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: 10614552
• 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 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10614552
• 关键词: Affect; Afghanistan; Alleles; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; 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; Development; Diagnosis; Diagnostic; Diet; 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; 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; Pathogenesis; Pathology; Patients; Persons; Phospholipids; Plasma; Polyunsaturated Fatty Acids; Population; Post-Traumatic Stress Disorders; Predictive Value; Process; Productivity; Prognosis; Quality of life; Resolution; Risk; Role; Sampling; Scientist; Series; Site; Soldier; Sphingomyelins; Sphingosine; Survivors; Symptoms; System; TBI Patients; Technology; Testing; Time; Tissues; Traumatic Brain Injury; Variant; War; Work; accurate diagnosis; biobank; biomarker identification; biomarker panel; blood lipid; brain tissue; candidate marker; cohort; comorbidity; comparison control; disability; experience; follow-up; healthy volunteer; high risk; improved; lipidomics; mass spectrometer; mild cognitive impairment; mild traumatic brain injury; military veteran; nano; neuropathology; novel; operation; pre-clinical; 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.

创伤性脑损伤（TBI）影响了伊拉克自由行动（OIF）/行动的30万名士兵 持久自由（OEF）。轻度TBI（MTBI）是这些冲突和 代表所有脑损伤的90％。但是，MTBI与受试者的临床呈现重叠 患有创伤后应激障碍（PTSD），这也是一种普遍的条件，即30％ 从OIF/OEF返回的士兵。 TBI的病理生理学仍然很难剖析 军事人口发生的伤害的异质性质。许多神经病理学研究 使用职业足球运动员和退伍军人的脑组织，他们在生活中维持TBI 淀粉样蛋白和tau的积累，这都是阿尔茨海默氏病（AD）的关键病理。最近的 研究表明，MTBI受试者的血液中血液Aβ和TAU水平也会改变。进行的研究 罗斯坎普研究所的科学家和其他人表明，具有载脂蛋白（APOE）ε4等位基因的人 对TBI的诊断遭受与AD一致的学习和记忆障碍。 然而，检测MTBI受试者中与AD相关的病理仍然是一个关键挑战，因此 血液生物标志物的发现将大大增强我们在MTBI受试者中检测临床前广告的能力。 我们已经表明，omega-3和Omega-6多不饱和脂肪酸（PUFA）含量 在临床前轻度认知障碍（MCI）或AD的ε4载体中，磷脂（PL）改变。这些 与对照组和非ε4载体相比，具有TBI的ε4载体中的血PL也会改变。 Omega-3和 Omega-6 PUFA可以经历一系列酶促和非酶过程，这些过程导致产生 生物活性脂质代谢产物，这些代谢产物影响了一系列炎症和氧化应激参数 与AD和TBI病理相关。 AD和TBI患者的鞘磷脂（SM）水平改变了 这些脂质可以进一步代谢，以生成旋转量的潜在调节剂的神经酰胺。我们 因此，假设对生物活性脂质代谢产物的检查（即类固醇，异丙烷，异丙烷基 resolvins，lipoxins，ceramides和鞘氨酸）将有用 对照和具有类似症状的条件的人。这些生物活性脂质代谢产物将 还有助于预测表明随后的AD风险的认知下降。我们已经开发了脂科学测定法 利用纳米流量超高压液相色谱（UHPLC）系统和高 Q-激活杂种四边形轨道质量的质量准确性和高分辨率功能 光谱仪，使我们能够有效，准确地识别和量化数百种生物活性脂质 代谢物。我们将应用这项技术来识别可以区分的新型血脂代谢产物 来自其他诊断组的MTBI受试者。我们将确定人体内和人际关系的变化 血脂代谢物以识别那些较低的变异性，然后将其纵向评估 短期和长期。从这些研究中，我们将确定与认知相关的代谢产物 MTBI受试者经历的下降。本文提出的工作将在很大程度上使用现有样品 在从参与的受试者中收集的生物重定位者中可用 Neurotrauma财团和军事人群。我们期望提出的脂肪态技术一起 借助APOE基因型信息，我们将允许我们开发一个生物标志物面板，以帮助临床医生 提供了MTBI的准确诊断和与AD相关的认知障碍的预后 mtbi。这些研究将提高我们为患有患者提供更好护理和疾病管理的能力 MTBI是为了减少其发展AD和相关疾病的风险。