Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis

被引：104

作者：

Thompson, Alexander G. ^{[1
]}

Gray, Elizabeth ^{[1
]}

Thezenas, Marie-Laetitia ^{[2
]}

Charles, Philip D. ^{[2
]}

Evetts, Samuel ^{[1
]}

Hu, Michele T. ^{[1
]}

Talbot, Kevin ^{[1
]}

Fischer, Roman ^{[2
]}

Kessler, Benedikt M. ^{[2
]}

Turner, Martin R. ^{[1
]}

机构：

[1] Univ Oxford, Nuffield Dept Clin Neurosci, Oxford, England

[2] Univ Oxford, Target Discovery Inst, Oxford, England

来源：

ANNALS OF NEUROLOGY | 2018年 / 83卷 / 02期

基金：

英国医学研究理事会;

关键词：

CHITOTRIOSIDASE; ACTIVATION;

D O I：

10.1002/ana.25143

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

ObjectiveThe 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. MethodsLiquid 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). ResultsThree 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). InterpretationNeuroinflammatory 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

引用

页码：258 / 268

页数：11

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