Biomarker for Alzheimer's Related Cognitive Deficits

描述（由申请人提供）：阿尔茨海默病（AD）潜在的分子和细胞细节正在加速定义，导致新的治疗发现努力，目标是减少A-β或ADDL（A-β衍生的扩散配体），A-β 1-42的神经毒性寡聚体组装体。ADDL水平升高与突触功能障碍相关，并且脑组织中ADDL的出现与转基因AD动物模型Tg 2576 AD小鼠的认知下降一致。最近的研究表明，ADDL在AD脑组织中升高70倍，并且ADDL直接干扰突触功能、学习和记忆。即使血清样本中的ADDL水平较低，也可能预测认知能力下降。该提案旨在开发可以测量人体体液和组织样本中ADDL水平的诊断测试。这些测试将有助于建立ADDL水平和认知缺陷之间的联系。血清或脑脊液（CSF）ADDL诊断将是一个有价值的工具，用于识别相关的AD和轻度认知障碍（MCI）患者作为临床试验参与者。对于降低Abeta或ADDL水平的药物的测试，定量ADDL诊断将是关键，以确定症状疗效与ADDL水平下降平行。Acumen及其合作者开发了灵敏的基于ELISA的技术，可以检测人类CSF样本中飞摩尔水平的ADDL。ADDL选择性抗体的实验提供了初步证据，ADDL存在于Tg 2576小鼠和唐氏综合征患者的血浆样品中。这些令人鼓舞的初步数据作为该提议的基础，以：1）优化ADDL检测能力，2）优化适合作为人类临床样品的参考测试的ADDL诊断测定形式，以及3）验证ADDL水平与人类认知缺陷相关的假设。目标一和目标二将是第一阶段的重点，目标三将是第二阶段的重点。

DESCRIPTION (provided by applicant): The molecular and cellular details underlying Alzheimer's disease (AD) are being defined at an accelerating pace, leading to new therapeutic discovery efforts that target reduction of A-beta or ADDLs (A-beta-derived diffusible ligands), the neurotoxic oligomeric assemblies of A-beta 1-42. Elevated ADDL levels correlate with synaptic dysfunction, and the appearance of ADDLs in brain tissue coincides with cognitive decline in Tg2576 AD mice, a transgenic AD animal model. Recent studies have demonstrated that ADDLs are 70-fold elevated in AD brain tissue, and that ADDLs interfere directly with synaptic function, learning and memory. It is possible that even low levels of ADDLs in serum samples may predict cognitive decline. This proposal aims to develop diagnostic tests that can measure ADDL levels in human fluid and tissue samples. Such tests will help establish a connection between ADDL levels and cognitive deficits. A serum or cerebrospinal fluid (CSF) ADDL diagnostic will be a valuable tool for identification of relevant patients with AD and mild cognitive impairment (MCI) as clinical trial participants. For testing of drugs that lower Abeta or ADDL levels, a quantitative ADDL diagnostic will be pivotal to establish that symptomatic efficacy parallels a drop in ADDL levels. Acumen and its collaborators have developed sensitive ELISA-based technology that detects ADDLs at femtomolar levels in human CSF samples. Experiments with ADDL-selective antibodies have provided preliminary evidence that ADDLs are present in plasma samples from Tg2576 mice and Down's syndrome patients. These encouraging preliminary data serve as the foundation for this proposal to: 1) optimize ADDL detection capabilities, 2) optimize an ADDL diagnostic assay format suitable as a reference test for human clinical samples, and 3) validate the hypothesis that ADDL levels correlate with human cognitive deficits. Objectives one and two will be the focus of Phase I, and objective three will be the focus of Phase II.