Exercise and Intensive Vascular Risk Reduction in Preventing Dementia

 描述（由申请人提供）：我们正面临着21世纪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并预防痴呆症。阿尔茨海默病（AD）是最常见的痴呆类型。目前，没有预防或治愈AD的治疗方法。越来越多的证据表明，迟发性AD是一种年龄相关的多因素疾病，具有复杂的遗传背景，其发病和进展在很大程度上受到心血管危险因素和身体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。本提案的总体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风险因素（IRVR、血压和血脂）和运动（Ex）对AD高风险老年人神经认知功能的独立和联合作用（主要结局）。此外，我们将确定这些干预措施对AD的神经影像学、血液和CSF生物标志物的影响（次要结局）。我们将入组640名年龄在65 - 79岁、认知功能正常、有AD家族史（FH）、患有高血压（SBP≥140 mmHg）和血脂异常（根据2013年新的ACC/AHA指南）的老年人。他们将被随机分配至IRVR（SBP≤ 130 mmHg，阿托伐他汀降脂）、Ex、IRVR+Ex的2年干预组和标准治疗对照组（2 x 2析因设计）。目的1：确定IRVR和Ex对神经认知功能的独立和联合作用。假设：IRVR和Ex将改善整体认知功能，而IRVR+Ex将提供比单独IRVR或Ex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测量神经认知功能，以使用线性混合效应模型进行分析，从而优化研究把握度。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作用。假设：IRVR和Ex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将提供比单独使用IRVR或Ex更大的益处。将在基线、12个月和24个月时使用MRI测量脑体积、结构和DMN功能连接的变化。目的3：探讨IRVR、Ex和IRVR+Ex对脑结构和功能影响的机制。假设：1）IRVR和Ex减少AD病理，如脑脊液（CSF）Aβ42、tau和磷酸化tau（p-tau）以及CNS炎症的变化所示; 2）脑灌注增加和/或脑源性神经营养因子（BDNF）介导脑结构和功能的变化; 3）IRVR+Ex对改善AD生物标志物的影响大于IRVR或Ex单独使用。新的经颅多普勒超声（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.