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

Importance: Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared to healthy controls (HC), and is a candidate biomarker for neuro-axonal damage. The influence of sex and age is largely unknown, and levels across neurological disorders have not been compared systematically. Objective: To assess the effects of age, sex and diagnosis on CSF NfL (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 in neurological or psychiatric conditions and/or in HC. Study Selection: Studies reporting NfL levels measured in lumbar CSF using 139 a commercially available immuno-assay, as well as age and sex. Data Extraction and Synthesis: Participant-level data were requested from study authors. Generalized linear mixed effects models were used to estimate the fixed effects of diagnosis, age, and sex on log transformed NfL levels, with cohort of origin modelled as random intercept. The Preferred Reporting Items for Systematic Reviews and Meta-analyses recommendations were followed. Main Outcome and Measure: cNfL levels adjusted for age and sex across diagnoses. Results: Data were collected for 10,059 participants. Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n=2795), dementias (n=4284), parkinsonian disorders (n=984), bipolar disorder (n=133) and HC (n=1332). cNfL was elevated compared to HC in most neurological conditions. Highest levels were observed in cognitively impaired HIV positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% diagnoses including HC, multiple sclerosis, Alzheimer’s disease (AD), and PD, cNfL was higher in males than females. cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. cNfL overlapped in most clinically similar diagnoses except 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 biomarker of neuroaxonal damage, and indicate age- and sex-specific reference values may be needed. cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.