Lipidomics for Identifying APOE4-Associated Biomarkers of AD-Related Cognitive Decline in TBI Patients
Abstract
Traumatic brain injury (TBI) is one of the leading causes of death and disability in the United States of America, where nearly two million individuals are diagnosed with TBI each year. Survivors of TBI could experience lifelong disabilities, which can significantly affect their quantity of life and productivity. While the rate of severe TBI has decreased to 1% of the total TBI sustained by the military personnel, improvements made in military body armor and combat helmets over the past two decades have resulted in an increase in the rates of mild and moderate TBI, which now make up nearly 90% of all TBI reported since the inception of Operation Iraqi Freedom (OIF)/Operation Enduring Freedom (OEF). Mild and moderate brain injuries remain difficult to diagnose given the overlap in their clinical presentation with other conditions, such as post-traumatic stress disorder (PTSD), which can also affect the military population. In addition, studies have shown that individuals with repeat mild, moderate, and severe TBI are at high risk of developing Alzheimer’s disease (AD), particularly among individuals with the apolipoprotein E (APOE) e4 allele who have genetic predisposition to developing AD. In fact, e4 carriers who sustained TBI as young adults experience persistent and chronic cognitive impairment that is characterized by learning and memory problems that are reported by patients with early AD. These individuals represent a high-risk population, and therefore detecting cognitive decline characteristic of AD in e4 carriers who have suffered TBI is of significant importance in reducing the burden of AD among TBI patients. The studies proposed in this application will apply state-of-the-art mass spectrometry technology to develop biomarkers of TBI, which can help distinguish mild to moderate TBI from other comorbid conditions and detect cognitive decline indicative of AD after injury. The Roskamp Institute scientists have been applying lipidomic technologies that allow an examination of a large variety of lipids (i.e., fats) that are generally acquired from diet and delivered to the brain from blood in order to facilitate neuronal membrane repair and combat inflammation in the brain, pathologies that occur after AD and TBI. These lipids include omega-3 and omega-6 polyunsaturated fatty acids (PUFA), which include docosahexaenoic acid (DHA) and arachidonic acid (AA), respectively. These lipids can be broken down to perform a wide range of functions in the brain that combat the effects of brain injury. Our work thus far has shown that in the presence of the e4 allele, transit of these lipids to the brain is reduced and this appears as accumulation of these lipids in e4 carries in early stages of AD and in patients with TBI. In this proposal, we will validate our original findings using our recently developed high resolution and high accuracy lipidomics technology that allows examination of about 1000 lipids in blood using much larger cohorts of military and Veteran populations to determine if these lipids can differentiate mild and moderate TBI from other diagnostic groups. Using another valuable longitudinal cohort that was followed for almost a decade, we will also validate whether these lipids can identify e4-positive individuals at risk of developing AD within 5 years and examine lipid changes in samples collected at several time points spanning the time period when these individuals had normal cognition up to the time point when they converted to AD. We will also determine if these lipids can also provide an indication of the changes in memory function in TBI, which are generally seen in individuals with the diagnosis of AD. The existing expertise and collaborations between the Roskamp Institute, the Chronic Effects of Neurotrauma Consortium (CENC), and the James A. Haley VA Hospital will expedite successful translation of this endeavor so that appropriate biomarker tools are made available to the clinicia
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710625
Entities
People
- Laila Abdullah
Organizations
- Roskamp Institute
- United States Army