Author(s): Srikanth Ranganathan (1), Eric Williams (2), Philip Ganchev (2), Vanathi Gopalakrishnan (2), David Lacomis (3), Leo Urbinelli (4), Kristyn Newhall (4), Merit E. Cudkowicz (4), Robert H. Brown Jr. (5) and Robert Bowser (1)
1) Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
2) Center for Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA
3) Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
4) Neurology Clinical Trials Unit, Massachusetts General Hospital East, Charlestown, MA, USA
5) Day Neuromuscular Research Laboratory, Massachusetts General Hospital East, Charlestown, MA, USA
Title: Proteomic Profiling of Cerebrospinal Fluid Identifies Biomarkers for Amyotrophic Lateral Sclerosis
Summary: Amyotrophic lateral sclerosis (ALS) is the most common adult motor neuron disease, affecting one in every 40 000 individuals (Jackson and Bryan 1998). It typically affects individuals in their mid-50s and is characterized by rapidly progressive degeneration of motor neurons in the cerebral cortex, brainstem and spinal cord. The median survival in ALS is three to five years (Jackson and Bryan 1998; Cleveland and Rothstein 2001). ALS exists in both sporadic and familial forms. Familial ALS (FALS) comprises only 5–10% of all ALS cases.
Since amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons, the study tested the hypothesis that proteomic analysis will identify protein biomarkers that provide insight into disease pathogenesis and are diagnostically useful.
To identify ALS specific biomarkers, the research team compared the proteomic profile of cerebrospinal fluid (CSF) from ALS and control subjects using surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF-MS).
The investigation identified 30 mass ion peaks with statistically significant (p < 0.01) differences between control and ALS subjects. Initial analysis with a rule-learning algorithm yielded biomarker panels with diagnostic predictive value as subsequently assessed using an independent set of coded test subjects.
Three biomarkers were identified that are either decreased (transthyretin, cystatin C) or increased (carboxy-terminal fragment of neuroendocrine protein 7B2) in ALS CSF.
The research team validated the SELDI-TOF-MS results for transthyretin and cystatin C by immunoblot and immunohistochemistry using commercially available antibodies. These findings identify a panel of CSF protein biomarkers for ALS.
Source: J. Neurochem. (2005) 95, 1461–1471.