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From the Departments of Neurosurgery (R.M.M., W.T.R., J.R.C.), Pharmacology (W.M.F.), and Neurology (H.E.S., Z.S.), George M. Leader Family Laboratory, Pennsylvania State University College of Medicine/Milton S. Hershey Medical Center, Hershey; and Department of Nutrition (J.L.B.), Pennsylvania State University, College Park.
Address correspondence and reprint requests to Dr. James R. Connor, Department of Neurosurgery, H110, The Pennsylvania State University College of Medicine, 500 University Drive (H110), Hershey, PA 17033-0850 jconnor{at}psu.edu
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.
Abbreviations: 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.
Supplemental data at www.neurology.org
Editorial, page 11
e-Pub ahead of print on November 5, 2008, on www.neurology.org.
Supported by funds from The Judith and Jean Pape Adams Charitable Foundation, The Paul and Harriett Campbell Fund for ALS Research, The Zimmerman Family Love Fund, and the ALS Association Greater Philadelphia Chapter.
Disclosure: The authors report no disclosures.
Received January 7, 2008. Accepted in final form May 21, 2008.
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