The proteins associated with Alzheimer’s disease and Parkinson’s disease interact to increase each other’s distinct degenerative effects, indicating that therapies blocking the production or accumulation of either protein may have broader benefits than previously thought. According to a report in the October 9 Proceedings of the National Academy of Sciences, researchers developed strains of transgenic mice that produce human amyloid precursor protein (hAPP) and human alpha-synuclein (hSYN), which are known to accumulate in patients with Alzheimer’s and Parkinson’s disease, respectively. Mice that produced one of the proteins developed the symptoms of the respective disease. However, when both proteins were produced in the same mouse, the Alzheimer’s-like symptoms of the hAPP mice were exacerbated by production of hSYN. The Parkinson’s-like motor deficits of the hSYN mice developed earlier in the mice that also expressed hAPP.

The number of Americans who are hospitalized for stroke continues to increase, but the death rate is declining, as reported in the October Stroke. From 1988 to 1997, the number of hospitalizations for stroke increased by 38.6%, and the age-adjusted stroke hospitalization rate—the number per 100,000—increased by 18.6%, said epidemiologists from the Albert Einstein College of Medicine. The investigators said that changes in admission practices could account for the increase. On the other hand, the age-adjusted stroke death rate declined by 13.4%, from 29.9 to 25.9 per 100,000 in the same 10-year period. The in-hospital death rate declined steadily from 12.7% to 7.6%. The researchers suggest that the improved death rate may be due to better treatment rather than to improved prevention.

Bilateral stimulation of the subthalamic nucleus or pars interna of the globus pallidus provides significant motor benefits for patients with advanced Parkinson’s disease, while reducing dyskinesia and motor fluctuations, as reported in the September 27 New England Journal of Medicine. Researchers implanted electrodes in the subthalamic nucleus of 96 patients and in the pars interna of the globus pallidus of 38 patients. Three months after bilateral, high-frequency deep-brain stimulation was performed, double-blind, crossover evaluations demonstrated that stimulation of the subthalamic nucleus was associated with a median improvement in the motor score of 49% of patients who underwent the procedure, and stimulation of the pars interna of the globus pallidus with a median improvement of 37%. Although a direct comparison was not conducted, the researchers believe these benefits are of greater magnitude than those that have been achieved with thalamotomy, unilateral pallidotomy, thalamic stimulation, or fetal nigral transplantation.

The risk of developing Alzheimer’s disease is increased for people with small head sizes who also carry an Alzheimer’s-related gene, according to research findings reported in the October 23 Neurology. Investigators found that people with small head size and the gene variant apolipoprotein Ee4 (APOE e4) were 14 times more likely to develop Alzheimer’s disease than were people without that combination. Eighteen percent of the risk of Alzheimer’s disease was attributable solely to small head size. Only study participants in the group with the smallest head circumference (less than 21.4 inches) and APOE e4 had a significantly greater risk of Alzheimer’s disease. “Those with large brain reserves may have the same changes in their brains, but they don’t show symptoms of the disease until much later,” said Amy Borenstein Graves, PhD, of the University of South Florida.

Pharmaceuticals currently used to treat cancer and other diseases may be beneficial in treating Huntington’s disease, according to University of California, Irvine, researchers. The investigators, using Drosophila fruit flies, examined the genetic and molecular interactions in Huntington’s disease and discovered that histone deacetylase (HDAC) inhibitors might counteract the course of the disease and possibly that of other progressive neurologic disorders. They also found that HDAC inhibitors curbed the neuronal degeneration caused by the genetic mutations that lead to Huntington’s disease. “While there is presently no cure for Huntington’s disease, we believe we have traced one way that the mutation changes chemical pathways to cause the disease,” said Leslie Thompson, PhD. “By reversing the key changes in these pathways, we have identified a potentially effective way to slow or prevent the disease.”

The ketogenic diet not only reduces the number of seizures in children with severe seizure disorders but also lowers the frequency of attacks for years after the diet is discontinued, indicated a report in the October Pediatrics. More than half the children examined on the rigorously high-fat, low-carbohydrate diet continued to experience at least a 50% reduction in seizures three to six years after resuming a normal diet. “Also notable,” said John Freeman, MD, of the Johns Hopkins Medical Institutions, “is that many of the children who had success after ending the diet were free of both anticonvulsant drugs and seizures.” Three years after the last child was enrolled in the study, one third of the original 150 children were either seizure-free or had greater than a 90% reduction in seizures.

