Culprit found for increased stroke injury with diabetes

ScienceDaily (Jan. 24, 2011) — Strokes are a leading cause of mortality and adult disability. Those that involve intracerebral hemorrhage (bleeding in the brain) are especially deadly, and there are no effective treatments to control such bleeding. Moreover, diabetes and hyperglycemia (high blood glucose levels) are associated with increases in bleeding during hemorrhagic stroke and worse clinical outcomes.

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But Joslin Diabetes Center researchers now have identified one key player that contributes to this increased bleeding, a discovery that may pave the way toward treatments that minimize adverse stroke outcomes both for people with pre-existing diabetes and those with hyperglycemia identified at the time of stroke.

Studies in the lab of Joslin Investigator Edward Feener, Ph.D., pinpointed a new mechanism involving a protein called plasma kallikrein that interferes with the normal clotting process in the brain following blood vessel injury with diabetes. Their work is reported online in the journal Nature Medicine.

The scientists began by injecting a small amount of blood into the brains of rats with diabetes and of control animals without diabetes. The difference was dramatic -- the diabetic animals bled over a much greater area of the brain.

Work in the Feener lab had previously implicated plasma kallikrein in diabetic eye complications. When the experimenters pre-treated the diabetic animals with a molecule that inhibits the protein's effects, brain damage from the blood injections dropped to levels similar to that in the control animals. Conversely, when pure plasma kallikrein was injected into the brain, it produced little impact on the control animals but rapidly increased major bleeding in the animals with diabetes.

Further studies by the Joslin researchers showed that normalizing blood glucose levels in diabetic animals could block the effect from plasma kallikrein, and that rapidly inducing hyperglycemia in control animals mimicked the effects of diabetes on brain hemorrhage. This suggests that high blood sugar at the time of brain hemorrhage, rather than diabetes per se, is responsible for the increased bleeding.

"Given the prevalence of strokes and the damage they inflict, these findings are exciting because they suggest the possibility that rapid control of blood sugar levels may provide an opportunity to reduce intracerebral hemorrhage, which is a clinical situation that has very limited treatment options," says Dr. Feener, who is also an associate professor of medicine at Harvard Medical School. "This work could have broad implications since about half of patients with acute hemorrhagic stroke have hyperglycemia, whether or not they have pre-existing diabetes."

The work also raises the possibility of developing drugs that target plasma kallikrein and may provide protective measures in people with diabetes or others at high risk for stroke. Such drugs might also prove useful for patients suffering from the more common ischemic strokes, which usually begin as blocked vessels in the brain but can transform into hemorrhages.

Surprisingly, while plasma kallikrein has been studied for decades, the Joslin scientists found that the protein boosts brain bleeding through a previously unknown mechanism -- by blocking platelet activation near damaged blood vessels.

Joslin's Jia Liu and Ben-Bo Gao were co-lead authors on the Nature Medicine paper. Other contributors include Joslin's Allen Clermont, and Price Blair and Robert Flaumenhaft of Beth Israel Deaconess Medical Center, and Tamie Chilcote and Sukanto Sinha of ActiveSite Pharmaceuticals. Lead funding came from the National Institutes of Health and the American Heart Association.

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Advanced macular degeneration is associated with an increased risk of bleeding stroke, study finds

ScienceDaily (Feb. 10, 2011) — Older people with late-stage, age-related macular degeneration (AMD) appear to be at increased risk of brain hemorrhage (bleeding stroke), but not stroke caused by brain infarction (blood clot), according to research presented at the American Stroke Association's International Stroke Conference 2011.

See Also:Health & MedicineStroke PreventionElder CareBrain TumorMind & BrainBrain InjuryStrokeDisorders and SyndromesReferencePeripheral visionMulti-infarct dementiaCerebral contusionBrain damage

"Other studies have found there are more strokes in older individuals with late AMD, but ours is the first to look at the specific types of strokes," said Renske G. Wieberdink, M.D., study researcher and epidemiologist at Erasmus Medical Center in Rotterdam, the Netherlands. "We found the association is with brain hemorrhage, but not brain infarction."

AMD is degeneration of the macula, which is the part of the retina responsible for the sharp, central vision needed to read or drive. Because the macula primarily is affected in AMD, central vision loss may occur. Age-related macular degeneration usually produces a slow, painless loss of vision. Early signs of vision loss from AMD include shadowy areas in your central vision or unusually fuzzy or distorted vision.

Because the number of brain hemorrhages observed in the study was small, the findings will need to be corroborated in a larger group, Wieberdink said.

"These findings should be considered preliminary," she said. "Patients and physicians must be very careful not to over-interpret them. We don't know why there are more brain hemorrhages in these patients or what the relationship with AMD might be. This does not mean that all patients with late-stage AMD will develop brain hemorrhage."

