Neuroscience

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Posts tagged dementia

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Scientists identify molecular trigger for Alzheimer’s disease Researchers have pinpointed a catalytic trigger for the onset of Alzheimer’s disease – when the fundamental structure of a protein molecule changes to cause a chain reaction that leads to the death of neurons in the brain. For the first time, scientists at Cambridge’s Department of Chemistry, led by Dr Tuomas Knowles, Professor Michele Vendruscolo and Professor Chris Dobson working with Professor Sara Linse and colleagues at Lund University in Sweden have been able to map in detail the pathway that generates “aberrant” forms of proteins which are at the root of neurodegenerative conditions such as Alzheimer’s. They believe the breakthrough is a vital step closer to increased capabilities for earlier diagnosis of neurological disorders such as Alzheimer’s and Parkinson’s, and opens up possibilities for a new generation of targeted drugs, as scientists say they have uncovered the earliest stages of the development of Alzheimer’s that drugs could possibly target. The study, published today in the Proceedings of the US National Academy of Sciences, is a milestone in the long-term research established in Cambridge by Professor Christopher Dobson and his colleagues, following the realisation by Dobson of the underlying nature of protein ‘misfolding’ and its connection with disease over 15 years ago. The research is likely to have a central role to play in diagnostic and drug development for dementia-related diseases, which are increasingly prevalent and damaging as populations live longer. In 2010, the Alzheimer’s Research UK showed that dementia costs the UK economy over £23 billion, more than cancer and heart disease combined. Just last week, PM David Cameron urged scientists and clinicians to work together to “improve treatments and find scientific breakthroughs” to address “one of the biggest social and healthcare challenges we face.” The neurodegenerative process giving rise to diseases such as Alzheimer’s is triggered when the normal structures of protein molecules within cells become corrupted. Protein molecules are made in cellular ‘assembly lines’ that join together chemical building blocks called amino acids in an order encoded in our DNA. New proteins emerge as long, thin chains that normally need to be folded into compact and intricate structures to carry out their biological function. Under some conditions, however, proteins can ‘misfold’ and snag surrounding normal proteins, which then tangle and stick together in clumps which build to masses, frequently millions, of malfunctioning molecules that shape themselves into unwieldy protein tendrils. The abnormal tendril structures, called ‘amyloid fibrils’, grow outwards around the location where the focal point, or ‘nucleation’ of these abnormal “species” occurs. Amyloid fibrils can form the foundations of huge protein deposits – or plaques – long-seen in the brains of Alzheimer’s sufferers, and once believed to be the cause of the disease, before the discovery of ‘toxic oligomers’ by Dobson and others a decade or so ago. A plaque’s size and density renders it insoluble, and consequently unable to move. Whereas the oligomers, which give rise to Alzheimer’s disease, are small enough to spread easily around the brain - killing neurons and interacting harmfully with other molecules - but how they were formed was until now a mystery. The new work, in large part carried out by researcher Samuel Cohen, shows that once a small but critical level of malfunctioning protein ‘clumps’ have formed, a runaway chain reaction is triggered that multiplies exponentially the number of these protein composites, activating new focal points through ‘nucleation’. It is this secondary nucleation process that forges juvenile tendrils, initially consisting of clusters that contain just a few protein molecules. Small and highly diffusible, these are the ‘toxic oligomers’ that careen dangerously around the brain cells, killing neurons and ultimately causing loss of memory and other symptoms of dementia. “There are no disease modifying therapies for Alzheimer’s and dementia at the moment, only limited treatment for symptoms. We have to solve what happens at the molecular level before we can progress and have real impact,” said Dr Tuomas Knowles from Cambridge’s Department of Chemistry, lead author of the study and long-time collaborator of Professor Dobson and Professor Michele Vendruscolo. “We’ve now established the pathway that shows how the toxic species that cause cell death, the oligomers, are formed. This is the key pathway to detect, target and intervene – the molecular catalyst that underlies the pathology.” The researchers brought together kinetic experiments with a theoretical framework based on master equations, tools commonly used in other areas of chemistry and physics but had not been exploited to their full potential in the study of protein malfunction before. The latest research follows hard on the heels of another ground breaking study, published in April of this year again in PNAS, in which the Cambridge group, in Collaboration with Colleagues in London and at MIT, worked out the first atomic structure of one of the damaging amyloid fibril protein tendrils. They say the years spent developing research techniques are really paying off now, and they are starting to solve “some of the key mysteries” of these neurodegenerative diseases. “We are essentially using a physical and chemical methods to address a biomolecular problem, mapping out the networks of processes and dominant mechanisms to ‘recreate the crime scene’ at the molecular root of Alzheimer’s disease,” explained Knowles. “Increasingly, using quantitative experimental tools and rigorous theoretical analysis to understand complex biological processes are leading to exciting and game-changing results. With a disease like Alzheimer’s, you have to intervene in a highly specific manner to prevent the formation of the toxic agents. Now we’ve found how the oligomers are created, we know what process we need to turn off.”

