Sleep Medicine Research Program

Sleep Disordered Breathing (SDB), the most frequent form of which is Obstructive Sleep Apnea (OSA), is a common condition. It has been recognized since the 1970s and is now considered to be an important risk for daytime sleepiness, cardiovascular complications and memory problems. The most widely used treatment is Continuous Positive Airway Pressure (CPAP) which consists of a nose or mouth mask connected to a simple blower.

Since 1980, our team has been involved in multiple aspects of this disorder:

Pathophysiology (Causes of OSA)

OSA is more than just an anatomic blockage of the upper airway. The interaction of basic sleep mechanisms and muscle tone, as well as the mechanical behavior of the collapsible upper airway at the level of the naso-, oro- and hypo-pharynx all contribute to the repetitive obstructions that characterize OSA. Our longstanding interests include:

1. Description of the passive mechanics of the upper airway, including modelling as a Starling resistor.
2. Role of tone of the muscles affecting pharyngeal patency
3. Role of nasal pathology and resistance
4. Distal effects on pharyngeal stiffness, including lung volume and tracheal traction
5. Role of transient arousals as a modifier of loop gain

Epidemiology

1. Prevalence and Incidence of Adult and Pediatric OSA
2. Prevalence of co-morbidities (cardiac, neurological, ENT and aging-related)

Consequences

1. Hypercapnia
2. Sleepiness and daytime neurological impairment (memory)
3. Hypertension and other cardiovascular and cerebrovascular events
4. Metabolic
5. Dementia and Alzheimer-related

Diagnostic Tools

1. Tools to capture OSA in the home
2. Definition of airway collapse through noninvasive analysis of the airflow waveform
3. Developing and evaluation of approaches to home monitoring for diagnosis and monitoring treatment
4. Portability of full or limited polysomnography to the home

Treatments

1. Treatment recommendations for different subgroups – sleepy, non-sleepy, comorbid conditions, elderly
2. CPAP and tools to improve adherence
3. Titration of CPAP       
• Use of flow limitation as a marker of residual obstruction 
• Auto-titration using flow limitation
• Detection of arousals (Sensawake) 
4. Non-invasive ventilation for hypoventilation syndromes (Obesity Hypoventilation Syndrome, neuromuscular weakness)
5. Mandibular advancement devices – results and remote titration  (MatrX)
6. Devices for positional therapy for positional SDB (OSA and CSA)
7. Nasal expiratory resistance (Provent)
8. Hypoglossal stimulation (Inspire) – prediction of success and evaluation
9. Implants (Pillar) and surgery of the upper airway – evaluation of results
10. Drug therapy for OSA

Selected Publications:

Unique medical issues in adult patients with mucopolysaccharidoses.
Mitchell J, Berger KI, Borgo A, Braunlin EA, Burton BK, Ghotme KA, Kircher SG, Molter D, Orchard PJ, Palmer J, Pastores GM, Rapoport DM, Wang RY, White K.
European journal of internal medicine. 2016; 34:2-10. 

Reduced Slow-Wave Sleep Is Associated with High Cerebrospinal Fluid Aβ42 Levels in Cognitively Normal Elderly.
Varga AW, Wohlleber ME, Giménez S, Romero S, Alonso JF, Ducca EL, Kam K, Lewis C, Tanzi EB, Tweardy S, Kishi A, Parekh A, Fischer E, Gumb T, Alcolea D, Fortea J, Lleó A, Blennow K, Zetterberg H, Mosconi L, Glodzik L, Pirraglia E, Burschtin OE, de Leon MJ, Rapoport DM, Lu SE, Ayappa I, Osorio RS.
Sleep. 2016

Effects of aging on slow-wave sleep dynamics and human spatial navigational memory consolidation.
Varga AW, Ducca EL, Kishi A, Fischer E, Parekh A, Koushyk V, Yau PL, Gumb T, Leibert DP, Wohlleber ME, Burschtin OE, Convit A, Rapoport DM, Osorio RS, Ayappa I.
Neurobiology of aging. 2016; 42:142-9.

