Cerebrospinal fluid inflammatory proteomic profiling identifies biomarkers linked to disease progression in amyotrophic lateral sclerosis

BACKGROUND: Neuroinflammation is a key component of amyotrophic lateral sclerosis (ALS), but its association with disease progression heterogeneity remains unclear. We aimed to identify CSF inflammation-related proteins associated with disease progression phenotype in patients with ALS. METHODS: Patients with ALS were stratified into slow progressors (SP) and fast progressors (FP) according to the disease progression rate. CSF inflammatory proteins were measured using the Olink Target 96 Inflammation panel. Disease-associated biomarkers were identified using limma package and elastic net (EN) analysis. We assessed the discriminatory power of disease-associated biomarkers using receiver operating characteristic curve analysis and estimated the optimism-adjusted area under the curve (AUC) using the bootstrapping method. RESULTS: Among 77 patients (SP: n=40; FP: n=37), limma analysis identified 11 differentially expressed proteins, with functional enrichment in chemokine signaling, TNF-related responses and NF-κB pathways. EN analysis identified 12 candidate proteins, among which CST5, CCL11, SIRT2, CD6, CCL4, MMP-1, TNFRSF9, CCL19, and MCP-4 showed positive associations with the SP phenotype. A model combining SIRT2, MMP-1, BMI, and site of onset yielded an apparent area under the curve of 0.769 (95% CI 0.662 to 0.876) and an optimism-corrected area under the curve of 0.729. CONCLUSION: Our study uncovered a CSF inflammatory proteomic signature associated with slow disease progression in ALS. These findings indicate that specific CSF neuroinflammatory protein signatures reflect biological heterogeneity in ALS disease progression rather than non-specific neurodegeneration. SIRT2 and MMP-1 warrant further investigation as components of progression-stratification models, although validation in larger, longitudinal, and independent cohorts is required.