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: 9212684
• 负责人: Gil Dan Rabinovici
• 金额: $ 61.7万
• 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/9212684
• 关键词: 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; Comorbidity; Data; Dementia; Deposition; Diagnosis; Diagnostic; Diagnostic tests; Diffuse; Disease; Dissociation; Early Diagnosis; Elements; Employee Strikes; Episodic memory; Functional disorder; Gold; Heterogeneity; Hippocampus (Brain); Imaging Techniques; Impairment; Investigation; Language; Late Onset Alzheimer Disease; Light; Magnetic Resonance Imaging; Measures; Memory; Modality; Modeling; Nerve Degeneration; Neurofibrillary Tangles; Nodal; Onset of illness; Pathology; Patients; Pattern; Performance; Phenotype; Population; Positron-Emission Tomography; Presenile Alzheimer Dementia; Primary Progressive Aphasia; Process; Recruitment Activity; Reference Values; Rest; Sensitivity and Specificity; Stress; Symptoms; Syndrome; Testing; Variant; Vision; Visual; Visuospatial; accurate diagnosis; angular gyrus; cerebral atrophy; clinical Diagnosis; clinical phenotype; comparative; disease phenotype; early onset; executive function; fluorodeoxyglucose positron emission tomography; graph theory; imaging biomarker; improved; molecular pathology; neuroimaging; public health relevance; tau Proteins

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 岁之前罹患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谜团。从临床角度来看，早发 (EO) 患者通常是一个难题。存在主要的执行、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。新兴的 AD 生物标志物可能有助于准确诊断，但由于退行性模式和参考范围的差异，“典型”迟发性 (LO) AD 的研究中生物标志物的表现很少被推广到 EO 患者。 β-淀粉样蛋白 (A�) 病理学（在所有综合征中都是弥漫性和对称性）与大脑变性（与症状相似，并且可以是不对称的或局灶性的）之间存在显着的分离，这提出了关于驱动临床和解剖多样性的机制的基本问题。该提案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，并利用 UCSF ADRC 在早发性痴呆方面的专业知识来研究 AD 的异质性机制，该研究将包括 150 名轻度受损的患者。 (CDR 0.5-1) EO AD 患者，每人 50 名具有显着的执行/记忆、语言和视觉空间临床表型，以及 40 名患有LO-AD。纳入时需要进行阳性淀粉样蛋白 (PIB) PET 扫描、结构 MRI、功能连接（“静息状态”）MRI (fcMRI)、FDG-PET 和来自匹配的正常对照的比较数据。 (NC) 和非 AD 痴呆患者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 变体的神经变性都集中在构成默认模式后部的颞顶区域。目标 1 通过比较颞顶与海马 MRI/FDG 测量在区分 EO-AD 与 NC 和非 AD 痴呆方面的敏感性和特异性，来测试该假设的诊断应用。并比较了 EO 与 LO-AD 中成像生物标志物的表现，目标 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了每个 AD 变体的临床表型，目标 3 研究了健康成人的功能连接与 AD 变体中淀粉样蛋白沉积和神经变性模式的关系，以测试 A� 沉积的模型。 EO 是由皮质中枢的节点应力驱动的，而神经变性起源于 DMN 内的综合征特异性“震中”，引发疾病的跨神经元传播并驱动临床表型。这些研究将有助于 EO 的早期和准确诊断。 AD 变异，并将进一步加深我们对 AD 临床表型、大脑结构和功能变化以及分子病理学之间关系的理解。