Simvastatin: Proof-of-Concept for Prevention of Neurodegeneration in Mild TBI

辛伐他汀：预防轻度 TBI 神经退行性变的概念验证

• 批准号: 8990876
• 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: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2017-09-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8990876
• 关键词: Adverse effects; Afghanistan; Age; Age of Onset; Aging; Alcohol consumption; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Autopsy; Biological Markers; Blast Cell; Brain; Brain Concussion; Brain Diseases; Brain-Derived Neurotrophic Factor; Case Study; Cerebrospinal Fluid; Cholesterol; Clinical; Clinical Trials; Cognitive; Craniocerebral Trauma; Dementia; Devices; Diffuse Axonal Injury; Disease; Double-Blind Method; Drug usage; Elderly; Emotional; Environmental Risk Factor; Epidemiologic Studies; Exposure to; F2-Isoprostanes; Growth; Growth Factor; IL8 gene; Incidence; Injury; Interleukin-6; Interleukins; Iraq; Laboratories; Manufactured football; Memory; Mental Depression; Minority; Monitor; Naproxen; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic; Observational Study; Outcome; Outcome Measure; Oxidative Stress; Pathologic Processes; Pathology; Patients; Penetration; Pharmaceutical Preparations; Pilot Projects; Placebos; Post-Traumatic Stress Disorders; Pravastatin; Prevention; Prevention trial; Preventive; Primary Prevention; Process; Proteins; Recovery of Function; Recruitment Activity; Risk; Safety; Secondary to; Services; Simvastatin; Surrogate Endpoint; Symptoms; Synapses; Tauopathies; Therapeutic Agents; Threonine; Time; Toxic effect; Trauma; Veterans; War; cardiovascular risk factor; celecoxib; chronic traumatic encephalopathy; clinical risk; cognitive function; cohort; effective therapy; experience; follow-up; functional status; health related quality of life; improved; innovation; member; middle age; mild traumatic brain injury; mouse model; neurocognitive test; neurodegenerative dementia; neurogenesis; neuroimaging; neuroinflammation; neuronal survival; neuropathology; neurotrophic factor; prevent; protein metabolism; randomized placebo controlled trial; tau Proteins; tau-1; tool; trend; weapons

DESCRIPTION (provided by applicant): Many Iraq and Afghanistan Veterans have experienced repetitive blast exposure mild traumatic brain injury (mTBI) with persistent cognitive, emotional, and neurological postconcussive symptoms. Our own neuroimaging and cerebrospinal fluid (CSF) biomarker studies demonstrate consistent evidence of diffuse axonal injury and functional deficits on neuroimaging and preliminary CSF biomarker evidence of incipient tauopathy. There is an urgent need to develop effective treatments to reduce both the intensity of these Veterans' current symptoms as well as their potential long-term risks for developing neurodegenerative dementing disorders related to repetitive mTBI: chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD). Converging evidence from: 1) studies of neuroprotective effects of statins in animal models of TBI; 2) our epidemiological studies of statin effects on clinical and neuropathological manifestations of AD; and 3) our 14 week pilot study of simvastatin vs. pravastatin effects on CSF AD biomarkers in middle-aged, non- demented subjects suggest that statins may possess neuroprotective effects against pathologic processes related to tau protein metabolism that appear to be a common feature of CTE, AD, and other neurodegenerative sequelae of repetitive mTBI. In addition, our extensive CSF biomarker studies in AD patients and normal controls, our past and current pilot clinical trials of simvastatin in cognitively normal subjects, and our neuroimaging and CSF biomarker studies in Iraq and Afghanistan Veterans together demonstrate the feasibility of using CSF biomarkers of neurodegenerative processes (such as total (t)-tau and phosphorylated (p)-tau181) and neurogenesis (brain derived neurotrophic factor) as viable and reliable outcome measures in trials of putative preventive treatments in Iraq and Afghanistan subjects at risk of developing neurodegenerative dementing disorders due to repetitive blast-exposure mTBI. We propose a 12-month, double-blind, randomized, placebo-controlled trial to establish proof-of- concept for use of simvastatin (40 mg/d) for decreasing CSF biomarkers of neurodegeneration and increasing CSF neurotrophins in 120 Iraq and Afghanistan Veterans with repetitive blast trauma mTBI. Specific Aims are: Specific Aim 1: To examine the effects of 12 months of treatment with simvastatin 40 mg/day on CSF concentrations of tau biomarkers (t-tau, p-tau181, and t-tau:p-tau181 ratio) and brain-derived neurotrophic factor (BDNF) in Iraq and Afghanistan Veterans with repetitive blast concussion mTBI. Hypothesis 1: Compared to placebo, simvastatin will reduce levels of CSF t-tau, p-tau181, and p-tau181:t- tau ratio; and will increase level of CSF BDNF. Specific Aim 2: To explore the effects of 12 months of treatment with simvastatin 40mg/day on CSF A�42, and biomarkers of oxidative stress and neuroinflammation in Iraq and Afghanistan Veterans with repetitive blast concussion mTBI. Hypothesis 2: Compared to placebo, simvastatin will reduce levels of CSF A�42, and biomarkers of oxidative stress (F2-isoprostanes) and neuroinflammation (interleukin-6 [IL-6], IL-8, and S100�). Because of concerns regarding potential adverse effects of statins, we will also administer a neurocognitive test battery to monitor memory and other cognitive functions during the study period. We will also monitor potential effects of simvastatin treatment on persistent postconcussive symptoms (PPCS), posttraumatic stress disorder (PTSD), depression, alcohol use, functional status, and health-related quality of life. The findings of the proposed study may provide, in a relatively short period of time, proof-of- concept in support of larger scale primary prevention trials to prevent neurodegeneration and dementia in Iraq and Afghanistan Veterans and service members with repetitive mTBI.