Scientists identify molecular trigger for Alzheimer’s disease

Researchers have pinpointed a catalytic trigger for the onset of Alzheimer’s disease – when the fundamental structure of a protein molecule changes to cause a chain reaction that leads to the death of neurons in the brain.

For the first time, scientists at Cambridge’s Department of Chemistry, led by Dr Tuomas Knowles, Professor Michele Vendruscolo and Professor Chris Dobson working with Professor Sara Linse and colleagues at Lund University in Sweden have been able to map in detail the pathway that generates “aberrant” forms of proteins which are at the root of neurodegenerative conditions such as Alzheimer’s.

They believe the breakthrough is a vital step closer to increased capabilities for earlier diagnosis of neurological disorders such as Alzheimer’s and Parkinson’s, and opens up possibilities for a new generation of targeted drugs, as scientists say they have uncovered the earliest stages of the development of Alzheimer’s that drugs could possibly target.

The study, published today in the Proceedings of the US National Academy of Sciences, is a milestone in the long-term research established in Cambridge by Professor Christopher Dobson and his colleagues, following the realisation by Dobson of the underlying nature of protein ‘misfolding’ and its connection with disease over 15 years ago.

The research is likely to have a central role to play in diagnostic and drug development for dementia-related diseases, which are increasingly prevalent and damaging as populations live longer.

In 2010, the Alzheimer’s Research UK showed that dementia costs the UK economy over £23 billion, more than cancer and heart disease combined. Just last week, PM David Cameron urged scientists and clinicians to work together to “improve treatments and find scientific breakthroughs” to address “one of the biggest social and healthcare challenges we face.”

The neurodegenerative process giving rise to diseases such as Alzheimer’s is triggered when the normal structures of protein molecules within cells become corrupted.

Protein molecules are made in cellular ‘assembly lines’ that join together chemical building blocks called amino acids in an order encoded in our DNA. New proteins emerge as long, thin chains that normally need to be folded into compact and intricate structures to carry out their biological function.

Under some conditions, however, proteins can ‘misfold’ and snag surrounding normal proteins, which then tangle and stick together in clumps which build to masses, frequently millions, of malfunctioning molecules that shape themselves into unwieldy protein tendrils.

The abnormal tendril structures, called ‘amyloid fibrils’, grow outwards around the location where the focal point, or ‘nucleation’ of these abnormal “species” occurs.

Amyloid fibrils can form the foundations of huge protein deposits – or plaques – long-seen in the brains of Alzheimer’s sufferers, and once believed to be the cause of the disease, before the discovery of ‘toxic oligomers’ by Dobson and others a decade or so ago.

A plaque’s size and density renders it insoluble, and consequently unable to move. Whereas the oligomers, which give rise to Alzheimer’s disease, are small enough to spread easily around the brain - killing neurons and interacting harmfully with other molecules - but how they were formed was until now a mystery.

The new work, in large part carried out by researcher Samuel Cohen, shows that once a small but critical level of malfunctioning protein ‘clumps’ have formed, a runaway chain reaction is triggered that multiplies exponentially the number of these protein composites, activating new focal points through ‘nucleation’.

