Objective: This study aims to investigate the association between serum neurofilament light chain (NfL), microstructural changes in the substantia nigra, and clinical manifestations in Parkinson’s disease (PD) patients, both cross-sectionally and longitudinally. Furthermore, we seek to determine whether NfL contributes to clinical symptom progression by driving microstructural alterations in the substantia nigra.

Background: Parkinson’s disease is a progressive neurodegenerative disorder characterized by the degeneration of the substantia nigra. Serum NfL has been well established as a robust biomarker of axonal injury and neurodegeneration. Previous studies have demonstrated significant correlations between elevated serum NfL levels and structural alterations in various brain regions in PD. However, it remains unclear whether increased NfL specifically contributes to degeneration in the substantia nigra.

Method: We analyzed data from the Parkinson’s Progression Markers Initiative. The analyses included: (i)comparing NfL levels and nigral free-water imaging in 158 PD patients and 60 healthy controls and examining their correlations with clinical manifestations at baseline; (ii)evaluating the predictive value of baseline NfL and DTI metrics for clinical progression; (iii)assessing longitudinal changes in these markers and symptoms in 81 patients and 40 controls at one year, with 51 patients followed up at two years; and (iv)constructing a longitudinal mediation model using baseline NfL and DTI metrics to predict UPDRS III scores at 1, 2, and 4 years.

Results: PD patients exhibited significantly higher serum NfL levels than controls (Figure 1). NfL levels correlated positively with nigral free water and mean diffusivity values, and predicted the progression of both motor and non-motor symptoms(Figure 2). During follow-up, progressive changes in NfL levels correlated with progressive alterations in nigral free water values(Figure 3). Mediation analysis demonstrated that nigral free water partially mediated the effect of elevated NfL on clinical progression(Figure 4).

Conclusion: These findings confirm that NfL is associated with nigral degeneration in PD and that nigral degeneration acts as a mediator linking elevated NfL to clinical progression. These findings enhance the understanding of PD pathogenesis and support the potential of NfL as a biomarker for tracking nigral degeneration and disease progression in PD.

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Figure 1

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MDS Abstracts - https://www.mdsabstracts.org/abstract/association-of-neurofilament-light-chain-with-substantia-nigra-degeneration-in-parkinsons-disease/