Modulators of Cognitive Transifion from MCI to AD

项目总结（见说明）：先前的死后研究和体内淀粉样蛋白成像研究现已明确证实，大脑中淀粉样蛋白- β (abbbb3)负担相似的个体可能认知正常，患有轻度认知障碍（MCI）或阿尔茨海默病（AD）。因此，似乎很有可能存在可以加速或延缓AB对大脑的影响的调节剂。死后研究也表明，大脑中血管病变的存在和数量可能是一种调节剂。总体概念是，大脑中血管病理的存在建立了一种脆弱状态，在这种状态下，AB的沉积更快地导致认知障碍的发生和进展，以及MCI和AD的临床症状。从正常认知到MCI过渡的调节因子将在项目4中探讨。在这个项目（项目5）中，我们将探索从轻度认知损伤到临床AD转变的调节因子。基本的假设是，大脑和身体的其他部分一样，在面对损伤（在这种情况下，是由AP引起的）时试图维持体内平衡。我们认为，成功的体内平衡和补偿的最重要机制之一是脑血流的调节，甚至亚临床脑血管疾病也可以显著加速AB沉积的不良反应。我们建议通过使用PiB PET来测量AB沉积（毒素）对三个主要结果的影响来验证这一假设：1)脑代谢（FDG PET）；2)脑容量（结构MRI）；3)认知（神经心理测试）。我们还将测量潜在的AB调节剂，如脑和全身亚临床血管疾病和脑血流（灌注MRI）。我们进一步提出，随着年龄的增长，认知易感性与血管疾病标志物一起积累，在非常年长的个体中，血管和AB负担的相对重要性可能与年轻人不同。因此，我们将使用在本项目前期已研究24个月及以上的年轻MCI受试者组和已有的老年组（bb0 - 83岁），该老年组已参加了为期7年的银杏叶衰老研究，并且在本研究之前也曾研究过一次PiB。

PROJECT SUMMARY (See instructions): Postmortem studies previously suggested, and in vivo amyloid imaging studies have now unambiguously confirmed that individuals with a similar burden of amyloid-beta (A|3) in their brains can be cognitively normal, have Mild Cognitive Impairment (MCI) or Alzheimer's disease (AD). Thus, it seems highly likely that there are modulators that can accelerate or retard the effects of AB on the brain. Postmortem studies also have suggested that the presence and amount of vascular pathology in the brain is a likely modulator. The overall concept is that the presence of vascular pathology in the brain establishes a vulnerable state in which the deposition of AB much more quickly leads to the onset and progression of cognitive impairment and the clinical syndromes of MCI and AD. The modulators of the transition from normal cognition to MCI will be explored in Project 4. In this project (Project 5) we will explore the modulators of the transition from MCI to clinical AD. The fundamental hypothesis is that the brain, like the rest of the body, tries to maintain homeostasis in the face of injury (induced, in this case, by AP). We propose that one of the most important mechanisms for successful homeostasis and compensation is modulation of cerebral blood flow and even subclinical cerebrovascular disease can significantly accelerate the adverse effects of AB deposition. We propose to test this hypothesis by using PiB PET to measure the effect of AB deposition (the toxin) on three main outcomes: 1) cerebral metabolism (FDG PET); 2) brain volume (structural MRI); and 3) cognition (neuropsychological testing). We also will measure potential AB modulators such as cerebral and systemic subclinical vascular disease and cerebral blood flow (perfusion MRI). We further propose that cognitive vulnerability accumulates along with markers of vascular disease with aging and in very elderly individuals, the relative importance of vascular and AB burden may be different than in younger persons. Thus, we will make use of a younger group of MCI subjects that have been studied for 24 months or more in the previous project period of this Program Project and an existing older group (>83 years) who have participated in a seven-year study of gingko biloba in aging and who have also been studied once with PiB prior to this study.