Researchers have uncovered a potentially useful strategy to treat familial amyloid polyneuropathy (FAP), an approach that may be generally useful for intervention in other amyloid diseases. In the September 28 Science, Jeffery W. Kelly, PhD, and colleagues at the Scripps Research Institute said that it is possible to prevent the protein shape changes that cause FAP, a disease analogous to Alzheimer’s disease. The strategy is to introduce another protein that interacts with the protein capable of aberrant shape changes, thereby preventing them. FAP is caused by the misfolding of the protein transthyretin (TTR). The investigators discovered that a “suppressor” TTR subunit incorporated into a TTR tetramer with disease-associated destabilizing subunits prevents the tetramer from dissociating into potential fibril-forming monomers. “The suppressor protein subunits prevent misfolding by preventing dissociation,” said Dr. Kelly.

A second gene mutation that causes an inherited form of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, has been identified, as reported in the October 3 Nature Genetics. Teepu Siddique, MD, of Northwestern University, who with collaborators from Massachusetts General Hospital discovered the first ALS gene (ALS1) in 1993, found the new gene, located on chromosome 2q33, in four Tunisian and Saudi Arabian families. The newly identified gene mutation is responsible for a rare, slowly progressive, early onset form of the disease, called juvenile inherited ALS (ALS2), which is found in highly inbred populations in North Africa and the Middle East. Dr. Siddique and colleagues believe that, unlike ALS1, which is caused by a novel new property in a mutated gene (called a toxic gain of function), ALS2 results from a loss of physiologic function. This means that the protein’s functions can be predicted based on its structure, thus providing an opportunity for direct examination of the molecular consequence of the loss in model systems.

Carotid artery stenting can be performed safely and effectively as an outpatient procedure at experienced centers, according to researchers reporting in the October Stroke. In an effort to improve patient comfort and minimize hospital costs, the researchers sought an alternative to carotid endarterectomy surgery, the current standard for opening blocked neck arteries, in which patients required close monitoring after a catheter carrying the stent was removed. “Now there is a new closure device, a suture that effectively closes the wound and reduces the risk of bleeding,” said Nadim Al-Mubarak, MD, of the Lenox Hill Heart and Vascular Institute of New York. Patients who undergo ambulatory stenting do not require anesthesia and can be walking within three to four hours after surgery. In the 92 patients studied, there were no strokes, deaths, or need for repeat procedures during one year of follow-up.

Hyperthermia is associated with an unfavorable functional neurologic recovery after cardiopulmonary resuscitation of patients who have experienced cardiac arrest with a presumed cardiac cause, according to the September 10 Archives of Internal Medicine. Investigators found that for each degree Celsius higher than 37°C, the risk of an unfavorable neurologic recovery—including severe disability, coma, or a persistent vegetative state—increases, with an odds ratio of 2.26. Although the cause and effect of elevated temperature on survival have not been proven, researchers in Austria advised rigorously controlling temperature in such patients. They explained that an elevated temperature should be aggressively treated and should not exceed normal values for an extended period of time, especially because mild resuscitative hypothermia, used for resuscitation in patients who experience cardiac arrest, seems to mitigate neurologic damage.

Diphenhydramine administration in older hospitalized patients is associated with an increased risk of cognitive decline and other adverse effects with a dose-response relationship, as reported in the September 24 Archives of Internal Medicine. In addition, diphenhydramine use contributes to behavioral disturbance and a need for bladder catheterization, which may be markers of the anticholinergic effects of delirium resulting in agitation and urinary retention, according to researchers from the Yale University School of Medicine. The widely used sedative-type medication was inappropriately administered to 24% of patients evaluated. The investigators recommend that diphenhydramine be used with caution in elderly patients and not, for instance, be administered as a routine sleep aid.

