Identification of potential CSF biomarkers in ALS.
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.


CONCLUSIONS
Additional application of a "three-protein" biomarker model to current diagnostic criteria may provide an objective biomarker pattern to help identify patients with ALS.
Geriatric Research, Education, and Clinical Center, Bronx Veterans Affairs Medical Center, Bronx, NY, USA. giulio.pasinetti@mssm.edu
G M
GM
Pasinetti
L H
LH
Ungar
D J
DJ
Lange
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Yemul
H
H
Deng
X
X
Yuan
R H
RH
Brown
M E
ME
Cudkowicz
K
K
Newhall
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Peskind
S
S
Marcus
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L
Ho
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000134:cerebrospinal fluid* / Q000175:diagnosis* / Q000503:physiopathology; D015415:Biomarkers / Q000134:cerebrospinal fluid; D002556:Cerebrospinal Fluid Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000302:isolation & purification*; D055316:Cystatin C; D015891:Cystatins / Q000134:cerebrospinal fluid / Q000302:isolation & purification; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000302:isolation & purification*; D009479:Neuropeptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000134:cerebrospinal fluid* / Q000302:isolation & purification; D010523:Peripheral Nervous System Diseases / Q000134:cerebrospinal fluid / Q000175:diagnosis / Q000503:physiopathology; D011237:Predictive Value of Tests; D040901:Proteomics / Q000379:methods; D012680:Sensitivity and Specificity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D015415:Biomarkers; C525030:CST3 protein, human; D002556:Cerebrospinal Fluid Proteins; D055316:Cystatin C; D015891:Cystatins; D009414:Nerve Growth Factors; D009479:Neuropeptides; C510637:VGF protein, human