Inflammatory profiles relate to survival in subtypes of amyotrophic lateral sclerosis

Objective To investigate inflammatory cytokines in patients with motor neuron disease (MND) evaluating the putative contribution of amyotrophic lateral sclerosis (ALS)-causing gene variants. Methods This study is a retrospective case series with prospective follow-up (1994-2016) of 248 patients with MND, of whom 164 had ALS who were screened for mutations in the genes forSOD1andC9orf72. Paired CSF and plasma were collected at the diagnostic evaluation before treatment. A panel of cytokines were measured blindly via digital ELISA on the Simoa platform. Results Time from disease onset to death was longer for patients with ALS-causingSOD1mutations (mSOD1, n = 24) than those withC9orf72hexanucleotide repeat expansion (C9orf72HRE) ALS (n = 19;q= 0.001) and other ALS (OALS) (n = 119;q= 0.0008). Patients with OALS had higher CSF tumor necrosis factor alpha (TNF-alpha) compared with those with C9orf72HRE ALS (q= 0.014). Patients with C9orf72HRE ALS had higher CSF interferon alpha compared with those with OALS and mSOD1 ALS (q= 0.042 andq= 0.042). In patients with ALS, the survival was negatively correlated with plasma interleukin (IL) 10 (hazard ratio [HR] 1.17, 95% CI 1.05-1.30). Plasma TNF-alpha, IL-10, and TNF-related apoptosis-inducing ligand (TRAIL) (HR 1.01 [1.00-1.02], 1.15 [1.02-1.30], and 1.01 [1.00-1.01], respectively) of patients with OALS, plasma IL-1 beta (HR 5.90 [1.27-27.5]) of patients with C9orf72HRE ALS, and CSF TRAIL (10.5 [1.12-98.6]) of patients with mSOD1 ALS all correlated negatively with survival. Conclusions Differences in survival times in ALS subtypes were correlated with cytokine levels, suggesting specific immune responses related to ALS genetic variants.