Mediterranean Diet Associated With Lower Risk Of Cognitive Impairment

Eating a Mediterranean diet appears to be associated with less risk of mild cognitive impairment—a stage between normal aging and dementia—or of transitioning from mild cognitive impairment into Alzheimer's disease, according to a report in the February issue of Archives of Neurology, one of the JAMA/Archives journals."Among behavioral traits, diet may play an important role in the cause and prevention of Alzheimer's disease," the authors write as background information in the article. Previous studies have shown a lower risk for Alzheimer's disease among those who eat a Mediterranean diet, characterized by high intakes of fish, vegetables, legumes, fruits, cereals and unsaturated fatty acids, low intakes of dairy products, meat and saturated fats and moderate alcohol consumption.

Nikolaos Scarmeas, M.D., and colleagues at Columbia University Medical Center, New York, calculated a score for adherence to the Mediterranean diet among 1,393 individuals with no cognitive problems and 482 patients with mild cognitive impairment. Participants were originally examined, interviewed, screened for cognitive impairments and asked to complete a food frequency questionnaire between 1992 and 1999.

Over an average of 4.5 years of follow-up, 275 of the 1,393 who did not have mild cognitive impairment developed the condition. Compared with the one-third who had the lowest scores for Mediterranean diet adherence, the one-third with the highest scores for Mediterranean diet adherence had a 28 percent lower risk of developing mild cognitive impairment and the one-third in the middle group for Mediterranean diet adherence had a 17 percent lower risk.

Among the 482 with mild cognitive impairment at the beginning of the study, 106 developed Alzheimer's disease over an average 4.3 years of follow-up. Adhering to the Mediterranean diet also was associated with a lower risk for this transition. The one-third of participants with the highest scores for Mediterranean diet adherence had 48 percent less risk and those in the middle one-third of Mediterranean diet adherence had 45 percent less risk than the one-third with the lowest scores.

The Mediterranean diet may improve cholesterol levels, blood sugar levels and blood vessel health overall, or reduce inflammation, all of which have been associated with mild cognitive impairment. Individual food components of the diet also may have an influence on cognitive risk. "For example, potentially beneficial effects for mild cognitive impairment or mild cognitive impairment conversion to Alzheimer's disease have been reported for alcohol, fish, polyunsaturated fatty acids (also for age-related cognitive decline) and lower levels of saturated fatty acids," they write.

Additional studies are needed to confirm the role of this or other dietary factors in the development of cognitive impairment and Alzheimer's disease, they conclude.

This work was supported by grants from the National Institute on Aging.

Genetic Change Prevents Cell Death In Mouse Model Of Parkinson's Disease

By shifting a normal protective mechanism into overdrive, a University of Wisconsin-Madison scientist has completely shielded mice from a toxic chemical that would otherwise cause Parkinson's disease.Parkinson's disease is a disabling and sometimes fatal disease that afflicts 1.5 million Americans, with about 60,000 new cases annually. Its major symptoms, including tremors and sluggish movement, have been traced to death of small numbers of nerve cells in the substantia nigra, a brain region that helps regulate movement.

Adding extra copies of a gene that makes a normal, protective protein neutralized a toxic chemical that would normally devastate the substantia nigra. "This complete abolition of toxicity was far greater than we expected," says Jeffrey Johnson, a UW-Madison professor of pharmacy. "It was striking. We thought we would see a 20 or 30 or 40 percent reduction in cell death."

The protective mechanism is initiated by a protein called Nrf-2, which is present in people and in mice, says Johnson. Nrf-2 (transcription factor NF-E2-related factor) is made by astrocytes, brain cells that play a supportive role to the neurons, which are the cells that actually carry nerve signals.

In recent years, researchers looking at a range of neurodegenerative diseases, including Alzheimer's and Lou Gehrig's diseases as well as Parkinson's, have focused on the astrocytes in their quest to help the brain protect itself from stressful conditions that are deadly to neurons. "Astrocytes way outnumber neurons and are found throughout the central nervous system," says Johnson. "Neurons have always gotten the Academy Awards, but astrocyte dysfunction is becoming a central theme in neurodegenerative disease. If we can figure out how to fix a sick astrocyte, or even prevent it from getting sick, that could offer profound protection against almost all neurodegenerative diseases."

Because neurons are impossible to replace, the present research focus in neurodegenerative disease is on preventing their death in the first place. Parkinson's disease can be treated for a time by replacing dopamine, the brain chemical made by the substantia nigra, but the treatment loses its efficacy over time.

In a study funded by the National Institute of Environmental Health Sciences and published in today's Proceedings of the National Academy of Sciences, Johnson and UW-Madison colleagues Pei-Chun Chen, Marcelo Vargas and Delinda Johnson studied mice with extra Nrf-2 genes. The astrocytes in these mice produced about twice the normal level of Nrf-2 protein.

