Contact: Erin Doonan
In the vast majority of Parkinson’s disease (PD) patients, the disorder arises not because of a genetic defect, but because some external insult triggers the death of dopamine-producing neurons. Now, researchers have reported progress in understanding the mechanism underlying that death, which they say suggests a new treatment pathway.
In both mice and human patients, the researchers have found evidence that neurons die because of a crippling of a particular protective enzyme that eliminates potentially damaging “reactive oxygen species” normally generated in the cell’s power plants, called mitochondria.
David Park, of the Ottawa Health Research Institute, and colleagues published their findings in the July 5, 2007 issue of the journal Neuron, published by Cell Press.
The researchers studied the mechanism of PD using a mouse model of the disease, in which a mitochondria-affecting toxin called MPTP is used to produce Parkinson’s-like brain pathology. In earlier studies, they had found that MPTP activates protein-snipping enzymes called calpains in mitochondria. They also found evidence that calpains, in turn, activate a cellular switch called Cdk5. The question, however, was how this abnormal activation ultimately kills neurons.
In their new studies, the researchers analyzed neurons to determine that Cdk5 regulates yet another enzyme called Prx2. This enzyme is known as a peroxidase and acts to render harmless the chemically active reactive oxygen species that are produced inside mitochondria in the process of generating energy for the cell.
Specifically, the researchers found that treating neurons with MPTP activates Cdk5 to switch off Prx2. What’s more, they found that activating Prx2 in MPTP-treated mice prevented the loss of dopamine-producing neurons. And they experimentally demonstrated that the action of Cdk5 on Prx2 “plays a pivotal role” in the neuronal damage from MPTP.
Importantly, the researchers discovered evidence that the loss of Prx2 activity also plays a role in human PD. They found reduced Prx2 activity in brain tissue from PD patients.
“These findings provide a mechanistic link of how a mitochondrial damaging agent, through calpain-mediated Cdk5 activation and downregulation of an important antioxidant enzyme, can increase oxidative load, leading ultimately to death,” concluded the scientists.
“Taken together, our findings suggest that strategies to modulate Prx2 activity serve as beneficial targets for treatment of PD,” they concluded. “This is of particular importance since Cdk5 is thought to have normal beneficial roles in neurons and modulating a relevant downstream target rather than Cdk5 directly may be a better therapeutic strategy with regard to this pathway.”
The researchers include Dianbo Qu, Juliet Rashidian, Matthew P. Mount, Hossein Aleyasin, Mohammad Parsanejad, Arman Lira, Emdadul Haque, Yi Zhang, Steve Callaghan, Mireille Daigle, Maxime W.C. Rousseaux, Ruth S. Slack, Paul R. Albert, John M. Woulfe, and David S. Park of University of Ottawa, Ottawa, Ontario, Canada; Inez Vincent of University of British Columbia, Vancouver, British Columbia, Canada.
This work was partially supported by the Parkinson’s Disease Foundation and the Parkinson’s Society of Canada (D.Q.) and the Heart and Stroke Foundation (J.R., H.A.) and by funds from the Canadian Institutes of Health Research, the Parkinson’s Society Canada, the Parkinson’s Disease Foundation, the Parkinson’s Research Consortium, the US army, and the Heart and Stroke Foundation of Ontario (D.S.P.).
Qu et al.: “Role of Cdk5-Mediated Phosphorylation of Prx2 in MPTP Toxicity and Parkinson’s Disease.” Publishing in Neuron 55, 37–52, July 5, 2007. DOI 10.1016/j.neuron.2007.05.033. http://www.neuron.org.
Contact: Emily Butler
Kennedy Krieger Institute
Researchers at the Kennedy Krieger Institute recognize children with autism earlier than ever before, paving the way for earlier intervention and improved outcomes
(Baltimore, MD) — In a study published today in the Archives of General Psychiatry, researchers from the Kennedy Krieger Institute in Baltimore, Maryland found that autism can be diagnosed at close to one year of age, which is the earliest the disorder has ever been diagnosed. The study, which evaluated social and communication development in autism spectrum disorders (ASD) from 14 to 36 months of age, revealed that approximately half of all children with autism can be diagnosed around the first birthday. The remaining half will be diagnosed later, and their development may unfold very differently than children whose ASD is diagnosable around the first birthday. Early diagnosis of the disorder allows for early intervention, which can make a major difference in helping children with autism reach their full potential.
