Thousands of people with early stage Alzheimer's are being denied access to the only drugs for the disease due to fundamental flaws in the way their cost effectiveness has been calculated.
There has been widespread condemnation of the National Institute for Health and Clinical Excellence's (NICE) decision to restrict Alzheimer's drugs that cost just £2.50 a day on the NHS.
Following a ruling by the Court of Appeal in May 2008, NICE was ordered to release the health economic model used to make the decision to key stakeholders. Alzheimer's Society has reviewed the calculations and submitted a detailed analysis to NICE. The charity has today appealed for NICE to review its decision on Alzheimer's drugs.
Neil Hunt, Chief Executive of Alzheimer's Society, says,
'We have always argued that the way NICE calculated the cost effectiveness of Alzheimer's drugs was fundamentally flawed. Now that we have examined NICE's calculations first hand and taken expert advice, Alzheimer's Society remains convinced that denying people with Alzheimer's effective drugs makes no sense.
NICE must urgently review its decision. One in three people over 65 will die with dementia; the current state of dementia care and treatment in the UK is a national scandal.' Alzheimer's Society cannot release its full response to NICE due to NICE's confidentiality rules. However, previously the charity has highlighted the following concerns about the way cost effectiveness is calculated:
- NICE assumes everyone who starts treatment continues on it. In reality, only those who benefit from drugs would stay on them.
- NICE has drastically underestimated the cost savings to the State of people receiving treatment and remaining active in the community (rather than cared for in homes or hospitals)
- NICE does not take into account the full benefit drug treatment can have on a carer's quality of life.
In October 2008, the House of Lords denied NICE the right to appeal the high court decision which ordered it to release a copy of the executable model.
- Since May 2006 three Alzheimer's drugs have been denied to people in the early stages of the disease on the NHS.
- On 1 May 2008 the Court of Appeal found in favor of Eisai/Pfizer ruling NICE should have allowed public access to the health economic model that it used to make its decision.
- On 17 June 2008 NICE sought permission from the House of Lords to appeal the Court of Appeal decision.
- 1 in 3 people over the age of 65 will die with dementia.
- 700,000 people in the UK have a form of dementia, more than half have Alzheimer's disease. In less than 20 years nearly a million people will be living with dementia. This will soar to 1.7 million people by 2051.
- Dementia is not a natural part of aging; it is caused by diseases of the brain and robs people of their lives.
- Alzheimer's Society champions the rights of people living with dementia and those who care for them. Alzheimer's Society works in England, Wales and Northern Ireland.
Monday, January 26, 2009
Lower Risk Of Dementia And Alzheimer's Linked To Midlife Coffee Drinking
Researchers in Finland and Sweden who followed over 1,400 middle-aged people over twenty years, found that those who drank three to five cups of coffee a day in their midlife years were less likely to develop dementia or Alzheimer's disease in old age compared with those who drank either no coffee at all or very little.
The findings came from the Finnish Cardiovascular Risk Factors, Aging and Dementia (CAIDE) Study, conducted by researchers at the University of Kuopio, Finland and the Karolinska Institutet, Stockholm, Sweden, and the National Public Health Institute, Helsinki, Finland. It is published in the January 2009 issue of the Journal of Alzheimer's Disease, currently in press, although abstracts can be viewed online.
The participants of the study included survivors from other research programs, such as the North Karelia Project and the FINMONICA study in 1972, 1977, 1982 and 1987. After the midlife examination, the average follow up was 21 years, and a total of 1,409 participants, aged between 65 and 79 years, completed the project and undertook the end of follow up re-examination in 1998, when 61 of them were diagnosed with dementia, including 48 with Alzheimer's Disease (AD).
At the midlife examination, participants filled in questionnaires that asked them, among other things, how much coffee and tea they drank, and how often.
For this study, the researchers categorized coffee consumption into three bands: low (0-2 cups a day), moderate (3 to 5 cups) and high (over 5 cups a day). Tea drinking was categorized only into two bands: tea drinking and no tea drinking.
Lead researcher Miia Kivipelto, who is an associate professor at the University of Kuopio, Finland and the Karolinska Institutet, Sweden, explained why they did the study:
"We aimed to study the association between coffee and tea consumption at midlife and dementia/AD risk in late-life, because the long-term impact of caffeine on the central nervous system was still unknown, and as the pathologic processes leading to Alzheimer's disease may start decades before the clinical manifestation of the disease."
The results showed that:
* Those who drank coffee in midlife had a lower risk of developing dememtia and AD later in life than those who drank little or no coffee.
* The lowest risk (65 per cent lower risk) was among those who drank moderate amounts of coffee in midlife (3 to 5 cups a day).
* Removing the effect of potential confounders did not change the figures significantly.
* Tea drinking was relatively uncommon and no links were found between this and dementia/AD.
Kivipelto said:
"Given the large amount of coffee consumption globally, the results might have important implications for the prevention of or delaying the onset of dementia/AD. "
The researchers said the findings need to be confirmed by other studies, but nevertheless they highlight the possibility that diet can change a person's risk of late-life dementia or AD.
If, following confirmation of these findings by further research, scientists also discover the mechanisms by which coffee protects against dementia and AD, then it may also be possible to develop new therapies for these conditions, said Kivipelto.
