Sleep apnea syndrome affects at least 3 percent - 5 percent of the adult population in this country and available data suggest that significant morbidity and mortality result from this disorder. It is now well established that the prevalence of sleep-related apnea is dramatically elevated in the elderly with recent estimates ranging from 28 percent - 67 percent for elderly males and from 20 percent - 54 percent for elderly females. However, the mechanisms underlying the age related increase in apnea genesis remain poorly understood. This uncertainly stems in part from a paucity of appropriate animal models to study spontaneous apneas in all stages of sleep. Rapid eye movement (REM) sleep is associated with apneas, reductions in respiratory and upper airway motor outputs, and increased variability of respiration, heart rate and blood pressure. We present novel preliminary evidence suggesting that increased apnea expression with aging results from dysregulation of brainstem respiratory control systems by brainstem phasic events (BPE) in the elderly. Ponto-geniculo-occipital (PGO) waves are a close marker of BPE and are closely associated with cardio- respiratory changes, including apnea. The overall goals of this proposal are to (i) investigate the neural mechanisms by which BPE influence apnea genesis, and (ii) establish the importance of these mechanisms to the age-related increase in apnea. To achieve these goals, we will combine descriptive and interventional human studies with invasive central nervous system measurements and manipulations in rats using a model of sleep-related respiratory instability which we have characterized. We will focus our attention on the pedunculopontine tegmental nucleus (PPT), the putative site of the burst generator responsible brainstem phasic events detectable as PGO waves. We will manipulate BPE expression in two directions: 1) we will augment expression by acoustic stimulation and sleep deprivation in man and rat and by microinjection of cholinergic agonists into PPT in the rat; and 2) we will reduce expression by electrolytic lesions of the PPT in the rat. These manipulations in old and young patients, controls, and rats will provide a comprehensive approach to define the mechanisms and importance of brainstem phasic event-induced respiratory instability in aging.
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