Sleep Disorders and Circadian Rhythms*

This presentation will provide an overview of the relationship between sleep apnea and stroke as it pertains to stroke prevention.

Disruptions in sleep have been described in patients with TDP-43 proteinopathies, including amyotrophic lateral sclerosis and frontotemporal dementia, but sleep studies in corresponding animal models are lacking. We previously showed that ubiquitous TDP-43 overexpression in Drosophila resulted in severe sleep disturbance that was ameliorated by knockdown of the RNA binding protein Ataxin-2 (ATXN2), reductions in which are known to reduce TDP-43 pathology in flies and mice. Translatability of these studies would be clarified by delineating cell types responsible for sleep phenotypes and studying a mammalian correlate. We will discuss our findings in Drosophila overexpressing TDP-43 selectively in neurons. We will then describe our findings in aged TAR4 mice that also overexpress TDP-43 neuronally, including therapeutic effects of AAV-RNAi-mediated reduction of ATXN2. Collectively, these results provide important information regarding the role of neuronal TDP-43 pathology on sleep over time, as well as the role of a potential therapeutic approach.

Sleep apnea is associated with cognitive decline and increased risk for dementia in older adults, but the exact features of sleep apnea driving this association and the downstream mechanisms of this association remain unclear. In this presentation, I will show data from two independent studies linking severity of hypoxemia during REM sleep with memory impairment. In the first study, this association is moderated by older age and APOE4 positive status, such that older adults and those with APOE4 positive status show stronger associations between sleep apnea severity during REM sleep and memory performance. In the second study, this association is mediated by the effects of hypoxemia during REM sleep on cerebrovascular pathology in the frontal cortex, with downstream associations with medial temporal lobe structural integrity. These findings have important implications for how sleep apnea severity should be evaluated in older adults and in populations with REM-dominant expression profiles.

The presentation will review the potential mechanisms and consequences of sleep disorders in people with multiple sclerosis, as well as treatment considerations.