Effects of Simvastatin on CSF AD biomarkers in cognitively normal subjects

辛伐他汀对认知正常受试者脑脊液 AD 生物标志物的影响

• 批准号: 7906800
• 负责人: Gail Li
• 金额: $ 47.47万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906800
• 关键词: Abbreviations; Adult; Adverse effects; Age; Alleles; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antioxidants; Apolipoprotein E; Ascorbic Acid; Attention; Autopsy; Biological Markers; Biological Markers; Blood - brain barrier anatomy; Body mass index; Brain; C-reactive protein; Cerebrospinal Fluid; Cholesterol; Cholesterol Homeostasis; Clinical; Clinical Trials; Clinical dementia rating scale; Coenzyme A; Cognitive; Communication impairment; Complete Blood Count; Complex; Conflict (Psychology); Controlled Clinical Trials; Coronary Arteriosclerosis; Creatine Kinase; Cyclin-Dependent Kinase 5; DSM-IV; Data; Dementia; Diagnostic and Statistical Manual of Mental Disorders; Disease; Dose; Economics; Education; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Epidemiology; Equation; Erythrocytes; F2-Isoprostanes; Family; Gas Chromatography; Generations; Growth; Growth Factor; Guanine; Guanosine Triphosphate Phosphohydrolases; Hamilton Rating Scale for Depression; Healthcare; Healthcare Systems; High Density Lipoproteins; Hormone replacement therapy; Hydroxycholesterols; Hydroxymethylglutaryl-CoA Reductase Inhibitors; IL8 gene; Incidence; Institutes; Interleukin-6; Interleukin-8; Interleukins; Ions; Jupiter; Laboratories; Lipids; Liver Function Tests; Low-Density Lipoproteins; Mass Spectrum Analysis; Measures; Medical center; Memory; Mental disorders; Minority; Mitogen-Activated Protein Kinases; Monitor; Monocyte Chemoattractant Protein-1; Naproxen; Nerve Degeneration; Neuraxis; Neurofibrillary Tangles; Neurologic; Neurons; Neuropsychological Tests; Outcome; Outcome Measure; Outcome Study; Oxidative Stress; Pathologic Processes; Patients; Penetration; Persons; Pharmaceutical Preparations; Phase; Phosphoric Monoester Hydrolases; Pilot Projects; Pittsburgh Compound-B; Placebo Control; Placebos; Polymerase Chain Reaction; Positron-Emission Tomography; Pravastatin; Prevention; Preventive; Primary Prevention; Process; Psychometrics; Recruitment Activity; Research; Risk; Safety; Sample Size; Screening procedure; Senile Plaques; Serum; Simvastatin; Societies; Spinal Puncture; Stroke; Surrogate Endpoint; Symptoms; Synapses; Testing; Therapeutic Agents; Threonine; Time; Toxic effect; Transforming Growth Factor beta; Triglycerides; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Universities; Variant; Very low density lipoprotein; Veterans; Vitamin E; Washington; Woman; Work; apolipoprotein E-4; cardiovascular risk factor; celecoxib; cognitive function; cohort; cooperative study; design; follow-up; hazard; high risk; impression; improved; in vivo; inflammatory marker; innovation; instrument; mental state; middle age; mild neurocognitive impairment; neuroinflammation; neuronal survival; neurotropic; prevent; primary outcome; public health relevance; randomized placebo controlled trial; secondary outcome; sound; tau Proteins; tau-1; tool; trend; tripolyphosphate

