In a recent publication, researchers of the Computational Biology group at the Luxembourg Centre for Systems Biomedicine showed that neuro-inflammation plays a crucial role in initiating prion disease.
Prion diseases represent a family of neurodegenerative disorders associated with the loss of brain cells and caused by proteins called prions (derived from ‘protein’ and ‘infection’). The diseases are found in both humans and animals, such as Creutzfeld-Jakob disease and mad cow disease respectively. Although mostly harmless, prions can transform into infectious agents, which accumulate in the brain and destroy the nervous tissue.
But how exactly does the accumulation of prions cause destruction of the brain? “Understanding the process by which prions destroy neurons is critical for finding a cure for prion disease”, says Isaac Crespo, first author of the publication. He and his colleagues tackled this question with a computational approach: They ran their own computer programmes on experimental data generated by other research groups, and identified a set of 16 proteins that seems to control the onset of the disease. Interestingly, almost all of these proteins have known functions in neuro-inflammation.
“What we consider remarkable and constitutes our main finding, is the key role that neuro-inflammation plays in initiating prion disease. This finding is not only relevant for prion diseases, but also for other ‘protein misfolding diseases’ such as Parkinson’s and Alzheimer diseases” says Prof. Dr. Antonio del Sol, group leader of the Computational Biology group.
Since its publication on October 15th, Crespo’s paper was accessed so frequently, that it received the mark ‘Highly Accessed’, only awarded to articles that are downloaded very frequently. The strong interest that scientists are showing for these research findings reflects the urgency with which researchers are trying to understand prion diseases for which there is no cure until today.
Thursday, 29 November 2012
Wednesday, 28 November 2012
Amyloid Imaging Aids in Measuring Potential Alzheimer Disease
A test to detect brain amyloid deposits associated with Alzheimer disease (AD) provides doctors with useful information on treatment and further testing for patients with cognitive impairment, according to a study published online by the journal Alzheimer Disease & Associated Disorders.
The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.
Positron emission tomography (PET) scans using a biomarker called florbetapir F18 can show amyloid plaques in the brain -- a characteristic feature of AD. "Amyloid imaging results altered physicians' diagnostic thinking, intended testing and management of patients undergoing evaluation for cognitive decline," according to the study by Dr Mark Mintun of Avid Pharmaceuticals, Philadelphia, and colleagues.
Is It Alzheimer Disease? Florbetapir Scan Provides Evidence
The researchers designed a "real-world" study to determine how florbetapir would affect clinical management of patients with cognitive impairment. While a florbetapir PET scan showing amyloid plaques doesn't prove that AD is present, it provides a previously unavailable piece of evidence to support the diagnosis.
The study included 229 patients seen by neurologists or other specialists for evaluation of cognitive decline or impairment of uncertain etiology. Before the florbetapir PET scan, doctors provided a provisional diagnosis, an estimate of their diagnostic confidence, and their plans for further testing and treatment. The goal was to assess the value of florbetapir PET in making the final diagnosis and in providing doctors with useful information for clinical decision making.
The florbetapir PET scans showed amyloid deposits in 113 out of 229 patients. The information provided led doctors to change their diagnosis in 55 percent of cases.
When the provisional diagnosis was AD, imaging results led to a change in diagnosis in 37 percent of cases. When the pre-scan diagnosis was either "indeterminate" or another cause of dementia, the diagnosis changed in over 60 percent of cases. In either direction, the scans increased the physicians' ratings of diagnostic confidence by about 20 percent.
Impact on Treatment and Testing Decisions
Florbetapir PET also provided useful information for treatment decision-making: in 87 percent of patients, the results contributed to at least one change in the treatment plan. The main impact was in deciding whether or not to use medications that are helpful in AD. The scan results also affected decisions on further testing -- in many cases, physicians dropped plans to perform additional brain imaging studies or neuropsychological tests.
