This proposal will provide protected time and support to Dr. Ayappa while she (1) mentors graduate students, post-doctoral fellows and junior faculty pursuing careers in patient-oriented research in sleep disorders;(2) conducts clinical research in patients with sleep disordered breathing (SDB) and (3) augments her capabilities to conduct patient-oriented research and mentoring. Dr. Ayappa is actively involved in research in physiology, diagnosis, treatment and outcomes of SDB that provides research opportunities for mentoring. Obstructive sleep apnea (OSA) is a highly prevalent disorder estimated to affect 15% of the US population. Untreated OSA has significant morbidity and mortality including cardiovascular and neurocognitive impairment. Multiple directions are proposed for the research. The first project (1U01OH010415-01) uses the coexistence of the high prevalence of nasal complaints and OSA in World Trade Center responders to examine the role of nasal pathology in the development of OSA and its impact on CPAP adherence.
The Specific aims are to (i) Examine the relationships between post-9/11 OSA (using home sleep monitoring) and upper airway disease, in 1000 subjects without evidence of pre-9/11OSA (ii) Determine the relationship between post-9/11 OSA, upper airway disease, nasal inflammation (leukocyte counts and soluble IL-8, IL-6, TNF?) and nasal resistance (rhinomanometry) (iii) Relate nasal resistance to CPAP adherence in patients with OSA to show that reduction of expiratory pressure using CPAPFlex will improve CPAP adherence. The goal of the second project (candidate's prior R01with renewal revision Feb 2013) is to understand the relationship (or reasons for lack thereof) between SDB and daytime function in OSA patients. Although majority of patients with OSA report excessive daytime sleepiness (EDS), the correlation between measures of SDB and sleepiness is poor. It is increasingly clear that factors such as individual susceptibility may contribute to differences in how individual patients respond to the stress of SDB.
The specific aim i s to demonstrate a correlation between the level of EDS that develops after controlled suboptimal CPAP (a standardized dose of SDB) and the level of EDS after 24 hours of sleep deprivation. The hypothesis is that susceptibility to these two different forms of sleep disruption is correlated and defines a "trait" for an individual. An extension of this work i a third collaborative project (currently funded pilots) that examines the relationship between SDB and Alzheimer's Disease (AD) biomarkers in a cohort of elderly subjects. The study examines whether AD causes SDB in the elderly, or if SDB acts as a factor promoting neurodegeneration. The activities outlined in the proposal have implications for science and public health. The mentoring work will address a critical shortage of researchers in sleep disorders as documented by the National Center on Sleep Disorders. The experimental work is relevant for understanding the physiology of SDB and its outcomes, its diagnosis and treatment with potential for improving health and quality of life in millions of patients who suffer from sleep apnea.

Public Health Relevance

Obstructive sleep apnea (OSA) affects 15% of the adult U.S. population. The present study contributes to understanding the role of nasal pathology in OSA seen in WTC responders, explores the concept of differential susceptibility to sleep disruption and examines the relationship between OSA and Alzheimer's Disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Special Emphasis Panel (ZHL1-CSR-X (M1))
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Twery, Michael
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New York University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Varga, Andrew W; Kishi, Akifumi; Mantua, Janna et al. (2014) Apnea-induced rapid eye movement sleep disruption impairs human spatial navigational memory. J Neurosci 34:14571-7
Osorio, R S; Pirraglia, E; Gumb, T et al. (2014) Imaging and cerebrospinal fluid biomarkers in the search for Alzheimer's disease mechanisms. Neurodegener Dis 13:163-5
Osorio, Ricardo S; Ayappa, Indu; Mantua, Janna et al. (2014) Interaction between sleep-disordered breathing and apolipoprotein E genotype on cerebrospinal fluid biomarkers for Alzheimer's disease in cognitively normal elderly individuals. Neurobiol Aging 35:1318-24