SBIR-STTR Award

Prototype Multiple Electrode Liquid Chromatogrampy (n-ELC) systems have been developed for simultaneous analysis of several hundred components in biological samples at the femtogram level. A major market for n-ELC systems depends on the demonstration of the relevance of multicomponent measurements to degenerative neurological disorders. Recently, quinolinic acid (QA) has been shown to replicate the histological and neurochemical features of Huntington's Disease (HD), a progressive degenerative neurological disorder. We propose to develop and apply n-ELC methods for the analysis of the kynurenine (KY) pathway leading to QA. The intent is to develop procedures capable of locating a metabolic defect in HD leading to increased QA accumulation. Simultaneously, the n-ELC procedures will provide information on approximately 40 other components of the tyrosine and tryptophan pathways. These data will be used to qualify the KY pathway and improve interclass correlations between HD and normals. The measurements will be carried out on CSF from Massachusetts General Hospital, Boston, MA (MGH) and brain tissue from the McLean Hospital Brain Tissue Resource Center, Belmont, MA. As part of an ongoing program at MGH, the samples will also be assayed for QA, amino acids and neuropeptides. The long-range aim of the project is to define the neurochemical pathways in HD in sufficient detail to guide pharmacological intervention

The analysis of an initial multiparameter data base of 227-43 components in 144 brain samples indicated significant differences in the kynurenic, serotonergic and dopaminergic systems between Huntington's Disease (HD) and control putamen. These were consistent with the quinolinic acid hypothesis of neuronal degeneration. In the Phase II study, we purpose to create a larger data base of approximately 4000 samples from additional tissues and among different disorders using the methods for multiparameter measurements and the procedures for rapid data reduction, transfer and management developed for the ESA Neurochemical Analyzer (NCA). Tissues will be analyzed from several different HD and control brain regions to examine whether the kynurenic abnormalities are primary or secondary to gliosis, and in plasma and CSF to determine if they are general expressions of a defect. Similar tissues will be examined among other disorders (Alzheimer;s and Parkinson"s disease, ALS, Schizophrenia) to determine if the abnormalities are unique to HD and to rule out drug related anomalies. Measurements to test the HD model will be made on animal models of acute and chronic excitotoxin lesions and in feeding models with and without portacaval shunts. The long term goal of the work is to provide a data base and biochemical model of HD that can be used as a guide to develop therapeutic strategies