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From the Geriatric Research, Education, and Clinical Center (G.M.P., S.Y., L.H.), Bronx Veterans Affairs Medical Center, Bronx, NY; Neuroinflammation Research Laboratories (G.M.P., S.Y., L.H.) of the Department of Psychiatry (G.M.P., S.Y., S.M., L.H.) and MDA/ALS Program (D.J.L.), Department of Neurology, Mount Sinai School of Medicine, and Proteomics Resource Center (H.D., X.Y.), Rockefeller University, New York, NY; Department of Computation and Informatics Sciences (L.H.U.), University of Pennsylvania, Philadelphia; Day Laboratory for Neuromuscular Research (R.H.B., M.E.C., K.N.), Massachusetts General Hospital, Boston; and Department of Psychiatry and Behavioral Sciences (E.P.), University of Washington School of Medicine, and VA Mental Illness Research, Education, and Clinical Center, Harborview Medical Center, Seattle, WA.
Address correspondence and reprint requests to Dr Pasinetti, Neuroinflammation Research Laboratories, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1668, New York, NY 10029; e-mail: giulio.pasinetti{at}mssm.edu
Background: The clinical diagnosis of ALS is based entirely on clinical features. Identification of biomarkers for ALS would be important for diagnosis and might also provide clues to pathogenesis.
Objective: To determine if there is a specific protein profile in the CSF that distinguishes patients with ALS from those with purely motor peripheral neuropathy (PN) and healthy control subjects.
Methods: CSF obtained from patients with ALS, disease controls (patients with other neurologic disorders), and normal controls were analyzed using the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry proteomics technique. Biomarker sensitivity and specificity was calculated with receiver operating characteristic curve methodology. ALS biomarkers were purified and sequence identified by mass spectrometry–directed peptide sequencing.
Results: In initial proteomic discovery studies, three protein species (4.8-, 6.7-, and 13.4-kDa) that were significantly lower in concentration in the CSF from patients with ALS (n = 36) than in normal controls (n = 21) were identified. A combination of three protein species (the "three-protein" model) correctly identified patients with ALS with 95% accuracy, 91% sensitivity, and 97% specificity from the controls. Independent validation studies using separate cohorts of ALS (n = 13), healthy control (n = 25), and PN (n = 7) subjects confirmed the ability of the three CSF protein species to separate patients with ALS from other diseases. Protein sequence analysis identified the 13.4-kDa protein species as cystatin C and the 4.8-kDa protein species as a peptic fragment of the neurosecretory protein VGF.
Conclusion: Additional application of a "three-protein" biomarker model to current diagnostic criteria may provide an objective biomarker pattern to help identify patients with ALS.
Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the April 25 issue to find the title link for this article.
This article was previously published in electronic format as an Expedited E-Pub on February 15, 2006, at www.neurology.org.
Supported in part by MDA, ALS Association, NIH AG02219, and Department of Veterans Affairs ALS research grant to G.M.P. R.H.B. receives support from the National Institute of Neurological Disease and Stroke, the National Institute for Aging, Project ALS, the ALS Association, the Muscular Dystrophy Association, the Angel Fund, the ALS Therapy Alliance, the Al-Athel ALS Research Foundation, and the Pierre L. de Bourgknecht ALS Research Foundation. M.E.C. is supported by the ALS Association and the NIEHS.
Disclosure: The authors report no conflicts of interest.
Received October 28, 2005. Accepted in final form December 29, 2005.
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