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

基本信息

批准号：
8111814
负责人：
Gail Li
金额：
$ 45.52万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8111814
关键词：
AD 20 Abbreviations Adult Adverse effects Aging Alleles Alzheimer&apos 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 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 Hamilton Rating Scale for Depression Health Healthcare Healthcare Systems High Density Lipoproteins Hormone replacement therapy Hydroxycholesterols Hydroxymethylglutaryl-CoA Reductase Inhibitors Incidence Institutes Interleukin-6 Interleukin-8 Interleukins Ions 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 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 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 nervous system disorder neuroinflammation neuronal survival neurotropic prevent primary outcome randomized placebo controlled trial secondary outcome sound tau Proteins tau-1 tool trend tripolyphosphate

项目摘要

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的病理过程早于痴呆的临床症状数年甚至数十年，使用脑脊液（CSF）AD。生物标志物（例如总 tau [t-tau]、苏氨酸 181 处磷酸化的 tau [p-tau181] 和 A¿42）作为临床试验根据我们实验室的流行病学研究，辛伐他汀是一种安全且广泛使用的降胆固醇药物，它是一种有吸引力的候选预防药物。和其他人表明，他汀类药物的使用与临床 AD 风险的降低和尸检时神经原纤维缠结负担的减少有关。此外，我们最近证明了 14 周的辛伐他汀治疗（其中。具有高中枢神经系统[CNS]渗透性）降低了认知正常高胆固醇血症受试者脑脊液中的t-tau和p-tau181水平，而普伐他汀（具有低中枢神经系统渗透性）治疗则没有。这项初步研究提供了有价值的“证据”。 “概念”的证据表明使用 CSF AD 生物标志物作为临床试验终点既安全又可行。这里提出的研究是一项为期 1 年的固定剂量、随机、安慰剂对照试验，旨在评估辛伐他汀（40 mg/d）与安慰剂对认知正常的中年（45-64 岁）受试者（每组 N=50）的 CSF AD 生物标志物进行比较，主要结果指标为 CSF t-tau、p-tau181、A¿ 42 和脑源性神经营养因子 (BDNF) 次要结果指标包括炎症标记物（白介素 [IL]-6、IL-8、S1002）、氧化应激标记物（F2-异前列腺素）和脑胆固醇代谢物（24S-羟基胆固醇）。研究结果和认知安全评估（简单和持续注意力、工作和陈述性记忆以及复杂推理的心理测量）将在研究之前和 12 个月时进行测量治疗的不良反应（包括血脂、肝功能测试和肌酸磷酸激酶水平）将在 6 周、3、6 和 12 个月时进行监测。拟议研究的结果可能为进行大规模治疗提供支持。使用脑脊液生物标志物作为主要结果衡量指标的 AD 高危人群的大规模一级预防试验：阿尔茨海默病 (AD) 的一级预防不仅能为患者及其家人带来临床益处，还能为患者带来巨大的经济效益。推迟 AD 发病 5 年将使一代人的 AD 病例数减少 50%，从而节省数十亿美元的医疗费用。这项研究的结果可能会被广泛用于预防冠状动脉疾病。提供概念证明，支持针对 AD 高危人群进行大规模初级预防试验。