Neurofilament light chain predicts future dementia risk in cerebral small vessel disease

Abstract

Objectives: Serum neurofilament light chain (NfL) has been proposed as prognostic markers in neurogenerative disease. A cross-sectional study in cerebral small vessel disease (SVD) reported an association with cognition and disability. If NfL is to be used to predict outcome, studies are required to demonstrate baseline NfL predicts future dementia risk. Furthermore, if it is to be used as a surrogate marker in clinical trials, change in NfL over time periods typical of a clinical trial must be linked to clinical progression. In a longitudinal study of patients with lacunar stroke and confluent white matter hyperintensities, we determined whether both baseline, and change, in NfL levels were linked to changes in MRI markers, cognitive decline and dementia risk.

Methods: Patients underwent MRI, cognitive testing and blood taking at baseline and annually for 3 years. Clinical and cognitive follow-up continued for 5 years.

Results: NfL data were available for 113 subjects for baseline analysis, and 90 patients for the longitudinal analysis. Baseline NfL predicted cognitive decline (global cognition β=-0.335, SE=0.094, p=0.001) and risk of converting to dementia (HR=1.676 (95% CI 1.183 to 2.373), p=0.004). In contrast to imaging, there was no change in NfL values over the follow-up period.

Conclusions: Baseline NfL predicts changes in MRI markers, cognitive decline and dementia rate over a 5 years follow-up period in SVD, suggesting NfL may be a useful prognostic marker. However, change in NfL values was not detected, and therefore NfL may not be a useful surrogate marker in clinical trials in SVD.

Figure 1

Higher levels of NfL was associated with a higher SVD marker on imaging. Spearman’s rank correlation shows the cross-sectional associations between MRI markers and NfL. Blue and red quartiles show significant positive and negative correlations. White tiles show no significant association. CMB, cerebral microbleed count; Lac, lacune count; MDPH, mean diffusivity normalised peak height; NfL, neurofilament light chain; NBV, normalised brain volume; PSMD, peak width of skeletonised mean diffusivity; SVD, small vessel disease; WMH, white matter hyperintensity.

Figure 2

NfL measures and incidences of new lacune over time per patient. The grey line refers to NfL levels over time in patients without dementia conversion. The dotted black line refers to NfL levels over time in patients with dementia conversion. The red (left), green (middle) and orange (right) dotted vertical lines represent an incidence of a new lacune in a patient between baseline and TP 1, TP 1 and 2, TP 2 and 3, respectively. NfL, neurofilament light chain; TP, time point.