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

Abstract

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.

Figure 1.. Neurofilament Light Protein in Control Participants and Participants With Mild Cognitive Impairment, Dementias, and Amyotrophic Lateral Sclerosis

A, Cerebrospinal fluid levels of neurofilament light in control participants, participants with mild cognitive impairment, and participants with Alzheimer disease. The graph omits outlier data points (neurofilament light levels >5000 pg/mL) for 1 control participant, 1 with mild cognitive impairment, and 3 with Alzheimer disease. B, The levels of neurofilament light in cerebrospinal fluid in control participants, participants with forms of dementia, and participants with amyotrophic lateral sclerosis. The graph omits outlier data points (neurofilament light levels >10 000 pg/mL) for 1 participant with dementia with Lewy bodies, 1 with Alzheimer disease, and 7 with amyotrophic lateral sclerosis.

Figure 2.. Neurofilament Light (NFL) Protein in Control Participants and Participants With Movement Disorders

The graph omits outlier data points (neurofilament light levels >5000 pg/mL) for 1 participant with progressive supranuclear palsy, 2 with corticobasal degeneration, 1 with dementia with Lewy bodies, 1 with Parkinson disease, 1 with Parkinson disease with mild cognitive impairment, and 1 control participant.

Figure 3.. Neurofilament Light Protein in Participants With Autopsy-Verified Neurodegenerative Diseases

Neurofilament light levels in clinically diagnosed control participants are added as a dotted line for reference. The graph omits outlier data points (neurofilament light levels >5000 pg/mL) for 1 participant with frontotemporal lobe degeneration and 2 with amyotrophic lateral sclerosis.

Figure 4.. Correlations Between Neurofilament Light Protein and Annual Mini-Mental State Examination Score Decline

Correlations between cerebrospinal fluid levels of neurofilament light and the magnitude of annual decline in Mini-Mental State Examination scores in participants with Alzheimer disease (ρ = 0.25; P < .001) (A), frontotemporal dementia (ρ = 0.46; P = .003) (B), and all participants (ρ = 0.36; P < .001) (C).