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 血管对认知障碍和痴呆（VCID）的贡献，由于与 记忆丧失和存在心血管（CV）风险因素（例如高血压、血脂异常）。虽然CV 危险因素有可用的药物治疗，增加体力活动也显着降低这些共同， 病态不幸的是，将CV和运动干预与预防认知能力下降联系起来的证据 目前尚无定论，也没有生物标志物可用于确定痴呆前生活方式干预的疗效。 该辅助R 01将使用入组我们的NIH的受试者的基于血浆的生物标志物和神经成像， 资助的试验“降低阿尔茨海默病的风险（rrAD; NCT 02913664）”。第二阶段随机 对照试验将确定强化药物减少的独立和联合作用， 血管风险因素（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2年干预组（IRVR，Ex，IRVR+Ex，以及标准对照组）。 护理（SC）），在基线和每年收集血浆和神经成像。在513名初始rrAD受试者中， (63%女性; 34%年龄71-85岁; 13%非洲裔美国人; 4%拉丁美洲人），89%（458例受试者）有纵向 可用于线性混合模型分析的血清和神经影像学生物标志物。倾斜纵向rrAD 血浆样本将用于检验以下假设：1）基准AD，2）基准VCID，和/或3）新型 循环的脑源性生物标志物可以通过积极的生活方式干预来调节。目标1将测试 AD的基准生物标志物Aβ42/Aβ40比值将增加，而pTau 181和pTAu 231将减少， 最佳IRVR+Ex。较高的比率和较低的tau将与我们的次要结局指标相关 保留海马体积（T1加权MRI）。目标2将测试主要基准VCID生物标志物 将揭示血管和运动干预对脑血管健康的影响。我们将测试是否更低 病理性促血管生成蛋白（即VEGF-D、PlGF、bFGF）随着时间的推移而纵向降低。 干预低表达将与局部脑缺血增加的次要结局指标相一致。 血流（即动脉自旋标记，MRI）和较少的白色高信号（即T2 FLAIR，MRI）。目标3 将测试血管和运动干预是否会改变循环中富含神经元的 细胞外囊泡（EV）。我们将测试IRVR+Ex降低脑源性神经营养因子（即未裂解的） 因子（BDNF），并增加神经元富集EV中的成熟BDNF。更高的BDNF将与 通过静息状态测量的保留默认模式网络（DMN）连通性的次要结果 功能性（rs-f）MRI。我们假设AD、VCID和EV生物标志物不仅可以识别高血压患者， AD/ADRD的风险，但也可以跟踪独立和联合生活方式干预的疗效， 脑血管健康和延迟痴呆发作。

Project Summary It is often hard to distinguish between Alzheimer’s disease (AD) and AD-related dementias (ADRDs), 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 initial rrAD subjects (63% females; 34% aged 71-85; 13% African-American; 4% LatinX), 89% (458 subjects) have longitudinal serum and neuroimaging biomarkers available for linear mixed-models analyses. 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 and pTAu 231 will decrease, the greatest with IRVR+Ex. Higher ratios and lower tau will be associated with our secondary outcome measures of preserved hippocampal volume (T1-weighted MRI). Aim 2 will test if primary benchmark VCID biomarkers will reveal effects of vascular and exercise interventions on cerebrovascular health. We will test if lower pathologic pro-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 of preserved default-mode network (DMN) connectivity measured by resting-state functional (rs-f)MRI. 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 in sedentary adults.