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Researchers uncover clue to Alzheimer's pathology
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Researchers uncover clue to Alzheimer’s pathology “Our grafting approach has shown that β-amyloid Rights were not granted to include formation starts, or can this image in electronic media. start, extracellularly and is toxic to the Please refer to the printed journal. surrounding neurons. We cannot exclude the intracellular hypothesis; however, so far, nobody has provided evidence for the intracellular hypothesis in vivo”, one of the researchers, Mathias Jucker (University of Basel, Switzerland), told The Lancet. William Thies, vice-president of medical and scientific affairs at the US Alzheimer’s Association (Chicago, A cell engineered to produce amyloid precursor protein IL, USA), says the results indicate that β-amyloid should be prevent Alzheimer’s disease (see Lancet targeted for treatment of Alzheimer’s 2002; 360: 1227). disease. “It should be obvious that the “This work suggests that treatments understanding of the mechanism of that can eliminate such soluble amyloid formation in brain has great molecules can be useful for treatment”, implications for the development of says Theis. “This is very basic research, therapeutic options”, Jucker says. “For but eventually it may influence the example, our results are clearly in line kinds of molecules that are chosen to with why amyloid immunotherapy is treat or prevent Alzheimer’s disease.” successful in removing amyloid from Jucker agrees with Thies’s assessment the brain.” that the results may contribute to the David Lawrence development of a therapy to treat or Science Photo Library
laques formed by β-amyloid peptide have long been fingered as a suspect in the progression to Alzheimer’s disease. Uncertainty has reigned, however, over whether intracellular or extracellular accumulation of β-amyloid causes the neurodegeneration that is a hallmark of the disease. A new study published this week by an international team of researchers lends credence to the extracellular hypothesis. The researchers did several transplantation experiments in transgenic mice that overexpress a mutant form of the amyloid precursor protein (APP), and in wildtype mice to determine the source of β-amyloid accumulations. Amyloid deposits formed within grafts in the brains of transgenic mice in as little as 3 months—irrespective of whether the source of the graft was a wildtype or transgenic donor. Grafts from transgenic mice into the brains of wildtype mice did not develop plaques over a span of 20 months —again, irrespective of the source. (Nat Neurosci; published online Feb 24; DOI: 10.1038/nn1022). “Our results suggest that the phenotype of the transplanted tissue is strongly influenced by the properties of the host, and that extracellular diffusion of β-amyloid is centrally involved in cerebral amyloidogenesis”, the researchers write.
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Low-dose warfarin prevents recurrent thromboembolism he multicentre Prevention of Recurrent Venous Thromboembolism (PREVENT) trial, due to run until 2005, has been suspended and the interim results released this week so that changes can be made to clinical practice. “Using low doses of warfarin over a long period of time prevents recurrence of venous thromboembolism, but is not associated with an increased risk of major haemorrhage or stroke. We conclude it can be readily implemented in patient treatment”, says lead researcher Paul Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital (Boston, MA. USA). The study’s Data and Safety Monitoring Board reviewed the results in December and their recommendation to halt the study was approved by the National Heart, Lung, and Blood Institute (Bethesda, MA, USA). The results were posted on the New England Journal of Medicine website on Feb 24 (www.nejm.org). The current standard treatment for idiopathic deep vein thrombosis and pulmonary embolism is 5–10 days of intravenous or subcutaneous heparin followed by 3–6 months of full-dose warfarin. This must then be discontinued
T
THE LANCET • Vol 361 • March 1, 2003 • www.thelancet.com
because long-term use of full-dose warfarin can lead to major bleeding. “Instead of giving the full dose of warfarin to achieve a target international normalised ratio of between 2·0 and 3·0, the lower dose is given to achieve a target level of between 1·5 and 2·0. The reduction may mean the difference between life and death for many patients”, says Ridker. Of 508 patients followed up for just over 2 years, 37 of 253 who were given a placebo had recurrent venous thromboembolism, but this occurred in only 14 of 255 patients given low-dose warfarin. The risk reduction of 64% (hazard ratio 0·36, 95% Cl 0·19–0·67) was similar in all groups, including patients with inherited thrombophilia. Andrew Schafer (University of Pennsylvania School of Medicine, Philadelphia, PA, USA) welcomes the results but points out that preliminary results for a study of a similar size argue that a slight higher dose may still be safe for long-term use. “Until we develop newer antithrombotic agents with better safety profiles and a specific action, we will continue to walk the tightrope of anticoagulant dosing”, he concludes. Kathryn Senior
