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名初始RRAD受试者中 (63%的女性；34%的71-85岁；13%的非裔美国人；4%的拉丁裔)，89%(458名受试者) 可用于线性混合模型分析的血清和神经成像生物标记物。倾斜式纵向RRAD 血浆样本将被用来检验这样的假设：1)基准AD，2)基准VCID，和/或3)新颖 循环的脑源性生物标记物可以通过积极的生活方式干预来调节。目标一号将测试是否 基准AD生物标志物Aβ42/Aβ40比值将增加，而pTau181和ptau231将下降， 使用IRVR+Ex是最棒的。较高的比率和较低的tau将与我们的次要结果衡量标准相关。 保留的海马区体积(T1加权MRI)。AIM 2将测试主要基准VCID生物标记物 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(即血管内皮生长因子-D、平台生长因子、碱性成纤维细胞生长因子)在纵向上随 干预。较低的表达将与局部大脑增加的次要结果指标一致 血流(即动脉自旋标记，MRI)和较少的白质高信号(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神经营养物质 细胞外小泡(EVS)。我们将测试IRVR+Ex降低前(即未切割的)脑源性神经营养 因子(BDNF)和增加成熟的BDNF在神经元丰富的EVS。更高的BDNF将与 通过休眠状态测量保留的默认模式网络(DMN)连通性的次要结果 功能性(RS-F)磁共振成像。我们假设AD、VCID和EV生物标记物不仅能识别高血压病患者 AD/ADRD的风险，但也可以跟踪改善的独立和联合生活方式干预的有效性 久坐不动的成年人的脑血管健康和延缓痴呆的发病。

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.