Testosterone Deficiency and Sleep Apnea.
Burschtin O, Wang J.
Urol Clin North Am. 2016 May;43(2):233-7. doi: 10.1016/j.ucl.2016.01.012. Review.

Orexin-A is Associated with Increases in Cerebrospinal Fluid Phosphorylated-Tau in Cognitively Normal Elderly Subjects.
Osorio RS, Ducca EL, Wohlleber ME, Tanzi EB, Gumb T, Twumasi A, Tweardy S, Lewis C, Fischer E, Koushyk V, Cuartero-Toledo M, Sheikh MO, Pirraglia E, Zetterberg H, Blennow K, Lu SE, Mosconi L, Glodzik L, Schuetz S, Varga AW, Ayappa I, Rapoport DM, de Leon MJ.
Sleep. 2016; 39(6):1253-60. 

Mentoring junior URM scientists to engage in sleep health disparities research: experience of the NYU PRIDE Institute.
Jean-Louis G, Ayappa I, Rapoport D, Zizi F, Airhihenbuwa C, Okuyemi K, Ogedegbe G.
Sleep medicine. 2016; 18:108-17. NIHMSID: NIHMS741560

Best practices in the evaluation and treatment of foramen magnum stenosis in achondroplasia during infancy.
White KK, Bompadre V, Goldberg MJ, Bober MB, Campbell JW, Cho TJ, Hoover-Fong J, Mackenzie W, Parnell SE, Raggio C, Rapoport DM, Spencer SA, Savarirayan R.
American journal of medical genetics. Part A. 2016; 170A(1):42-51.

An Official American Thoracic Society Research Statement: Impact of Mild Obstructive Sleep Apnea in Adults.
Chowdhuri S, Quan SF, Almeida F, Ayappa I, Batool-Anwar S, Budhiraja R, Cruse PE, Drager LF, Griss B, Marshall N, Patel SR, Patil S, Knight SL, Rowley JA, Slyman A.
American journal of respiratory and critical care medicine. 2016; 193(9):e37-54

POINT: Is the Apnea-Hypopnea Index the Best Way to Quantify the Severity of Sleep-Disordered Breathing? Yes.
Rapoport DM.
Chest. 2016; 149(1):14-6.

Sleep-disordered breathing advances cognitive decline in the elderly.
Osorio RS, Gumb T, Pirraglia E, Varga AW, Lu SE, et al.
Neurology. 2015; 84(19):1964-71.

A comparison of CPAP and CPAPFLEX in the treatment of obstructive sleep apnea in World Trade Center responders: study protocol for a randomized controlled trial.
Ayappa I, Sunderram J, Black K, Twumasi A, Udasin I, Harrison D, Carson JL, Lu SE, Rapoport DM.
Trials. 2015; 16:403.

Detection of K-complexes and sleep spindles (DETOKS) using sparse optimization.
Parekh A, Selesnick IW, Rapoport DM, Ayappa I.
Journal of neuroscience methods. 2015; 251:37-46.

New insights on the pathophysiology of inspiratory flow limitation during sleep.
de Godoy LB, Palombini LO, Martinho Haddad FL, Rapoport DM, de Aguiar Vidigal T, Klichouvicz PC, Tufik S, Togeiro SM.
Lung. 2015; 193(3):387-92.

Sleep-disordered breathing advances cognitive decline in the elderly.
Osorio RS, Gumb T, Pirraglia E, Varga AW, Lu SE, Lim J, Wohlleber ME, Ducca EL, Koushyk V, Glodzik L, Mosconi L, Ayappa I, Rapoport DM, de Leon MJ.
Neurology. 2015; 84(19):1964-71.

Scoring respiratory events in sleep medicine: who is the driver--biology or medical insurance?
Thomas RJ, Guilleminault C, Ayappa I, Rapoport DM.
Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. 2014; 10(11):1245-7.

