Previous work has identified a subgroup of chronic alcoholism subjects with severe, generalized cognitive impairment and a very poor outcome. What is critically lacking are brain molecular biomarkers that antedate both the cognitive impairment and the earliest, most minimal brain structural changes. Given the increased morbidity associated with cognitive impairment in chronic alcoholism subjects, further insights into the molecular basis for the cognitive changes are essential and could lead to future therapeutic and preventative measures as well as the ability to monitor neuromolecular responses to those therapeutic measures. The purpose of Phase I of the present SBIR Phase I/Phase II Fast Track application is to analyze existing NIH-funded multi-voxel 31P and 1H magnetic resonance spectroscopic imaging data sets to refine brain molecular biomarkers for neural membrane degeneration demonstrated in our STTR Phase I application. The STTR Phase I data strongly suggests it is the brain membrane phospholipid degeneration in the absence of adequate repair that results in cognitive impairment in chronic alcoholism. The neuromolecular biomarkers will reflect molecular changes that antecede brain structural changes observed by quantitative MRI-based neuromorphometrics and will predict which subjects with chronic alcoholism are at increased risk to develop cognitive impairment. Phase II of this proposal will focus on developing a software package in partnership with SterlingTech Software for analyses of MRSI data obtained from individual subjects to be compared to a normative basis set, analyze the data for abnormalities found in comparison with the normative basis set, and display changes in the individual subject. The proposed approach is unique because it directly and non-invasively measures critical aspects of brain molecular composition and metabolism in living subjects, specifically: 1) key aspects of membrane phospholipid metabolism;2) utilization of high-energy phosphates;3) dynamic aspects of protein phosphorylation - dephosphorylation;4) the number of brain synaptic and transport vesicles;5) key intermediates in the glycosylation of lipids and proteins;and 6) a marker of neuronal integrity. 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 the specificity of the biomarker for cognitive impairment in alcoholism. Brain molecular biomarkers which could distinguish molecular findings associated with cognitive impairment in chronic alcoholism from that observed in other neuropsychiatric disorders would be of great theoretical and practical clinical importance.
Brain molecular biomarkers such as proposed in this application could be used to guide further understanding of the molecular underpinnings of cognitive impairment in chronic alcoholism This will enhance future therapeutic and preventative approaches designed to repair or prevent neural membrane damage observed in alcoholism. The molecular biomarkers will be used to develop a software package in partnership with SterlingTech Software that will analyze individual 31P and 1H magnetic resonance spectroscopic imaging data and produce a color-coded brain image showing how that subject compares to a control population. The software package will be commercialized and marketed to corporations (primarily MR manufacturers), institutions, and individuals worldwide.
