NEUROPATHOLOGY OF THE AGING SYMPATHETIC NERVOUS SYSTEM

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Dysfunction of the aged human autonomic nervous system is an increasingly recognized, but poorly understood, clinical problem, the pathologic basis of which is largely unknown. Our initial studies of aging human sympathetic ganglia have demonstrated: i) neuroaxonal dystrophy comparable to that we have characterized in aged experimental animals; ii) preferential damage of prevertebral versus paravertebral sympathetic ganglia; iii) an age-related increase in the number of dystrophic axons; and, iv) selective involvement of NPY containing nerve terminals. The studies proposed in this research plan represent a significant expansion of our initial investigation of aging human sympathetic ganglia to precisely characterize the pathologic effects of age on the human sympathetic nervous system, to integrate these findings with animal models of aging, and ultimately to define the pathogenesis of autonomic dysfunction in aging. We will characterize neuroaxonal dystrophy in human ganglia and determine if it is associated with a particular clinical entity or presentation. Other studies will investigate the dendritic structure of aging principal sympathetic neurons and identify the origin of dystrophic nerve terminals using intraneuronal labeling and lipophilic dyes (di-I) in both animal and human ganglia. In an attempt to identify the earliest alterations in human dystrophic axons we will use immunoelectron microscopy to concentrate on NPY containing nerve terminals, which are selectively targeted in human aging. RIAs will be used to quantitate the ganglionic content of NPY as a measure of the severity of the axonopathy. Finally, we will test the proposed hypothesis that abnormal neurofilament metabolism underlies the development of dystrophic axons in aging human sympathetic ganglia. Specifically, e will: test for unusual forms of ganglionic neurofilament proteins by SDS-PAGE with Western blotting; immunohistochemically probe for abnormally distributed neurofilament proteins and assay enzymes responsible for neurofilament degradation (calpains); and, finally, attempt to mimic the axonopathy in the sympathetic ganglia of young animals using local application of calpain inhibitors in vivo. Overall, this research proposal represents a multi-faceted investigation into the effects of age on the sympathetic nervous system. Minimally, these investigations will yield a wealth of data on aging human sympathetic ganglia and may provide clues to the pathogenesis (and possible treatment) of autonomic dysfunction in aged humans.