Tau Biomarkers following Blast mTBI in OEF/OIF Veterans

OEF/OIF 退伍军人中爆炸性 mTBI 后的 Tau 生物标志物

• 批准号: 8396425
• 负责人: Ann C. McKee
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8396425
• 关键词: Acute; Address; Afghanistan; Amnesia; Attention; Autopsy; Behavioral; Biological; Biological Markers; Blast Cell; Boston; Brain; Brain imaging; Caring; Center for Translational Science Activities; Cerebrospinal Fluid; Clinical; Control Groups; Craniocerebral Trauma; DSM-IV; Data; Development; Diagnosis; Differential Diagnosis; Disease; Enzyme-Linked Immunosorbent Assay; Executive Dysfunction; Exhibits; Fiber; Imaging Techniques; Individual; Injury; Interview; Iraq; Life; Magnetic Resonance Imaging; Measures; Memory Loss; Mental disorders; Metabolism; Monitor; Nervous System Trauma; Neurobehavioral Manifestations; Neurocognitive; Neurodegenerative Disorders; Participant; Pathology; Personality; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Recording of previous events; Recruitment Activity; Research; Risk; Sample Size; Sampling; Severities; Structure; Unconscious State; Veterans; War; base; chronic traumatic encephalopathy; cohort; combat; cost; executive function; high risk; indexing; injured; mental state; mild traumatic brain injury; nervous system disorder; pre-clinical; public health relevance; stress disorder; tau Proteins; tau-1

DESCRIPTION (provided by applicant): Chronic Traumatic Encephalopathy (CTE) is a progressive neurodegenerative disease that occurs as a consequence of repetitive mild traumatic brain injury (mTBI). CTE causes personality and behavioral changes, executive dysfunction and memory loss and is characterized by the accumulation of phosphorylated tau protein in the brain. The ongoing wars in Iraq and Afghanistan have resulted in a large cohort of OEF/OIF veterans with mTBI from blast exposure who may be at increased risk for CTE. Presently, CTE can only be diagnosed at autopsy and there are no known clinical biomarkers. The development of biomarkers to diagnose this disorder in living individuals would be a major scientific and clinical advance. We hypothesize that multiple combat blast-induced mTBIs cause altered tau metabolism indicative of preclinical CTE. We expect that increased tau biomarkers will be detected in cerebrospinal fluid (CSF) and in brain using advanced brain imaging techniques in veterans with a history of multiple blast mTBIs. In addition, recent data from our Translational Research Center for TBI and Stress Disorders (TRACTS) show that veteran with significant blast exposure exhibit greater rates and more severe post-traumatic stress disorder (PTSD) than veterans not exposed to blast neurotrauma. This suggests that the same individuals at risk for PTSD may also be at high risk for CTE. This project will draw its sample from the TRACTS cohort, which presently consists of 200 OEF/OIF veterans and will increase to ~400 during the proposed study period. History of blast exposure and TBI are documented via a semi-structured interview using the Boston Assessment of TBI: Lifetime (BAT-L). PTSD and other psychiatric illnesses are diagnosed using DSM-IV criteria. The proposed study will investigate the correlative relationship between mTBI metrics (number, severity, distance from blast) and neurocognitive measures of attention and executive function, phosphorylated tau pathology, axonal fiber tract damage, and structural brain changes. We will recruit two groups of 30 participants (total sample size of 60) from the TRACTS cohort that differ maximally in their history of combat TBI: (1) two or more blast mTBIs with associated cognitive symptoms (i.e., acute change in mental status, post-traumatic amnesia or loss of consciousness immediately after the blast) ("mTBI"); and (2) a matched control group without history of blast exposure or impact head injury ("CON"). All participants will have served in either OEF or OIF and have a diagnosis of PTSD based on DSM-IV criteria. We will measure tau biomarkers (phosphorylated tau (ptau), total tau, exosome ptau, oligomeric tau) in cerebrospinal fluid (CSF) by plate-based ELISA and conduct advanced brain imaging techniques using simultaneous PET/MRI. We will determine whether there is an association between CSF tau biomarkers, regional (dorsolateral frontal and orbital frontal) PET index metrics, mTBI metrics (number, severity, distance from blast), and neurocognitive measures of attention and executive function, Blast associated mTBI, PTSD and CTE represent significant scientific challenges in terms of determining their biological origins, their differential diagnosis and respective treatments. If not addressed immediately, the VA will be faced with daunting costs and responsibilities associated with caring for these debilitating neurological and psychiatric disorders. The development of reliable biomarkers to detect CTE will enable the diagnosis and monitoring of this condition during life and assessing the efficacy of potential therapies as they are developed. ! PUBLIC HEALTH RELEVANCE: Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease that occurs as a consequence of mild traumatic brain injury (mTBI). CTE causes personality and behavioral changes, executive dysfunction and memory loss and is characterized by the accumulation of tau protein in the brain. OEF/OIF veterans with a history of mTBI from blast exposure may be at increased risk for CTE. We will measure tau in cerebrospinal fluid (CSF) and conduct advanced brain imaging techniques in blast-injured OEF/OIF veterans in order to develop biomarkers for CTE, as currently none exist. If research geared at determining biomarkers and treatments for blast associated mTBI and CTE is not addressed immediately, the VA will be faced with daunting costs and responsibilities associated with caring for these debilitating neurological and psychiatric disorders. !

