Blood-based lipid biomarkers reflective of Alzheimer-associated neurodegeneration

描述(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。来自文献的发现以及在本申请中报告的初步数据表明，血脂测量，包括脑源性胆固醇和脂质过氧化产物，可能会在AD患者的血液中产生容易检测到的信号。这些信号可能是AD相关神经变性的指示物，产生疾病进展的候选生物标记物。基于血液的生物标记物在成本、侵袭性和可行性方面都优于基于脑脊液或脑成像的生物标记物。神经退变的生物标记物将有几个应用，包括在新兴疗法的临床试验中用作替代或次要结果衡量标准。到目前为止，这方面的纵向研究还很少。这一点很重要，因为生物标记物的变化或积累的速度可能比一个时间点上的单个值或范围更好地指示疾病的进展。这样的生物标记物可以作为AD新疗法临床试验中的替代或次要结果指标，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比值、24S-OHC/胆固醇比值和F2a-异前列腺素作为神经退行性变和AD进展的血液生物标志物的临床应用价值。在一项纵向成像研究中，我们目前跟踪了75名特征良好的个体，其中25人分别患有早期AD、MCI和年龄匹配的对照组。参与者在一年内接受了4次成像，同时他们还提供了血液样本，并进行了彻底的临床和认知评估。作为这项研究的一部分，采集的血液样本和形态核磁共振扫描将用于本提案，为在RFA 2年时间框架内确定神经变性的候选血液标记物提供了一个独特的机会。我们不仅将能够评估这些脂质是否与疾病进展有关，而且我们还将能够将这些生物标记物与形态计量磁共振相关联，以确定这些基于血液的脂质是否确实是神经退化的间接生物标记物。分析将：(1)评估基线、3个月、6个月和12个月时个体内和个体之间每个生物标记物水平的变异性，并确定影响这种变异性的因素；(2)比较三组患有不同AD病理的个体的生物标记物的横截面和纵向变异性和轨迹；(3)确定基线生物标记物水平是否预测和/或与记忆和执行功能测试的变化相关；(4)在阿尔茨海默病早期受阿尔茨海默病相关神经变性影响最严重的区域(例如海马体、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)，通过形态计量磁共振测量，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。这项R21应用提出了一项概念验证研究，以探索基于血液的脂质生物标记物的临床用途，包括24S-羟基胆固醇和F2a-异前列腺素，作为阿尔茨海默病(AD)相关神经退化的指标。经过验证的基于血液的生物标记物将优于更具侵入性和更昂贵的基于脑脊液或脑成像的生物标记物。这种神经退行性疾病的生物标志物将有几个应用，包括痴呆症发病后的预后，从轻度认知障碍转变为痴呆症的预后，或者在神经退行性疾病新疗法的临床试验中用作替代或次要结果衡量标准。

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.