It is this secondary nucleation process that forges juvenile tendrils, initially consisting of clusters that contain just a few protein molecules. Small and highly diffusible, these are the ‘toxic oligomers’ that careen dangerously around the brain cells, killing neurons and ultimately causing loss of memory and other symptoms of dementia.

“There are no disease modifying therapies for Alzheimer’s and dementia at the moment, only limited treatment for symptoms. We have to solve what happens at the molecular level before we can progress and have real impact,” said Dr Tuomas Knowles from Cambridge’s Department of Chemistry, lead author of the study and long-time collaborator of Professor Dobson and Professor Michele Vendruscolo.

“We’ve now established the pathway that shows how the toxic species that cause cell death, the oligomers, are formed. This is the key pathway to detect, target and intervene – the molecular catalyst that underlies the pathology.”

The researchers brought together kinetic experiments with a theoretical framework based on master equations, tools commonly used in other areas of chemistry and physics but had not been exploited to their full potential in the study of protein malfunction before.

The latest research follows hard on the heels of another ground breaking study, published in April of this year again in PNAS, in which the Cambridge group, in Collaboration with Colleagues in London and at MIT, worked out the first atomic structure of one of the damaging amyloid fibril protein tendrils. They say the years spent developing research techniques are really paying off now, and they are starting to solve “some of the key mysteries” of these neurodegenerative diseases.

“We are essentially using a physical and chemical methods to address a biomolecular problem, mapping out the networks of processes and dominant mechanisms to ‘recreate the crime scene’ at the molecular root of Alzheimer’s disease,” explained Knowles.

“Increasingly, using quantitative experimental tools and rigorous theoretical analysis to understand complex biological processes are leading to exciting and game-changing results. With a disease like Alzheimer’s, you have to intervene in a highly specific manner to prevent the formation of the toxic agents. Now we’ve found how the oligomers are created, we know what process we need to turn off.”

Filed under alzheimer's disease dementia amyloid plaques oligomers neurons cell death neuroscience science

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Brain diseases affecting more people and starting earlier than ever before Professor Colin Pritchard’s latest research published in Public Health Journal has found that the sharp rise of dementia and other neurological deaths in people under 74 cannot be put down to the fact that we are living longer – the rise is because a higher proportion of old people are being affected by such conditions, and what is really alarming, it is starting earlier and affecting people under 55 years. Of the 10 biggest Western countries the USA had the worst increase in all neurological deaths, men up 66% and women 92% between 1979-2010. The UK was 4th highest, men up 32% and women 48%. In terms of numbers of deaths, in the UK, it was 4,500 and now 6,500, in the USA it was 14,500 now more than 28,500 deaths! Professor Pritchard of Bournemouth University says: “These statistics are about real people and families, and we need to recognise that there is an ‘epidemic’ that clearly is influenced by environmental and societal changes.” Tessa Gutteridge, Director YoungDementia UK says that our society needs to learn that dementia is increasingly affecting people from an earlier age: “The lives of an increasing number of families struggling with working-age dementia are made so much more challenging by services which fail to keep pace with their needs and a society which believes dementia to be an illness of old age.” Bournemouth University researchers, Professor Colin Pritchard and Dr Andrew Mayers, along with the University of Southampton’s Professor David Baldwin show that there are rises in total neurological deaths, including the dementias, which are starting earlier, impacting upon patients, their families and health and social care services, exemplified by an 85% increase in UK Motor Neurone Disease deaths. The research highlights that there is an alarming ‘hidden epidemic’ of rises in neurological deaths between 1979-2010 of adults (under 74) in Western countries, especially the UK. Total neurological deaths in both men and women rose significantly in 16 of the countries covered by the research, which is in sharp contrast to the major reductions in deaths from all other causes. Over the period the UK has the third biggest neurological increase, up 32% in men and 48% in women, whilst women’s neurological deaths rose faster than men’s in most countries. Professor Pritchard said, “These rises in neurological deaths, with the earlier onset of the dementias, are devastating for families and pose a considerable public health problem. It is NOT that we have more old people but rather more old people have more brain disease than ever before, including Alzheimer’s. For example there are two new British charities, The Young Parkinson’s Society and Young Dementia UK, which are a grass-roots response to these rises. The need for such charities would have been inconceivable a little more than 30 years ago.” When asked what he thought caused the increases he replied, “This has to be speculative but it cannot be genetic because the period is too short. Whilst there will be some influence of more elderly people, it does not account for the earlier onset; the differences between countries nor the fact that more women have been affected, as their lives have changed more than men’s over the period, all indicates multiple environmental factors. Considering the changes over the last 30 years – the explosion in electronic devices, rises in background non-ionising radiation- PC’s, micro waves, TV’s, mobile phones; road and air transport up four-fold increasing background petro-chemical pollution; chemical additives to food etc. There is no one factor rather the likely interaction between all these environmental triggers, reflecting changes in other conditions. For example, whilst cancer deaths are down substantially, cancer incidence continues to rise; levels of asthma are un-precedented; the fall in male sperm counts - the rise of auto-immune diseases - all point to life-style and environmental influences. These `statistics’ are about real people and families, and we need to recognise that there is an `epidemic’ that clearly is influenced by environmental and societal changes.”

