Development of Pharmacotherapies for the Treatment of Hydrocephalus and Associated Sequelae
Abstract
OVERALL PROGRAM The focus of our proposed research is to develop drugs that can be used to treat hydrocephalus. Hydrocephalus is a general term for excess cerebrospinal fluid (CSF) in the brain. Babies can be born with this or it can happen because of conditions such as traumatic brain injury (TBI), infection, or hemorrhage. There is even a form called idiopathic normal pressure hydrocephalus (iNPH) that arises from an unknown cause in the elderly. Thus, there are multiple forms of hydrocephalus. If too much CSF collects in the brain, then a person can develop symptoms from the increased pressure in the head such as pain, vision changes, sleep disturbance, and trouble walking. If left untreated, this can lead to cognitive changes and even death. Currently, the only effective intervention for hydrocephalus is brain surgery. The type most applicable to active military personnel is called post-traumatic hydrocephalus or PTH. The incidence of PTH has been reported to be quite high in severe head injury patients. Injured Soldiers treated in the field may not have timely access to neurosurgical care and advanced diagnostic testing, leading to under-reporting of the condition. While injury-associated hydrocephalus may get better over time, the effects of the long-term damage remain unknown. Retired military personnel are more likely to be at risk for hydrocephalus that develops after a stroke or from the poorly understood condition called iNPH. The latter affects the elderly with symptoms that mimic other neurodegenerative diseases such as Alzheimer’s and Parkinson disease. Young military families are more likely to be affected by childhood forms of the disease, most commonly caused by brain bleeds in premature births, spina bifida or trauma, all which result in chronic hydrocephalus. Civilian populations of similar ages are also affected by the multiple forms of hydrocephalus. Currently, the only long-term treatment is surgery. Shunts, the most common treatment require that a tube is implanted in the brain in order to drain the excess CSF from the brain to another part of the body. Unfortunately, shunts are prone to failure, blockage, and infection and require additional surgery when they malfunction. There are no long-term, effective drugs to treat hydrocephalus, and this represents a large, world-wide medical need. We are addressing this need by conducting studies to try to find safe and effective compounds that can be developed as drugs to treat all forms of hydrocephalus. While distinct causes of hydrocephalus exist, there is extensive overlap in both acute and chronic symptoms. Common symptoms include disorientation, chronic pain, cognitive and executive function changes, vision and sleep disturbances, and difficulties walking normally. The similar clinical presentation, as well as the effectiveness of shunt placement for multiple types of hydrocephalus, suggests overlapping cellular and molecular mechanisms. Importantly, the overlap implies treatment strategies may show effectiveness regardless of initial cause. The studies in these five proposed research projects are applicable to the Neuroscience Category – primarily to the Hydrocephalus Topic Area and secondarily to the Trauma Topic Area. Within these Topic Areas, the studies address the Strategic Goal of Foundational Studies by identifying underlying disease mechanisms and physiological processes that contribute to the development of all causes of hydrocephalus including from traumatic brain injury (TBI). Importantly, the studies also address the Strategic Goal of Treatment because we have identified several novel treatments for hydrocephalus and will test these in preclinical models, including novel therapies to address disease progression, cognitive function, vision disturbances, chronic pain, and to improve quality of life. The overarching challenge is to discover versatile, safe treatment options for use on the battlefield, athletic settings, and in ho
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310296
Entities
People
- Bonnie Blazer-Yost
Organizations
- Indiana University
- United States Army