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.

爆炸装置冲击波效应引起的轻度创伤性脑损伤（mTBI）是脑损伤的“标志性损伤” 部署在伊拉克和阿富汗作战的军人。结果持久 脑震荡后症状（PCS），如记忆力和注意力受损、易怒、情绪 不稳定性、睡眠障碍和偏头痛经常使个人、专业和 国内后果。除了这些直接后果外，重复性mTBI可能会引发一些过程， 导致神经退化和痴呆 这一竞争性续期申请建议继续纵向目前资助的VA RR&D Merit审查：B77421，“轻度TBI和神经变性生物标志物”。在目前的融资期内，我们 在以下方面取得了实质性进展：1）鉴定客观的结构和功能神经影像学生物标志物 表征胚细胞诱导的mTBI的临床表型，2）鉴定客观损伤， 使用我们完善的神经心理学评估，研究mTBI退伍军人认知功能的纵向下降 电池，和3）在脑脊液（CSF）和血浆中鉴定一组mTBI特异性相互相关的 神经炎性化学引诱物、血管紊乱和神经变性生物标志物。我们有 将神经影像学、认知和生物标志物结果整合到一个一致的区域小脑模型中， 重复冲击波mTBI中的丘脑-额顶叶皮质和脑干功能障碍本延续的目标 建议确定认知表现是否与神经影像学和/或CSF相关， mTBI的血浆生物标志物和/或神经退行性痴呆的遗传风险因素，并确定 无论神经影像学和CSF和血浆生物标志物异常是短暂的、静态的还是进行性的。我们 还提出1）新的血浆生物标志物目标：中枢神经系统（CNS）衍生的血浆外泌体货物 蛋白质，2）新的睡眠临床评估：在剧院睡眠史和睡眠/活动监测，通过 体动记录仪，和3）额外的高级神经成像分析：扩散张量成像自动化-纤维- 道定量。 具体目标1：继续纵向表征临床（神经认知、神经病学、行为） 小脑-丘脑-额顶叶皮质破坏的结构/功能神经影像学特征 OIF/OEF/OND退伍军人反复冲击伤mTBI的脑干功能。 具体目标2：确定OEF/OIF/OND重复mTBI退伍军人是否表现出CSF和血浆 与发病相关的神经血管、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。 具体目标3：确定神经变性（载脂蛋白E）的遗传风险因素的影响 [APOE]多态性和微管相关蛋白tau [MAPT]亚单元型）对临床 OEF/OIF/OND退伍军人反复mTBI的特征和神经影像学和生物液体生物标志物。 本提案是对RFA RX-18-014：神经创伤慢性效应研究的回应， 重点关注重复性mTBI的长期后果。通过识别客观的神经成像和CSF， 根据原始细胞mTBI和神经退行性痴呆的血浆生物标志物，拟议的研究具有以下潜力： 1)提高原始细胞mTBI诊断的准确性; 2）鉴定 提示潜在治疗并提供跟踪对潜在治疗的反应的能力的原始mTBI; 以及3）确定爆炸性mTBI退伍军人特有的卫生保健需求。圆满完成拟议的 研究很有可能产生短期和长期的临床影响。该项目将产生 为mTBI的客观生物标志物诊断提供工具，并为临床试验的合理设计提供证据基础 以治疗mTBI的当前症状并防止进展为神经变性痴呆症。