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: 10490311
• 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: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490311
• 关键词: Address; Afghanistan; Alzheimer' s Disease; Apolipoprotein E; Behavioral; Biological Markers; Blood Vessels; Brain; Brain Concussion; Brain Stem; Brain imaging; Brain region; Central Nervous System; Cerebrospinal Fluid; Characteristics; Chemicals; Chemotactic Factors; Chronic; Clinical; Clinical Trials Design; Clinical assessments; Cognitive; Dementia; Development; Devices; Diagnosis; Diffusion Magnetic Resonance Imaging; Disease; Exhibits; Fiber; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Genetic Polymorphism; Goals; Haplotypes; Healthcare; Imaging Techniques; Impaired cognition; Impairment; Iraq; K-Series Research Career Programs; Liquid substance; MAPT gene; Magnetic Resonance; Manufactured football; Marines; Measurement; Memory impairment; Migraine; Modality; Modeling; Monitor; Moods; Nerve Degeneration; Nervous System Trauma; Neurocognitive; Neuroimmune; Neurologic; Neuropsychology; Outcome; Performance; Plasma; Play; Post-Concussion Syndrome; Post-Traumatic Stress Disorders; Process; Proteins; Recording of previous events; Research; Rest; Risk; Role; Short-Term Memory; Signs and Symptoms; Sleep; Sleep disturbances; Symptoms; Thalamic structure; Veterans; War; actigraphy; blast trauma; brain dysfunction; clinical phenotype; cognitive function; cognitive performance; cognitive task; combat zone; comorbidity; demented; diagnostic criteria; evidence base; exosome; fluorodeoxyglucose positron emission tomography; genetic risk factor; improved; middle age; mild traumatic brain injury; neurodegenerative dementia; neuroimaging; neuroimaging marker; neuroinflammation; neurovascular; potential biomarker; prevent; prospective memory; protein biomarkers; rational design; response; service member; tool; tractography; wounded service member; wounded soldier

Mild traumatic brain injury (mTBI) caused by blast effects of explosive devices is the “signature injury” of Servicemembers deployed to combat operations in Iraq and Afghanistan. Resultant persistent postconcussive symptoms (PCS), such as impairment of memory and concentration, irritability, mood instability, sleep disturbances, and migraine headaches frequently have disabling personal, professional and domestic consequences. In addition to these immediate consequences, repetitive mTBI may initiate processes leading to neurodegeneration and dementia. This competitive renewal application proposes to continue longitudinally a currently funded VA RR&D Merit Review: B77421, "Mild TBI and Biomarkers of Neurodegeneration". In the current funding period, we have made substantial progress in 1) identifying objective structural and functional neuroimaging biomarkers that characterize the clinical phenotype of blast-induced mTBI, 2) identifying objective impairment and longitudinal decline in cognitive function in mTBI Veterans using our refined neuropsychological assessment battery, and 3) identifying in cerebrospinal fluid (CSF) and plasma a group mTBI-specific inter-related neuroinflammatory chemoattractant, vascular disturbance, and neurodegeneration biomarkers. We have integrated neuroimaging, cognitive, and biomarker findings into a consistent model of regional cerebellar- thalamic-frontoparietal cortical and brainstem dysfunction in repetitive blast mTBI. Goals of this continuation proposal are to determine whether cognitive performance is associated with neuroimaging and/or CSF and plasma biomarkers of mTBI and/or genetic risk factors for neurodegenerative dementia, and to determine whether neuroimaging and CSF and plasma biomarker abnormalities are transient, static, or progressive. We also propose 1) a new plasma biomarker goal: central nervous system (CNS)-derived plasma exosomal cargo proteins, 2) new clinical assessments of sleep: in-theater sleep history and sleep/activity monitoring via Actigraphy, and 3) an additional advanced neuroimaging analyses: diffusion tensor imaging Automating-Fiber- Tract Quantification. Specific Aim 1: To continue characterizing longitudinally the clinical (neurocognitive, neurologic, behavioral) and structural/functional neuroimaging characteristics of disrupted cerebellar-thalamic-frontoparietal cortical and brainstem function in OIF/OEF/OND Veterans with repetitive blast trauma mTBI. Specific Aim 2: To determine if OEF/OIF/OND Veterans with repetitive mTBI exhibit CSF and plasma neurovascular, neuroinflammatory, and neurodegeneration biomarker changes associated with the onset and progression of neurodegenerative dementing disorders. Specific Aim 3: To determine the effects of genetic risk factors for neurodegeneration (apolipoprotein E [APOE] polymorphisms and microtubule associated protein tau [MAPT] subhaplotypes) on clinical characteristics and neuroimaging and biofluid biomarkers in OEF/OIF/OND Veterans with repetitive mTBI. This proposal is in response to RFA RX-18-014: Studies on the Chronic Effects of Neurotrauma and focuses on the long-term consequences of repetitive mTBI. By identifying objective neuroimaging and CSF and plasma biomarkers of blast mTBI and neurodegenerative dementias, the proposed research has potential for: 1) improving the accuracy of blast mTBI diagnoses; 2) identifying clinical characteristics and biomarkers of blast mTBI that suggest potential treatments and provide the ability to track response to potential treatments; and 3) identifying health care needs unique to blast mTBI Veterans. Successful completion of the proposed research has a high likelihood of yielding both short-term and long-term clinical impacts. The project will yield tools for objective biomarker diagnosis of mTBI and form the evidence base for rational design of clinical trials to treat current symptoms of mTBI and to prevent progression to neurodegenerative dementing disorders.

