Postmortem neuropathological studies indicate that excessive chronic intake of ethanol decreases the number of neurons in the superior frontal region of the cerebral cortex. Biochemical studies on postmortem tissue of chronically alcohol-dependent subjects suggest that GABA- A/benzodiazepine (BDZ) receptors may be decreased in the frontal cortex and hippocampus but not in other areas of the cerebral cortex. Utilizing positrons emission tomography (PET) with [11C]Flumazenil, we propose to determine whether the density of BDZ receptors is reduced within the frontal cortex in living chronically alcohol-dependent persons as compared with a group of normal control subjects with similar age and sex distributions. Using PET with [18F]fluorodeoxyglucose in the same subjects, we will examine the local cerebral metabolic rate for glucose (LCMRG) and compare the distribution of BDZ receptor binding with the pattern of LCMRG. We anticipate finding in chronically alcohol-dependent patients a decrease in the density of BDZ receptors and a decrease in LCMRG in the superior frontal region of the cerebral cortex. We will use neuropsychological tests t study frontal lobe function in the same patients, and anticipate finding that performance is diminished and correlated with the level of reduction of BDZ receptors and of LCMRG in the superior frontal cortex. Neuropathological studies also demonstrate that excessive chronic intake of ethanol decreases the number of neurons in the superior vermis of the cerebellum, even in patients who had no symptoms of cerebellar disorder in life. Biochemical studies on postmortem tissue of chronically alcohol-dependent subjects suggest that BDZ receptor binding may be decreased in the cerebellum. We propose to use [11C]flumazenil and [18F]fluorodeoxyglucose with PET to examine the density of BDZ receptors and the pattern of LCMRG in patients with clinically symptomatic alcoholic cerebellar degeneration (ACD), in chronically alcohol-dependent patients without evidence of cerebellar degeneration and in normal control subjects of similar age and sex distribution. In order to detect any biochemical changes resulting from the anatomical connections between the cerebral cortex and the cerebellum, we also propose to study patients with a chronic cerebellar degeneration (dominantly inherited olivopontocerebellar atrophy, OPCA) using the same PET probes to determine whether focal disturbances in BDZ binding and decrease LCMRG confined to the anterior superior cerebellum. We anticipate finding decreased BDZ binding and decreased LCMRG confined to and in alcohol- dependent patients without ACD, and reduced BDZ binding and decreased LCMRG widely i the cerebellum but not focally in the cerebral cortex in patients with OPCA.
Showing the most recent 10 out of 70 publications
