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反复爆炸暴露轻度创伤性脑损伤（mTBI），并伴有持续的认知、情感和神经性脑震荡后症状。我们自己的神经影像学和脑脊液（CSF）生物标志物研究表明，弥漫性轴突损伤和神经影像学功能缺陷的一致证据和早期tau蛋白病的初步CSF生物标志物证据。迫切需要开发有效的治疗方法来降低这些退伍军人当前症状的强度以及他们发展与重复性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）和阿尔茨海默病（AD）。证据来自：1）他汀类药物在脑外伤动物模型中的神经保护作用研究; 2）他汀类药物对AD临床和神经病理表现影响的流行病学研究;和3）我们的14周初步研究辛伐他汀与普伐他汀对中年人CSF AD生物标志物的影响，非痴呆受试者提示他汀类药物可能对与tau蛋白代谢相关的病理过程具有神经保护作用，是CTE、AD和重复性mTBI的其他神经退行性后遗症的共同特征。此外，我们在AD患者和正常对照中进行的广泛CSF生物标志物研究，我们过去和目前在认知正常受试者中进行的辛伐他汀初步临床试验，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神经退行性过程的CSF生物标志物的可行性（如总（t）-tau和磷酸化（p）-tau 181）和神经发生脑源性神经营养因子在伊拉克和阿富汗有神经退行性痴呆风险的受试者中进行的假定预防性治疗试验中，作为可行和可靠的结局指标是因为反复的冲击波暴露 我们提出了一项为期12个月的双盲、随机、安慰剂对照试验，以建立使用辛伐他汀（40 mg/d）降低120名伊拉克和阿富汗退伍军人反复冲击伤mTBI的CSF神经变性生物标志物和增加CSF神经营养因子的概念验证。具体目标是：具体目标1：研究辛伐他汀40 mg/天治疗12个月对反复冲击波脑震荡mTBI的伊拉克和阿富汗退伍军人的CSF tau生物标志物（t-tau、p-tau 181和t-tau：p-tau 181比值）和脑源性神经营养因子（BDNF）浓度的影响。 假设1：与安慰剂相比，辛伐他汀将降低CSF t-tau、p-tau 181和p-tau 181：t-tau比率的水平;并将增加CSF BDNF的水平。 具体目标二：探讨辛伐他汀40 mg/天治疗12个月对反复冲击波脑震荡mTBI的伊拉克和阿富汗退伍军人CSF A42和氧化应激和神经炎症生物标志物的影响。 假设二：与安慰剂相比，辛伐他汀将降低CSF A β 42水平，以及氧化应激（F2-异前列腺素）和神经炎症（白细胞介素-6 [IL-6]，IL-8和S100 β）的生物标志物。 由于担心他汀类药物的潜在不良反应，我们还将在研究期间进行神经认知测试，以监测记忆和其他认知功能。我们还将监测辛伐他汀治疗对持续性脑震荡后症状（PPCS）、创伤后应激障碍（PTSD）、抑郁症、酒精使用、功能状态和健康相关生活质量的潜在影响。拟议研究的结果可以在相对较短的时间内提供概念验证，以支持更大规模的一级预防试验，以预防伊拉克和阿富汗退伍军人和重复性mTBI的服务人员的神经变性和痴呆症。