Blood-based lipid biomarkers reflective of Alzheimer-associated neurodegeneration

反映阿尔茨海默相关神经变性的血液脂质生物标志物

• 批准号: 7329114
• 负责人: Michelle M Mielke
• 金额: $ 21.53万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7329114
• 关键词: Affect; Age; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Apolipoprotein E; Area; Atrophic; Biological Assay; Biological Markers; Blood; Blood specimen; Brain; Brain imaging; Brain region; Ceramides; Cholesterol; Clinical; Clinical Trials; Cognitive; Condition; Data; Data Reporting; Dementia; Demographic Factors; Development; Diffusion Magnetic Resonance Imaging; Disease Progression; Genotype; Hippocampus (Brain); Hydroxycholesterols; Image; Individual; Invasive; Isoprostanes; Lipid Peroxidation; Lipids; Literature; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Medical; Membrane Lipids; Memory; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome Measure; Participant; Pathology; Patients; Plasma; Protocols documentation; Range; Rate; Research; Smoking Status; Sphingomyelins; Spin Labels; Standards of Weights and Measures; Testing; Thalamic structure; Time; United States National Institutes of Health; Variant; base; blood lipid; cerebral atrophy; concept; cost; entorhinal cortex; executive function; follow-up; interest; mild neurocognitive impairment; outcome forecast; prognostic; putamen

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Findings from the literature, and preliminary data reported in this application, suggest lipid measures, including brain-derived cholesterol species and lipid peroxidation products, may produce readily detectable signatures in the blood of AD patients. These signatures may be indicators of AD-associated neurodegeneration, producing candidate biomarkers of disease progression. A blood-based biomarker would be superior to CSF-based or brain imaging biomarkers with regard to cost, invasiveness and feasibility. A biomarker of neurodegeneration would have several applications, including use as a surrogate or secondary outcome measure in clinical trials of emerging therapies. Thus far, few longitudinal studies have been conducted in this area. This is important because the rate of change or accumulation of a biomarker may be a better indicator of disease progression than a single value or range at one time point. Such a biomarker could be used as a surrogate or secondary outcome measure in clinical trials of emerging therapies for AD, or may be a prognostic indicator of disease progression. We propose a proof-of-concept study to explore the clinical utility of 24S-OHC, 24S-OHC/27-OHC ratio, 24S- OHC/cholesterol ratio, and F2a-isoprostanes as blood-based biomarkers of neurodegeneration and, therefore, AD progression. We are currently following 75 well-characterized individuals, 25 each with early AD, MCI, and age-matched controls in a longitudinal imaging study. Participants are imaged 4 times over a year, at which time they also provide blood samples and have a thorough clinical and cognitive assessment. Blood samples and morphometric MRI scans collected as part of this study will be used for the present proposal, providing a unique opportunity to identify candidate blood markers of neurodegeneration within the RFA 2-year time frame. Not only will we be able to assess whether these lipids are associated with disease progression but we will be able to correlate the biomarkers to morphometric MRI, an established measure of brain atrophy, to determine whether these blood-based lipids are indeed indirect biomarkers of neurodegeneration. Analyses will: (1) Estimate the variability of plasma levels of each biomarker both within and between individuals at baseline, 3, 6, and 12 months and determine factors that effect this variability; (2) Compare the cross-sectional and longitudinal variations and trajectories in biomarkers for the three groups of individuals with varying AD pathology; (3) Determine whether baseline biomarker levels predict and/or correlate with change in tests of memory and executive functioning; (4) Examine the cross-sectional and longitudinal relationship between the plasma lipid biomarkers and brain atrophy or change in brain atrophy, as measured by morphometric MRI, in regions most affected early by Alzheimer-associated neurodegeneration (e.g. hippocampus, entorhinal cortex) and control regions not affected in early Alzheimer's (e.g. thalamus, putamen). This R21 application proposes a proof-of-concept study to explore the clinical utility of blood-based lipid biomarkers, including 24S-hydroxycholesterol and F2a-isoprostanes, as indicators of Alzheimer's disease (AD)-associated neurodegeneration. A validated blood-based biomarker would be superior to more invasive and costly CSF-based or brain imaging biomarkers. Such a biomarker of neurodegeneration would have several applications, including prognosis after the onset of dementia, prognosis of conversion from mild cognitive impairment to dementia, or use as a surrogate or secondary outcome measure in clinical trials of emerging therapies for neurodegenerative disorders.

描述（由申请人提供）：阿尔茨海默病（AD）是一种进行性神经退行性疾病。来自文献的结果和本申请中报告的初步数据表明，脂质测量（包括脑源性胆固醇物质和脂质过氧化产物）可能在AD患者的血液中产生易于检测的特征。这些特征可能是AD相关神经变性的指标，产生疾病进展的候选生物标志物。基于血液的生物标志物在成本、侵入性和可行性方面上级基于CSF或脑成像的生物标志物。神经变性的生物标志物将有几种应用，包括在新兴疗法的临床试验中用作替代或次要结果测量。迄今为止，在这一领域进行的纵向研究很少。这一点很重要，因为生物标志物的变化率或累积率可能是比一个时间点的单个值或范围更好的疾病进展指标。这样的生物标志物可用作AD新兴疗法的临床试验中的替代或次要结果测量，或者可以是疾病进展的预后指标。我们提出了一项概念验证研究，以探索24 S-OHC、24 S-OHC/27-OHC比率、24 S-OHC/胆固醇比率和F2 a-异前列腺素作为神经退行性变以及因此AD进展的血液生物标志物的临床效用。我们目前正在跟踪75名特征良好的个体，其中25名患有早期AD，MCI和年龄匹配的对照组。参与者在一年内接受4次成像，同时他们还提供血液样本并进行全面的临床和认知评估。作为本研究的一部分收集的血液样本和形态测量MRI扫描将用于本提案，为在RFA 2年时间范围内识别神经变性的候选血液标志物提供了独特的机会。我们不仅能够评估这些脂质是否与疾病进展相关，而且还能够将生物标志物与形态测量MRI（一种已建立的脑萎缩测量方法）相关联，以确定这些血液脂质是否确实是神经变性的间接生物标志物。分析将：（1）估计在基线、3、6和12个月时个体内和个体之间每种生物标志物的血浆水平的变异性，并确定影响这种变异性的因素;（2）比较具有不同AD病理学的三组个体的生物标志物的横截面和纵向变异和轨迹;（3）确定基线生物标志物水平是否预测记忆和执行功能测试的变化和/或与记忆和执行功能测试的变化相关;（4）检查血浆脂质生物标志物与脑萎缩或脑萎缩变化之间的横向和纵向关系，如通过形态测量MRI所测量的，在早期受阿尔茨海默病相关神经变性影响最大的区域（例如海马、内嗅皮层）和在早期阿尔茨海默病中未受影响的对照区域（例如丘脑、壳核）中。该R21申请提出了一项概念验证研究，以探索基于血液的脂质生物标志物（包括24 S-羟基胆固醇和F2 a-异前列烷）作为阿尔茨海默病（AD）相关神经变性指标的临床效用。经验证的基于血液的生物标志物将上级更具侵入性和昂贵的基于CSF或脑成像的生物标志物。这种神经变性的生物标志物将具有几种应用，包括痴呆发作后的预后、从轻度认知障碍转化为痴呆的预后，或在神经变性疾病的新兴疗法的临床试验中用作替代或次要结果测量。