Intrathecal humoral response and blood–CSF barrier integrity in amyotrophic lateral sclerosis

Background Neuroinflammation and dysfunction of central nervous system barriers have been proposed as contributors to amyotrophic lateral sclerosis (ALS) pathogenesis. Biomarkers reflecting intrathecal immunoglobulin synthesis and blood–CSF barrier integrity may provide insight into these mechanisms and their clinical implications. Objectives To investigate the clinical and biological significance of markers of intrathecal humoral immunity and blood–CSF barrier function in ALS. Design Observational study. Methods CSF and serum biomarkers related to intrathecal immunoglobulin synthesis and blood–CSF barrier integrity were analyzed in 87 patients with ALS and 41 controls. Assessed measures included oligoclonal bands (OCBs), kappa free light chain (κFLC)-derived indices, K-index, albumin quotient, CSF total protein, IgG-related indices and neurofilaments levels. Group differences were evaluated to detect biomarkers correlated with ALS. Associations with clinical outcomes and selected systemic biomarkers in ALS patients were evaluated through regression models and survival analyses. Results Markers of blood–CSF barrier dysfunction and intrathecal immunoglobulin synthesis were largely comparable between ALS patients and controls, arguing against widespread barrier disruption or sustained humoral intrathecal immune activation as characteristic features of ALS. Neurofilament levels showed the strongest discriminatory performance between ALS patients and the NNDC group and the most consistent associations with disease trajectory. Moreover, higher K-index values and increased CSF/serum κFLC ratio were associated with shorter tracheostomy-free survival, despite limited associations with other clinical measures of disease progression, an association that appeared more pronounced at lower serum albumin levels in exploratory, post-hoc interaction analyses. Conclusion These findings do not support generalized intrathecal immunoglobulin synthesis or blood–CSF barrier disruption in ALS. However, κFLC-derived biomarkers, particularly the K-index and CSF/serum κFLC ratio, may identify a subgroup of patients with poorer prognosis. Because CSF κFLC concentrations were below the assay detection limit in most patients, these prognostic findings rely on imputation and should be regarded as exploratory and hypothesis-generating.