The findings came from the Finnish Cardiovascular Risk Factors, Aging and Dementia (CAIDE) Study, conducted by researchers at the University of Kuopio, Finland and the Karolinska Institutet, Stockholm, Sweden, and the National Public Health Institute, Helsinki, Finland. It is published in the January 2009 issue of the Journal of Alzheimer's Disease, currently in press, although abstracts can be viewed online.
The participants of the study included survivors from other research programs, such as the North Karelia Project and the FINMONICA study in 1972, 1977, 1982 and 1987. After the midlife examination, the average follow up was 21 years, and a total of 1,409 participants, aged between 65 and 79 years, completed the project and undertook the end of follow up re-examination in 1998, when 61 of them were diagnosed with dementia, including 48 with Alzheimer's Disease (AD).
At the midlife examination, participants filled in questionnaires that asked them, among other things, how much coffee and tea they drank, and how often.
For this study, the researchers categorized coffee consumption into three bands: low (0-2 cups a day), moderate (3 to 5 cups) and high (over 5 cups a day). Tea drinking was categorized only into two bands: tea drinking and no tea drinking.
Lead researcher Miia Kivipelto, who is an associate professor at the University of Kuopio, Finland and the Karolinska Institutet, Sweden, explained why they did the study:
"We aimed to study the association between coffee and tea consumption at midlife and dementia/AD risk in late-life, because the long-term impact of caffeine on the central nervous system was still unknown, and as the pathologic processes leading to Alzheimer's disease may start decades before the clinical manifestation of the disease."
The results showed that:
* Those who drank coffee in midlife had a lower risk of developing dememtia and AD later in life than those who drank little or no coffee.
* The lowest risk (65 per cent lower risk) was among those who drank moderate amounts of coffee in midlife (3 to 5 cups a day).
* Removing the effect of potential confounders did not change the figures significantly.
* Tea drinking was relatively uncommon and no links were found between this and dementia/AD.
Kivipelto said:
"Given the large amount of coffee consumption globally, the results might have important implications for the prevention of or delaying the onset of dementia/AD. "
The researchers said the findings need to be confirmed by other studies, but nevertheless they highlight the possibility that diet can change a person's risk of late-life dementia or AD.
If, following confirmation of these findings by further research, scientists also discover the mechanisms by which coffee protects against dementia and AD, then it may also be possible to develop new therapies for these conditions, said Kivipelto.
Thursday, January 22, 2009
Promising Hormone Treatment For Alzheimer's Disease And Stroke
Saint Louis University researchers have identified a novel way of getting a potential treatment for Alzheimer's disease and stroke into the brain where it can do its work.
"We found a unique approach for delivering drugs to the brain," says William A. Banks, M.D., professor of geriatrics and pharmacological and physiological science at Saint Louis University. "We're turning off the guardian that's keeping the drugs out of the brain."
The brain is protected by the blood-brain barrier (BBB), a gate-keeping system of cells that lets in nutrients and keeps out foreign substances. The blood-brain barrier passes no judgment on which foreign substances are trying to get into the brain to treat diseases and which are trying to do harm, so it blocks them without discrimination.
"The problem in treating a lot of diseases of the central nervous system - such as Alzheimer's disease, HIV and stroke - is that we can't get drugs past the blood-brain barrier and into the brain," says Banks, who also is a staff physician at Veterans Affairs Medical Center in St. Louis.
"Our new research shows a way of getting a promising treatment for these types of devastating diseases to where they need to be to work."
The therapy - known as PACAP - is a hormone produced by the body that is a general neuro-protectant.
PACAP stands for pituitary adenylate cyclase-activating polypeptide. "It is a general protector of the brain against many types of insult and injury," Banks says.
He compares a specific guarding mechanism in the BBB - efflux pumps - to bouncers at exclusive nightclubs. While they welcome those on the approved guest list, they look for trouble-makers trying to crash the party, refuse to let them in and evict them if they do get in.
The scientists isolated the particular gatekeeper than evicts PACAP. Then they designed an anti sense, a specific molecule that turned off the impediment.
"We went after the guard and essentially told him to go on break for a while so PACAP could get into the brain," Banks says.
They used mouse models of Alzheimer's disease and stroke to test what would happen if PACAP could get into the brain.
"We reversed the symptoms of the illnesses," Banks says. "The mice that had a version of Alzheimer's disease became smarter and in the stroke model, we reduced the amount of damage caused by the blockage of blood to the brain and improved brain recovery."
Simply turning off the gatekeeper that kept PACAP out of the brain allowed enough of the hormone that already is in the body to get inside the brain, where it effectively treated strokes. However, the mice that had a version of Alzheimer's disease needed both an extra dose of PACAP and the anti sense that turned off the gatekeeper to improve learning.
"These findings are significant for three reasons. We have found a therapy that reverses symptoms of Alzheimers's disease and stroke in a mouse model. We have isolated the particular roadblock that keeps the treatment from getting into the brain. And we have found a way to finesse that obstacle so the medicine can get into the brain to do its work," Banks says. "This could have implications in treating many diseases of the central nervous system."
