The following brief reports summarize some of the findings presented at the American Neurological Association's 125th Annual Meeting, held in Boston. More in–depth coverage of the meeting will be featured in upcoming issues of Neurology Reviews.

CAFFEINE MAY DECREASE RISK OF PARKINSON'S DISEASE

People who consume moderate amounts of caffeine daily are substantially less likely to develop Parkinson's disease, according to researchers from the Harvard School of Public Health. The results provide strong support for a report earlier this year of a link between coffee intake and reduced risk of Parkinson's disease. The present study takes the story several steps further, confirming that it is caffeine in particular, and not other substances in coffee, that is linked to a reduced risk of Parkinson's disease.

The study also revealed that, while those with moderate caffeine intake have a lower risk of Parkinson's disease, those who consume larger amounts may have a higher risk—similar to those who consume little or no caffeine.

"This is the largest investigation of its kind, and it is based on a detailed and repeated assessment of consumption not only of coffee, but also of other caffeinated beverages and decaffeinated coffee," said lead author Alberto Ascherio, MD, DrPH. "Because of this, we were able to separate the possible effects of caffeine from those of other compounds contained in coffee."

Dr. Ascherio also noted that previous studies had been limited to caffeine intake in men. In contrast, he and his colleagues drew data from 88,565 women and 47,355 men involved in two ongoing studies: the Nurses Health Study and the Health Professionals Follow-up Study.

The major results of Dr. Ascherio's study were that both men and women consuming moderate amounts of total caffeine (the equivalent of one to three cups of coffee a day) had a substantially reduced risk of getting Parkinson's disease. Among women, the researchers noted that as coffee intake climbed above the equivalent of three cups of coffee a day, the protective effect was gradually lost.

"The data support the hypothesis that consumption of moderate amounts of caffeine reduce the risk of Parkinson's disease. However, they do not provide proof of a causal association," said Dr. Ascherio. He pointed out that caffeine might not reduce the number of people with the disease but may instead lessen the severity of Parkinson's disease. This would mean that some people with the disease but with minimal symptoms weren't picked up by the study.

Another possibility is that caffeine has no beneficial effect at all. Rather, the same brain chemistry that predisposes certain people to Parkinson's disease may also make them less likely to consume addictive substances such as caffeine or nicotine, which has also been linked to a lower risk of Parkinson's disease.

Nonetheless, contends Dr. Ascherio, "These results suggest that the possibility of a beneficial effect of caffeine should be carefully explored in clinical trials. If a therapeutic effect of moderate amounts of caffeine were proven in clinical trials, caffeine could become an important part of the treatment of Parkinson's disease."

A CLOSER LOOK AT DOPAMINE RECEPTORS

The fate of the D3 type of dopaminergic receptor may play an important role in the management of Parkinson's disease, according to a recent study. "Our results demonstrate that it is not the D2 receptor, but the D3 receptor, that is reduced in Parkinson's disease patients with loss of clinical response to levodopa," said Jeffrey N. Joyce, PhD, of the Sun Health Research Institute in Sun City, Arizona, and lead author of the report. "Patients who continue to respond to antiparkinsonian medication show elevated numbers of D3 receptors," he said.

Dr. Joyce and his colleagues examined brain tissue from two groups of patients who had died with Parkinson's disease: those who had lost their response to levodopa and those who had not. They determined that in the striatum, D3 receptor levels had dropped only in those patients who had lost their response to levodopa. The D2 receptor levels, however, had not dropped in this group of patients.

Further evidence should soon be available on whether drugs that activate only D3 receptors have the same beneficial effects as levodopa, Dr. Joyce noted. If these drugs are initially as effective as levodopa but then lose their effectiveness, the focus in efforts to extend the utility of such antiparkinsonian drugs would then shift to the D3 receptor. "We need to identify what controls the brain levels of the D3 receptor and what produces the loss in Parkinson's disease. Then we may be able to prevent or treat this loss," said Dr. Joyce.