Alzheimer disease is the most common cause of dementia, but the diagnosis can be challenging to make. The only definitive way to diagnose AD is by autopsy examination of the brain after death. Up to 20 percent of patients diagnosed with AD turn out not to have had AD on autopsy, while up to 40 percent of patients diagnosed with other causes of dementia have evidence of AD at autopsy.
Florbetapir PET is the first FDA-approved imaging that can estimate amyloid deposits in the brain of a living patient. Previous studies have shown that the scans are accurate in identifying patients later shown to have AD at autopsy.
The new results show that florbetapir PET scans can have a significant effect in "real world" clinical evaluation of patients with cognitive impairment. By strengthening the case for or against a diagnosis of AD, this test can have a significant impact on patient management -- particularly related to the use of AD medications and the need for further testing. Additional studies will be needed to confirm whether "clinical care that includes amyloid imaging will translate into better outcomes" for patients with cognitive impairment and possible AD.
The journal is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.
Positron emission tomography (PET) scans using a biomarker called florbetapir F18 can show amyloid plaques in the brain -- a characteristic feature of AD. "Amyloid imaging results altered physicians' diagnostic thinking, intended testing and management of patients undergoing evaluation for cognitive decline," according to the study by Dr Mark Mintun of Avid Pharmaceuticals, Philadelphia, and colleagues.
Is It Alzheimer Disease? Florbetapir Scan Provides Evidence
The researchers designed a "real-world" study to determine how florbetapir would affect clinical management of patients with cognitive impairment. While a florbetapir PET scan showing amyloid plaques doesn't prove that AD is present, it provides a previously unavailable piece of evidence to support the diagnosis.
The study included 229 patients seen by neurologists or other specialists for evaluation of cognitive decline or impairment of uncertain etiology. Before the florbetapir PET scan, doctors provided a provisional diagnosis, an estimate of their diagnostic confidence, and their plans for further testing and treatment. The goal was to assess the value of florbetapir PET in making the final diagnosis and in providing doctors with useful information for clinical decision making.
The florbetapir PET scans showed amyloid deposits in 113 out of 229 patients. The information provided led doctors to change their diagnosis in 55 percent of cases.
When the provisional diagnosis was AD, imaging results led to a change in diagnosis in 37 percent of cases. When the pre-scan diagnosis was either "indeterminate" or another cause of dementia, the diagnosis changed in over 60 percent of cases. In either direction, the scans increased the physicians' ratings of diagnostic confidence by about 20 percent.
Impact on Treatment and Testing Decisions
Florbetapir PET also provided useful information for treatment decision-making: in 87 percent of patients, the results contributed to at least one change in the treatment plan. The main impact was in deciding whether or not to use medications that are helpful in AD. The scan results also affected decisions on further testing -- in many cases, physicians dropped plans to perform additional brain imaging studies or neuropsychological tests.
Alzheimer disease is the most common cause of dementia, but the diagnosis can be challenging to make. The only definitive way to diagnose AD is by autopsy examination of the brain after death. Up to 20 percent of patients diagnosed with AD turn out not to have had AD on autopsy, while up to 40 percent of patients diagnosed with other causes of dementia have evidence of AD at autopsy.
Florbetapir PET is the first FDA-approved imaging that can estimate amyloid deposits in the brain of a living patient. Previous studies have shown that the scans are accurate in identifying patients later shown to have AD at autopsy.
The new results show that florbetapir PET scans can have a significant effect in "real world" clinical evaluation of patients with cognitive impairment. By strengthening the case for or against a diagnosis of AD, this test can have a significant impact on patient management -- particularly related to the use of AD medications and the need for further testing. Additional studies will be needed to confirm whether "clinical care that includes amyloid imaging will translate into better outcomes" for patients with cognitive impairment and possible AD.
Friday, 23 November 2012
Diabetes Drug Improves Memory, Study Indicates
An FDA-approved drug initially used to treat insulin resistance in diabetics has shown promise as a way to improve cognitive performance in some people with Alzheimer's disease.
