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

描述(申请人提供)：65岁前发展为散发性阿尔茨海默病(AD)的患者(约占所有AD患者的5%)是一个临床挑战和科学谜团。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(记忆相对较少)，由于与非阿尔茨海默病和非退行性疾病重叠，准确诊断具有挑战性。新兴的AD生物标志物有助于准确的诊断，但在这一人群中很少被研究。由于退变模式和参考范围的不同，生物标记物在“典型”晚发性AD研究中的表现不能推广到EO患者。从科学的角度来看，EO综合征显示出淀粉样β蛋白(A？)病理和脑变性之间的显著分离，前者在所有综合征中都是弥漫的和对称的，后者与症状平行，可以是不对称的或局灶性的。这对推动AD临床和解剖多样性的机制提出了根本性的问题。这项建议应用详细的临床表型和多模式神经成像来优化EO综合征的诊断，并研究AD的异质性机制。利用加州大学旧金山分校ADRC对早发性痴呆的专门研究，这项研究将包括150名轻度受损(CDR 0.5-1)的EO AD患者，其中50人具有主要的执行/记忆、语言和视觉空间临床表型，以及40名Lo-AD患者。需要进行阳性淀粉样蛋白(PIB)PET扫描才能纳入。患者将接受结构磁共振、功能连接(静息状态)磁共振成像(FcMRI)、FDG-PET和脑脊液分析。来自匹配的正常对照组(NC)和非AD痴呆患者的比较数据将从其他正在进行的研究中获得。该方案的中心假设是，所有AD变异体的神经退行性变都集中在组成默认模式网络(DMN)后部的颞顶区域，默认模式网络是AD中的一个核心、选择性脆弱的网络。目的1通过比较颞顶叶和海马区MRI/FDG指标在鉴别EO-AD与NC和非AD痴呆中的敏感性和特异性，并比较EO与LO-AD的成像生物标志物的表现，检验这一假说的诊断应用。目的2应用fcMRI验证后部DMN在EO综合征和LO-AD中受到影响的假说，而其他功能网络的相对参与驱动了每个AD变异体的临床表型。目的3研究健康成人的功能连接性如何与AD变异体中淀粉样蛋白沉积和神经退行性变的模式相关，以测试一个模型，在该模型中，A？沉积由皮质中枢的节点应力驱动，而神经退行性变起源于DMN内启动疾病跨神经元扩散并驱动临床表型的综合征特异性“震中”。这些研究将有助于对EO AD变异体的早期和准确诊断，并将进一步加深我们对AD的临床表型、结构和功能改变与分子病理学之间关系的理解。

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.