LAUSR

BACKGROUND AND OBJECTIVES Blood biomarkers may allow earlier identification of Parkinson's disease (PD), parkinsonism, and poor PD-related outcomes, such as physical functioning. Neurofilament light (Nf-L), a neuronal cytoplasmic protein, is a biomarker of neurodegeneration measurable in biofluids. Our objective is to examine the association of serum Nf-L at baseline with clinically diagnosed PD, parkinsonian signs, and physical functioning change over 16 years in a population-based sample of older adults. METHODS Data came from 1,327 older participants from the Chicago Health and Aging Project (CHAP), a longitudinal population-based study. Clinical evaluations included assessing parkinsonian signs in four domains, bradykinesia, parkinsonian gait, rigidity, and tremors using a structured version of the United Parkinson's Disease Rating Scale. Board-certified neurologists diagnosed PD. Physical functioning was assessed using chair stands, tandem walk, and timed walk. An ultrasensitive immunoassay was used to measure the concentration of Nf-L in blood. RESULTS Of the 1,254 participants where clinical PD was examined, 77 (6.1%) developed clinical PD and parkinsonian signs were on average 9.5 (range = 0-66.0). After adjusting for demographic characteristics, the APOE-e4 allele, and global cognition, a 2-fold higher concentration of serum Nf-L was associated with incident clinical PD (OR = 2.54, 95% CI: 1.70, 3.81) and global parkinsonian signs (OR = 2.44, 95% CI: 1.94, 2.94). This association was significant over five years before diagnosis. Compared to participants below 18.5 pg/mL of serum Nf-L at baseline, participants between 18.5-25.4 pg/mL, 25.4-37.3 pg/mL, and above 37.3 pg/mL had a higher odds ratio of clinical PD at all time intervals ranging from the time of diagnosis to greater than five years before diagnosis. A higher concentration of serum Nf-L was associated with a faster rate of physical functioning decline. In participants with 2-fold higher concentrations of serum Nf-L, the annual rate of decline in physical functioning increased by 0.15 units (95% CI: 0.21, 0.08). CONCLUSIONS Serum Nf-L was associated with incident clinical PD, parkinsonian signs, and physical functioning decline in a population-based sample. Our findings suggest that Nf-L may serve as a potential biomarker for neurodegeneration, including Parkinson's disease outcomes. CLASSIFICATION OF EVIDENCE This study provides Class II evidence that serum Nf-L levels are associated with incident PD, parkinsonian signs, and physical functioning decline.