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


OBJECTIVE
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 beta2-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.
Mitchell
R M
RM
Department of Neurosurgery, Pennsylvania State University College of Medicine/Milton S. Hershey Medical Center, Hershey, PA 17033-0850, USA.
Freeman
W M
WM
Randazzo
W T
WT
Stephens
H E
HE
Beard
J L
JL
Simmons
Z
Z
Connor
J R
JR
D000596:Amino Acids / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D016207:Cytokines / Q000097:blood / Q000134:cerebrospinal fluid; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000134:cerebrospinal fluid* / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood / Q000134:cerebrospinal fluid; D008297:Male; D008565:Membrane Proteins / Q000097:blood / Q000134:cerebrospinal fluid* / Q000235:genetics*; D008875:Middle Aged; D009422:Nervous System Diseases / Q000097:blood / Q000134:cerebrospinal fluid; D011110:Polymorphism, Genetic / Q000235:genetics*; D018709:Statistics, Nonparametric; D001613:beta 2-Microglobulin / Q000134:cerebrospinal fluid
D000596:Amino Acids; D015415:Biomarkers; D016207:Cytokines; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D001613:beta 2-Microglobulin