The findings were published in the Nov. Early online issue of the Journal of Cerebral Blood Flow & Metabolism.
"We found a unique approach for delivering drugs to the brain," says William A. Banks, M.D., professor of geriatrics and pharmacological and physiological science at Saint Louis University. "We're turning off the guardian that's keeping the drugs out of the brain."
The brain is protected by the blood-brain barrier (BBB), a gate-keeping system of cells that lets in nutrients and keeps out foreign substances. The blood-brain barrier passes no judgment on which foreign substances are trying to get into the brain to treat diseases and which are trying to do harm, so it blocks them without discrimination.
"The problem in treating a lot of diseases of the central nervous system - such as Alzheimer's disease, HIV and stroke - is that we can't get drugs past the blood-brain barrier and into the brain," says Banks, who also is a staff physician at Veterans Affairs Medical Center in St. Louis.
"Our new research shows a way of getting a promising treatment for these types of devastating diseases to where they need to be to work."
The therapy - known as PACAP - is a hormone produced by the body that is a general neuro-protectant.
PACAP stands for pituitary adenylate cyclase-activating polypeptide. "It is a general protector of the brain against many types of insult and injury," Banks says.
He compares a specific guarding mechanism in the BBB - efflux pumps - to bouncers at exclusive nightclubs. While they welcome those on the approved guest list, they look for trouble-makers trying to crash the party, refuse to let them in and evict them if they do get in.
The scientists isolated the particular gatekeeper than evicts PACAP. Then they designed an anti sense, a specific molecule that turned off the impediment.
"We went after the guard and essentially told him to go on break for a while so PACAP could get into the brain," Banks says.
They used mouse models of Alzheimer's disease and stroke to test what would happen if PACAP could get into the brain.
"We reversed the symptoms of the illnesses," Banks says. "The mice that had a version of Alzheimer's disease became smarter and in the stroke model, we reduced the amount of damage caused by the blockage of blood to the brain and improved brain recovery."
Simply turning off the gatekeeper that kept PACAP out of the brain allowed enough of the hormone that already is in the body to get inside the brain, where it effectively treated strokes. However, the mice that had a version of Alzheimer's disease needed both an extra dose of PACAP and the anti sense that turned off the gatekeeper to improve learning.
"These findings are significant for three reasons. We have found a therapy that reverses symptoms of Alzheimers's disease and stroke in a mouse model. We have isolated the particular roadblock that keeps the treatment from getting into the brain. And we have found a way to finesse that obstacle so the medicine can get into the brain to do its work," Banks says. "This could have implications in treating many diseases of the central nervous system."
The findings were published in the Nov. Early online issue of the Journal of Cerebral Blood Flow & Metabolism.
Wednesday, January 21, 2009
Alzheimer's Disease Could Be Prevented And Treated By Common Epilepsy Drug
The team led by UBC Psychiatry Prof. Weihong Song, who is also the Jack Brown and Family Professor and Chair in Alzheimer's Disease at UBC, found that if Valproic Acid (VPA) is used as a treatment in early stages of AD memory deficit is reversed.
The study, published in the Journal of Experimental Medicine, reveals that VPA works by inhibiting the activity of an enzyme that produces a neurotoxic protein called beta Amyloid. In doing so, plaque formation is discontinued. Amyloid beta-proteins are the central component of neurotoxic plaques in AD.
"We found that if we used VPA in the early stage of Alzheimer's disease, in model mice, it reduced plaque formation and further prevented brain cell death and axon damage," says Song, who is a Canada Research Chair in Alzheimer's disease and Director of the Townsend Family Laboratories in UBC's Faculty of Medicine. "The drug also improved performance in memory tests."
The results will help inform the design of human clinical trials because researchers now understand the mechanisms and pathology of VPA in AD animal models.
"We are very excited about these results because we now know when VPA should be administered to be most effective and we now know how VPA is working to prevent AD," says Song, who is also a member of the Brain Research Centre at UBC and VCHRI. "A small human clinical trial is currently underway and we expect results to be available in the next year."
AD is a neurodegenerative disorder characterized by progressive cognitive deterioration and is the most common form of dementia. The Alzheimer Society of Canada estimates that AD affects close to 300,000 Canadians and accounts for two-thirds of all cases of dementia. By 2031, about 750,000 Canadians will suffer from AD and related dementias.
Approximately $5.5 billion per year is spent caring for persons with AD and related dementias in Canada. The Alzheimer's Association in the U.S. estimates there are approximately 500,000 Americans younger than 65 with Alzheimer's or other dementia.
Major funding for this research has been provided by the Canadian Institutes of Health Research, the Canadian Government agency for health research. CIHR's mission is to create new scientific knowledge and to catalyze its translation into improved health, more effective health services and products, and a strengthened Canadian health care system. Composed of 13 Institutes, CIHR provides leadership and support to more than 10,000 health researchers and trainees across Canada.
Additional funding has been provided by: the Michael Smith Foundation for Health Research, British Columbia's provincially mandated health research organization and through a donation from the Townsend Family as well as from a private donation from the Jack Brown and Family Alzheimer Foundation.
