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

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的轻度创伤性脑损伤(MTBI)，并伴有持续的认知、情绪和神经震荡后症状。我们自己的神经影像和脑脊液(CSF)生物标记物研究表明，神经影像上有一致的证据表明弥漫性轴突损伤和功能缺陷，初步的脑脊液生物标记物证据表明早期脑脊液病变。迫切需要开发有效的治疗方法，以降低这些退伍军人目前症状的强度，以及他们发展与重复性mTBI相关的神经退行性痴呆的潜在长期风险：慢性创伤性脑病(CTE)和阿尔茨海默病(AD)。1)他汀类药物神经保护作用的动物模型研究；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；3)辛伐他汀与普伐他汀对中年非痴呆受试者脑脊液AD生物标志物影响的14周初步研究表明，他汀类药物可能具有神经保护作用，阻止与tau蛋白代谢相关的病理过程，这似乎是CTE、AD和其他重复性脑损伤的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的脑脊液生物标记物研究，我们过去和目前在认知正常受试者中进行的辛伐他汀的试点临床试验，以及我们在伊拉克和阿富汗退伍军人中进行的神经成像和脑脊液生物标记物研究，共同证明了在伊拉克和阿富汗有可能因反复冲击波暴露mTBI而患上神经退行性痴呆的患者的试验中，使用神经退行性变过程的脑脊液生物标记物(如总(T)-tau和磷酸化(P)-tau181)和神经再生(脑源性神经营养因子)作为可行和可靠的结果指标的可行性。我们提出了一项为期12个月的双盲、随机、安慰剂对照试验，以确定在120名伊拉克和阿富汗退伍军人中使用辛伐他汀(40 mg/d)来减少神经变性的脑脊液生物标记物和增加脑脊液神经营养因子的概念验证。具体目标是：特定目标1：观察辛伐他汀40 mg/d治疗12个月对伊拉克和阿富汗反复冲击性脑震荡患者脑脊液中tau生物标志物(t-tau、p-tau181和t-tau/p-tau181比率)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，辛伐他汀会降低脑脊液中t-tau、p-tau181和p-tau181/t-tau的水平，并会增加脑脊液中BDNF的水平。具体目的2：探讨辛伐他汀40 mg/d治疗12个月对伊拉克和阿富汗退伍军人反复冲击性脑震荡mTBI患者脑脊液A°42及氧化应激和神经炎症生物标志物的影响。假设2：与安慰剂相比，辛伐他汀将降低脑脊液A？42水平，以及氧化应激(F2-异前列腺素)和神经炎症(IL-6、IL-8和S100？)的生物标志物。出于对他汀类药物潜在不良影响的担忧，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、酒精使用、功能状态和与健康相关的生活质量的潜在影响。拟议研究的结果可能会在相对较短的时间内为支持更大规模的初级预防试验提供概念验证，以防止伊拉克和阿富汗的退伍军人和患有反复mTBI的军人患上痴呆症。 公共卫生相关性： 由于简易爆炸装置是伊拉克和阿富汗叛乱分子的首选武器，我们的许多退伍军人都遭受过反复爆炸暴露，导致轻度创伤性脑损伤(MTBI)。不祥的是，越来越多的证据表明，反复的MTBI会导致一种非常严重的中年发作的大脑疾病，称为慢性创伤性脑病(CTE)，这种疾病已经在职业足球运动员和拳击手中观察到。MTBI还会增加老年阿尔茨海默病(AD)的风险。一种名为tau的大脑蛋白质的异常是CTE和AD的核心。我们已经证明，降胆固醇药物辛伐他汀也可能使大脑tau正常化。在这项研究中，我们将用辛伐他汀治疗伊拉克和阿富汗的退伍军人，以证明使用这种药物降低CTE和AD风险的可行性。

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. PUBLIC HEALTH RELEVANCE: Because improvised explosive devices are the weapons of choice of the insurgents in Iraq and Afghanistan, many of our Veterans have suffered repeated blast exposures producing mild traumatic brain injury (mTBI). Ominously, accumulating evidence suggests that repeated mTBIs can produce a very serious middle age onset brain disorder called chronic traumatic encephalopathy (CTE) that has been observed in professional football players and boxers. mTBI also increases the risk for later life Alzheimer's disease (AD). Abnormalities of a brain protein called tau are central to CTE and AD. We have demonstrated that the cholesterol-lowering drug, simvastatin, may also normalize brain tau. In this study, we will treat Iraq and Afghanistan Veterans with simvastatin to demonstrate feasibility of using this drug to reduce risk for CTE and AD.