Back to main neuroscience page SAFBANA.GIF (7835 bytes)

NeuroNews

A neuro-related selection of items from the news services...

Mutant Gene Tied to Brain Diseases

1 September 1999

Reuters

A gene defect that impairs cell's ability to "houseclean" proteins can lead to degeneration of brain cells, report Japanese researchers.

The findings are the first to confirm the theory that proteins that cannot be broken down accumulate in brain cells, leading to neurodegenerative disorders such as Alzheimer's, Huntington and Parkinson's disease.

Normally, cells mark proteins that are destined to be broken down as waste, with a protein called ubiquitin. Ubiquitin is subsequently released from the degraded proteins and recycled for future use.

The team of researchers found that mice with neurodegenerative disorders have a defective gene, which prevents an enzyme from producing and recycling ubiquitin. As a result, there is a build-up of waste in nerve cells, which leads to their degeneration.

"Our data suggest that altered function of the ubiquitin system directly causes neurodegeneration," they write in the September issue of Nature Genetics.

The team of researchers, led by Kazumasa Saigoh and Yu-Lai Wang of the National Center of Neurology and Psychiatry in Tokyo, studied a strain of genetically altered mice called "gad" mice whose brains show changes similar to those of humans with inherited neurodegenerative diseases. They compared the diseased mouse brains with those of normal mice, homing in on the enzyme responsible for producing ubiquitin.

The authors write that their findings provide "a useful model for investigating human neurodegenerative disorders."

In an accompanying editorial, Marcy Macdonald of Harvard Medical School notes that it remains to be seen why the genetic defect affects neurons specifically.

"This is not an easy challenge," she writes. "Certainly, the discovery bodes well for our understanding of this complex and essential cellular pathway in the nervous system."

PRIMARY SOURCE: Nature Genetics 1999;23:10-11, 47-51.
© Reuters News Service

Head Trauma Linked to Degenerative Changes in the Brain

1 September 1999

Reuters

Trauma to the head may trigger a cascade of biochemical events in the brain, in time resulting in neurodegenerative changes similar to those found in patients with Alzheimer's disease, report researchers at the University of Pennsylvania in Philadelphia.

The findings back previous studies that suggested brain trauma increases the risk of Alzheimer's disease, a leading cause of dementia, later in life.

In a statement, the researchers say that they hope their study will lead to a renewed commitment to educate the public about behaviors that reduce the risk of head injury, such as wearing seatbelts while traveling in an automobile and helmets while riding bicycles or motorcycles.

Dr. Douglas H. Smith, who led the research effort, told Reuters Health that these findings support "several epidemiologic reports (that have suggested) a link between a single episode of brain trauma and the development of Alzheimer's disease later in life."

Smith's team induced brain injury in anesthetized pigs via very rapid acceleration/deceleration of the animals' heads without direct impact, similar to what humans often experience in an automobile accident. They describe their experiments in the September issue of the Journal of Neuropathology and Experimental Neurology.

"Brain trauma is the only environmental risk factor for Alzheimer's disease, so there is something about brain trauma that might initiate these insidious neurodegenerative cascades," Smith said in the interview with Reuters Health.

Analysis of brain tissue from the animals revealed diffuse axonal pathology, the scientists report. "The most remarkable and consistent finding," they write in the paper, "was extensive (amyloid beta) and tau accumulation in damaged (brain cells) following trauma." Amyloid beta protein is a characteristic finding in the brains of patients with Alzheimer's disease. In the study animals, these changes were evident as early as 3 to 10 days post-injury.

Smith said that some of the brain-injured animals, his group also observed plaque formation, another typical finding in Alzheimer's disease.

The team conclude that microscopic injury to the brain caused by trauma can be linked to the development of Alzheimer's disease many years after the injury.

The finding may also lead to new drugs aimed at preventing the process. "This study adds to the body of knowledge that might aid us in the development of an anti-plaque-making compound," Smith said in a statement.

