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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.
* To whom correspondence should be addressed. E-mail: giulio.pasinetti{at}mssm.edu.
Abstract-- 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.
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