The researchers then dosed the mice with MPTP, a chemical that kills neurons in the substantia nigra and has become the major mechanism for studying Parkinson's disease in mice. The toxicity of MPTP was discovered in 1982, when young drug users in California developed the classic symptoms of Parkinson's disease, a disease that usually strikes those over age 60. Researchers found that the synthetic heroin these people had used was contaminated with MPTP, and further studies showed that MPTP is highly toxic to nerve cells in the substantia nigra.

When astrocytes make Nrf-2, the protein attaches to their DNA, kick-starting activity in hundreds of genes that release chemicals that can protect nearby neurons from oxidation – a series of chemical reactions that can injure or kill cells. "The astrocytes are also probably sucking up the bad stuff, thereby reducing the oxidative environment and stress on the neurons," says Johnson, adding that his laboratory is trying to identify those specific protective chemicals.

Nobody can predict when a manipulation of Nrf-2 could reach clinical trials, which Johnson says are at the very least two years in the future. While these experiments altered the mouse cells with genetic engineering, human trials would probably use drugs to boost Nrf-2 production in astrocytes. Several labs, including Johnson's, are already searching for candidate drugs.

The stakes are high, Johnson says, because Nrf-2 also protects brain cells in models of such fatal brain diseases as Alzheimer's, ALS, and Huntington's disease.

Normally, neurons die in these neurodegenerative diseases to "commit suicide" through a process called programmed cell death. "Nrf-2 seems to rebalance the system," Johnson says, "in favor of what we call programmed cell life."

Molecule That Suppresses Immune Response Under Study In Type 1 Diabetes

he idea is to teach the immune system of children at high risk for type 1 diabetes not to attack the insulin-producing cells of the pancreas."We want to create a no-go zone," said Dr. Andrew Mellor, immunologist who directs the Medical College of Georgia Immunotherapy Center. Type 1 diabetes is classified as an autoimmune disease because the immune system targets healthy islet cells for destruction, leaving young patients unable to use glucose, a major fuel source for the body.

MCG researchers think they may be able to delay or even prevent that destruction by boosting the body's levels of an enzyme fetuses uses to escape the mother's immune response or by packaging islet cell antigens, which get the immune system's attention, with this suppressor. T-cells are immune cells that decide whether to attack or ignore an antigen. Dr. Mellor believes they'll ignore insulin-producing cells if they see them for the first time with indoleomine 2,3-dioxegenase, or IDO, a powerful immune system inhibitor.

"We are going to be in a situation, in the not too distant future where you can identify an individual at risk, such as a 5-year-old child who has a 90 percent chance of becoming a type 1 diabetic within 10 years," he said. "Once you know that information the onus is on medicine to do something about reducing that risk."

A three-year, $646,000 grant from the Juvenile Diabetes Research Foundation International will enable studies in a classic model of type 1 diabetes: a normal-weight mouse that develops diabetes. Eighty percent of the female mice get diabetes by age 12 to 15 weeks. MCG researchers suspect it's because they have a transient defect in their dendritic cells that hurts IDO expression. Dendritic cells, which can express IDO, show antigens to the T-cells.

A Journal of Immunology paper last year reported that when dendritic cells and IDO are depleted in the mouse, the disease gets worse. Dr. Mellor's research partner Dr. David Munn collaborated with Dr. Jonathan Katz, who directs the Diabetes Research Center at the Cincinnati Children's Hospital Medical Center, on the study. "That was formal evidence that the dendritic cells with IDO were putting the brakes on the disease," said Dr. Mellor, Georgia Research Alliance Eminent Scholar in Molecular Immunogenetics. "It leads to the hypothesis that by reinforcing the IDO mechanism in these mice, you can slow or even prevent the disease." He'll further explore IDO's role in type 1 diabetes by using several different methods to get rid of IDO and observe what happens. He'll also enhance IDO expression in the females by giving a drug commonly used to treat rheumatoid arthritis that the MCG team has learned can boost IDO expression. "The mouse has an endogenous mechanism; it's just defective," said Dr. Mellor. "If you have the IDO come on earlier and stronger, maybe you can slow or halt disease progression or maybe even prevent it."

They'll also deliver a two-step treatment: prompting inflammation, which causes dendritic cells to express IDO, at the same time they give antigens to the insulin-producing cells. "The presence of the antigen excites the T cells if you will, but the presence of IDO tells it to stop getting excited," said Dr. Mellor. The approach has its risks. "The opposite would be disastrous: you would accelerate the disease," said Dr. Mellor. However novel strategies are needed, not just to treat the disease, but to try to prevent it, he said.

Dr. Jin-Xiong She, director of the MCG Center for Biotechnology and Genomic Medicine and Georgia Research Alliance Eminent Scholar in Genomic Medicine, is leading efforts to identify these children. He's a principal investigator on an international effort looking at thousands of babies with genes that put them at high risk for diabetes then following them for years to see how genetics and environment work together to cause the disease. His laboratory studies include identifying additional high-risk genes as well as biomarkers for children at risk.