Brain diseases affecting more people and starting earlier than ever before

Professor Colin Pritchard’s latest research published in Public Health Journal has found that the sharp rise of dementia and other neurological deaths in people under 74 cannot be put down to the fact that we are living longer – the rise is because a higher proportion of old people are being affected by such conditions, and what is really alarming, it is starting earlier and affecting people under 55 years.

Of the 10 biggest Western countries the USA had the worst increase in all neurological deaths, men up 66% and women 92% between 1979-2010. The UK was 4th highest, men up 32% and women 48%. In terms of numbers of deaths, in the UK, it was 4,500 and now 6,500, in the USA it was 14,500 now more than 28,500 deaths!

Professor Pritchard of Bournemouth University says: “These statistics are about real people and families, and we need to recognise that there is an ‘epidemic’ that clearly is influenced by environmental and societal changes.”

Tessa Gutteridge, Director YoungDementia UK says that our society needs to learn that dementia is increasingly affecting people from an earlier age: “The lives of an increasing number of families struggling with working-age dementia are made so much more challenging by services which fail to keep pace with their needs and a society which believes dementia to be an illness of old age.”

Bournemouth University researchers, Professor Colin Pritchard and Dr Andrew Mayers, along with the University of Southampton’s Professor David Baldwin show that there are rises in total neurological deaths, including the dementias, which are starting earlier, impacting upon patients, their families and health and social care services, exemplified by an 85% increase in UK Motor Neurone Disease deaths.

The research highlights that there is an alarming ‘hidden epidemic’ of rises in neurological deaths between 1979-2010 of adults (under 74) in Western countries, especially the UK.

Total neurological deaths in both men and women rose significantly in 16 of the countries covered by the research, which is in sharp contrast to the major reductions in deaths from all other causes.

Over the period the UK has the third biggest neurological increase, up 32% in men and 48% in women, whilst women’s neurological deaths rose faster than men’s in most countries.

Professor Pritchard said, “These rises in neurological deaths, with the earlier onset of the dementias, are devastating for families and pose a considerable public health problem. It is NOT that we have more old people but rather more old people have more brain disease than ever before, including Alzheimer’s. For example there are two new British charities, The Young Parkinson’s Society and Young Dementia UK, which are a grass-roots response to these rises. The need for such charities would have been inconceivable a little more than 30 years ago.”

When asked what he thought caused the increases he replied,

“This has to be speculative but it cannot be genetic because the period is too short. Whilst there will be some influence of more elderly people, it does not account for the earlier onset; the differences between countries nor the fact that more women have been affected, as their lives have changed more than men’s over the period, all indicates multiple environmental factors. Considering the changes over the last 30 years – the explosion in electronic devices, rises in background non-ionising radiation- PC’s, micro waves, TV’s, mobile phones; road and air transport up four-fold increasing background petro-chemical pollution; chemical additives to food etc. There is no one factor rather the likely interaction between all these environmental triggers, reflecting changes in other conditions. For example, whilst cancer deaths are down substantially, cancer incidence continues to rise; levels of asthma are un-precedented; the fall in male sperm counts - the rise of auto-immune diseases - all point to life-style and environmental influences. These `statistics’ are about real people and families, and we need to recognise that there is an `epidemic’ that clearly is influenced by environmental and societal changes.”

