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Neuroscience Graduate Program at UCSF

Faculty - William Seeley, M.D.

Selective Vulnerability in Neurodegenerative Disease


Research Description

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.

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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.

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Lab Members

Stephanie Gaus, Lab Manager
Jesse Brown, Postdoctoral Fellow
Alissa Nana Li, Postdoctoral Fellow
Sarat Vatsavayai, Postdoctoral Fellow
Anke Dijkstra, Postdoctoral Fellow
Andrew Tucker, Lead Technician

Research Assistants and Students
Alice Hua
Norbert Lee
Andrew Truhillo
Jian Yang
Jihye Lee-Hwang
Youngsoon Park

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Selected Publications

Seeley WW, Carlin DA, Allman JM, Macedo MN, Bush C, Miller BL, DeArmond SJ. Early frontotemporal dementia targets neurons unique to apes and humans. Ann Neurol 2006;60(6):660-667.

Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, Reiss AL, Greicius MD. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci 2007;27(9):2349-2356.

Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD.  Neurodegenerative diseases target large-scale human brain networks. Neuron 2009; 62:42–52.

Kim EJ, Sidhu M, Gaus S, Huang E, Hof PR, Miller BL, DeArmond SJ, Seeley WW. Selective frontoinsular von Economo neuron and fork cell loss in early behavioral variant frontotemporal dementia. Cerebral Cortex. 2011 Jun 14.

Seeley WW, Zhou J, Kim EJ. Frontotemporal dementia: what can the behavioral variant teach us about human brain organization? The Neuroscientist. 2011 Jun 13. [Epub ahead of print].

Zhou J, Gennatas ED, Kramer JH, Miller BL, Seeley WW. Predicting regional neurodegeneration from the healthy brain functional connectome. Neuron. 2012 Mar 22;73(6):1216-27.

Gardner RC, Boxer AL, Trujillo A, Mirsky JB, Guo CC, Gennatas ED, Heuer HW, Fine E, Zhou J, Kramer JH, Miller BL, Seeley WW. Intrinsic connectivity network disruption in progressive supranuclear palsy. Annals of neurology. 2013 May;73(5):603-16.

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William Seeley, M.D.



Email

wseeley@memory.ucsf.edu

Phone

415-476-2793

Office Address

UCSF Mission Bay, Box 1207
675 Nelson Rising Lane, room 211
San Francisco, CA 94158

Other Websites

Seeley Lab