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 one 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 observed in both types of these individuals are not clear. We have recently demonstrated that the pro-inflammatory and fatigue-inducing cytokines, tumor necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6), assayed in single plasma samples, are elevated in subjects with disorders of EDS. In addition, in preliminary studies, we demonstrated that these two cytokines are elevated in obese, compared to lean subjects, and that both sleep disturbance and obesity contribute to the cytokine elevation. More recently, we showed that daytime plasma levels of IL-6 are elevated in experimentally-induced EDS by the use of sleep deprivation and that a good night's sleep is associated with decreased daytime levels in healthy young subjects. There is a large literature implicating several pro-inflammatory cytokines in the regulation of sleep in animals; however, cytokine research on sleep in humans has been very limited. The fundamental hypothesis to be tested by the proposed studies is that the pro-inflammatory cytokines, TNFalpha and IL-6, are associated with and may contribute to EDS. We will test this hypothesis by determining the circadian secretory patterns of TNFalpha and IL-6 in plasma obtained from subjects that exhibit EDS associated with OSA or obesity. Also, we will determine whether nighttime nasal CPAP reduces daytime plasma TNFalpha and IL-6 concentrations in sleep apneics. In addition, we will experimentally induce EDS in healthy young subjects by the use of total sleep deprivation or one week of sleep restriction, which mimics real life-situations, to determine the relationship between the pattern of daytime plasma TNFalpha and IL-6 concentrations and daytime sleepiness as measured objectively using MSLT. Finally, we will assess the effects of daytime napping, in healthy subjects, on post-nap sleepiness and TNFalpha and IL-6 secretion. In these studies, we will use a series of experimental techniques including nighttime polysomnography, MSLT, computerized EEG, actigraphy, 24-hour blood sampling, 24-hour recording of core body temperature, and assays for TNFalpha and IL-6. These studies collectively will provide additional evidence for a role of TNFalpha and IL-6 in EDS and lay the foundation for the development of potential therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL064415-01A1
Application #
6197071
Study Section
Special Emphasis Panel (ZRG1-IFCN-3 (01))
Program Officer
Kitt, Cheryl A
Project Start
2000-08-01
Project End
2004-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
1
Fiscal Year
2000
Total Cost
$234,900
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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