757
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Researchers uncover clue to Alzheimer’s pathology “Our grafting approach has shown that β-amyloid Rights were not granted to include formation starts, or can this image in electronic media. start, extracellularly and is toxic to the Please refer to the printed journal. surrounding neurons. We cannot exclude the intracellular hypothesis; however, so far, nobody has provided evidence for the intracellular hypothesis in vivo”, one of the researchers, Mathias Jucker (University of Basel, Switzerland), told The Lancet. William Thies, vice-president of medical and scientific affairs at the US Alzheimer’s Association (Chicago, A cell engineered to produce amyloid precursor protein IL, USA), says the results indicate that β-amyloid should be prevent Alzheimer’s disease (see Lancet targeted for treatment of Alzheimer’s 2002; 360: 1227). disease. “It should be obvious that the “This work suggests that treatments understanding of the mechanism of that can eliminate such soluble amyloid formation in brain has great molecules can be useful for treatment”, implications for the development of says Theis. “This is very basic research, therapeutic options”, Jucker says. “For but eventually it may influence the example, our results are clearly in line kinds of molecules that are chosen to with why amyloid immunotherapy is treat or prevent Alzheimer’s disease.” successful in removing amyloid from Jucker agrees with Thies’s assessment the brain.” that the results may contribute to the David Lawrence development of a therapy to treat or Science Photo Library
laques formed by β-amyloid peptide have long been fingered as a suspect in the progression to Alzheimer’s disease. Uncertainty has reigned, however, over whether intracellular or extracellular accumulation of β-amyloid causes the neurodegeneration that is a hallmark of the disease. A new study published this week by an international team of researchers lends credence to the extracellular hypothesis. The researchers did several transplantation experiments in transgenic mice that overexpress a mutant form of the amyloid precursor protein (APP), and in wildtype mice to determine the source of β-amyloid accumulations. Amyloid deposits formed within grafts in the brains of transgenic mice in as little as 3 months—irrespective of whether the source of the graft was a wildtype or transgenic donor. Grafts from transgenic mice into the brains of wildtype mice did not develop plaques over a span of 20 months —again, irrespective of the source. (Nat Neurosci; published online Feb 24; DOI: 10.1038/nn1022). “Our results suggest that the phenotype of the transplanted tissue is strongly influenced by the properties of the host, and that extracellular diffusion of β-amyloid is centrally involved in cerebral amyloidogenesis”, the researchers write.
P
Low-dose warfarin prevents recurrent thromboembolism he multicentre Prevention of Recurrent Venous Thromboembolism (PREVENT) trial, due to run until 2005, has been suspended and the interim results released this week so that changes can be made to clinical practice. “Using low doses of warfarin over a long period of time prevents recurrence of venous thromboembolism, but is not associated with an increased risk of major haemorrhage or stroke. We conclude it can be readily implemented in patient treatment”, says lead researcher Paul Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital (Boston, MA. USA). The study’s Data and Safety Monitoring Board reviewed the results in December and their recommendation to halt the study was approved by the National Heart, Lung, and Blood Institute (Bethesda, MA, USA). The results were posted on the New England Journal of Medicine website on Feb 24 (www.nejm.org). The current standard treatment for idiopathic deep vein thrombosis and pulmonary embolism is 5–10 days of intravenous or subcutaneous heparin followed by 3–6 months of full-dose warfarin. This must then be discontinued
T
THE LANCET • Vol 361 • March 1, 2003 • www.thelancet.com
because long-term use of full-dose warfarin can lead to major bleeding. “Instead of giving the full dose of warfarin to achieve a target international normalised ratio of between 2·0 and 3·0, the lower dose is given to achieve a target level of between 1·5 and 2·0. The reduction may mean the difference between life and death for many patients”, says Ridker. Of 508 patients followed up for just over 2 years, 37 of 253 who were given a placebo had recurrent venous thromboembolism, but this occurred in only 14 of 255 patients given low-dose warfarin. The risk reduction of 64% (hazard ratio 0·36, 95% Cl 0·19–0·67) was similar in all groups, including patients with inherited thrombophilia. Andrew Schafer (University of Pennsylvania School of Medicine, Philadelphia, PA, USA) welcomes the results but points out that preliminary results for a study of a similar size argue that a slight higher dose may still be safe for long-term use. “Until we develop newer antithrombotic agents with better safety profiles and a specific action, we will continue to walk the tightrope of anticoagulant dosing”, he concludes. Kathryn Senior
757
For personal use. Only reproduce with permission from The Lancet Publishing Group.