Dynamic Functional Connectivity MRI in Preclinical AD

项目3 -摘要 阿尔茨海默病（Alzheimer's disease，AD）的病理变化具有较好的解剖学规律， 病理变化在AD的临床前阶段和痴呆阶段之间和之内变化。此外，多个 病理过程，主要是AD和脑微血管疾病，不同程度地共同导致记忆 问题和痴呆症。尽管在研究环境中非常成功和至关重要， 仍然是分层评估方案的一部分，CSF生物标志物和PET成像可能会遇到障碍 作为数百万人的初始屏幕或连续治疗监视器。我们寻求解决这一预期的障碍 通过开发基于功能性MRI（fMRI）的方法， 痴呆症的临床前阶段。功能连接fMRI（fcMRI）研究显示， 默认模式网络（DMN）中的连通性作为临床前AD的标志，但尚不清楚其特异性 AD的变化，或者DMN功能连接如何预测记忆衰退或AD进展。 此外，目前的数据主要来自研究队列，并没有集中在可能的大规模 尸检表明，脑微血管疾病的贡献。的确，成年人的变化， 思想（ACT）研究，一项以社区为基础的研究，在西雅图地区的大脑老化和痴呆事件， 在大型尸检研究中表明，ACT中痴呆的人群归因风险为45%， AD和33%的脑微血管疾病。使用作为UW一部分的ACT参与者队列 ADRC临床核心（ACT-Plus），我们将评估DMN功能连接变化的特异性， 临床前AD，以及MRI测量脑微血管疾病的影响。具体目标1。通过 在无CSF生物标志物的受试者中确定临床前AD的新型fcMRI相关性 痴呆症，我们将测试的假设，功能连接措施可以区分个人与 没有AD的患者的CSF特征，并将功能连接性测量与常用的 参数，包括海马体积和皮质厚度，以及代理措施的区域 大脑代谢具体目标2。通过确定新的fcMRI与认知障碍的相关性， 在基线时没有痴呆症的个体中， 实验领先的认知能力下降的措施，我们将测试的假设，动态功能 使用我们开发的方法，连接性是一种比现有生物标志物更敏感和信息量更大的生物标志物。 用于识别当前和预测未来认知的成像方法或固定功能连接 损伤成功完成后，该项目将确定新型功能磁共振成像的实用性 更接近反映最终目标的样本中的脑老化和临床前AD方法 人口

PROJECT 3 - ABSTRACT Alzheimer's disease (AD) pathologic change develops in an orderly anatomic sequence but the level of pathologic change varies among and within preclinical and dementia stages of AD. Moreover, multiple pathological processes, primarily AD and cerebral microvascular disease, varyingly conspire to cause memory problems and dementia. Although very successful and critically important in research settings, and likely to remain part of tiered assessment protocols, CSF biomarkers and PET imaging are likely to encounter barriers as initial screens or serial treatment monitors for millions of people. We seek to address this anticipated barrier to health care effectiveness by developing functional MRI (fMRI)-based approaches that are informative in preclinical stages of dementia. Functional connectivity fMRI (fcMRI) studies show altered functional connectivity in the default mode network (DMN) as a marker of preclinical AD, but it is not known how specific the changes are to AD, or how predictive DMN functional connectivity is of memory decline or AD progression. Moreover, current data derive mostly from research cohorts and have not focused on the likely large contribution from cerebral microvascular disease as indicated by autopsy. Indeed, the Adult Changes in Thought (ACT) study, a community-based study of brain aging and incident dementia in the Seattle area, has demonstrated in large autopsy studies that the population-attributable risk of dementia in ACT was 45% from AD and 33% from cerebral microvascular disease. Using a cohort of ACT participants that is part of the UW ADRC Clinical Core (ACT-Plus), we will evaluate the specificity of DMN functional connectivity changes in preclinical AD, as well as MRI measures of the impact of cerebral microvascular disease. Specific Aim 1. By determining novel fcMRI correlates of preclinical AD as defined by CSF biomarkers in participants without dementia, we will test the hypothesis that functional connectivity measures can discriminate individuals with CSF profiles of AD from those without, and will compare functional connectivity measures to commonly used parameters including hippocampal volume and cortical thickness, as well as to proxy measures of regional cerebral metabolism. Specific Aim 2. By determining novel fcMRI correlates of cognitive impairment and decline in individuals without dementia at baseline, and analyzing them with respect to established and experimental leading measures of cognitive decline, we will test the hypothesis that dynamic functional connectivity, using an approach we developed, is a more sensitive and informative biomarker than existing imaging approaches or stationary functional connectivity for identifying present and predicting future cognitive impairment. When successfully completed, this Project will have determined the utility of novel fMRI approaches to brain aging and preclinical AD in a sample that more closely reflects the ultimate target population.