Identifying APOE related lipid biomarkers for diagnosing chronic neurocognitive deficits in TBI patients

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Traumatic brain injury (TBI) affects over 300,000 troops from the Operation Iraqi Freedom (OIF)/Operation Enduring Freedom (OEF). Mild TBI (mTBI) is the most prevalent brain injury from these conflicts and represents 90% of all brain injuries. However, clinical presentation of mTBI overlaps with those of subjects suffering from post-traumatic stress disorder (PTSD), which is also a prevalent condition that afflicts 30% of the soldiers returning from the OIF/OEF. The pathophysiology of TBI remains difficult to dissect owing to the heterogenous nature of the injuries that occur in the military population. A number of neuropathological studies using brain tissue from professional football players and military veterans who sustained TBI in life showed accumulation of amyloid and tau, both of which are key pathologies of Alzheimer's disease (AD). Recent studies show that blood Aβ and tau levels are also altered in blood of subjects with mTBI. Studies conducted by the Roskamp Institute scientists and others showed that individuals with the apolipoprotein (APOE) ε4 allele and a diagnosis of TBI suffered from learning and memory impairment that was consistent with AD. Nevertheless, detecting AD related pathology in mTBI subjects remains a critical challenge and therefore discovery of blood biomarkers will greatly enhance our ability to detect preclinical AD in subjects with mTBI. We have shown that omega-3 and omega-6 polyunsaturated fatty acid (PUFA) content within blood phospholipids (PL) are altered in ε4 carriers with preclinical mild cognitive impairment (MCI) or AD. These blood PL are also altered in ε4 carriers with TBI compared to controls and non-ε4 carriers. The omega-3 and omega-6 PUFA can undergo a series of enzymatic and non-enzymatic processes which result in generation of bioactive lipid metabolites that influence a range of inflammatory and oxidative stress parameters which are relevant to both AD and TBI pathologies. Levels of sphingomyelin (SM) are altered in AD and TBI patients and these lipids can be further metabolized to generate ceramides that are potent modulators of inflammation. We therefore hypothesize that an examination of bioactive lipid metabolites (i.e. eicosanoids, isoprostanes, resolvins, lipoxins, ceramides and sphingosine) will be useful in differentiating mTBI subjects from healthy controls and those with conditions which present with similar symptoms. These bioactive lipid metabolites will also help predict cognitive decline indicative of subsequent AD risk. We have developed lipidomic assays that take advantage of the nano-flow Ultra high pressure liquid chromatography (UHPLC) systems and the high mass accuracy and high resolution capabilities of the Q-Exactive hybrid quadruple Orbitrap mass spectrometer, allowing us to efficiently and accurately identify and quantify hundreds of bioactive lipid metabolites. We will apply this technology to identify novel blood lipid metabolites that can differentiate subjects with mTBI from other diagnostic groups. We will determine the intra- and inter-person variations of blood lipid metabolites to identify those with low variability which will then be evaluated longitudinally over short- and long-term periods. From these studies, we will identify metabolites that are associated with cognitive decline experienced by subjects with mTBI. The work proposed herein will largely use the existing samples available in the bio-repositories that were collected from subjects enrolled in the Chronic Effects of Neurotrauma Consortium and military cohorts. We expect that the proposed lipidomics technology, together with the APOE genotype information, will allow us to develop a biomarker panel that will aid clinicians in providing an accurate diagnosis of mTBI and in prognosis of cognitive impairment associated with AD after mTBI. These studies will improve our ability to provide better care and disease management to patients with mTBI in order to reduce their risk of developing AD and related disorders.