Using MRI, researchers may predict which adults will develop Alzheimer's


Using MRI, researchers may be able to predict which adults with mild cognitive impairment are more likely to progress to Alzheimer's disease, according to the results of a study published online and in the June issue of Radiology.

Mild cognitive impairment (MCI) is an intermediate stage between the decline in mental abilities that occurs in normal aging and the more pronounced deterioration associated with dementia, a group of brain disorders that includes Alzheimer's disease (AD).

Individuals with MCI develop AD at a rate of 15 to 20 percent per year, which is significantly higher than the one to two percent rate for the general population. Some people with MCI remain stable while others gradually decline and some quickly deteriorate.

"Being able to better predict which individuals with MCI are at greatest risk for developing Alzheimer's would provide critical information if disease-modifying therapies become available," said the study's lead author, Linda K. McEvoy, Ph.D., assistant professor in the Department of Radiology at the University of California, San Diego School of Medicine.

Dr. McEvoy and a team of researchers analyzed MRI exams from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a large publicly and privately sponsored study, which performed imaging and other tests on hundreds of healthy individuals and others with MCI and early AD between 2005 and 2010 in hopes of identifying valuable biomarkers of the disease process.

Included in the study were a baseline MRI exam, serving as an initial point of measurement, and a second MRI performed a year later on 203 healthy adults, 317 patients with MCI and 164 patients with late-onset AD. The average age of the study participants was 75.

Using MRI, the researchers measured the thickness of the cerebral cortex — the outermost layer of the cerebral hemispheres of the brain that plays a key role in memory, attention, thought and language — and observed the pattern of thinning to compute a risk score. One of the characteristics of AD is a loss of brain cells, called atrophy, in specific areas of the cortex.

"MRI is very sensitive to brain atrophy," Dr. McEvoy said. "There's a pattern of cortical thinning associated with AD that indicates the patient is more likely to progress to AD."

Using the baseline MRI, the researchers calculated that the patients with MCI had a one-year risk of conversion to AD ranging from three to 40 percent.

"Compared to estimating a patient's risk of conversion based on a clinical diagnosis only, MRI provides substantially more informative, patient-specific risk estimates," Dr. McEvoy said. "The baseline MRI helped identify which patients were at very low risk of progressing to Alzheimer's and those whose risk was doubled."

By combining results of the baseline MRI and the MRI exam performed one year later, the researchers were able to calculate a rate of change in brain atrophy that was even more informative. The MCI patients' risk of disease progression based on the serial MR exams ranged from 3 to 69 percent.

"Rapid thinning of the cortex is reflective of a degenerative disorder," Dr. McEvoy explained.

Although no treatments currently exist that slow or prevent the neurodegeneration associated with AD, Dr. McEvoy said patients at high risk of progressing to AD might want to enroll in clinical trials of disease-modifying therapies. She said the information would also help ensure patients receive optimal care and allow families more time for planning.

More information: "Mild Cognitive Impairment: Baseline and Longitudinal Structural MR Imaging Measures Improve Predictive Prognosis." Collaborating with Dr. McEvoy were Dominic Holland, Ph.D., Donald J. Hagler, Jr., Ph.D., Christine Fennema-Notestine, Ph.D., James B. Brewer, M.D., Ph.D., and Anders M. Dale, Ph.D. http://radiology.rsna.org/

Provided by Radiological Society of North America (news : web)

Most recent mammography recommendations confuse public


When the U.S. Preventive Services Task Force (USPSTF), an independent panel of experts in primary care and prevention, released its recommendations on mammography screenings for US women on November 16, 2009, there was immediate and considerable controversy. In a study published in the May 2011 issue of the American Journal of Preventive Medicine, investigators report that these new recommendations confused women (30.0%) more than they helped them understand when to get a mammogram (6.2%). Confusion was greatest among women aged 40-49 years and women who had never had a mammogram or who had one more than 2 years ago.

The USPSTF announcement included three sets of recommendations for women aged 40-49, 50-74 and 75 and over. Investigators from RTI International (Bethesda, MD, and Research Triangle Park, NC) assessed the volume and framing of the public discourse around the mammography recommendations to determine if women were knowledgeable about the new recommendations.