PRIMARY SOURCE: Journal of Neuropathology and Experimental Neurology 1999;58:982-992.
c. Reuters News Service

Hydrocephalus: The Pressure Is Off

RICHARD SALTUS
© 1999 The Boston Globe

Almost overnight, in the late 1950s, the outlook for a baby born with hydrocephalus improved dramatically, thanks to a treatment as conceptually simple as a piece of plumbing.

Because hydrocephalus sometimes called ``water on the brain'' is caused by a blockage in the brain's circulatory system leading to excess fluid pressure, surgeons began installing shunts that diverted the extra fluid from the brain through a tube into the abdomen or elsewhere in the body.

Devised by a surgeon who placed one in his son's head, shunts have made it possible for many hydrocephalic children to grow to adulthood with relatively normal intelligence and to live pretty much as other people do. In years past, a child would have been mentally retarded and lived out his or her life vastly shortened in an institution.

Although shunts revolutionized the treatment of hydrocephalus, they are far from perfect; they can become infected or blocked, malfunction, be outgrown by a child, or become dislodged. They often require a few or even numerous surgeries (called revisions) to fix.

In the past year, however, a ``programmable'' shunt valve whose pressure can be changed simply by holding a magnetic controller against the head has been approved by the U.S. Food and Drug Administration. It's already been shown to cut down on the need for shunt surgeries, and surgeons say they like it because they just ``dial in'' different pressures to see how the patient responds, instead of having to operate each time.

One recipient of the programmable valve, Lindsay Corkin, 13, of Hanover, Mass., developed hydrocephalus four years ago from a brain tumor and had a standard shunt implanted.

She was fine until last year, says her mother, Lauren, when she began having severe daily headaches and vomiting that got worse, despite repeated visits to doctors.

Finally, she became so miserable that Lauren Corkin pulled her daughter out of summer camp and took her to Children's Hospital, where a spinal tap showed her fluid pressure was too high. Dr. Peter Black, a neurosurgeon at Brigham and Women's and Children's hospitals in Boston, replaced her shunt with a new one equipped with the programmable valve.

Black set the valve at one pressure level, and following the operation monitored her condition and reduced the pressure using the magnetic programmer.

Since then, Lindsay has had no more headaches, vomiting or other symptoms.

A Malden, Mass. man with hydrocephalus, 32-year-old Greg Tocco, says, ``As far as I'm concerned this device has probably saved me a couple of surgeries'' already, after having had the programmable valve implanted as part of a clinical trial of the device.

Tocco, who developed the condition after being hit in the head with a baseball when he was 13, has established the Hydrocephalus Foundation, Inc., a Saugus, Mass. advocacy group for affected people.

``A lot of our families are very, very pleased with it,'' said Emily Fudge, executive director of the Hydrocephalus Association in San Francisco, another support and advocacy group.

Hydrocephalus occurs about once in every 1,000 births, either as an isolated problem or part of another congenital malformation like spina bifida or Dandy-Walker syndrome. Often it's not diagnosed until a child's head continues to grow past normal dimensions. The condition can also begin in adulthood when blockages of fluid are caused by tumors, trauma, bleeding or infections.

Dr. Carlos Hakim, a neurosurgeon, invented the programmable valve while training in a combined MIT -- Harvard biomedical engineering program. His father invented an earlier shunt valve, and after Hakim designed the programmable version, it was then developed and manufactured in Switzerland by craftsmen previously employed in watchmaking, Hakim said in an interview.

The valve, now called the Codman Hakim Programmable Valve System and sold by Johnson and Johnson Professional Inc., can be adjusted to any of 18 different pressures using a magnet that's held over the skin of the head.

``This allows us to match the pressure to the patient's needs'' without performing an operation to adjust the valve, says Black.

Johnson and Johnson estimates that $100 million is spent annually in the United States on shunting operations half of it on revisions. Presumably the valve, by eliminating a proportion of these revisions, will reduce the need for invasive procedures and save money.

