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

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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.