Working with genetically engineered mice designed to serve as models for Alzheimer's, University of Texas Medical Branch at Galveston researchers found that treatment with the anti-insulin-resistance drug rosiglitazone enhanced learning and memory as well as normalized insulin resistance. The scientists believe that the drug produced the response by reducing the negative influence of Alzheimer's on the behavior of a key brain-signaling molecule.
The molecule, called extracellular signal-regulated kinase (ERK), becomes hyperactive both in the brains of Alzheimer's patients and in the mice at a disease stage corresponding to mild cognitive impairment in human Alzheimer's. This excessive activity leads to improper synaptic transmission between neurons, interfering with learning and memory.
Rosiglitazone brings ERK back into line by activating what's known as the peroxisome proliferator-activated receptor gamma (PPARγ) pathway, which interacts with genes that respond to both PPARγ and ERK.
"Using this drug appears to restore the neuronal signaling required for proper cognitive function," said UTMB professor Larry Denner, the lead author of a paper describing this work now online in the Journal of Neuroscience. "It gives us an opportunity to test several FDA-approved drugs to normalize insulin resistance in Alzheimer's patients and possibly also enhance memory, and it also gives us a remarkable tool to use in animal models to understand the molecular mechanisms that underlie cognitive issues in Alzheimer's."
ERK dysfunction in the Alzheimer's mouse model was discovered several years ago by UTMB associate professor Kelly Dineley, senior author of the Journal of Neuroscience paper. But putting together the protein, gene and memory pieces of the puzzle required a multidisciplinary translational research team including animal cognitive neuroscientists, biochemists, molecular biologists, mass spectrometrists, statisticians and bioinformaticists.
"We were extraordinarily lucky to have this diverse group of experts right here on our campus at UTMB that could coalesce to bring such different ways of thinking to bear on a common problem," Denner said. "It was quite a challenge to get all of these experts communicating in a common scientific language. But now that we have this team working, we can move on to even more detailed and difficult questions."
Now the UTMB research team and other investigators across the world are starting clinical trials to investigate the value of therapies for insulin resistance in early-stage Alzheimer's disease in humans.
Other authors of the Journal of Neuroscience paper include predoctoral fellows Jennifer Rodriguez-Rivera and Jordan Jahrling, research associate Sigmund Haidacher, scientist Russ Carmichael, assistant professors Rovshan Sadygov, Jonathan Starkey and Heidi Spratt, and professors Bruce Luxon and Thomas Wood. This research was supported by the National Institutes of Health, the American Health Assistance Foundation, the Sealy Foundation for Biomedical Research, the Emmett and Miriam McCoy Foundation, the Cullen Trust for Health Care and Jerry and Winkie Mohn.
Working with genetically engineered mice designed to serve as models for Alzheimer's, University of Texas Medical Branch at Galveston researchers found that treatment with the anti-insulin-resistance drug rosiglitazone enhanced learning and memory as well as normalized insulin resistance. The scientists believe that the drug produced the response by reducing the negative influence of Alzheimer's on the behavior of a key brain-signaling molecule.
The molecule, called extracellular signal-regulated kinase (ERK), becomes hyperactive both in the brains of Alzheimer's patients and in the mice at a disease stage corresponding to mild cognitive impairment in human Alzheimer's. This excessive activity leads to improper synaptic transmission between neurons, interfering with learning and memory.
Rosiglitazone brings ERK back into line by activating what's known as the peroxisome proliferator-activated receptor gamma (PPARγ) pathway, which interacts with genes that respond to both PPARγ and ERK.
"Using this drug appears to restore the neuronal signaling required for proper cognitive function," said UTMB professor Larry Denner, the lead author of a paper describing this work now online in the Journal of Neuroscience. "It gives us an opportunity to test several FDA-approved drugs to normalize insulin resistance in Alzheimer's patients and possibly also enhance memory, and it also gives us a remarkable tool to use in animal models to understand the molecular mechanisms that underlie cognitive issues in Alzheimer's."
