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 (rrAD) 风险降低”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: 10746197
• 负责人: DWIGHT C. German
• 金额: $ 229.78万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10746197
• 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-42; Amyloid beta-Protein; Angiogenic Proteins; Benchmarking; Biological Assay; Biological Markers; Biological Specimen Banks; Blood; Blood Pressure; Blood Vessels; Blood specimen; Brain; Brain Ischemia; Brain-Derived Neurotrophic Factor; Cardiovascular Diseases; 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; Hypertension; Impaired cognition; Individual; Intervention; Knowledge; Latinx; Link; Lipid Binding; Lipids; Magnetic Resonance Imaging; Measurable; Measures; Memory; Memory Loss; Modeling; National Institute of Neurological Disorders and Stroke; Neurocognitive; Neurons; Outcome Measure; PGF gene; Participant; Pathologic; Pharmacotherapy; Phase; Physical activity; Plasma; Prevention; Randomized; Randomized, Controlled Trials; Rest; Risk Reduction; Sampling; Serum; Site; Structure; Testing; United States National Institutes of Health; Validation; Vascular Endothelial Growth Factor D; White Matter Hyperintensity; abeta deposition; aged; arm; arterial spin labeling; biomarker identification; blood lipid; blood-brain barrier disruption; brain health; brain-derived neurotrophic factor precursor; cardiovascular disorder risk; cardiovascular risk factor; cerebrovascular health; cognitive function; comorbidity; effective intervention; efficacy evaluation; exercise intervention; extracellular vesicles; follow-up; high risk; high risk population; improved; lifestyle intervention; nervous system disorder; neural network; neurobiological mechanism; neuroimaging; neuroimaging marker; neuroprotection; novel; novel marker; particle; pharmacologic; preservation; primary outcome; prodromal Alzheimer' s disease; secondary outcome; sedentary; specific biomarkers; standard care; tau Proteins; theranostics; trial enrollment; 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 (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.

项目摘要 通常很难区分阿尔茨海默氏病（AD）和与广告相关的痴呆症（ADRDS），包括 由于类似的临床表现，对认知障碍和痴呆（VCID）的血管贡献 记忆力丧失和心血管危险因素（例如高血压，血脂异常）的存在。同时简历 危险因素可获得药物疗法，体育锻炼的增加也显着降低了这些共同疗法 病态。不幸的是，将简历和运动干预与预防认知能力下降联系起来的证据 尚无定论，也无法使用生物标志物来确定止动前生活方式干预的效率。 该辅助R01将使用基于等离子体的生物标志物和来自我们NIH-的受试者的神经影像学 资助的试验“阿尔茨海默氏病的风险降低（RRAD； NCT02913664）。”该阶段II随机 对照试验将确定密集型药理减少的独立和综合作用 血管危险因素（IRVR；即血压，脂质）和有氧运动（EX）的认知功能。 参与者被随机分为两年干预措施（IRVR，EX，IRVR+EX，以及标准的控制组 在基线和每年收集的血浆和神经影像学的护理（SC））。在513个初始RRAD受试者中 （63％的女性； 34％年龄71-85； 13％的非裔美国人； 4％拉丁裔），89％（458名受试者）有纵向 血清和神经影像学生物标志物可用于线性混合模型分析。银行纵向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）新颖 积极的生活方式干预措施可以调节循环的脑源性生物标志物。 AIM 1将测试是否 基准AD生物标志物Aβ42/Aβ40比率将增加，而PTAU181和PTAU 231将减少， 与irvr+ex一起使用的最大。较高的比率和较低的tau将与我们的次要结果度量相关 保留的海马体积（T1加权MRI）。 AIM 2将测试主要基准VCID生物标志物是否 将揭示血管和运动干预对脑血管健康的影响。我们将测试是否降低 病理促血管生成蛋白（即VEGF-D，PLGF，BFGF）纵向降低，随着 干涉。较低的表达将与增加区域大脑的次要结局度量相吻合 血流（即动脉自旋标记，MRI）和较少的白质超强度（即T2 Flair，MRI）。目标3 将测试血管和运动干预是否改变了循环神经元富集的神经营养货物 细胞外蔬菜（EV）。我们将测试IRVR+EX降低pro-（即未切除的）脑衍生的神经营养 因子（BDNF），并增加了富含神经元的EV中的成熟BDNF。较高的BDNF将与 通过静止状态测量的保留默认模式网络（DMN）连接的次要结果 功能性（RS-F）MRI。我们假设AD，VCID和EV生物标志物不仅识别出较高的人 AD/ADRD的风险，但也可以跟踪独立和联合生活方式干预的效率，以改善 久坐成年人的脑血管健康和延迟痴呆发作。