Development of blood lipid biomarkers for Alzheimer's disease progression

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患者的血液中产生独特的、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。到目前为止，还没有在这一领域进行纵向研究。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。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。我们提出了一项概念验证研究，采用纵向研究设计，探索24S-羟基胆固醇(24S-OHC)、24S-OHC/27-羟基胆固醇比值、24S-OHC/胆固醇比值和F2a-异前列腺素作为AD相关神经变性的血液生物标志物的临床应用价值。我们将从约翰霍普金斯阿尔茨海默病研究中心(JHADRC)招募特征良好的轻度可能AD(PAD)患者、遗忘性轻度认知障碍(MCI)患者和年龄匹配的认知正常对照组，每组30人。作为该中心临床核心的一部分，这些人已经每年接受跟踪。在这项拟议的研究中，个人将被要求在三个时间点提供空腹血液样本，在两次定期的年度访问期间，以及在其间的六个月访问期间，他们将接受额外的认知测试。在本研究期间以外的额外年度后续行动将通过JHADRC提供。分析将(1)评估基线、6个月和1岁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向和纵向变化以及轨迹；(3)确定基线生物标记物水平是否预测一年的认知衰退；(4)评估生物标记物水平的变化作为认知衰退的后续预测指标；以及(5)确定一年以上的生物标记物水平的总和是否与个体内部认知变化有关。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。这种神经退变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，或疾病临床前阶段的预后。一个主要的应用将是作为AD新疗法临床试验的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 unique, readily detectable signatures in the blood of AD patients. These signatures may be indicators of AD-associated neurodegeneration, producing candidate biomarkers of disease progression. Thus far no 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. A blood-based biomarker would be superior to CSF-based or brain imaging biomarkers with regard to cost, invasiveness and feasibility. We propose a proof-of-concept study to explore the clinical utility of 24S-hydroxycholesterol (24S-OHC), 24S-OHC/27- hydroxycholesterol ratio, 24S-OHC/cholesterol ratio and F2a-isoprostanes as blood-based biomarkers of AD-associated neurodegeneration using a longitudinal study design. We will recruit well-characterized patients with mild probable AD (pAD), amnestic mild cognitive impairment (MCI), and age-matched cognitively normal controls, 30 per group, from the Johns Hopkins Alzheimer Disease Research Center (JHADRC). These individuals are already followed annually as part of the Center's Clinical Core. For the proposed study, individuals will be asked to provide fasting blood samples at three time points, during two regularly scheduled annual visits, and during a six month visit in between, at which point they will undergo additional cognitive testing. Additional years of follow-up beyond the duration of this study will be available through the JHADRC. Analyses will (1) Estimate the variability of plasma levels of each biomarker both within and between individuals at baseline, 6 months and 1 year 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 one-year cognitive decline; (4) Assess change in biomarker levels as subsequent predictors of cognition decline; and (5) Determine whether the sum of the biomarker levels over one year are related to intra-individual cognitive change. 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. 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 prognosis in the preclinical phases of the disease. A major application would be as a surrogate or secondary outcome measure in clinical trials of emerging therapies for AD.