Beginning in 1990, the Rotterdam Study is a prospective, population-based cohort investigation into factors that determine the occurrence of cardiovascular, neurological, ophthalmological, endocrinological and psychiatric diseases in older people.

The researchers tallied stroke incidence among 6,207 participants 55 years and older. All of the participants were stroke-free at the study's outset. AMD was assessed during scheduled eye examinations, and participants with the condition were divided into five different stages of AMD, and whether their condition was wet AMD or dry AMD. Participants were tracked for an average of 13 years. Of the 726 persons who suffered a stroke in that time, 397 were brain infarctions, 59 were brain hemorrhages and the stroke type was not available for 270.

Late AMD (stage 4) was associated with a 56 percent increased risk of any type of stroke. Late AMD, both the dry and the wet form, was strongly associated with more than six times the risk of brain hemorrhage, but not with brain infarction. Early AMD (stages 1-3) did not increase the risk of any stroke. Associations were adjusted for possible confounders, such as diabetes, blood pressure, anti-hypertensive medications, smoking status, body mass index, alcohol use and C-reactive protein levels.

"We cannot yet say if there is a common causal pathway or mechanism of action yet -- this association needs to be further investigated," Wieberdink said. "But I don't think it is a causal relationship. It seems more likely that late AMD and brain hemorrhage both result from some as yet unknown common mechanism."

If the findings are replicated, it may be possible to develop some stratification of risk among such patients, Wieberdink said.

Co-authors are: Lintje Ho, M.D.; Kamran Ikram, M.D., Ph.D.; Peter Koudstaal, M.D., Ph.D.; Albert Hofman, M.D., Ph.D.; Hans Vingerling, M.D., Ph.D.; and Monique Breteler, M.D., Ph.D. Author disclosers and funding information are on the abstract.

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Healthy welders may be at increased risk for early brain damage

ScienceDaily (Apr. 6, 2011) — New research suggests that workers exposed to welding fumes may be at risk for developing brain damage in an area of the brain also affected in Parkinson's disease. The study is published in the April 6, 2011, online issue of Neurology®, the medical journal of the American Academy of Neurology.

See Also:Health & MedicineParkinson's ResearchBrain TumorNervous SystemMind & BrainParkinson'sDisorders and SyndromesBrain InjuryReferenceDementia with Lewy bodiesEssential tremorNeurologyBrain damage

Fumes produced by welding contain manganese. Manganese is a chemical element that, even at low levels, has been linked to neurologic problems, including Parkinson's disease-like symptoms.

"There are over one million workers who perform welding as part of their job functions in the United States," said Brad A. Racette, MD, with Washington University School of Medicine in St. Louis and a Fellow with the American Academy of Neurology. "If a link between neurotoxic effects and these fumes were proven, it would have a substantial public health impact for the U.S. workforce and economy."

The study involved 20 welders with no symptoms of Parkinson's disease, 20 people with Parkinson's disease who were not welders and 20 people who were not welders and did not have Parkinson's. The welders were recruited from two Midwest shipyards and one metal fabrication company. All participants were given brain PET and MRI scans, motor skills tests and examined by a neurologist who specializes in movement disorders. The welders had an average of 30,000 hours of lifetime welding exposure. Their average manganese levels were found to be two times the upper limits of normal.

Scientists found that welders had an average 11.7 percent reduction in a marker of dopamine in one area of the brain on PET scans as compared to people who did not weld. Dopamine is a chemical messenger that helps nerve cells communicate and is decreased in specific brain regions in people with Parkinson's disease. The welders' motor skills test scores also showed mild movement difficulties that were about half of that found in the early Parkinson's disease patients.

"While these changes in the brain and dopamine dysfunction may be an early marker of neuron death related to welding exposure, the damage appeared to be different from those of people with full-fledged Parkinson's disease," said Racette. "MRI scans also revealed brain changes in welders that were consistent with manganese deposits in the brain."

"Although this study shows that these workers had dopamine dysfunction in the brain, the study authors could not determine whether this was specifically related to manganese," said W. R. Wayne Martin, MD, who wrote an accompanying editorial on the topic. Martin is with the University of Alberta in Edmonton, Alberta, Canada and a member of the American Academy of Neurology. "Will these individuals develop full-fledged Parkinson's disease? We can't answer that question based on the study but more research should be done to explore this possibility."

The study was supported by the Michael J. Fox Foundation, the National Institutes of Health, the American Parkinson Disease Association, Advanced Research Center at Washington University, the Great St. Louis Chapter of the ADPA, the McDonnell Center for Higher Brain Function and the Barnes-Jewish Hospital Foundation.

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