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（由申请人提供）：65岁之前发生散发性阿尔茨海默病（AD）的患者（约占所有AD患者的5%）构成了临床挑战和科学之谜。从临床角度来看，早发性（EO）患者通常表现为主要的执行、语言或视觉空间症状（记忆相对保留），由于与非AD痴呆和非退行性疾病重叠，准确诊断具有挑战性。新出现的AD生物标志物可能有助于准确诊断，但很少在该人群中进行研究。由于退化模式和参考范围的差异，“典型”迟发性（LO）AD研究中生物标志物的性能不能推广至EO患者。从科学的角度来看，EO综合征显示出淀粉样蛋白β（A？）病理学与脑变性之间的显著分离，淀粉样蛋白β（A？）病理学在所有综合征中均为弥漫性和对称性，而脑变性与症状平行，可以是不对称的或局灶性的。这提出了关于驱动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态神经影像学来优化EO综合征的诊断，并研究AD异质性的机制。利用UCSF ADRC在早发性痴呆中的专业化，该研究将纳入150例轻度受损（CDR 0.5-1）EO AD患者，其中各50例具有主要的执行/记忆、语言和视觉空间临床表型，40例LO-AD患者。入选时需要进行阳性淀粉样蛋白（PIB）PET扫描。患者将接受结构MRI、功能连接（“静息状态”）MRI（fcMRI）、FDG-PET和CSF分析。将从其他正在进行的研究中获得匹配的正常对照（NC）和非AD痴呆患者的比较数据。该提案的中心假设是，所有AD变体中的神经变性都集中在颞顶区域，该区域包括默认模式网络（DMN）的后部，这是AD中的核心选择性脆弱网络。目的1通过比较颞顶与海马MRI/FDG测量在区分EO-AD与NC和非AD痴呆中的灵敏度和特异性，并比较EO与LO-AD中成像生物标志物的性能，来测试该假设的诊断应用。目的2应用fcMRI来检验后DMN在EO综合征和LO-AD中受到影响的假设，而其他功能网络的相对参与驱动每个AD变体的临床表型。目的3研究健康成年人的功能连接如何与AD变体中的淀粉样蛋白沉积和神经变性模式相关，以测试一个模型，其中A？沉积由皮质枢纽中的节点应力驱动，而神经变性起源于DMN内的综合征特异性“震中”，其启动疾病的跨神经元传播并驱动临床表型。这些研究将有助于早期和准确的诊断EO AD变异，并将进一步了解AD的临床表型，结构和功能的脑变化和分子病理学之间的关系。