The UBC Faculty of Medicine provides innovative programs in the health and life sciences, teaching students at the undergraduate, graduate and postgraduate levels, and generates more than $200 million in research funding each year.
The Brain Research Centre comprises more than 200 investigators with multidisciplinary expertise in neuroscience research ranging from the test tube, to the bedside, to industrial spin-offs. The center is a partnership of UBC and VCHRI.
VCHRI is the research body of Vancouver Coastal Health Authority. In academic partnership with UBC, the institute advances health research and innovation across B.C., Canada, and beyond.
The study, published in the Journal of Experimental Medicine, reveals that VPA works by inhibiting the activity of an enzyme that produces a neurotoxic protein called beta Amyloid. In doing so, plaque formation is discontinued. Amyloid beta-proteins are the central component of neurotoxic plaques in AD.
"We found that if we used VPA in the early stage of Alzheimer's disease, in model mice, it reduced plaque formation and further prevented brain cell death and axon damage," says Song, who is a Canada Research Chair in Alzheimer's disease and Director of the Townsend Family Laboratories in UBC's Faculty of Medicine. "The drug also improved performance in memory tests."
The results will help inform the design of human clinical trials because researchers now understand the mechanisms and pathology of VPA in AD animal models.
"We are very excited about these results because we now know when VPA should be administered to be most effective and we now know how VPA is working to prevent AD," says Song, who is also a member of the Brain Research Centre at UBC and VCHRI. "A small human clinical trial is currently underway and we expect results to be available in the next year."
AD is a neurodegenerative disorder characterized by progressive cognitive deterioration and is the most common form of dementia. The Alzheimer Society of Canada estimates that AD affects close to 300,000 Canadians and accounts for two-thirds of all cases of dementia. By 2031, about 750,000 Canadians will suffer from AD and related dementias.
Approximately $5.5 billion per year is spent caring for persons with AD and related dementias in Canada. The Alzheimer's Association in the U.S. estimates there are approximately 500,000 Americans younger than 65 with Alzheimer's or other dementia.
Major funding for this research has been provided by the Canadian Institutes of Health Research, the Canadian Government agency for health research. CIHR's mission is to create new scientific knowledge and to catalyze its translation into improved health, more effective health services and products, and a strengthened Canadian health care system. Composed of 13 Institutes, CIHR provides leadership and support to more than 10,000 health researchers and trainees across Canada.
Additional funding has been provided by: the Michael Smith Foundation for Health Research, British Columbia's provincially mandated health research organization and through a donation from the Townsend Family as well as from a private donation from the Jack Brown and Family Alzheimer Foundation.
The UBC Faculty of Medicine provides innovative programs in the health and life sciences, teaching students at the undergraduate, graduate and postgraduate levels, and generates more than $200 million in research funding each year.
The Brain Research Centre comprises more than 200 investigators with multidisciplinary expertise in neuroscience research ranging from the test tube, to the bedside, to industrial spin-offs. The center is a partnership of UBC and VCHRI.
VCHRI is the research body of Vancouver Coastal Health Authority. In academic partnership with UBC, the institute advances health research and innovation across B.C., Canada, and beyond.
Possible Alzheimer's Disease Marker Discovered In Rare Genotype
Researchers at Banner Health's Sun Health Research Institute have uncovered evidence that Alzheimer's disease (AD) may be clinically confirmed in patients with apolipoprotein E2 homozygote.
The results of their study are published in the January 2009 issue of the Journal of Alzheimer's Disease.
Apolipoprotein E2 homozygote has been associated with a protective effect against AD and contributes to delaying the onset of symptoms. However previously, no significant data had pointed to clinically confirmed AD in persons with apolipoprotein E2 homozygote. The reverse is true of apolipoprotein E4. Previous studies have confirmed that apolipoprotein E4 is a predictive risk factor for AD and indicates an increased genetic risk of AD.
Clinical confirmation of the apolipoprotein E2 homozygote Alzheimer's disease finding in this study was confirmed by MRI, PET and neuropsychological evaluation and testing. AD pathology is yet to be determined and will occur at post mortem.
"Clinical diagnosis of possible AD has now become extremely accurate and is especially helpful to physicians looking for the best outcomes in treating patients," says Marwan Sabbagh, MD, Sun Health Research Institute's chief medical/scientific officer and lead investigator of the study.
"This study may hold many clues to the nature of how Alzheimer's genetics work. Although clinically rare, the information gleaned in this study allows us to ask new questions and possibly answer others," says Sabbagh.
The results of their study are published in the January 2009 issue of the Journal of Alzheimer's Disease.
Apolipoprotein E2 homozygote has been associated with a protective effect against AD and contributes to delaying the onset of symptoms. However previously, no significant data had pointed to clinically confirmed AD in persons with apolipoprotein E2 homozygote. The reverse is true of apolipoprotein E4. Previous studies have confirmed that apolipoprotein E4 is a predictive risk factor for AD and indicates an increased genetic risk of AD.
Clinical confirmation of the apolipoprotein E2 homozygote Alzheimer's disease finding in this study was confirmed by MRI, PET and neuropsychological evaluation and testing. AD pathology is yet to be determined and will occur at post mortem.
