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（由适用提供）：主要预防阿尔茨海默氏病（AD）有望获得巨大的临床和经济益处，但面临着巨大的挑战，因为AD的病理过程在痴呆症的临床症状之前几年甚至几十年。使用脑脊液（CSF）AD生物标记物（例如Total Tau [T-Tau]，Tau在苏氨酸181 [p-Tau181]和A€42上磷酸化，作为临床试验终点，可以证明具有合理设计和随后量的定期预防剂的疾病效果，可证明预防剂的疾病效果，并逐渐适应了良好的量。辛伐他汀是一种安全且使用的降低胆固醇的药物，是一种有吸引力的候选预防剂，因为我们实验室的流行病学研究表明，他汀类药物的使用均与临床AD的降低以及尸检时的神经纤维纤维缠结降低有关。此外，我们最近证明，用辛伐他汀（中枢神经系统高[CNS]渗透率）进行14周的治疗可在认知上正常的高胆固醇患者中降低T-TAU和P-TAU181的CSF水平，而Pravastatin治疗PRAVASTATIN（CNS渗透率较低）则降低了。这项试点研究提供了有价值的“概念证明”证据，证明使用CSF AD生物标志物作为临床试验端点既安全又可行。此处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，以评估辛伐他汀（40 mg/d）与安慰剂对中年（45-64岁）认知上正常受试者的CSF AD生物标志物的影响（每组n = 50）。主要结局指标是CSF T-TAU，P-TAU181，A€42和脑衍生的神经性因子（BDNF）。次要结局指标包括炎症标记（白介素[IL] -6，IL-8，S1002），以及氧化应激标志物（F2-异前列腺素）和脑胆固醇代谢物（24S-羟基羟基胆固醇）。研究结果和认知安全评估（对简单和持续的关注，工作和声明性记忆以及复杂推理的心理测量测量）将在治疗之前和12个月之前进行测量。不良反应（包括血清脂质，肝功能测试和创建磷酸激酶水平）将在6周和3个月，6个月和12个月中进行监测。拟议研究的发现可能会为使用CSF生物标志物作为主要结果指标的AD高风险的大规模初级预防试验提供支持。公共卫生相关性：初级预防阿尔茨海默氏病（AD）有望为患者及其家人提供临床益处，以及对社会的实质性经济利益。将广告发作延迟5年将使一代人的AD病例数量减少50％，从而节省了数十亿美元的保健资金。辛伐他汀已被广泛用于预防冠状动脉疾病。拟议研究的发现可能会提供概念证明，以支持AD高风险的大规模初级预防试验。