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: 8256521
• 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/8256521
• 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役人员的“标志性伤害”。部署到伊拉克自由行动/持久自由行动 (OIF/OEF) 的部队重复的 mTBI 特征可能会造成毁灭性的个人、职业和家庭后果。记忆力和注意力受损、焦虑、烦躁和情绪不稳定增加以及睡眠障碍会干扰工作和家庭关系，造成严重残疾。除了 mTBI 的这些直接后果外，爆炸对脑组织的损伤和/或随后的脑修复效应可能会引发导致神经退行性变和痴呆的过程。 该提案将应用先进的功能和结构神经影像和脑脊液 (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和 CSF 生物标志物： a) 表征爆炸诱发的 mTBI 的行为表型； b) 区分 mTBI 和战斗创伤创伤后应激障碍 (PTSD)？ 2) 重复性突发 mTBI 是否存在长期认知障碍，如果是，认知障碍是否与神经退行性痴呆的脑脊液生物标志物和遗传危险因素相关？这里的术语“mTBI”用于表示持续性脑震荡后症状（[PCS]认知、行为和躯体）的综合征，这些症状在产生 mTBI 的爆炸性脑震荡事件数月和数年后继续表现出来。我们的初步神经影像学结果表明，患有 mTBI 和持续性 PCS 的 OIF/OEF 退伍军人中存在以前未被识别的结构和功能异常，与共病 PTSD 无关。 具体目标 1：描述患有 PCS 的 OIF/OEF 退伍军人中爆炸伤重复性轻度创伤性脑损伤 (mTBI) 的临床（神经认知、神经学、行为）和结构/功能神经影像学特征。 具体目标 2：确定患有重复性 mTBI 并持续性 PCS 的 OIF/OEF 退伍军人是否表达与神经退行性痴呆症的发病和进展相关的 CSF 生物标志物变化。 具体目标 3：确定神经变性遗传风险因素（载脂蛋白 E [APOE] 多态性和微管相关蛋白 tau [MAPT] 亚单倍型）对患有重复性 mTBI 和持续性 PCS 的 OIF/OEF 退伍军人的临床特征以及神经影像学和脑脊液生物标志物的影响。 该提案涉及诊断成像技术的验证和改进以及针对 TBI 后期或长期后果的创新方法等 RR&D 优先领域。 VHA 面临着为这一弱势群体提供初级医疗、康复、心理健康和长期护理的巨大负担。鉴定 mTBI 的客观神经影像和脑脊液生物标志物，并澄清 mTBI 中神经退行性痴呆的长期风险将：1）改善 mTBI 的诊断，2）为改善退伍军人的医疗保健提供目标； 3）允许适当分配有限的医疗保健、补偿和养老金以及社会资源。成功完成拟议的研究很有可能产生短期和长期的临床影响。 24 个月内，该项目将产生用于 mTBI 客观生物标志物诊断的工具。 4 年内，拟议项目的结果将成为合理设计临床试验的证据基础，以治疗目前的 mTBI 症状并防止进展为神经退行性痴呆症。