Excessive daytime sleepiness (EDS) is a major public health concern in part because individuals suffering from EDS often are not productive at work, are more susceptible to accidents and generally are unable to function normally during the day. EDS is 1 of the major manifestations of individuals suffering from obstructive sleep apnea (OSA) and is frequently reported by obese individuals without sleep apnea. The mechanisms underlying EDS are not clear. We have demonstrated that the pro-inflammatory and fatigue-inducing cytokines, tumor necrosis factor-a (TNFa) and interleukin-6 (IL-6) are elevated in conditions of pathological sleepiness, e.g., sleep apnea, or in experimentally-induced sleepiness, e.g., following total sleep deprivation. Further work funded by the initial grant (HL-64415) demonstrated that (1) even mild sleep restriction to 6 hours per night for 1 week is associated with increased sleepiness, decreased performance, and increased levels of TNFa and IL-6, and (2) hypercytokinemia and its associated insulin resistance in obese OSA patients is not reversed by the most common treatment for this disorder, i.e., continuous positive airway pressure (CPAP). Additionally, neutralizing TNFa in obese apneics reduces EDS markedly and significantly. In this application, we propose to study the effects of recovery sleep, obesity, and middle-age on sleepiness, performance, and inflammatory cytokines after one week of sleep restriction in normal sleepers (specific aims 1-3). We hypothesize that recovery sleep for 2 nights does not adequately reverse the adverse effects of mild sleep restriction, whereas obesity and middle-age augment the adverse effects of mild sleep restriction. Furthermore, we propose to test (a) 24-hour circadian pattern of cytokines and adipokines (leptin and adiponectin), and insulin resistance/visceral fat in nonobese apneics, and in weight, age, and gender matched controls;and (b) the effects of CPAP use in a cross-over placebo controlled design (specific aim 4). We hypothesize that symptomatic nonobese apneics exhibit higher levels of IL-6, TNFa, and insulin resistance/visceral fat compared to controls and that CPAP compared to sham CPAP has a mild but significant effect on the immune/metabolic aberrations. In these studies, we will use a series of experimental techniques including nighttime polysomnography, MSLT, PVT, actigraphy, 24-hour blood sampling, and assays for cortisol, TNFa, IL-6, leptin, adiponectin, and abdominal computerized tomography (CT) for body fat distribution, CPAP, and Sham CPAP. These studies collectively will provide additional evidence for a role of TNFa and IL-6 in EDS and OSA and lay the foundation for the development of novel therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064415-09
Application #
7667761
Study Section
Biobehavioral Mechanisms of Emotion, Stress and Health Study Section (MESH)
Program Officer
Twery, Michael
Project Start
1999-12-01
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2011-06-30
Support Year
9
Fiscal Year
2009
Total Cost
$243,090
Indirect Cost
Name
Pennsylvania State University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Gaines, Jordan; Vgontzas, Alexandros N; Fernandez-Mendoza, Julio et al. (2018) Obstructive sleep apnea and the metabolic syndrome: The road to clinically-meaningful phenotyping, improved prognosis, and personalized treatment. Sleep Med Rev 42:211-219
Li, Yun; Vgontzas, Alexandros N; Fernandez-Mendoza, Julio et al. (2017) Objective, but Not Subjective, Sleepiness is Associated With Inflammation in Sleep Apnea. Sleep 40:
LaGrotte, C; Fernandez-Mendoza, J; Calhoun, S L et al. (2016) The relative association of obstructive sleep apnea, obesity and excessive daytime sleepiness with incident depression: a longitudinal, population-based study. Int J Obes (Lond) 40:1397-404
Fernandez-Mendoza, Julio; Vgontzas, Alexandros N; Kritikou, Ilia et al. (2015) Natural history of excessive daytime sleepiness: role of obesity, weight loss, depression, and sleep propensity. Sleep 38:351-60
Pejovic, Slobodanka; Natelson, Benjamin H; Basta, Maria et al. (2015) Chronic fatigue syndrome and fibromyalgia in diagnosed sleep disorders: a further test of the 'unitary' hypothesis. BMC Neurol 15:53
Gaines, Jordan; Vgontzas, Alexandros N; Fernandez-Mendoza, Julio et al. (2015) Short- and Long-Term Sleep Stability in Insomniacs and Healthy Controls. Sleep 38:1727-34
Fernandez-Mendoza, Julio; Shea, Sarah; Vgontzas, Alexandros N et al. (2015) Insomnia and incident depression: role of objective sleep duration and natural history. J Sleep Res 24:390-8
Gaines, Jordan; Vgontzas, Alexandros N; Fernandez-Mendoza, Julio et al. (2015) Gender differences in the association of sleep apnea and inflammation. Brain Behav Immun 47:211-7
Vgontzas, A N; Fernandez-Mendoza, J; Miksiewicz, T et al. (2014) Unveiling the longitudinal association between short sleep duration and the incidence of obesity: the Penn State Cohort. Int J Obes (Lond) 38:825-32
Kritikou, Ilia; Basta, Maria; Vgontzas, Alexandros N et al. (2014) Sleep apnoea, sleepiness, inflammation and insulin resistance in middle-aged males and females. Eur Respir J 43:145-55

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