"Clinical diagnosis of possible AD has now become extremely accurate and is especially helpful to physicians looking for the best outcomes in treating patients," says Marwan Sabbagh, MD, Sun Health Research Institute's chief medical/scientific officer and lead investigator of the study.
"This study may hold many clues to the nature of how Alzheimer's genetics work. Although clinically rare, the information gleaned in this study allows us to ask new questions and possibly answer others," says Sabbagh.
Education Can Help Stave Off Alzheimer's Disease
Even with evidence of brain plaques associated with Alzheimer's disease, highly educated individuals manage to score higher on cognitive tests. Results from this study are published in the November issue of Archives of Neurology.
Currently there exists a popular notion - the "cognitive reserve" hypothesis - that people with greater thinking, learning, and memory capabilities can delay symptom of Alzheimer's disease even as the brain is changing. Since cognitive reserve is somewhat difficult to measure, researchers use education level as a proxy. "Adjusting for level of Alzheimer disease pathological burden determined at autopsy, greater education has been associated with better cognitive function during life," write Catherine M. Roe, Ph.D. and colleagues at the Washington University School of Medicine, St. Louis. "Education interacts with Alzheimer disease pathological burden such that a greater pathological burden is required to show an effect on cognition among persons with more education."
Between 2003 and 2008, the researchers analyzed 37 individuals diagnosed with Alzheimer's-like dementia and 161 individuals without dementia. Cognitive reserve measurements included education history as well as cognitive test scores. In addition, study participants received an injection of carbon 11-labeled Pittsburgh Compound B (PiB) prior to a 60-minute positron emission tomography (PET) brain scan. This contrast compound (PiB) has been shown to stick to beta-amyloid brain plaques that are linked to Alzheimer's disease, and thus researchers could identify the disease state in each patient.
Results of the study demonstrated that there were significant difference in the level of PiB uptake among patients with different years of education and cognitive test scores. For example, individuals with beta-amyloid plaques in the brain (organs that took up higher levels of PiB) showed increased performance on tests as education levels increased. For individuals without plaques, education was not significantly associated with cognitive scores.
"The results support the hypothesis that cognitive reserve influences the association between Alzheimer disease pathological burden and cognition," conclude Roes and colleagues. "Based on autopsy data, there may be a ceiling effect when extensive beta-amyloid pathological burden is present as in late-stage dementia of the Alzheimer type. Presumably, as the Alzheimer disease pathological burden increases, a greater proportion of highly educated participants reaches the threshold for dementia and the initial advantage provided by cognitive reserve decreases. Longitudinal imaging of beta-amyloid pathology in vivo will soon allow us to determine whether these inferences from cross-sectional studies are accurate."
Currently there exists a popular notion - the "cognitive reserve" hypothesis - that people with greater thinking, learning, and memory capabilities can delay symptom of Alzheimer's disease even as the brain is changing. Since cognitive reserve is somewhat difficult to measure, researchers use education level as a proxy. "Adjusting for level of Alzheimer disease pathological burden determined at autopsy, greater education has been associated with better cognitive function during life," write Catherine M. Roe, Ph.D. and colleagues at the Washington University School of Medicine, St. Louis. "Education interacts with Alzheimer disease pathological burden such that a greater pathological burden is required to show an effect on cognition among persons with more education."
Between 2003 and 2008, the researchers analyzed 37 individuals diagnosed with Alzheimer's-like dementia and 161 individuals without dementia. Cognitive reserve measurements included education history as well as cognitive test scores. In addition, study participants received an injection of carbon 11-labeled Pittsburgh Compound B (PiB) prior to a 60-minute positron emission tomography (PET) brain scan. This contrast compound (PiB) has been shown to stick to beta-amyloid brain plaques that are linked to Alzheimer's disease, and thus researchers could identify the disease state in each patient.
Results of the study demonstrated that there were significant difference in the level of PiB uptake among patients with different years of education and cognitive test scores. For example, individuals with beta-amyloid plaques in the brain (organs that took up higher levels of PiB) showed increased performance on tests as education levels increased. For individuals without plaques, education was not significantly associated with cognitive scores.
"The results support the hypothesis that cognitive reserve influences the association between Alzheimer disease pathological burden and cognition," conclude Roes and colleagues. "Based on autopsy data, there may be a ceiling effect when extensive beta-amyloid pathological burden is present as in late-stage dementia of the Alzheimer type. Presumably, as the Alzheimer disease pathological burden increases, a greater proportion of highly educated participants reaches the threshold for dementia and the initial advantage provided by cognitive reserve decreases. Longitudinal imaging of beta-amyloid pathology in vivo will soon allow us to determine whether these inferences from cross-sectional studies are accurate."
Potential Protection For The Brain Against Alzheimer's Disease From A Special Type Of Collagen
Scientists from the Gladstone Institute of Neurological Disease (GIND), UCSF, and Stanford have discovered that a certain type of collagen, collagen VI, protects brain cells against amyloid-beta (Aβ ) proteins, which are widely thought to cause Alzheimer's disease (AD).
While the functions of collagens in cartilage and muscle are well established, before this study it was unknown that collagen VI is made by neurons in the brain and that it can fulfill important neuroprotective functions.
