Abstract
ObjectiveTo evaluate the CSF levels of chitinase proteins during the presymptomatic and early symptomatic phases of amyotrophic lateral sclerosis (ALS).MethodsCSF 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.ResultsSlowly 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.InterpretationThe 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.
Highlights
Inflammatory cell infiltration is a consistent neuropathological feature of the neurodegenerative disorder amyotrophic lateral sclerosis (ALS).[1,2,3,4] In vivo microglial activity has been demonstrated using positron emission tomography (PET)[5] and through analysis of cerebrospinal fluid (CSF) cytokines and proteins secreted by microglia.[6]
Previous cross-sectional studies have shown elevated CSF chitinase protein levels in ALS patients versus controls and no elevation in asymptomatic gene carriers compared with healthy controls.[11,12]
chitotriosidase 1 (CHIT1), CHI3L1 and CHI3L2 concentrations, as well as CHIT1 activity, to be similar in healthy controls and atrisk individuals who have not yet phenoconverted, but elevated in symptomatic ALS compared to both healthy controls and at-risk individuals
Summary
Inflammatory cell infiltration is a consistent neuropathological feature of the neurodegenerative disorder amyotrophic lateral sclerosis (ALS).[1,2,3,4] In vivo microglial activity has been demonstrated using positron emission tomography (PET)[5] and through analysis of cerebrospinal fluid (CSF) cytokines and proteins secreted by microglia.[6] The precise role of glia in the pathophysiology of ALS is a matter of controversy. It remains unresolved whether microglia are involved in the initiation of motor neuron degeneration, are an exacerbating factor promoting disease progression, or even exert a neuroprotective effect.[7].
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