Researchers examined social and communication development in infants at high and low risk for ASD starting at 14 months of age and ending at 30 or 36 months (a small minority of the children exited the study at 30 months). Half of the children with a final diagnosis of ASD made at 30 or 36 months of age had been diagnosed with the disorder at 14 months, and the other half were diagnosed after 14 months. Through repeated observation and the use of standardized tests of development, researchers identified, for the first time, disruptions in social, communication and play development that were indicative of ASD in 14-month olds. Multiple signs indicating these developmental disruptions appear simultaneously in children with the disorder.
Dr. Rebecca Landa, lead study author and director of Kennedy Krieger’s Center for Autism and Related Disorders, and her colleagues identified the following signs of developmental disruptions for which parents and pediatricians should be watching:
Abnormalities in initiating communication with others: Rather than requesting help to open a jar of bubbles through gestures and vocalizations paired with eye contact, a child with ASD may struggle to open it themselves or fuss, often without looking at the nearby person.
Compromised ability to initiate and respond to opportunities to share experiences with others: Children with ASD infrequently monitor other people’s focus of attention. Therefore, a child with ASD will miss cues that are important for shared engagement with others, and miss opportunities for learning as well as for initiating communication about a shared topic of interest. For example, if a parent looks at a stuffed animal across the room, the child with ASD often does not follow the gaze and also look at the stuffed animal. Nor does this child often initiate communication with others. In contrast, children with typical development would observe the parent’s shift in gaze, look at the same object, and share in an exchange with the parent about the object of mutual focus. During engagement, children have many prolonged opportunities to learn new words and new ways to play with toys while having an emotionally satisfying experience with their parent.
Irregularities when playing with toys: Instead of using a toy as it is meant to be used, such as picking up a toy fork and pretending to eat with it, children with ASD may repeatedly pick the fork up and drop it down, tap it on the table, or perform another unusual act with the toy.
Significantly reduced variety of sounds, words and gestures used to communicate: Compared to typically developing children, children with ASD have a much smaller inventory of sounds, words and gestures that they use to communicate with others.
“For a toddler with autism, only a limited set of circumstances – like when they see a favorite toy, or when they are tossed in the air – will lead to fleeting social engagement,” said Landa. “The fact that we can identify this at such a young age is extremely exciting, because it gives us an opportunity to diagnose children with ASD very early on when intervention may have a great impact on development.”
The current study reveals that autism often involves a progression, with the disorder claiming or presenting itself between 14 and 24 months of age. Some children with only mild delays at 14 months of age could go on to be diagnosed with ASD. Landa and her colleagues observed distinct differences in the developmental paths, or trajectories, of children with early versus later diagnosis of ASD. While some children developed very slowly and displayed social and communication abnormalities associated with ASD at 14 months of age, others showed only mild delays with a gradual onset of autism symptoms, culminating in the diagnosis of ASD by 36 months.
If parents suspect something is wrong with their child’s development, or that their child is losing skills during their first few years of life, they should talk to their pediatrician or another developmental expert. This and other autism studies suggest that the “wait and see” method, which is often recommended to concerned parents, could lead to missed opportunities for early intervention during this time period.
“What’s most exciting about these important advancements in autism diagnosis is that ongoing intervention research leads us to believe it is most effective and least costly when provided to younger children,” said Dr. Gary Goldstein, President and CEO of the Kennedy Krieger Institute. “When a child goes undiagnosed until five or six years old, there is a tremendous loss of potential for intervention that can make a marked difference in that child’s outcome.”
While there are currently no standardized, published criteria for diagnosing children with autism at or around one year of age, Landa’s goal is to develop these criteria based on this and other autism studies currently underway at the Kennedy Krieger Institute. Landa and her colleagues at the Institute plan on releasing preliminary diagnostic criteria for very young children with autism in an upcoming report.
Participants in the current study included infants at high risk for ASD (siblings of children with autism, n=107) and low risk for ASD (no family history of autism, n=18). Standardized tests of development and play-based assessment tools were used to evaluate social interaction, communication and play behaviors in both groups at 14, 18 and 24 months of age. Researchers assigned diagnostic impressions at every age, indicating whether there were clinically significant signs of delay or impairment. After their last evaluation at 30 or 36 months, each participant was then given a final diagnostic classification of ASD, non-ASD impairment, or no impairment. The ASD group was further divided into an Early ASD diagnosis group and a Later ASD diagnosis group based on whether they were given a diagnosis of ASD at 14 or 24 months.
