THE MULTIDIMENSIONAL MIND
PART 1: Creative Brains: Music, Art and Emotion
Bruce L. Miller, MD
BIOGRAPHY:
Dr. Miller is Professor of Neurology at the University of California, San Francisco (UCSF) where he holds the A.W. & Mary Margaret Clausen Distinguished Chair. Dr. Miller directs the busy UCSF dementia center where patients in the San Francisco Bay Area receive comprehensive clinical evaluations. His goal is the delivery of model care to all of the patients who enter the clinical and research programs at the UCSF Memory and Aging Center. Dr. Miller teaches extensively and runs the Behavioral Neurology Fellowship at UCSF.
Dr. Miller is a behavioral neurologist focused in dementia with special interests in brain and behavior relationships as well as the genetic and molecular underpinnings of disease. His work in frontotemporal dementia (FTD) emphasizes both the behavioral and emotional deficits that characterize these patients, while simultaneously noting the visual creativity that can emerge in the setting of FTD. He is the principal investigator of the NIH‐sponsored Alzheimer’s Disease Research Center (ADRC) and an NIH‐funded program project on FTD called Frontotemporal Dementia: Genes, Imaging and Emotions. He oversees a healthy aging program supported through the Larry H. Hillblom Foundation and the Hellman Center, which includes an artist in residence program. In addition, he helps lead two philanthropy‐funded research consortia, the Tau Consortium and Consortium for Frontotemporal Research, focused around developing treatments for tau and progranulin disorders respectively.
Dr. Miller has received many awards including the Potamkin Award from the American Academy of Neurology, the Raymond Adams Lecture at the American Neurological Association, the Elliot Royer Award from the San Francisco Neurological community, the UCSF Annual Faculty Research Lectureship in Clinical Science, the UCSF Academic Senate Distinction in Mentoring Award, and the Gene D. Cohen Research Award in Creativity and Aging from the National Center for Creative Aging. He has authored The Human Frontal Lobes, The Behavioral Neurology of Dementia and extensive publications regarding dementia. He has been featured in Fortune Magazine, Charlie Rose Show, The PBS NewsHour, The New York Times, and other media. For nearly three decades, Dr. Miller has been the scientific director for the philanthropic organization The John Douglas French Alzheimer’s Foundation, a private philanthropic organization that funds basic science research in Alzheimer’s disease.
BIBLIOGRAPHY:
1. Liu A, Werner K, Roy S, Trojanowski JQ, Morgan‐Kane U, Miller BL, Rankin KP. A case study of an emerging visual artist with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurocase. 2009 Jun;15(3):235‐47.
2. Cummings JL, Miller BL, Christensen DD, Cherry D. Creativity and dementia: emerging diagnostic and treatment methods for Alzheimer’s disease. CNS Spectr. 2008;13:1‐20; quiz 22.
3. Seeley WW, Matthews BR, Crawford RK, Gorno‐Tempini ML, Foti D, Mackenzie IR, Miller BL. Unravelling Boléro: progressive aphasia, transmodal creativity and the right posterior neocortex. Brain. 2008;131:39‐49.
4. Rankin KP, Liu AA, Howard S, Slama H, Hou CE, Shuster K, Miller BL. A case‐controlled study of altered visual art production in Alzheimer's and FTLD. Cogn Behav Neurol. 2007;20:48‐61.
5. Miller BL, Hou CE. Portraits of artists: emergence of visual creativity in dementia. Arch Neurol. 2004;61:842‐4.
PART 2: Mouse Models, Jellyfish and Stem Cells: Mechanisms for Disease
Keith Vossel, MD, MSc
BIOGRAPHY: Keith Vossel, MD, MSc is a Staff Scientist in the Gladstone Institute of Neurological Disease and Assistant Professor of Neurology in the UCSF Memory and Aging Center. Dr. Vossel received a BS in engineering science and mechanics and MSc in biomedical engineering at the University of Tennessee. He received an MD at the University of Tennessee and subsequently completed residency training in neurology at Massachusetts General Hospital and Brigham and Women’s Hospital, where he served his final year as a chief resident. In addition to caring for patients, Dr. Vossel investigates mechanisms and novel treatment approaches for neural network dysfunction in Alzheimer's disease. His laboratory investigation focuses on the microtubule‐associated protein tau and regulation of axonal transport and his clinical study investigates seizures and epileptiform activity in Alzheimer’s disease and related dementias. BIBLIOGRAPHY: 1. Vossel KA, Zhang K, Brodbeck J, et al. Tau reduction prevents Abeta‐induced defects in
axonal transport. Science 2010;330:198.