ERK dysfunction in the Alzheimer's mouse model was discovered several years ago by UTMB associate professor Kelly Dineley, senior author of the Journal of Neuroscience paper. But putting together the protein, gene and memory pieces of the puzzle required a multidisciplinary translational research team including animal cognitive neuroscientists, biochemists, molecular biologists, mass spectrometrists, statisticians and bioinformaticists.
"We were extraordinarily lucky to have this diverse group of experts right here on our campus at UTMB that could coalesce to bring such different ways of thinking to bear on a common problem," Denner said. "It was quite a challenge to get all of these experts communicating in a common scientific language. But now that we have this team working, we can move on to even more detailed and difficult questions."
Now the UTMB research team and other investigators across the world are starting clinical trials to investigate the value of therapies for insulin resistance in early-stage Alzheimer's disease in humans.
Other authors of the Journal of Neuroscience paper include predoctoral fellows Jennifer Rodriguez-Rivera and Jordan Jahrling, research associate Sigmund Haidacher, scientist Russ Carmichael, assistant professors Rovshan Sadygov, Jonathan Starkey and Heidi Spratt, and professors Bruce Luxon and Thomas Wood. This research was supported by the National Institutes of Health, the American Health Assistance Foundation, the Sealy Foundation for Biomedical Research, the Emmett and Miriam McCoy Foundation, the Cullen Trust for Health Care and Jerry and Winkie Mohn.
Sunday, 18 November 2012
Researchers study possible new treatment to halt Alzheimer's disease
Last March, researchers at UCLA reported the development of a molecular compound called CLR01 that prevented toxic proteins associated with Parkinson's disease from binding together and killing the brain's neurons.
Building on those findings, they have now turned their attention to Alzheimer's disease, which is thought to be caused by a similar toxic aggregation or clumping, but with different proteins, especially amyloid-beta and tau.
And what they've found is encouraging. Using the same compound, which they've dubbed a "molecular tweezer," in a living mouse model of Alzheimer's, the researchers demonstrated for the first time that the compound safely crossed the blood-brain barrier, cleared the existing amyloid-beta and tau aggregates, and also proved to be protective to the neurons' synapses -- another target of the disease -- which allow cells to communicate with one another.
The report appears in the current online edition of the journal Brain.
"This is the first demonstration that molecular tweezers work in a mammalian animal model," said Gal Bitan, an associate professor of neurology at UCLA and the senior author of the study. "Importantly, no signs of toxicity were observed in the treated mice. The efficacy and toxicity results support the mechanism of this molecular tweezer and suggest these are promising compounds for developing disease-modifying therapies for Alzheimer's disease, Parkinson's and other disorders."
Molecular tweezers are complex molecular compounds capable of binding to other proteins. Shaped like the letter "C," these compounds wrap around chains of lysine, a basic amino acid that is a constituent of most proteins. Bitan and his colleagues, including Aida Attar, first author of the study and a graduate student in Bitan's lab, have been working with a particular molecular tweezer called CLR01.
In collaboration with scientists at the Università Cattolica in Rome, the researchers, working first in cell cultures, found that CLR01 effectively inhibited a process known as synaptotoxicity, in which clumps of toxic amyloid damage or destroy a neuron's synapses.
Even though synapses in transgenic mice with Alzheimer's may shut down and the mice may lose their memory, upon treatment, they form new synapses and regain their learning and memory abilities.
"For humans, unfortunately, the situation is more problematic because the neurons gradually die in Alzheimer's disease," Bitan said. "That's why we must start treating as early as possible. The good news is that the molecular tweezers appear to have a high safety margin, so they may be suitable for prophylactic treatment starting long before the onset of the disease."
