Exercise and Intensive Vascular Risk Reduction in Preventing Dementia

 描述（由申请人提供）：我们正面临 21 世纪最重大的挑战之一；如何在快速老龄化的人口中保持大脑健康并预防痴呆症。阿尔茨海默病（AD）是最常见的痴呆症类型。目前，尚无预防或治愈 AD 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，具有复杂的遗传背景，AD的发病和进展在很大程度上受到心血管危险因素和缺乏身体活动等可改变因素的影响。然而，目前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。该提案的总体目标是进行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综合影响（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志物的影响（次要结果）。我们将招募 640 名年龄 65 至 79 岁、认知正常、有 AD 家族史 (FH)、患有高血压 (SBP≥140 mmHg) 和血脂异常的老年人（根据 2013 年新的 ACC/AHA 指南）。他们将被随机分为 2 年干预组：IRVR（SBP≤130mmHg，用阿托伐他汀降脂）、Ex、IRVR Ex 和标准护理对照组（2 x 2 析因设计）。目标 1：确定 IRVR 和 Ex 对神经认知功能的独立影响和综合影响。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 提供更大的益处。将在基线、6、12、18 和 24 个月时使用经过充分验证的测试来测量神经认知功能，以使用线性混合效应模型进行分析来优化研究功效。目标 2：确定 IRVR 和 Ex 对大脑结构和神经网络可塑性的独立和综合影响。假设：IRVR 和 Ex 可以预防或减缓海马和全脑萎缩，并改善大脑默认模式网络 (DMN) 功能连接，而 IRVR Ex 将比单独使用 IRVR 或 Ex 提供更大的益处。将使用 MRI 在基线、12 个月和 24 个月时测量大脑体积、结构和 DMN 功能连接的变化。目标 3：探索 IRVR、Ex 和 IRVR Ex 影响大脑结构和功能的潜在机制。假设：1) IRVR 和 Ex 减轻 AD 病理，如脑脊液 (CSF) Aβ42、tau 和磷酸化 tau (p-tau) 的变化以及 CNS 炎症的变化所示； 2）脑灌注和/或脑源性神经营养因子（BDNF）的增加介导脑结构和功能的变化； 3) IRVR Ex 对改善 AD 生物标志物的影响比单独使用 IRVR 或 Ex 更大。新型经颅多普勒超声（TCD）方法将用于评估大脑自动调节。

 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.