Defining and diagnosing neurodegenerative Movement Disorders through integrated analysis of Genetics And neuroPathology (MD-GAP)

通过遗传学和神经病理学的综合分析 (MD-GAP) 定义和诊断神经退行性运动障碍

• 批准号: MR/T018569/1
• 负责人: Huw Morris
• 金额: $ 124.28万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT018569%2F1
• 关键词: Defining; diagnosing; neurodegenerative; Movement; Disorders

We are entering an era in which therapies for degenerative diseases such as Parkinson's and Alzheimer's will be directed towards the underlying protein pathology. Most progressive later onset neurological diseases involve the deposition of abnormal insoluble proteins as aggregates, for example Lewy bodies in Parkinson's and amyloid plaques in Alzheimer's. There are now an increasing number of experimental therapies which are directed towards protein pathology, for example involving antibodies and gene based therapies. Genetics has provided tremendous insights into neurological disease, largely based on studies in clinically diagnosed patients. Neuropathology is the "gold standard" for the diagnosis of neurological diseases, and the MRC and UK charities have invested in developing the MRC UK Brain Banks Network (BBN) to enable better understanding of these conditions. Here, we will integrate high throughput genetic analysis with neuropathology to improve the diagnosis and understanding of neurological disease. Early diagnosis: is a major barrier to the delivery of effective treatment. At the earliest disease stages typical disease features may not be apparent. For example, slowness of movement (Parkinsonism) can be due to multiple different diseases including Parkinson's disease, and a definite diagnosis may not become apparent until the clinical course and response to treatment are established. We will study genetic variant data from pathologically diagnosed cases to improve early diagnosis. We believe that diagnostic algorithms based on analyzing many genetic markers (polygenic risk) will improve the clinical diagnosis. Improved case-control analysis: will be achieved by comparing individuals with pathologically proven diseases such as Parkinson's with controls unaffected by neurological disease. This will remove the effect of clinical misdiagnosis in the analysis of neurological disease. Disease heterogeneity: is an important feature of conditions such as Parkinson's. Some patients develop dementia and rapidly progressive disease whereas others have a more benign, milder disease course. We believe that this heterogeneity is driven by differential neuropathology. For example, dementia in Parkinson's is associated with Alzheimer's co-pathology (amyloid plaques and neurofibrillary tangles). We will directly study the genetic drivers of co-pathology and integrate this with analyses of clinical heterogeneity to decode the different patterns of neurological disease, which may ultimately respond to different therapies. Improving resources: The BBN is used by researchers into neurological disease from around the world. There is a growing need to understand the implications of genetic risk factors - and one of the most straightforward ways to do this is to look at brain tissue from individuals with and without the genetic risk factor. This genetic data will be made available to bona fide researchers which will speed up this process and allow researchers to select tissue and samples of interest, maximising the usefulness of these patient tissue archives.