Filed under brain diseases dementia alzheimer's disease health neuroscience science

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One step closer to a blood test for Alzheimer’s Australian scientists are much closer to developing a screening test for the early detection of Alzheimer’s disease, the leading cause of dementia. A quarter of a million Australians currently suffer from dementia and given our ageing population, this is predicted to increase to one million by 2050. Researchers identified blood-based biological markers that are associated with the build up of amyloid beta, a toxic protein in the brain, which occurs years before symptoms appear and irreversible brain damage has occurred. “Early detection is critical, giving those at risk a much better chance of receiving treatment earlier, before it’s too late to do much about it,” said Dr Samantha Burnham from CSIRO’s Preventative Health Flagship. This research is just one part of the Australian Imaging and Biomarkers Lifestyle Study of Aging (AIBL), a longitudinal study in conjunction with research partners from Austin Health, Edith Cowan University, the Florey Institute of Neurosciences and Mental Health and the National Aging Research Institute. The AIBL study aims to discover which biomarkers, cognitive characteristics and health and lifestyle factors are linked with the development of Alzheimer’s disease. “Another recent study from the AIBL team showed that amyloid beta levels become abnormal about 17 years before dementia symptoms appear,” said Dr Burnham. “This gives us a much longer time to intervene to try to slow disease progression if we are able to detect cases early. “We hope our continued research will lead to the development of a low cost, minimally invasive population based screening test for Alzheimer’s in the next five to ten years. A blood test would be the ideal first stage to help identify many more people at risk before a diagnosis is confirmed more specialised testing.” The results have been published today in the journal Molecular Psychiatry.

One step closer to a blood test for Alzheimer’s

Australian scientists are much closer to developing a screening test for the early detection of Alzheimer’s disease, the leading cause of dementia.

A quarter of a million Australians currently suffer from dementia and given our ageing population, this is predicted to increase to one million by 2050.

Researchers identified blood-based biological markers that are associated with the build up of amyloid beta, a toxic protein in the brain, which occurs years before symptoms appear and irreversible brain damage has occurred.

“Early detection is critical, giving those at risk a much better chance of receiving treatment earlier, before it’s too late to do much about it,” said Dr Samantha Burnham from CSIRO’s Preventative Health Flagship.

This research is just one part of the Australian Imaging and Biomarkers Lifestyle Study of Aging (AIBL), a longitudinal study in conjunction with research partners from Austin Health, Edith Cowan University, the Florey Institute of Neurosciences and Mental Health and the National Aging Research Institute. The AIBL study aims to discover which biomarkers, cognitive characteristics and health and lifestyle factors are linked with the development of Alzheimer’s disease.

“Another recent study from the AIBL team showed that amyloid beta levels become abnormal about 17 years before dementia symptoms appear,” said Dr Burnham. “This gives us a much longer time to intervene to try to slow disease progression if we are able to detect cases early.

“We hope our continued research will lead to the development of a low cost, minimally invasive population based screening test for Alzheimer’s in the next five to ten years. A blood test would be the ideal first stage to help identify many more people at risk before a diagnosis is confirmed more specialised testing.”

The results have been published today in the journal Molecular Psychiatry.

Filed under alzheimer's disease dementia blood test amyloid beta biomarkers neuroscience science

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Alzheimer’s Researchers Creating “Designer Tracker” to Quantify Elusive Brain Protein, Provide Earlier Diagnosis

One of the biggest challenges with Alzheimer’s disease (AD) is that by the time physicians can detect behavioral changes, the disease has already begun its irreversibly destructive course. Scientists know toxic brain lesions created by amyloid beta and tau proteins are involved. Yet, emerging therapies targeting these lesions have failed in recent clinical trials. These findings suggest that successful treatments will require diagnosis of disease at its earliest stages.