由爆炸装置的爆炸作用引起的轻度脑损伤（MTBI）是“签名损伤” 部署在伊拉克和阿富汗作战行动的服务人员的工作。结果持久 引起症状后症状（PC），例如记忆和集中障碍，易怒，情绪 不稳定性，睡眠障碍和偏头痛的标题经常使个人，专业和 国内后果。除了这些直接的后果外，重复的MTBI可能会启动流程 导致神经变性和痴呆。 该竞争性更新申请提案，以纵向延长当前资助的VA RR＆D 优点评论：B77421，“神经变性的轻度TBI和生物标志物”。在当前的资金期间，我们 在1）确定客观的结构和功能神经影像生物标志物中取得了重大进展 这是爆炸引起的mTBI的临床表型的特征，2）确定客观障碍和 使用我们精致的神经心理学评估，MTBI退伍军人认知功能的纵向下降 电池和3）识别脑脊液（CSF）和血浆A组MTBI特异性相关 神经炎症性化学吸引剂，血管灾难和神经变性生物标志物。我们有 综合的神经影像学，认知和生物标志物的发现，成为局部小脑的一致模型 重复性爆炸MTBI中的丘脑 - 额叶皮质和脑干功能障碍。这个延续的目标 建议是确定认知表现是否与神经影像学和/或CSF相关 神经退行性痴呆的MTBI和/或遗传危险因素的血浆生物标志物，并确定 神经影像学和CSF和血浆生物标志物异常是短暂的，静态的还是进行的。我们 另外建议1）新的等离子体生物标志物目标：中枢神经系统（CNS）衍生的血浆外泌体货物 蛋白质，2）睡眠的新临床评估：剧院内睡眠病史和睡眠/活动监测 Actraphy和3）附加的晚期神经成像分析：扩散张量成像自动化纤维 - 区域定量。 特定目的1：继续纵向表征临床（神经认知，神经系统，行为） 小脑 - 丘脑甲状腺皮质的破坏的结构/功能性神经影像特征 和重复性爆炸创伤的OIF/OEF/OND退伍军人中的脑干功能。 特定目标2：确定具有重复MTBI的OEF/OIF/OND退伍军人是否展示了CSF和等离子体 与发作和发作相关的神经血管，神经炎症和神经变性生物标志物变化 神经退行性痴呆症的进展。 特定目的3：确定遗传危险因素对神经退行性的影响（载脂蛋白E [apoE]多态性和微管相关蛋白tau [mapt]亚辣椒型）在临床上 具有重复MTBI的OEF/OIF/OND退伍军人的特征和神经成像和生物流体生物标志物。 该提案是对RFA RX-18-014的回应：关于神经曲和神经曲的慢性作用的研究 重点关注重复MTBI的长期后果。通过识别客观神经影像学和CSF以及 爆炸MTBI和神经退行性痴呆的血浆生物标志物，拟议的研究具有： 1）提高MTBI诊断的准确性； 2）确定临床特征和生物标志物 爆炸MTBI建议潜在治疗，并提供跟踪对潜在治疗的反应的能力； 3）确定爆炸MTBI退伍军人所特有的医疗保健需求。成功完成拟议的 研究很有可能产生短期和长期临床影响。该项目将产生 MTBI的客观生物标志物诊断工具，并构成了临床试验合理设计的证据基础 治疗MTBI的当前症状并防止发展为神经退行性痴呆症。