Bill Seeley, MD

Selective Vulnerability in Neurodegenerative Disease

My laboratory studies the onset and spread of neurodegenerative disease. We focus on frontotemporal dementia (FTD), a major cause of early age of onset dementia in which most patients develop social-emotional or language dysfunction and progress to death within 5-8 years of diagnosis. We combine clinical and neuroimaging data from living patients with post-mortem pathological observations in the same patients to build more comprehensive models of disease pathogenesis. 

Regarding disease onset, we have identified an early-vulnerable neuron subtype in the behavioral variant of FTD and seek to clarify mechanisms that render these neurons susceptible to the disease. In addition, we study disease onset in asymptomatic living individuals who carry FTD-causing genetic mutations by following these individuals with clinical, laboratory, and brain imaging metrics from health to disease. With respect to disease spread, we use brain imaging to follow neurodegeneration over time in living patients, seeking to develop disease-monitoring biomarkers for clinical trials. Our approach blends traditional neuroanatomy, novel histological methods, and cell and tissue-level protein and mRNA expression profiling with cutting-edge neuroimaging techniques (task-free fMRI, diffusion tensor imaging, structural imaging). These integrative studies are facilitated by the UCSF Neurodegenerative Disease Brain Bank, which I direct and house within my laboratory.

Current Projects

Our ongoing projects seek to:
(1) Understand the normal human anatomy and physiology of frontotemporal dementia-related brain regions. For these goals we are embarking upon studies in post-mortem human brain tissues from healthy controls using advanced histological methods (DiOlistics, CLARITY, array tomography, in situ hybridization) and laser capture microdissection-based single cell mRNA/protein expression profiling. We are also using brain imaging to characterize network architecture and function in healthy living individuals.  

(2) Clarify how neurodegeneration propagates within local microcircuitry and then throughout large-scale distributed networks. We are mapping the spatiotemporal progression of FTD-related pathology within the most vulnerable brain regions post-mortem and following longitudinal changes in brain structure and network connectivity in patients during life. We also use post-mortem observations from patients who underwent brain imaging during life to clarify the neuropathological correlates of antemortem imaging abnormalities. This approach allows us to validate imaging metrics in patient tissues while exploring the functional impact of neuropathological findings whose clinical relevance remains unclear.

Lab Members

Lab Website