More than one area of the brain is responsible for autistic behavior in children with tuberous sclerosis and brain lesions, research findings published in the October 9 Neurology suggest. Researchers conducted magnetic resonance imaging and positron emission tomography examinations in 26 children with tuberous sclerosis complex to study how the brain lesions resulted in common behaviors of autism. “We found that in these children, autism results from a complex combination of events in different parts of the brain, rather than from one single source,” said Diane C. Chugani, PhD, of the Children’s Hospital of Michigan. Dr. Chugani determined that biochemical abnormalities in the brain’s cortex had a major impact on the children’s communication skills and that changes in the brain’s subcortical circuits resulted in the development of stereotypical behaviors and lack of social interaction.

Two plant-derived chemicals can reduce the damage from a simulated stroke in cultured mouse brain cells, according to a report in the October 9 Proceedings of the National Academy of Sciences. The chemicals work by shutting down the enzyme poly-ADP-ribose glycohydrolase (PARG), which contributes to cell death after a stroke. The investigators believe that by inhibiting PARG they can protect brain cells from the type of cell death that happens during a stroke. The two chemicals tested were plant-derived molecules known as tannins: gallotannin, which can be extracted from green tea leaves or pine cones, and nobotanin B, from a flower that grows in Japan. Investigators hope that further research may lead to a new class of stroke drugs.

Generic substitution of the individual components of Aggrenox® is associated with an unacceptably high rate of adverse reactions, reported Daniel E. Hilleman, PharmD, at the North American Stroke Meeting. Aggrenox is a combination of immediate-release aspirin (ASA) 25 mg and extended-release dipyridamole (DIP) 200 mg, given twice daily for the secondary prevention of stroke. Dr. Hilleman, from the Creighton University School of Pharmacy, concluded that generic substitution of the ASA and DIP for Aggrenox is, therefore, not recommended. Dr. Hilleman presented his findings from a short-term, adverse reaction profile in 33 patients receiving Aggrenox who were switched to a generic combination of ASA and DIP. Patients were asked about side effects—including headache, dizziness, abdominal pain, and others—during therapy with Aggrenox and following four weeks of therapy with the generic substitute.

Serologic screening for celiac disease should be routinely performed in patients with childhood partial epilepsy with occipital paroxysms (CPEO), because clinically or radiologically observable abnormalities are often absent. Researchers found that the percentage of CPEO patients with silent celiac disease was significantly greater than the estimated prevalence reported in the general population. As reported in the September Epilepsia, of 72 patients evaluated, 25 patients had CPEO, and the remaining 47, none of whom had positive antibody tests, had childhood partial epilepsy with centrotemporal spikes. Two patients with CPEO had antiendomysium immunoglobulin A antibodies. In both patients, the jejunal biopsy showed atrophy of the villi and hyperplasia of the crypts, consistent with a diagnosis of celiac disease. Investigators found no indication to extend celiac disease screening to those patients with infantile extraoccipital seizures.

A new study’s findings support a microvascular role in the pathogenesis of clinical strokes. The study further suggests that retinal photography may be useful for cerebrovascular risk stratification in appropriate patient populations. According to a report in the October 6 Lancet, a biracial, population-based cohort of 10,358 men and women underwent retinal photography and standard grading for retinal microvascular abnormalities. During an average of 3.5 years, 110 participants had incident strokes. After adjusting for age, sex, race, six-year mean arterial blood pressure, diabetes, and other stroke risk factors, investigators found that most retinal microvascular characteristics were predictive of incident stroke. Relative risk of stroke increased with decreasing arteriole-to-venule ratio. The associations were similar for ischemic strokes specifically, and for strokes in individuals with hypertension, either with or without diabetes.

Using specially designed and bred laboratory mice, researchers have discovered that a well-known protein, tumor necrosis factor-alpha, plays a central role in how nerves and the brain repair themselves. As reported in the November Nature Neuroscience, investigators disabled a gene responsible for producing tumor necrosis factor-alpha in rats and then bred successive generations of the rodents. Those mice and others whose genes were functional were then treated with cuprizone, which stripped away the myelin coating on nerves in their brains. Mice with normally functioning genes recovered completely, but those lacking the functioning tumor necrosis factor-alpha gene did not, leading researchers to conclude that these tumor necrosis factor molecules are very important for the white matter in the brain to repair itself.

NR

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