According to Linda B. Squiers, PhD, senior health communication analyst, RTI, Bethesda, MD, and her co-authors, results from this study will allow public health professionals to understand how the USPSTF's 2009 mammography screening recommendations were discussed in the media and whether women understood the reason for the debate and the new recommendations approximately one month after their release. Media coverage of the new recommendations peaked immediately following their release and was unbalanced. The majority of news articles and social media posts were unsupportive of the recommendations. The new recommendations were released during the heated debate about healthcare reform legislation, so it is not surprising that they were portrayed by some as an example of how the Obama administration planned to ration health care if the legislation passed.

RTI researchers analyzed news reports and social media posts around the time of the announcement, both of which shape public perceptions of and opinions about new information and topics. In addition, they surveyed 1,221 women for two months beginning one month after the announcement.

From 233 newspaper articles, blog posts, and tweets analyzed, 51.9% were unsupportive, and only 17.6% were supportive. Most newspaper articles and blog posts expressed negative sentiment (55.0% and 66.2%, respectively), whereas tweets were predominantly neutral (48.8%). The most common reasons mentioned for being unsupportive of the new recommendations were the belief that delaying screening would lead to later detection of more advanced breast cancer and subsequently more breast cancer–related deaths (22.5%) and the belief that the recommendations reflected government rationing of healthcare (21.9%). 

In the web-based survey, the majority of respondents reported paying attention to the recommendations and those who paid more attention understood better the reasons for the controversy. However, despite the media flurry, only 20.3% of women aged 40-49 years and 23.4% of all women in the sample correctly identified the mammography recommendation for women aged 40󈞝 years. Overall, the new recommendations confused women more than they helped them understand when to get a mammogram. Women aged 40-49 years were significantly more likely to be confused about when they should get a mammogram than the older age group.

"The USPSTF plays a vital role in reviewing the latest scientific evidence and advising providers and consumers about prevention," concluded Squiers and her co-investigators. "For recommendations to be accepted by both groups, they first must be understood. In the field of health communication, message testing with individuals is frequently used to ensure that messages are understandable, credible, and use language that resonates with the target audience. Using message testing in the future may help identify specific components or words (e.g., routine, against) within the recommendations that could cause providers, consumers, and advocacy agencies to be confused or concerned."

In an accompanying commentary, Diana B. Petitti, MD, MPH, from Arizona State University and Ned Calonge, MD, MPH, from the Colorado Trust, note that while the USPSTF has played a leadership role in the evidence-based medicine movement, there seems to be "a media bias in favor of mammography screening" which may be due to vested interests in the women's health and breast cancer advocacy groups. They suggest that "further application of qualitative research methods to the data on media coverage of the mammography screening guidelines might yield insights into the kinds of interests that underlay the most negative media accounts about the mammography recommendations. This information might contribute to a better understanding of the sources of negative media responses to evidence and evidence-based recommendations."

More information: The article is "The Public's Response to the U.S. Preventive Services Task Force's 2009 Recommendations on Mammography Screening" by Linda B. Squiers, PhD, Debra J. Holden, PhD, Suzanne E. Dolina, MPH, Annice E. Kim, PhD, Carla M. Bann, PhD and Jeanette M. Renaud, PhD (doi: 10.1016/j.amepre.2010.12.027). The commentary is "Media Coverage of U.S. Preventive Services Task Force Recommendations" by Diana B. Petitti, MD, MPH, and Ned Calonge, MD, MPH (doi: 10.1016/j.amepre.2011.02.009).

Both appear in the American Journal of Preventive Medicine, Volume 40, Issue 5 (May 2011)

Provided by Elsevier

Risk of death from opioid overdose related to higher prescription dose


In an analysis of opioid prescription patterns and deaths, receiving higher prescribed doses is associated with an increased risk of opioid overdose death, but receiving both as-needed and regularly scheduled doses is not associated with overdose risk, according to a study in the April 6 issue of JAMA.

The rate of overdose death has increased sharply in the United States in the past decade and overdose death is a pressing public health problem, according to background information in the article. "Between 1999 and 2007, the rate of unintentional overdose death in the United States increased by 124 percent, largely because of increases in prescription opioid overdoses. Achieving a better understanding of the factors contributing to prescription opioid overdose death is an essential step toward addressing this troubling and dramatic increase in overdose mortality."

Amy S. B. Bohnert, Ph.D., of the Department of Veterans Affairs, Ann Arbor, Mich., and colleagues examined the relationship between opioid prescribing patterns (dose and schedule ["as needed," regularly scheduled, or both]) and risk of opioid-related deaths from 2004 through 2008 among diagnostic subgroups of patients (chronic pain, cancer, acute pain, and substance use disorders) in a national sample of Veterans Health Administration (VHA) patients. The study included data on all unintentional prescription opioid overdose decedents (n = 750) and a random sample of patients (n = 154,684) among those individuals who used medical services in 2004 or 2005 and received opioid therapy for pain.

