Prazosin and CSF Biomarkers in mTBI

 描述(由申请人提供)： 简易爆炸装置和其他爆炸物爆炸震荡造成的轻度创伤性脑损伤是部署在阿富汗的持久自由行动和伊拉克的伊拉克自由和新黎明行动(OEF/OIF/OND)的美国军人的“标志性损伤”。重复的MTBI增加了两种导致痴呆的进行性神经退行性疾病的风险：中年起病的慢性创伤性脑病(CTE)和晚年起病的阿尔茨海默病(AD)。神经毒肽的产生和沉积被认为是CTE和AD发病机制的核心。CTE和AD的特征都是过度磷酸化的tau多肽(p-tau181)以神经原纤维缠结的形式在神经元内沉积。AD的进一步特征是β-淀粉样蛋白(A--42)多肽以斑块形式沉积在脑实质中。脑脊液中tau、p-tau181和AB42的浓度是AD神经退行性变的生物标志物。最近被描述的大脑“淋巴”系统是从大脑中清除神经毒性蛋白质和其他分子的主要机制。通过增加脑淋巴流量来增加tau、p-tau181、A-42和其他神经毒性分子的清除，是减轻脑外伤后CTE和AD风险增加的潜在有效方法。临床前研究已经证实，mTBI减少了淋巴流量，从而减少了脑tau的清除，增加了脑tau的沉积。幸运的是，在临床前研究中，α-1肾上腺素受体拮抗剂哌唑嗪显著增加了脑淋巴流量和神经毒素清除，这是一种临床上可用的药物，广泛用于治疗夜间PTSD症状。我们提出了一项概念验证的随机安慰剂对照试验研究，研究对象是具有重复MTBI的退伍军人，以确定哌唑嗪是否能降低脑脊液中tau、p-tau181和A42的浓度。这一发现将与神经毒性分子从脑中的淋巴清除增加相一致，并为更大规模的临床研究提供理论依据，以评价哌唑嗪预防脑外伤后CTE和AD的临床效果。40名有多个MTBI病史的OEF/OIF退伍军人将随机服用哌唑嗪或安慰剂，为期8周。于治疗前基线腰穿采集脑脊液，药物治疗10周后再次采集脑脊液。据推测，哌唑嗪(但不是安慰剂)会降低脑脊液中tau、p-tau181和A42的浓度。如果这一假设得到证实，这项研究将支持将哌唑嗪作为一种潜在的一级预防治疗来降低MTBI后CTE和AD的风险的进一步试验。脑脊液tau、p-tau181和A42浓度将通过Luminex多珠法测定。

 DESCRIPTION (provided by applicant): Mild traumatic brain injury (mTBI) caused by blast concussion from improvised explosive devices and other explosive ordnance is the "signature injury" of United States Service Members deployed to Operation Enduring Freedom in Afghanistan and Operations Iraqi Freedom and New Dawn in Iraq (OEF/OIF/OND). Repetitive mTBIs increase the risk for two progressive neurodegenerative disorders that cause dementia: chronic traumatic encephalopathy (CTE) with onset in midlife and Alzheimer's disease (AD) with onset in later life. Production and deposition of neurotoxic peptides are believed central to the pathogenesis of CTE and AD. Both CTE and AD are characterized by the intraneuronal deposition of hyperphosphorylated tau peptide (p- tau181) as neurofibrillary tangles. AD is further characterized by the deposition in brain parenchyma of beta amyloid (A42) peptide as plaques. Concentrations of tau, p-tau181 and AB42 in cerebrospinal fluid (CSF) are established biomarkers of neurodegeneration in AD. The recently described brain "glymphatic" system is a major mechanism for clearance of neurotoxic proteins and other molecules from the brain. Increasing brain clearance of tau, p-tau181, A42 and other neurotoxic molecules by increasing brain glymphatic flow is a potentially effective approach to mitigating the increased risk of CTE and AD following mTBI. Preclinical studies have established that mTBI reduces glymphatic flow, thus decreasing brain tau clearance and increasing brain tau deposition. Fortunately, brain glymphatic flow and neurotoxin clearance are substantially increased in preclinical studies by the alpha-1 adrenoreceptor antagonist prazosin, a clinically available drug widely prescribed for nighttime PTSD symptoms. We propose a proof-of-concept randomized placebo controlled pilot study in Veterans with repetitive mTBIs to determine if prazosin decreases concentrations of tau, p-tau181 and A42 in CSF. Such a finding would be consistent with increased glymphatic clearance of neurotoxic molecules from brain and provide rationale for larger scale studies of clinical evaluation of prazosin for prevention of CTE and AD subsequent to TBI. Forty OEF/OIF Veterans with a history of multiple mTBIs will be randomized to prazosin or placebo for 8 weeks. CSF will be collected by lumbar puncture at pretreatment baseline and again after 10 weeks of study drug treatment. It is hypothesized that prazosin (but not placebo) will decrease CSF concentrations of tau, p- tau181 and A42. If this hypothesis is confirmed, this study will support further trials of prazosin as a potential primary prevention treatment to reduce risk of CTE and AD following mTBIs. CSF tau, p-tau181 and A42 concentrations will be determined by Luminex multibead assays.