Brain Atrophy and Neuron Loss

A significant decrease in brain weight is a widely documented sign of aging. In neurologically normal elderly individuals, it has been estimated that this decrease begins at the age of 60 years and proceeds at a rate of 2 to 3 grams/year. Considering the average brain weights of adult men (1400 g) and women (1250 g), by the age of 80, an overall reduction of about 3 to 5% has occurred. In addition to brain weight another more reliable measurement of the extent of the brain macroscopic decline in elderly subjects is the ratio between brain and skull volume, which is reported to remain constant around the value of 95% up to the age of 60, but decreases to 80% beyond 90 years of age. Widening of sulci and enlargement of ventriculi are also estimations accounting for an age-related brain atrophy and are reported to progress according to the reduction in brain weight. It has been estimated that the average volume of the lateral and third ventricles undergoes a fourfold increase in elderly over 60 when compared with young subjects between 13 and 19.

Handbook of Models for Human Aging

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Studies in vivo by imaging methodologies have confirmed this data obtained from autopsy studies, and have shown a great individual variability, suggesting that age-related changes, at least at macroscopic level, may be significantly influenced by genetic determinants and environmental factors, first of all the very specific lifestyle of each individual. During the past two decades, neuron loss has been supported to occur at a significant extent in the aging brain (it commonly was accepted that adults lose as many as 100,000 neurons a day). As reported by an extensive review by Coleman and Flood (1987), some early papers on this research topic documented that most neocortical areas and hippo-campal subfields lose 25 to 50% of their neurons, and they were able to influence successive investigations that substantially confirmed a consistent and widespread neuronal death in aging, although these data were reporting different degrees of neuronal loss. The common feature of these studies is that, as a morpho-metric parameter, they took into account the density of neurons within a given structure and not the total neuron number. Thus, although all these studies agreed in supporting an extensive neuron loss in aging, over the past several years it was increasingly evident that confounding factors might have influenced neuron counting and led to obtaining erroneous results. Namely, tissue processing, method of sampling, strain differences, and the specific anatomy of the area of the central nervous system (CNS) where neuronal counts were performed have been reported to represent sources of potential mistakes in estimating the number of neurons. Contrary to the previously held conviction that with advancing age there is a progressive neuron loss, the development of more accurate counting procedures produced more reliable estimations and led to the conclusion that normal aging does not involve a significant neuronal numeric decrease through neuron death. Unbiased stereological analyses (i.e., the disector; see the section, ''Age-related Alterations of Synaptic Structural Dynamics'') have shown that, across the overall lifespan, the loss of neurons is around 10%, but this cannot be interpreted as a specific time-related significant impairment since sex has been found to be more important than age in modulating the total neuron number in a given brain region, for example, the neocortex (Pakkenberg and Gundersen, 1997). The marked heterogeneity of the whole brain and even of specific brain regions makes it difficult to interpret any decrease of neuron number from a functional standpoint, thus only those studies conducted in localized CNS zones with clearly demonstrated functions and connections have provided useful information on age-related impairments in which neuron loss may play a role. In this context, because of their documented direct implication in memory, enthorinal cortex and hippocampus have been investigated in different animal models and in human beings. In these CNS areas from old rodents, old nonhuman primates, as well as old human beings, there is no significant neuron loss that may account for the known decay in memory functions due to age (Gomez-Isla et al., 1997). However, these CNS areas show a significant neuron loss in Alzheimer's disease (AD), and this lends support to the assumption that the severity of neuronal death is different in physiological aging and age-related pathological conditions, and that selected areas of the CNS are preferentially affected by age and pathology-related changes (West et al., 1994). It must be stressed that neuronal loss reflects the cumulative tissue damage accrued with age (and, eventually, an age-related neuro-pathological status). Thus even if the lack of significant neuron loss cannot be considered as the main causative alteration of a manifest functional decline, the neuronal circuits on which the specific function, for example, memory, relies may undergo a progressive damage leading to a subtle deterioration and resulting in impaired brain performances.

Summarizing the results on neuron number and changes in brain size in aging, at present, the well-documented brain shrinkage due to age does not appear to be due to the numeric loss of neurons that has been demonstrated to be far less significant than previously thought and occurs in localized CNS regions, whereas other zones are not affected at all. Atrophy of neurons and of their connections is reported to be the main causative event responsible for the age-related reduction in brain volume, and this provides a rationale for interventional strategies to repair dysfunctional neuronal networks.

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