GENE THERAPY RESCUES NEURONS IN PARKINSON'S DISEASE MODEL

A gene therapy "cocktail" can successfully prevent the destruction of critical brain cells in an animal model of Parkinson's disease, according to researchers from the University of Tübingen in Germany. They were able to prevent the death of dopamine neurons by simultaneously interfering with "executioner" molecules called caspases and nourishing brain cells with growth factors.

"We combined neuroprotective and neurorestorative strategies which acted in synergy, whereas both treatments on their own were only partially protective," said Jörg B. Schulz, MD, lead author of the report. "The results suggest that for the treatment of neurodegenerative diseases, and Parkinson's disease in particular, combinations of treatment strategies that interfere with different pathways may be superior."

Their experimental approach involved injecting a viral vector for the caspase inhibitor gene into the brain of a mouse model. As a result, cells in the substantia nigra were kept from dying. However, the treatment was not able to protect the nerve fibers.

In a second set of mice, the researchers added a gene for a growth factor. The "cocktail" approach saved nearly all the dopamine neurons, as well as preserving the function of delivering dopamine to the striatum.

"For slowly progressing neurodegenerative diseases such as Parkinson's disease, gene transfer methods that can target specific neuronal populations may be superior to systemic treatment and should be developed since they may prevent unwanted side effects of caspase inhibition," said Dr. Schulz.

MULTIPLE SCLEROSIS AND CHLAMYDIS BACTERIUM—THE DEBATE CONTINUES

The bacterium Chlamydia pneumoniae,a common cause of "walking pneumonia," is found in the nervous systems of most patients with multiple sclerosis, according to researchers from the University of Heidelberg in Germany.

Employing more sensitive methods than previously used to address this controversial issue, the researchers found signs of the bacterium in 66% of patients with multiple sclerosis, versus only 21% of patients with other neurologic illnesses. "If these results can be confirmed by others and if further evidence can be collected that confirms an association between C pneumoniaeand multiple sclerosis, clinical trials are required that attempt to treat multiple sclerosis patients with antibiotics effective against C pneumoniae," said Dr. Armin Grau, MD, senior author of the report.

Several studies have produced conflicting evidence about the presence of the C pneumoniaein the nervous systems of patients with multiple sclerosis. Researchers have debated whether the various assays used were correctly applied or sufficiently sensitive. In this study, Dr. Grau and his colleagues used a particularly sensitive form of polymerase chain reaction technique to look for evidence of C pneumoniaegenes in the cerebrospinal fluid of patients.

They found that 12 of 18 patients with multiple sclerosis, but only four of 19 patients with other neurologic diseases, tested positive for the presence of C pneumoniae.Already in progress is a study by the same researchers involving much larger groups of patients, as well as attempts to replicate the data with other methods of detection.

If these results continue to be reproduced with other detection methods, a clinical trial with antibiotics may be able to discern whether the bacteria cause multiple sclerosis or whether patients who already have the disease are simply more susceptible to C pneumoniae,he said.

CAN HUMAN NEURAL STEM CELLS REPLACE DAMAGED BRAIN CELLS?

Human neural stem cells can replace and take over the functions of damaged nervous system cells in a mouse model of multiple sclerosis, according to the findings of a recent study.

"Our results indicate that cell replacement therapy using human neural stems cells could be an effective therapy" for patients with multiple sclerosis, said lead author Seung U. Kim, MD, a neurologist at the University of British Columbia, Vancouver. According to Dr. Kim, the results may also be significant for patients with other neurologic disorders, such as Parkinson's disease or stroke, in whom researchers hope neural stem cells will be able to replace damaged cells.

One goal of Dr. Kim's research is to replace the lost oligodendrocytes with new ones derived from neural stem cells. A first step in that direction was achieved recently when Dr. Kim and colleagues managed to induce stem cells from the brains of human fetuses to continue to grow and produce new cells in vitro.

"In the present study, we transplanted these human neural stem cells into the brains of mutant 'shiverer' mice, which have myelin disease throughout the brain and spinal cord, and demonstrated remyelination of previously unmyelinated fibers by the implanted cells," Dr. Kim reported.

