of total neuron counts, yet have transitional intraneuronal pathology resembling an NFT. Such neurons are confusing in that they could be misconstrued as "normal neurons" in a Nissl stain or NFTs in a tau immunohistochemical stain, the two stains that are most commonly used to quantify total "healthy" neurons and NFT, respectively. But these neurons may actually be the key to understanding the difference between early Alzheimer's disease and senescence.

For example, when neurons in layer II of the entorhinal cortex are counted in three categories—ghost tangles, transitional neurons, and healthy neurons—the data are far more revealing with respect to early pathologic events in layer II of entorhinal cortex, and it is quite clear that there might be significant "transitional" pathology in neurologically normal individuals or individuals with a clinical dementia rating of 0.5 in the absence of quantifiable neuron death and in the absence of massive NFT formation (Gimmel et al., 1998; Bussière et al., 1999; see Figure A-2).

These estimates of neuron number in three classes can also be related to each other as ratios in a given case, establishing a case-by-case "index of neurodegeneration" that is not hampered by the individual variability in raw number of neurons that invariably occurs in studies of neuron number. It will be very important to continue to study patients with a clinical dementia rating of 0.5 to try and determine whether this condition is a precursor to Alzheimer's disease or whether it is a condition that can be sustained and stabilized over a long period of time without cascading to Alzheimer's disease. It will be even more enlightening to do these kinds of neuropathologic analyses in patients with prospective neuropsychological assessment. In addition, other molecules linked to degeneration (e.g., neurofilament, presenilin) can be incorporated into the analyses of transitional neurons to obtain even more discrete molecular information on the changes that occur in these neurons in aging and the nature of their selective vulnerability. However, even a more precise delineation of the events surrounding degeneration will not provide a full understanding of the vulnerability of this circuit, since, as described below, the entorhinal-hippocampal connections display age-related changes short of degeneration that could also impact function.

Age-Related Neurochemical Shifts in Identified Circuits and Cell Classes

Introduction and Technical Considerations

Modern neuroanatomy is often centered on circuit analysis within the context of biochemical attributes, as described earlier. The most common methods used to link gene expression patterns with cell classes and circuits are immunohistochemistry and in situ hybridization, the localization of proteins



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