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 10 059 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.

1st Faculty of Medicine Institute of Medical Biochemistry Prague Czech Republic

3rd Faculty of Medicine Department of Neurology Charles University and General University Hospital Prague Czech Republic

Alzheimer Centre and Department of Neurology Erasmus Medical Centre Rotterdam the Netherlands

Barts Health NHS Trust Barts United Kingdom

Clinical Memory Research Unit Department of Clinical Sciences Faculty of Medicine Lund University Lund Sweden

Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden

Dementia Research Centre UCL Institute of Neurology Queen Square London United Kingdom

Dementia Research Institute at UCL London United Kingdom

Department of Basic Medical Sciences Neurosciences and Sense Organs University of Bari Bari Italy

Department of Biomedical and Specialist Surgical Sciences University of Ferrara Ferrara Italy

Department of Biomedical Sciences Reference Centre for Biological Markers of Dementia Institute Born Bunge University of Antwerp Antwerp Belgium

Department of Biomedicine Aarhus University Aarhus Denmark

Department of Clinical Genetics VU University Medical Centre Amsterdam the Netherlands

Department of Clinical Immunology Copenhagen University Hospital Righospitalet Copenhagen Denmark

Department of Clinical Sciences Karolinska Institutet Danderyd Hospital Stockholm Sweden

Department of Endocrinology Sahlgrenska University Hospital Gothenburg Sweden

Department of Epidemiology and Biostatistics VU University Medical Centre Amsterdam the Netherlands

Department of Infectious Diseases Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Department of Internal Medicine and Clinical Nutrition Institute of Medicine Sahlgrenska Academy at the University of Gothenburg

Department of Laboratory Medicine Radboud Alzheimer Centre Nijmegen the Netherlands

Department of Mathematics VU University Amsterdam the Netherlands

Department of Medicine University Hospital and University of Basel Basel Switzerland

Department of Molecular Neuroscience UCL Institute of Neurology Queen Square London United Kingdom

Department of Neurology and Alzheimer Centre VU University Medical Centre Neuroscience Campus Amsterdam Amsterdam the Netherlands

Department of Neurology China Medical University Hospital Taichung City Taiwan

Department of Neurology Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Neurology Faculty of Medicine and Health Orebro University Hospital Orebro Sweden

Department of Neurology Karolinska University Hospital Stockholm Sweden

Department of Neurology Medical University of Graz Graz Austria

Department of Neuroscience Uppsala University Uppsala Sweden

Department of Neurosurgery Kuopio University Hospital Kuopio Finland

Department of Pharmacology and Clinical Neuroscience Umeå University Umeå Sweden

Department of Psychiatry and Neuropsychology School for Mental Health and Neuroscience Alzheimer Centre Limburg Maastricht University Maastricht the Netherlands

Department of Psychological Science and Neuroscience Program Belmont University Nashville Tennessee

Division of Infectious Diseases University of California San Diego

Evotec AG Manfred Eigen Campus Hamburg Germany

Immunology Department Ramon y Cajal University Hospital Madrid Spain

Institute of Cell and Molecular Medicine Barts United Kingdom

Institute of Clinical Medicine Neurosurgery University of Eastern Finland Kuopio

Institute of Neuroscience and Physiology Department of Psychiatry and Neurochemistry Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden

Laboratory Diagnostics Charles University and General University Hospital Prague Czech Republic

London School of Medicine and Dentistry Barts United Kingdom

Memory and Aging Center Department of Neurology University of California San Francisco

Multiple Sclerosis Unit Ramon y Cajal University Hospital Madrid Spain

National Institute of Mental Health Klecany Czech Republic

Neurochemistry Laboratory Department of Clinical Chemistry VU University Medical Centre Neuroscience Campus Amsterdam Amsterdam the Netherlands

Neuroimmunology Unit Department of Clinical Neurosciences Karolinska Institutet Stockholm Sweden

North East London and Essex MND Care Centre Neuroscience and Trauma Centre Blizard United Kingdom

Nuffield Department of Clinical Neurosciences University of Oxford Oxford United Kingdom

Pia Fondazione Cardinale G Panico Tricase Lecce Italy

Puerto Rico OMICS Centre University of Puerto Rico Comprehensive Cancer Centre San Juan

Radboud University Medical Centre Donders Institute for Brain Cognition and Behaviour Department of Neurology Nijmegen the Netherlands

Reta Lila Weston Institute of Neurological Studies UCL Institute of Neurology Queen Square London United Kingdom

San Camillo Forlanini Hospital Rome Italy

UCL Institute of Neurology Queen Square London United Kingdom

Unit of Neurodegenerative Diseases Department of Clinical Research in Neurology University of Bari Bari Italy

Wallenberg Center for Molecular Medicine Lund University Lund Sweden

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Alzheimer disease seen through the lens of sex and gender

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