Imaging-Guided Microarray Identifies Molecular Markers in Schizophrenia and Parkinson's Disease.

Imaging-guided microarray is an approach that utilizes in vivo human functional magnetic resonance imaging to successfully guide a microarray experiment in order to elucidate molecular markers in neurological disorders. The approach is useful in attenuating many of the inherent problems that are seen with microarray experiments such as low signal amplitude, noise, and the occurrence of false positive results. The goal of this study is to demonstrate the utility of this approach by applying it to two different neurological disorders, schizophrenia and Parkinson's disease. The first possibly having a more developmental origin with no known specific marker, and the latter being more of a neurodegenerative disorder with known histological hallmarks. Studies have long implicated the hippocampal formation in schizophrenia pathology. Although the hippocampal subregion that is most vulnerable in the disease remains unknown. The following studies have shown a hypermetabolic state within the cornu ammonis (CA1) hippocampal subfield. This hypermetabolism may be due to a decrease in glutamate dehydrogenase 1 (GLUD1), a key enzyme in the catabolism of glutamate that was found through molecular studies. Through the administration of gabapentin (a known activator of GLUD1) a decrease in metabolism was seen in mice, which may hold promise for drug therapy in schizophrenia. Studies have also implicated the dorsal motor nucleus of the vagus (DMNV) as one of the first pathological sites in Parkinson's disease (PD). The following studies have shown a hypometabolic state within the DMNV, which may be due to the observed decrease in spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate limiting enzyme in polyamine catabolism. This deficiency in polyamine metabolism was validated in a Saccharomyces cerevisiae PD model, by exogenously adding spermine (a higher order polyamine) which enhanced the toxicity of the human alpha-synuclein that was expressed in this PD yeast model. Further validation was shown by identifying a rare but novel disease associated mutation in SAT1 within PD patients. Taken together these findings support the utility of imaging guided microarray in elucidating pathogenic molecular markers that contribute to various neurological disorders.