Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis
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- Alexander G. Thompson
- Nuffield Department of Clinical Neurosciences University of Oxford United Kingdom
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- Elizabeth Gray
- Nuffield Department of Clinical Neurosciences University of Oxford United Kingdom
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- Marie‐Laëtitia Thézénas
- Target Discovery Institute University of Oxford Oxford United Kingdom
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- Philip D. Charles
- Target Discovery Institute University of Oxford Oxford United Kingdom
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- Samuel Evetts
- Nuffield Department of Clinical Neurosciences University of Oxford United Kingdom
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- Michele T. Hu
- Nuffield Department of Clinical Neurosciences University of Oxford United Kingdom
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- Kevin Talbot
- Nuffield Department of Clinical Neurosciences University of Oxford United Kingdom
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- Roman Fischer
- Target Discovery Institute University of Oxford Oxford United Kingdom
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- Benedikt M. Kessler
- Target Discovery Institute University of Oxford Oxford United Kingdom
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- Martin R. Turner
- Nuffield Department of Clinical Neurosciences University of Oxford United Kingdom
Abstract
<jats:sec><jats:title>Objective</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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, <jats:italic>r</jats:italic> = 0.56, <jats:italic>p</jats:italic> < 0.001; CHI3L1, <jats:italic>r</jats:italic> = 0.31; <jats:italic>p</jats:italic> = 0.028; CHI3L2, <jats:italic>r</jats:italic> = 0.29, <jats:italic>p</jats:italic> = 0.044). CHIT1, CHI3L1, and CHI3L2 levels correlated with phosphorylated neurofilament heavy chain (pNFH; <jats:italic>r</jats:italic> = 0.62, <jats:italic>p</jats:italic> < 0.001; <jats:italic>r</jats:italic> = 0.49, <jats:italic>p</jats:italic> < 0.001; <jats:italic>r</jats:italic> = 0.41, <jats:italic>p</jats:italic> < 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, <jats:italic>p</jats:italic> = 0.001). High CHIT1 was associated with shortened survival (hazard ratio [HR] 2.84; <jats:italic>p</jats:italic> = 0.009). Inclusion of pNFH in survival models left only an association of pNFH and survival (HR 1.26; <jats:italic>p</jats:italic> = 0.019).</jats:p></jats:sec><jats:sec><jats:title>Interpretation</jats:title><jats:p>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</jats:p></jats:sec>
Journal
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- Annals of Neurology
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Annals of Neurology 83 (2), 258-268, 2018-02
Wiley
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Details 詳細情報について
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- CRID
- 1361981469974636672
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- ISSN
- 15318249
- 03645134
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- Data Source
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- Crossref