Plasma neurofilament light chain (NfL) relates to preclinical changes in cognition, structural white matter integrity and markers of cerebral small‐vessel disease: A population‐based study

Abstract

AbstractBackgroundNeurofilament light chain (NfL) is known as a promising biomarker for risk stratification and disease monitoring of dementia due to Alzheimer’s disease, but the underlying pathophysiological substrates remain largely elusive. Moreover, it is uncertain whether NfL levels are able to capture changes in cognitive performance prior to the onset of clinical cognitive decline. We studied the relation of plasma NfL with cognition and structural brain imaging markers in a general population without dementia.MethodPlasma level of NfL was measured using the Simoa NF‐light™ assay in 4,207 dementia‐free participants of the population‐based Rotterdam Study cohort (mean age 71.6 years, 57% women). Participants underwent repeated cognitive assessment, and a subset of 970 had brain MRI. We used linear and logistic regression (cross‐sectional) and mixed‐effects models (longitudinal) to determine the association of plasma NfL with (changes in) cognition and brain tissue volumetry, white matter integrity and markers of cerebral small‐vessel disease (lacunes, white matter hyperintensities and microbleeds).ResultAt baseline, higher plasma NfL level was significantly associated with a worse cognitive performance (g‐factor: β=‐0.06 95%CI ‐0.12;0), and more specifically with lower test scores on the Stroop 3 test (β=‐0.07 95%CI ‐0.12;‐0.01), and Perdue Pegboard (β=‐0.12 95%CI ‐0.18;‐0.06). Similarly, among 2,850 participants with repeated cognitive assessment, baseline NfL level was significantly associated with a stronger decline in cognition (g‐factor (β=‐0.02 95%CI ‐0.04;0), driven by faster decline on Stroop 1 & 2 tests (β=‐0.03 95% ‐0.04;‐0.01, β=‐0.03 95%CI ‐0.05;‐0.02, Figure 1). In participants with brain MRI, NfL level was significantly associated at baseline with larger volumes of white matter hyperintensities (β= 0.12 95%CI 0.04;0.20), more lacunar infarcts (OR= 1.69 95%CI 1.20;2.39), and worse fractional anisotropy (β=‐0.10 95%CI ‐0.18;‐0.02) and mean diffusivity (β=0.09 95%CI 0.02;0.16), but not with grey matter volumes. Plasma NfL level was not significantly related to progression of structural brain changes over time (n=738).ConclusionIn this large community‐dwelling population, higher plasma NfL levels are associated with accelerated cognitive decline and larger burden of white matter pathology. These findings suggest NfL as a predominant biomarker of axonal rather than neuronal damage in monitoring of disease progression and treatment effects.