The researchers approximated the rate of overdose among individuals treated with opioids to be 0.04 percent. Opioid overdose decedents were statistically significantly more likely to be middle-aged and white; more likely to have chronic or acute pain, substance use disorders, and other psychiatric diagnoses; and less likely to have cancer.

The authors found that the overdose rate was higher at higher maximum daily doses compared with lower maximum daily doses (100 mg/day or more vs. 1 mg/day to less than 20 mg/day) across all subgroups examined, including those with cancer, substance use disorders, chronic and acute pain.

Having as-needed opioids only compared with having regularly scheduled opioids was associated with an increase in risk of opioid overdose among patients with cancer. Receiving both as-needed and regularly scheduled doses was not associated with overdose risk after adjustment.

"The present findings highlight the importance of implementing strategies for reducing opioid overdose among patients being treated for pain," the authors write. "This study documents a relationship between opioid prescribing and opioid overdose in a large, national, prospective cohort of individuals receiving opioid therapy for a variety of medical conditions. The risk of opioid overdose should continue to be evaluated relative to the need to reduce pain and suffering and be considered along with other risk factors."

More information: JAMA. 2011;305[13]1315-1321

Provided by JAMA and Archives Journals (news : web)

Fox Chase researchers report that naproxen reduces tumors in a mouse model of colon cancer


Numerous studies show that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of colon cancer. However, animal studies testing the NSAID naproxen or its derivative, NO-naproxen, have focused primarily on chemically-induced tumor formation. Now, researchers at Fox Chase Cancer Center find that naproxen and NO-naproxen reduce tumor formation in a strain of mutant mice that spontaneously develop colon tumors. The data also suggest that naproxen blocks a gatekeeper step that initiates tumor formation.

Margie Clapper, PhD, Co-Leader of the Cancer Prevention and Control Program at Fox Chase, will present the data in a late-breaking abstract session at the AACR 102nd Annual Meeting 2011 on Wednesday, April 6.

"There is a major effect on the very small lesions, about a 90% reduction in themutant mice treated with naproxen compared with control animals," says Clapper. "That tells us this drug may be very appropriate for intervening early in people, far in advance of the development of large tumors. We might be able to have a significant impact on the very early and small lesions, thus reducing the morbidity associated with the disease."

Scientists have shown previously that both naproxen and NO-naproxen kill colon cancer cells in culture, with NO-naproxen appearing to be more powerful than naproxen. In the current study, the team fed mice genetically predisposed to spontaneously develop colon tumors either regular food or food supplemented with high- or low-dose naproxen or high- or low-dose NO-naproxen. After 45 days, they found that mice fed low-dose naproxen had 70.3% fewer small tumors than the control animals and mice fed low-dose NO-naproxen had 64.0% fewer tumors than control animals. Moreover, a 89.3% reduction in very small tumors, known as microadenomas, was observed when mice were fed high-dose naproxen.

Although Clapper and first author Wen-Chi Chang, PhD, Assistant Research Professor at Fox Chase, had expected that NO-naproxen would be a more powerful chemopreventive agent based on cell culture data, the current study indicates this is not the case in animals.

Clapper says their results, which favor naproxen, fit well with a recent decision by the U.S. Food and Drug Administration (FDA). Scientists had developed NO-naproxen with the goal of reducing gastrointestinal toxicity associated with regular use of NSAIDs. The FDA, however, declined to approve NO-naproxen saying there was not enough evidence that it was less toxic than the older drug. "Our data are highly supportive of using what is already on the market, and FDA approved for arthritis, for the prevention of cancer," Clapper says.

Chang says a key aspect of the new data is naproxen's ability to block a very early step in colon cancer formation. "If we can identify the exact mechanism that naproxen uses to block tumor formation, then, in the future, we can work with chemists to design a compound that hits that pathway, without the broad spectrum of effects – and side effects – seen with NSAIDs," Chang says.

