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April 3, 2008

RESEARCH NOTES

PiB found to pinpoint beta-amyloids

Pitt researchers have confirmed that Pittsburgh Compound-B (PiB) binds to the telltale beta-amyloid deposits found in the brains of patients with Alzheimer’s disease. The finding, reported in the journal Brain, is a significant step toward enabling clinicians to provide a definitive diagnosis of Alzheimer’s disease in living patients.

Until now, the beta-amyloid deposits to which PiB binds have been definitively confirmed only in the autopsied brains of Alzheimer’s patients. The new findings, which correlate PiB-identified beta-amyloid deposits from living patients to their post-mortem autopsy results, will ultimately aid in the early diagnosis of Alzheimer’s, help clinicians monitor the progression of the disease and further the development of potential treatments.

“This is final confirmation of what we have believed all along — that Pittsburgh Compound-B allows us to accurately assess the amount of beta-amyloid plaques in brains of people afflicted with Alzheimer’s,” said senior author Steven DeKosky, professor of neurology, psychiatry, neurobiology and human genetics and director of the Alzheimer’s Disease Research Center.

Invented and developed by Pitt researchers Chester Mathis, professor of radiology and pharmaceutical sciences, and William Klunk, professor of psychiatry and neurology, PiB is a radioactive compound that, when coupled with positron emission tomography (PET) imaging, can be injected into the bloodstream to enable researchers to visualize the brains of people with the memory-robbing illness and see the location and distribution of the beta-amyloid plaque deposits associated with Alzheimer’s. The distinguishing factor between Alzheimer’s disease and other dementias is the presence of these amyloid plaques, which are thought to kill brain cells.

In the study, a 63-year-old woman with a clinical diagnosis of Alzheimer’s underwent PiB PET imaging. The PET scan showed significant retention of PiB in distinct regions of her brain. Upon her death 10 months later, her autopsied brain was analyzed for amyloid deposits, including the beta-amyloid plaques. The regions of her brain where the PET scans had identified the highest PiB levels correlated precisely with the regions of high beta-amyloid plaque concentrations in her autopsied brain.

Beta-amyloid plaques, the hallmark of Alzheimer’s disease, are just one type of amyloid structure that can be found in diseased brains. However, other forms of amyloid are not thought to be specific to Alzheimer’s, or they have significantly different roles in the pathogenesis of this disease. To further validate the binding properties of PiB to beta-amyloid and the presence of Alzheimer’s disease, studies were performed on the autopsied brains of 27 other patients with confirmed Alzheimer’s disease.

“In every subject, and with each test that we performed, our results supported the idea that PiB binds almost exclusively to beta-amyloid, which means that we can, with confidence, look to PiB to indicate the troublesome beta-amyloid deposits in brains of living patients,” said lead author Milos Ikonomovic, assistant professor of neurology and psychiatry.

“This work is an important step forward in the development of new tools for both research and clinical care,” noted Neil Buckholtz, chief of the Dementias of Aging Branch of the National Institute on Aging, National Institutes of Health, which supported the study. “It provides additional evidence validating the use of PiB to identify beta-amyloid deposits in living individuals and advancing the potential use of PiB as an outcome measure in clinical trials of anti-beta-amyloid therapeutics.”

Other Pitt researchers involved in the study were Eric Abrahamson, William Paljug, Caroline Hope and Barbara Isanski of neurology; Julie Price, Brian Lopresti, Scott Ziolko and Wenzhu Bi of radiology; Nicholas Tsopelas and Manik Debnath of psychiatry and Ronald Hamilton of neuropathology.

The study was supported by grants from the National Institutes of Health, the Alzheimer’s Association, The U.S. Department of Energy and the Dana Foundation.

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Nano spinoff wins funding

NanoLambda, Inc., a 2005 spinoff from Pitt, has been awarded $258,238 from the Pittsburgh-based Pennsylvania NanoMaterials Commercialization Center. The Harmar Township-based company uses technology developed by Petersen Institute of Nanoscience and Engineering co-director Hong Koo Kim.

The state funds, combined with matching funds from the company, will be used to develop a new sensor chip utilizing nano-imprint lithography.

NanoLambda is developing Spectrum Sensor, an ultra-compact, low-cost spectrometer-on-a-chip, based on novel plasmonic nanowire arrays. According to the company, initial applications are expected to be in high-resolution RGB color sensing. The sensor also may be used for chemical detection, blood diagnostics, biochips and wearable health monitors.

The funding is a portion of $1 million in state Ben Franklin Technology Development Authority money the nanomaterials commercialization center is awarding to local projects.

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ReSET Center awards funding

Pitt’s Reduce Smoking and Exposure to Tobacco (ReSET) Center recently awarded funding to three projects through the center’s pilot research program.

