Mild TBI and Biomarkers of Neurodegeneration

轻度 TBI 和神经退行性变的生物标志物

• 批准号: 8838166
• 负责人: ELAINE R. PESKIND
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838166
• 关键词: Address; Afghanistan; Alzheimer' s Disease; American; Amnesia; Anxiety; Apolipoprotein E; Area; Behavioral; Biological Markers; Blast Cell; Brain; Brain Concussion; Brain imaging; Cerebrospinal Fluid; Characteristics; Chemicals; Clinical; Clinical Trials Design; Conflict (Psychology); Congresses; Conscious; Dementia; Devices; Diagnosis; Diagnostic Imaging; Disease; Event; Face; Family Relationship; Financial compensation; Freedom; Genetic Polymorphism; Goals; Healthcare; Hour; Imaging Techniques; Imaging technology; Impaired cognition; Injury; Iraq; Liquid substance; Long-Term Care; Magnetic Resonance Imaging; Manufactured football; Marines; Measurement; Medical; Memory impairment; Mental Health; Moods; Nerve Degeneration; Neurobehavioral Manifestations; Neurocognitive; Neurologic; Occupations; Pensions; Phenotype; Physical Medicine; Post-Traumatic Stress Disorders; Process; Rehabilitation therapy; Research; Resources; Risk; Secondary to; Services; Sleep disturbances; Soldier; Structure; Symptoms; Syndrome; Therapeutic Intervention; Trauma; Traumatic Brain Injury; Validation; Veterans; Vulnerable Populations; War; base; brain tissue; combat; disability; evidence base; genetic risk factor; improved; innovation; member; middle age; neurodegenerative dementia; neuroimaging; operation; prevent; response; social; tau Proteins; tool

DESCRIPTION (provided by applicant): Mild traumatic brain injury (mTBI) caused by blast effects of explosive devices is the "signature injury" of soldiers, Marines, and other service members in the current Iraq and Afghanistan conflicts. Repetitive mTBI characteristic of troops deployed to Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF), may have devastating personal, professional and domestic consequences. Impairment of memory and concentration, increased anxiety, irritability and mood instability, and sleep disturbance interfere with job and family relationships, producing substantial disability. In addition to these immediate consequences of mTBI, blast trauma damage to brain tissue and/or subsequent brain reparative effects may initiate processes leading to neurodegeneration and dementia. This proposal will apply advanced functional and structural neuroimaging and cerebrospinal fluid (CSF) biomarkers to address the following questions: 1) Are there objective neuroimaging and CSF biomarkers that: a) characterize the behavioral phenotype of blast-induced mTBI; and b) distinguish mTBI from combat trauma posttraumatic stress disorder (PTSD)? 2) Is there long-term cognitive impairment in repetitive blast mTBI and, if so, is cognitive impairment associated with CSF biomarkers of and genetic risk factors for neurodegenerative dementia? The term "mTBI" here is used to denote a syndrome of persistent postconcussive symptoms ([PCS] cognitive, behavioral, and somatic) that continue to be expressed months and years after blast concussion events that produce mTBI. Our preliminary neuroimaging results demonstrate previously unrecognized structural and functional abnormalities independent of comorbid PTSD in OIF/OEF Veterans with mTBI and persistent PCS. Specific Objective 1: To characterize the clinical (neurocognitive, neurologic, behavioral) and structural/functional neuroimaging characteristics of blast trauma repetitive mild traumatic brain injury (mTBI) in OIF/OEF Veterans with PCS. Specific Objective 2: To determine if OIF/OEF Veterans with repetitive mTBI with persistent PCS express CSF biomarker changes associated with the onset and progression of neurodegenerative dementing disorders. Specific Objective 3: To determine the effects of genetic risk factors for neurodegeneration (apolipoprotein E [APOE] polymorphisms and microtubule associated protein tau [MAPT] subhaplotypes) on both clinical characteristics, and neuroimaging and CSF biomarkers in OIF/OEF Veterans with repetitive mTBI and persistent PCS. This proposal addresses the RR&D priority areas of Validation and Refinement of Diagnostic Imaging Technology and Innovative Approaches to Late or Long-Term Consequences of TBI. VHA faces a huge burden of providing primary medical, rehabilitative, mental health and long term care to this vulnerable population. Identification of objective neuroimaging and CSF biomarkers of mTBI and clarification of the long- term risks of neurodegenerative dementias in mTBI will: 1) improve diagnosis of mTBI, 2) provide targets for improving Veterans' health care; and 3) allow appropriate allocation of limited health care, compensation and pension, and social resources. Successful completion of the proposed research has a high likelihood of yielding both short-term and long-term clinical impacts. Within 24 months, the project will yield tools for objective biomarker diagnosis of mTBI. Within 4 years, results from the proposed project will form the evidence base for rational design of clinical trials to treat current symptoms of mTBI and to prevent progression to neurodegenerative dementing disorders.

