OSA is characterized by the quintessential triad of intermittent apnea, hypoxia, and hypoxemia due to pharyngeal collapse. This paper highlights the upstream mechanisms that may trigger cognitive decline in OSA. Three interrelated steps underpin cognitive dysfunction in OSA patients. First, several risk factors upregulate peripheral inflammation; these crucial factors promote neuroinflammation, cerebrovascular endothelial dysfunction, and oxidative stress in OSA. Secondly, the neuroinflammation exerts negative impact globally on the CNS, and thirdly, important foci in the neocortex and brainstem are rendered inflamed and dysfunctional. A strong link is known to exist between neuroinflammation and neurodegeneration. A unique perspective delineated here underscores the importance of dysfunctional brainstem nuclei in etiopathogenesis of cognitive decline in OSA patients. Nucleus tractus solitarius (NTS) is the central integration hub for afferents from upper airway (somatosensory/gustatory), respiratory, gastrointestinal, cardiovascular (baroreceptor and chemoreceptor) and other systems. The NTS has an essential role in sympathetic and parasympathetic systems also; it projects to most key brain regions and modulates numerous physiological functions. Inflamed and dysfunctional NTS and other key brainstem nuclei may play a pivotal role in triggering memory and cognitive dysfunction in OSA. Attenuation of upstream factors and amelioration of the NTS dysfunction remain important challenges. 1. Introduction Obstructive sleep apnea syndrome (OSA) is characterized by the upper airway instability during sleep, reduction or elimination of airflow (hence oxygen desaturation), periodic arousals (hence sleep disruption), and daytime hypersomnolence. About 40% of adults are habitual snorers. The prevalence of OSA has been estimated to be 24% in men and 9% in women [1]. The male？:？female ratio of the OSA patients has been reported to range from 4 to 1 to 4 to 2 [2]. OSA therefore is a major intrinsic sleep disorder. The alarming degree to which OSA is clinically diagnosed in middle-aged men and women makes it a significant public health problem, and increasing evidence indicates that untreated OSA can lead to several comorbid disorders. OSA is a risk factor for cardiovascular disorders including hypertension, congestive heart failure (CHF), myocardial ischemia, arrhythmias and infarction, and cerebrovascular conditions including stroke [3]. The normal physiologic interactions are disrupted by OSA, and the cardiovascular and cerebrovascular systems are therefore impacted
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