Dr. Joseph Madsen, a neurosurgeon at Children's Hospital, says he has implanted about 20 of the programmable valves. He said they make it easier to fine-tune pressure inside the brain. For example, when a patient is bothered by headaches, although the shunt is doing its job, he said, ``it wouldn't necessarily be worth doing a whole operation just to see if your headaches would improve'' with a shunt that has a different presssure.

But with the Hakim valve, he said, ``You could adjust it at a different pressure, and if it doesn't solve the problem, come back next week and we'll try another pressure.''

Other recent shunt innovations include catheters coated with antibiotics designed to reduce infections, and a shunt with an electronic sensor that can transmit pressure readings from inside the brain to a bedside monitor.

Shunts are made up of a catheter placed through a hole in the skull into the fluid-filled spaces inside the brain; a small pressure valve under the skin of the head to control the flow; and a flexible tube that snakes under the skin of the neck and body to the abdomen, where it dumps the extra fluid.

By lowering the pressure of the fluid that is squeezing the brain, shunting vastly reduces the risk of mental retardation, headaches, gait problems, lethargy and other complications.

Even when they are working well, shunts may have to be replaced because the pressure inside the patient's brain changes, so that the set pressure at which the valve opens becomes too high or too low.

``If the pressure is too low, and too much fluid escapes from the brain, the brain collapses around the shunt and you can get bad headaches'' and other problems, says Black. ``If the pressure is too high, then the shunt doesn't work and the patient doesn't get better.''

At one time, the life expectancy for someone with hydrocephalus averaged 10 years. But in the last 25 years, the death rate from the condition has plunged from 54 percent to 5 percent, and the chance of retardation is down from 62 to 30 percent. And this almost entirely due to shunting.

Today, ``the first generation of kids who were shunted are now adults,'' says Fudge at the Hydrocephalus Association. ``With shunts, many of them are doing very well, but we're just beginning to learn about the long-term effects'' of the disorder and its treatment, she says.

Kellie Robinson, the California co-author of a new book on hydrocephalus, says, ``my head is a little bigger than normal, but it's not noticeable. To look at me, you wouldn't know I have anything wrong.'' But she says that she has problems in concentrating and remembering, and finds mathematical concepts particularly difficult.

Fudge told the FDA at a hearing earlier this year that a Hydrocephalus Association survey found that ``while most people with hydrocephalus and their families are grateful that shunts either provide them with a normal life or saved their life, they are deeply concerned about revisions, mechanical failures, infections, long-term complications and the difficulty of assessing whether or not'' the shunt is working properly.

Nevertheless, the fruits of the efforts by surgeons and biomedical inventors like Hakim appear to be paying off. The adjustable shunt ``has made a world of difference to this girl,'' says Lindsay Corkin's mother. ``We have our old Lindsay back.''

Less Is More When It Comes to Aspirin

ED UNGAR
© 1999 Medical Tribune News Service

Low doses of aspirin may prevent the onset of the most common form of stroke in healthy women, but high doses may help bring on the most deadly type of stroke.

This finding is from a study of the medication habits of 79,319 nurses over a 14-year period. Results are published in the September issue of Stroke: Journal of the American Heart Association. Anyone contemplating regular aspirin therapy should check with a physician first.

Researchers at Harvard Medical School used data from the Womens' Health Survey, which monitored the health of nurses ages 34 to 59 between 1980 and 1994. They found that those who took between one and six aspirins a week had a lower risk of ischemic stroke than those who took no aspirin at all.

Ischemic stroke is caused by blockage of large arteries of the brain and accounts for 85 percent of all strokes.

However, those nurses who routinely took more than 15 aspirins a week had an increased chance of developing hemorrhagic stroke. Hemorrhagic strokes, which account for 8 percent of all strokes, occur when blood floods over the brain usually when an aneurysm, or malformation of an artery, bursts like a bubble.

