This Phase I, STTR application focuses on developing a novel brain molecular metabolomic biomarker for cognitive impairment in chronic alcoholism. Approximately 1 1/2 to 2/3rds of recently detoxified chronic alcoholics have cognitive impairment. The molecular underpinnings for the cognitive impairment and why some chronic alcoholics became cognitively impaired and not others is unknown. At a molecular level, ethanol has been shown to have both acute and chronic effects on membrane associated function and properties. The purpose of the present application is to analyze existing NIHfunded multi-voxel 31P and 1H magnetic resonance spectroscopic imaging (31P-1H MRSI) data sets to develop a brain molecular biomarker for the Cognitive impairment observed in some chronic alcoholism subjects. Since cognitive deficits are present in other neuropsychiatric disorders, for example chronic schizophrenia, a comparison of molecular measures associated with cognitive impairment in chronic schizophrenia with those of chronic alcoholism will help to establish a biomarker specific for cognitive impairment in alcoholism. Since the majority of alcoholics smoke, the effect of nicotine on the MRSI measures will be provided by a (NIH-funded) nicotine challenge to middle age smokers which will be included in the analysis. Funds are requested for Phfr, Inc., a small business focused on the development and commercialization of novel, non-invasive brain imaging biomarkers for neuropsychiatric disorders such as chronic alcoholism, Alzheimer's disease, major-depressive disease, and schizophrenia with the University of Pittsburgh as the nonprofit partner. In Phase I, we propose to analyze 31P-1H data from: a pilot study of cognition in chronic alcoholism (males, cognitively impaired N=4; cognitively unimpaired N=5; control subjects N=16); an NIH funded study (MH058308) of cognition in chronic schizophrenia (males, cognitively impaired N=19; cognitively unimpaired N=16; control subjects N=10); and an NIH funded study (DA11735) of the effect of nicotine (smokers, males N=4, females N=4). The data from these in vivo multi-voxel 31P-1H MRSI studies provide measures of molecular alterations in brain membrane phospholipid and high-energy phosphate metabolism, synaptic/transport vesicles and phosphorylated proteins and metabolites with N-acetyl moieties from right and left prefrontal, superior temporal, inferior parietal, occipital, basal ganglia, and centrum semiovale brain regions. The brain molecular biomarker will provide insights into the molecular basis for cognitive impairment in chronic alcoholism which could lead to future therapeutic and preventative measures. ? ? ?
