Defining diseases and tracking progression in frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a common form of dementia, particularly in younger people, and places a heavy burden on sufferers, families, carers and society at large. FTLD is not usually caused by Alzheimer?s disease, and it may be caused by a number of other diseases. Treatments that could slow or reverse these diseases are urgently needed, but before such treatments can become a reality, we need much more accurate and reliable ways of diagnosing the different types of FTLD and in particular, methods of measuring how these diseases first develop and progress in the brain. Brain scan technology (in particular, MRI) and psychological tests, alone and in combination, have promise as measurement tools but have not been adequately tested in people with FTLD. We plan a large study of patients with FTLD and people from FTLD families that are at risk of developing the disease, to test possible methods of measuring disease as it begins and spreads in the brain, and to decide with measurement methods could best be used in future treatment trials. We will use repeated MRI brain scans and psychology testing to measure disease changes and we will combine this information with other information, including the results of genetic tests, to build up a picture of the variation within the FTLD population. We will also compare these with the same measurements in patients with Alzheimer?s disease. This will tell us how to diagnose FTLD early and accurately, how we should measure the ways that the disease affects the brain over time, and which kinds of measurement would best allow us to assess a treatment in future. In carrying out this work we will draw upon a large number of volunteer patients with FTLD and members of FTLD families who are already involved in research at our Centre, and we will capitalise on our Centre?s long experience in developing new methods of assessing the onset and effects of dementia diseases. We hope that this work will help us find methods of measuring disease effects that will help with diagnosis and treatment trials in the large population of FTLD sufferers, and help guide future health care delivery in younger people with dementia.

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of neurodegenerative diseases that collectively constitute a common cause of young onset dementia and a substantial source of human, clinical and socio-economic hardship. If disease-modifying therapy for FTLD is to be realised, robust biomarkers of disease onset and progression and accurate diagnosis and stratification of FTLD subtypes informed by emerging information about disease mechanisms will be required. Here we propose a comprehensive 5 year longitudinal programme of research designed to identify and validate biomarkers of disease onset and progression in FTLD and its subtypes, and to assess their translational potential to other health care delivery and clinical trials settings. The specific aims of the programme are to assess biomarkers of earliest disease manifestation through the study of at-risk individuals; to assess biomarkers of disease progression; to classify diseases and disease subtypes; and to evaluate novel techniques and disease mechanisms. To address these aims we will recruit from an established large longitudinal cohort of FTLD patients, and in particular, presymptomatic and ?at risk? individuals from a number of genetic FTLD pedigrees, allowing detection and tracking of earliest disease manifestations. We will draw on a successful track record of developing and applying innovative and translatable image analysis techniques and novel neuropsychological instruments to define and track neurodegenerative diseases. The programme will capitalise on established collaborations with partner laboratories in image computing, tractography, functional brain imaging, neurogenetics and neuropathology. Subjects entering the study will be assessed prospectively and longitudinally with detailed clinical evaluation, neuropsychology, structural and functional MRI, and post mortem data on patients with FTLD whom we have followed historically will be correlated retrospectively with candidate biomarkers to assess their predictive and neurobiological validity. A suite of techniques will be used to analyse behavioural and imaging data, including linear and nonlinear registration, tractography, cortical thickness and unbiased voxel-based pattern recognition and morphometric techniques, with particular emphasis on techniques with diagnostic and translational potential. Mixed linear models and multivariate statistical techniques will be applied to the identification and evaluation of candidate biomarkers. The programme will yield robust, generalisable and novel biomarkers of disease onset, evolution and classification in FTLD, and offers significant follow-on opportunities for guiding clinical trial design and shaping health care delivery in young onset dementia.