Background: Prodromal biomarkers heralding symptom conversion are under investigation for people with ALS. Indicators of axonal degeneration, such as neurofilament, may elevated prior to symptom onset in some ALS genotypes. Chitinases, markers of glial activation, are significantly increased in ALS and correlate with rate of disease progression. However, it is not known if chitinase protein levels increase before symptomatic conversion.
Objective: To evaluate baseline and longitudinal chitinases in the CSF of pre-symptomatic ALS gene carriers.
Results: Asymptomatic first-degree relatives of people with familial ALS were enrolled in the DIALS Network and genotyped at Massachusetts General Hospital and Washington University. Participants undergo deep phenotyping and biofluid collection (plasma, serum, whole blood, PBMCs, urine) every 6 months, and CSF collection annually.
Over 100 participants are followed within the DIALS Network. Evaluation of chitinases were performed on the CSF of an exploratory subset of DIALS participants (n=30). Mean baseline CHI3L1 and CHIT-1 levels were comparable and in normal range in gene positive (n=20) and gene negative (n=10) groups (CHI3L1: 203ng/mL and 221ng/mL; CHIT-1: 2.6ng/mL and 1.0ng/mL, respectively). One SOD1A4V carrier exhibited elevated CHI3L1 levels (>400ng/mL) that have been relatively stable for over 1 year. A VAPB carrier exhibited CHIT-1 levels above 12 ng/mL at baseline and rising to 15ng/mL in 1 year. Both asymptomatic carriers are being monitored closely for potential symptom onset.
Conclusions: Further evaluation of chitinases is needed in a larger population of pre-symptomatic ALS carriers prior to symptom conversion, along with comparison to other leading candidate biomarkers of conversion. The validation of sensitive biomarkers to follow the earliest signs of disease and predict symptom onset will set the stage to conduct successful trials aimed at disease prevention in gene carriers.