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Original Investigation
December 3, 2018

Association of Cerebrospinal Fluid Neurofilament Light Protein Levels With Cognition in Patients With Dementia, Motor Neuron Disease, and Movement Disorders

Author Affiliations
  • 1Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
  • 2Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  • 3Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
  • 4Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology, London, United Kingdom
  • 5United Kingdom Dementia Research Institute, London, United Kingdom
  • 6Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia
  • 7Parkinson’s Disease Research, Education and Cinical Centers, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania
  • 8Mental Illness Research, Education and Cinical Centers, Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania
  • 9Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia
  • 10Department of Neurology, Houston Methodist Hospital, Houston, Texas
JAMA Neurol. 2019;76(3):318-325. doi:10.1001/jamaneurol.2018.3746
Key Points

Question  Is cerebrospinal fluid neurofilament light (CSF NFL) a general marker of neurodegeneration, and is it associated with disease progression?

Findings  In this study, there was a stepwise increase in CSF NFL protein concentration between control participants, participants with mild cognitive impairment, and those with Alzheimer disease, and a correlation with annual decreases in Mini-Mental State Examination scores in individuals with Alzheimer disease, frontotemporal dementia, and the cohort overall. Levels of CSF NFL were higher in patients with all forms of dementia, with the highest levels in frontotemporal dementia, amyotrophic lateral sclerosis, and atypical parkinsonian disorders.

Meaning  Concentration of CSF NFL is a general marker of neurodegeneration and is associated with cognitive decline in Alzheimer disease and frontotemporal dementia; the most pronounced alterations are seen in frontotemporal dementia, amyotrophic lateral sclerosis, and atypical parkinsonian disorders.


Importance  Neuronal and axonal destruction are hallmarks of neurodegenerative diseases, but it is difficult to estimate the extent and progress of the damage in the disease process.

Objective  To investigate cerebrospinal fluid (CSF) levels of neurofilament light (NFL) protein, a marker of neuroaxonal degeneration, in control participants and patients with dementia, motor neuron disease, and parkinsonian disorders (determined by clinical criteria and autopsy), and determine its association with longitudinal cognitive decline.

Design, Setting, and Participants  In this case-control study, we investigated NFL levels in CSF obtained from controls and patients with several neurodegenerative diseases. Collection of samples occurred between 1996 and 2014, patients were followed up longitudinally for cognitive testing, and a portion were autopsied in a single center (University of Pennsylvania). Data were analyzed throughout 2016.

Exposures  Concentrations of NFL in CSF.

Main Outcomes and Measures  Levels of CSF NFL and correlations with cognition scores.

Results  A total of 913 participants (mean [SD] age, 68.7 [10.0] years; 456 [49.9%] women) were included: 75 control participants plus 114 patients with mild cognitive impairment (MCI), 397 with Alzheimer disease, 96 with frontotemporal dementia, 68 with amyotrophic lateral sclerosis, 41 with Parkinson disease (PD), 19 with PD with MCI, 29 with PD dementia, 33 with dementia with Lewy bodies, 21 with corticobasal syndrome, and 20 with progressive supranuclear palsy. Cognitive testing follow-up occurred for 1 to 18 years (mean [SD], 0.98 [2.25] years); autopsy-verified diagnoses were available for 120 of 845 participants with diseases (14.2%). There was a stepwise increase in CSF NFL levels between control participants (median [range] score, 536 [398-777] pg/mL), participants with MCI (831 [526-1075] pg/mL), and those with Alzheimer disease (951 [758-1261] pg/mL), indicating that NFL levels increase with increasing cognitive impairment. Levels of NFL correlated inversely with baseline Mini-Mental State Examination scores (ρ, −0.19; P < .001) in the full cohort (n = 822) and annual score decline in the full cohort (ρ, 0.36, P < .001), participants with AD (ρ, 0.25; P < .001), and participants with FTD (ρ, 0.46; P = .003). Concentrations of NFL were highest in participants with amyotrophic lateral sclerosis (median [range], 4185 [2207-7453] pg/mL) and frontotemporal dementia (2094 [230-7744] pg/mL). In individuals with parkinsonian disorders, NFL concentrations were highest in those with progressive supranuclear palsy (median [range], 1578 [1287-3104] pg/mL) and corticobasal degeneration (1281 [828-2713] pg/mL). The NFL concentrations in CSF correlated with TDP-43 load in 13 of 17 brain regions in the full cohort. Adding NFL to β-amyloid 42, total tau, and phosphorylated tau increased accuracy of discrimination of diseases.

Conclusions and Relevance  Levels of CSF NFL are associated with cognitive impairments in patients with Alzheimer disease and frontotemporal dementia. In other neurodegenerative disorders, NFL levels appear to reflect the intensity of the neurodegenerative processes.