Blood-based lipid biomarkers reflective of Alzheimer-associated neurodegeneration

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。来自文献的发现和本应用报告的初步数据表明，脂质测量，包括脑源性胆固醇种类和脂质过氧化产物，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相关神经退行性变的指标，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优于基于csf或脑成像的生物标志物。神经退行性疾病的生物标志物将有多种应用，包括在新兴疗法的临床试验中作为替代或次要结果测量。到目前为止，这方面的纵向研究还很少。这一点很重要，因为生物标志物的变化率或积累率可能比一个时间点的单一值或范围更好地指示疾病进展。这种生物标志物可以作为阿尔茨海默病新疗法临床试验的替代指标或次要结果指标，也可以作为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24S-OHC、24S-OHC/27-OHC比率、24S-OHC/胆固醇比率和f2a -异前列腺素作为神经变性和AD进展的血液生物标志物的临床应用。我们目前在纵向成像研究中跟踪了75名特征良好的个体，其中25名分别患有早期AD、轻度认知障碍和年龄匹配的对照组。参与者每年进行4次成像，同时提供血液样本，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年时间框架内确定候选神经退行性变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，而且我们将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，以确定这些基于血液的脂质是否确实是神经退行性变的间接生物标志物。分析将：(1)在基线、3个月、6个月和12个月时，估计个体内部和个体之间每种生物标志物血浆水平的可变性，并确定影响这种可变性的因素；(2)比较三组不同AD病理个体的生物标志物的横断面和纵向变化和轨迹；(3)确定基线生物标志物水平是否预测和/或与记忆和执行功能测试的变化相关；(4)在早期受阿尔茨海默病相关神经变性影响最大的区域（如海马、内嗅皮质）和早期阿尔茨海默病未受影响的控制区域（如丘脑、壳核），通过形态测量MRI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断面和纵向关系。这项R21申请提出了一项概念验证研究，以探索血脂生物标志物的临床应用，包括24s -羟基胆固醇和f2 -异前列腺素，作为阿尔茨海默病（AD）相关神经变性的指标。经过验证的基于血液的生物标志物将优于更具侵入性和昂贵的基于csf或脑成像的生物标志物。这种神经退行性疾病的生物标志物将有多种应用，包括痴呆发病后的预后，从轻度认知障碍到痴呆的预后，或用作神经退行性疾病新疗法临床试验的替代或次要结果测量。

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.