Association of Plasma Neurofilament Light With Small Vessel Disease Burden in Nondemented Elderly: A Longitudinal Study

Background and purpose: Neurofilament light chain (NfL) is a promising predictive biomarker of active axonal injury and neuronal degeneration diseases. We aimed to evaluate if an increase in plasma NfL levels could play a monitoring role in the progression of cerebral small vessel disease (CSVD) among the nondemented elders, which are highly prevalent in elderly individuals and associated with an increased risk of stroke and dementia.

Methods: The study included 496 nondemented participants from the Alzheimer disease neuroimaging initiative database. All participants underwent plasma NfL measurements and 3.0-Tesla magnetic resonance imaging of the brain; 387 (78.0%) underwent longitudinal measurements. The number of cerebral microbleeds, lacunar infarcts, and volumetric white matter hyperintensities, as well as Fazekas scores, were measured. Cross-sectional and longitudinal associations between CSVD burden and NfL levels were evaluated using multivariable-adjusted models.

Results: Plasma NfL was higher in the moderate-severe CSVD burden group (45.2±16.0 pg/mL) than in the nonburden group (34.3±15.1 pg/mL; odds ratio [OR]=1.71 [95% CI, 1.24-2.35]) at baseline. NfL was positively associated with the presence of cerebral microbleeds (OR=1.29 [95% CI, 1.01-1.64]), lacunar infarcts (OR=1.43 [95% CI, 1.06-1.93]), and moderate-severe white matter hyperintensities (OR=1.67 [95% CI, 1.24-2.25]). Longitudinally, a higher change rate of NfL could predict more progression of CSVD burden (OR=1.38 [95% CI, 1.08-1.76]), white matter hyperintensities (OR=1.41 [95% CI, 1.10-1.79]), and lacunar infarcts (OR=1.99 [95% CI, 1.42-2.77]).

Conclusions: Plasma NfL level is a valuable noninvasive biomarker that supplements magnetic resonance imaging scans and possibly reflects the severity of CSVD burden. Furthermore, high plasma NfL levels tend to represent an increased CSVD risk, and dynamic increases in NfL levels might predict a greater progression of CSVD.