Deep and Frequent Phenotyping; combinatorial biomarkers for dementia experimental medicine

深入而频繁的表型分析；

• 批准号: MR/N029941/1
• 负责人: Simon Lovestone
• 金额: $ 1032.32万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN029941%2F1
• 关键词: Deep; Frequent; Phenotyping; combinatorial; biomarkers

After years of failure the first promising signs of progress in disease modification of Alzheimer's disease (AD), arguably the disorder with the greatest unmet need relative to prevalence and cost in the developed world, are emerging. Already though it is clear that there are lessons for drug development. First, that biomarkers are essential - it is only with their use that it became apparent that 20-30% of trial participants do not have the targeted pathology. Second, that efficacy is most likely in early phases of disease including prodromal stage. Third, and most important, that the proof of concept phase for disease modification is significantly deficient using currently available approaches. It is hard, if not impossible, to conduct short term, modest-size proof of concept in prodromal disease whilst outcome measures remain long term and clinical. The Deep and Frequent Phenotyping study is designed to rectify this by generating a biomarker set for proof of concept in prodromal AD. The objective is to build on previous studies, focussing largely on established biomarkers in annual assessment, with very deep phenotyping using established, developing and novel biomarker modalities applied frequently over a year. A pilot study demonstrated that such complex protocols can be effectively established across multiple sites and that trials participants are sufficiently committed to research for this devastating disease that they remain engaged despite taxing study demands. Specifically, we aim to implement PET imaging and CSF biochemistry for amyloid and tau, functional and structural MRI, electrophysiology for synaptic function including EEG and MEG, measures of gait and use of remote monitoring for ecologically valid assessment of a range of phenotypes, measures of retinal pathology and a collection of bio-samples unparalleled in potential utility for molecular biomarkers and to establish stem cells for in vitro studies. Some measures such as PET will be applied at baseline and follow up, others up to every 2 months and some, such as the peripheral devices, continuously. The study builds upon the Dementias Platform UK; we will recruit from constituent cohorts using the information workstream, will utilise the imaging workstream and will bank materials through the cells workstream. Furthermore, the programme will be nested within the IMI-European Prevention of AD combined registry, cohort and adaptive trial programme (www.ep-ad.org), the largest and the leading initiative within the rapidly growing Global Alzheimer's Platform Prevention of Alzheimer's Disease (GAP-PAD) initiative. These international public-private partnerships have committed over £100m to a linked proof of concept phase trials initiative; an initiative dependent on identifying biomarkers to speed the trials process. This proposal is designed to provide the data for such markers. Taking the lead from ADNI and its partner studies, we will make summary data very widely available to the scientific community and work to enable access to the immense volumes of underlying primary data. Within group we will use modelling and machine learning approaches to analyse these data for markers of change in prodromal AD, combining different modalities for markers that track or improve upon advanced measures of cognition and PET measures of pathology. The outcome will be definitive for biomarkers in this phase of disease; if such markers are achievable then this study will identify them. The deliverable will be both the data to the scientific community for wide further analysis as well as a combinatorial biomarker for use in phase II, proof of concept trials. Such a marker would speed decision making, reduce expense of clinical trials, increase the number of compounds tested at this phase. The absence of such a marker is one of the most grievous single obstacles to progress in the search for a disease modification or secondary prevention therapy for AD.