The team of investigators led by GIND director Lennart Mucke, MD, reported in a recent edition of the journal Nature Neuroscience, that collagen VI is increased in brain tissues of Alzheimer's patients.
"We first noticed the increase in collagen VI in the brain of AD mouse models, which inspired us to look for it in the human condition and to define its role in the disease," said Dr. Mucke.
The Gladstone team had profiled changes in gene expression using DNA microarrays, which provides an unbiased method for identifying key biological pathways. By comparing all of the genes that are active in disease and normal tissue, one can get valuable information on new pathways and potential therapeutic targets.
The researchers looked at the dentate gyrus, a specific area of the brain that is critical to memory and particularly vulnerable in AD, and compared the genes that were turned on and off in normal mice and a mouse model of AD. This analysis revealed the striking increase in collagen VI in the brains of mice that model AD.
Building on this initial finding, the team examined brain tissue from AD patients and normal non-demented humans and found that collagen VI expression was also higher in the AD patients. They further discovered that the cellular source of the collagen VI in the brain was neurons, the very cells that the disease attacks and that we all need to think and remember.
"These findings were really surprising and exciting to us because nobody knew anything about collagen VI in the brain," said Jason Cheng, MD, co-lead author of the study. "We were particularly curious whether collagen VI contributed to neuronal damage in AD or was produced as a defense mechanism against it," added Dena Dubal, MD, PhD, co-lead author of the study.
To answer this and other questions, the scientists carried out a series of informative cell culture experiments. These experiments revealed found that Aβ added to neurons grown in culture increased the expression of collagen VI and that this process involved the immune regulatory cytosine TGFβ. What is more, the team discovered that increasing the amount of collagen VI in the cultures effectively protected the neurons against Aβ toxicity.
"This striking protective effect suggests that increased neuronal production of collagen VI is an important component of the brain's defense against Aβ," said Dr. Mucke. "It made us really curious about the underlying mechanisms."
To clinch these mechanisms, Dr. Mucke's team examined the direct interactions of collagen VI with Aβ. They looked at how Aβ attacks individual neurons in cell culture. Small poisonous Aβ assemblies, called oligomers, bind strongly to vulnerable neurons in the brain, but in the presence of collagen VI, this binding was blocked. Using immunohistochemistry and atomic force microscopy, they showed that collagen VI and Aβ form large aggregates with each other that may sequester the smaller, more toxic Aβ complexes away from neurons.
"We are eager to explore how this kind of process might be enhanced therapeutically and how we can best leverage it for the development of more effective treatments for this devastating condition," said Dr. Dubal.
While the functions of collagens in cartilage and muscle are well established, before this study it was unknown that collagen VI is made by neurons in the brain and that it can fulfill important neuroprotective functions.
The team of investigators led by GIND director Lennart Mucke, MD, reported in a recent edition of the journal Nature Neuroscience, that collagen VI is increased in brain tissues of Alzheimer's patients.
"We first noticed the increase in collagen VI in the brain of AD mouse models, which inspired us to look for it in the human condition and to define its role in the disease," said Dr. Mucke.
The Gladstone team had profiled changes in gene expression using DNA microarrays, which provides an unbiased method for identifying key biological pathways. By comparing all of the genes that are active in disease and normal tissue, one can get valuable information on new pathways and potential therapeutic targets.
The researchers looked at the dentate gyrus, a specific area of the brain that is critical to memory and particularly vulnerable in AD, and compared the genes that were turned on and off in normal mice and a mouse model of AD. This analysis revealed the striking increase in collagen VI in the brains of mice that model AD.
Building on this initial finding, the team examined brain tissue from AD patients and normal non-demented humans and found that collagen VI expression was also higher in the AD patients. They further discovered that the cellular source of the collagen VI in the brain was neurons, the very cells that the disease attacks and that we all need to think and remember.
"These findings were really surprising and exciting to us because nobody knew anything about collagen VI in the brain," said Jason Cheng, MD, co-lead author of the study. "We were particularly curious whether collagen VI contributed to neuronal damage in AD or was produced as a defense mechanism against it," added Dena Dubal, MD, PhD, co-lead author of the study.
To answer this and other questions, the scientists carried out a series of informative cell culture experiments. These experiments revealed found that Aβ added to neurons grown in culture increased the expression of collagen VI and that this process involved the immune regulatory cytosine TGFβ. What is more, the team discovered that increasing the amount of collagen VI in the cultures effectively protected the neurons against Aβ toxicity.
"This striking protective effect suggests that increased neuronal production of collagen VI is an important component of the brain's defense against Aβ," said Dr. Mucke. "It made us really curious about the underlying mechanisms."
To clinch these mechanisms, Dr. Mucke's team examined the direct interactions of collagen VI with Aβ. They looked at how Aβ attacks individual neurons in cell culture. Small poisonous Aβ assemblies, called oligomers, bind strongly to vulnerable neurons in the brain, but in the presence of collagen VI, this binding was blocked. Using immunohistochemistry and atomic force microscopy, they showed that collagen VI and Aβ form large aggregates with each other that may sequester the smaller, more toxic Aβ complexes away from neurons.
