Effect of OSA & Chronic Intermittent Hypoxia on Cerebral Metabolic O2 Consumption

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

? DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) is associated with significant comorbidities, including hypertension, cardiovascular disease, stroke and cognitive dysfunction. The causes of neurovascular changes in apneics are not well understood, but they may be related to the effects of chronic intermittent hypoxia (CIH) on the cerebral metabolic rate of oxygen consumption (CMRO2). The basis of the CMRO2 measurement is the simultaneous quantification of venous blood oxygen metabolism and total cerebral blood flow, which allows calculation of CMRO2 by Fick's law. The objectives of this proposal are to explore the relationships between the severity of OSA, CIH, and CMRO2 in both humans and rats. Preliminary results indicate that CMRO2 is reduced in apneics compared to controls and in rats exposed to CIH. The global hypotheses motivating this proposal are that: 1) CMRO2 reflects brain injury and dysfunction in OSA; 2) reductions in CMRO2, will be associated with the severity of cognitive dysfunction in humans with OSA and in rats exposed to CIH; 3) CMRO2 decline will reverse with CPAP therapy, concordantly with improvements in cognitive function; and 4) preventing brain oxidative stress will prevent both reductions in CMRO2 and cognitive performance. Specific Aim 1: To assess CMRO2 and neurocognitive status in apneics (AHI>15) at baseline and 6 months after CPAP treatment and in gender, age, BMI and race-matched non-apneics (AHI<10). Specifically, will test whether: 1) apneics have lower CMRO2 values compared to non-apneics at baseline; 2) among apneics, more severe OSA is associated with lower CMRO2 values; 3) CPAP treatment improves CMRO2 levels, with the increases correlated with amount of CPAP use; and 4) differences in CMRO2 correlate with cognitive deficits in apneics. Specific Aim 2: To assess CMRO2, cognition and hippocampal markers of oxidative stress in 150 male Sprague-Dawley rats at 1, 2, and 3 months of CIH exposure via one of the following five conditions: 1) sham; 2) moderate CIH (O2=11%); 3) severe CIH (O2=6%); 4) severe CIH treated with the antioxidant apocynin; and 5) severe CIH treated with a vehicle implant. Specifically, we will test whether: 1) increased severity of CIH yields a dose- response relationship in changes in CMRO2 levels, cognitive function (determined with a Barnes maze) and hippocampal measures of oxidative stress; 2) changes in CMRO2 measured at 1, 2 and 3 months are temporally related to changes in cognitive function and measures of oxidative stress in the hippocampus; and 3) rats treated with apocynin (no brain oxidative stress) will not show a decrease in CMRO2 or cognitive function.