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Neurodegeneration and Aging
Posted on: March 19, 2003

Many elderly individuals exhibit mild motor and cognitive alterations reminiscent of those found in neurodegeneration. This observation gave birth to the popular idea that aging might be a "benign" form of neurodegeneration. This idea was supported by the notion, widely accepted until recently, that normal aging, like neurodegeneration, is inevitably associated with neuronal death. From as early as the 1950s, decreased numbers of neurons in different regions of the brain were reported in aged humans with no overt neurological or psychiatric conditions. Subsequent studies have estimated these losses to be as high as 100,000 neurons per day, which could easily explain the cognitive decline and decrease in brain weight traditionally associated with normal aging. However, with the development of more accurate procedures for counting neurons, this view has been modified over the last several years, particularly as stereological procedures for estimating neuron numbers have been applied to aging research. As reviewed by Morrison and Hof, the application of stereological techniques has shown in several species, including humans, that the age-related decline in neuron number via neuronal death is not significantly involved in normal aging, at least with respect to the neocortex and to the hippocampal subregions most implicated in memory, such as entorhinal cortex and CA1. These results, therefore, challenge the notion that neurodegeneration invariably occurs in normal aging. If significant neuronal loss is lacking, some other pathological features of neurodegeneration, such as the presence of Lewy bodies, so typical of PD, and neurofibrillary tangles (NFTs) and senile plaques, so typical of AD, can be detected in brains of asymptomatic aged individuals. The critical question thus becomes: Do these changes occur "normally" during aging or reflect a "presymptomatic" stage of these diseases? Because it is impossible to perform longitudinal neuropathological studies, it is impossible to determine whether these individuals would have developed full disease expression if they had lived longer. In fact, hitherto, there been no definitive evidence supporting such a progression. Instead, neuropathological and functional brain-imaging studies have revealed striking quantitative and qualitative differences between aged nondemented and demented individuals, suggesting that aging and neurodegeneration may represent very distinct entities. For instance, in the nondemented elderly, no NFTs are observed in the frontal and temporal cortices and only a few NFTs are found in the entorhinal cortex and the hippocampal CA1 subregion, even in the absence of any neuronal loss. Conversely, in the demented elderly, even with the mildest cognitive impairments, some NFTs are observed in the frontal and temporal cortices and high densities of NFTs are found in the entorhinal cortex and the hippocampal CA1 subregion together with significant neuronal loss. Therefore, the definition of normal aging is critical to any conclusion about the effect of the passage of time on the brain. Despite intense clinical-neuropathological correlative investigations, to date, experts remain unsure about whether the fact that a change is commonplace makes it normal and, conversely, whether changes, however slight, that are known to be associated with definite diseases of the nervous system are necessarily pathological. It is still difficult to know exactly to what extent neurons are damaged or lost in aged humans as a result exclusively of the passage of time. It seems clear, however, that the impact of the passage of time on the number of neurons is much less important than was previously believed, and that compelling evidence is lacking to support the idea that aging is a form of neurodegeneration at minima.

Abbreviations used:
Neurofibrillary tangle (NFT);
Parkinson disease (PD);
Alzheimer disease (AD);

Source: Serge Przedborski, Miquel Vila and Vernice Jackson-Lewis; Neurodegeneration: What is it and where are we? The Journal of Clinical Investigation, January 2003, Volume 111, Number 1.
http://www.jci.org/cgi/reprint/111/1/3.pdf
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