Early Age-of-Onset AD: Clinical Heterogeneity and Network Degeneration

早期 AD 发病年龄：临床异质性和网络退化

• 批准号: 8696557
• 负责人: Gil Dan Rabinovici
• 金额: $ 66.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8696557
• 关键词: Accounting; Adult; Affect; Age; Age of Onset; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Anatomy; Atrophic; Attention; Binding; Biological Markers; Biological Neural Networks; Biology; Brain; Brain imaging; Caring; Clinical; Data; Dementia; Deposition; Diagnosis; Diagnostic; Diagnostic tests; Diffuse; Disease; Dissociation; Early Onset Familial Alzheimer' s Disease; Elements; Employee Strikes; Episodic memory; Functional Magnetic Resonance Imaging; Functional disorder; Gold; Graph; Heterogeneity; Hippocampus (Brain); Image; Imaging Techniques; Investigation; Language; Late Onset Alzheimer Disease; Light; Magnetic Resonance Imaging; Measures; Memory; Metric; Modeling; Nerve Degeneration; Neurofibrillary Tangles; Neurons; Nodal; Pathology; Patients; Pattern; Performance; Population; Positron-Emission Tomography; Presenile Alzheimer Dementia; Primary Progressive Aphasia; Process; Recruitment Activity; Reference Values; Relative (related person); Rest; Sensitivity and Specificity; Staging; Stress; Symptoms; Syndrome; Testing; Variant; Vision; Visual; Visuospatial; cerebral atrophy; clinical Diagnosis; clinical phenotype; comparative; disease phenotype; early onset; executive function; improved; molecular pathology; neuroimaging; public health relevance; tau Proteins; theories

DESCRIPTION (provided by applicant): Patients who develop sporadic Alzheimer's disease (AD) before age 65 (~5% of all AD patients) pose a clinical challenge and a scientific enigma. From a clinical perspective, early-onset (EO) patients often present with primary executive, language or visuospatial symptoms (with relative sparing of memory), and accurate diagnosis is challenging due to overlap with non-AD dementia and non-degenerative conditions. Emerging AD biomarkers could facilitate accurate diagnosis but have rarely been studied in this population. The performance of biomarkers in studies of "typical" late-onset (LO) AD cannot be generalized to EO patients because of differences in degenerative patterns and reference ranges. From a scientific perspective, EO syndromes show a striking dissociation between amyloid-beta (A¿) pathology, which is diffuse and symmetric in all syndromes, and brain degeneration, which parallels symptoms and can be asymmetric or focal. This raises fundamental questions about the mechanisms that drive clinical and anatomic diversity in AD. This proposal applies detailed clinical phenotyping and multi-modal neuroimaging to optimize the diagnosis of EO syndromes, and to study mechanisms of heterogeneity in AD. Leveraging the specialization of the UCSF ADRC in early-onset dementia, the study will include 150 mildly impaired (CDR 0.5-1) EO AD patients, 50 each with a predominant executive/memory, language and visuospatial clinical phenotype, and 40 patients with LO-AD. A positive amyloid (PIB) PET scan will be required for inclusion. Patients will undergo structural MRI, functional connectivity ("resting state") MRI (fcMRI), FDG-PET and CSF analysis. Comparative data from matched normal controls (NC) and non-AD dementia patients will be obtained from other ongoing studies. The central hypothesis of the proposal is that neurodegeneration in all AD variants converges in temporoparietal regions that comprise the posterior portion of the default mode network (DMN), a core, selectively vulnerable network in AD. Aim 1 tests the diagnostic applications of this hypothesis by comparing the sensitivity and specificity of temporoparietal versus hippocampal MRI/FDG measures in discriminating EO-AD versus NC and non-AD dementia, and compares the performance of imaging biomarkers in EO vs. LO-AD. Aim 2 applies fcMRI to test the hypothesis that the posterior DMN is affected across EO syndromes and in LO-AD, while the relative involvement of other functional networks drives the clinical phenotype in each AD variant. Aim 3 investigates how functional connectivity in healthy adults relates to the patterns of amyloid deposition and neurodegeneration in AD variants, in order to test a model in which A¿ deposition is driven by nodal stress in cortical hubs, while neurodegeneration originates in syndrome-specific "epicenters" within the DMN that initiate the trans-neuronal spread of disease and drive the clinical phenotype. These investigations will facilitate the early and accurate diagnosis of EO AD variants, and will further our understanding of the relationships between clinical phenotype, structural and functional brain changes and molecular pathology in AD.

描述（由适用提供）：在65岁之前发展零星阿尔茨海默氏病（AD）的患者（所有AD患者的5％）构成了临床挑战和科学的谜。从临床的角度来看，早期发作（EO）患者通常出现主要执行，语言或视觉症状（记忆相对较高），并且由于与非AD痴呆症和非分类状况的重叠，挑战了准确的诊断。新兴的AD生物标志物可以促进准确的诊断，但在该人群中很少进行研究。由于退化模式和参考范围的差异，生物标志物在“典型”晚期（LO）AD的研究中的性能不能推广到EO患者。从科学的角度来看，EO综合征表明淀粉样蛋白β（a¿这引发了有关推动AD临床和解剖学多样性的机制的基本问题。该建议应用详细的临床表型和多模式神经影像学来优化EO综合征的诊断，并研究AD中异质性的机制。该研究利用UCSF ADRC在早发痴呆症中的专业化，包括150名轻度损害（CDR 0.5-1）EO AD患者，每个患者50例，每个患者具有主要的执行/记忆/记忆，语言，语言和视觉临床表型，以及40名LO-AD患者。包含阳性淀粉样蛋白（PIB）PET扫描。患者将接受结构性MRI，功能连通性（“静止状态”）MRI（FCMRI），FDG-PET和CSF分析。来自匹配的正常对照组（NC）和非AD痴呆症患者的比较数据将从其他正在进行的研究中获得。该提案的中心假设是，所有AD变体中的神经变性都在颞型区域收敛，该区域构成了默认模式网络（DMN）的后部，核心，AD中有选择性易受伤害的网络。 AIM 1通过比较颞叶与海马MRI/FDG测量的敏感性和特异性在区分EO-AD与NC与非AD痴呆症中的敏感性和特异性来测试该假设的诊断应用，并比较了EO VS. LO-AD中成像生物标志物的性能。 AIM 2应用FCMRI来检验以下假设：DMN后DMN在EO综合征和LO-AD中受到影响，而其他功能网络的相对参与则驱动每个AD变体中的临床表型。 AIM 3研究了健康成年人的功能连通性如何与AD变体中淀粉样蛋白沉积和神经变性的模式相关联，以测试一个模型，在该模型中，a的沉积是由皮质中心中的淋巴结压力驱动的，而神经变性是综合征特异性的“ cepIcenters”的临床疾病，该模型是在dmn中驱动的，该模型驱动了临床疾病。这些研究将促进EO AD变体的早期和准确诊断，并将进一步了解AD中临床表型，结构和功能性脑变化和分子病理学之间的关系。