Disruption of sleep and alertness is one of the most disabling non-motor symptoms of Parkinson's disease (PD). Mechanisms leading to impaired sleep and alertness in PD are not well understood, and treatment options remain limited. This application for a K23 Mentored Patient-Oriented Research Career Development Award entitled """"""""Circadian rhythms and sleep-wake cycles in Parkinson's Disease"""""""" is designed to provide Dr. Aleksandar Videnovic with the research skills and experience to bridge the areas of movement disorders, sleep and circadian biology in order to understand the basis for sleep and wake disturbances in PD. Dr. Videnovic is an Assistant Professor of Neurology at Northwestern University in Chicago. He completed residency training in Neurology at Northwestern University, a clinical fellowship in Movement Disorders at Rush University, and obtained a master's degree in clinical research from Rush Graduate College. Dr. Videnovic's long term career goal is to understand the role of circadian rhythms and sleep on neurological outcomes in movement disorders, and to utilize this knowledge to improve patients'health and quality of life by innovative circadian and sleep based strategies. His immediate goals are to gain knowledge and skills in circadian biology, sleep medicine, and clinical research methodology so as to investigate potential circadian rhythm abnormalities in PD. Dr. Videnovic has assembled a team of researchers who will mentor him during this award. His primary mentor, Dr. Phyllis Zee, and co-mentor Dr. Fred Turek are renowned investigators in the field of circadian biology with complementary expertise in patient oriented and basic science research. Expertise in mathematical modeling of circadian rhythms, statistical analyses, and clinical research in PD, will be provided by consultants, Drs. Elizabeth Klerman, Alfred Rademaker, and Tanya Simuni. The proposed training plan encompasses didactic and hands-on training on the characterization of the circadian system using physiological and molecular markers, assessments of the sleep-wake cycle, applications of circadian based treatments including light therapy, and further training in clinical research methods. The first part of the proposed research will examine the amplitude and stability of the circadian system using biological markers of the circadian system (e.g., melatonin, clock genes and the rest-activity cycle). The primary hypothesis is that disruption of circadian rhythmicity plays an important role in the development of poor sleep quality and daytime somnolence in PD. These markers of circadian rhythmicity will be correlated with sleep quality and degree of daytime somnolence in PD participants and healthy controls. The second part of the project is to test the hypothesis that increasing the strength and stability of circadian rhythms, using bright light exposure, will improve sleep quality and daytime somnolence in PD. Results from this research and the proposed training plan will form the foundation for an independent clinical research program at the interface of sleep, circadian biology and PD which may lead to novel and more effective treatments aimed to improve the health and quality of life of patients with PD.

Public Health Relevance

Sleep dysfunction and excessive daytime somnolence are common and poorly understood symptoms of Parkinson 's disease (PD), affecting both patients and caregivers, and have a negative impact on the quality of life, safety, morbidity and mortality in the PD population. The proposed research is designed to provide new insight into a potential circadian rhythm etiology of sleep dysfunction in PD, form the foundation for novel circadian-based treatment strategies, and provide mentored training for the candidate as he continues to develop his career in patient-oriented research.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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NST-2 Subcommittee (NST)
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Sieber, Beth-Anne
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Northwestern University at Chicago
Schools of Medicine
United States
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Alibiglou, Laila; Videnovic, Aleksandar; Planetta, Peggy J et al. (2016) Subliminal gait initiation deficits in rapid eye movement sleep behavior disorder: A harbinger of freezing of gait? Mov Disord 31:1711-1719
Chahine, Lama M; Amara, Amy W; Videnovic, Aleksandar (2016) A systematic review of the literature on disorders of sleep and wakefulness in Parkinson's disease from 2005 to 2015. Sleep Med Rev :
Videnovic, Aleksandar; Willis, Gregory L (2016) Circadian system - A novel diagnostic and therapeutic target in Parkinson's disease? Mov Disord 31:260-9
Abbott, Sabra M; Videnovic, Aleksandar (2016) Chronic sleep disturbance and neural injury: links to neurodegenerative disease. Nat Sci Sleep 8:55-61
Simuni, Tanya; Caspell-Garcia, Chelsea; Coffey, Christopher et al. (2015) Correlates of excessive daytime sleepiness in de novo Parkinson's disease: A case control study. Mov Disord 30:1371-81
Videnovic, Aleksandar; Zee, Phyllis C (2015) Consequences of Circadian Disruption on Neurologic Health. Sleep Med Clin 10:469-80
Augustine, Erika F; Pérez, Adriana; Dhall, Rohit et al. (2015) Sex Differences in Clinical Features of Early, Treated Parkinson's Disease. PLoS One 10:e0133002
Writing Group for the NINDS Exploratory Trials in Parkinson Disease (NET-PD) Investigators; Kieburtz, Karl; Tilley, Barbara C et al. (2015) Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial. JAMA 313:584-93
Videnovic, Aleksandar; Noble, Charleston; Reid, Kathryn J et al. (2014) Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol 71:463-9
Videnovic, Aleksandar; Breen, David P; Barker, Roger A et al. (2014) The central clock in patients with Parkinson disease--reply. JAMA Neurol 71:1456-7

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