Statin Effects on Beta-Amyloid and Cerebral Perfusion in Adults at Risk for AD

他汀类药物对 AD 风险成人的 β-淀粉样蛋白和脑灌注的影响

• 批准号: 8703975
• 负责人: CYNTHIA M CARLSSON
• 金额: $ 14.5万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703975
• 关键词: Adult; Adult Children; Affect; Age; Alleles; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Amino Acids; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animals; Apolipoprotein E; Biological; Biological Markers; Blood; Brain; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrum; Cholesterol; Clinical Trials; Cognition; Cognitive; Collaborations; Deposition; Development; Disease; Disease Progression; Double-Blind Method; Elderly; Emotional; Epidemiologic Studies; Family Caregiver; Functional disorder; Health; High Prevalence; Impaired cognition; Individual; Investigation; Magnetic Resonance Imaging; Measures; Metabolism; Nerve Degeneration; Observational Study; Outcome; Outcome Measure; Pathology; Patients; Peptide Fragments; Perfusion; Persons; Pharmaceutical Preparations; Pilot Projects; Placebos; Population; Population Study; Prevalence; Prevention strategy; Process; Publishing; Randomized; Randomized Controlled Trials; Recording of previous events; Registries; Research; Risk; Role; Senile Plaques; Simvastatin; Spin Labels; Therapeutic Intervention; Time; Wisconsin; Work; cerebrovascular; clinical efficacy; clinical trials in animals; cohort; disorder risk; high risk; hypercholesterolemia; improved; middle age; neuroimaging; neuropsychological; novel; pre-clinical; prevent; primary outcome; secondary outcome; surface enhanced laser desorption ionization; tau Proteins; tau-1

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating illness that will affect an increasing number of older adults in the coming decades unless effective preventive strategies are developed. Therapies that delay the onset of AD by just five years may reduce the prevalence of AD significantly. High blood cholesterol levels in midlife increase the risk of developing AD decades later, possibly via their negative effects on 2-amyloid (A2) metabolism and cerebrovascular dysfunction. Both A2 deposition in the brain and cerebrovascular dysregulation are two early findings in preclinical AD pathology and work synergistically to accelerate neuronal degeneration. Thus, therapies that both reduce A2 levels and improve cerebral blood flow (CBF) may interrupt this cascade effect to delay the development of AD. Use of cholesterol-lowering medications called statins has been associated with a significant reduction in the prevalence of AD in observational studies, suggesting a potentially promising role for statins in AD prevention. Statins lower A2 levels in the cerebrospinal fluid (CSF) and brains of animals and improve CBF in animals, but clinical trials to date have not shown conclusively that statins beneficially modify A2 metabolism or CBF in asymptomatic adults at increased risk for AD. Building upon previous investigations, we propose an 18-month randomized, controlled, double-blind pilot clinical trial evaluating the effects of simvastatin 40 mg daily on CSF A2 levels and cerebral perfusion in asymptomatic adults at high risk for AD due to their parental history of AD and high prevalence of apolipoprotein E 54 (APOE4) allele. For this study, CSF A242 levels will be the primary outcome, but CSF A240, total tau and phosphorylated tau, and other novel CSF biomarkers will also be measured to increase the ability of A242 to predict underlying disease. Quantitative cerebral perfusion will be assessed using arterial spin-labeling magnetic resonance imaging (ASL-MRI). Interim assessments of CSF and MRI biomarkers will be collected to clarify whether longer term statin therapy has a cumulative effect in modifying these markers of AD progression. In addition, this pilot clinical trial will evaluate the impact of changes in CSF A2 metabolism and CBF on cognitive measures. The findings from this pilot clinical trial will help guide the development of pivotal trials ultimately needed to demonstrate clinical efficacy. PUBLIC HEALTH RELEVANCE: If simvastatin improves some of the changes that occur in the brain decades before the onset of AD, these findings would strengthen the evidence that there may be a role for statins in Alzheimer's prevention. If statins prevent or delay the onset of AD, they could have a profound impact not only on the physical and emotional health of millions of individual patients at risk for the disease, but also on their families and caregivers.

描述（由申请人提供）：阿尔茨海默氏病（AD）是一种毁灭性的疾病，在未来几十年中会影响越来越多的老年人，除非开发有效的预防策略。将AD发作延迟仅五年的疗法可能会大大降低AD的患病率。中年的高血胆固醇水平增加了数十年后发展广告的风险，可能会通过对2-淀粉样蛋白（A2）代谢和脑血管功能障碍的负面影响。大脑中的A2沉积和脑血管失调都是临床前AD病理学中的两个早期发现，并协同起作用，以加速神经元变性。因此，既降低A2水平又改善脑血流（CBF）的疗法可能会中断这种级联反应以延迟AD的发展。降低胆固醇的药物称为他汀类药物与观察性研究中AD患病率的显着降低有关，这表明他汀类药物在AD预防中的潜在有希望的作用。他汀类药物在脑脊液（CSF）和动物的大脑中的A2水平较低，并改善了动物的CBF，但迄今为止的临床试验尚未得出结论表明，他汀类药物在AD风险增加的无症状成年人中有益地改变了A2代谢或CBF。 Building upon previous investigations, we propose an 18-month randomized, controlled, double-blind pilot clinical trial evaluating the effects of simvastatin 40 mg daily on CSF A2 levels and cerebral perfusion in asymptomatic adults at high risk for AD due to their parental history of AD and high prevalence of apolipoprotein E 54 (APOE4) allele.在这项研究中，CSF A242水平将是主要结果，但是CSF A240，To Tau和磷酸化的TAU以及其他新型的CSF生物标志物也将测量以提高A242预测潜在疾病的能力。定量脑灌注将使用动脉自旋标记磁共振成像（ASL-MRI）评估。将收集对CSF和MRI生物标志物的临时评估，以阐明长期汀类药物治疗在修改这些AD进展的这些标记方面是否具有累积作用。此外，该试验临床试验将评估CSF A2代谢和CBF对认知措施的变化的影响。该试验临床试验的发现将有助于指导最终需要证明临床功效的关键试验的发展。公共卫生相关性：如果辛伐他汀改善了AD发作前几十年大脑中发生的一些变化，那么这些发现将加强证据表明他汀类药物在阿尔茨海默氏症预防中可能有作用。如果他汀类药物预防或延迟了AD的发作，他们不仅会对数百万个有疾病风险的患者的身体和情感健康产生深远的影响，还可能对他们的家人和看护者产生深远的影响。