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

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.

Frontotemporal dementia (FTD) is a unique neurodegenerative syndrome characterised by progressive impairments of behaviour, social or language functioning. Although most patients have a sporadic form of FTD, a third of patients have an underlying mutation in one of three main genes: MAPT, C9ORF72 or GRN. We do not fully understand the steps in FTD disease pathogenesis, and there are no effective treatments. Previous research suggests a role for neuroinflammatory mechanisms in FTD, with small studies showing altered levels of inflammatory markers in brain tissue and cerebrospinal fluid (CSF) samples from patients with FTD. This project aims to identify CSF biomarkers of neuroinflammation in patients with FTD and to investigate their relationship with measures of disease severity and progression. Post-mortem brain tissue from patients with both genetic and sporadic FTD as well as healthy controls will be used initially to identify abnormalities in neuroinflammatory pathways. Assays of candidate biomarkers identified in these analyses will then be developed and tested in CSF samples from groups of patients with genetic subtypes of FTD, their presymptomatic relatives, sporadic FTD cases and healthy controls. These results will be used to examine whether such markers correlate with measures of disease severity and/or progression established from clinical and neuroimaging analyses. CSF biomarkers identified in this project, once validated, might be used to develop novel therapeutic targets, guide clinical trials of future or existing anti-inflammatory therapies, and predict more accurately progression of disease and response to treatment in sporadic or genetic forms of FTD.

1. Key stakeholders - FTD patients and families
FTD often strikes younger people and exacts a devastating human and socioeconomic cost for these individuals, their extended families, and their support networks. In relatives of those with the familial form there is great anxiety about the risk and age at onset of developing disease. Specific timelines for benefits are summarised as follows:

Within the lifetime of the project:
*New information about the role of neuroinflammation in disease pathogenesis in patients with FTD, leading to novel molecular therapeutic targets, or to support trials of existing immunomodulatory treatments.
*Improved diagnostic and monitoring strategies, using measurements from routinely obtainable and repeatable fluid samples. This may reduce late or incorrect diagnosis and allow prediction of disease progression.

Follow-on benefits (next five to ten years):
*New biomarkers of disease stage: to allow initiation of effective pharmacological treatments at the correct stage of disease, or before clinical or imaging evidence of disease, to ensure maximum benefit prior to irreversible neurodegeneration.
*New biomarkers of pharmacological efficacy: to assist in the rational design of clinical trials and monitoring of response to disease-modifying therapies. Without such biomarker information it will be difficult to mount large-scale clinical trials, particularly in disease prevention trials in presymptomatic patients.

2. Impact on other neurodegenerative diseases
The identification of new CSF biomarkers in this study has potentially far-reaching implications for other, more common dementias, particularly those where dysregulation of neuroinflammation has been implicated in disease pathogenesis, such as Alzheimer's disease. New knowledge and techniques arising from the proposed project will benefit patients, clinicians and researchers in these areas, and in other neuroinflammatory diseases such as multiple sclerosis.

3. Impact on collaborations with other academic partners and with industry
Collaboration with other academic partners and with industry is important in order to facilitate development of novel pharmacological approaches and large multicentre therapeutic trials. The DRC continues to take a lead role in such collaborations. The findings of the proposed research will guide progress in both of these areas, thereby increasing the potential benefits of such collaborations. Pharmaceutical companies who have developed existing immunomodulatory treatments (such as anti-tumour necrosis factor therapies) may also benefit should this study indicate that the molecular targets of these treatments are also implicated in FTD.

4. Improved public awareness
Dementia presents a huge challenge to society, both now and increasingly in the future. The Department of Health National Dementia Strategy highlighted as its first objective "Improving public and professional awareness and understanding of dementia". The research supported by this Fellowship will be actively promulgated in public engagement activities as detailed in 'Communications Plan' and 'Pathways to Impact'. An improved public awareness of FTD and other dementias is essential, to improve awareness of the importance of early diagnosis and treatment, and reduce social exclusion and discrimination.

5. Impact on government health policy
Dementia currently costs the UK over £23 billion per year and has become an increasing priority to the NHS and Department of Health. The DRC actively engages with national and international policy makers and Professor Rossor, a senior member of the DRC, is the National Institute for Health Research (NIHR) National Director of Dementia Research. By developing methods for earlier detection of FTD and better monitoring potential responses to novel treatments, this project aims to help improve the options available for those who develop management guidelines for dementia, both in the NHS and beyond.