CSF chitinases before and after symptom onset in amyotrophic lateral sclerosis

Objective: To evaluate the CSF levels of chitinase proteins during the presymptomatic and early symptomatic phases of amyotrophic lateral sclerosis (ALS). Methods: CSF samples were obtained from 16 controls, 55 individuals at-risk for ALS (including 18 carrying a mutation in C9ORF72, 33 in SOD1), 12 ALS patients, and 7 phenoconverters (individuals diagnosed with ALS during follow-up). At-risk individuals and phenoconverters were enrolled through the Pre-fALS study, which includes individuals carrying an ALS-associated gene mutation without disease manifestations at initial assessment. Longitudinal CSF collections, where possible, took place every 3-12 months for ALS patients and every 1-2 years for others. CSF levels of chitotriosidase 1 (CHIT1), chitinase-3-like protein 1 (CHI3L1, YKL-40) and chitinase-3-like protein 2 (CHI3L2, YKL-39) were measured by ELISA, along with CHIT1 activity. Longitudinal changes in at-risk individuals and phenoconverters were fitted to linear mixed effects models. Results: Slowly rising levels of CHIT1 were observed over time in the at-risk individuals (slope 0.059 log(10)[CHIT1] per year, P < 0.001). Among phenoconverters, CHIT1 levels and activity rose more sharply (0.403 log(10)[CHIT1] per year, P = 0.005; 0.260 log(10) [CHIT1 activity] per year, P = 0.007). Individual levels of both CHI3L1 and CHI3L2 remained relatively stable over time in all participant groups. Interpretation: The CHIT1 neuroinflammatory response is a feature of the late presymptomatic to early symptomatic phases of ALS. This study does not suggest a long prodrome of upregulated glial activity in ALS pathogenesis, but strengthens the place of CHIT1 as part of a panel of biomarkers to objectively assess the impact of immune-modulatory therapeutic interventions in ALS.