Immune Mediators as Biomarker Candidates in Familial Amyotrophic Lateral Sclerosis (P4.133)

Objective: To identify immune mediators as pathogenic disease biomarkers in cerebrospinal fluid (CSF) and serum in familial amyotrophic lateral sclerosis (FALS) patients. Background: ALS produces severe disability and high rates of mortality, with 80% of the patients dying within 5 years of onset. FALS cases, caused by C9ORF72 hexanucleotide repeat expansion appear to be more aggressive than sporadic cases. Nonetheless, the pathophysiology of these cases has not been fully elucidated and requires the exploration for distinctive biomarkers. Design/Methods: CSF and serum were obtained from the Natural History and Biomarkers of C9ORF72 ALS and FTD study at NIH and the Johns Hopkins Neuroimmunology Biorepository. Immune meditors which included chemokines and cytokines were quantified using multiplexed microbead array assays (Luminex®, EMD Millipore Corp., MA) in cases of FALS and frontotemporal dementia (n=15), sporadic ALS (n=9) and neurological disease controls (n=14). Non-parametric statistics was used to analyze the 3 groups. Results: IL-1 pro-inflammatory pathway appeared to be significantly increased in the CSF of familial ALS cases vs. neurological disease controls. In serum, significant increase were identified among the same groups for interferon α2, platelet derived growth factor AA (PDGF-AA) and soluble CD40 ligand. Differences were also observed between familial and sporadic ALS cases in serum concentrations of Flt3 ligand (Flt3-L), granulocyte-macrophage colony-stimulating factor (GM-CSF) and CXCL5 (RANTES). Conclusions: Cases of FALS appear to have a pro-inflammatory immune mediators profile in the CSF and serum. Selective increases of IL-1 pro-inflammatory pathway were observed in cases of FALS compared to neurological disease controls. Increases in levels of Flt3-L, GM-CSF were seen in FALS cases compared with sporadic ALS. Despite no correspondence between the immune profile of CSF and serum, evidence of increase of immune mediators was observed in cases of FALS in both serum and CSF, a finding that support the presence of possible immune disturbances in cases of FALS. Study Supported by: Clinical Research Training Fellowship in ALS Research and Bart McLean Fund for Neuroimmunology Research Disclosure: Dr. Kumar has nothing to disclose. Dr. Pinilla has nothing to disclose. Dr. Floeter, M.D., PhD. has nothing to disclose. Dr. Pardo-Villamizar has nothing to disclose. Dr. Rothstein has received personal compensation for activities with Psyadon Pharmaceuticals, Cytokinetics, and Vertex. Dr. Ilieva has received research support from the AAN: ALS Clinical Training Fellowship.