我们正在进入一个时代，在这个时代中，帕金森氏症和阿尔茨海默氏症等退行性疾病的治疗将直接针对潜在的蛋白质病理学。大多数进行性迟发性神经系统疾病涉及异常不溶性蛋白质作为聚集体的沉积，例如帕金森氏症中的路易体和阿尔茨海默氏症中的淀粉样斑块。现在有越来越多的针对蛋白质病理学的实验疗法，例如涉及抗体和基于基因的疗法。遗传学为神经系统疾病提供了巨大的见解，主要是基于对临床诊断患者的研究。神经病理学是诊断神经系统疾病的“黄金标准”，MRC和英国慈善机构投资开发了MRC英国脑库网络（BBN），以更好地了解这些疾病。在这里，我们将整合高通量遗传分析与神经病理学，以提高神经系统疾病的诊断和理解。早期诊断：是提供有效治疗的主要障碍。在最早的疾病阶段，典型的疾病特征可能不明显。例如，运动缓慢（帕金森综合征）可能是由于多种不同的疾病，包括帕金森病，明确的诊断可能不会变得明显，直到临床过程和对治疗的反应建立。我们将研究病理诊断病例的遗传变异数据，以提高早期诊断。我们相信，基于分析许多遗传标记（多基因风险）的诊断算法将改善临床诊断。改进病例对照分析：将通过比较患有病理学证实的疾病（如帕金森病）的个体与未受神经系统疾病影响的对照组来实现。这将消除神经系统疾病分析中临床误诊的影响。疾病异质性：是帕金森病等疾病的重要特征。一些患者发展为痴呆和快速进展的疾病，而另一些患者则具有更良性，更温和的疾病过程。我们认为这种异质性是由不同的神经病理学驱动的。例如，帕金森氏症中的痴呆与阿尔茨海默氏症的共同病理学（淀粉样斑块和神经元缠结）有关。我们将直接研究共同病理学的遗传驱动因素，并将其与临床异质性分析相结合，以解码神经系统疾病的不同模式，这些模式最终可能对不同的疗法产生反应。改善资源：BBN被世界各地的研究人员用于神经系统疾病。人们越来越需要了解遗传风险因素的影响，而最直接的方法之一就是观察有和没有遗传风险因素的个体的脑组织。这些遗传数据将提供给真正的研究人员，这将加快这一过程，并允许研究人员选择感兴趣的组织和样本，最大限度地发挥这些患者组织档案的作用。

项目成果

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

• DOI: 10.1016/j.neuron.2020.11.005
• 发表时间: 2021-02-03
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Dewan R;Chia R;Ding J;Hickman RA;Stein TD;Abramzon Y;Ahmed S;Sabir MS;Portley MK;Tucci A;Ibáñez K;Shankaracharya FNU;Keagle P;Rossi G;Caroppo P;Tagliavini F;Waldo ML;Johansson PM;Nilsson CF;American Genome Center (TAGC);FALS Sequencing Consortium;Genomics England Research Consortium;International ALS/FTD Genomics Consortium (iAFGC);International FTD Genetics Consortium (IFGC);International LBD Genomics Consortium (iLBDGC);NYGC ALS Consortium;PROSPECT Consortium;Rowe JB;Benussi L;Binetti G;Ghidoni R;Jabbari E;Viollet C;Glass JD;Singleton AB;Silani V;Ross OA;Ryten M;Torkamani A;Tanaka T;Ferrucci L;Resnick SM;Pickering-Brown S;Brady CB;Kowal N;Hardy JA;Van Deerlin V;Vonsattel JP;Harms MB;Morris HR;Ferrari R;Landers JE;Chiò A;Gibbs JR;Dalgard CL;Scholz SW;Traynor BJ
• 通讯作者: Traynor BJ

MD-GAP: Defining and diagnosing neurodegenerative movement disorders through integrated analysis of genetics and neuropathology

MD-GAP：通过遗传学和神经病理学的综合分析来定义和诊断神经退行性运动障碍

• 发表时间: 2021
• 作者: Lesley Wu

Investigation of the genetic aetiology of Lewy body diseases with and without dementia.

伴有和不伴有痴呆的路易体疾病的遗传病因学调查。

• DOI: 10.1101/2023.10.17.23297157
• 发表时间: 2023
• 期刊: the preprint server for health sciences
• 作者: Wu L

A case of Lewy body disease and anaplastic astrocytoma presenting with atypical parkinsonism.

• DOI: 10.1111/neup.12848
• 发表时间: 2022-12
• 期刊: NEUROPATHOLOGY
• 影响因子: 2.3
• 作者: Leahy, Christopher B.;Robinson, Andrew C.;Jabbari, Edwin;Morris, Huw R.;Lally, Imogen;Djoukhadar, Ibrahim;Roncaroli, Federico;Kobylecki, Christopher
• 通讯作者: Kobylecki, Christopher

Neurodegenerative Disease Risk in Carriers of Autosomal Recessive Disease.

• DOI: 10.3389/fneur.2021.679927
• 发表时间: 2021
• 期刊: Frontiers in neurology
• 影响因子: 3.4
• 作者: Vieira SRL;Morris HR
• 通讯作者: Morris HR