Patricia A. Cluss, an associate professor in psychiatry, was awarded $12,000 for her project, “Dissemination and Back Again: Developing a Research Methodology From an Evidence-informed Prenatal Smoking Cessation Program.” The project aims to upgrade the quality of the existing STOP program database to inform investigators’ design of a large-scale research application, prepare research-quality preliminary studies information from this database for such an application, complete a research-quality intervention manual based on the current evidence-informed program, and refine and upgrade an interventionist training and supervision curriculum to support a research application.

Stephen Grant, an associate professor of environmental and occupational health in the Graduate School of Public Health, was awarded $12,000 for his project, “Hypersensitivity to Tobacco Smoke Mutagens Among BRCA Carriers.” In the research, Grant plans to analyze blood samples from known and suspected carriers of the BRCA-1 and BRCA-2 breast cancer predisposing genes to look initially for an association with tobacco smoke exposure, and subsequently for an association with the development of cancer in this population.

GSPH graduate students in the Department of Behavioral and Community Health Chieremma Nnadi and Christy Lawson were awarded $4,000 for their project, “Knowledge, Attitudes and Expectations of Young Adult Smokers Towards Smoking Cessation Services in Pittsburgh.”

In this study, researchers will assess young adult smokers’ knowledge of smoking cessation services and why they do not use the help available through these programs. They also will seek to understand young adult smokers’ perceptions of smoking cessation services as currently organized and what their expectations of these services are and will seek input about a potential smoking cessation program aimed at young adults.

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Drug, alcohol use higher in gay youth

The odds of substance use for lesbian, gay and bisexual (LGB) youth are on average 190 percent higher than for heterosexual youth, according to a study by Pitt researchers published in the current issue of Addiction. In some sub-populations of LGB youth, the odds were substantially higher, including 340 percent for bisexual youth and 400 percent for lesbians, researchers found.

“Homophobia, discrimination and victimization are largely what are responsible for these substance use disparities in young gay people,” said Michael P. Marshal, assistant professor of psychiatry at the Western Psychiatric Institute and Clinic, who led the study. “History shows that when marginalized groups are oppressed and do not have equal opportunities and equal rights, they suffer. Our results show that gay youth are clearly no exception.”

In a meta-analysis of 18 previous studies from 1994 to 2006, which tested the association between sexual orientation and teen substance use, Pitt researchers found that gay youth reported higher rates of cigarette, alcohol and marijuana use, as well as other illicit drugs, including cocaine, methamphetamines and injection drugs. Almost all of the studies in their review were cross-sectional, suggesting that very little is known about the long-term patterns or consequences of drug use in this vulnerable population. The authors also conducted a systematic review of the prevention and intervention guidelines published by the American Medical Association, the National Institute on Drug Abuse, the National Institute on Alcohol and Alcoholism and the Institute of Medicine and found none mentioned sexual orientation as a potential risk factor for substance use in teens, or provided information for researchers and health care professionals on how to prevent such problems.

Co-authors of the study include Oscar G. Bukstein, Jonathan Miles and Jennifer Q. Morse of psychiatry; Mark S. Friedman and Ron Stall of behavioral and community health sciences in the Graduate School of Public Health, and Melanie A. Gold of the medical school’s Division of Adolescent Medicine.

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Gynecologic research presented

Researchers from the University-affiliated Magee-Womens Research Institute (MWRI) presented clinical and basic science research findings of nearly two dozen studies at the annual meeting of the Society for Gynecologic Investigation (SGI), held March 26-29.

Among the findings presented were:

* Docs talk more about tobacco than drinks, drugs

A study of conversational points covered during patients’ first obstetric visits shows physicians and other caregivers are far more comfortable discussing smoking cessation than they are alcohol or illegal drug use during pregnancy. For the study, Judy C. Chang, assistant professor of obstetrics, gynecology and reproductive sciences at the School of Medicine, and colleagues analyzed audiotapes of 51 prenatal visits to 29 physicians, midwives and nurse practitioners.

While all providers asked their patients about their use of tobacco, alcohol and illegal drugs, discussion was more thorough concerning the adverse effects of smoking and related resources for smoking cessation compared to other risk factors. “Provider responses to alcohol or drug disclosures included only general statements regarding effects on pregnancy, such as ‘We find this is bad for babies,’” said Chang, who also is an MWRI investigator. “Few alcohol or drug discussions assessed whether the patient had concerns regarding continued use during the pregnancy or strategies for behavioral change.”

Providers who talked about alcohol and drug use tended to refer their substance-using patients to genetics specialists for further evaluation rather than confront the issue more directly. In follow-up interviews, however, patients said they expected to be asked about substance use, and voiced a need for more information on possible fetal effects.

Other study authors were Diane Dado of Magee-Womens Hospital and Robert Arnold of the School of Medicine.

