serum and survival time.
Figure 6
Figure 6
Clinical trial sample size requirements based on neurofilaments. (A,B) Sample size requirements for a placebo-controlled clinical trial of a treatment aimed at reducing neurofilament levels in cases relative to controls. Sample sizes are plotted against potential treatment effectiveness (A) or effect size (Cohen’s d) estimates (B). The gray dashed vertical line indicates the 25% effectiveness level used in trials of drug intervention in other neurodegenerative diseases [34].
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