. "Appendix A: Age-Related Shifts in Neural Circuit Characteristics and Their Impact on Age-Related Cognitive Impairments." The Aging Mind: Opportunities in Cognitive Research. Washington, DC: The National Academies Press, 2000.
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The Aging Mind: Opportunities in Cognitive Research
as the perforant path, as well as certain circuits intrinsic to the hippocampus (Hyman et al., 1984); and (3) key diffuse projections to the cerebral cortex, such as the cholinergic projection from nucleus basalis (Whitehouse et al., 1982; for a review, see Kemper, 1999). In contrast to the selective but extensive neuron loss reflective of Alzheimer's disease, neuron death is minimal in the regions classically associated with cognition and memory in the normal course of aging (Peters et al., 1998a). The lack of significant hippocampal and neocortical neuron death in normal aging has now been demonstrated in humans, monkeys, and rats (West et al., 1993b; Gomez-Isla et al., 1996; Rapp and Gallagher, 1996; Gazzaley et al., 1997; Peters et al., 1998a), although some neuron loss appears to occur in humans in the hilus of the dentate and in the subiculum (West, 1993b).
However, a lack of quantifiable neuron loss does not necessarily mean that no degenerative changes are occurring in a given brain region, and it does not rule out more subtle changes that lead to compromised function without cell loss. The entorhinal cortex is a particularly instructive case in this regard. It appears that the neurons within layer II of entorhinal cortex, which serve as a neocortical conduit to the hippocampus through the perforant path, are likely to be the single most vulnerable class of neurons in the brain with respect to both aging and Alzheimer's disease. While these neurons are clearly devastated early in Alzheimer's disease, their status in cognitively normal, aged individuals and those with mild cognitive impairment has been more difficult to pinpoint. Neuron counts in neurologically normal individuals suggest that there is no neuron loss in the entorhinal cortex (Gomez-Isla et al., 1996; West, 1993b). However, analyses of neurofibrillary tangles (NFT), the classic reflection of a degenerating neuron in Alzheimer's disease, suggest that virtually all humans over the age of 55 have some NFT in layer II of entorhinal cortex (Vickers et al., 1992; Bouras et al., 1994).
How does one reconcile these two findings and draw a distinction between age-related degenerative events in the entorhinal cortex that are progressive and those that are not? While the answer to this question continues to be elusive, one approach that appears promising is the use of a comprehensive panel of antibodies in a quantitative experimental design in order to distinguish and quantify transitional events in the neurons within the entorhinal cortex that can be correlated with the clinical dementia rating scale. This approach has led to a focus on patients with a rating of 0.5 that have mild cognitive impairment, yet it is unclear whether their condition represents early Alzheimer's disease or a more stable condition that might be referred to as age-related memory impairment.
The key to reconciling the presence of NFT in this region with the fact that there does not appear to be neuron loss is that the various neuronal profile counts that have been done have not taken into consideration "transitional neurons," i.e., neurons that are still intact and included in an analysis