Exercise and Intensive Vascular Risk Reduction in Preventing Dementia

 描述(申请人提供)：我们正面临着21世纪最重大的挑战之一；如何在我们迅速老龄化的人口中保持大脑健康和预防痴呆症。阿尔茨海默病(AD)是最常见的痴呆症类型。目前，没有预防或治愈阿尔茨海默病的治疗方法。越来越多的证据表明，迟发性AD是一种与年龄相关的多因素疾病(S)，具有复杂的遗传背景，AD的发生和发展在很大程度上受心血管危险因素和体力活动不足等可变因素的影响。然而，目前还没有直接证据表明减少这些可改变的风险因素可以预防或减缓AD。这项建议的主要目标是进行一项严格设计的随机对照II期试验，以确定强化药物降低血管危险因素(IRVR、血压和血脂)和运动(Ex)对AD高危老年人神经认知功能的独立和联合影响(主要结果)。此外，我们将确定这些干预措施对AD的神经影像、血液和脑脊液生物标记物的影响(次要结果)。我们将招募640名认知正常的老年人，年龄在65岁到79岁之间，有AD家族史(FH)，他们有高血压(SBP，≥，140毫米汞柱)和血脂异常(根据2013年美国心脏病协会/美国心脏病协会的新指南)。他们将被随机分成IRVR(SBP≤130 mmHg，阿托伐他汀降脂)、Ex、IRVR Ex和标准护理对照组(2x2析因设计)干预2年。目的1：确定IRVR和Ex对神经认知功能的独立作用和联合作用。假设：IRVR和Ex将改善整体认知功能，而IRVR Ex将比单独使用IRVR或Ex提供更大的好处。神经认知功能将在基线、6个月、12个月、18个月和24个月使用经过良好验证的测试进行测量，以使用线性混合效应模型进行分析，以优化学习能力。目的2：确定IRVR和Ex对脑结构和神经网络可塑性的独立和联合影响。假设：IRVR和Ex可预防或减缓海马区和全脑萎缩，并改善大脑默认模式网络(DMN)的功能连接，而IRVR Ex将提供比单独使用IRVR或Ex更大的益处。在基线、12个月和24个月时，将使用MRI测量脑体积、结构和DMN功能连接性的变化。目的3：探讨IRVR、Ex和IRVR Ex影响脑结构和功能的潜在机制。假设：1)IRVR和Ex可减少AD的病理改变，如脑脊液Aβ42、tau和磷酸化tau(p-tau)以及中枢神经系统炎症的变化所表明的；2)脑血流灌注和/或脑源性神经营养因子的增加介导了脑结构和功能的改变；3)IRVR Ex在改善AD生物标志物方面将比单独使用IRVR或Ex产生更大的影响。新的经颅多普勒超声(TCD)方法将被用来评估脑自动调节。

 DESCRIPTION (provided by applicant): We are facing one of the most significant challenges of the 21st century; how to maintain brain health and prevent dementia in our rapidly aging population. Alzheimer's disease (AD) is the most common type of dementia. Currently, there is no treatment to prevent or cure AD. Mounting evidence indicates that late-onset AD is an age-related, multi-factorial disease(s), which has a complex genetic background and the onset and progression of AD are influenced to a large extent by modifiable factors such as cardiovascular risk factors and physical inactivity. However, at present, there is no direct evidence that reducing these modifiable risk factors prevents or slows AD. The overarching goal of this proposal is to conduct a rigorously designed randomized controlled phase II trial to determine the independent and combined effects of Intensive pharmacological Reduction of Vascular Risk factors (IRVR, blood pressure and lipids) and Exercise (Ex) on neurocognitive function in older adults at high risk of AD (primary outcome). Furthermore, we will determine the effects of these interventions on the neuroimaging, blood, and CSF biomarkers of AD (secondary outcomes). We will enroll 640 cognitively normal older adults age 65 to 79 with a family history (FH) of AD who have hypertension (SBP≥140 mmHg) and dyslipidemia (according to the new 2013 ACC/AHA guidelines). They will be randomized into 2-yr interventions of IRVR (SBP≤130mmHg, lowering lipids with atorvastatin), Ex, IRVR+Ex, and a control arm of standard care (a 2 x 2 factorial design). Aim 1: Determine the independent and combined effects of IRVR and Ex on neurocognitive function. Hypothesis: IRVR and Ex will improve global cognitive function, while IRVR+Ex will provide a greater benefit than either IRVR or Ex alone. Neurocognitive function will be measured using well-validated tests at baseline, 6, 12, 18, and 24 months to optimize study power using linear mixed effects models for analysis. Aim 2: Determine the independent and combined effects of IRVR and Ex on brain structural and neural network plasticity. Hypothesis: IRVR and Ex prevent or slow hippocampal and whole brain atrophy and improve brain default-mode network (DMN) functional connectivity, while IRVR+Ex will provide greater benefits than either IRVR or Ex alone. Changes in brain volume, structural and DMN functional connectivity will be measured using MRI at baseline, 12 and 24 months. Aim 3: Explore the underlying mechanisms by which IRVR, Ex and IRVR+Ex impact brain structure and function. Hypotheses: 1) IRVR and Ex reduce AD pathology as indicated by the changes in cerebrospinal fluid (CSF) Aβ42, tau and phosphorylated tau (p-tau), and CNS inflammation; 2) increases in brain perfusion and/or brain-derived neurotrophic factor (BDNF) mediate changes in brain structure and function; 3) IRVR+Ex will have greater impacts on improving AD biomarkers than either IRVR or Ex alone. Novel transcranial Doppler ultrasonography (TCD) methods will be used to assess cerebral autoregulation.