Cerebrospinal Fluid Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative neuromuscular disease that affects motor neurons controlling voluntary muscles. Survival is usually 2–5 years after onset, and death occurs due to respiratory failure. The identification of biomarkers would be very useful to help in disease diagnosis and for patient stratification based on, e.g., progression rate, with implications in therapeutic trials. Neurofilaments constitute already-promising markers for ALS and, recently, chitinases have emerged as novel marker targets for the disease. Here, we investigated cerebrospinal fluid (CSF) chitinases as potential markers for ALS. Chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1), chitinase-3-like protein 2 (CHI3L2) and the benchmark marker phosphoneurofilament heavy chain (pNFH) were quantified by an enzyme-linked immunosorbent assay (ELISA) from the CSF of 34 ALS patients and 24 control patients with other neurological diseases. CSF was also analyzed by UHPLC-mass spectrometry. All three chitinases, as well as pNFH, were found to correlate with disease progression rate. Furthermore, CHIT1 was elevated in ALS patients with high diagnostic performance, as was pNFH. On the other hand, CHIT1 correlated with forced vital capacity (FVC). The three chitinases correlated with pNFH, indicating a relation between degeneration and neuroinflammation. In conclusion, our results supported the value of CHIT1 as a diagnostic and progression rate biomarker, and its potential as respiratory function marker. The results opened novel perspectives to explore chitinases as biomarkers and their functional relevance in ALS.

Chitotriosidase 1 in the cerebrospinal fluid as a putative biomarker for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) progression

“…To our knowledge, this study is the first to associate CHIT1 expression with HAM/TSP development. Altered levels of CHIT1 in the CSF have been shown as a biomarker for other neurodegenerative disorders, such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis ( 41 – 43 ). In ALS, it was observed an association between CSF CHIT1 levels and both disease severity and progression ( 44 , 45 ).…”

“…This suggests that CHIT1 was intrathecally produced. In ALS, controversial results indicate that only CSF CHIT1 levels or both CSF and serum levels are useful as disease biomarker ( 43 , 44 ). However, the lack of paired CSF and serum samples in these studies might limited to obtain consistent conclusions.…”

“…In addition, CHIT1 and sVCAM-1 also showed an association with pNfH, a component of neurofilaments and a biomarker for the destruction of myelinated axons. In ALS patients, pNfH has been associated with higher CHIT1 levels of in the CSF ( 43 , 53 ). The neurofilament light chain (NfL) protein, another biomarker for axonal loss, also correlates with CSF CHIT1 levels in patients with ALS and multiple sclerosis ( 42 , 54 ).…”

Inflammatory checkpoints in amyotrophic lateral sclerosis: From biomarkers to therapeutic targets

“…A series of studies on CHIT1 corroborated previous findings that inflammatory components are involved in the death of motor neurons, and suggested that CHIT1 expression levels correlate with ALS progression and prognosis, i.e., higher CHIT1 levels lead to shorter survival time. In addition, an interesting study in 2021 found that CHIT1 was significantly negatively correlated with the respiratory function index of forced vital capacity (FVC), which is often used to measure potential respiratory damage in patients with ALS and is a predictor of survival and disease progression ( 19 ). Therefore, these studies emphasized the idea that measuring CHIT1 has advantages with regard to monitoring disease progression, predicting survival time, and potentially evaluating treatment response in patients with ALS.…”

Filtered Cerebrospinal Fluid From Patients With Amyotrophic Lateral Sclerosis Displays an Altered Proteome and Affects Motor Phenotype in a Mouse Model

“…Chitinases are produced by astrocytes and microglia and play a role in the nervous system's immune response [37]. CHIT1, CHI3L1, and CHI3L2 have been found to be elevated in the CSF of patients with ALS, with levels correlating with disease progression [37][38][39][40][41][42].…”