Prazosin and CSF Biomarkers in mTBI

mTBI 中的哌唑嗪和脑脊液生物标志物

• 批准号: 9312137
• 负责人: MURRAY A RASKIND
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9312137
• 关键词: Address; Afghanistan; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Area; Biological Assay; Biological Markers; Blast Cell; Brain; Brain Concussion; Brain Diseases; Brain Injuries; Cerebrospinal Fluid; Cessation of life; Chemicals; Clinical; Cognitive deficits; Coma; Conflict (Psychology); Dementia; Deposition; Devices; Disease; Drops; Elderly; Evaluation Studies; Excision; Explosion; Freedom; Future; Impairment; Injury; Iraq; Laboratories; Lead; Measures; Mild Concussions; Nerve; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurotoxins; Oral; Paralysed; Pathogenesis; Peptides; Persons; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Placebo Control; Placebos; Post-Traumatic Stress Disorders; Prazosin; Prevention; Preventive treatment; Primary Prevention; Production; Proteins; Randomized; Recording of previous events; Risk; Risk Factors; Signal Transduction; Sleep; Spinal Puncture; Symptoms; System; United States; Veterans; War; brain parenchyma; chronic traumatic encephalopathy; experience; glymphatic system; hyperphosphorylated tau; innovation; middle age; mild traumatic brain injury; neurotoxic; noradrenergic; novel; operation; peptide P; persistent symptom; preclinical study; public health relevance; rapid eye movement; research clinical testing; service member; tau Proteins; tau-1; treatment effect

 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.

 描述（由申请人提供）： 简易爆炸装置和其他爆炸性弹药造成的爆炸性脑震荡造成的轻度创伤性脑损伤，是部署到阿富汗持久自由行动和伊拉克自由行动和伊拉克新黎明行动的美国军人的“标志性损伤”。重复性mTBI增加了两种导致痴呆的进行性神经退行性疾病的风险：中年发病的慢性创伤性脑病（CTE）和晚年发病的阿尔茨海默病（AD）。神经毒性肽的产生和沉积被认为是CTE和AD发病机制的中心。CTE和AD的特征都是神经元内过度磷酸化的tau肽（p-tau 181）沉积为神经元缠结。AD的进一步特征在于β淀粉样蛋白（A β 42）肽作为斑块沉积在脑实质中。脑脊髓液（CSF）中tau、p-tau 181和AB 42的浓度是AD中神经变性的既定生物标志物。最近描述的脑“胶质淋巴”系统是从脑中清除神经毒性蛋白和其他分子的主要机制。通过增加脑胶质淋巴流来增加tau、p-tau 181、A β 42和其他神经毒性分子的脑清除率是减轻mTBI后CTE和AD风险增加的潜在有效方法。临床前研究已经确定mTBI减少胶质淋巴流，从而减少脑tau清除并增加脑tau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（一种广泛用于夜间PTSD症状的临床可用药物）大大增加了脑胶质淋巴流和神经毒素清除。我们提出了一个概念验证的随机安慰剂对照的试点研究，在退伍军人与重复的mTBI，以确定是否哌唑嗪降低浓度的tau，p-tau 181和A β 42在CSF中。这一发现与神经毒性分子从脑中的胶质淋巴清除增加一致，并为哌唑嗪预防TBI后CTE和AD的临床评价的更大规模研究提供了依据。40名有多次mTBI病史的OEF/OIF退伍军人将随机接受哌唑嗪或安慰剂治疗8周。将在治疗前基线和研究药物治疗10周后再次通过腰椎穿刺采集CSF。假设哌唑嗪（而不是安慰剂）将降低CSF中tau、p-tau 181和A β 42的浓度。如果这一假设得到证实，本研究将支持进一步试验哌唑嗪作为潜在的一级预防治疗，以降低mTBI后CTE和AD的风险。CSF tau、p-tau 181和Δ tau 42浓度将通过Luminex multibead测定法测定。