Dementia of the Alzheimer's type (DAT) is marked by the progressive loss of neurons from many brain regions, including the cerebral cortex, hippocampus, and basal forebrain. Pyramidal cells are the predominant cell type affected in the former two structures. These cells contain a high density of excitatory amino acid (EAA) receptors and use EAA's as their primary neurotransmitters. Excessive release of EAA's is known to produce a sequelae of neuronal damage and cell death. It has been suggested that the neuronal loss and cognitive impairment observed in DAT may reflect a pathological alteration in central EAA levels. Given the proximity of cortical and hippocampal structures to cerebrospinal fluid (CSF) spaces, analysis of CSF EAA levels may offer an accessible, yet sensitive antemortem assay of brain tissue EAA content in DAT patients. Plasma levels of the putative EAA, L-Cysteine (Cys) may offer an additional antemortem index of DAT, since a recent report has described changes in the plasma Cys:sulfate ratio in DAT patients. The proposed project will directly assess DAT stage-specific changes in CSF EAA levels and Cys:sulfate ratios in CSF and plasma. Specifically, glutamate, aspartate and glycine concentrations in CSF, and L-cysteine:sulfate ratios in both CSF and plasma will be compared between patients exhibiting severe dementia (CDR 3, Washington University Clinical Dementia Rating), moderate dementia (CDR 2), mild dementia (CDR 1), questionable dementia (CDR 0.5), and age-matched patients with no reported dementia (CDR 0). Each biological measure will then be correlated with patient performance on neuropsychological tests sensitive to hippocampal and/or frontal cortical dysfunction, as well as tests of global cognitive functioning. Overall, it is hoped that these studies will characterize the utility of antemortem EAA markers as indicators of disease progression. Furthermore, the results of this research may provide valuable insights into neurodegenerative processes involved in DAT.
Showing the most recent 10 out of 130 publications
