Molecular and structural imaging in atypical Alzheimer's disease: a longitudinal study

 描述(申请人提供)：阿尔茨海默病(AD)是一个主要的公共卫生问题，在美国有超过500万人受到影响。AD患者有β-淀粉样蛋白(A-β)和tau病理，典型的表现为记忆力丧失。然而，大约25%的AD受试者并不存在早期记忆丧失，而是存在其他认知症状，被称为非典型AD。最常见的非典型AD综合征包括对数失语(LPA)，一种语言综合征，以及后脑皮质萎缩(PCA)，一种视觉空间/知觉综合征。这些非典型AD综合征的生物学基础尚不清楚。此R01的目标是使用纵向分子正电子发射计算机断层扫描(Aβ和tau-PET成像)和结构磁共振来评估Aβ和tau沉积与LPA、PCa和典型AD的结构性脑损伤之间的关系，最终目的是增加我们对这些AD综合征变种的疾病生物学的了解。这些分析还将允许评估疾病进展的神经成像生物标记物，这可能在未来的临床试验中有用。为了实现我们的目标，我们将招募60名符合临床要求的受试者。 诊断标准为LPA(n=30)或Pca(n=30)，并在正电子发射计算机断层显像上显示Aβ沉积。每个受试者将接受相隔24个月的两次系列评估，包括神经和神经心理测试、3T结构核磁共振和扩散张量成像、匹兹堡化合物B PET和使用AV-1451配体进行的tau-PET。这些受试者将与梅奥诊所已经跟踪的典型AD和认知正常队列进行比较。对于LPA、Pca和典型AD，将评估Aβ和tau沉积的区域分布以及蛋白质沉积随时间的变化。还将评估蛋白质沉积与灰质萎缩和白质束变性之间的关系。然后，将根据每种成像模式生成区域一级的测量，并将使用统计建模来确定哪些区域或区域的组合提供了疾病进展的最佳生物标记。生物标志物将通过为临床试验生成样本大小估计并评估与认知能力下降的关系来验证。我们的R01将对公共卫生产生重大影响，因为非典型AD影响约100万美国人。我们的研究将增加对LPA和PCa疾病生物学和进展的了解，并提供生物标记物，使这些受试者能够纳入未来的试验。

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a major public health problem affecting over 5 million people in the US. Patients with AD have beta-amyloid (Aβ) and tau pathology and typically present with memory loss. However, approximately 25% of AD subjects do not present with early memory loss and instead present with other cognitive complaints, and are referred to as atypical AD. The most common atypical AD syndromes include logopenic aphasia (LPA), a language syndrome, and posterior cortical atrophy (PCA), a visuospatial/perceptual syndrome. The biological underpinnings of these atypical AD syndromes are unclear. The goal of this R01 is to use longitudinal molecular PET (Aβ and tau-PET imaging) and structural MRI to assess the relationship between Aβ and tau deposition and structural brain damage in LPA, PCA and typical AD, with the ultimate goal of increasing our understanding of disease biology in these syndromic variants of AD. These analyses will also allow the assessment of neuroimaging biomarkers of disease progression that could be useful in future clinical trials. To accomplish our aims we will recruit 60 subjects that fulfill clinical criteria for LPA (n=30) or PCA (n=30) and show Aβ deposition on PET imaging. Each subject will undergo two serial assessments 24 months apart that will include neurological and neuropsychological testing, 3T structural MRI and diffusion tensor imaging, Pittsburgh Compound B PET and tau-PET performed with the AV-1451 ligand. These subjects will be compared to typical AD and cognitively normal cohorts already followed at Mayo Clinic. The regional distribution of Aβ and tau deposition, and change in protein deposition over time, will b assessed for LPA, PCA and typical AD. The relationship between protein deposition and grey matter atrophy and white matter tract degeneration will also be assessed. Region-level measures will then be generated from each imaging modality and statistical modelling will be used to determine what regions, or combinations of regions, provides the optimum biomarkers of disease progression. Biomarkers will be validated by generating sample size estimates for clinical trials and assessing the relationship with cognitive decline. Our R01 will have a major impact on public health since atypical AD effects ~1,000,000 Americans. Our research will increase understanding of disease biology and progression in LPA and PCA and provide biomarkers which will allow the inclusion of these subjects in future trials.