Since shiverer mice show functional deficits such as tremor and a "shivering" gait, the researchers intend to determine whether neural cell transplantation reverses this motor dysfunction. Their preliminary observations of the animals in this study indicated that there was considerable reduction in tremor in many of the mice.

The implications of this line of research go well beyond multiple sclerosis and other demyelinating diseases. "Since the neural stem cells exhibit self-renewal and possess multilineage potential, they could be utilized for cell replacement therapy for other neurologic diseases, such as Parkinson's disease, Huntington's disease, motor neuron diseases, Alzheimer's disease, and stroke. Previous transplantation studies in animal models of these diseases indicate that cell replacement therapy is feasible," said Dr. Kim.

In a separate study, Dr. Kim and colleagues genetically modified the same human neural stem cells to produce dopamine. Implantation of these cells into the brain of a rat model of Parkinson's disease ameliorated movement problems, they reported.

DRUGS SAFE FOR ADHD CHILDREN WITH TICS

Methylphenidate and clonidine, two drugs used commonly to treat children with attention deficit hyperactivity disorder (ADHD), do not worsen unwanted movements or vocal outbursts in children with Tourette's syndrome, according to a recent report. Furthermore, a combination of methylphenidate and clonidine was more effective against ADHD symptoms than either drug alone and produced the lowest severity of tics.

"Previous recommendations have been to avoid the use of [methylphenidate], the most commonly used and most effective medication for ADHD, in children with tics since it was thought that the drug worsened tics," said primary investigator Roger Kurlan, MD, a neurologist at the University of Rochester in New York. "Also, no study had yet shown that the primary alternative drug, clonidine, was truly effective."

In a 16–week, double–blind study, ADHD patients with a chronic tic disorder were randomly assigned to receive methylphenidate, clonidine, a combination of the two, or a placebo. The researchers assessed whether the tics were more or less frequent during the trial. The effectiveness of the drugs in reducing ADHD symptoms such as inattention, distractibility, impulsive behavior, and hyperactivity was assessed by the subjects' teachers.

"Not only does [methylphenidate] not worsen tics, tics actually improved during treatment with this drug. Thus, there does not appear to be any reason to avoid the use of [methylphenidate] in children with tics," said Dr. Kurlan.

Clonidine was about equally effective as methylphenidate at reducing ADHD symptoms, but the two drugs together were significantly more effective than placebo or either drug alone and produced the lowest levels of tics. Another significant safety finding was that the combination of methylphenidate and clonidine showed no evidence of heart toxicity, a concern that had been previously raised. "The study also has important implications for all children with ADHD, suggesting that clonidine may be effective and should be tested further, that the use of medication combinations may be more effective than using individual drugs on their own, and that the combination of [methylphenidate] and clonidine is probably safe," said Dr. Kurlan.

CLINICAL TRIAL FAILS TO SHOW EFFICACY FOR TREATMENT OF SPINAL MUSCULAR ATROPHY

Hopes for the first effective treatment for adult patients with spinal muscular atrophy, a rare peripheral nerve disease, have been dashed by a recent multicenter clinical trial; the drug gabapentin performed no better than placebo.

"The results were particularly disappointing because this was the first-ever clinical trial of a drug that might help adult patients with spinal muscular atrophy," said Robert Miller, MD, Chairman of Neurology at California Pacific Medical Center in San Francisco and lead author of the report.

The study included 84 patients (average age, 35) who had been diagnosed with the disease in their mid teens. Patients received either gabapentin or a placebo for 12 months and were evaluated every three months. Patients taking gabapentin performed no better on muscle strength tests than did those taking placebo. In addition, there was no difference in tests that measured the strength of breathing muscles or quality of life.

Dr. Miller hopes that news of the study will spread, because many other patients may already be using gabapentin. Gabapentin was considered promising because it had protected nerve cells in an animal model of the disorder.

Although the drug does not appear to help adults, this study did show that it was safe to use in patients with spinal muscular atrophy. There remains the possibility that gabapentin could help younger patients, for whom the course of the disease is much more severe. According to Dr. Miller, clinical trials of gabapentin and another candidate drug in this population are scheduled to begin in the very near future.

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