Next, using a radioactive "label," the researchers were able to confirm that the compound had crossed the mouse's blood-brain barrier and was effective in clearing the brain of amyloid-beta and tau aggregates.
"This work shows that molecular tweezers do a number of things -- they help to ameliorate multiple pathologic features of Alzheimer's, including amyloid plaques, neurofibrillary tangles and brain inflammation, and our cell culture experiments demonstrated that molecular tweezers block the toxic effect of amyloid-beta on synaptic integrity and communication," Bitan said.
"We call these unique tweezers 'process-specific,' rather than the common protein-specific inhibitors," he added, meaning the compound only attacks the targeted toxic aggregates and not normal body processes. "That's a big deal, because it helps confirm evidence that the molecular tweezers can be used safely, ultimately supporting their development as a therapy for humans."
The next step, Bitan hopes, is to confirm that the tweezers improve memory and not just brain pathology. The researchers say they are working on this question and already have encouraging preliminary data.
Building on those findings, they have now turned their attention to Alzheimer's disease, which is thought to be caused by a similar toxic aggregation or clumping, but with different proteins, especially amyloid-beta and tau.
And what they've found is encouraging. Using the same compound, which they've dubbed a "molecular tweezer," in a living mouse model of Alzheimer's, the researchers demonstrated for the first time that the compound safely crossed the blood-brain barrier, cleared the existing amyloid-beta and tau aggregates, and also proved to be protective to the neurons' synapses -- another target of the disease -- which allow cells to communicate with one another.
The report appears in the current online edition of the journal Brain.
"This is the first demonstration that molecular tweezers work in a mammalian animal model," said Gal Bitan, an associate professor of neurology at UCLA and the senior author of the study. "Importantly, no signs of toxicity were observed in the treated mice. The efficacy and toxicity results support the mechanism of this molecular tweezer and suggest these are promising compounds for developing disease-modifying therapies for Alzheimer's disease, Parkinson's and other disorders."
Molecular tweezers are complex molecular compounds capable of binding to other proteins. Shaped like the letter "C," these compounds wrap around chains of lysine, a basic amino acid that is a constituent of most proteins. Bitan and his colleagues, including Aida Attar, first author of the study and a graduate student in Bitan's lab, have been working with a particular molecular tweezer called CLR01.
In collaboration with scientists at the Università Cattolica in Rome, the researchers, working first in cell cultures, found that CLR01 effectively inhibited a process known as synaptotoxicity, in which clumps of toxic amyloid damage or destroy a neuron's synapses.
Even though synapses in transgenic mice with Alzheimer's may shut down and the mice may lose their memory, upon treatment, they form new synapses and regain their learning and memory abilities.
"For humans, unfortunately, the situation is more problematic because the neurons gradually die in Alzheimer's disease," Bitan said. "That's why we must start treating as early as possible. The good news is that the molecular tweezers appear to have a high safety margin, so they may be suitable for prophylactic treatment starting long before the onset of the disease."
Next, using a radioactive "label," the researchers were able to confirm that the compound had crossed the mouse's blood-brain barrier and was effective in clearing the brain of amyloid-beta and tau aggregates.
"This work shows that molecular tweezers do a number of things -- they help to ameliorate multiple pathologic features of Alzheimer's, including amyloid plaques, neurofibrillary tangles and brain inflammation, and our cell culture experiments demonstrated that molecular tweezers block the toxic effect of amyloid-beta on synaptic integrity and communication," Bitan said.
"We call these unique tweezers 'process-specific,' rather than the common protein-specific inhibitors," he added, meaning the compound only attacks the targeted toxic aggregates and not normal body processes. "That's a big deal, because it helps confirm evidence that the molecular tweezers can be used safely, ultimately supporting their development as a therapy for humans."
The next step, Bitan hopes, is to confirm that the tweezers improve memory and not just brain pathology. The researchers say they are working on this question and already have encouraging preliminary data.
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