在多年的失败之后，阿尔茨海默病（AD）的疾病改良进展的第一个有希望的迹象正在出现，可以说阿尔茨海默病是发达国家相对于患病率和成本最大的未满足需求的疾病。但很明显，药物开发已经有了经验教训。首先，生物标志物是必不可少的-只有使用它们，才能明显看出20-30%的试验参与者没有目标病理学。第二，这种疗效最有可能在疾病的早期阶段，包括前驱期。第三，也是最重要的，使用目前可用的方法，疾病修改的概念验证阶段明显不足。即使不是不可能，也很难在前驱疾病中进行短期、中等规模的概念验证，而结局指标仍然是长期和临床的。深度和频繁表型研究旨在通过生成用于前驱AD概念验证的生物标志物集来纠正这一点。其目的是建立在以前的研究基础上，主要集中在年度评估中的既定生物标志物上，使用一年内频繁应用的既定，发展和新型生物标志物模式进行非常深入的表型分析。一项试点研究表明，这种复杂的方案可以在多个地点有效地建立，并且试验参与者充分致力于研究这种毁灭性的疾病，尽管研究要求繁重，但他们仍然参与其中。具体而言，我们的目标是实现PET成像和CSF生物化学淀粉样蛋白和tau，功能和结构MRI，电生理学突触功能，包括EEG和MEG，步态的措施和使用远程监测生态有效的评估一系列表型，视网膜病理学的措施和生物样品的收集无与伦比的潜在效用的分子生物标志物，并建立干细胞体外研究。一些措施（如PET）将在基线和随访时应用，其他措施最多每2个月应用一次，还有一些措施（如外围设备）将持续应用。该研究建立在英国痴呆症平台的基础上;我们将使用信息工作流从组成队列中招募人员，将利用成像工作流，并将通过细胞工作流储存材料。此外，该计划将嵌套在IMI-欧洲预防AD联合登记，队列和适应性试验计划（www.ep-ad.org）中，这是快速增长的全球阿尔茨海默病平台预防阿尔茨海默病（GAP-PAD）倡议中最大和领先的倡议。这些国际公私合作伙伴关系已承诺投入超过1亿英镑用于相关的概念验证阶段试验计划;该计划依赖于识别生物标志物以加快试验过程。本提案旨在为这些标志提供数据。在ADNI及其合作伙伴研究的领导下，我们将向科学界提供非常广泛的摘要数据，并努力使人们能够获得大量的基础原始数据。在组内，我们将使用建模和机器学习方法来分析这些数据，以获得前驱AD变化的标志物，并结合不同的模式来跟踪或改善高级认知测量和PET病理测量的标志物。对于疾病的这个阶段的生物标志物，结果将是明确的;如果这些标志物是可实现的，那么本研究将识别它们。可交付成果将是科学界用于广泛进一步分析的数据，以及用于第二阶段概念验证试验的组合生物标志物。这样的标记将加快决策，减少临床试验的费用，增加在这个阶段测试的化合物的数量。缺乏这样的标记物是在寻找AD的疾病修饰或二级预防疗法中取得进展的最严重的单一障碍之一。

项目成果

Increased choroidal thickness in adults with Down syndrome.

• DOI: 10.1002/dad2.12170
• 发表时间: 2021
• 期刊: Alzheimer's & dementia (Amsterdam, Netherlands)
• 作者: Csincsik L;Nelson R;Walpert MJ;Peto T;Holland A;Lengyel I
• 通讯作者: Lengyel I

Tau pathology in early Alzheimer's disease is linked to selective disruptions in neurophysiological network dynamics

• DOI: 10.1016/j.neurobiolaging.2020.03.009
• 发表时间: 2020-08-01
• 期刊: NEUROBIOLOGY OF AGING
• 影响因子: 4.2
• 作者: Kocagoncu, Ece;Quinn, Andrew;Rowe, James B.
• 通讯作者: Rowe, James B.

Deep and Frequent Phenotyping study protocol: an observational study in prodromal Alzheimer's disease

• DOI: 10.1136/bmjopen-2018-024498
• 发表时间: 2019-06-01
• 期刊: BMJ OPEN
• 影响因子: 2.9
• 作者: Koychev, Ivan;Lawson, Jennifer;Lovestone, Simon
• 通讯作者: Lovestone, Simon

Retinal phenotyping of variants of Alzheimer's disease using ultra-widefield retinal images.

• DOI: 10.1002/dad2.12232
• 发表时间: 2021
• 期刊: Alzheimer's & dementia (Amsterdam, Netherlands)
• 作者: Csincsik L;Quinn N;Yong KXX;Crutch SJ;Peto T;Lengyel I
• 通讯作者: Lengyel I

Deep and Frequent Phenotyping study protocol: an observational study in prodromal Alzheimer's disease.

深入而频繁的表型研究方案：阿尔茨海默病前驱期的观察性研究。

• DOI: 10.17863/cam.36486
• 发表时间: 2019
• 作者: Koychev I