Journal article
Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis
- Abstract:
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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 samples.
Methods: Liquid chromatography-tandem mass spectrometry with label-free quantification was used to identify cerebrospinal fluid proteins using samples from a well-characterised longitudinal cohort comprising patients with ALS (n=43), the upper motor neuron variant primary lateral sclerosis (PLS, n=6), cross-sectional healthy (n=20) and disease controls (Parkinsons’s 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 (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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 735.5KB, Terms of use)
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- Publisher copy:
- 10.1002/ana.25143
Authors
- Publisher:
- Wiley
- Journal:
- Annals of Neurology More from this journal
- Volume:
- 83
- Issue:
- 2
- Pages:
- 258-268
- Publication date:
- 2018-02-09
- Acceptance date:
- 2018-01-09
- DOI:
- EISSN:
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1531-8249
- ISSN:
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0364-5134
- Keywords:
- Pubs id:
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pubs:817634
- UUID:
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uuid:6f15622a-8760-47c8-9c68-381a77d517a6
- Local pid:
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pubs:817634
- Source identifiers:
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817634
- Deposit date:
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2018-01-11
- ARK identifier:
Terms of use
- Copyright holder:
- Thompson et al
- Copyright date:
- 2018
- Notes:
- © 2018 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Licence:
- CC Attribution (CC BY)
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