Thursday, October 6, 2011

New Potential ALS Multiprotein Biomarker: Going Beyond Nerve Pathology

In the October 5th issue of PLos One, Nardo and colleagues (link) present the results of their work on a new peripheral blood cell-bases biomarker for the diagnosis and monitoring of Amyotrophic Lateral Sclerosis (ALS: a disease of the nerve cells in the brain and spinal cord that control voluntary muscle movement).
Based on the assumption that ALS pathobiology is no restricted to the nervous system, the authors conducted a classic proteomics analysis (2D-DIGE) of pooled peripheral blood mononuclear cells (PBMC) collected from healthy controls and patients suffering from ALS (grouped into two disease severity cohorts based on the ALS functional rating scale revised [ALSFRS-R]).  The first set of 71 candidate biomarkers was first refined to a 14-protein biomarker panel by validation against healthy controls.  This subset was further refined to a 5-protein ALS-specific biomarker panel (table 1) by validation against other neurological disease controls that may clinically resemble ALS.  

Table 1

Out of this 5-protein panel, the combination of IRAK4 and CypA was the most associated with ALS versus other neurological disorders, yielding a discriminatory power of 91% at the appropriate cut-off value (Receiver Operator Curve AUC = 0.905).
From the original 14-protein biomarker panel, the authors also derived a 3-protein ALS severity biomarker panel (table 2) by comparing patient samples from moderate disease (ALSFRS-R > 24) to samples from patients with severe disease (ALSFRS 24).  Out of this 3-protein panel, ERp57 was the most associated with disease severity with 89% discriminatory power at the appropriate cut-off level (Receiver Operator Curve AUC = 0.893).
Table 2
Finally, the authors investigated the translational value of the 14-protein biomarker panel by analyzing those proteins in the PBMC and the spinal cord from a rat model of ALS (G93A SOD1-transgenic rats).
By showing that disease biomarkers for a neurological disease can be identified in easily obtainable PBMC, this work represents an important step in the evolution of biomarker research.  Instead of limiting the scope of biomarker research to the specific anatomical compartment primarily affected by the disease, which in the case of the central nervous system is essentially inaccessible, the field may significantly benefit from considering accessible peripheral tissues which may display secondary pathobiology similar to that affecting the primary tissues. 

Thierry Sornasse for Integrated Biomarker Strategy

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