描述（由申请人提供）： 由爆炸装置的爆炸效应引起的轻度创伤性脑损伤（MTBI）是当前伊拉克和阿富汗冲突中士兵，海军陆战队和其他服务人员的“签名伤害”。部署在伊拉克行动自由/持久自由行动（OIF/OEF）行动的部队的重复MTBI特征可能会造成个人，专业和家庭后果。记忆和集中障碍，焦虑，烦躁不稳和情绪不稳定以及睡眠障碍会干扰工作和家庭关系，从而产生实质性残疾。除了MTBI的这些直接后果外，爆炸创伤对脑组织和/或随后的脑部修复作用可能会引发导致神经变性和痴呆的过程。 该提案将采用先进的功能和结构神经影像学和脑脊液（CSF）生物标志物来解决以下问题：1）是否存在客观的神经影像学和CSF生物标志物，其表征：a）表征了爆炸引起的MTBI的行为表型； b）将MTBI与创伤后应激障碍（PTSD）区分开？ 2）重复性爆炸MTBI中是否存在长期认知障碍，如果是的，则与CSF生物标志物和神经退行性痴呆的遗传危险因素有关吗？这里的“ MTBI”一词用于表示持续的脑震荡症状（[PCS]认知，行为和躯体）的综合征，该症状是在产生MTBI的爆炸脑震荡事件后数月和几年继续表达的。我们的初步神经影像学结果表明，与MTBI和持久性PC中的OIF/OEF退伍军人中的合并症PTSD无关，其结构和功能异常与合并症无关。 特定目标1：表征具有PC的OIF/OEF退伍军人中BLAST创伤重复轻度创伤性脑损伤（MTBI）的临床（神经认知，神经系统，行为）和结构/功能性神经成像特征。 具体目标2：确定具有持久PC的重复MTBI的OIF/OEF退伍军人是否表达与神经退行性痴呆症的发作和进展相关的CSF生物标志物变化。 具体目标3：确定遗传危险因素对神经退行性的影响（载脂蛋白E [APOE]多态性和微管相关的蛋白质TAU [MAPT]亚脑型型）对OIF/OEF/OEF兽医的临床特征以及具有重复的MTBI和Persent Pcs的临床特征和CSF生物标记。 该建议介绍了诊断成像技术的RR＆D优先领域，以及针对TBI的晚期或长期后果的创新方法。 VHA面临为这一脆弱人群提供主要医疗，康复，心理健康和长期护理的巨大负担。 MTBI的客观神经成像和CSF生物标志物的鉴定以及MTBI中神经退行性痴呆的长期风险的澄清将：1）改善MTBI的诊断，2）为改善退伍军人的医疗保健提供了目标； 3）允许适当分配有限的医疗保健，薪酬和养老金以及社会资源。拟议研究的成功完成很有可能产生短期和长期临床影响。在24个月内，该项目将产生用于MTBI的客观生物标志物诊断的工具。在4年内，拟议项目的结果将构成临床试验合理设计的证据基础，以治疗MTBI的当前症状并防止神经退行性痴呆症。