Cognitive Consequences of Obstructive Sleep Apnea in Schizophrenia: An Investigation of Inflammatory Mechanisms

ABSTRACT People with schizophrenia (PwS) have high rates of cognitive dysfunction and associated disability, especially with aging, and there is a lack of effective treatments to improve cognition in PwS. Obstructive sleep apnea (OSA) is a key modifiable risk factor for cognitive deficits in PwS as it is often underdiagnosed and undertreated. Untreated OSA may cause cognitive decline and dementia, which can be particularly dire in middle-aged and older PwS due to lower cognitive reserve stemming from the onset of illness. The inflammatory mechanisms by which OSA leads to cognitive deficits may intersect with the pathobiology of schizophrenia. Thus, inflammatory biomarkers may be a key surrogate biomarker of OSA-related cognitive deficits. There is a critical unmet need for interventions to improve cognition in PwS. However, to design and power future OSA intervention trials in PwS, the proposed observational naturalistic study is needed to gather relevant data in PwS and a non-psychiatric comparison (NC) group and include objective assessments of OSA, cognitive functioning, and comprehensive inflammatory assessments. The overall objectives of the proposed study are: (1) to assess the contribution of OSA to cognitive impairment, (2) to comprehensively investigate inflammation as a surrogate marker of OSA and cognitive deficits, and (3) to identify key cognitive correlates among PwS. The expected outcome of this proposed project is to lay the groundwork necessary for future OSA treatment trials in PwS. We propose a cross-sectional case-control study of 150 PwS with and without untreated OSA and 150 non- psychiatric comparison subjects with and without OSA, age 40-70 years. The research plan aims to: 1) examine differences in cognitive functioning in PwS and NCs with and without co-morbid OSA; 2) examine the relationships of inflammatory biomarkers with OSA and with cognitive functioning; and 3) explore how general and schizophrenia-related OSA risk factors affect cognitive functioning. The innovative approach of this proposal includes a comprehensive multi-level inflammatory assessment that incorporates systemic biomarkers and gene expression to highlight specific mechanistic pathways and immune cells and the use of mobile cognitive testing that may be more sensitive to OSA-related changes. The team for this proposed project includes expertise in aging in schizophrenia (Ellen Lee, MD), OSA physiology and assessment (Atul Malhotra, MD; Christopher Schmickl, MD, PhD), neurocognitive functioning (Barton Palmer, PhD), mobile cognitive assessments (Raeanne Moore, PhD), psychoneuroimmunology and sleep (Michael Irwin, MD), comprehensive inflammatory assessments (Steve Cole, PhD), and biostatistics (Xin Tu, PhD). Ultimately, this work’s positive impact will be future development of personalized, biologically-based interventions to improve cognition among middle-aged and older PwS.