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: 8033241
• 负责人: GARY William SMALL
• 金额: $ 63.64万
• 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/8033241
• 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; Health; 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; 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（申请人提供）：尸检研究表明，患有唐氏综合症（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神经原纤维缠结（NFT）。临床、神经影像学和遗传风险研究表明，痴呆 DS 患者和 AD 患者之间存在相似之处。由于与普通人群相比，DS 患者患痴呆症的风险更高且发病年龄更早，因此 DS 被提议作为 AD 研究的模型，据估计，美国有 450 万人患有 AD。我们的试点正电子发射断层扫描对成人 DS 的 (PET) 研究表明，有痴呆证据的受试者的脑葡萄糖代谢率（用氟脱氧葡萄糖或 [18F]FDG 测量）较低，并且与SP 和 NFT 的新测量方法：[18F]FDDNP，年龄较大且信号较高。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，并且显示高信号的大脑区域表明死后 SP 和 NFT 浓度很高。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 名年龄匹配的患者进行临床、神经心理学和 PET 成像（[18]FDG 和 [18]FDDNP）研究控制。我们还将进行磁共振成像扫描以协助图像分析、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测试以下假设：(1) [18F]FDDNP 信号将患有 DS 的痴呆受试者比非痴呆受试者的信号更强，后者的信号比对照组更高； (2) 与患有 DS 的痴呆患者相比，对照组和患有 DS 的非痴呆患者通过 [18F]FDG 测量的顶叶和颞叶代谢率更高。 (3) 在每个诊断组中，年龄将与更大的 [18F]FDDNP 信号相关。 (4) 在 2 年随访中，与对照组相比，DS 受试者（患有或不患有痴呆症）的 [18F]FDDNP 信号将会增加。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讨 2 年后 [18F]FDDNP 信号变化的差异。 (5) 经过两年的随访，那些患有 DS 的受试者中，[18F]FDG 信号将比其他组表现出下降迹象（包括发展为痴呆或痴呆恶化）减少。除了这些假设之外，我们还将探讨 APOE-4 对 DS 患者中 [18F]FDDNP 和 [18F]FDG 信号的影响。在为期 5 年的研究期间，我们预计大约 6 名老年 DS 受试者将会死亡，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。该项目将有助于更好地了解 DS 患者痴呆症的临床和神经影像学相关性，并为未来的研究奠定基础，旨在改善 DS 和 AD 的早期检测、诊断和治疗，从而提高 DS 患者的生活质量。数以百万计的患者及其家人受到这些疾病的困扰。 公共健康相关性：该项目将有助于更好地了解唐氏综合症患者痴呆的临床和神经影像学相关性，并为旨在改善唐氏综合症和阿尔茨海默病的早期检测、诊断和治疗的未来研究奠定基础。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。