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Articles by Virginia M.-Y. Lee
Total Records ( 5 ) for Virginia M.-Y. Lee
  Shaohua Xu , Kurt R. Brunden , John Q. Trojanowski and Virginia M.-Y. Lee
  Background The assembly of tau proteins into paired helical filaments, the building blocks of neurofibrillary tangles, is linked to neurodegeneration in Alzheimer's disease and related tauopathies. A greater understanding of this assembly process could identify targets for the discovery of drugs to treat Alzheimer's disease and related disorders. By using recombinant human tau, we have delineated events leading to the conversion of normal soluble tau into tau fibrils. Methods Atomic force microscopy and transmission electron microscopy methodologies were used to determine the structure of tau assemblies that formed when soluble tau was incubated with heparin for increasing lengths of time. Results Tau initially oligomerizes into spherical nucleation units of 18- to 21-nm diameter that appear to assemble linearly into nascent fibrils. Among the earliest tau fibrils are species that resemble a string of beads formed by linearly aligned spheres that with time seem to coalesce to form straight and twisted ribbon-like filaments, as well as paired helical filaments similar to those found in human tauopathies. An analysis of fibril cross sections at later incubation times revealed three fundamental axial structural features. Conclusions By monitoring tau fibrillization, we showed that different tau filament morphologies coexist. Temporal changes in the predominant tau structural species suggest that tau fibrillization involves the generation of structural intermediates, resulting in the formation of tau fibrils with verisimilitude to their authentic human counterparts.
  Mary D. Naylor , Jason H. Karlawish , Steven E. Arnold , Ara S. Khachaturian , Zaven S. Khachaturian , Virginia M.-Y. Lee , Matthew Baumgart , Sube Banerjee , Cornelia Beck , Kaj Blennow , Ron Brookmeyer , Kurt R. Brunden , Kathleen C. Buckwalter , Meryl Comer , Kenneth Covinsky , Lynn Friss Feinberg , Giovanni Frisoni , Colin Green , Renato Maia Guimaraes , Lisa P. Gwyther , Franz F. Hefti , Michael Hutton , Claudia Kawas , David M. Kent , Lewis Kuller , Kenneth M. Langa , Robert W. Mahley , Katie Maslow , Colin L. Masters , Diane E. Meier , Peter J. Neumann , Steven M. Paul , Ronald C. Petersen , Mark A. Sager , Mary Sano , Dale Schenk , Holly Soares , Reisa A. Sperling , Sidney M. Stahl , Vivianna van Deerlin , Yaakov Stern , David Weir , David A. Wolk and John Q. Trojanowski
  To address the pending public health crisis due to Alzheimer‘s disease (AD) and related neurodegenerative disorders, the Marian S. Ware Alzheimer Program at the University of Pennsylvania held a meeting entitled "State of the Science Conference on the Advancement of Alzheimer's Diagnosis, Treatment and Care," on June 21-22, 2012. The meeting comprised four workgroups focusing on Biomarkers; Clinical Care and Health Services Research; Drug Development; and Health Economics, Policy, and Ethics. The workgroups shared, discussed, and compiled an integrated set of priorities, recommendations, and action plans, which are presented in this article.
  Jon B. Toledo , Estefania Toledo , Michael W. Weiner , Clifford R. Jack , William Jagust , Virginia M.-Y. Lee , Leslie M. Shaw and John Q. Trojanowski
  Background There is epidemiological evidence that cardiovascular risk factors (CVRF) also are risk factors for Alzheimer‘s disease, but there is limited information on this from neuropathological studies, and even less from in vivo studies. Therefore, we examined the relationship between CVRF and amyloid-β (Aβ) brain burden measured by Pittsburgh Compound B-positron emission tomography (PiB-PET) studies in the Alzheimer‘s Disease Neuroimaging Initiative. Methods Ninety-nine subjects from the Alzheimer‘s Disease Neuroimaging Initiative cohort who had a PiB-PET study measure, apolipoprotein E genotyping data, and information available on CVRF (body mass index [BMI], systolic blood pressure, diastolic blood pressure [DBP], and cholesterol and fasting glucose test results) were included. Eighty-one subjects also had plasma cortisol, C-reactive protein, and superoxide dismutase 1 measurements. Stepwise regression models were used to assess the relation between the CVRF and the composite PiB-PET score. Results The first model included the following as baseline variables: age, clinical diagnosis, number of apolipoprotein ɛ4 alleles, BMI (P = .023), and DBP (P = .012). BMI showed an inverse relation with PiB-PET score, and DBP had a positive relation with PiB-PET score. In the second adjusted model, cortisol plasma levels were also associated with PiB-PET score (P = .004). Systolic blood pressure, cholesterol, or impaired fasting glucose were not found to be associated with PiB-PET values. Conclusion In this cross-sectional study, we found an association between Aβ brain burden measured in vivo and DBP and cortisol, indicating a possible link between these CVRF and Aβ burden measured by PiB-PET. These findings highlight the utility of biomarkers to explore potential pathways linking diverse Alzheimer‘s disease risk factors.
  John Q. Trojanowski , Steven E. Arnold , Jason H. Karlawish , Mary Naylor , Kurt R. Brunden and Virginia M.-Y. Lee
  The emerging global epidemic of Alzheimer‘s disease (AD) demands novel paradigms to address the two unmet needs of the field: (a) cost-effective health care delivery programs/services, and (b) clinical and basic research to accelerate therapy discovery/development. This report outlines a model demonstration project, the Marian S. Ware Alzheimer Program at the University of Pennsylvania, which was designed to achieve four specific aims: (1) improve the integration and continuity of AD care; (2) identify biomarkers that detect the earliest presence of AD and related neurodegenerative cognitive disorders; (3) enhance both the design and conduct of clinical trials as well as review their results to more effectively test new AD therapies and translate valuable therapies into clinical practice; and (4) discover and develop novel disease-modifying small molecule treatments for AD. The ”Ware-UPenn“ program has been presented in this report as a useful prototype for partnerships between private philanthropy and academia in planning and developing programs to address a major national public health problem.
  Matthew J. Winton , Lionel M. Igaz , Margaret M. Wong , Linda K. Kwong , John Q. Trojanowski and Virginia M.-Y. Lee
  TAR DNA-binding protein 43 (TDP-43) is the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Although normal TDP-43 is a nuclear protein, pathological TDP-43 is redistributed and sequestered as insoluble aggregates in neuronal nuclei, perikarya, and neurites. Here we recapitulate these pathological phenotypes in cultured cells by altering endogenous TDP-43 nuclear trafficking and by expressing mutants with defective nuclear localization (TDP-43-ΔNLS) or nuclear export signals (TDP-43-ΔNES). Restricting endogenous cytoplasmic TDP-43 from entering the nucleus or preventing its exit out of the nucleus resulted in TDP-43 aggregate formation. TDP-43-ΔNLS accumulates as insoluble cytoplasmic aggregates and sequesters endogenous TDP-43, thereby depleting normal nuclear TDP-43, whereas TDP-43-ΔNES forms insoluble nuclear aggregates with endogenous TDP-43. Mutant forms of TDP-43 also replicate the biochemical profile of pathological TDP-43 in FTLD-U/ALS. Thus, FTLD-U/ALS pathogenesis may be linked mechanistically to deleterious perturbations of nuclear trafficking and solubility of TDP-43.
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