Background: and Purpose Serum neurofilament light (NfL)-chain is a circulating marker for neuroaxonal injury and is also associated with severity of cerebral small vessel disease (SVD) cross-sectionally. Here we explored the association of serum-NfL with imaging and cognitive measures in SVD longitudinally. Methods: From 503 subjects with SVD, baseline and follow-up magnetic resonance imaging (MRI) was available for 264 participants (follow-up 8.7±0.2 years). Baseline serum-NfL was measured by an ultrasensitive single-molecule-assay. SVD-MRI-markers including white matter hyperintensity (WMH)-volume, mean diffusivity (MD), lacunes, and microbleeds were assessed at both timepoints. Cognitive testing was performed in 336 participants, including SVD-related domains as well as global cognition and memory. Associations with NfL were assessed using linear regression analyses and analysis of covariance (ANCOVA). Results: Serum-NfL was associated with baseline WMH-volume, MD-values and presence of lacunes and microbleeds. SVD-related MRI- and cognitive measures showed progression during follow-up. NfL-levels were associated with future MRI-markers of SVD, including WMH, MD and lacunes. For the latter, this association was independent of baseline lacunes. Furthermore, NfL was associated with incident lacunes during follow-up (P=0.040). NfL-levels were associated with future SVD-related cognitive impairment (processing speed: β=–0.159; 95% confidence interval [CI], –0.242 to –0.068; P=0.001; executive function β=–0.095; 95% CI, –0.170 to –0.007; P=0.033), adjusted for age, sex, education, and depression. Dementia-risk increased with higher NfL-levels (hazard ratio, 5.0; 95% CI, 2.6 to 9.4; P<0.001), however not after adjusting for age. Conclusions Longitudinally, serum-NfL is associated with markers of SVD, especially with incident lacunes, and future cognitive impairment affecting various domains. NfL may potentially serve as an additional marker for disease monitoring and outcome in SVD, potentially capturing both vascular and neurodegenerative processes in the elderly.

BACKGROUND AND PURPOSE: Neurofilament light chain (NfL) is a blood marker for neuroaxonal damage. We assessed the association between serum NfL and cerebral small vessel disease (SVD), which is highly prevalent in elderly individuals and a major cause of stroke and vascular cognitive impairment. METHODS: Using a cross-sectional design, we studied 53 and 439 patients with genetically defined SVD (Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy [CADASIL]) and sporadic SVD, respectively, as well as 93 healthy controls. Serum NfL was measured by an ultrasensitive single-molecule array assay. We quantified magnetic resonance imaging (MRI) markers of SVD, i.e., white matter hyperintensity volume, lacune volume, brain volume, microbleed count, and mean diffusivity obtained from diffusion tensor imaging. Clinical characterization included neuropsychological testing in both SVD samples. CADASIL patients were further characterized for focal neurological deficits (National Institutes of Health stroke scale [NIHSS]) and disability (modified Rankin scale [mRS]). RESULTS: Serum NfL levels were elevated in both SVD samples (P < 1e-05 compared with controls) and associated with all SVD MRI markers. The strongest association was found for mean diffusivity (CADASIL, R2=0.52, P=1.2e-09; sporadic SVD, R2=0.21, P < 1e-15). Serum NfL levels were independently related to processing speed performance (CADASIL, R2=0.27, P=7.6e-05; sporadic SVD, R2=0.06, P=4.8e-08), focal neurological symptoms (CADASIL, NIHSS, P=4.2e-05) and disability (CADASIL, mRS, P=3.0e-06). CONCLUSIONS: We found serum NfL levels to be associated with both imaging and clinical features of SVD. Serum NfL might complement MRI markers in assessing SVD burden. Importantly, SVD needs to be considered when interpreting serum NfL levels in the context of other age-related diseases.
Academies and Institutes ; Aged ; Biomarkers ; Brain ; CADASIL ; Cerebral Small Vessel Diseases ; Cognition Disorders ; Complement System Proteins ; Dementia, Vascular ; Diffusion Tensor Imaging ; Humans ; Intermediate Filaments* ; Leukoencephalopathies ; Magnetic Resonance Imaging ; Neuropsychological Tests ; Stroke ; White Matter