描述（由申请人提供）： 许多伊拉克和阿富汗退伍军人经历了重复的爆炸暴露轻度创伤性脑损伤（MTBI），具有持续的认知，情感和神经系统脑震荡症状。我们自己的神经影像学和脑脊液（CSF）生物标志物研究表明，关于神经影像学和初步的CSF生物标志物的弥散性轴突损伤和功能性缺陷的一致证据表明，初期的tauopathy证据。迫切需要开发有效的治疗方法，以降低这些退伍军人当前症状的强度，以及它们可能发展与重复MTBI相关的神经退行性痴呆症的潜在长期风险：慢性创伤性脑病（CTE）和阿尔茨海默氏病（Alzheimer）病（AD）。来自以下方面的融合证据：1）汀类药物在TBI动物模型中的神经保护作用的研究； 2）我们对他汀类药物对AD临床和神经病理学表现的影响的流行病学研究； and 3) our 14 week pilot study of simvastatin vs. pravastatin effects on CSF AD biomarkers in middle-aged, non-demented subjects suggest that statins may potentially provide neuroprotective effects against pathological processes related to tau protein metabolism that appears to be a common feature of CTE, AD, and other neurodegenerative sequelae of repetitive mTBI.此外，我们在AD患者和正常对照中进行的广泛的CSF生物标志物研究，我们过去和当前的辛伐他汀在认知正常受试者中的临床试验以及我们在伊拉克和阿富汗退伍军人中的神经影像学和CSF生物标志物研究共同证明了使用CSF生物标记的csf生物标准（aSF） - （p）-TAU181）和神经发生（脑衍生的神经营养因子）作为可行且可靠的结果测量，在伊拉克和阿富汗受试者的假定预防性治疗试验中，由于患有重复性的爆炸性爆炸性曝光MTBI而产生神经退行性痴呆症的风险。我们提出了一个12个月，双盲，随机，安慰剂对照试验，以建立使用辛伐他汀（40 mg/d）的概念证明，以减少神经变性的CSF生物标记物，并增加CSF CSF神经蛋白酶，增加120 iraq和Afghanistan veterans veterans具有重建性爆炸性爆炸性的神经蛋白。具体目的是：具体目的1：检查辛伐他汀40 mg/天的12个月治疗对TAU生物标志物（T-TAU，P-TAU181和T-TAU：p-TAU181比率）的CSF浓度对脑部和阿富汗Veterans in iraq和Afghimansistans vetterans的CSF浓度。假设1：与安慰剂相比，辛伐他汀将降低CSF T-TAU，P-TAU181和P-TAU181：T-TAU比率；并将增加CSF BDNF的水平。具体目的2：探索辛伐他汀40毫克治疗40毫克的治疗对CSF A 32的影响，以及通过重复的爆炸咨询MTBI在伊拉克和阿富汗退伍军人中对伊拉克和阿富汗退伍军人的氧化应激和神经炎症的生物标志物。假设2：与安慰剂相比，辛伐他汀将降低CSF A�42的水平，以及氧化应激（F2-异丙烷）和神经炎症的生物标志物（interleukin-6 [IL-6]，IL-8和S100。）。由于对统计的潜在不利影响的担忧，我们还将管理神经认知测试电池，以监测研究期间的记忆和其他认知功能。我们还将监测辛伐他汀治疗对持续的脑震荡症状（PPC），创伤后应激障碍（PTSD），抑郁症，酒精使用，功能状态和与健康相关的生活质量的潜在影响。拟议研究的发现可以在相对较短的概念概念上提供支持，以支持大规模的初级预防试验，以防止伊拉克和阿富汗退伍军人的神经退行性和痴呆症以及具有重复性MTBI的服务成员。