Changes In Brain Glucose Metabolism Research Articles

Changes in brain glucose metabolism as a key to the pathogenesis of Alzheimer's disease.

The article discusses some aspects demonstrating that a decrease in acetylcholine synthesis in senile dementia of the Alzheimer type (SDAT) is a consequence of the strong decline in glucose turnover in the brain. This becomes obvious by the fact that acetylcoenzyme A, the key substrate of acetylcholine synthesis, is exclusively synthesized in the glycolytic pathway in the brain. This means that a single molecule of glucose synthesizes only two molecules of acetylcoenzyme A but 38 molecules of ATP. This is critically changed if glucose metabolism of the brain decreases in SDAT. beta-Amyloid precursor protein (beta-APP) of chromosome 21 is a regular protein of repair of any cellular membrane in the body. It is integrated into the cellular membranes and split off by proteases in the beta-region. This process is ATP-dependent. If in SDAT ATP synthesis is critically lowered by a decreased glucose turnover, beta-APP cannot be built into the cellular membranes and the beta-APP molecule is not split off in the beta-region either. The consequence is a generation of beta-amyloid from beta-APP fragments, which are progressively accumulated in senile plaques and vascular walls. The missing repair of cellular membranes and synapses in the brain results in nerve cell atrophy and a shrinkage of the brain. It is concluded that the cholinergic deficit, nerve cell atrophy and the amyloid accumulation in the brain are secondary phenomena caused by the 50-70% decline of glucose metabolism in SDAT.

Decreased brain metabolism in neurologically intact healthy alcoholics.

The extent to which cerebral dysfunction in alcoholics is related to the direct effects of alcohol in the brain rather than to indirect mechanisms and/or alcohol withdrawal remains unclear. The purpose of this study was to evaluate whether healthy alcoholics with no evidence of alcohol-associated complications showed changes in brain glucose metabolism. Positron emission tomography and [18F]-fluorodeoxyglucose were used to measure regional brain metabolism. The study group consisted of 22 normal, healthy, right-handed volunteers and 22 neurologically intact, healthy, right-handed alcoholics tested 6 to 32 days after alcohol discontinuation. Alcoholics showed significantly lower whole brain metabolism than normal control subjects. Normalization of regional metabolic values to the whole brain metabolic rate revealed that the left parietal and right frontal cortices were the most affected regions. Although the whole brain metabolic rate was correlated with the amount of time since alcohol discontinuation, the "normalized" decreases in left parietal and right frontal glucose metabolism were not. These findings support the contribution of the direct effect of alcohol as well as alcohol withdrawal on the changes in regional brain metabolism seen in alcoholics. They also provide evidence of cerebral changes in neurologically intact healthy alcoholics.

Changes in brain glucose metabolism in cocaine dependence and withdrawal

The authors investigated changes in brain function associated with cocaine dependence and withdrawal to provide clues regarding the processes that lead to the uncontrollable self-administration of cocaine. They measured regional brain metabolism with [18F]-fluorodeoxyglucose (FDG) and positron emission tomography in 15 outpatients with the diagnosis of cocaine abuse and 17 normal comparison subjects. Ten of the patients were studied less than 1 week after they had last had cocaine, and five were studied 2-4 weeks after withdrawal. Patients studied within 1 week of cocaine withdrawal but not those studied within 2-4 weeks of cocaine withdrawal had higher levels of global brain metabolism as well as higher levels of regional brain metabolism in the basal ganglia and orbitofrontal cortex than did normal subjects, probably as a consequence of less brain dopamine activity. There was also a significant relationship between the number of days since cocaine withdrawal and regional brain glucose metabolism in the orbitofrontal cortex and in the basal ganglia, and the correlations between cocaine craving and metabolic activity were significant in the prefrontal cortex and the orbitofrontal cortex. Although the time-dependent fall in metabolic activity suggests that the higher metabolic activity observed less than a week after cocaine withdrawal may represent a nonspecific expression of drug withdrawal, the selectivity of changes in glucose metabolism for the basal ganglia and for the orbitofrontal cortex suggests that the regional metabolic changes seen in cocaine abusers during detoxification are related to changes in brain dopamine activity.

