Senile dementia: a threshold phenomenon of normal aging? A contribution to the functional reserve hypothesis of 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.

Stereological changes in the capillary network and nerve cells of the aging human brain.

Stereologic parameters of the capillaries and nerve cells of the brain cortex and putamen were investigated. Thirty-eight brains from subjects aged between 19 and 94 years were examined. All cases were free of metabolic, neurologic and psychiatric diseases. It is demonstrated that the capillary diameter remains unchanged during aging in both brain cortex and putamen. However, in the putamen the total capillary length per unit volume and the capillary volume fractions increase (approximately 60%) progressively with age. Consequently the mean inter-capillary distances in the putamen decrease (approximately 15%). These age-induced changes in the putamen indicate shrinking of subcortical brain structures. In contrast to those of the putamen, the morphometric data of the capillaries in the cortex remain unchanged during the aging process. Stereologic investigations of nerve cells in the brain cortex and putamen revealed that only in brains over 85 years of age can a significant decrease in nerve cell size be demonstrated. A correlation of all the data by a correspondence analytical procedure showed that only the surface/volume ratio of the capillaries correlates with the nerve cell size. This observation suggests a functional interaction between the nerve cells and the capillaries. From the data presented it becomes apparent that the shrinkage of the gyri in the aging brain is not a change in the volume of the cortex, but a decrease in the volume of subcortical structures.

Comparative studies of neuronal perikaryon size and shape in the aging cerebral cortex.

The stereological investigation comprised three groups of people aged 19 to 44, 65 to 74 and 85 to 94. Perikaryal area and circumference of cortical neurons in the superior part of the cerebral precentral gyrus were determined. Opening classes of single neurons were measured with the Leitz texture analyzer to calculate size and shape. A multivariate statistical procedure allowed comparison of the neuronal parameters between all groups. The measurements yielded smaller perikarya in the oldest group as opposed to larger ones in the young subjects. No differences were seen between young subjects and the 65 to 74-year-old group, which, in contrast, revealed as only group age-dependent changes in cerebral capillaries and small blood vessels. The differences in perikaryal size indicated that senile atrophy of neurons was most apparent in the external pyramidal layer. An influence of decreased motor impulses from the periphery on the atrophic process of neurons with predominant receptor function cannot be excluded.

[Quantitative-morphological changes of capillaries and neurons in the aging human putamen (author's transl)]. / Quantitativ-morphologische Altersveränderungen von Kapillaren und Neuronen im menschlichen Putamen.

Stereological investigations (Classimat) of the capillary net of 4 age-groups, ranging between 19 and 94 years, revealed significant increase of capillary volume and total length, and decreased intercapillary distances in the aging putamen. Neuronal size and shape measurements (Texture-Analyzer-System) of the same brain region showed significant changes between the young (19-44 y.) and oldest (85-94 y.) group, indicating senile atrophy of the neuronal perikarya. Quantitative image-analysis facilitates to evaluate new morphometrical data of the aging process in the human brain, which are important for a pharmacological concept of treating cerebral insufficiency symptoms.

Postmortem changes in stereological parameters of cerebral neurons.

The form and size of neurons in the cat cerebral cortex were stereologically investigated intravitally, and 30 sec., 5 hours, and 22 hours postmortem. For comparison, the human cerebral cortex of a 60 year old male subject was deep frozen 16 hours postmortem, and fixed in formalin. The stereologic parameters of the cat experiment included neuronal surface Ai, perimeter LPi, and formfactor fi. In our experiment, the neurons showed swelling and metachromasia 30 sec. postmortem, which disappeared with progressive autolysis. Postmortem neuronal swelling was attributed to circulatory disturbances in the course of fatal cardiac arrest, whereas metachromasia of nucleoli and Nissl bodies appeared together with increased lysosomal acid phosphatase activity. "Dark neurons were only found in the human cerebral cortex fixed by immersion, and are thus recognized as artefact due to fixation. The intravital occurence of "dark" neurons could not be excluded, however. Size and form determinations of the neuronal perikaryon are expected to give additional information on pathologic changes during the aging process of the human brain, especially in senile dementia and organic brain syndrome.

