CSF chitinases before and after symptom onset in amyotrophic lateral sclerosis

• Published in: Annals of clinical and translational neurology Vol. 7; no. 8; pp. 1296 - 1306
• Main Authors: Gray, Elizabeth, Thompson, Alexander G., Wuu, Joanne, Pelt, Joe, Talbot, Kevin, Benatar, Michael, Turner, Martin R.
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.08.2020; John Wiley and Sons Inc; Wiley
• Subjects: Adult; Age; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - cerebrospinal fluid; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Biomarkers; Chitinase; Chitinase-3-Like Protein 1 - cerebrospinal fluid; Chitinases - cerebrospinal fluid; Disease Progression; Female; Hexosaminidases - cerebrospinal fluid; Humans; Longitudinal Studies; Male; Middle Aged; Mutation; Prodromal Symptoms; Proteins; Standard deviation; Statistical analysis; United Kingdom > UK
• ISSN: 2328-9503; 2328-9503
• DOI: 10.1002/acn3.51114

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 log10[CHIT1] per year, P < 0.001). Among phenoconverters, CHIT1 levels and activity rose more sharply (0.403 log10[CHIT1] per year, P = 0.005; 0.260 log10[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.