PROJECT SUMMARY—Frontotemporal Dementia (FTD): Genes, Images, and Emotions Frontotemporal dementia (FTD) research is entering a new era of therapeutic discovery, spurred in part by contributions from this program project grant (PPG), entitled “Frontotemporal Dementia: Genes, Images, and Emotions,” which has a 20-year history of productivity and collaboration. In renewal, this PPG has been designed to close important clinical-translational knowledge gaps that could, if unaddressed, impede progress toward new therapies. The PPG will include four projects and seven cores. Project 1 will dissect the cognitive and emotional processes disrupted in FTD using novel laboratory and neuroimaging approaches and will translate this knowledge into automated, scalable tools for pathology prediction and disease-monitoring. Project 2 will link transcriptomic and proteomic discovery platforms to TDP-43 loss-of-function biology, seeking to develop new plasma-based molecular diagnostic and disease monitoring biomarkers. Project 3 will use laboratory-based emotions research methods to evaluate FTD caregivers, a group at risk for poor health outcomes, with an eye toward enhanced caregiver wellbeing and patient clinical trial participation. Project 4 will seek to identify sources of heterogeneity in FTD clinical progression and treatment goals. Core A (Administration) will oversee all aspects of the PPG to assure success of the project. Core B (Clinical) will recruit and evaluate patients and caregivers, including those from groups historically underrepresented in research, and collect clinical, neuropsychological, and functional assessments. Core C (Data Management and Biostatistics) will ensure data quality and availability and provide biostatistical consultation to all projects. Core D (Neuropathology) will coordinate autopsies and render neuropathological diagnoses, serving as the diagnostic gold standard and providing tissue for basic science and biomarker discovery efforts. Core E (Imaging) will acquire and process MRI scans and obtain amyloid-PET to detect AD in selected diagnostically uncertain patients. Core F (Genetics) will identify known genetic FTD pathogenic and risk variants through whole-exome sequencing and provide gene expression profiling in support of Project 2. Core G (Biospecimens) will obtain and bank biofluid specimens, provide samples and proteomics data to Projects 2 and 4, and use established fluid biomarkers to detect neurodegeneration and AD pathophysiology. These tightly integrated projects and cores will support our overall aim of accelerating progress in the era of FTD therapeutic discovery.