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Review
. 2016 Oct 12;11(10):e0164625.
doi: 10.1371/journal.pone.0164625. eCollection 2016.

Neurofilaments as Biomarkers for Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis

Zhouwei Xu  1 , Robert David Henderson  2 , Michael David  3 , Pamela Ann McCombe  1
Affiliations
Review

Neurofilaments as Biomarkers for Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis

Zhouwei Xu et al. PLoS One. .

Abstract

Background: To allow early diagnosis and monitoring of disease progression, there is a need for biomarkers in amyotrophic lateral sclerosis (ALS). Neurofilaments (NF) are emerging protein biomarkers in other neurological diseases, and are of possible use in ALS.

Objective: The aim of this study is to evaluate the utility of NF levels as blood or cerebrospinal fluid (CSF) biomarker in patients with ALS.

Methods: A systematic search of Pubmed, Embase and Scopus was performed. Methodological quality assessment was applied to refine the final search results. Meta-analysis of the data was performed.

Results: Level of NF heavy chain and light chains were significantly elevated in the CSF of ALS patients compared to healthy controls/controls without parenchymal central nervous system (CNS) involvement and ALS mimic disease patients. NF light chain level in CSF was higher in ALS patients than in neurological patients with CNS involvement (SMD = 1.352, P = 0.01). NF light chain concentration in blood was higher in ALS patients than healthy controls/controls without CNS involvement (SMD = 1.448, P<0.0001). NF heavy chain levels in CSF were negatively correlated disease duration and ALSFRS-R ((r = -0.447, P<0.0001; r = -0.486, P<0.0001). NF light chain levels in CSF were negatively correlated with disease duration (r = -0.273, P = 0.011).

Conclusion: NF heavy and light chain levels have potential use as a marker of neural degeneration in ALS, but are not specific for the disease, and are more likely to be used as measures of disease progression.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. PRISMA Flow diagram.
Flow diagram of systematic search in the 3 databases. After removal of duplicates, reviews and quality control, 20 papers were suitable for analysis.
Fig 2
Fig 2. NFH CSF ALS-healthy.
Meta-analysis of NFH levels in CSF between ALS patients and healthy controls/controls without parenchymal CNS disease. The random effect model was used. There was a highly significant difference between the two groups (P <0.0001).
Fig 3
Fig 3. NFH CSF ALS-mimics.
Meta-analysis of NFH levels in CSF between ALS patients and ALS mimics. The random effect was applied. There was a significant difference between the two groups (P = 0.013).
Fig 4
Fig 4. NFH CSF ALS-CNS disease.
Meta-analysis of NFH levels in CSF between ALS patients and other neurological disease with CNS involvement. The random effect model was used. There is no significant difference between the two groups (P = 0.075).
Fig 5
Fig 5. NFH Blood ALS-healthy.
Meta-analysis of NFH levels in blood between ALS patients and healthy controls /controls without parenchymal CNS disease. The random effect model was applied. There is no significant difference between the two groups (P = 0.068).
Fig 6
Fig 6. NFL CSF ALS-healthy.
Meta-analysis of NFL levels in CSF between ALS patients and healthy controls/controls without parenchymal CNS disease. The random effect model was applied. There is significant difference between the two groups (P <0.0001).
Fig 7
Fig 7. NFL ALS-mimic.
Meta-analysis of NFL levels in CSF between ALS patients and ALS mimics. Because the I2 = 0, the fixed effect model was applied. There is significant difference between the two groups (P<0.0001).
Fig 8
Fig 8. NFL CSF ALS-CNS disease.
Meta-analysis of NFL levels in CSF between ALS patients and other neurological disease with CNS involvement. The random effect model was applied. There is significant difference between the two groups (P = 0.001).
Fig 9
Fig 9. NFL blood ALS-healthy.
Meta-analysis of NFL levels in blood between ALS patients and healthy controls/controls without parenchymal CNS disease. The fixed effect model was applied. There is significant difference between the two groups (P< 0.0001).
Fig 10
Fig 10. CSF NFH and disease duration.
Meta-analysis of correlation between CSF NFH and disease duration. The fixed effect model was applied. There is significant negative correlation between two variables (P< 0.0001).
Fig 11
Fig 11. CSF NFL and disease duration.
Meta-analysis of correlation between CSF NFL and disease duration. The random effect model was applied. There is significant negative correlation between two variables (P< 0.0001).
Fig 12
Fig 12. CSF NFH and ALSFRS-R.
Meta-analysis of correlation between CSF NFH and ALSFRS-R. The random effect model was applied. There is significant negative correlation between two variables (P = 0.011).
Fig 13
Fig 13. CSF NFL and ALSFRS-R.
Meta-analysis of correlation between CSF NFL and ALSFRS-R. The random effect model was applied. There is no significant negative correlation between two variables (P = 0.156).
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Grants and funding

The first author Zhouwei Xu's PhD scholarship was funded by the Chinese scholarship council.