The objective of this Phase I application is to develop a sensitive biomarker for quantifying neuronal damage resulting from acute alcohol abuse. Specifically, we will determine whether elevated serum levels of cleaved-tau observed after acute alcohol abuse reflect neuronal damage. MAP-tau is a cytoskeletal protein localized in neuronal axons; after neuronal damage MAP-tau is proteolytically cleaved. Our previous research demonstrates that cleaved-tau is a reliable biomarker of neuronal damage after severe head trauma and stroke. Our Preliminary Studies indicate that individuals admitted to the Emergency Department for acute alcohol abuse demonstrated elevated plasma cleaved-tau levels suggesting that acute alcohol abuse results in acute neuronal damage. Alternately, acute alcohol abuse may cause hepatotoxicity. Low liver MAP-tau levels, 0.3 percent of brain, have been reported. In Preliminary Studies elevated cleaved-tau levels were observed in the absence of hepatotoxicity (AST < 3X ULN), therefore it its unlikely that the elevated cleaved-tau observed after acute alcohol abuse originated from liver.
Our Specific Aims will assess the magnitude of serum cleaved-tau elevation after acute alcohol abuse, determine the correlation between serum cleaved-tau levels and blood alcohol levels, and explore whether cleaved-tau may be of hepatic origin.
Specific Aim 1 : Determine if serum cleaved-tau levels are elevated after acute alcohol abuse compared to controls.
Specific Aim 2 : Determine the statistical relationship between serum cleaved-tau levels and blood alcohol levels after acute alcohol abuse.
Specific Aim 3 : Determine whether serum cleaved-tau levels are elevated in patients with acute liver failure.
The proposed biomarker for ethanol-induced neuronal damage can ultimately be formatted in a point-of-care assay to assist physicians in developing individualized interventions for alcohol abuse and dependence. United States hospital discharged more than 1.8 million patients with all-listed, including first-listed, alcohol-related diagnoses. If these hospitalized patients had neurotoxicity measured using the proposed biomarker, then the potential market for the assay is $56 million per year.