Apnea-induced rapid eye movement sleep disruption impairs human spatial navigational memory.
Varga AW, Kishi A, Mantua J, Lim J, Koushyk V, Leibert DP, Osorio RS, Rapoport DM, Ayappa I.
The Journal of neuroscience : the official journal of the Society for Neuroscience. 2014; 34(44):14571-7.

Interaction between sleep-disordered breathing and apolipoprotein E genotype on cerebrospinal fluid biomarkers for Alzheimer’s disease in cognitively normal elderly individuals.
Osorio RS, Ayappa I, Mantua J, Gumb T, Varga A, et al.
Neurobiology of aging. 2014; 35(6):1318-24.

Effects of acute sleep deprivation on motor and reversal learning in mice.
Varga AW, Kang M, Ramesh PV, Klann E.
Neurobiology of learning and memory. 2014; 114:217-22.

Obstructive sleep apnea and acute myocardial infarction severity: ischemic preconditioning?
Shah N, Redline S, Yaggi HK, Wu R, Zhao CG, Ostfeld R, Menegus M, Tracy D, Brush E, Appel WD, Kaplan RC.
Sleep Breath. 2013 May;17(2):819-26.

David Rapoport, MD
Indu Ayappa, PhD
Neomi Shah, MD, MPH
Andrew Varga, MD, PhD, (Varga Laboratory) 
Emmanuel During, MD

Clinical Research Coordinators:

Akosua Twumasi received her BA in Geography and her MPA in Health Care Administration from Pace University. In 2014, she was a recipient of a Postmasters Research Supplement from the National Heart, Lung, and Blood Institute (NHLBI) where her research was presented in 2015 and 2016 in national sleep conferences. Her research interests include obstructive sleep apnea, sleep medicine and neurodegenerative diseases.

Haley Sanders earned her BS in Biology from St. Louis University and is soon to earn her BFA in Photography from the School of Visual Arts. She previously held an internship position at the Clayton Sleep Institute in St. Louis, Missouri, working on a variety of clinical studies related to asthma, COPD, narcolepsy and obstructive sleep apnea. Haley is currently working primarily on the role of nasal pathology in World Trade Center first responders in relation to obstructive sleep apnea, but her clinical interests lie within many areas of sleep medicine, including the impact of sleep disorders on neurodegenerative diseases and spatial memory.

Nicholas Chua is currently working on a project investigating the relationship between slow wave sleep and spatial memory. In addition, Nicholas does collaborative work with the Center for Brain Health at NYU Langone Medical Center, looking at sleep’s effect on neurodegenerative disorders such as Alzheimer’s disease. He completed his B.S. at the Center for Neural Science at New York University. At NYU, he worked with Dr. Jonathan Winawer investigating gamma oscillations in the visual cortex. His academic interests include signal processing, spatial perception, and the cognitive function(s) of dreams.

Research Program Coordinator:

Elizabeth Brush received her BA in Neuroscience from Middlebury College. She is the Research Program Coordinator for Dr. Neomi Shah’s ongoing research studies at the Icahn School of Medicine at Mount Sinai. Prior to Mount Sinai, Elizabeth worked with Dr. Shah at Montefiore Medical Center/Albert Einstein College of Medicine as a Research Coordinator in the Department of Medicine. Dr. Shah’s research focuses on the relationship between sleep apnea and coronary artery disease- specifically in the setting of an acute myocardial infarction.  As such, Elizabeth has aided Dr. Shah in crafting numerous institution, foundation and federal grant applications including 1) Montefiore Medical Center Junior Investigator Research Award “Sleep Apnea and Myocardial Infarction” 2) Einstein CTSA KL-2 Career Development Award “Understanding the Role of Sleep Apnea Among Patients with an Acute Myocardial Infarction” 3) American Sleep Medicine Foundation Junior Faculty Research Award “Sleep apnea in the Hispanic Community Health Study/Study of Latinos” 4) American Academy of Sleep Medicine Bridge to K “Vascular Endothelial Growth Factor Levels and Coronary Collaterals Among Patients with Acute Myocardial Infarction Screened for Sleep Apnea” 5) American Academy of Sleep Medicine Focused Project Award “Measuring Atherosclerotic Plaque Activity (Using FDG-PET-MRI) Before and After Treatment of Sleep Apnea” 6) National Heart Lung and Blood Institute (NHLBI) K23 “Sleep Apnea and ST-Elevation Myocardial Infarction: A Multidisciplinary Translational Study.” Further, Elizabeth has co-authored a published manuscript (“Obstructive Sleep Apnea and Acute Myocardial Infarction Severity: Ischemic Preconditioning?”) a book chapter (“Sleep and Coronary Heart Disease”) and numerous abstracts based on her involvement with Dr. Shah’s research. 

