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

创伤性脑损伤影响了伊拉克自由行动(OIF)/行动中的30多万名士兵 持久自由(OEF)。轻度颅脑损伤是这些CONflICT最常见的脑损伤 占所有脑损伤的90%。然而，mTBI的临床表现与受试者有重叠之处。 患有创伤后应激障碍(PTSD)，这也是一种普遍存在的疾病，在flICT中有30%的人 从OIF/OEF返回的士兵。颅脑损伤的病理生理学仍然很难解剖，因为fi 在军事人口中发生的伤害的异质性。一些神经病理学研究 使用职业橄榄球运动员和生活中遭受脑外伤的退伍军人的脑组织显示 淀粉样蛋白和tau蛋白的堆积，这两个都是阿尔茨海默病(AD)的关键病理机制。近期 研究表明，重型颅脑损伤患者的血液A、β和tau水平也会发生变化。进行的研究 罗斯坎普研究所的科学家和其他人发现，携带载脂蛋白ε4等位基因的个体 脑损伤的诊断是学习和记忆障碍，这与阿尔茨海默病一致。 然而，在mTBI受试者中检测AD相关病理仍然是一个关键的挑战，因此 血液生物标志物的发现将极大地提高我们在mTBI受试者中检测临床前AD的能力。 我们已经证明，血液中omega-3和omega-6多不饱和脂肪酸(PUFA)的含量 ε-4携带者临床前轻度认知功能障碍或AD患者的磷脂发生改变.这些 与对照组和非ε4携带者相比，合并脑损伤的ε4携带者的血PL也发生了改变。欧米茄-3和 Omega-6多不饱和脂肪酸可以经历一系列的酶和非酶过程，导致产生 生物活性脂质代谢物，在fl中存在一系列fl、炎症和氧化应激参数，这些参数包括 与阿尔茨海默病和脑外伤的病理都有关。AD和脑外伤患者的鞘磷脂(SM)水平改变 这些脂类可以进一步代谢产生神经酰胺，神经酰胺是fl氨化的有力调节器。我们 因此，假设对生物活性脂类代谢物(即二十烷类、异前列烷、 溶血素、脂氧素、神经酰胺和鞘氨醇)将有助于区分mTBI患者和健康患者 对照组和那些出现类似症状的患者。这些生物活性脂类代谢物将 也有助于预测认知能力下降，预示着随后的阿尔茨海默病风险。我们已经开发出脂类分析方法， 利用纳米flow超高压液相色谱系统和高密度的 Q激射混合四重轨道质量的精度和高分辨能力 分光计，使我们能够科学和准确地鉴定和定量数以百计的生物活性脂质fi 代谢物。我们将应用这项技术来识别可以区分的新的血脂代谢产物 来自其他诊断组的mTBI受试者。我们将确定人员内部和人员之间的差异 血脂代谢物，以识别那些低变异性的，然后将进行纵向评估 短期和长期。从这些研究中，我们将确定与认知相关的代谢物 患有mTBI的受试者所经历的衰退。本文建议的工作将主要使用现有的样本 可在生物信息库中获得，这些生物信息库是从参与慢性影响的受试者那里收集的 神经创伤联盟和军队队列。我们预计，拟议的脂质组学技术，连同 利用APOE基因信息，我们将开发一个生物标记物小组，帮助临床医生 提供对mTBI的准确诊断和对AD相关认知障碍预后的预测 MTBI。这些研究将提高我们为患有疾病的患者提供更好的护理和疾病管理的能力 MTBI，以降低他们患AD和相关疾病的风险。

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.