"We are eager to explore how this kind of process might be enhanced therapeutically and how we can best leverage it for the development of more effective treatments for this devastating condition," said Dr. Dubal.
Breakthrough In Screening For Alzheimer's Disease
CSIRO scientists have developed a new system to screen for compounds that can inhibit one of the processes that takes place during the progression of Alzheimer's disease.
In a paper published in the latest edition of the Journal of Alzheimer's Disease, folate is shown to be beneficial in the screening system.
Lead author, CSIRO's Dr Ian Macreadie says folate is already well known to have a protective effect against Alzheimer's disease which is believed to be caused by the loss of neurons in the brain due to a process whereby toxic multimers of a small protein called Aβ are formed.
"However, a team of scientists working within CSIRO's Preventative Health Flagship has discovered a rapid screening system to identify inhibitors of this process. Compounds that inhibit the formation of the toxic multimers may lead to the prevention or delay of the disease," Dr Macreadie says.
"Although many other research groups and drug companies around the world are trying to find compounds that act in the same way, the advance by the Flagship team involves using live yeast with the Aβ protein fused to a green fluorescent protein that comes from jellyfish.
"The significance of this development is that the yeast trial we developed could lead to the discovery of new agents which may prove useful in preventing or delaying the onset of Alzheimer's disease."
Currently Alzheimer's disease is an incurable illness and the fourth leading cause of death in people aged 65 years and over.
Although folate is abundant in foods like leafy green vegetables, pulses and liver, CSIRO studies have shown that many Australians do not consume enough folate to benefit from its ability to prevent cell damage. Folate levels can, however, be readily restored by dietary folate supplementation.
In a paper published in the latest edition of the Journal of Alzheimer's Disease, folate is shown to be beneficial in the screening system.
Lead author, CSIRO's Dr Ian Macreadie says folate is already well known to have a protective effect against Alzheimer's disease which is believed to be caused by the loss of neurons in the brain due to a process whereby toxic multimers of a small protein called Aβ are formed.
"However, a team of scientists working within CSIRO's Preventative Health Flagship has discovered a rapid screening system to identify inhibitors of this process. Compounds that inhibit the formation of the toxic multimers may lead to the prevention or delay of the disease," Dr Macreadie says.
"Although many other research groups and drug companies around the world are trying to find compounds that act in the same way, the advance by the Flagship team involves using live yeast with the Aβ protein fused to a green fluorescent protein that comes from jellyfish.
"The significance of this development is that the yeast trial we developed could lead to the discovery of new agents which may prove useful in preventing or delaying the onset of Alzheimer's disease."
Currently Alzheimer's disease is an incurable illness and the fourth leading cause of death in people aged 65 years and over.
Although folate is abundant in foods like leafy green vegetables, pulses and liver, CSIRO studies have shown that many Australians do not consume enough folate to benefit from its ability to prevent cell damage. Folate levels can, however, be readily restored by dietary folate supplementation.
In Early Diagnosis Of Alzheimer's Disease, MRI Brain Scans Accurate
MRI scans that detect shrinkage in specific regions of the mid-brain attacked by Alzheimer's disease accurately diagnose the neurodegenerative disease, even before symptoms interfere with daily function, a study by the Florida Alzheimer's Disease Research Center (ADRC) in Miami and Tampa found.
The study, reported earlier this month in the journal Neurology, adds to a growing body of evidence indicating MRI brain scans provide valuable diagnostic information about Alzheimer's disease. The findings are important in light of many new disease-modifying drugs in trials -- treatments that may prevent mild memory loss from advancing to full-blown dementia if administered early enough.
"We advocate, based on these findings, that the criteria for the diagnosis of Alzheimer's disease should include MRI scans," said the study's lead author Ranjan Duara, MD, medical director of the Wien Center for Alzheimer's Disease and Memory Disorders at Mount Sinai Medical Center who is affiliated with the University of Miami Miller School of Medicine and University of South Florida College of Medicine. "By incorporating MRIs into the assessment of patients with memory problems, early diagnosis can be standardized and done far more accurately."
"This study demonstrates that MRI brain scans are accurate enough to be clinically useful, both in diagnosing Alzheimer's disease itself at an early stage and in identifying people at risk of developing Alzheimer's," said Florida ADRC Center Director Huntington Potter, PhD, a neuroscientist at the Byrd Alzheimer's Center and Research Institute, University of South Florida.
Alzheimer's disease, the most common cause of dementia, is characterized by memory loss, disorientation, difficulty with reasoning and the decline of language and thinking skills. Alzheimer's is diagnosed by a process of elimination since many other diseases and related disorders can mimic its symptoms, and autopsy is currently the only definitive way a diagnosis can be confirmed. The diagnosis often includes a medical history, mental status tests, neurological evaluations and blood tests. Physicians typically use brain scans only to exclude conditions that can also cause memory deficits, such as strokes and brain tumors.
The Florida researchers used a new visual rating system to evaluate the severity of shrinkage, or atrophy, in the brain's medial temporal lobe - specifically in three structures essential for the conscious memory of facts and events. They compared the MRI brain scans of 260 people - a group with probable Alzheimer's disease, two groups with varying degrees of mild cognitive impairment (mild memory problems), and a control group of normal elderly with no discernable memory loss. They found that scores generated by this MRI-facilitated test accurately distinguished each group from the other and correlated with the types of memory problems most frequently caused by Alzheimer's disease. The more extensive the brain atrophy, the more advanced the clinical stage of Alzheimer's disease.
