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

描述(申请人提供)：尸检研究表明，患有唐氏综合症(DS)的中年成年人表现出阿尔茨海默病(AD)的神经病理特征：淀粉样老年斑(SPS)和tau神经原纤维缠结(NFTs)。临床、神经成像和遗传风险研究表明痴呆DS患者和AD患者之间有相似之处。由于与普通人群相比，DS患者患痴呆症的风险更高，发病年龄更早，因此DS已被建议作为AD研究的模型，在美国估计有450万人受到影响。我们对患有DS的成年人进行的试点正电子发射断层扫描(PET)研究显示，有痴呆症证据的受试者大脑葡萄糖代谢率较低(用氟脱氧葡萄糖或[18F]FDG测量)，而且年龄较大与SPS和NFTs的新指标[18F]FDDNP的信号较高之间存在显著相关性。其他PET研究表明，[18F]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表明死后SPS和NFTs浓度较高。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名年龄匹配的对照组进行临床、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，以协助图像分析，并对载脂蛋白E(APOE)进行分型以确定AD的遗传风险，并在两年后重复评估和扫描，以检验下列假设：(1)患有DS的痴呆患者的[18F]FDDNP信号将比非痴呆患者更大，后者的信号将比对照组更高；(2)[18F]FDG测得的顶叶和颞叶代谢率在对照组和非痴呆DS患者中将高于患有DS的痴呆患者。(3)在每个诊断组中，年龄将与更大的[18F]FDDNP信号相关。(4)在两年的随访中，与对照组相比，DS患者(有痴呆和无痴呆)的[18F]FDDNP信号将增加。在患有DS的受试者组中，我们将根据基线有无痴呆来探索两年后[18F]FDDNP信号变化的差异。(5)随访两年后，与其他组相比，DS患者的[18F]FDG信号将降低(包括发展为痴呆或痴呆恶化)。除了这些假设，我们还将探索APOE-4对DS患者[18F]FDDNP和[18F]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患者将死亡，我们将探索这些病例的神经病理特征与活体扫描和神经心理测量之间的相关性。该项目将有助于更好地了解DS患者痴呆症的临床和神经影像相关性，并为未来旨在改进DS和AD的早期发现、诊断和治疗的研究奠定基础，从而提高数百万患有这些疾病的患者及其家人的生活质量。公共卫生相关性：该项目将有助于更好地了解唐氏综合症患者痴呆症的临床和神经影像相关性，并为未来旨在改善唐氏综合症和阿尔茨海默病的早期发现、诊断和治疗的研究奠定基础。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.