Provided by Fox Chase Cancer Center (news : web)

Scientists discover new drug target for inflammatory bowel disease: cytokine (IL-23)



A new discovery published in the April 2001 issue of Journal of Leukocyte Biology raises hope that new treatments for illnesses like Crohn's disease and ulcerative colitis are on the horizon. That's because they've identified IL-23, a cytokine used by the immune system to ward off disease, as a major contributor to the inflammation that is the hallmark of these illnesses. With this information, it is now possible to develop new treatments that stop or reduce the damaging effects of IL-23, potentially bringing relief to millions of people with inflammatory bowel disease (IBD) and possibly other inflammatory illnesses as well.

"Our studies highlight the pathogenic role of IL-23 in the induction of mucosal injury in the gut," said Zhanju Liu, M.D., Ph.D., a researcher involved in the work from the Department of Gastroenterology at The Shanghai Tenth People's Hospital at Tongji University in Shanghai, China. "Moreover, our work also provides a novel approach in the management of IBD and some autoimmune diseases."

To make this discovery, Liu and colleagues analyzed IL-23 expression in intestinal mucosa using laboratory techniques that amplify and simultaneously quantify a specific DNA molecule, allowing for both detection and quantification of one or more specific sequences in a DNA sample. IL-23R expression was detected in a variety of cells from peripheral blood and intestinal mucosa of IBD patients, suggesting that IL-23 plays an important role in the induction of proinflammatorycytokine secretion as well as different types of immune cells including recently discovered Th17 helper T cells that are often important in inflammatory diseases.

"This research is important because it helps us better understand why people develop IBD, and defines one of the key pathways driving the excessive inflammation," said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. "Even more important, however, is that this study moves us a step closer to new treatments for these illnesses by targeting IL-23 and related proteins."

More information: hanju Liu, Praveen K. Yadav, Xiaorong Xu, Jingling Su, Chi Chen, Maochun Tang, Hui Lin, Jifeng Yu, Jiaming Qian, Ping-Chang Yang, and Xingpeng Wang. The increased expression of IL-23 in inflammatory bowel disease promotes intraepithelial and lamina propria lymphocyte inflammatory responses and cytotoxicity. J Leukoc. Biol. April 2011 89:597-606;doi:10.1189/jlb.0810456

Provided by Federation of American Societies for Experimental Biology (news :web)

A new signaling pathway of the immune system is elucidated



A new signaling pathway, which is important for the regulation of the immune response and inflammation, was discovered by an international team of scientists led by prof Ivan Dikic from the Goethe University, Frankfurt, Germany. The scientists studied the involvement of ubiquitin, a universally present signaling protein in the cell. In today's issue of the scientific journal "Nature" the scientists report a novel type of modified ubiquitin chains involved in regulation of various processes within the cell.

The researchers have shown that linear ubiquitin, where ubiquitin proteins are attached to each other in a head to tail fashion, regulates signaling cascades initiated by cytokine receptors at the cell membrane. Cytokines are essential for the proper immune response – e. g. tumor necrosis factor (TNF-alpha) alpha is released mainly by the macrophages and plays an important role in local and body-wide inflammation.

When a cytokine docks on the receptor of a cell, it induces a signaling cascade in many cell types, which transmits a signal to the nucleus – the DNA centre of the cell. After cytokine activation of its receptor, the linear ubiquitin ligase complex (LUBAC), which links ubiquitin into head-to-tail chains, is activated at the start of this cascade. This enzyme stimulates nuclear factor kappaB (NF-kappaB), which coordinates the expression of important genes for the immune response, including the production of antibodies. However, how the molecules of this cascade function in detail and which structures interact is still under investigation.

The Dikic group solved an integral part of this puzzle. Sharpin, a protein containing a Ubiquitin-like and Ubiquitin-binding domain (UBD), constitutes a key component of the linear Ubiquitin ligase complex. Using animal models, they show that a lack of Sharpin causes heavy inflammation of numerous organs and in particular the skin. This is characterized as chronic proliferative dermatitis with death of keratinocytes, the predominant cells of the epidermis in charge of protecting the skin against environmental damage. This effect is dependent on the TNF signaling pathways.

The research reported allows us to reshape our thinking about how chronic proliferative dermatitis arises in humans, as well as opening new avenues of therapeutic intervention in the TNF-alpha signalling pathway. Moreover, a potential source of this disease may arise from mutations in a critical region of the linear ubiquitin ligase complex (LUBAC) allowing identification of patients that may respond well to targeted therapy. "In patients suffering from chronic proliferative dermatitis with unclear origin, it is now possible to specifically look for a mutation in LUBAC components", suggests Ivan Dikic.

Provided by Goethe University Frankfurt