Biomarkers to track effective interventions that delay dementia onset in participants of the "Risk Reduction for Alzheimer's Disease (rrAD)" trial

项目摘要 通常很难区分阿尔茨海默病(AD)和AD相关痴呆(ADRD)，包括 血管对认知损害和痴呆的贡献(VCID)，由于相似的临床表现 记忆丧失和心血管(CV)危险因素(如高血压、血脂异常)的存在。而CV 危险因素有可用的药物治疗，增加的体力活动也显著降低了这些共同的 病态。不幸的是，将个人简历和运动干预与预防认知衰退联系在一起的证据 没有定论，也没有生物标志物来确定痴呆症前生活方式干预的效果。 这一辅助R01将使用基于血浆的生物标志物和来自我们NIH登记的受试者的神经成像- 资助的试验“降低阿尔茨海默病的风险”(RRAD；NCT02913664)。这个第二阶段是随机的 对照试验将确定密集药物减少的独立和联合影响 血管危险因素(IRVR；即血压、血脂)和有氧运动(Ex)对认知功能的影响。 参与者被随机分为两年的干预(IRVR、Ex、IRVR+Ex和标准对照组 CARE(SC))，在基线和每年收集血浆和神经成像。在513名RRAD受试者中(63% 女性；34%的71-85岁；13%的非裔美国人；4%的西班牙裔/拉丁裔)，41%的登记受试者已经完成 他们两年的随访期。RRAD试验预计将于2021年10月底完成，总体 流失率为15%。储存的纵向RRAD等离子体样本将用来检验假设1) 基准AD，2)基准VCID，和/或3)新的循环脑衍生生物标记物可以通过 积极的生活方式干预。Aim 1将测试基准AD生物标记物Aβ42/Aβ40的比率是否会增加， 而pTau181将下降，IRVR+Ex。更高的比率和更低的tau将与我们的第二 与SC相比，3D T1加权MRI测量保存的海马体体积的结果。 Aim 2将测试主要基准内皮VCID生物标记物是否会揭示血管和运动的影响 关于脑血管健康的干预措施。我们将测试较低的病理血管生成蛋白(即血管内皮生长因子-D， PlGF、bFGF值随干预时间的延长而纵向降低。较低的表达将与 局部脑血流量增加的次要结果指标(即动脉自旋标记，MRI)和 脑白质高信号较少(如T2 FLAIR、MRI)。目标3将测试血管和运动干预 改变循环中富含神经元的细胞外小泡(EVS)的神经营养物质。我们将测试IRVR+Ex 降低脑源性神经营养因子前体(即未切割的)和增加成熟的脑源性神经营养因子在神经元中的表达 丰富的电动汽车。更高的BDNF将与更强的静息状态的次要结果指标相一致 与默认模式网络相关联的功能性MRI连接。我们假设AD、VCID和EV 生物标志物不仅可以识别AD/ADRD的高危个体，还可以追踪独立的 以及改善脑血管健康和延缓痴呆症发病的综合生活方式干预。

Project Summary It is often hard to distinguish between Alzheimer’s disease (AD) and AD-related dementias (ADRD), including Vascular contributions to Cognitive Impairment and Dementia (VCID), due to a similar clinical presentation of memory loss and the presence of cardiovascular (CV) risk factors (e.g. hypertension, dyslipidemia). While CV risk factors have available drug therapies, increased physical activity also significantly lowers these co- morbidities. Unfortunately, evidence linking CV and exercise interventions to the prevention of cognitive decline is inconclusive, nor are biomarkers available to determine the efficacy of pre-dementia lifestyle interventions. This ancillary R01 will use plasma-based biomarkers and neuroimaging from subjects enrolled in our NIH- funded trial “Risk Reduction for Alzheimer’s Disease (rrAD; NCT02913664).” This phase II randomized controlled trial will determine the independent and combined effects of Intensive pharmacological Reduction of Vascular Risk factors (IRVR; i.e. blood pressure, lipids) and aerobic exercise (Ex) on cognitive function. Participants were randomized into 2-year interventions (IRVR, Ex, IRVR+Ex, and a control arm of standard care (SC)) with plasma and neuroimaging collected at baseline and yearly. Of the 513 rrAD subjects (63% females; 34% aged 71-85; 13% African-American; 4% Hispanic/Latino), 41% of enrolled subjects have finished their 2-year follow-up. The rrAD trial is anticipated to be completed by the end of October 2021 with an overall attrition rate <15%. Banked longitudinal rrAD plasma samples will be used to test the hypothesis that 1) benchmark AD, 2) benchmark VCID, and/or 3) novel circulating brain-derived biomarkers can be modulated by positive lifestyle interventions. Aim 1 will test if the benchmark AD biomarkers Aβ42/Aβ40 ratio will increase, while pTau181 will decrease, with IRVR+Ex. Higher ratios and lower tau will be associate with our secondary outcome measure of preserved hippocampal volume measured by 3D T1-weighted MRI, as compared to SC. Aim 2 will test if primary benchmark endothelial VCID biomarkers will reveal effects of vascular and exercise interventions on cerebrovascular health. We will test if lower pathologic angiogenic proteins (i.e. VEGF-D, PlGF, bFGF) measured longitudinally decrease with intervention. Lower expression will coincide with secondary outcome measures of increased regional cerebral blood flow (i.e. arterial spin labeling, MRI) and fewer white matter hyperintensities (i.e. T2 FLAIR, MRI). Aim 3 will test if vascular and exercise interventions alter the neurotrophic cargo of circulating neuronal-enriched extracellular vesicles (EVs). We will test IRVR+Ex lowers pro- (i.e. uncleaved) brain-derived neurotrophic factor (BDNF) and increases mature BDNF in neuronal- enriched EVs. Higher BDNF will coincide with the secondary outcome measure of stronger resting-state functional MRI connectivity associated with the default mode network. We hypothesize that AD, VCID, and EV biomarkers not only identify individuals with high risk for AD/ADRDs but can also track efficacy of independent and combined lifestyle interventions that improve cerebrovascular health and delay dementia onset.