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）：阿尔茨海默病（AD）是一种毁灭性疾病，除非制定有效的预防策略，否则将在未来几十年影响越来越多的老年人。将 AD 发病时间推迟五年的治疗可能会显着降低 AD 的患病率。中年时期的高血液胆固醇水平会增加几十年后患 AD 的风险，这可能是由于其对 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 A2 沉积和脑血管失调是临床前 AD 病理学的两个早期发现，并且协同作用加速神经元变性。因此，既降低 A2 水平又改善脑血流量 (CBF) 的疗法可能会中断这种级联效应，从而延缓 AD 的发展。在观察性研究中，使用他汀类降胆固醇药物与 AD 患病率显着降低相关，这表明他汀类药物在 AD 预防中具有潜在的前景。他汀类药物可降低动物脑脊液 (CSF) 和大脑中的 A2 水平，并改善动物的 CBF，但迄今为止的临床试验尚未最终表明他汀类药物有益于改变 AD 风险增加的无症状成人的 A2 代谢或 CBF。基于之前的研究，我们提出了一项为期 18 个月的随机、对照、双盲试点临床试验，评估每日 40 毫克辛伐他汀对由于父母患有 AD 病史而处于 AD 高风险的无症状成人的 CSF A2 水平和脑灌注的影响。 AD 和载脂蛋白 E 54 (APOE4) 等位基因的高患病率。对于这项研究，CSF A242 水平将是主要结果，但也将测量 CSF A240、总 tau 和磷酸化 tau 以及其他新型 CSF 生物标志物，以提高 A242 预测潜在疾病的能力。将使用动脉自旋标记磁共振成像（ASL-MRI）评估定量脑灌注。将收集 CSF 和 MRI 生物标志物的中期评估，以阐明长期他汀类药物治疗是否对改变 AD 进展的这些标志物具有累积效应。此外，该试点临床试验将评估 CSF A2 代谢和 CBF 的变化对认知测量的影响。该试点临床试验的结果将有助于指导最终证明临床疗效所需的关键试验的开发。公共健康相关性：如果辛伐他汀能改善 AD 发病前几十年大脑中发生的一些变化，那么这些发现将强化他汀类药物在预防阿尔茨海默病中可能发挥作用的证据。如果他汀类药物能够预防或延缓 AD 的发病，那么它们不仅会对数百万面临这种疾病风险的患者的身体和情感健康产生深远的影响，而且还会对他们的家人和护理人员产生深远的影响。