Alzheimer's disease: a blood diagnostic and biomarker of disease progression

描述（由申请人提供）：脑淀粉样蛋白¿肽（A¿）是阿尔茨海默病（AD）神经病理学诊断的要求。先前的研究表明，A¿也存在于外周血中。虽然阿尔茨海默病患者血液中A¿水平通常较高，但受试者之间的差异使使用这一指标作为阿尔茨海默病诊断的尝试变得混乱。申请人的研究表明，血液中的一些A¿与红细胞结合，作为清除A¿到肝脏降解的机制的一部分。这一机制的两个特征似乎在AD患者中发生了显著改变。单个AD红细胞似乎缺乏携带A¿的能力，这表明每个红细胞A¿的数量可能是一种简单、廉价、相对非侵入性的诊断AD的方法。然而，血液循环中约有2-3 × 1013个红细胞，远远足以弥补单个红细胞的缺陷。因此，如果观察红细胞室中A¿的总量，就会发现AD患者中A¿的值显著增加，这提示了第二种诊断方法。此外，申请人的初步研究发现，两种红细胞a¿生物诊断指标与一种常见的精神状态测试MMSE有显著的相关性。如果这是真的，那么纵向研究可能会表明这些指标是疾病进展的生物学标记，这将极大地促进新药的临床试验。最后，被诊断为轻度认知障碍（MCI）的患者，在许多情况下被认为是阿尔茨海默病的早期阶段，其红细胞a¿测量值与阿尔茨海默病组的红细胞a¿测量值基本重叠。因此，这些措施可能会挑选出那些MCI患者，他们最有可能转变为AD。特定的目的。测试红细胞Ab是A)一种敏感和特异性的AD诊断，B)一种预示MCI患者向AD转变的措施，和/或C)疾病进展的有用生物标志物的假设。共招募125名AD、125名MCI、125名非痴呆性正常老年人（ND）和125名AD以外的神经系统疾病患者（OND），评估、测试六项认知状态测量，并采集血样进行红细胞A¿水平测定。这些程序将每年重复一次，获得基线、1年、2年和3年的红细胞诊断、预后和生物标志物潜力数据。此外，预计约有96名受试者将进行尸检，为评估生物诊断方法的真正敏感性和特异性提供了一个金标准。NIA为主要研究者提供了一笔过桥资金，用于招募、基线测量和一个比较阿尔茨海默病神经影像学受试者的红细胞和脑脊液a¿的试点项目。然而，如果没有目前项目的纵向和神经病理学成分，任何这样的数据将仍然是有希望的，但只是初步的。

DESCRIPTION (provided by applicant): Brain amyloid ¿ peptide (A¿) is a requirement for the neuropathologic diagnosis of Alzheimer's disease (AD). Previous research has shown that A¿ is also present in the peripheral blood. Although A¿ blood levels have typically been found to be higher in AD patients, variability among subjects has confounded attempts to use this measure as an AD diagnostic. Studies by the applicant have demonstrated that some of the A¿ in blood is bound to erythrocytes as part of a mechanism for clearing A¿ to the liver for degradation. Two characteristics of this mechanism appear to be significantly altered in AD patients. Individual AD erythrocytes appear to be deficient in their ability to carry A¿, suggesting that the amount of A¿ per erythrocyte might be a simple, inexpensive, relatively non-invasive way to diagnose AD. However, there are some 2-3 X 1013 erythrocytes in the circulation2many more than enough to compensate for individual erythrocyte deficits. Thus, if one looks at the total amount of A¿ in the erythrocyte compartment, significantly increased values are found in AD patients, suggesting a second diagnostic approach. In addition, the applicant6s preliminary studies observed a significant correlation of the two erythrocyte A¿ biodiagnostic measures with a common mental status test, the MMSE. If true, then a longitudinal study might show these measures to be biological markers of disease progression, something that would greatly facilitate clinical trials of new drugs. Finally, patients diagnosed with mild cognitive impairment (MCI), a presumptive early stage of AD in many cases, had erythrocyte A¿ measures that substantially overlapped those of the AD group. It is possible, therefore, that the measures may be picking out those MCI patients in whom the conversion to AD is most imminent. Specific Aim. Test the hypothesis that erythrocyte Ab is A) a sensitive and specific AD diagnostic, B) a measure that presages the transition of MCI patients to AD, and/or C) a useful biomarker of disease progression. A total of 125 AD, 125 MCI, 125 nondemented normal elderly (ND), and 125 patients with a neurologic disorder other than AD (OND) will be recruited, evaluated, tested on six cognitive status measures, and blood sampled for assays of erythrocyte A¿ levels. These procedures will be repeated annually, yielding baseline, 1, 2, and 3 year data on diagnostic, prognostic, and biomarker potential of the erythrocyte measures. In addition, it is projected that some 96 of the subjects will come to autopsy, providing a 3gold standard4 for evaluating true sensitivity and specificity of the biodiagnostic approaches. NIA has provided a bridge grant to the principal investigator to cover recruiting, baseline measures, and a pilot project to compare erythrocyte and CSF A¿ in Alzheimer6s Disease Neuroimaging Initiative subjects. However, without the present project6s longitudinal and neuropathology components, any such data will remain promising but preliminary.