Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology: A Systematic Review and Meta-analysis

Bridel, C.; Van Wieringen, W. N.; Zetterberg, H.; Tijms, B. M.; Teunissen, C. E.; Alvarez-Cermeno, J. C.; Andreasson, U.; Axelsson, M.; Backstrom, D. C.; Bartos, A.; Bjerke, M.; Blennow, K.; Boxer, A.; Brundin, L.; Burman, J.; Christensen, T.; Fialova, L.; Forsgren, L.; Frederiksen, J. L.; Gisslen, M.; Gray, E.; Gunnarsson, M.; Hall, S.; Hansson, O.; Herbert, M. K.; Jakobsson, J.; Jessen-Krut, J.; Janelidze, S.; Johannsson, G.; Jonsson, M.; Kappos, L.; Khademi, M.; Khalil, M.; Kuhle, J.; Landen, M.; Leinonen, V.; Logroscino, G.; C. -H., Lu; Lycke, J.; Magdalinou, N. K.; Malaspina, A.; Mattsson, N.; Meeter, L. H.; Mehta, S. R.; Modvig, S.; Olsson, T.; Paterson, R. W.; Perez-Santiago, J.; Piehl, F.; Pijnenburg, Y. A. L.; Pyykko, O. T.; Ragnarsson, O.; Rojas, J. C.; Romme Christensen, J.; Sandberg, L.; Scherling, C. S.; Schott, J. M.; Sellebjerg, F. T.; Simone, I. L.; Skillback, T.; Stilund, M.; Sundstrom, P.; Svenningsson, A.; Tortelli, R.; Tortorella, C.; Trentini, A.; Troiano, M.; Turner, M. R.; Van Swieten, J. C.; Vagberg, M.; Verbeek, M. M.; Villar, L. M.; Visser, P. J.; Wallin, A.; Weiss, A.; Wikkelso, C.; Wild, E. J.

doi:10.1001/jamaneurol.2019.1534

Importance: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date. Objectives: To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions. Data Sources: PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC. Study Selection: Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex. Data Extraction and Synthesis: Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept. Main Outcome and Measure: The cNfL levels adjusted for age and sex across diagnoses. Results: Data were collected for 10059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes. Conclusions and Relevance: These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.