The risks of such strokes tripled in older women who had high blood pressure and took more than 15 aspirin a week.

``The public health message,'' said lead researcher, Dr. JoAnn E. Mason, professor of medicine at Harvard, is to avoid high doses of aspirin and taking more than 15 a week, especially for extended periods of time.

Aspirin interferes with blood clotting and that, said Mason, is why high doses of the drug may trigger bleeding.

On the other hand, low doses may allow blood to flow more easily through blood vessels to and in the brain and help prevent them from clogging. This may reduce the risk of ischemic stroke.

Mason cautioned that the ``jury is still out'' regarding aspirin's role in both preventing and causing stroke in women who were previously healthy. That has to wait for the results of trials that are currently under way.

``I think that the take-home message,'' said Dr. Mason, ``is that you may want to talk with your physician about beginning aspirin therapy if your are at increased risk of heart disease.'' People at risk include those with high blood pressure or diabetes. `` No one should begin taking aspirin regularly on their own without first consulting with a physician, `` she added.

``What's nice about this nurses health study,'' observed Dr. Ralph Sacco, associate chairman of neurology at the Neuralgic Institute at Columbia University in New York, ``is that it's the first one that documents the benefits of reasonable amounts of aspirin in protecting healthy women from the most prevalent type of stroke. But if we go too high in dosage there could be serious risk.''

In addition to possibly causing hemorrhaging, aspirin can increase the risk of stomach ulcers and intestinal bleeding.

Stroke is a leading cause of disability in the elderly. There are four million stroke survivors in the U.S., and there are approximately 700,000 strokes a year. Strokes especially affect the elderly and women are more likely to get strokes because they tend to live longer.

Seeking to Understand the Path of Memorization

AMY NORTON
© 1999 Medical Tribune News Service

By placing electrodes deep inside the brains of patients about to undergo surgery, researchers have gained a greater understanding of how the mind decides whether information will be stored in memory or quickly forgotten.

German scientists were able to follow the path of words as they were either memorized or discarded in 12 patients scheduled to have surgery for epilepsy. In memory research, electrodes that measure brain activity are normally placed on the scalp, giving researchers a general idea of what brain areas are involved in recall.

In certain epileptic patients who must have surgery to deal with their seizures, physicians must implant electrodes in the brain to determine the origin of the seizures. Through these electrodes, researchers led by Dr. Guillen Fernandez of the University of Bonn tracked patients' memory processes.

The researchers asked each patient to memorize a list of words that were presented one at a time on a computer screen. The electrodes recorded the brain's activity as each patient took in the words. Then the patients had to perform a ``distraction task'' to keep them from repeatedly going over the words in their minds. Finally, the patients were asked to freely recall the words they had seen.

Looking back at the recorded electrical activity in each patient's brain, Fernandez's team found that words that were later remembered generated greater activity than forgotten words in two brain regions called the rhinal cortex and the hippocampus. The memory process passed through the rhinal cortex before traveling to the hippocampus.

Rhinal and hippocampal cell damage, said Fernandez, are the initial pathological findings in Alzheimer's patients. ``Our findings,'' he noted, ``help explain the severe declarative memory impairment found in these patients.''

Fernandez and colleagues reported their study results in this week's issue of Science.

Just what the two brain regions do with information why certain experiences are retained and others forgotten remains unknown, two psychologists from Harvard University in Boston noted in an editorial accompanying the report.

Still, the German study ``gets us closer to understanding the components of memory,'' said Daniel L. Schacter, chairman of Harvard's department of psychology.

The rhinal cortex and the hippocampus are parts of the medial temporal lobe, a brain region that is already known to be important in memory and learning, Schacter noted.

Like other recent studies of memory, the German research refines scientists' knowledge of how when and where memories are formed, he said.

This knowledge is important, Schacter said, in helping researchers ``know where in the brain to look when memory goes wrong.''

PRIMARY SOURCE: Science (1999;285:1582-84)