Longitudinal study of membrane lipids: pre-clinical Alzheimer's biomarkers

描述（由申请人提供）：目前还没有确定的生物标志物可以预测无症状个体中谁会发展为阿尔茨海默病（AD），或者记忆障碍的人会转化为AD。找到这样的生物标志物对于在疾病过程的早期识别需要治疗的个体至关重要;一旦症状开始，病理可能是不可逆转的。AD是一种进行性神经退行性疾病，膜脂和脂质代谢产物参与了神经退行性变。动物和人类实验室研究表明，神经酰胺、鞘磷脂、24 S-羟基胆固醇（24 S-OHC）或F2 a-异前列烷与神经变性之间存在关联。少数可用的临床研究和我们的初步数据表明，这些脂质在AD的最早阶段（CDR 0.5）在血液、CSF和脑中发生改变，并因AD的严重程度而异。我们假设这些脂质是正在进行的神经退行性变的标志物，以及即将发生的AD的临床前风险因素或指标;从而有望成为AD进展的候选生物标志物。如果它们可以发展成基于血液的生物标志物，它们在成本、侵入性和重复测量的可行性方面将上级CSF或神经影像学测量。拟议研究的总体目标是将这一系列实验室和临床研究扩展为一项特征良好的、纵向的、基于人群的研究。大多数AD生物标志物研究都集中在诊断标志物上，并结合了临床人群的横断面研究。虽然临床研究有助于确定生物标志物是否随AD严重程度而变化，但基于人群的纵向研究对于辨别生物标志物是否最适合疾病的早期阶段，是否可预测进展速度以及提供生物标志物变异性的描述性数据至关重要。为此，我们将在已从参加女性健康与衰老研究（WHAS）II的老年女性中收集的数据中检查上述血脂。这项基于人群的纵向研究将使我们能够检查这些脂质的基线测量是否预测9年随访期间跨领域的后续认知障碍和偶发性痴呆（AD和全因），从而确定潜在的临床前生物标志物。PI之前获得了一项试点资助，用于使用WHAS II的基线血清开发脂质测定。我们现在申请资金进行二级数据分析。具体而言，分析将：（1）描述血脂的个体间变异性以及影响这种变异性的因素，如人口统计学因素、医疗条件、吸烟和APOE e4;（2）检查这些血脂与特定认知领域测试中的偶发性损害之间的横向和纵向关联;（3）检查血脂与AD偶发性之间的关系。公共卫生相关性：该R 03申请建议将当前的实验室和临床研究线扩展到纵向的、基于人群的研究，以检查膜脂质和代谢物（神经酰胺、鞘磷脂、24 S-羟基胆固醇（24 S-OHC）和F2 a-异前列烷），以确定它们是否预测随后的认知障碍和阿尔茨海默病（AD）。大多数AD生物标志物研究都集中在诊断标志物上，并结合了临床人群的横断面研究。虽然临床研究有助于确定生物标志物是否随AD严重程度而变化，但基于人群的纵向研究对于辨别生物标志物是否最适合疾病的早期阶段，是否可预测进展速度以及提供生物标志物变异性的描述性数据至关重要。

DESCRIPTION (provided by applicant): There currently are no established biomarkers that predict who among asymptomatic individuals will develop Alzheimer's disease (AD), or who with memory impairment will convert to AD. Finding such a biomarker is critical in identifying individuals for treatment early in the disease course; once symptoms begin, the pathology may be irreversible. AD is a progressive neurodegenerative disorder and membrane lipids and lipid metabolites are involved in the neurodegeneration. Animal and human laboratory studies suggest associations between ceramides, sphingomyelins, 24S-hydroxycholesterol (24S-OHC), or F2a-Isoprostanes and neurodegeneration. The few available clinic studies, and our preliminary data, suggest these lipids are altered in blood, CSF and brain in the earliest stages of AD (CDR 0.5), and vary by AD severity. We hypothesize these lipids are markers of ongoing neurodegeneration, and preclinical risk factors or indicators of impending AD; thereby holding promise as candidate biomarkers of AD progression. If they could be developed into blood-based biomarkers, they would be superior to CSF or neuroimaging measures with regards to cost, invasiveness, and feasibility for repeated measures. The overall aim of the proposed study is to extend this line of laboratory and clinical research to a well-characterized, longitudinal, population-based study. Most AD biomarker studies have focused on diagnostic markers, incorporating cross-sectional studies of clinic populations. While clinic studies are helpful in determining whether a biomarker varies by AD severity, a longitudinal population-based study is critical to discern whether a biomarker may best be suited to the earlier stages of the disease, whether it is predictive of the rate of progression, and to provide descriptive data on the variability of the biomarker. To this regard, we will examine the above-mentioned serum lipids in data already collected from older women enrolled in the Women's Health and Aging Study (WHAS) II. This population- based longitudinal study will allow us to examine whether baseline measures of these lipids predict subsequent cognitive impairment across domains and incident dementia (AD and all-cause) over 9 years of follow-up, thereby identifying a potential pre-clinical biomarker. The PI previously obtained a pilot grant to develop the lipid assays using baseline serum from WHAS II. We now apply for funds to conduct the secondary data analysis. Specifically, analyses will: (1) Characterize the between-individual variability of the serum lipids and factors that affect this variability such as demographic factors, medical conditions, smoking, and APOE e4; (2) Examine the cross-sectional and longitudinal associations between these lipids and incident impairment on tests of specific cognitive domains; and (3) Examine the relationship between the serum lipids and incident AD. PUBLIC HEALTH RELEVANCE: This R03 application proposes to extend the current line of laboratory and clinical research examining membrane lipids and metabolites (ceramides, sphingomyelins, 24S-hydroxycholesterol (24S-OHC), and F2a-Isoprostanes) to a longitudinal, population-based study in order to determine whether they are predictive of subsequent cognitive impairment and Alzheimer's disease (AD). Most AD biomarker studies have focused on diagnostic markers, incorporating cross-sectional studies of clinic populations. While clinic studies are helpful in determining whether a biomarker varies by AD severity, a longitudinal population-based study is critical to discern whether a biomarker may best be suited to the earlier stages of the disease, whether it is predictive of the rate of progression, and to provide descriptive data on the variability of the biomarker.