Effect of Statins on Pathobiology of Alzheimer's Disease

描述(申请人提供)：候选人：卡尔松博士的长期目标是成为阿尔茨海默病(AD)及其与血管危险因素和血管生物学的关系的独立临床研究员。作为比森职业发展奖(BCDA)的一部分，Carlsson博士将通过威斯康星大学(UW)研究生院的课程、UW临床研究基础卡普斯通证书项目和国际医学磁共振学会(ISMRM)提供的研讨会，获得临床研究设计、生物统计学、认知理论和测试以及磁共振脑血流测量方面的高级培训，从而在以患者为导向的老龄化研究领域发展自己的职业生涯。她还将接受管理人类受试者研究的伦理和监管问题方面的高级培训。 环境：威斯康星大学医学院是一家首屈一指的研究机构，已将老年病学和神经科学确定为五大优先研究领域中的两个。除了威斯康星州综合记忆计划和老年病学与老年病学部，Carlsson博士还将获得拟议的BCDA奖所需的下列资源：威斯康星州阿尔茨海默氏症研究所、威斯康星州阿尔茨海默氏症预防登记处、退伍军人事务部老年研究、教育和临床中心(GRECC)、威斯康星州综合临床研究中心(GCRC)以及威斯康星州医院和韦斯曼实验室的3T磁共振脑成像扫描仪。研究：鉴于流行病学、动物和临床研究的证据表明他汀类药物可能对AD具有预防作用，Carlsson博士建议评估辛伐他汀对AD进展的脑脊液(CSF)和血浆标志物的影响，包括脑脊液B-淀粉样蛋白(AB)水平、中枢神经系统(CNS)胆固醇代谢和中枢神经系统炎症。此外，她还将评估辛伐他汀对脑血流的影响及其与这些生物标志物的整体关系。来自威斯康星州阿尔茨海默病预防登记处的100名非痴呆症男性和女性将被招募参加一项为期9个月的随机对照试验，评估辛伐他汀每晚80毫克与安慰剂相比对以下方面的影响：1)脑脊液AP水平；2)中枢神经系统胆固醇代谢的血浆标记物；以及3)脑脊液和血浆炎症标记物。此外，50名参与者将在基线和9个月时接受MRI检查，以测量脑血流灌注。参与者将在基线和9个月的随访中抽出空腹实验室，收集脑脊液，并进行认知测试。在1个月、3个月和6个月的额外检查将评估副作用。认知测试也将在3个月的随访中重复进行。9个月时的结果测量将与基线进行比较。结果将通过载脂蛋白E4状态进行分析。

DESCRIPTION (provided by applicant): Candidate: Dr. Carlsson's long-term goal is to become an independent clinical investigator in Alzheimer's disease (AD) and its relationship to vascular risk factors and vascular biology. As part of this Beeson Career Development Award (BCDA), Dr. Carlsson will develop a career in patient-oriented aging research by obtaining advanced training in clinical research design, biostatistics, cognitive theory and testing, and measures of cerebral perfusion by MRI through courses in the University of Wisconsin (UW) Graduate School, the UW Capstone Certificate Program in Fundamentals of Clinical Research, and workshops offered by the International Society for Magnetic Resonance in Medicine (ISMRM). She will also obtain advanced training in ethical and regulatory issues that govern human subjects research. Environment: The University of Wisconsin Medical School is a premier research institution that has identified Geriatrics and Neurosciences as 2 of the top 5 priority areas for research. In addition to the Wisconsin Comprehensive Memory Program and Section of Geriatrics and Gerontology, Dr. Carlsson will have access to the following resources for the proposed BCDA award: the Wisconsin Alzheimer's Institute the Wisconsin Registry for Alzheimer's Prevention; the VA Geriatric Research, Education and Clinical Center (GRECC); the UW General Clinical Research Center (GCRC); and 3T MR scanners in the UW Hospital and Waisman Laboratory for Brain Imaging. Research: Given the evidence from epidemiological, animal, and clinical research suggesting that statins may have a preventive role in AD, Dr. Carlsson proposes to evaluate the effect of simvastatin on cerebrospinal fluid (CSF) and plasma markers of AD progression, including CSF B-amyloid (AB) levels, central nervous system (CNS) cholesterol metabolism, and CNS inflammation in a population of middle-aged adults at increased risk for developing AD. In addition, she will evaluate the effects of simvastatin on cerebral perfusion and its integral relationship with these biomarkers. 100 men and women without dementia from the Wisconsin Registry for Alzheimer's Prevention will be recruited for participation in a 9-month randomized, controlled trial evaluating the effects of simvastatin 80 mg nightly vs. placebo on 1) CSF Ap levels; 2) plasma markers of CNS cholesterol metabolism; and 3) CSF and plasma markers of inflammation. Additionally, 50 participants will have a MRI to measure cerebral perfusion at baseline and month 9. Participants will have fasting labs drawn, CSF collected, and cognitive testing done at baseline and 9-month follow-up. Additional visits at 1, 3, and 6 months will assess side effects. Cognitive testing will also be repeated at the 3-month follow-up. Outcome measures at 9 months will be compared to baseline. Results will be analyzed by apolipoprotein E4 status.