A different kind of vaccine – one that teaches the immune system to avoid something rather than attack it – may be the best option for these high-risk children, Dr. Mellor said. So he's also using disabled viral vectors, which are good at infecting cells, to deliver IDO as an off switch for the immune system. "We've been thinking IDO for a long time on this one," said Dr. Mellor.

A team of MCG scientists led by Drs. Mellor and Munn showed in research published in Science in 1998 that the fetus expresses IDO to help avoid rejection by the mother’s immune system. They also are exploring its therapeutic potential in transplantation and cancer.

Cancer Diagnosis: Now In 3-D

University of Washington researchers have helped develop a new kind of microscope to visualize cells in three dimensions, an advance that could bring great progress in the field of early cancer detection. The technique could also bridge a widening gap between cutting-edge imaging techniques used in research and clinical practices, researchers said.

Eric Seibel, a UW mechanical engineering associate professor, and his colleagues have worked in collaboration with VisionGate, Inc., a privately held company in Gig Harbor, Wash., that holds the patents on the technology. The machine works by rotating the cell under the microscope lens and taking hundreds of pictures per rotation, and then digitally combining them to form a single 3-D image.

The 3-D visualizations could lead to big advances in early cancer detection, since clinicians today identify cancerous cells by using 2-D pictures to assess the cells' shape and size.

"It's a lot easier to spot a misshapen cell if you can see it from all sides," Seibel said. "A 2-D representation of a 3-D object is never perfectly accurate -- imagine trying to get an exact picture of the moon, seeing only one side."

The new microscope, known by the trademarked name Cell-CT, is so named because it works similarly to a CT-scan -- though on a very small scale, and using visible light instead of X-rays. In a CT-scan, the patient is immobile while the X-ray machine rotates. In the Cell-CT microscope, each cell is embedded in a special gel inside a glass tube that rotates in front of a fixed camera that takes many pictures per rotation. The gel has similar optical properties to the tube's so that no light reflects off the glass. In both processes, the end result is that hundreds of pictures are assembled to form a 3-D image that can be viewed and rotated on a computer screen.

The new 3-D microscope also helps to bring imaging techniques from the lab to the doctor's office. Although great advances have been made in microscope technology through the years, clinicians have been using essentially the same technique for cancer diagnoses for the last 300 years, Seibel said. Pathologists today still use a cell stain invented in the 1700s to examine sections of suspected cancers. Pathologists do not use any of the newer fluorescent molecular dyes that produce the precise, detailed cellular portraits found in biology journals.

"Scientists have been using fluorescent dyes in research for decades, but these techniques have not yet broken into everyday clinical diagnoses," Seibel said. "There's a big gap between the research and clinical worlds when it comes to cancer, and it's getting wider. We're trying to bridge that gap."

Part of the reason for this gap, Seibel said, is that there is no way to accurately match an image taken using the fluorescent dyes with an image taken using the traditional stains that currently form the basis for cancer diagnoses, and for which diagnostic standards exist. The new 3-D microscope will allow that matchup -- Seibel and his colleagues have shown simultaneous fluorescent and traditional staining of the same cells. The new device is the first 3-D microscope that can use both traditional and fluorescent stains, Seibel said.

"Now that we have a way to compare these stains, we hope this will provide a way to get some of those sophisticated research techniques into clinical use," Seibel said.

The new microscope is also more precise than other 3-D machines currently available. All other microscopes producing 3-D images have poor resolution in the up-down direction, the direction between the sample and the microscope's lens, Seibel said.

Qin Miao, a UW bioengineering doctoral student, used a tiny plastic particle of known dimensions to show the microscope's resolution. He found that the UW group's machine has three times better accuracy in that up-down direction than standard microscopes used in cancer detection. Miao will present the group's findings for the microscope's performance Feb. 9 at the SPIE Medical Imaging conference in Orlando, Fla.

"This means we can do quantitative analysis of cells," Miao said. "This kind of undistorted image is difficult to achieve using other technology."

In another recent publication, Seibel and his colleagues describe a study comparing cancer detection using traditional methods with their 3-D microscope. Pathologists using 3-D technology detected cancer with one-third the error rate compared to those using the traditional microscope. The authors also describe using their microscope to discover a "pre-cancer" cell, a cell that was on the verge of turning cancerous.

"This is where we can make an impact in medicine -- looking for these earliest changes," Seibel said.

Other authors of the paper are J. Richard Rahn, Ryland Bryant, Christy Lancaster, Anna Tourovskaia, Dr. Thomas Neumann and Alan Nelson, all of VisionGate.

Funding was provided by VisionGate and the Washington Technology Center.