* High heart risk found in moms of preemies

Women with a previous preterm birth had higher concentrations of total cholesterol than women whose babies were born at term, and those whose babies were born earliest — less than 34 weeks gestation — had the highest concentrations, Janet M. Catov and her colleagues report.

“Women with preterm birth are at increased risk for cardiovascular disease, but mechanisms relating to these conditions are not well understood,” said Catov, assistant professor of obstetrics, gynecology and reproductive sciences at Pitt. “We wanted to see whether some of these cardiovascular risk factors observed during pregnancy persist into the postpartum period.”

Catov and her colleagues compared information on 47 women who had delivered prior to 37 weeks’ gestation with data on 104 women with term births, at or more than 37 weeks’ gestation. Concentrations of total cholesterol, triglycerides, LDL and HDL also were collected an average of 7.4 years postpartum and compared.

“We found that total cholesterol was an average of two to three times higher for women with a history of preterm birth compared to those with normal gestation births,” said Catov, adding that results were similar for LDL and HDL cholesterol, even after adjustment for race, age, smoking and body weight.

Other Pitt authors were James M. Roberts and Roberta B. Ness of the School of Medicine.

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Clinical research scholars named

Kerry Empey and Stasa Tadic are the newest members of Pitt’s multidisciplinary clinical research scholars program. Appointed Jan. 1 to two-year appointments, the scholars receive a $25,000 research budget each year, $2,700 for travel to an NIH annual meeting and one other professional meeting each year, 75 percent salary support up to $75,000 and tuition for coursework proposed in their career development plans.

Empey is an assistant professor of pharmacy and therapeutics; Tadic is an assistant professor of medicine in the Division of Geriatric Medicine.

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Grant given for microtubule stabilizer assays

Billy Day, professor of pharmaceutical sciences in Pitt’s School of Pharmacy, was awarded a one-year, $25,000 grant from the National Institutes of Health.

The goal of Day’s project is to transfer a cell-based screening method that provides rich data to a Molecular Library Screening Center. The screen provides the most rapidly available and statistically significant approach to gain detailed information of a small molecule’s effects on microtubule architecture, nuclear morphology and a cell’s DNA content as well as on cell proliferation. The work may identify new microtubule stabilizers, a class of agents important to public health in terms of their clinical utility against solid tumors.

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Armstrong foundation makes grant

Lin Ewing, associate director of WPIC’s behavioral medicine program and assistant professor of psychiatry, psychology and pediatrics in the School of Medicine, recently received a $25,000 one-year community-based partnership grant from the Lance Armstrong Foundation to study sibling cancer survivors.

The goals of this grant include: reviewing the quantitative and qualitative literature to produce an integrative review paper that will set the agenda for future research in sibling survivorship; developing and testing a recruitment mechanism capable of reaching a large sample of sibling survivors for future research efforts that will address their adaptation/adjustment, and developing the specific aims and methodology for a grant application that proposes a theoretically driven, large-scale descriptive research study to elucidate the needs of sibling survivors and inform future intervention efforts.

Ewing’s grant was one of 21 awarded to community non-profit organizations across the country to support cancer research and survivorship initiatives.

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Pitt, CMU, WVU join in fossil energy research

Pitt, Carnegie Mellon University and West Virginia University make up a consortium that will receive up to $26 million in funding over the next two years to develop clean and efficient technologies for the use of fossil fuels. The results of the work could reduce regional as well as national dependence on foreign oil.

The partnership, CWP Inc., will receive the funding through a subcontract with RDS Inc., an onsite contractor at the National Energy Technology Laboratory (NETL), the national laboratory for the U.S. Department of Energy’s Office of Fossil Energy.

Pennsylvania and West Virginia hold millions of tons of coal, a fuel that can meet the country’s energy needs far into the future. Policymakers are calling on the region and the nation to use more of its plentiful coal reserves to increase the nation’s energy security. Scientists can advance research into better ways to use coal and convert it into cleaner-burning fuels, said CMU chemical engineering professor Andrew Gellman, research director for the consortium. Under his direction, the research team will aim to develop new technologies for fossil fuel utilization, reducing the environmental impact of fossil energy use and optimizing the efficiency of energy production from fossil fuel sources.

“We need to develop improved turbine generators and new fuel cell technologies that use coal-derived synthetic fuels, along with new ways to capture and store greenhouse gases instead of releasing them into the atmosphere,” Gellman said.

The consortium will focus its research in eight program areas: materials for energy technologies; process and dynamic systems modeling; catalyst and reactor development; carbon management; sensor systems and diagnostics; energy conversion devices; gas hydrates, and ultradeep and unconventional oil and gas production technology.

More than 75 scientists will work with student researchers at the three universities in conjunction with more than 150 NETL scientists and researchers to address key areas of fossil fuel research.

Chancellor Mark A. Nordenberg chairs the CWP board. CMU President Jared L. Cohon and WVU President Mike Garrison also are members of the board.