DESCRIPTION (provided by applicant): Primary prevention of Alzheimer's disease (AD) promises great clinical and economic benefits but poses great challenges because the pathologic processes of AD start years or even decades prior to clinical symptoms of dementia. Using cerebrospinal fluid (CSF) AD biomarkers (e.g., total tau [t-tau], tau phosphorylated at threonine 181 [p-tau181] and A¿42) as clinical trial endpoints offers the potential to demonstrate disease- modifying effects of putative preventive agents in designs with reasonable sample sizes and follow up periods. Simvastatin, a safe and widely used cholesterol-lowering drug, is an attractive candidate preventive agent, as epidemiologic studies from our laboratory and others indicate that statin use is associated with both a reduced risk of clinical AD and reduced neurofibrillary tangle burden at autopsy. In addition, we recently demonstrated that 14 weeks of treatment with simvastatin (which has high central nervous system [CNS] penetration) reduced CSF levels of t-tau and p-tau181 in cognitively normal hypercholesterolemic subjects while treatment with pravastatin (which has low CNS penetration) did not. This pilot study provided valuable "proof-of-concept" evidence that using CSF AD biomarkers as clinical trial endpoints is both safe and feasible. The study proposed here is a 1-year fixed dose, randomized, placebo-controlled trial to evaluate the effects of simvastatin (40 mg/d) vs. placebo on CSF AD biomarkers in middle-aged (45-64 years) cognitively normal subjects (N=50 per group). Primary outcome measures are CSF t-tau, p-tau181, A¿42 and brain derived neurotropic factor (BDNF). Secondary outcome measures include inflammatory markers (Interleukin [IL]-6, IL-8, S1002), and oxidative stress markers (F2-isoprostanes) and the brain cholesterol metabolite (24S-hydroxycholesterol). Study outcomes and cognitive safety assessments (psychometric measures of simple and sustained attention, working and declarative memory, and complex reasoning) will be measured prior to and at 12 months of treatment. Adverse effects (including serum lipids, liver function tests, and creatine phosphokinase levels) will be monitored at 6-weeks and at 3-, 6-, and 12-months. The findings of the proposed study may provide support for conducting large-scale primary prevention trials in persons at high risk for AD using CSF biomarker as primary outcome measures. PUBLIC HEALTH RELEVANCE: Primary prevention of Alzheimer disease (AD) promises both clinical benefits for patients and their families and substantial economic benefits for society. Delaying the onset of AD by 5 years would reduce the number of AD cases by 50% in a generation, saving billions of health care dollars. Simvastatin has been widely used for prevention of coronary artery disease. The findings of the proposed study may provide proof of concept in support of large scale primary prevention trials in persons at high risk for AD.

描述（由申请人提供）：阿尔茨海默病（AD）的一级预防有望带来巨大的临床和经济效益，但也带来了巨大的挑战，因为AD的病理过程在痴呆的临床症状之前数年甚至数十年就开始了。使用脑脊液（CSF）AD生物标志物（例如，总tau [t-tau]、在苏氨酸181 [p-tau 181]和A 42处磷酸化的tau）作为临床试验终点提供了在具有合理样本大小和随访期的设计中证明推定预防剂的疾病改善作用的可能性。辛伐他汀是一种安全且广泛使用的降胆固醇药物，是一种有吸引力的候选预防药物，因为我们实验室和其他实验室的流行病学研究表明，他汀类药物的使用与临床AD风险降低和尸检时神经系统缠结负担降低相关。此外，我们最近证明，在认知正常的高胆固醇血症受试者中，辛伐他汀（具有高中枢神经系统[CNS]渗透性）治疗14周可降低CSF中t-tau和p-tau 181的水平，而普伐他汀（具有低CNS渗透性）治疗则没有。这项初步研究提供了有价值的“概念验证”证据，证明使用CSF AD生物标志物作为临床试验终点既安全又可行。本文拟定的研究是一项为期1年的固定剂量、随机化、安慰剂对照试验，旨在评价辛伐他汀（40 mg/d）与安慰剂相比对认知正常的中年（45-64岁）受试者（每组N=50）CSF AD生物标志物的影响。主要结果指标为CSF t-tau、p-tau 181、A 42和脑源性神经营养因子（BDNF）。次要结果指标包括炎症标志物（白细胞介素[IL]-6，IL-8，S1002），氧化应激标志物（F2-异前列腺素）和脑胆固醇代谢物（24 S-羟基胆固醇）。将在治疗前和治疗12个月时测量研究结局和认知安全性评估（简单和持续注意力、工作记忆和陈述性记忆以及复杂推理的心理测量）。将在6周和3、6和12个月时监测不良反应（包括血脂、肝功能检查和肌酸磷酸激酶水平）。拟议研究的结果可能为使用CSF生物标志物作为主要结局指标在AD高危人群中进行大规模一级预防试验提供支持。公共卫生相关性：阿尔茨海默病（AD）的一级预防既可为患者及其家庭带来临床效益，又可为社会带来可观的经济效益。将AD的发病时间推迟5年将使一代人的AD病例数减少50%，节省数十亿美元的医疗保健费用。辛伐他汀已广泛用于预防冠状动脉疾病。拟议研究的结果可能提供概念证明，支持在AD高危人群中进行大规模一级预防试验。