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

描述（由申请人提供）：痴呆症是一个主要的公共卫生问题，将随着我们社会的老龄化而显着增长。最近，多个汇聚的临床和神经病理学数据表明，痴呆通常是一个多因素的过程。痴呆症生物学思想的这种演变正值痴呆症成像最重要的最新发展是淀粉样斑块标记化合物的引入;在这一点上研究最广泛的是匹兹堡化合物- B（PiB）。这一更新的核心原则是这样的。淀粉样蛋白成像无疑是一项重大进展。然而，由于痴呆的生物学比单独的脑淀粉样变性更复杂，因此痴呆的成像比单独的脑淀粉样蛋白成像更复杂。我们在这次更新中的主要目标是使用各种成像方式来识别痴呆症的不同机制。这是AG 11378竞争性更新的首次重新提交。我们根据评论中提出的每一点修改了补助金，我们相信这会导致更强有力的申请。这五个目标中的每一个都是为了回答以下问题的变化：基于特定成像的病理学代理对临床/认知衰退的贡献是什么？在疾病过程中，这些关系何时成立？对谁来说这是真的？相关的病理表现在大脑的哪个部位？主要结局指标将是临床和心理测量随时间的下降，我们将其用作疾病进展的指标。我们的预测变量将包括各种成像方式，这些成像方式将作为痴呆症潜在的特定病理机制的代理。PiB将作为斑块负荷的指标，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。将该更新与AG 11378的过去周期区分开的特征包括机制焦点、包括多种MRI模态以及PET淀粉样蛋白成像的多模态成像、现在在3 T的MR成像、包括遗忘和非遗忘MCI两者、以及基于体素的分析方法，包括令人兴奋的新计算方法，其采用支持向量机算法来提供个体受试者中的诊断。此外，现在将从一项新的基于人群的衰老和痴呆研究中招募受试者，该研究将这种更新与过去的周期以及大多数痴呆成像研究区分开来，这些研究从转诊实践中招募，因此存在风险抽样偏倚。该补助金的前几个周期为认识到成像在痴呆症中的实用性做出了重大贡献。目前正在积极讨论修订AD的临床标准，特别是是否应将成像和液体生物标志物信息纳入标准。这项更新拨款的结果将为这场辩论提供信息，这些辩论涉及通过成像在活体受试者中可获得的导致痴呆症的多种时间依赖性机制。公共卫生相关性：痴呆症的识别机制：MRI在分子成像时代的作用（AG 11378）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.