Identifying the role of neuroinflammation in frontotemporal dementia - a pathological and cerebrospinal fluid biomarker study

确定神经炎症在额颞叶痴呆中的作用——病理学和脑脊液生物标志物研究

• 批准号: MR/M018288/1
• 负责人: Ione Woollacott
• 金额: $ 28.15万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM018288%2F1
• 关键词: Identifying; role; neuroinflammation; frontotemporal; dementia

Development of effective treatments for dementia depends on improved understanding of how brain damage develops and causes symptoms. This project will focus on one important but poorly understood category of dementia, frontotemporal dementia (FTD), which leads to progressive behavioural decline with an inability to conduct oneself appropriately in social situations, or difficulties with producing or understanding words or speech. It is associated with shrinkage of the frontal and temporal lobes of the brain. The rising incidence of dementia as people live longer is well known, as is the progressive impact on the affected person's ability to function as a normal individual, both within society and within their family. There are currently no treatments for this devastating disease. Although the majority of patients with FTD have no known cause (termed sporadic FTD), around a third of people with FTD have a mutation in a gene which is thought to cause the disease. Relatives of these patients are at risk of inheriting this abnormal gene and developing the genetic form of FTD. Carriers of such mutations are often said to be in a 'presymptomatic' stage of genetic FTD. There is increasing evidence that there is abnormal inflammation in the brains of people with dementias such as Alzheimer's disease or FTD, and particularly in genetic forms of FTD. This suggests that inflammation may contribute to the disease process in FTD. If this is indeed the case, since there is a range of current treatments for inflammatory disorders, then existing anti-inflammatory treatments could be helpful for patients with FTD. This study therefore aims to increase our understanding of the role that neuroinflammation plays in FTD. There are four main objectives to this study. First, it will aim to identify new markers of inflammation by analysing brain tissue from FTD patients who have died and donated their brains for research. Second, information from this first study will be used to develop new markers of inflammation in samples of cerebrospinal fluid (CSF). Third, these markers will be tested in CSF samples from living patients with both sporadic and genetic FTD as well as individuals who are in the presymptomatic stage of genetic FTD and also a group of healthy control participants. Lastly, the study will examine whether there is a relationship between these CSF markers of inflammation and measures of a) the severity of the disease in FTD, and b) how the disease progresses over time. These measures will be established from clinical, neuropsychological and brain imaging assessments performed in the same group of participants. Detailed study and identification of such markers will not only be important in understanding the role that neuroinflammation plays in the disease process in FTD, but may also be helpful in guiding development of new treatments for FTD and lead to markers that can be used in clinical trials for monitoring disease progression and response to treatment.

开发有效的痴呆症治疗方法取决于对脑损伤如何发展和引起症状的更好理解。该项目将重点关注一个重要但知之甚少的痴呆症类别，额颞叶痴呆症（FTD），它导致行为进行性衰退，无法在社交场合适当地表现自己，或难以产生或理解单词或言语。它与大脑额叶和颞叶的萎缩有关。众所周知，随着人们寿命的延长，痴呆症的发病率不断上升，这对受影响的人在社会和家庭中作为正常人的能力产生了渐进的影响。目前还没有治疗这种毁灭性疾病的方法。虽然大多数FTD患者没有已知的病因（称为散发性FTD），但约三分之一的FTD患者的基因突变被认为是导致该疾病的原因。这些患者的亲属有遗传这种异常基因和发展FTD遗传形式的风险。这种突变的携带者通常被认为处于遗传性FTD的“症状前”阶段。有越来越多的证据表明，在患有痴呆症（如阿尔茨海默病或FTD）的人的大脑中存在异常炎症，特别是在遗传形式的FTD中。这表明炎症可能促进FTD的疾病进程。如果情况确实如此，由于目前有一系列炎症性疾病的治疗方法，那么现有的抗炎治疗可能对FTD患者有帮助。因此，本研究旨在增加我们对神经炎症在FTD中所起作用的理解。这项研究有四个主要目标。首先，它将通过分析已经死亡并捐赠大脑用于研究的FTD患者的脑组织来识别新的炎症标志物。第二，这项首次研究的信息将用于开发脑脊液（CSF）样本中的新炎症标志物。第三，将在来自散发性和遗传性FTD存活患者以及遗传性FTD症状前期个体和一组健康对照受试者的CSF样本中检测这些标志物。最后，研究将检查这些CSF炎症标志物与a）FTD中疾病严重程度和B）疾病如何随时间进展的测量值之间是否存在关系。这些指标将通过在同一组受试者中进行的临床、神经心理学和脑成像评估来确定。详细研究和鉴定这些标志物不仅对了解神经炎症在FTD疾病过程中的作用非常重要，而且可能有助于指导FTD新治疗的开发，并产生可用于临床试验监测疾病进展和治疗反应的标志物。

项目成果

[P2-347]: SQSTM1 MUTATIONS IN FRONTOTEMPORAL DEMENTIA ARE ASSOCIATED WITH ASYMMETRICAL FOCAL TEMPORAL LOBE ATROPHY

[P2-347]：额颞叶痴呆中的 SQSTM1 突变与不对称局灶性颞叶萎缩有关

• DOI: 10.1016/j.jalz.2017.06.1001
• 发表时间: 2017
• 期刊: Alzheimer's & Dementia
• 作者: Boretska S

[11C]PBR28 inflammatory PET imaging in frontotemporal dementia

[11C]额颞叶痴呆中的 PBR28 炎症 PET 成像

• 发表时间: 2019
• 期刊: JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
• 影响因子: 6.3
• 作者: Clarke M. T.

[P1-504]: TACTILE PROCESSING IN DEMENTIA

[P1-504]：痴呆症中的触觉处理

• DOI: 10.1016/j.jalz.2017.06.520
• 发表时间: 2017
• 期刊: Alzheimer's & Dementia
• 作者: Bond R

Plasma tau is increased in frontotemporal dementia.

• DOI: 10.1136/jnnp-2017-317260
• 发表时间: 2018-08
• 期刊: Journal of neurology, neurosurgery, and psychiatry
• 作者: Foiani MS;Woollacott IO;Heller C;Bocchetta M;Heslegrave A;Dick KM;Russell LL;Marshall CR;Mead S;Schott JM;Fox NC;Warren JD;Zetterberg H;Rohrer JD
• 通讯作者: Rohrer JD

[P2-479]: SELF-SCHEMA ALTERATIONS IN DEMENTIA

[P2-479]：痴呆症中的自我图式改变

• DOI: 10.1016/j.jalz.2017.06.1136
• 发表时间: 2017
• 期刊: Alzheimer's & Dementia
• 作者: Bond R