Non-invasive biomarkers for Neurosarcoidosis: Complement activation as a tool for diagnosis and prognosis

Neurosarcoidosis (NS) is a rare inflammatory disorder of the nervous system with significant morbidity. Diagnostic challenges stem from non-specific clinical features and the lack of sensitive and specific biomarkers. While complement dysregulation has been implicated in systemic sarcoidosis, its role in NS remains unclear. This study explores the diagnostic and prognostic value of complement and neuronal injury biomarkers in serum and cerebrospinal fluid (CSF) of individuals with NS.

We conducted a case-control study using paired serum and CSF samples from NS patients and non-sarcoidosis controls. Concentrations of complement activation products: iC3b, Ba, Terminal Complement Complex [TCC]), regulators: C1 inhibitor [C1inh], factor H [FH], and components: C3, C5, C9, Factor B [FB], and other markers such as CXCL12 and neurofilament light chain (NfL) were quantified using ultrasensitive assays. Multivariable logistic regression and receiver operating characteristic (ROC) curve analysis were employed to assess the diagnostic and prognostic performance of individual and combined biomarkers.

Significant differences in biomarker profiles were observed between neurosarcoidosis patients (n = 28) and controls (n = 30). In serum, patients with neurosarcoidosis exhibited lower C3 levels (915.24 vs 1380.07 ng/ml; p < 0.001) and higher Factor B (205.21 vs 168.51 ng/ml; p = 0.010) and neurofilament light chain (2.07 × 10^-5 vs 8.96 × 10^-6 pg/ml; p = 0.023), indicating complement dysregulation and neuronal injury. In cerebrospinal fluid, complement components including C3 (12.98 vs 4.45 μg/ml), Factor B (0.55 vs 0.18 μg/ml), and C5 (0.63 vs 0.13 μg/ml) were significantly elevated (all p < 0.001). C3 demonstrated strong diagnostic performance (AUC = 0.937), while multi-biomarker panels, including C3 + Factor B (AUC = 0.996) and C3 + Factor B + C9 (AUC = 1.0), provided near-perfect discrimination. These findings remained robust following adjustment for age and sex. In differentiating relapsing (n = 18) from stable (n = 8) neurosarcoidosis, individual serum biomarkers showed modest performance (AUC 0.65-0.67), but combinations such as Factor B + C5 + Ba + NfL improved classification (AUC = 0.944). In CSF, multi-biomarker panels including TCC + FH + C5 and iC3b + C3 + C5 achieved excellent discrimination (AUC = 1.0).

Our findings highlight the central role of complement system dysregulation as a driver of neuroinflammation in NS. Multi-biomarker panels, particularly those involving complement components, enhance diagnostic and prognostic accuracy. These results support the development of biomarker-driven, minimally invasive approaches for diagnosing and monitoring NS.