Fifty-six brains from middle-aged and elderly normal as well as demented subjects and patients with provisional clinical diagnosis of other neurological and psychiatric diseases were assessed histologically. On this basis the specimens were classified into 14 diagnostic groups. A survey of potential indices of specific neurons has been carried out on these brains in which neurotransmitter-related enzymes, gamma-GTP (a potential index of capillaries) and specific proteins have been determined in up to 20 brain regions. In addition, the agonal state has been tentatively assessed by examining the post-mortem states of the circulatory and respiratory systems. CAT and gamma-GTP activities and the concentration of a soluble neuronal-type protein (neuronin S-5) were found to be relatively unaffected by the agonal state. When cases of senile dementia were compared to controls (matched with respect to the cause of death) the activity of CAT (the potential index of cholinergic neurons) appears to be reduced in the cerebral cortex. This is a preliminary finding, although a correlation was indicated between CAT activity and 'senile' morphological changes, the activity was markedly reduced in only 3 brains. However, despite inconsistencies in the literature (Karczmar, 1975) at least one pharmacological study on humans appears to show that the cholinergic system may be involved in age-related memory degeneration (Drachman and Leavitt, 1974). Cholinergic neurons may be abnormal in the other abiotrophies examined (Huntington's chorea, motor neuron disease and mixed vascular and senile dementia). gamma-GTP and neuronin S-5 (identical in most respects to the soluble acidic neuronal protein 14-3-2 of antigen alpha) were not reduced in senile dementia. The activities of brain decarboxylase (GAD and AAD) and the concentration of another soluble acidic brain protein (neuronin S-6) appear to be affected by the agonal state. This is remarkable because GAD and, in particular, neuronin S6, are relatively unaffected by post-mortem autolysis. As judged by the state of the extraneural systems which regulated the blood and oxygen supply to the brain it appears that terminal 'cerebral hypoxia' is responsible for the depletion of these brain constituents. This effect appears to be particularly marked in deep grey matter. In non-demented patients that die of bronchopneumonia, the areas of the cortex which are depleted in neuronin S-6 are consistent with the pattern of the 'selective vulnerability' of the cortex to hypoxia, suggesting that the terminal state can also affect the neocortex. If so, then this is particularly relevant to studies on senile dementia, for the effect of the terminal bronchopneumonia that so often occurs in these patients (and in patients with other abiotrophies) may be exacerbated by a terminal reduction in cerebral blood flow...

Protein synthesis (PS) has been considered essential to sustain mammalian life, yet was found to be virtually arrested for weeks in brain and other organs of the hibernating ground squirrel, Spermophilus tridecemlineatus. PS, in vivo, was below the limit of autoradiographic detection in brain sections and, in brain extracts, was determined to be 0.04% of the average rate from active squirrels. Further, it was reduced 3-fold in cell-free extracts from hibernating brain at 37°C, eliminating hypothermia as the only cause for protein synthesis inhibition (active, 0.47 ؎ 0.08 pmol͞mg protein per min; hibernator, 0.16 ؎ 0.05 pmol͞mg protein per min, P < 0.001). PS suppression involved blocks of initiation and elongation, and its onset coincided with the early transition phase into hibernation. An increased monosome peak with moderate ribosomal disaggregation in polysome profiles and the greatly increased phosphorylation of eIF2␣ are both consistent with an initiation block in hibernators. The elongation block was demonstrated by a 3-fold increase in ribosomal mean transit times in cell-free extracts from hibernators (active, 2.4 ؎ 0.7 min; hibernator, 7.1 ؎ 1.4 min, P < 0.001). No abnormalities of ribosomal function or mRNA levels were detected. These findings implicate suppression of PS as a component of the regulated shutdown of cellular function that permits hibernating ground squirrels to tolerate ''trickle'' blood f low and reduced substrate and oxygen availability. Further study of the factors that control these phenomena may lead to identification of the molecular mechanisms that regulate this state.

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