Do compensatory processes underlie the preclinical phase of neurodegenerative disease? Insights from an animal model of parkinsonism.

Lesions of the DA neurons innervating the striatum is accompanied by permanent gross neurological deficits only when the loss of striatal DA is almost complete, a finding reminiscent of Parkinson's disease. This appears to result at least in part from an enhanced capacity of the remaining DA neurons to continue to modulate DA-sensitive targets in the striatum. Among the neurochemical changes that may be responsible for this enhanced capacity are a loss of high-affinity DA uptake sites and time-dependent increases in the synthesis and release of DA. Following very large lesions, an increase in the sensitivity of striatal cells to DA also gradually occurs (Fig. 1). A lesion-induced increase in the functional activity of residual neurons may be a rather general phenomenon. We have made analogous observations in the sympathoadrenal system (Fluharty et al., 1985) and in the noradrenergic (Acheson & Zigmond, 1981; Chiodo et al., 1983; Abercrombie et al., 1989) and serotonergic (Stachowiak et al., 1986) systems of CNS. Thus, during many neurodegenerative diseases, compensatory changes in the affected neural system and its targets may be involved in the extended preclinical stage that often is observed. This hypothesis has several implications. First, many clinical disorders that appear late in life may in fact have their origins in events that had occurred many years earlier, and the emergence of neurological or psychiatric symptoms may represent the end stage of the neurodegenerative-process, rather than its onset. Second, to reverse clinical symptoms one may not need to reverse the entire neurobiological deficit; instead, clinical recovery might be achieved with a relatively modest restoration of the injured projections. Third, it may be possible to achieve recovery even without restoring the connections that have been lost if the capacity of the remaining elements of the injured system can be enhanced further. Finally, in some cases arresting the degenerative process may be sufficient; the natural compensatory processes of the nervous system might then be permitted the time needed to restore function.