Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis.

Abstract

OBJECTIVE:

The neurodegenerative disease, amyotrophic lateral sclerosis (ALS), is a heterogeneous clinical syndrome involving multiple molecular pathways. The development of biomarkers for use in therapeutic trials is a priority. We sought to use a high-throughput proteomic method to identify novel biomarkers in individual cerebrospinal fluid (CSF) samples.

METHODS:

Liquid chromatography/tandem mass spectrometry with label-free quantification was used to identify CSF proteins using samples from a well-characterized longitudinal cohort comprising patients with ALS (n = 43), the upper motor neuron variant, primary lateral sclerosis (PLS; n = 6), and cross-sectional healthy (n = 20) and disease controls (Parkinsons' disease, n = 20; ALS mimic disorders, n = 12).

RESULTS:

Three macrophage-derived chitinases showed increased abundance in ALS: chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1), and chitinase-3-like protein 2 (CHI3L2). Elevated CHI3L1 was common to ALS and PLS, whereas CHIT1 and CHI3L2 levels differed. Chitinase levels correlated with disease progression rate (CHIT1, r = 0.56, p < 0.001; CHI3L1, r = 0.31; p = 0.028; CHI3L2, r = 0.29, p = 0.044). CHIT1, CHI3L1, and CHI3L2 levels correlated with phosphorylated neurofilament heavy chain (pNFH; r = 0.62, p < 0.001; r = 0.49, p < 0.001; r = 0.41, p < 0.001). CHI3L1 levels, but not CHIT1 or CHI3L2, increased over time in those with low initial levels (gradient = 0.005 log abundance units/month, p = 0.001). High CHIT1 was associated with shortened survival (hazard ratio [HR] 2.84; p = 0.009). Inclusion of pNFH in survival models left only an association of pNFH and survival (HR 1.26; p = 0.019).

INTERPRETATION:

Neuroinflammatory mechanisms have been consistently implicated through various experimental paradigms. These results support a key role for macrophage activity in ALS pathogenesis, offering novel target engagement and pharmacodynamic biomarkers for neuroinflammation-focused ALS therapy. Ann Neurol 2018;83:258-268.

• Authors: Alexander G Thompson, Elizabeth Gray, Marie-Laëtitia Thézénas, Philip D Charles, Samuel Evetts, Michele T Hu, Kevin Talbot, Roman Fischer, Benedikt M Kessler, Martin R Turner
• Journal: Annals of neurology (Ann Neurol) Vol. 83 Issue 2 Pg. 258-268 (02 2018) ISSN: 1531-8249 [Electronic] United States
• PMID: 29331073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

Chemical References

• Biomarkers
• Chitinases

Topics

• Amyotrophic Lateral Sclerosis (cerebrospinal fluid)
• Biomarkers (cerebrospinal fluid)
• Chitinases (cerebrospinal fluid)
• Cohort Studies
• Cross-Sectional Studies
• Disease Progression
• Female
• Humans
• Macrophages (enzymology)
• Male
• Middle Aged
• Proteomics (methods)