Glucose Metabolic, Amyloid, and Tau Brain Imaging in Down's Syndrome and Dementia

描述（由申请人提供）：尸检研究表明，患有唐氏综合征（DS）的中年人表现出阿尔茨海默病（AD）的神经病理学特征：淀粉样老年斑（SP）和tau神经元缠结（NFT）。临床、神经影像学和遗传风险研究表明，痴呆DS患者和AD患者之间存在相似性。由于与一般人群相比，DS患者痴呆的风险增加且发病年龄较早，因此DS已被提议作为AD研究的模型，在美国，估计有450万人患有这种疾病。我们对患有DS的成年人进行的试验性正电子发射断层扫描（PET）研究显示，大脑葡萄糖代谢率较低（用氟脱氧葡萄糖或[18 F]FDG测量）在有痴呆证据的受试者中，以及年龄较大与SP和NFT的新测量：[18 F]FDDNP的较高信号之间的显著相关性。其他PET研究表明，[18 F]FDDNP可以区分AD与轻度认知障碍和正常衰老，显示高信号的大脑区域显示出高的SP和NFT死后浓度。为了阐明这些观察结果，我们建议对72名45岁及以上的DS患者（36名痴呆患者和36名非痴呆患者）和36名年龄匹配的对照者进行临床，神经心理学和PET成像（[18]FDG和[18]FDDNP）研究。我们还将进行磁共振成像扫描以辅助图像分析，载脂蛋白E（APOE）分型以确定AD遗传风险，并在2年后重复评估和扫描以检验以下假设：（1）患有DS的痴呆受试者的[18 F]FDDNP信号将大于非痴呆受试者，后者的信号将高于对照组;（2）对照组和非痴呆DS患者的[18 F]FDG测量的顶叶和颞叶代谢率高于痴呆DS患者。(3)在每个诊断组中，年龄将与更大的[18F]FDDNP信号相关。(4)在2年随访时，与对照组相比，DS受试者（伴痴呆和不伴痴呆）的[18 F]FDDNP信号将增加。在患有DS的受试者组中，我们将根据基线时是否存在痴呆来探索2年后[18 F]FDDNP信号变化的差异。(5)随访2年后，与其他组相比，DS受试者的[18 F]FDG信号将下降，显示出下降的证据（包括发展痴呆或痴呆恶化）。除了这些假设之外，我们还将探讨APOE-4对DS患者[18 F]FDDNP和[18 F]FDG信号的影响。在5年的研究期间，我们预计大约6名老年DS受试者将死亡，我们将探讨这些病例的神经病理学特征与体内扫描和神经心理学测量之间的相关性。该项目将导致更好地了解DS患者痴呆的临床和神经影像学相关性，并为未来旨在改善DS和AD的早期检测，诊断和治疗的研究提供基础，从而改善数百万受这些疾病困扰的患者及其家庭的生活质量。 公共卫生相关性：该项目将导致更好地了解唐氏综合征患者痴呆的临床和神经影像学相关性，并为未来旨在改善唐氏综合征和阿尔茨海默病的早期检测，诊断和治疗的研究提供基础。鉴于许多人患有这些神经退行性疾病，这项研究的潜在影响将是相当大的，可能会改善数百万患者及其家人的生活质量。

DESCRIPTION (provided by applicant): Autopsy studies have shown that middle-aged adults with Down's syndrome (DS) exhibit the neuropathological hallmarks of Alzheimer's disease (AD): amyloid senile plaques (SPs) and tau neurofibrillary tangles (NFTs). Clinical, neuroimaging, and genetic risk studies demonstrate similarities between demented DS patients and AD patients. Because of the increased risk and earlier age at onset for dementia in people with DS compared with the general population, DS has been proposed as a model for the study of AD, which afflicts an estimated 4.5 million people in the U.S. Our pilot positron emission tomography (PET) studies of adults with DS show lower brain glucose metabolic rates (measured with flurodeoxyglucose or [18F]FDG) in subjects with evidence of dementia, as well as a significant correlation between older age and higher signals for a novel measure of SPs and NFTs: [18F]FDDNP. Other PET studies show that [18F]FDDNP can distinguish AD from mild cognitive impairment and normal aging and that brain regions showing high signals demonstrate high postmortem concentrations of SPs and NFTs. To elucidate such observations, we propose performing clinical, neuropsychological, and PET imaging ([18]FDG and [18]FDDNP) studies on 72 people age 45 and older with DS (36 demented and 36 non-demented) and 36 age-matched controls. We will also perform magnetic resonance imaging scans to assist with image analysis, apolipoprotein E (APOE) typing for AD genetic risk determinations, and repeat assessments and scanning after 2 years to test the following hypotheses: (1) [18F]FDDNP signals will be greater in demented subjects with DS than in non-demented ones, who will have higher signals than controls; (2) Parietal and temporal metabolic rates measured by [18F]FDG will be higher in controls and non-demented people with DS compared with demented people with DS. (3) Within each diagnostic group, age will correlate with greater [18F]FDDNP signals. (4) At 2-year follow-up, [18F]FDDNP signals will increase in subjects with DS (both with and without dementia) compared to controls. Within the subject group with DS, we will explore differences in [18F]FDDNP signal change after 2 years according to the presence or absence of dementia at baseline. (5) After two years of follow-up, [18F]FDG signals will decrease in those subjects with DS showing evidence of decline (including developing dementia or worsening dementia) than in other groups. In addition to these hypotheses, we will explore the influence of APOE-4 on [18F]FDDNP and [18F]FDG signals in people with DS. Over the 5-year study period, we anticipate that approximately 6 older DS subjects will die, and we will explore correlations between neuropathological features of these cases and in vivo scanning and neuropsychological measures. This project will lead to a better understanding of the clinical and neuroimaging correlates of dementia in people with DS and provide the groundwork for future studies designed to improve early detection, diagnosis, and treatment of DS and AD, and thus improve the quality of life for millions of patients and their families afflicted by these conditions. PUBLIC HEALTH RELEVANCE: This project will lead to a better understanding of the clinical and neuroimaging correlates of dementia in people with Down's syndrome and provide the groundwork for future studies designed to improve early detection, diagnosis, and treatment of Down's syndrome and Alzheimer's disease. Given the many people suffering from these neurodegenerative diseases, the potential impact of this study will be considerable, possibly improving the quality of life for millions of patients and their families.