2. Vossel KA, Miller BL. New approaches to treatment of frontotemporal lobar degeneration. Current Opinion in Neurology 2008, 21(6):708–716. PMCID2744321
3. Morris M, Maeda S, Vossel K, Mucke L. The many faces of tau. Neuron. 2011, 70:410‐26. 4. Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Yu G, Palop JJ,
Mucke L. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in Alzheimer's disease mouse model. Proceedings of the National Academy of Sciences U.S.A. Epub 2012 Aug 6.
5. Palop JJ, Mucke L. Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol
2009;66:435‐440.
6. Miyawaki A. Green Fluorescent Protein Glows Gold. Cell 135;987‐990.
7. Lindvall L and Kokaia K. Stem cells in human neurodegenerative disorders — time for clinical translation? J Clinical Invest 2010;120:29‐40.
FINANCIAL STRENGTH
Grants from the National Institutes of Health (NIH) and other federal agencies are Gladstone’s major source of support. Foundations and private donors contri- bute other significant funding—which is critical towards advancing our mission to overcome some of the world’s most devastating diseases.
2011 SOURCES OF FUNDING
External Grants(including NIH) $60 MillionPhilanthropy 6 MillionOther revenues 6 Million
Revenue $72 Million
EMPLOYEESAt the beginning of 2012, we had approximately 400 employees.
UCSF AFFILIATION
Gladstone has a vibrant partnership with the University of California, San Francisco (UCSF), one of the nation’s premier medical schools. All of Gladstone’s principal investigators are seamlessly integrated faculty members at UCSF, where they regularly teach and mentor UCSF graduate students.
GLADSTONE HISTORY
Established in 1971 from the estate of J. David Gladstone, the Gladstone Trust is a 501(c)(3) tax-exempt charity. Valued at about $8 million at the time of Mr. Gladstone’s death, this original bequest has since multiplied more than 20-times its original value—while also supporting more than three decades of biomedical research and training.
Mr. Gladstone was a real estate devel- oper who made his fortune as the first developer to create enclosed shopping malls (such as the Northridge Fashion Center mall) in Southern California. His accidental death in 1971 left an estate dedicated to supporting medical students interested in research.
The Gladstone Trust was used to launch The J. David Gladstone Institutes in 1979, under the leadership of Robert W. Mahley, MD, PhD. Through an affiliation agreement with UCSF, Gladstone was founded as a research and training facility at San Francisco General Hospital. Initially focused on cardiovascular research, Gladstone added expertise in virology and immunology in 1991 and in neurological disease in 1998.
In 2004, the Gladstone Institutes moved to a new and dedicated facility in San Francisco’s Mission Bay, ushering in a renewed sense of collaboration among Gladstone’s growing scientific staff. In 2010, after three decades of leading Gladstone, Dr. Mahley stepped down in order to return to more active research.
That same year, R. Sanders “Sandy” Williams, MD, left Duke University, where he had been Dean of the School of Medicine—as well as Senior Vice Chancellor and Senior Advisor for International Strategy—to become Gladstone’s new president. The following year, the independent and philanthropic Gladstone Foundation formed with the mission of expanding the financial resources available to drive Gladstone’s mission.
ABOUT US
Gladstone is a nimble and independent nonprofit biomedical-research organiza-tion dedicated to rigorous, cutting-edge science—our mission is to unravel the basics of biology in order to better understand, prevent, treat and cure cardiovascular, viral and neurological conditions such as heart failure, HIV/AIDS and Alzheimer’s disease.
OUR SCIENCE
Gladstone combines the best of basic science with expertise in cardiovascular, viral and neurological diseases. Our scientists are at the forefront of stem cell biology research, using induced pluri- potent stem cell (see graphic) and other cellular reprogramming technologies in their research. We have a robust trans- lational research effort to transform our basic discoveries into solutions for patients. Another key component of our work at Gladstone is training tomorrow’s physicians and researchers. We are passionate about science and determined in our goal of preventing, treating and curing some of the world’s most relentless illnesses.
LEADERSHIP
Gladstone’s president, three research directors and three trustees strategically guide the organization to foster and enrich innovation, talent, entrepreneur-ship and financial strength.