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Orthodontist group funds jaw studies

Maria Tassopoulou-Fishell received a $15,000 award to develop the project entitled “Candidate Gene Studies of Mandibular Prognathism Using DNA Samples Acquired From Patient’s Saliva” from the American Association of Orthodontists.

In her project, she plans to use samples from Pitt’s Dental Registry and DNA Repository to better understand the reasons that some individuals develop a condition in which the lower jaw projects outward farther than the upper jaw and the lower front teeth are more prominent than the upper teeth.

The 2008 Orthodontic Faculty Development Fellowship Award aims to support the professional development of junior orthodontics faculty. Tassopoulou-Fishell is involved in the School of Dental Medicine research scholar program, which is designed to foster intellectual interactions among faculty and provide mentoring to develop clinical research projects.

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$11.4 million awarded for TB research

Pitt’s Center for Vaccine Research has received an $11.4 million grant from the Bill & Melinda Gates Foundation to use new imaging technologies to study tuberculosis in an attempt to develop new strategies for controlling the disease.

“One of the most challenging issues in treating TB and stopping its spread is the length of time it takes to adequately stem the infection,” said JoAnne Flynn, principal investigator of the grant and professor of microbiology and molecular genetics at the School of Medicine. “Current drugs are available, but we don’t fully understand how or why they work. TB treatment must be continued for at least six months to be effective, placing an undue burden on those who are infected — often from the poorest and most disadvantaged countries.”

According to Flynn, TB is difficult to control because the germs that cause the infection hide from the immune system in small tissue nodules called granulomas, enabling the infection to reactivate years or decades later. Although for the most part TB is a curable disease, patients must adhere to treatment long after symptoms have faded. This proves challenging in many regions of the world where medication is not readily accessible. In addition, an inadequate or incomplete course of treatment is the major factor that causes drug-resistant TB strains to develop.

“Current medications for TB were developed more than three decades ago,” said Flynn. “To create significantly shorter and simplified approaches to treatment, we must improve our understanding of this disease and how current drugs are localized at the site of infection.”

To understand more about the basic biology of TB, Flynn and colleagues are using the grant to develop positron emission tomography (PET) and computed tomography (CT) imaging studies in non-human primates. By using combined PET/CT, the researchers will be able to follow the progression of the disease in animals over time and analyze changes in tissue and responses to particular drugs. They will be using three imaging technologies — radionuclides, fluorescence and mass spectrometry — in combination to develop imaging probes and techniques to locate bacteria associated with TB precisely and to explore the underlying factors responsible for slow drug metabolism.

“By applying the tools of modern medicine to TB, we hope to lay the groundwork for real-time measurements of TB drug efficacy in clinical trials and develop new targeted therapies that will considerably shorten the length of treatment,” said Flynn.

Pitt co-investigators are radiology faculty members Chet Mathis, Jonathan P. Carney and Brian J. Lopresti.

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Pitt gets tobacco settlement grants

Pitt will share in research grants funded by Pennsylvania’s portion of the national tobacco settlement for 2007-08.

These non-formula awards are competitive grants that focus on specific research priorities that are established and reviewed annually by the statewide health research advisory committee. The priorities for 2007-08 are regenerative medicine and violence prevention. Each research grant also is required to address the reduction of health disparities among underserved segments of the population.

Pitt, in association with Auberle, Holy Family Services and the Kingsley Association, will receive $3.9 million to study the relationship of biological and environmental factors to violence and the effect of an intervention on aggressive behavior and brain function in at-risk boys. Violent behavior is associated with a complex set of factors including opportunity, environmental experiences and certain neurotransmitters that can be associated with genes. Links between aggression and brain function will be examined in the study of the effect of an intervention for at-risk boys.

Potential links between genes and violent behavior also will be explored in a sample of adults with a history of violence by studying the chain of connections between these genes, the functions and regions of the brain believed to underlie aggression and the course of violent behavior. The different studies have the potential to uncover key factors in aggressive behavior and improve understanding of how to break the cycle of violence.

Pitt is collaborating on another grant with the University of Pennsylvania, Penn State, Achieve Ability, the Children’s Hospital of Philadelphia and the Institute for the Development of African-American Youth. The group will receive $3.9 million to examine how environmental, social, psychological and neurobiological factors predict the risk of aggression and how other factors protect socially at-risk children from becoming aggressive. The project will test the effectiveness of cognitive behavioral therapy and nutritional supplements for the treatment of aggression in 11-year-old children.

Each project will include research training programs for minority students and faculty in order to diversify the applicant pool for high-level research positions. More information on the use of tobacco settlement funds can be found at www.health.state.pa.us/cure.

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The University Times Research Notes column aims to inform readers about funding awarded to Pitt researchers and to report briefly on findings arising from University research. We welcome submissions from all areas of the University, not only health sciences areas.

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