criteria (size, shape, extent of neuritic arborization), a more comprehensive definition of cell type might be a designated class of neurons that share key characteristics with regard to morphology, location, connectivity, and neurochemical phenotype. In fact, the concepts of cell type and neurochemical phenotype bear a critical relationship to selective vulnerability in aging or neurodegenerative diseases.
Selective vulnerability is most readily appreciated in the context of neurodegenerative disorders such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Each disease is characterized by its own, unique pattern of degeneration, with amyotrophic lateral sclerosis involving the loss of upper and lower motor neurons, Parkinson's disease noted for the selective degeneration of dopaminergic neuRons in substantia nigra, and Alzheimer's disease characterized primarily by the degeneration of key cortical circuits. In many cases, the vulnerable neurons in a given disorder share particular neurochemical characteristics that can be linked to their selective vulnerability. For example, both the neurons that provide the perforant path from the entorhinal cortex and the neurons that provide the long corticocortical interconnections are highly vulnerable in Alzheimer's disease, and both are marked by a particular cytoskeletal profile that can be linked to their vulnerability (Morrison et al., 1987; Hof et al., 1990: Hof and Morrison, 1990; Hof et al., 1999).
In order to define and understand the determinants of selective vulnerability in neurodegenerative diseases as well as in normal aging, it will be important to determine neuron number according to specific classes of neurons wherein class is based on morphology, connectivity, and neurochemical phenotype. In this way, hypotheses can be tested at a finer level of cell-type resolution, and links can be drawn between a particular element of the neurochemical phenotype and vulnerability. Quantitative analyses using chemically specific approaches (e.g., immunohistochemistry, in situ hybridization) allow for direct investigation of the molecular determinants of selective vulnerability, as reflected, for example, in intracellular biochemical changes in neurons as they change with age or begin to degenerate. This approach is particularly important with respect to links to gene expression, with the goal being a quantitative dataset that links gene expression patterns with circuits, vulnerability, and, potentially, with age-related changes in cognition.
Beyond the analysis of cell class(es), it is important to determine the degree to which biochemical characteristics of neuronal compartments in individual neurons are affected by age. Given that neuron death is unlikely to be the substrate for age-related memory impairment, it has become increasingly important to investigate more subtle changes in cellular morphology