Serum Neurofilament Light Chain and GFAP Levels Are Associated with Structural Brain Connectivity in Parkinson’s Disease

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms and widespread alterations in brain networks. Circulating biomarkers such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) reflect neuroaxonal damage and astroglial activation, respectively, but their relationship with large-scale brain connectivity remains poorly understood. Seventy-three PD patients and thirty-four healthy controls underwent diffusion magnetic resonance imaging. Whole-brain tractography was used to reconstruct structural connectivity networks, and graph-theoretical measures were derived. Serum NfL and GFAP levels were quantified, and their associations with network metrics and clinical variables were assessed. PD patients showed significant alterations in global and nodal network organization compared to controls. Higher NfL and GFAP levels were associated with reduced global clustering coefficient and efficiency, as well as increased path length and modularity. At the regional level, higher biomarker levels were associated with reduced network measures in the right thalamus and right cerebellar cortex. No significant associations were observed in healthy controls. These findings demonstrate that circulating biomarkers of neurodegeneration are linked to both global and regional disruptions of structural brain connectivity in PD, supporting the integration of blood-based biomarkers and connectomics to better characterize disease-related network alterations.