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

用于追踪“阿尔茨海默病风险降低 (rrAD)”试验参与者延迟痴呆发作的有效干预措施的生物标志物

• 批准号: 10459779
• 负责人: DWIGHT C. German
• 金额: $ 71.45万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459779
• 关键词: 3-Dimensional; Address; Adult; Aerobic Exercise; African American; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Angiogenic Proteins; Benchmarking; Biological Assay; Biological Markers; Biological Specimen Banks; Blood; Blood - brain barrier anatomy; Blood Pressure; Blood Vessels; Blood specimen; Brain; Brain Ischemia; Brain-Derived Neurotrophic Factor; Cardiovascular system; Cell Communication; Cell surface; Cells; Cerebral small vessel disease; Cerebrovascular Circulation; Clinical; Clinical Trials; Cognitive; Data; Dementia; Dyslipidemias; Endothelium; Enrollment; Exercise; FGF2 gene; Family history of; Female; Functional Magnetic Resonance Imaging; Funding; High Prevalence; Hippocampus (Brain); Hispanics; Hypertension; Impaired cognition; Individual; Intervention; Latino; Life Style; Link; Lipid Binding; Lipids; Magnetic Resonance Imaging; Measurable; Measures; Memory; Memory Loss; National Institute of Neurological Disorders and Stroke; Neurocognitive; Neurons; Outcome Measure; PGF gene; Participant; Pathologic; Patients; Pharmacology; Pharmacotherapy; Phase; Physical activity; Plasma; Prevention; Randomized; Randomized Controlled Trials; Rest; Risk Reduction; Sampling; Signal Transduction; Site; Spin Labels; Structure; Testing; United States National Institutes of Health; Validation; Vascular Cognitive Impairment; Vascular Endothelial Growth Factor D; White Matter Hyperintensity; abeta deposition; aged; arm; base; blood lipid; brain health; cardiovascular disorder risk; cardiovascular risk factor; cerebrovascular health; cognitive function; cohort; comorbidity; effective intervention; exercise intervention; extracellular vesicles; follow-up; high risk; high risk population; improved; lifestyle intervention; nervous system disorder; neural network; neuroimaging; novel; particle; preservation; primary outcome; secondary outcome; specific biomarkers; standard care; tau Proteins; theranostics; vascular cognitive impairment and dementia; vascular risk factor

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.

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例rrAD受试者中（63%）， 女性; 34%年龄71-85岁; 13%非裔美国人; 4%西班牙裔/拉丁裔），41%的入组受试者已完成 2年随访。rrAD试验预计将于2021年10月底完成，总体 损耗率<15%。储存的纵向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）新的循环脑源性生物标志物可以通过以下方式调节 积极的生活方式干预。目标1将测试基准AD生物标志物Aβ42/Aβ40比率是否会增加， 而pTau 181则随着IRVR+Ex.较高的比率和较低的τ将与我们的中学 与SC相比，通过3D T1加权MRI测量的保留海马体积的结果测量。 目标2将测试主要基准内皮VCID生物标志物是否将揭示血管和运动的影响 脑血管健康干预措施。我们将测试是否有较低的病理性血管生成蛋白（即VEGF-D， PlGF、bFGF）随着干预而纵向降低。较低的表达将与 局部脑血流量增加的次要结局指标（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 改变循环神经元富集的细胞外囊泡（EV）的神经营养货物。我们将测试IRVR+Ex 降低神经元中的原-（即未裂解的）脑源性神经营养因子（BDNF）并增加成熟BDNF， 丰富的电动汽车。较高的BDNF将与较强的静息状态的次要结局指标相一致 与默认模式网络相关的功能性MRI连接。我们假设AD、VCID和EV 生物标志物不仅可以识别AD/ADRD高风险个体，而且还可以跟踪独立治疗的疗效。 以及改善脑血管健康和延缓痴呆症发作的生活方式综合干预。