Obstructive sleep apnea (OSA) is a disorder resulting from failure of the upper airway to maintain patency during sleep. OSA is associated with extensive comorbidities, including hypertension, cardiovascular disease and stroke, as well as with significant cognitive dysfunction. The cardio- and neurovascular consequences of the disease are believed to result from periodic nocturnal hypoxia-reoxygenation cycles. While the normal physiologic response to volitional apnea (breath-holding) maintains cerebral oxygen delivery via reduced cardiac output, peripheral vasoconstriction, and central vasodilation, this response becomes blunted in OSA secondary to chronic intermittent hypoxia experienced during repeated nocturnal apneic events. Building on our recent work in developing techniques for quantifying the cerebral metabolic rate of oxygen consumption (CMRO2) to investigate brain oxygen metabolism, we propose to further develop and apply a new MRI method to study the neurometabolic-neurovascular consequences of OSA. Key to the method is the quantification of venous blood oxygen saturation from a measurement of magnetic susceptibility, which scales with deoxyhemoglobin concentration and which, along with cerebral blood flow, yields CMRO2. Since apnea represents a mixed hypercapnic/hypoxic stimulus for which no steady-state is reached, capturing the physiologic response requires high temporal resolution. Responding to this need, the investigators have developed a vastly accelerated CMRO2 measurement technique and shown its ability to resolve dynamic changes in CMRO2 in response to volitional apnea in healthy subjects at 3T and demonstrated its feasibility in OSA patients on a wide-bore 1.5T system. We posit that the breath-hold paradigm is a suitable model to evaluate the neurovascular response in OSA as it reflects the intermittent hypoxia experienced by apneics during sleep. In this project we hypothesize that the neurometabolic profiles in patients with OSA are impaired, including lower CMRO2 at baseline and blunted neurometabolic response to a breath-hold challenge. Further, we hypothesize that continuous positive airway pressure (CPAP) treatment will alleviate this abnormal response. These hypotheses will be addressed in four specific aims, comprising: (1) further development and validation of the method; (2) application to a cohort of OSA patients and their controls; (3) evaluation of the effect of CPAP in the cohort of Aim 2; and (4) an exploratory sleep study in a subset of patients to compare the neurometabolic effects of wakeful volitional and spontaneous nocturnal apnea. The proposed neurometabolic MRI measures could ultimately serve to identify patients at greatest risk of the neurocognitive and neurovascular sequelae from OSA, and to predict the efficacy of CPAP therapy. Further, the method could allow triaging of OSA patients to more invasive treatment approaches and provide an improved means for risk assessment in those affected by this increasingly prevalent disorder.
The project is designed to test the hypothesis that patients with obstructive sleep apnea have abnormal neurometabolism and impaired neurovascular reactivity and that treatment with continuous positive airway pressure partially reverses these conditions. The study is conducted with a novel noninvasive MRI technique that quantifies the cerebral rate of oxygen consumption with high temporal resolution both at rest and in response to an apneic stimulus.
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