Associations of Plasma Neurofilament Light Levels With Brain Microstructure and Macrostructure and Cognition in the Community-Based Rhineland Study

Plasma neurofilament light chain (NfL) level is a sensitive yet aspecific marker of neurodegeneration. Its neuroanatomical and functional correlates in the general population are not fully elucidated. We thus assessed how brain's macrostructures and microstructures and cognitive function are related to plasma NfL levels in cognitively unimpaired adults over a wide age range. Our analyses were based on cross-sectional data from the Rhineland Study, a community-based prospective cohort study. This study includes people from the age of 30 onwards who live in 2 geographically defined areas in Bonn, Germany, and have sufficient command of the German language. Plasma NfL levels were measured using the Simoa platform and then log-transformed and adjusted for plate position, batch number, and Analyzer (HD-1 or HD-X). Brain imaging data were collected on a 3 Tesla scanner and included volumetric measures, metrics of the diffusion tensor and the neurite orientation dispersion and density imaging model, and white matter hyperintensity load. Memory performance, processing speed, and executive function were assessed using traditional cognitive tasks and an eye movement battery. We used multivariable regression models to assess the relations between brain structure and plasma NfL levels and between plasma NfL levels and cognitive performance. The study sample consisted of 5,589 participants aged 30-95 years (mean age 55 ± 13.7 years, 56.1% women) without neurodegenerative diseases. Higher plasma NfL levels were associated with lower isotropic volume fraction (-0.030; 95% CI -0.051 to -0.010; pFDR = 0.011), lower neurite density index (ß = -0.031; 95% CI -0.053 to -0.008; pFDR = 0.014), and higher axial diffusivity (ß = 0.037; 95% CI 0.013-0.062; p = 0.005; pFDR = 0.011). The strongest association was with the orientation dispersion index (ß = -0.063; 95% CI -0.085 to -0.041; pFDR < 0.001). Furthermore, higher plasma NfL levels tended to be associated with a lower processing speed domain score (ß = -0.046; 95% CI -0.084 to -0.009; p = 0.014; pFDR = 0.056) and longer prosaccade latency (ß = 0.039; 95% CI 0.000-0.078; p = 0.049; pFDR = 0.480). Higher plasma NfL levels mainly reflect worse white matter microstructural integrity, especially lower axonal density, in a relatively healthy, community-based sample. This suggests that plasma NfL levels allow for early detection of subtle differences in brain microstructure.