Noradrenergic Dysregulation, Sleep and Cognition in Older Adults with Insomnia

PROJECT SUMMARY Insomnia is prevalent among middle and older age adults, with detrimental effects on daytime function as well as adverse health outcomes, including increased risk for Alzheimer’s disease-related dementias (ADRD). Yet, the mechanisms underlying the relationship between insomnia and cognitive function are not well understood.

The autonomic nervous system (ANS), and more specifically noradrenergic (NA) activity, plays an important role in the regulation of sleep, wake, and cognitive function. It is biologically plausible that age-related decline in NA activity contributes to poor sleep-wake quality and risk for cognitive impairment in older adults with

insomnia. Therefore, an improved understanding of the relationship between the NA system, sleep and cognition has the potential to provide novel insights into the mechanism linking insomnia with cognitive function. Based on the published evidence and data of older adults with insomnia from our own laboratory, we

hypothesize that in insomnia patients, reduced 24-h NA activity (particularly during the wake period) will be associated with reduced subjective and objective measures of sleep quality (i.e. electroencephalographic slow oscillatory activity: 0.5-1Hz and duration of wake after sleep onset). In addition, we hypothesize that lower 24-

h NA activity and objective sleep quality in older adults with insomnia will be associated with poorer cognitive function. In this project, we propose a systematic characterization of both central and peripheral measures of the NA system and their relationship with sleep quality and cognitive function in older adults with insomnia and

good sleeper controls. Measures of NA activity include 24-h plasma levels of norepinephrine (NE) and of 3- methoxy-4-hydroxyphenylglycol (MHPG), the main NE metabolite in the brain, and levels of NE and MHPG in response to clonidine suppression test (a presynaptic α2 adrenoreceptor agonist that reduces central NA

system activity). To further elucidate the mechanistic dynamics between NA system activity with sleep quality and cognition in insomnia, we will use daytime bright light (BL) exposure as a probe to potentially increase NA activity during wake and improve nocturnal sleep quality and daytime performance. Participants with insomnia

will be instructed on healthy sleep habits and randomized to either a 4-week bright light (BL) or dim red-light (RL, control condition) intervention. Measures of ANS, sleep and cognitive function will be assessed during a three-day in laboratory visit for both the insomnia and good sleeper control groups, a similar assessment will

be repeated after completion of the 4-week intervention in participants with insomnia. The findings from this study will provide novel insights into the mechanisms of ANS dysregulation in the pathophysiology of insomnia in older adults and will create the basis for the identification of novel biological targets and approaches to

enhance sleep and cognitive function in older adults with insomnia who are at higher risk for medical and neuropsychological comorbidities and ADRD.