Autism spectrum disorders (ASD) is the nation’s fastest growing developmental disorder, with current incidence rates estimated at 1 in 150 children. This year more children will be diagnosed with autism than AIDS, diabetes and cancer combined, yet profound gaps remain in our understanding of both the causes and cures of the disorder. Continued research and education about developmental disruptions in individuals with ASD is crucial, as early detection and intervention can lead to improved outcomes in individuals with ASD.
About the Kennedy Krieger Institute
Internationally recognized for improving the lives of children and adolescents with disorders and injuries of the brain and spinal cord, the Kennedy Krieger Institute in Baltimore, MD serves more than 13,000 individuals each year through inpatient and outpatient clinics, home and community services and school-based programs. Kennedy Krieger provides a wide range of services for children with developmental concerns mild to severe, and is home to a team of investigators who are contributing to the understanding of how disorders develop while pioneering new interventions and earlier diagnosis. For more information on Kennedy Krieger Institute, visit http://www.kennedykrieger.org.
Contact: Dr. Branwen Morgan
Professor Herbert Herzog, Director of the Neuroscience Research Program at the Garvan Institute of Medical Research, together with scientists from the US and Slovakia, have shown that neuropeptide Y (NPY), a molecule the body releases when stressed, can ‘unlock’ Y2 receptors in the body’s fat cells, stimulating the cells to grow in size and number. By blocking those receptors, it may be possible to prevent fat growth, or make fat cells die.
“We have known for over a decade that there is a connection between chronic stress and obesity,” said Professor Herzog. “We also know that NPY plays a major role in other chronic stress-induced conditions, such as susceptibility to infection. Now we have identified the exact pathway, or chain of molecular events, that links chronic stress with obesity.”
“There is not much we can do about the increased levels of NPY caused by stress, but we can do something about the damage it causes. If we can interfere before it causes fat to amass, it could have a major impact on cardiovascular disease, diabetes, and cancer (which all have links with obesity).”
“Basically, when we have a stress reaction, NPY levels rise in our bodies, causing our heart rate and blood pressure to go up, among other things. Stress reactions are normal, unavoidable, and generally serve a useful purpose in life. It’s when stress is chronic that its effects become damaging.”
Scientists at Georgetown University (Washington D.C), part of this collaborative study, have found a direct connection between stress, a high calorie diet and unexpectedly high weight gain. Stressed and unstressed mice were fed normal diets and high calorie (high fat and high sugar, or so called ‘comfort food’) diets. The mice on normal diets did not become obese. However, stressed mice on high calorie diets gained twice as much fat as unstressed mice on the same diet. The novel and unexpected finding was that when stressed and non-stressed animals ate the same high calorie foods, the stressed animals utilised and stored fat differently.
“Our findings suggest that we may be able to reverse or prevent obesity caused by stress and diet, including the worst kind of obesity; the apple-shaped type, which makes people more susceptible to heart disease and diabetes,” says senior author of the Nature Medicine paper, Professor Zofia Zukowska of Georgetown University. “Using animal models, in which we have either blocked the Y2 receptor, or selectively removed the gene from the abdominal fat cells, we have shown that stressed mice on high calorie diets do not become obese. “Even more surprisingly, in addition to having flatter bellies, adverse metabolic changes linked to stress and diet, which include glucose intolerance and fatty liver, became markedly reduced. We do not know yet exactly how that happens, but the effect was remarkable,” she said.
Professor Herzog believes that these research findings will have a profound effect on the way society will deal with the obesity epidemic. “There are millions of people around the world who have lived with high levels of stress for so long their bodies think it’s ‘normal’. If these people also eat a high fat and high sugar diet, which is what many do as a way to reduce their stress, they will become obese.”
“Until now, the pharmaceutical industry has focused on appetite suppressants with only moderate success. Our hope is that in the near future pharmaceutical companies, using the results of our research, will develop antagonists against the Y2 receptor that will bring about a reduction in fat cells.”
