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.

The fact that physiologically beta-amyloid precursor proteins are synthesized by all cells of the body without any amyloid deposition in other organs raises a question about an isolated deposition of amyloid in the brain. One of the most important mechanisms in the pathogenesis of senile dementia of the Alzheimer type is the marked decrease of the cerebral glucose metabolism, a cholinergic deficit, by a disturbed acetyl-CoA synthesis and a critically lowered oxidative phosphorylation. Remembering that aging is the most important predisposing factor in the development of Alzheimer's disease, it is argued that a decrease of the oxidative energy metabolism in senile dementia and the resulting ATP deficit may change protein degradation, synaptic transmission and ion homeostasis. Therefore, a more than 50% decline of oxidative energy turnover could be a trigger for an accumulation of beta-amyloid in the brain, because the degradation of beta-amyloid precursor protein could be directly or indirectly disturbed by an ATP deficit. Amyloidosis and a cholinergic deficit in SDAT would then be a secondary phenomenon of the decreased glucose metabolism in the brain.

Neurochemical investigations with normal aging brains show that in the first 70 years of life no major changes of the glycolytic pathway can be observed. Only in the following decades does a significant decrease of brain metabolic turnover occur. Changes in nerve cell size, one of the most relevant parameters in evaluating a diffuse nerve cell atrophy, appear in the brain cortex not earlier than between 85 and 94 years of age; a 21% nerve cell shrinkage is the mean. The results demonstrate that a significant decrease in turnover of the glycolytic pathway is followed by a significant but moderate shrinkage of the nerve cells after a delay of 10-15 years. Similar investigations in brains from senile demented subjects demonstrate that the change in glycolytic turnover is much more a quantitative than a qualitative phenomenon. In comparison with age-matched controls a decrease in glycolytic turnover of more than 60% is observed. Morphometric investigations of the nerve cell sizes in the brain cortex of senile demented subjects showed a decrease of 45-55% when compared with age-matched controls. When normal aging is compared with senile dementia it seems that old age dementia is a threshold phenomenon which starts if the glycolytic turnover drops below 50% of its value in young healthy adults. Physiological aging, however, stays within the range of the reserve capacity of normal brain performance. In conclusion, it seems that the exhaustion of the functional reserve capacity may shift an aging brain into a dementia syndrome.

Neurochemical investigations of the whole temporal lobe of cases with Alzheimer's disease (n = 15); 80.7 +/- 1.7 yr), Pick's disease (n = 3; 65 +/- 1.7 yr), and age-matched controls (n = 18; 74.7 +/- 2.6 yr), demonstrate that Alzheimer's and Pick's disease are primary degenerative brain diseases. The activities of glycolytic enzymes, ATPases, carbonic anhydrase, acetylcholinesterase and protein kinase were significantly lower in Alzheimer's and in Pick's disease than in age-matched controls. Pick's disease is characterised by a more pronounced reduction of the enzymes investigated, which is considered to be an expression of a more dramatic degenerative process. The differences between Alzheimer's disease and Pick's disease are quantitative.

The influence of aging and pre- and post-mortem conditions on the activities of glycolytic enzymes and of the ATPases was determined in samples of autoptic human cerebral cortex and putamen. These results were compared with results obtained from an aging collective of rats (four groups ranging from 20 to 120 weeks of age). The results revealed an interlinked significant age-related increase in soluble hexokinase (HK) and a significant decrease in phosphofructokinase (PFK) activity in human autoptic tissue, whereas no significant age-dependent differences could be observed in rat brain. Subdivision of the cases according to duration of agony and other pre-mortem conditions revealed reduced variance and therefore statistically more significant PFK age-dependence in cases with a short agony. All other cases are not dependent on age. In addition to the pre- and post-mortem effects, the age-dependence of PFK and soluble HK can be clearly demonstrated in human autoptic brain tissue.

We studied the influence of normal aging on 13 glycolytic enzymes, ATPase, carbonic anhydrase, and protein kinase in the human brain cortex and putamen, where there is a significant increase in soluble HK activity with age. This phenomenon is considered to be the result of an increased release of HK from mitochondrial membranes. A significant negative correlation of the activity of F6PK with age is observed in brain cortex and putamen. While the regulation of glycolysis imposes a limit on the formation of ATP with increasing age, no change appears to occur in the enzymatic capacity to break down ATP. Na+/K+-ATPase and Mg++-ATPase do not change with age. Carbonic anhydrase, important in the regulation of the pO2/pCO2 ratio in the brain tissue, demonstrates a significant decline with increasing age. Thus pCO2-dependent regulation of tissue pH, ionic transport processes, and cerebral blood flow regulation have the tendency to become more and more unstable. Protein kinase demonstrates a progressive age-dependent decline in cAMP-dependent activity, which is most significant in brain cortex and thalamus, followed by hippocampus, amygdala, and globus pallidus. The enzyme is of importance for the phosphorylation of the cell membrane and is thus of functional relevance for the nerve cell.

The activities of glycolytic enzymes were determined in human autoptic temporal lobes from patients with different forms of dementia. For some enzymes (hexokinase, phosphofructokinase and phosphoglycerate mutase) the effect seen in dementia can be regarded as an intensification of the normal ageing affect. For other enzymes (aldolase, phosphoglucose isomerase, triosephosphate isomerase and lactate dehydrogenase) no changes in enzyme activities corresponding to those found in dementia are observed in the normal ageing process. These effects are most pronounced in the non-vascular Alzheimer cases. With the exception of triosephosphate isomerase and lactate dehydrogenase, enzyme activity is also reduced in bronchopneumonia. The effects of dementia and bronchopneumonia on the activities of glycolytic enzymes in human autoptic brain tissue are often difficult to distinguish.

Extensive biochemical analysis of whole temporal lobe from cases of dementia and controls suggests that Alzheimer's disease is a primary degenerative nerve-cell disorder and not the result of accelerated ageing. There is selective loss of neocortical cholinergic neurones. Transmitter systems apart from the cholinergic system appear to be affected, but to a lesser extent, and there are no significant changes in the caudate nucleus. The change in cholinergic neurones has been confirmed in biopsy samples.

In three different experimental series with 22 experimental and 21 control cats it is demonstrated that DH-ergotoxine mesylate (Hydergine®) improves EEG energy, disturbed by temporary ischemia, in the isolated perfused cat head. It could be shown that improvement of EEG energy and lowering of arteriovenous lactate difference can be directly correlated. DH-ergonine improves experimentally induced metabolic decline as does DH-ergotoxine, but at one tenth of the dosage.

1 h after intravenous administration, 3H-DH-ergot alkaloids showed maximal uptake in the range of 10(-5)M in various visceral organs, and of 10(-7)M in most parts of the CNS of the cat. The clearance function in both groups of tissues was logarithmical linear, the slope of the straight line for the parts of the CNS being considerably flatter. Repeated administration of these drugs demonstrated a higher retention in the CNS than in the other organs. The single-dose level in the CNS is reinforced and, in contrast to liver and lung, maintained for at least 24 h.