Aging with Schizophrenia: A Multi-site Investigation of the Effects of Sleep Disturbances on Brain Connectivity and Cognitive Functioning
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Project Summary/Abstract Cognitive deficits are a core feature of schizophrenia that worsen with age, leading to high rates of dementia and disability for older people with schizophrenia. However, effective and mechanistically-driven interventions to improve cognitive functioning among older people with schizophrenia are lacking. Recent work has identified neural oscillations during sleep as a potentially actionable target to alleviate cognitive deficits. Specifically, two prominent oscillations that occur exclusively during non-rapid eye movement (NREM) sleep—sleep spindles and slow waves—play a causal role in memory and cognition. Deficits in the expression of NREM sleep spindles are a putative endophenotype of schizophrenia: individuals with schizophrenia and their first-degree relatives exhibit specific reductions in sleep spindles and disrupted temporal coordination of spindles with slow waves. Also, spindles arise from thalamocortical feedback loops, and MRI studies reveal that this circuitry shows abnormal connectivity in schizophrenia. Although this line of research identifies a well-defined circuit that is abnormal in schizophrenia, neurodegeneration of this NREM circuitry in people aging with schizophrenia and its contribution to cognitive decline is not known. One understudied risk factor for cognitive deficits among older people with schizophrenia is untreated obstructive sleep apnea (OSA), a sleep disorder in which repeated airway collapse causes hypoxic events. The risk and severity of OSA increase with age, and OSA is shown to interfere with NREM circuit functioning across the population. Importantly, older people with schizophrenia are particularly vulnerable to OSA-related cognitive deficits because OSA is often underdiagnosed and undertreated in schizophrenia. It is not known how OSA adds further damage to NREM circuitry and worsens cognitive decline in older people with schizophrenia. The primary goal of this proposal is to investigate the moderating effects of schizophrenia and OSA on age-related cognitive decline. The current proposal leverages the highly complementary expertise and proven record of successful collaborations of MPIs Baran and Lee and aims to identify the neural mechanisms that link OSA with cognitive deficits in older people with schizophrenia. They hypothesize that schizophrenia and OSA exert synergistic effects on NREM oscillatory functioning and impair cognition. This project will identify OSA as an actionable target for mitigating and preventing cognitive decline among older people with schizophrenia, and OSA-associated disruptions to NREM oscillations as a plausible underlying mechanism. The proposed project will lay the foundation for their longitudinal work examining the aging trajectories of NREM circuitry and cognition in schizophrenia and their future mechanistically-targeted intervention studies to mitigate OSA- related cognitive deficits among a highly vulnerable population.
