There is considerable evidence that cholinergic and glutaminergic neurons are both lost in both Alzheimer's disease (AD), and Huntington's disease (HD). The severity and site of this neuronal loss differs in these disorders, however, and the effect of this loss on patient symptomatology remains unclear. To further understand the role of acetylcholine and glutamate upon cognition in dementia, we will investigate the cognitive effects of intravenous ketamine, a glutaminergic antagonist, and scopolamine, a cholinergic antagonist, in these disorders. First we will determine the minimal doses of intravenous ketamine that are needed to induce significant cognitive effects in patients with AD. Next, we will compare the effects of this dose of ketamine, intravenous scopolamine at a dose that has been found to be subthreshold for aged normals, and placebo, in patients with AD and HD, and in normals. The result of neuropsychological testing performed during these drug challenges will be used to asses whether the cognitive effects differ between these two drugs, or whether they differ when given to patients with dementia due to AD and HD. The results of this study will suggest how cholinergic and glutamatergic deficits contribute to the cognitive impairments characteristic of these dementing disorders, and whether glutamatergic therapies are likely to be beneficial. A better understanding of the cognitive effects of glutamatergic antagonists will also be useful when considering whether these drugs ought to be used to treat neurological disorders.
| Murman, D L; Giordani, B; Mellow, A M et al. (1997) Cognitive, behavioral, and motor effects of the NMDA antagonist ketamine in Huntington's disease. Neurology 49:153-61 |