OSA in WTC responders: Role of nasal pathology (PI Indu Ayappa, PhD)
The goal of this study is evaluate the role of nasal pathology in the development of SDB in subjects exposed to WTC dust. It will also evaluate the impact of nasal resistance and chronic rhinosinusitis on CPAP adherence and test whether Cflex improves adherence to CPAP in those with higher nasal resistance.

Titration of Non-Invasive Ventilation for Hypoventilation (PI David M. Rapoport, MD)
The goal of this project is to develop a novel control algorithm for non-invasive bilevel ventilation based on arousals detected from the pattern of ventilation.

Daytime consequences of OSA (Dayfun) (PI Indu Ayappa, PhD)
This study examines the relationship between severity of OSA and daytime sleepiness and role of differential susceptibility. The technique we use is to take fully treated patients with OSA who are using nasal CPAP and lower their pressure to subtherapeutic levels to create known levels of mild OSA.

Sleep in the Elderly (SARA) (Co-I Indu Ayappa, PhD)
This grant (PI Ricardo Osorio, MD: NYU School of Medicine) examines the relationship between sleep disordered breathing and AD in normal elderly.

Sleep Apnea and ST-Elevation Myocardial Infarction: A Multidisciplinary Translational Study (PI: Neomi Shah, MD, MPH)
This study will determine the effect of sleep apnea on severity and prognosis of myocardial infarction through an integrated assessment of: (1) quantification of myocardial infarct size using cardiac imaging, (2) coronary collateral scoring and (3) biomarkers of hypoxic stress. 

Tailored Sleep Health Education: a community-engaged approach (Co-I David M. Rapoport)  
This project (PI Girardin Jean-Louis: NYU School of Medicine) will develop a community-based infrastructure to support implementation of translational and dissemination research in sleep health and circadian rhythm.

Cognitive consequences of stage-specific sleep apnea (PI Andrew Varga, MD, PhD)
In this project, we use stage-specific CPAP withdrawal in subjects with severe OSA to address questions about how sleep affects spatial navigational memory, and what the contributions are of sleep fragmentation versus intermittent hypoxia associated with OSA.

Brain sleep clearance of amyloid-beta peptides study (Brain SCRAPS) (Co-I Andrew Varga, MD, PhD)
In the first part of this study, (PI Ricardo Osorio, MD: NYU School of Medicine)  we examine relationships between sleep characteristics and levels of proteins in spinal fluid that are associated with the development of Alzheimer disease in cognitively normal elderly subjects. In the second part, we examine the effects of CPAP withdrawal on levels of proteins in spinal fluid that are associated with the development of Alzheimer disease in subjects with severe OSA.

Molecular mechanisms of sleep-dependent motor learning and memory (PI Andrew Varga, MD, PhD)
In this project, we explore the roles of cortical sleep spindles and signaling pathways that support the synthesis of new neuronal proteins in the sleep-dependent augmentation of motor skill learning in animal models.

Automated actigraphy analysis for identification of prodromal Parkinson’s disease and related disorders (PI: During)
In this study we develop a machine learning model using wrist wearable data to detect sleep disturbances (REM sleep behavior disorder, causing dream enactment episodes) and changes in patterns of activity during the day that could predict future risk of developing Parkinson’s disease and dementia with Lewy bodies 5 years later. This study tests our approach in 3 large datasets: the UK biobank, MrOS, and SOF datasets and also correlate the predictive model with cognitive function and genetic data.