Identifying Mechanisms of Dementia: Role for MRI in the Era of Molecular Imaging

描述（由申请人提供）：痴呆症是一个重大的公共卫生问题，随着我们社会的老龄化，这一问题将显著增加。最近，多项临床和神经病理学数据表明，痴呆是一个典型的多因素过程。这种对痴呆症生物学的思考的演变发生在痴呆症成像领域最近最重要的发展是引入淀粉样斑块标记化合物的时候；目前研究最广泛的是匹兹堡化合物- B （PiB）。这一复兴的核心原则是这样的。淀粉样蛋白成像无疑是一项重大进步。然而，由于痴呆症的生物学比单独的脑淀粉样变性更复杂，因此痴呆症的成像比单独的脑淀粉样变性成像更复杂。我们在此更新的主要目标是使用各种成像方式来确定痴呆的不同机制。这是AG11378竞争性续期的首次重新提交。我们已经根据批评中提出的每一点修改了拨款，我们相信这导致了更有力的申请。这五个目标中的每一个都是为了回答以下问题的变化：具体的基于成像的病理学代理对临床/认知能力下降的贡献是什么？在疾病过程中，这些关系在什么时候成立？这对谁是真的？相关的病理在大脑的哪个部位表现出来？主要的结果测量将是临床和心理测量随时间的下降，我们将用它作为疾病进展的指标。我们的预测变量将包括各种成像模式，这些模式将作为痴呆的特定病理机制的代理。PiB将作为斑块负荷的测量，我们将使用各种磁共振成像（MRI）模式来评估脑血管疾病、组织损失、组织灌注、扩散、神经元完整性和炎症。与以往的AG11378周期不同，这次更新的特点包括机制聚焦、多模态成像（包括多个MRI模式和PET淀粉样蛋白成像）、现在在3T的MR成像、包括健忘性和非健忘性MCI，以及基于体素的分析方法，包括一种令人兴奋的新计算方法，该方法采用支持向量机算法为个体受试者提供诊断。此外，现在将从一项新的基于人群的老龄化和痴呆症研究中招募受试者，这与过去的周期以及大多数从转诊实践中招募的痴呆症影像学研究不同，因此存在抽样偏差的风险。该资助的前几个周期对认知成像在痴呆症中的效用做出了重大贡献。目前正在进行一场关于修改AD临床标准的积极辩论，特别是影像学和液体生物标志物信息是否应包括在标准中。这项续期拨款的结果将为通过成像在活体受试者中可获得的导致痴呆的多重时间依赖性机制的辩论提供信息。公共卫生相关性：识别痴呆症的机制：MRI在分子成像时代的作用（AG11378）痴呆症是目前主要的公共卫生问题，随着老年人数量的增加，将对公共卫生产生越来越严重的影响。痴呆症有许多可能的潜在原因，在大多数老年痴呆症患者中，有几种不同的原因在起作用。在这项资助中，我们将使用现代脑成像来确定痴呆症进展的具体机制。

DESCRIPTION (provided by applicant): Dementia represents a major public health problem which will grow significantly with the aging of our society. Recently, multiple pieces of converging clinical and neuropathological data indicate that dementia is typically a multi-factorial process. This evolution in thinking about the biology of dementia comes at a time when the most significant recent development in dementia imaging has been the introduction of amyloid plaque labeling compounds; the most widely studied at this point is Pittsburgh Compound - B (PiB). A central principle underlying this renewal is this. Amyloid imaging is unquestionably a major advance. However, since the biology of dementia is more complex than brain amyloidosis alone, imaging of dementia is more complex than brain amyloid imaging alone. Our primary goal in this renewal is to use various imaging modalities to identify different mechanisms underlying dementia. This is the first resubmission of a competitive renewal of AG11378. We have revised the grant in accordance with each point raised in the critique and we believe this has resulted in a much stronger application. Each of the five aims is cast to answer variations on the questions: What is the contribution of specific imaging-based proxies of pathology to clinical/cognitive decline? When in the course of the disease do these relationships hold true? For whom is this true? Where in the brain are the relevant pathologies expressed? Principle outcome measures will be clinical and psychometric decline over time which we will use as indicators of disease progression. Our predictor variables will include various imaging modalities which will serve as proxies for specific pathologic mechanisms underlying dementia. PiB will serve as a measure of plaque burden and we will use various Magnetic Resonance Imaging (MRI) modalities to assess cerebro- vascular disease, tissue loss, tissue perfusion, diffusion, neuronal integrity, and inflammation. Features that distinguish this renewal from past cycles of AG11378 include a mechanistic focus, multi- modality imaging including multiple MRI modalities as well as PET amyloid imaging, MR imaging now at 3T, inclusion of both amnestic and non-amnestic MCI, and voxel-based analytic methods including an exciting new computational approach which employs a support vector machine algorithm to provide diagnosis in individual subjects. In addition, subjects will now be recruited from a new population-based study of aging and dementia, which differentiates this renewal from past cycles as well as from most dementia imaging studies which recruit from referral practices and thus risk sampling bias. Previous cycles of this grant have contributed significantly to recognition of the utility of imaging in dementia. An active debate is currently underway about revising clinical criteria for AD, specifically whether imaging and fluid biomarker information should be included among the criteria. Results from this renewal grant will inform this debate about multiple time dependent mechanisms leading to dementia that are accessible in living subjects through imaging. PUBLIC HEALTH RELEVANCE: Identifying Mechanisms of Dementia: Role for MRI in the Era of Molecular Imaging (AG11378) Dementia is a leading public health problem now and will have an increasingly serious impact on public health as the number of elderly individuals increase. Dementia has many possible underlying causes and several different causes are at work in most elderly demented subjects. In this grant, we will use modern brain imaging to identify specific mechanisms underlying progression to dementia.