Inflammatory markers in cerebrospinal fluid: independent prognostic biomarkers in amyotrophic lateral sclerosis?

Abstract

ObjectiveInflammation is a key pathological hallmark in amyotrophic lateral sclerosis (ALS), which seems to be linked to the disease progression. It is not clear what the added diagnostic and prognostic value are of inflammatory markers in the cerebrospinal fluid (CSF) of patients with ALS.MethodsChitotriosidase-1 (CHIT1), chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) were measured in CSF and serum of patients with ALS (n=105), disease controls (n=102) and patients with a disease mimicking ALS (n=16). The discriminatory performance was evaluated by means of a receiver operating characteristic curve analysis. CSF and serum levels were correlated with several clinical parameters. A multivariate Cox regression analysis, including eight other established prognostic markers, was used to evaluate survival in ALS.ResultsIn CSF, CHIT1, YKL-40 and MCP-1 showed a weak discriminatory performance between ALS and ALS mimics (area under the curve: 0.79, p<0.0001; 0.72, p=0.001; 0.75, p=0.001, respectively). CHIT1 and YKL-40 correlated with the disease progression rate (ρ=0.28, p=0.009; ρ=0.34, p=0.002, respectively). CHIT1 levels were elevated in patients with a higher number of regions displaying motor neuron degeneration (one vs three regions: 4248 vs 13 518 pg/mL, p = 0.0075). In CSF, YKL-40 and MCP-1 were independently associated with survival (HR: 29.7, p=0.0003; 6.14, p=0.001, respectively).ConclusionsOur findings show that inflammation in patients with ALS reflects the disease progression as an independent predictor of survival. Our data encourage the use of inflammatory markers in patient stratification and as surrogate markers of therapy response in clinical trials.

Cross-sectional and longitudinal measures of chitinase proteins in amyotrophic lateral sclerosis and expression of CHI3L1 in activated astrocytes

“…We confirmed recent findings that CSF Chit-1 is significantly higher in ALS samples as compared with both DCs and HCs using unbiased proteomic18 20 24 or targeted immunoassay methods 18 19 21 22 32. CSF CHI3L1 was also higher in ALS as compared with HCs, confirming results from some studies15 18 but contrasting with others 20–22 33.…”

“…Increased levels and activity of chitinases have been observed in biofluids from patients with multiple sclerosis (MS)14 15 and Alzheimer’s disease (AD) 15 16. Recently, Chit-1,17–22 CHI3L118 20–23 and CHI3L218 20 21 23 were explored as potential ALS biomarkers in cerebrospinal fluid (CSF) and blood.…”

CHIT1 at Diagnosis Reflects Long‐Term Multiple Sclerosis Disease Activity

“…CHIT1 levels and activity in ALS have repeatedly been associated with neurofilament levels and with a faster disease progression rate in large study populations. 10,28,29,[46][47][48] Our results demonstrate the correlation between baseline CSF CHIT1 levels and neuronal damage and prognosis in MS.…”

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

“…Some immune biomarkers associated with ALS have also been discovered in the CSF. For example, an increase in the level of macrophage-derived chitinases (CHIT1, CHI3L1 and CHI3L2), a signal of microglia/macrophage activation, was recently observed in ALS patients, and chitinase levels correlated with disease progression, severity, survival and other neurodegeneration markers such as phosphorylated neurofilament heavy chain ( Steinacker et al , 2018 ; Thompson et al , 2018 ; Gille et al , 2019 ; Vu et al , 2020 ). A more detailed analysis of inflammatory factors, in both serum and CSF, and their correlation to disease severity is provided in Table 1 .…”