The aging human cerebral cortex: a stereological characterization of changes in the capillary net.

Capillaries in the cerebral cortex of six age groups, ranging between 19 and 94 years (= 34 human brains) were stereologically investigated. Capillary parameters such as diameter, volume fraction, specific surface area, mean intercapillary distances and total length per unit cortex volume in patients older than 75 years were similar to those in young ones, 19 to 44 years old. Aged subjects between 64 and 74 years revealed increased capillary diameter, volume and total length per unit cortex volume, as well as decreased specific surface area. Frequency distributions in the same age indicate a real increase of capillary diameter and volume, as also an increase of these parameters on the level of blood vessels with diamteres greater than 8 micrometer, probably arterioles. The results of this study argue against the wide-spread assumption of a decreased blood supply in the cerebral cortex during old age. On the contrary, the capillary net is able to respond to changed metabolism and blood pressure.

[Stereological investigation in the cerebral cortex of aging subjects (author's transl)]. / Stereologische Untersuchungen am Grosshirncortex des alternden Menschen.

Involving cortical regions, capillaries of the human cerebrum of two 19 and 27 years old men, a 69 years old woman and a 72 years old man were stereologically investigated by optical-electronic image-analysis. The cortical capillary net work was demonstrated by the alkaline phosphatase activity. Each cortex region comprised a determination of the stereological parameters diameter, projected area, specific surface area, capillary distances in linear direction of TV-lines and total length per unit cortex volume. A comparison between different cortex regions revealed a good correlation between increased values of the diameter and the projected area, a decreased specific surface area and diminished capillary distances, which entail a shortened distance of oxygen diffusion through the cortical tissue. During aging a diminished capillary surface area, which results from increased values of diameter and projected area is compensated by shortened capillary distances. Presumably an augmented capillary length is due to a condensation of the capillary net per unit cortex tissue. The behaviour of the registered stereological parameters seems to be an accommodation of the capillary net in the human cerebrum to metabolic and circulatory changes during aging.

Quantitative studies in the cerebral cortex of aging humans.

The capillary network of the human cerebral cortex was morphometrically investigated in a young, aged and aged hypertonic group. In the aging cortex, augmented values of capillary diameter and volume are accompanied by smaller distances between capillaries and an extended length per unit cortex volume. An increased capillary diameter of the aged hypertonic group is probably due to a high blood pressure. The regulating influence of the surrounding astroglia and the extracellular fluid on capillaries seems to lack. In comparison to normotonic brains, higher distances between capillaries and a decreased capillary length were measured.

Postmortem changes in stereological parameters of cerebral capillaries.

The present study investigated the influence of different postmortem times on stereological parameters of capillaries in the cerebral cortex. For the human investigation different brain regions of two 77 and 79 year-old subjects were examined. The animal experiment, carried out on 10 male cats, allowed a comparison between intravitam deep-frozen cerebral cortex and tissue obtained after decapitation. The parameters were diameter Di, volume fraction VVi, surface-to-volume ratio Si/Vi, mean minimal distance between capillary centers of gravity deltaAB, length per unit cortex volume LVi, and number of fragments per measuring field Ni, AT. Neither the cat experiment nor the human investigation yielded a noteworthy change of the capillary diameter in the postmortem cortical tissue. Nevertheless, a significantly enlarged mean minimal distance between capillaries in the cat cerebral cortex shortly after decapitation (30 sec) suggests the formation of edema which then regresses. Furthermore the experiment revealed that 22 hours after death there is a significantly (p less than 0.01) diminished volume fraction and length per unit cortex volume with an augmented surface-to-volume ratio. These changes are thought to be a consequence of water loss. In contrast to the animal experiment the human cerebral capillaries showed no changes in stereological parameters at two different postmortem times. These results encourage continuation of further stereological investigations on human brains obtained at autopsy and may contribute to the understanding of the aging process in the human cerebral cortex.