Notes to editors:
Stress-activated adipogenic pathway in fat tissue exaggerates diet-induced obesity and metabolic syndrome.
Kuo, L.E., Kitlinska, J.B., Tilan, J.U., Li, L., Baker, S.B., Johnson, M.D., Lee, E.W., Burnett, M.S., Fricke, S.T., Kvetnansky, R.K., Herzog, H. & Zukowska, Z.
Nature Medicine advance online publication, 1 July 2007
The study was co-funded by the National Institutes of Health, the American Heart Association, and the Slovak Research and Development Agency.
The Garvan Institute of Medical Research was founded in 1963. Initially a research department of St Vincent’s Hospital in Sydney, it is now one of Australia’s largest medical research institutions with approximately 400 scientists, students and support staff. Garvan’s main research programs are: Cancer, Diabetes & Obesity, Arthritis & Immunology, Osteoporosis, and Neuroscience. The Garvan’s mission is to make significant contributions to medical science that will change the directions of science and medicine and have major impacts on human health. The outcome of Garvan’s discoveries is the development of better methods of diagnosis, treatment, and ultimately, prevention of disease.
Contact: Rachel Salis-Silverman
JAMA and Archives Journals
It is becoming more common for children with complex chronic conditions to die in their home than in a hospital, although black and Hispanic children with these conditions are less likely to die in their home, according to a study in the June 27 issue of JAMA, a theme issue on chronic diseases of children.
Chris Feudtner, M.D., Ph.D., M.P.H., of Children’s Hospital of Philadelphia, presented the findings of the study at a JAMA media briefing in New York.
Many pediatric palliative care clinicians suggest that the preferred place of death, by the family, of an infant, child, or adolescent with a medically complex chronic condition is the home. Advances in home-based medical technology and changes in attitudes about pediatric palliative care and hospice services may be making this a more viable option, according to background information in the article.
Dr. Feudtner and colleagues conducted a study to determine if the proportion of complex chronic condition-related deaths occurring at home among children and adolescents increased between 1989 and 2003, and to assess if there were any race and ethnicity disparities in the location of death. The researchers analyzed data from the National Center for Health Statistics’ Multiple Cause of Death Files.
Among the 22.1 percent of deaths (198,160 of 896,509 total deaths) attributed to a complex chronic condition between 1989 and 2003, the percentage of deaths occurring at home increased significantly for all age groups (overall, from 10.1 percent in 1989 to 18.2 percent in 2003), but with larger increases for deaths beyond infancy. The odds of death occurring at home increased by 3.8 percent annually.
The percentage of individuals dying at home increased significantly over time for infants (4.9 percent home deaths in 1989 to 7.3 percent in 2003); 1 to 9-year-olds (17.9 percent to 30.7 percent), and 10 to 19-year-olds (18.4 percent to 32.2 percent). During this same period, there was a significant decline in the percentage of deaths occurring in the hospital for each of these three age categories.
The authors suggest that this gradual change in place of death may be occurring because of advances in medical technology in the home setting and broad shifts in attitudes and decision-making processes regarding palliative and end-of-life care in U.S. culture.
The child’s race, ethnicity, and region of home residence were significantly associated with death occurring at home. The odds of dying at home were reduced by 50 percent among black individuals, and reduced by 48 percent among Hispanic individuals, when compared with whites.
Concerning possible reasons for the observed racial and ethnic differences, “ … differential access to health care services or medical technology, divergent cultural attitudes or approaches to palliative and end-of-life care decision making, or differing levels of financial or other support within the patient’s or family’s social network may make dying at home more or less likely.”
“… as efforts to improve understanding of the sources and remedies of racial and ethnic disparities in pediatric end-of-life care are completed, medical and other concerned professionals need to ensure that all patients have access to necessary care and that all dialogue and interactions regarding decisions about care—whether curative, life-extending, or palliative—are built on mutual understanding, trust, and respect,” the authors conclude.
(JAMA. 2007;297:2725-2732. Available pre-embargo to the media at http://www.jamamedia.org)
Editor’s Note: The conduct of this study was supported in part by grants from the Agency for Healthcare Research and Quality and the National Institute of Nursing Research of the National Institutes of Health. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.
For More Information: Contact the JAMA/Archives Media Relations Department at 312-464-JAMA or email: firstname.lastname@example.org.
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