R. Sanders Williams, MDPresident, Gladstone Institutes
Deepak Srivastava, MDDirector, Cardiovascular Research
Warner C. Greene, MD, PhDDirector, Immunology and Virology Research
Lennart Mucke, MDDirector, Neurological Research
TRUSTEES
Richard D. Jones, JDAlbert A. DormanAndrew S. Garb, JD
DERIVED FROM ADULT SKIN CELLS, THESEINDUCED PLURIPOTENT STEM CELLS— WHICH ACT VERY MUCH LIKE EMBRYONIC STEM CELLS—ARE DIFFERENTIATING INTO HEART AND NERVE CELLS.
| BACKGROUNDER
SCIENCE OVERCOMING DISEASE
Contact Press Relations: email: [email protected] | phone:
1650 Owens Street | San Francisco | California 94158 | www.gladstoneinstitutes.org
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Part II: Mouse Models, Jellyfish and Stem Cells: Mechanisms for Disease
Creative Brains: Music, Art and Emotion
Keith A. Vossel, MD, MScAssistant Professor of Neurology, UCSF
Staff Scientist, Gladstone Institute of Neurological Disease Research Scientists
Physician Scientists
Overview
Part II: Mouse Models, Jellyfish and Stem Cells: Mechanisms for Disease
• Mouse models of Alzheimer’s disease
• Jellyfish proteins illuminate inner workings of cells
• Transforming skin cells into stem cells
Alzheimer’s Disease
• 5.4 million Americanshave Alzheimer’s
• 6th leading causeof death in US
• Impending public health crisis
www.alz.org
Today
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Alzheimer’s Disease
Normal Brain Alzheimer’s Patient Brain
Alzheimer’s Disease: Multiple Factors
Why study mice?
• Short life span (30 months)
• Entire genome mapped
• Transgenic models isolate effects of single genes
• Relevant functional measures
• Biomarkers validated in humans
Tanzi R, N Engl J Med (1995) 332:1512–3
AD Brain
hAPP TransgenicMouse Brain
Amyloid Plaques
Transgenic Mouse Models of AD
hAPPFADhAPPFAD
Dystrophic Neurites
AD Brain
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Morris Water Maze: hAPP Mice Show Learning and Memory Deficits
Nontransgenic (Normal) hAPP (Alzheimer’s)
What hAPP Mice Have Taught Us
Biomarkers
Cell andMolecularChanges
Cognitive/Behavioral Deficits Seizures
Therapies
hAPP Mice
Overview
Part II: Mouse Models, Jellyfish and Stem Cells: Mechanisms for Disease
• Mouse models of Alzheimer’s disease
• Jellyfish proteins illuminate inner workings of cells
• Transforming skin cells into stem cells
2008 Nobel laureates from Miyawaki Cell 2008; Mouse cortex image courtesy of Robert Cudmore
Mouse CortexJellyfish
Roger Y. TsienMartin ChalfieOsamu Shimomura
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Axon
40µm
5µm
Mitochondrial Transport Mitochondrial Transport in Living Brain
Dimitrios Davalos and Katerina Akassoglou, Gladstone Institutes
Overview
Part II: Mouse Models, Jellyfish and Stem Cells: Mechanisms for Disease
• Animal models of Alzheimer’s disease
• Jellyfish proteins illuminate inner workings of cells
• Human-derived stem cells
What are stem cells?
• Definition: any cell with the capacity to differentiate into a more mature cell type
• Therapeutic applications
• Neurodegenerative disease
• Epilepsy
• Stroke
• Spinal cord injury
• etc
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A B C
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Induced Pluripotent Stem Cells (iPS Cells)
Shinya Yamanaka 2012 Nobel Prize
iPS-derived Neurons with FTD Mutation
Corrected MutationIncreased
FTD Mutations
Yadong Huang, MD, PhD, Gladstone/UCSF
Research Scientists
Physician ScientistsClinical Trials
Personalized Medicine
Regenerative Applications of Stem Cells
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GladstoneLennart MuckePascal SanchezJorge PalopLaure VerretJens BrodbeckSteve FinkbeinerAaron DaubPunita SharmaEva LaDowAlisha HollowayYadong HuangDimitrios DavalosKaterina AkassoglouJordan XuTim Sweeney
UABErik Roberson
StanfordBianxiao CuiKai Zhang
UCSFBruce MillerHeidi KirschPaul GarciaSrikantan NagarajanSusanne HonmaAnne F. DowlingJohn HoudeManu HegdeMary MantleGil RabinoviciWilliam JagustAlex BeagleKamalini RanisingheMAC Database, Imaging and Research StaffResearch Patients and their Families
FundingNIH/NIA/ADRC, JD French Alzheimer’s Foundation, Stephen Bechtel, Jr Foundation
Acknowledgements http://memory.ucsf.edu
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