In 2011, the discovery that a hexanucleotide expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), revealed a common mechanism for these two fatal diseases that have no cure. Since then, intensive research on C9ORF72 has culminated in the identification of its possible pathophysiological mechanisms and excitingly, new drug treatments. Promising drugs that target the effects of the repeat expansion reduce pathological changes in C9ORF72 mouse models and patient-derived cell models. Although these drugs are now ready for human clinical trials, the absence of established biomarkers for detecting disease and monitoring treatment is a major obstacle to the success of these trials. Thus, this proposal aims to advance the diagnosis and care of C9ORF72 expansion carriers by analyzing the trajectories of promising biomarkers throughout the natural history of the C9ORF72 lifespan. We will study 120 C9ORF72 expansion carriers (60 presymptomatic, 60 symptomatic) and 60 gene negative non- carrier family members for 3 longitudinal time points. All subject data will come from two NIH-funded parent projects for frontotemporal lobar degeneration: 1) Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS, 1U01AG045390) and 2) Advancing the Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL, U54NS092089). LEFFTDS and ARTFL employ fully harmonized data protocols to collect comprehensive longitudinal clinical, imaging and biospecimen data across 16 centers. We will model C9ORF72 disease trajectories by analyzing multimodal neuroimaging measures and fluid biomarkers to identify the earliest disease manifestations in C9ORF72 and how they track the natural history of disease.
Aim 1 will identify longitudinal changes in brain structure and neural network dysfunction in C9ORF72 carriers.
Aim 2 will model trajectories of candidate fluid biomarkers.
Aim 3 will determine associations between fluid biomarkers and brain structure and function. This study will be innovative as a comprehensive, longitudinal analysis of promising biomarkers to capture C9ORF72 disease trajectories. Upon completion of this study, we expect to lay the foundation for an integrated framework of biomarkers to monitor treatment response both at the biochemical level and at the brain-systems level.
The C9ORF72 hexanucleotide repeat expansion is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Promising drug treatments for C9ORF72 are entering human clinical trials, but there are no established biomarkers for detecting disease and monitoring treatment response in humans. This proposal will advance the diagnosis and care of C9ORF72 expansion carriers by studying promising biomarkers that may define disease onset, monitor disease progression, and evaluate treatment response. Beyond C9ORF72, this research has wider implications for understanding FTD and ALS and for the development of biomarkers for early neurodegenerative disease.