描述（由申请人提供）： 慢性创伤性脑病（CTE）是一种进行性神经退行性疾病，由于重复性轻度脑损伤（MTBI）而发生。 CTE会导致人格和行为变化，执行功能障碍和记忆丧失，其特征是磷酸化的Tau蛋白在大脑中的积累。伊拉克和阿富汗正在进行的战争导致了大量的OEF/OIF退伍军人与爆炸暴露的MTBI，可能会增加CTE的风险。目前，CTE只能在尸检时诊断出，并且没有已知的临床生物标志物。生物标志物在生物中诊断这种疾病的发展将是一个主要的科学和临床进步。我们假设多次战斗爆炸引起的MTBI会导致tau代谢的改变，指示临床前CTE。我们预计，使用具有多个爆炸史的退伍军人的高级脑成像技术，将在脑脊液（CSF）和大脑中检测到TAU生物标志物增加。此外，我们的TBI和应激障碍转化研究中心的最新数据表明，与未暴露于爆炸神经瘤的退伍军人相比，具有显着爆炸的退伍军人表现出更高的率和更严重的创伤后应激障碍（PTSD）。这表明有PTSD风险的同一个人也可能有CTE的高风险。 该项目将从区域组中获取样本，目前由200名OEF/OIF退伍军人组成，在拟议的研究期间将增加到〜400。通过使用Boston评估TBI：LIFETIME（BAT-L），通过半结构化访谈记录了爆炸式暴露和TBI的历史。使用DSM-IV标准诊断出PTSD和其他精神病疾病。拟议的研究将研究MTBI指标（数量，严重程度，与BLAST的距离）与注意力和执行功能的神经认知度量之间的相关关系，磷酸化的TAU病理学，轴突纤维道损伤以及结构性的大脑变化。我们将从区域队列中招募两组30名参与者（总样本量为60），这些参与者在战斗TBI的史上最大程度地不同：（1）两名或更多的BLAST MTBI，以及相关的认知症状（即心理状况的急性变化，创伤后的症状或意识后的急性变化或在爆炸后立即意识丧失） （2）没有爆炸史或撞击头部损伤的匹配对照组（“ con”）。所有参与者都将在OEF或OIF中服役，并根据DSM-IV标准诊断为PTSD。 我们将通过基于板的ELISA在脑脊液（CSF）中测量tau生物标志物（磷酸化的tau（PTAU），Total Tau，外部PTAU，寡聚TAU），并使用同时使用同时使用PET/MRI进行先进的脑成像技术。我们将确定CSF TAU生物标志物，区域（背外侧额叶和轨道额叶）PET指数指标，MTBI指标（数量，次数，严重性，与爆炸的距离）以及关注和执行功能的神经认知度量，BLAST与BLAST相关的MTBI，PTSD和CTE的神经认知能力的差异和差异性，他们的差异性地差异化。如果没有立即解决，VA将面临与照顾这些使人衰弱的神经系统和精神病有关的艰巨的成本和责任。可靠的生物标志物检测CTE的开发将使生活期间对这种情况进行诊断和监测，并评估潜在疗法的开发效果。呢 公共卫生相关性： 慢性创伤性脑病（CTE）是一种神经退行性疾病，由于轻度创伤性脑损伤（MTBI）而发生。 CTE引起人格和行为变化，执行功能障碍和记忆力丧失，其特征是tau蛋白在大脑中的积累。具有MTBI病史的OEF/OIF退伍军人可能会增加CTE的风险。我们将在脑脊液（CSF）中测量TAU，并在爆炸受损害的OEF/OIF退伍军人中进行晚期脑成像技术，以开发CTE的生物标志物，因为目前不存在。如果未立即解决旨在确定爆炸相关的MTBI和CTE的生物标志物和治疗方法的研究，则VA将面临与照顾这些使这些令人衰弱的神经系统和精神疾病有关的艰巨的成本和责任。呢