Pathological mechanisms of white matter hyperintensities - Project Summary This is a clinical observation study that will evaluate whether standard-of-care treatment for obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) therapy improves measures of perivascular fluid exchange or glymphatic clearance using non-invasive MRI-based assessment in Veteran patients with comorbid Post Traumatic Stress Disorder(PTSD). Co-occurring OSA+ PTSD is common and synergistically increases the risk for brain injury and Alzheimer’s disease (AD) and related neurodegenerative disorders compared to the risks conferred by either PTSD or OSA alone. Therefore, Veterans with OSA+ PTSD are a particularly vulnerable population who would benefit from OSA treatment with CPAP, the most commonly used treatment approach. The proposed study is to examine 1) whether Veterans with OSA + PTSD will exhibit more pronounced differences in AD-related neurodegenerative disease biomarkers compared to Veterans with OSA only and control Veterans (neither OSA nor PTSD), 2) whether treatment of OSA with CPAP improves the glymphatic function as measured by brain MRI, and 3) whether CPAP improves AD-related biomarkers. Given the proposed role that impairment of sleep-active glymphatic function plays in the development of AD-related disorder, this study seeks to find a novel and potentially important new understanding of the link between sleep disruption and the development of AD pathology. Veterans with PTSD with recently diagnosed with OSA will be recruited from the VA Puget Sound (VAPS) sleep clinic. The target sample size is 20 subjects. At baseline, subjects will undergo a confirmatory home sleep study, brain MRI, neurocognitive testing, and blood sampling of neurodegenerative biomarkers (e.g., abeta42 and 40, tau and p-tau). After 4 weeks of CPAP therapy, as clinically indicated, these tests will be repeated. The glymphatic function will be measured by multi-modal MRI by intravoxel incoherent motion (IVIM)-MRI, multi-echo, multi-delay ASL, functional MRI, and measurement of MV-perivascular space (PVS). White matter hyperintensities will be measured at baseline. Sleep phenotyping by sleep survey will be accompanied by a home sleep study in which cardiopulmonary endotypes related to OSA will be characterized by hypoxemia burden, heart rate variability, and blood pressure response to OSA events. We will examine the relationship between baseline OSA severity, adherence to the CPAP therapy, and the change in MRI-based glymphatic function. The team will consist of Dr. Cho (PI), MIRECC advanced fellow with expertise in sleep medicine, and a team of mentors including Dr. Rane, Director of the Diagnostic Imaging Sciences Center (DISC), Dr. Iliff, a translational neuroscientist, Dr. Peskind, an expert in Fluid Biomarkers in Neurodegeneration, and Dr. Lim who has expertise in a deep analysis of sleep architecture.
