Chitotriosidase as biomarker for early stage amyotrophic lateral sclerosis: a multicenter study

Abstract

Objective: Levels of chitotriosidase (CHIT1) are increased in the cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients reflecting microglial activation. Here, we determine the diagnostic and prognostic potential of CHIT1 for early symptomatic ALS.Methods: Overall, 275 patients from 8 European neurological centers were examined. We included ALS with <6 and >6 months from symptom onset, other motoneuron diseases (oMND), ALS mimics (DCon) and non-neurodegenerative controls (Con). CSF CHIT1 levels were analyzed for diagnostic power and association with progression and survival in comparison to the benchmark neurofilament. The 24-bp duplication polymorphism of CHIT1 was analyzed in a subset of patients (N=65).Results: Homozygous CHIT1 duplication mutation carriers (9%) invariably had undetectable CSF CHIT1 levels, while heterozygous carriers had similar levels as patients with wildtype CHIT1 (p=0.414). In both early and late symptomatic ALS CHIT1 levels was increased, did not correlate with patients' progression rates, and was higher in patients diagnosed with higher diagnostic certainty. Neurofilament levels correlated with CHIT1 levels and prevailed over CHIT1 regarding diagnostic performance. Both CHIT1 and neurofilaments were identified as independent predictors of survival in late but not early symptomatic ALS. Evidence is provided that CHIT1 predicts progression in El Escorial diagnostic category in the group of ALS cases with a short duration.Conclusions: CSF CHIT1 level may have additional value in the prognostication of ALS patients with a short history of symptoms classified in diagnostic categories of lower clinical certainty. To fully interpret apparently low CHIT1 levels knowledge of CHIT1 genotype is needed.

Cardiac troponin T is elevated and increases longitudinally in ALS patients

“…In the analysis of diagnostic performance, hs-cTnT performed moderately well in distinguishing mimics from ALS patients. NfL, however, performed better, at a level similar to previous reports (15,16,18,20,21).…”

“…Non-bulbar onset ALS patients had higher hs-cTnT levels compared to bulbar onset patients. Consistent with previous studies, NfL was found to correlate with a faster disease progression rate and was associated with a higher risk of death (15,16,18,20,21). No association was noted between the level of hs-cTnT and risk of death, however.…”

“…Studies with negative findings did not directly study cTnT (11,12), whereas studies with positive findings, like our study, directly studied cTnT (9,10). We confirmed earlier studies in demonstrating elevated levels of NfL in CSF among ALS patients compared with mimics and healthy controls (14)(15)(16)(18)(19)(20)(21). In the analysis of diagnostic performance, hs-cTnT performed moderately well in distinguishing mimics from ALS patients.…”

“…In the present study, we aimed to investigate the performance of high-sensitivity cTnT (hs-cTnT) in plasma as a diagnostic and prognostic biomarker for ALS, in comparison to NfL in CSF, which is currently one of the most promising biomarkers of ALS (13)(14)(15)(16)(17)(18)(19)(20)(21).…”

Cerebrospinal Fluid Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis

“…The value of chitinases as biomarkers for amyotrophic lateral sclerosis has been supported by strong recent evidence [ 12 , 26 , 27 ]. CHIT1 has been advanced as an ALS biomarker in diagnosis and progression [ 13 , 16 , 28 , 29 , 30 , 31 ], as has CHI3L1 [ 16 , 29 , 30 ]. Although less studied, CHI3L2 [ 29 , 30 , 32 ] also appeared promising.…”