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January 06, 2009; 72 (1) Articles

A CSF biomarker panel for identification of patients with amyotrophic lateral sclerosis

R. M. Mitchell, W. M. Freeman, W. T. Randazzo, H. E. Stephens, J. L. Beard, Z. Simmons, J. R. Connor
First published November 5, 2008, DOI: https://doi.org/10.1212/01.wnl.0000333251.36681.a5
R. M. Mitchell
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W. M. Freeman
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W. T. Randazzo
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H. E. Stephens
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J. L. Beard
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Z. Simmons
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J. R. Connor
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Citation
A CSF biomarker panel for identification of patients with amyotrophic lateral sclerosis
R. M. Mitchell, W. M. Freeman, W. T. Randazzo, H. E. Stephens, J. L. Beard, Z. Simmons, J. R. Connor
Neurology Jan 2009, 72 (1) 14-19; DOI: 10.1212/01.wnl.0000333251.36681.a5

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Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with complicated pathogenesis that poses challenges with respect to diagnosis and monitoring of disease progression.

Objectives: To identify a biomarker panel that elucidates ALS disease pathogenesis, distinguishes patients with ALS from neurologic disease controls, and correlates with ALS disease characteristics, and to determine the effect of HFE gene variants, a potential risk factor for sporadic ALS, on the biomarker profile.

Methods: We obtained CSF samples by lumbar puncture from 41 patients with ALS and 33 neurologic disease controls. All patients were genotyped for HFE polymorphisms. We performed a multiplex cytokine and growth factor analysis and immunoassays for iron-related analytes. Classification statistics were generated using a support vector machine algorithm.

Results: The groups of patients with ALS and neurologic disease controls were each associated with distinct profiles of biomarkers. Fourteen biomarkers differed between patients with ALS and the control group. The five proteins with the lowest p values differentiated patients with ALS from controls with 89.2% accuracy, 87.5% sensitivity, and 91.2% specificity. Expression of IL-8 was higher in those patients with lower levels of physical function. Expression of β2-microglobulin was higher in subjects carrying an H63D HFE allele, while expression of several markers was higher in subjects carrying a C282Y HFE allele.

Conclusions: A CSF inflammatory profile associated with amyotrophic lateral sclerosis (ALS) pathogenesis may distinguish patients with ALS from neurologic disease controls, and may serve as a biomarker panel to aid in the diagnosis of ALS pending further validation. Some of these biomarkers differ by HFE genotype.

Glossary

ALS=
amyotrophic lateral sclerosis;
ALSFRS-R=
ALS Functional Rating Scale-revised;
BSA=
bovine serum albumin;
FGF=
fibroblast growth factor;
G-CSF=
granulocyte colony stimulating factor;
GM-CSF=
granulocyte-monocyte colony stimulating factor;
IFN=
interferon;
IL=
interleukin;
MCP=
monocyte chemoattractant protein;
MIP=
macrophage inflammatory protein;
VEGF=
vascular endothelial growth factor.
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