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

鉴定用于诊断 TBI 患者慢性神经认知缺陷的 APOE 相关脂质生物标志物

• 批准号: 9910069
• 负责人: Laila Abdullah
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9910069
• 关键词: Affect; Afghanistan; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Apolipoproteins; Biological; Biological Assay; Biological Markers; Blood; Brain Injuries; Caring; Cause of Death; Ceramides; Chronic; Clinical; Cognition; Cognitive; Cognitive deficits; Collection; Conflict (Psychology); Development; Diagnosis; Diagnostic; Diet; Disease; Disease Management; Eicosanoids; Enrollment; Exhibits; Fasting; Freedom; Functional disorder; Future; Generations; Genetic Predisposition to Disease; Genotype; Glycerol; High Pressure Liquid Chromatography; Homeostasis; Hospitals; Hybrids; Immune response; Impaired cognition; Individual; Inflammation; Inflammatory; Inflammatory Response; Injury; Institutes; Iraq; Isoprostanes; Learning; Life; Life Experience; Lipids; Lipoxins; Longitudinal Studies; Manufactured football; Mass Spectrum Analysis; Memory; Memory Loss; Memory impairment; Military Personnel; Nature; Nerve Degeneration; Nervous System Trauma; Neurocognitive Deficit; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Outcome; Oxidative Stress; Oxides; Pathogenesis; Pathology; Patients; Persons; Phospholipids; Plasma; Play; Polyunsaturated Fatty Acids; Population; Post-Traumatic Stress Disorders; Predictive Value; Process; Productivity; Quality of life; Resolution; Risk; Role; Sampling; Scientist; Series; Site; Soldier; Sphingomyelins; Sphingosine; Survivors; Symptoms; System; Technology; Testing; Time; Tissues; Traumatic Brain Injury; Variant; Veterans; War; Work; accurate diagnosis; apolipoprotein E-4; biomarker panel; blood lipid; brain tissue; candidate marker; cohort; comorbidity; disability; experience; follow-up; healthy volunteer; high risk; improved; mass spectrometer; mild cognitive impairment; mild traumatic brain injury; nano; novel; operation; outcome forecast; pre-clinical; repository; sphingosine 1-phosphate; tau Proteins; ultra high pressure

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.

参与伊拉克自由行动 (OIF)/行动的超过 300,000 名士兵受到创伤性脑损伤 (TBI) 的影响 持久自由 (OEF) 是这些冲突和创伤性脑损伤 (mTBI) 中最常见的脑损伤。 占所有脑损伤的 90%，然而，mTBI 的临床表现与受试者的临床表现重叠。 患有创伤后应激障碍 (PTSD)，这也是一种影响 30% 的人的普遍病症 从 OIF/OEF 返回的士兵 由于 TBI 的病理生理学仍然难以剖析。 军队人群中发生的伤害的异质性 一些神经病理学研究。 使用生活中患有 TBI 的职业足球运动员和退伍军人的脑组织表明 淀粉样蛋白和 tau 蛋白的积累是阿尔茨海默病 (AD) 的关键病理。 研究表明，患有 mTBI 的受试者的血液 Aβ 和 tau 水平也会发生变化。 Roskamp 研究所的科学家和其他人发现，携带载脂蛋白 (APOE) ε4 等位基因的个体 TBI 的诊断患有与 AD 一致的学习和记忆障碍。 然而，检测 mTBI 受试者的 AD 相关病理仍然是一个严峻的挑战，因此 血液生物标志物的发现将大大增强我们检测 mTBI 受试者临床前 AD 的能力。 我们已经证明血液中的 omega-3 和 omega-6 多不饱和脂肪酸 (PUFA) 含量 患有临床前轻度认知障碍 (MCI) 或 AD 的 ε4 携带者的磷脂 (PL) 发生改变。 与对照组和非 ε4 携带者相比，患有 TBI 的 ε4 携带者的血液 PL 也发生了变化。 omega-6 PUFA 可以经历一系列酶促和非酶促过程，从而产生 影响一系列炎症和氧化应激参数的生物活性脂质代谢物 与 AD 和 TBI 病理相关 AD 和 TBI 患者的鞘磷脂 (SM) 水平发生改变。 这些脂质可以进一步代谢产生神经酰胺，神经酰胺是炎症的有效调节剂。 因此，生物活性脂质代谢物（即类二十烷酸、异前列烷、 分解素、脂氧素、神经酰胺和鞘氨醇）将有助于区分 mTBI 受试者与健康受试者 对照组和患有类似症状的患者会产生这些生物活性脂质代谢物。 还有助于预测表明后续 AD 风险的认知能力下降。 利用纳流超高压液相色谱 (UHPLC) 系统和高压 Q-Exactive 混合四重 Orbitrap 质量的质量精度和高分辨率能力 光谱仪，使我们能够高效、准确地识别和量化数百种生物活性脂质 我们将应用这项技术来识别可以区分的新型血脂代谢物。 我们将确定来自其他诊断组的 mTBI 受试者的人内和人际差异。 血脂代谢物，以确定那些具有低变异性的代谢物，然后对其进行纵向评估 从这些研究中，我们将确定与认知相关的代谢物。 mTBI 受试者经历的衰退本文提出的工作将主要使用现有样本。 可在生物存储库中找到，这些生物存储库是从参加慢性影响研究的受试者中收集的 我们期望神经创伤联盟和军事团体共同提出所提出的脂质组学技术。 有了 APOE 基因型信息，我们将能够开发一个生物标记物组，以帮助民兵 提供 mTBI 的准确诊断以及 AD 相关认知障碍的预后 这些研究将提高我们为患有这种疾病的患者提供更好的护理和疾病管理的能力。 mTBI 以降低患 AD 和相关疾病的风险。