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

唐氏综合症和痴呆症的葡萄糖代谢、淀粉样蛋白和 Tau 蛋白脑成像

• 批准号: 7777863
• 负责人: GARY William SMALL
• 金额: $ 62.33万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7777863
• 关键词: 16 year old; Adult; Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Apolipoprotein E; Autopsy; Brain; Brain imaging; Brain region; Cerebrum; Chromosomes, Human, Pair 21; Clinical; Control Groups; Data; Dementia; Diagnosis; Diagnostic; Down Syndrome; Early Diagnosis; Exhibits; Family; Future; General Population; Genes; Genetic Risk; Glucose; Hereditary Disease; Human; Image; Image Analysis; Investigation; Lateral; Lead; Life; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Medial; Mental Retardation; Metabolic; Neurodegenerative Disorders; Neurofibrillary Tangles; Parietal; Patients; Pattern; Positron-Emission Tomography; Prevalence; Procedures; Quality of life; Research; Research Design; Research Personnel; Risk; Scanning; Senile Plaques; Signal Transduction; Staging; Study models; Technology; Testing; United States; age group; aging brain; apolipoprotein E-4; dicyanmethane; experience; follow-up; improved; in vivo; middle age; mild neurocognitive impairment; neurochemistry; neuroimaging; neuropsychological; normal aging; novel; pre-clinical; programs; public health relevance; tau Proteins; tau aggregation

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.

描述（由申请人提供）：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氏病（AD）的神经病理学标志：淀粉样蛋白老年斑块（SPS）和Tau Neurofibrillary Tankles（NFTS）。临床，神经影像学和遗传风险研究表明，痴呆的DS患者和AD患者之间的相似性。由于与普通人群相比，DS的痴呆症患者的风险增加和较早的痴呆症年龄增加，因此已提出DS作为AD研究的模型，该模型遭受了美国估计有450万人在美国，我们的飞行正电子发射层析成像（PET）对成年人的飞行型发射层术（PET）研究ds的DS较低的脑葡萄糖代谢率（对富素化代谢的证据表明）或[18F]或[18F]或[18F] [18f] [18f]以及新的年龄和较高信号之间的显着相关性，用于新的SP和NFT量度：[18F] FDDNP。其他宠物研究表明，[18F] FDDNP可以将AD与轻度认知障碍和正常衰老区分开，并且显示高信号的大脑区域表现出较高的SPS和NFT的死后浓度。为了阐明这种观察，我们提出了对72岁及45岁以上的DS（36例痴呆症和36个非痴呆症）和36岁年龄匹配的对照对照进行临床，神经心理学和PET成像（[18] FDG和[18] FDDNP）的研究。我们还将执行磁共振成像扫描，以帮助进行图像分析，载脂蛋白E（APOE）进行AD遗传风险确定，并在2年后进行重复评估和扫描以测试以下假设：（1）[1）[18F] FDDNP信号在非ds ds中的摄入率更高，而在非ds ds中比对控制的ds ds; （2）[18F] FDG测量的顶叶和时间代谢率与患有DS的对照组和非痴呆的人相比，与患有DS的痴呆症患者相比。 （3）在每个诊断组中，年龄将与更大的[18F] FDDNP信号相关。 （4）在2年的随访中，与对照组相比，[18F] FDDNP信号将增加DS的受试者（有或没有痴呆症）。在具有DS的主题组中，我们将根据基线时存在或不存在2年后[18F] FDDNP信号变化的差异。 （5）经过两年的随访后，[18F] FDG信号的DS降低，DS显示出下降的证据（包括发展痴呆症或痴呆症恶化），而不是其他组。除这些假设外，我们还将探讨APOE-4对DS患者中[18F] FDDNP和[18F] FDG信号的影响。在5年的研究期内，我们预计将大约6个较旧的DS受试者死亡，我们将探讨这些病例的神经病理特征与体内扫描和神经心理学指标之间的相关性。该项目将更好地了解DS患者痴呆症的临床和神经影像学相关性，并为未来的研究提供旨在改善DS和AD治疗的未来研究的基础，从而改善了数百万患者及其家人的生活质量。 公共卫生相关性：该项目将更好地了解唐氏综合症患者痴呆症的临床和神经影像学相关性，并为未来的研究提供旨在改善早期发现，诊断和治疗唐氏综合症和阿尔茨海默氏病的基础。鉴于许多患有这些神经退行性疾病的人，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。