There is a fundamental gap in our understanding of the underlying mechanisms of the highly prevalent co- occurring symptoms (sleep disturbance, fatigue, and impaired cognition) in persons with subarachnoid hemorrhage (SAH). My goal in seeking this K23 is to acquire the necessary knowledge, skills, and research experience to become an independent investigator focused on identifying mechanisms triggering the development of these symptoms following SAH as well as identifying symptom management strategies. My long-term goal is to design precision interventions targeting symptoms post-SAH based upon mechanisms elucidated in the proposed study. My short-term goals through this K23 training award are to acquire didactic and mentored training in 1) physiology and pathophysiology of the inflammatory response post-SAH and its? laboratory measurement, 2) sleep science including objective measurement of sleep disturbance using actigraphy, 3) translational and longitudinal research methods and clinical trial design, and 4) advanced statistical methods. My research training will be supported by an interdisciplinary team of scientists: Drs. Hilaire Thompson (immune response, brain injury and longitudinal methods), Mark Opp (neuroimmunology and sleep), Susan McCurry (sleep and cognition), Kyra Becker (immune response, stroke, fatigue and genetics), and Kevin Cain (biostatistician). It is known that SAH triggers inflammation in the brain. Messenger RNA (mRNA) and protein expression of Toll-Like Receptor 4 (TLR4) are up-regulated after SAH and initiate the inflammatory response. This activation induces production of pro-inflammatory cytokines, which may play a role in symptom development. Polymorphisms inTLR4 and pro-inflammatory cytokine genes may also have a role in biologic pathways for symptom development post-SAH as they are associated with sleep disturbances and fatigue in other populations. I hypothesize that TLR4 up-regulation following SAH triggers an inflammatory response in the brain and the extent of the inflammatory response and polymorphisms in TLR4, Tumor Necrosis Factor-alpha (TNFA), Interleukin (IL)1B, and IL6 influence later symptom development, notably sleep disturbance, fatigue and impaired cognition. To test this hypothesis, a 6-month longitudinal study using a convenience sample of 100 SAH survivors will be conducted to 1) describe changes in sleep disturbance (actigraphy: total sleep time, efficiency, self-report: quality, daytime sleepiness), fatigue, and impaired cognition (attention, language, memory and global function) at 2, 3, and 6 months, 2) examine both early (to day 7 post- SAH) and concurrent (2, 3, 6 mo) TLR4 mRNA expression, and TNF-?, IL1?, IL6 plasma levels in relation to these symptoms over time, and 3) explore the associations of TLR4, TNFA, IL1B and IL6 polymorphisms with symptoms post-SAH over time. If development of sleep disturbance, fatigue and cognitive impairment after SAH share underlying inflammatory mechanisms, assessing and treating the inflammatory response may have a greater impact on improving health than targeting a single symptom.
Given the high prevalence of sleep disturbance, fatigue and impaired cognition in subarachnoid hemorrhage (SAH) survivors, efforts to understand underlying mechanisms are crucial. We aim to contribute to improving knowledge about the human brain and symptom development after SAH by integrating biological and behavioral sciences in the proposed study. This study will enable better understanding of the biological mechanisms related to sleep disturbance, fatigue, and impaired cognition in persons with SAH, help identify SAH survivors at high risk for developing these symptoms, and reveal potential target/therapeutic areas for potential intervention. !