The researchers even found brain atrophy in some people without memory complaints at the study's onset who demonstrated memory decline when assessed a year or two later. This suggests MRIs could predict who will get the disease well before signs of dementia become apparent by other diagnostic methods as well as rule out an Alzheimer's diagnosis in people experiencing memory problems, Dr. Duara said. "If you don't have changes in these three particular areas of the brain, then you don't have Alzheimer's."
Researchers at centers like Miami's Wien Center and USF's Byrd Institute are developing new Alzheimer's drugs that attack mechanisms leading to the death of nerve cells and their connections. The emergence of these disease-modifying treatments has made an earlier diagnosis of Alzheimer's increasingly important, Dr. Duara said. "Having an accurate diagnosis will allow us to start using drugs earlier. The earlier treatment begins, the more likely you are to stop disease progression and benefit the patient."
Most participants in the MRI study were enrolled in the clinical arm of the Florida ADRC, which is supported by a grant from the National Institute on Aging.
The Florida ADRC, the first statewide, multi-center ADRC in the United States, was critical for the successful implementation of the study, said Dr. Potter, the study's senior author. "To validate any new diagnostic test or treatment, you need a large number of diverse volunteers for good comparisons. Alzheimer's research is a partnership between the scientific community and study volunteers; we need both to solve the complexities of Alzheimer's disease."
The study, reported earlier this month in the journal Neurology, adds to a growing body of evidence indicating MRI brain scans provide valuable diagnostic information about Alzheimer's disease. The findings are important in light of many new disease-modifying drugs in trials -- treatments that may prevent mild memory loss from advancing to full-blown dementia if administered early enough.
"We advocate, based on these findings, that the criteria for the diagnosis of Alzheimer's disease should include MRI scans," said the study's lead author Ranjan Duara, MD, medical director of the Wien Center for Alzheimer's Disease and Memory Disorders at Mount Sinai Medical Center who is affiliated with the University of Miami Miller School of Medicine and University of South Florida College of Medicine. "By incorporating MRIs into the assessment of patients with memory problems, early diagnosis can be standardized and done far more accurately."
"This study demonstrates that MRI brain scans are accurate enough to be clinically useful, both in diagnosing Alzheimer's disease itself at an early stage and in identifying people at risk of developing Alzheimer's," said Florida ADRC Center Director Huntington Potter, PhD, a neuroscientist at the Byrd Alzheimer's Center and Research Institute, University of South Florida.
Alzheimer's disease, the most common cause of dementia, is characterized by memory loss, disorientation, difficulty with reasoning and the decline of language and thinking skills. Alzheimer's is diagnosed by a process of elimination since many other diseases and related disorders can mimic its symptoms, and autopsy is currently the only definitive way a diagnosis can be confirmed. The diagnosis often includes a medical history, mental status tests, neurological evaluations and blood tests. Physicians typically use brain scans only to exclude conditions that can also cause memory deficits, such as strokes and brain tumors.
The Florida researchers used a new visual rating system to evaluate the severity of shrinkage, or atrophy, in the brain's medial temporal lobe - specifically in three structures essential for the conscious memory of facts and events. They compared the MRI brain scans of 260 people - a group with probable Alzheimer's disease, two groups with varying degrees of mild cognitive impairment (mild memory problems), and a control group of normal elderly with no discernable memory loss. They found that scores generated by this MRI-facilitated test accurately distinguished each group from the other and correlated with the types of memory problems most frequently caused by Alzheimer's disease. The more extensive the brain atrophy, the more advanced the clinical stage of Alzheimer's disease.
The researchers even found brain atrophy in some people without memory complaints at the study's onset who demonstrated memory decline when assessed a year or two later. This suggests MRIs could predict who will get the disease well before signs of dementia become apparent by other diagnostic methods as well as rule out an Alzheimer's diagnosis in people experiencing memory problems, Dr. Duara said. "If you don't have changes in these three particular areas of the brain, then you don't have Alzheimer's."
Researchers at centers like Miami's Wien Center and USF's Byrd Institute are developing new Alzheimer's drugs that attack mechanisms leading to the death of nerve cells and their connections. The emergence of these disease-modifying treatments has made an earlier diagnosis of Alzheimer's increasingly important, Dr. Duara said. "Having an accurate diagnosis will allow us to start using drugs earlier. The earlier treatment begins, the more likely you are to stop disease progression and benefit the patient."
Most participants in the MRI study were enrolled in the clinical arm of the Florida ADRC, which is supported by a grant from the National Institute on Aging.
The Florida ADRC, the first statewide, multi-center ADRC in the United States, was critical for the successful implementation of the study, said Dr. Potter, the study's senior author. "To validate any new diagnostic test or treatment, you need a large number of diverse volunteers for good comparisons. Alzheimer's research is a partnership between the scientific community and study volunteers; we need both to solve the complexities of Alzheimer's disease."
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