Use of nonradioactive 2-deoxyglucose to study compartmentation of brain glucose metabolism and rapid regional changes in rate.

A method is presented for measuring rapid changes in the rate of glucose phosphorylation in mouse brain with nonradioactive 2-deoxyglucose (DG). After times as short as 1 min after DG injection, the mouse is frozen rapidly, and selected brain regions are analyzed enzymatically for DG, 2-deoxyglucose 6-phosphate (DG6P), and glucose. The rate of glucose phosphorylation can be directly calculated from the rate of change in DG6P, the average levels of DG and glucose, and a constant derived from direct comparison of the rate of changes in glucose and DG6P after decapitation. Experiments with large brain samples provided evidence for a 2% per min loss of DG6P and at least two compartments differing in their rates of glucose metabolism, one rapidly entered by DG with glucose phosphorylation almost double that of average brain and another more slowly entered with a much lower phosphorylation rate. The method is illustrated by changes in phosphorylation within 2 min after injection of a convulsant or an anesthetic and over a 48-min time course with and without anesthesia. The sensitivity of the analytical methods can be amplified as much as desired by enzymatic cycling. Consequently, the method is applicable to very small brain samples. Examples are given for regions with volumes of 5 x 10(-4) microliters, but studies with samples as small as single large cell bodies are feasible.

Brain Glucose Metabolism in Neurologically Normal Patients With Sickle Cell Disease

Neurologic dysfunction is a significant source of morbidity and mortality in the sickle cell diseases, occurring with a prevalence of 6% to 34%. Because changes in brain glucose metabolism may precede gross functional or morphologic alterations, we recently applied the technique of positron emission tomography with fluorodeoxyglucose F 18 in an exploratory study to compare six patients with sickle cell disease without prior neurologic abnormalities (and with normal cranial computed tomographic scans) with six healthy age-matched controls, with respect to overall and regional cerebral metabolic rates for glucose. We found no significant difference in the global metabolic rates for the two groups. However, we observed an unusual clustering of abnormal regional cerebral metabolic rates for glucose in the frontal lobes of these subjects. These results support previous observations that frontal lobe involvement may be quite prevalent in sickle cell disease, even among individuals with normal computed tomographic scans.

Two-day starvation does not alter the kinetics of blood--brain barrier transport and phosphorylation of glucose in rat brain.

The blood-brain barrier (BBB) transport and brain phosphorylation of glucose were assessed in conscious rats subjected to 2 days of starvation. Although plasma glucose decreased, no significant changes in brain blood flow, BBB glucose transport, or 2-deoxy-D-glucose phosphorylation were observed. The data suggest that adaptive changes of brain glucose metabolism previously observed in starvation are located beyond the initial steps of brain entry and phosphorylation.

Regional changes in brain glucose metabolism reflect cognitive impairments in aged rats

Aged rats (22 to 24 months) and young control rats (3 months) were tested in a battery of behavioral tests which included tests of learning, place navigation, sensorimotor integration, motor coordination, activity, and exploration. Following testing all animals were analyzed in an unanesthetized state for their local glucose utilization. Significant differences in glucose utilization were found between the aged and young groups on some behaviors and in some brain regions. There was considerable variability in the aged group in both their behavioral performance and their glucose utilization scores; thus, attempts were made to determine whether the variability in the degree of impairment within any particular behavioral test was correlated to the regional glucose utilization scores in any of the 45 brain regions analyzed. In two of the behavioral tests employed (i.e., one for learning and one for place navigation), the decline in performance correlated significantly with the decrement in regional glucose utilization. Moreover, the performance in these two tests showed significant correlation with glucose use in only five regions (dentate gyrus, medial septum-diagonal band area, hippocampal CA1, hippocampal CA3, and prefrontal cortex). These results show that the learning impairments in the aged rats are related to the extent of decrease in glucose utilization in restricted areas of the limbic system. In addition, the results show that the individual rats within an aged rat population develop cognitive impairments to a variable degree and that the aged rats with the most pronounced learning impairments are the ones exhibiting the most severe functional decrements, in terms of glucose utilization, in the septohippocampal system and the prefrontal cortex. This suggests that aging rats may be interesting not only for the study of the normal aging process, but also as a model of dementia.