Plasma neurofilament light chain as a prognostic biomarker of white matter hyperintensity progression and cognitive decline

Abstract

Introduction: In cross-sectional studies, plasma neurofilament light chain (NfL) is associated with higher white matter hyperintensities (WMH) burden, even in the absence of significant brain atrophy. Hence we hypothesise that plasma NfL is a potential prognostic biomarker for WM progression. Therefore, in this longitudinal study, we examined the association of baseline plasma NfL with WMH progression and other markers of incident cerebral small vessel disease. Furthermore, we assessed if the association between increased baseline NfL and cognitive decline is mediated by WMH progression (Figure 1). Methods: This study included 363 participants recruited from the memory clinic and community in Singapore. Of these, 289 participants were cognitively impaired: 164 with cognitive impairment no dementia and 125 with dementia. All participants underwent brain magnetic resonance imaging (MRI) and neuropsychological assessments at baseline and at 2-year follow-up. Baseline plasma NfL concentrations were measured by single molecule array (Simoa). Baseline and follow- up MRIs were graded for white matter hyperintensities (n=323), lacunes (n=353) and cerebral microbleeds (n=339). WMH progression was assessed using the modified Rotterdam Progression Scale (mRPS). Mediation analyses were performed using Hayes' PROCESS Macro. Results: During a follow-up of 2 years, 164 (50.8%) participants had WMH progression (mRPS: 0 to 1 versus ≥2), 25 (7.1%) incident lacunes and 63 (18.6%) incident CMBs. Higher levels of baseline plasma NfL were associated with WMH progression (odds ratio, 3.15 [95% CI, 1.09 – 9.08]), after adjustment for age, sex, baseline vascular risk factors and baseline WMH [age related white matter changes (ARWMC<8 versus ≥8)]. Similar results were obtained in the cognitively impaired subgroup (odds ratio, 5.10 [95% CI, 1.74 – 14.9]). No significant association was observed between plasma NfL and incident lacunes and incident CMBs (Table 1). Higher baseline plasma NfL was also associated with cognitive decline (Table 2). The association between baseline NfL and cognitive decline was partially mediated by WMH progression (proportion mediated: 10% to 18%, p<0.05; Figure 1). Discussion: Plasma NfL is a promising non-invasive biomarker for WMH progression, as well as cognitive decline.