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

描述(申请人提供)：痴呆症是一个主要的公共卫生问题，将随着我们的社会老龄化而显著增长。近年来，多项临床和神经病理学资料表明，痴呆是一个典型的多因素过程。关于痴呆症生物学思想的这种演变发生在痴呆症成像领域最重大的最新发展是引入淀粉样斑块标记化合物的时候；在这一点上，研究最广泛的是匹兹堡化合物B(PIB)。这种更新背后的一个核心原则是这样的。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大脑淀粉样变性更复杂，痴呆症的成像比单独的大脑淀粉样成像更复杂。我们这次更新的主要目标是使用不同的成像方式来识别痴呆的不同机制。这是AG11378竞争性续订的第一次提交。我们已根据评论中提出的每一点修改了赠款，我们相信这将导致更强有力的申请。五个目标中的每一个都被用来回答不同的问题：特定的基于成像的病理学指标对临床/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是真实的？对谁来说，这是真的？相关的病理在大脑的什么地方表达？主要的结果衡量标准将是临床和心理测量随着时间的推移而下降，我们将使用这些指标作为疾病进展的指标。我们的预测变量将包括各种成像方式，它们将作为痴呆症潜在的特定病理机制的替代。PIB将作为斑块负荷的衡量标准，我们将使用各种磁共振成像(MRI)方法来评估脑血管疾病、组织丢失、组织灌流、扩散、神经元完整性和炎症。与过去AG11378周期不同的是，此次更新的功能包括机械性焦点、包括多个MRI模式以及PET淀粉样成像的多模式成像、现在的3T磁共振成像、包括遗忘性和非遗忘性MCI的MR成像，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，它使用支持向量机算法在单个受试者中提供诊断。此外，受试者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，该研究将这次更新与过去的周期以及大多数痴呆症成像研究区分开来，后者从转诊实践中招募，因此存在抽样偏差的风险。这项资助的前几个周期已经为认识到成像在痴呆症中的作用做出了重大贡献。关于修订AD的临床标准，特别是是否应该将影像和液体生物标记物信息包括在标准中，目前正在进行一场激烈的辩论。这一续期拨款的结果将为这场关于导致痴呆症的多种时间依赖机制的辩论提供信息，这些机制可以通过成像在活着的受试者中获得。公共卫生相关性：确定痴呆症的机制：磁共振成像在分子成像时代的作用(AG11378)痴呆症是目前一个主要的公共卫生问题，随着老年人数量的增加，将对公共健康产生越来越严重的影响。痴呆症有许多可能的潜在原因，在大多数老年痴呆受试者中，有几种不同的原因在起作用。在这笔赠款中，我们将使用现代脑成像来确定导致痴呆症的具体机制。

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.