Now, by using computer-aided drug discovery, an Ohio State University molecular biochemist and molecular imaging chemist are collaborating to create an imaging chemical that attaches predominantly to tau-bearing lesions in living brain. Their hope is that the “designer” tracer will open the door for earlier diagnosis – and better treatments for Alzheimer’s, frontal temporal dementia and traumatic brain injuries like those suffered by professional athletes, all conditions in which tangled tau filaments accumulate in brain tissue.

“We’re creating agents that are specifically engineered to bind the surface of aggregated tau proteins so that we can see where and how much tau is collecting in the brain,” said Jeff Kuret, professor of molecular and cellular biochemistry at The Ohio State University College of Medicine. “We think the “tau signature” can be used to improve diagnosis and staging of disease.”

The study’s co-investigator, Michael Tweedle, a professor of radiology at Ohio State’s College of Medicine, notes that there may be more advantages to being able to image tau.

“Unlike beta amyloid, tau appears in specific brain regions in Alzheimer’s,” said Tweedle. “With a better view of how tau is distinct from amyloid, we’ll be able to create a much more accurate view of disease staging, and do a much better job getting the right therapeutics into the right populations at the right time.”

Tweedle notes that there are no drugs currently available that target tau, but that several are in development. Both investigators emphasized that being able to image tau in a living brain could be critical for identifying individuals that could benefit from tau-tackling drugs as they move into clinical trials.

The search for tau selective neuroimaging agents is proceeding with the help of a pilot grant awarded to the team by Ohio State’s Center for Clinical and Translational Science (CCTS). The award provided them with the funds needed to synthesize candidate radiotracers for testing. The team then received funding from the Alzheimer’s Drug Discovery Foundation to test how the compounds distribute throughout the body. This work also leverages several CCTS-funded core resources. So far, the team has prepared 12 ligands that have promising binding affinity for tau aggregates.

“It’s an iterative process, and each step gives us new information on what we need to be looking for,” said Tweedle. “Now we know what parts of the molecule to alter while trying to retain other good qualities.”

Tauopathies are neurodegenerative diseases associated with the accumulation of tau protein “tangles” in the human brain. Alzheimer’s disease is one of the most common tauopathies, but tau aggregates are also found in certain forms of frontal temporal dementia as well as traumatic brain injuries. Alzheimer’s disease has become one of the most common disorders in the aging population, and is predicted to be a major driver of health care costs in the coming decades.

(Source: newswise.com)

Filed under alzheimer's disease amyloid beta tau proteins TBI dementia neuroscience science

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Swedish study suggests reduced risk of dementia

A new Swedish study published in the journal Neurology shows that the risk of developing dementia may have declined over the past 20 years, in direct contrast to what many previously assumed. The result is based on data from SNAC-K, an ongoing study on aging and health that started in 1987.

"We know that cardiovascular disease is an important risk factor for dementia. The suggested decrease in dementia risk coincides with the general reduction in cardiovascular disease over recent decades", says Associate Professor Chengxuan Qiu of the Aging Research Center, established by Karolinska Institutet and Stockholm University. "Health check-ups and cardiovascular disease prevention have improved significantly in Sweden, and we now see results of this improvement reflected in the risk of developing dementia."

Dementia is a constellation of symptoms characterized by impaired memory and other mental functions. After age 75, dementia is commonly due to multiple causes, mainly Alzheimers disease and vascular dementia. In the current study, more than 3000 persons 75 years and older living in the central Stockholm neighborhood of Kungsholmen participated. Of the participants, 523 were diagnosed with some form of dementia. The key members of the research group have been essentially the same since 1987, including the neurologist responsible for the clinical diagnoses of dementia. All study participants were assessed by a nurse, a physician, and a psychologist.

The result shows the prevalence of dementia was stable in both men and women across all age groups after age 75 during the entire study period (1987-1989 and 2001-2004), despite the fact that the survival of persons with dementia increased since the end of the 1980s. This means that the overall risk of developing dementia must have declined during the period, possibly thanks to prevention and better treatment of cardiovascular disease.

"The reduction of dementia risk is a positive phenomenon, but it is important to remember that the number of people with dementia will continue to rise along with the increase in life expectancy and absolute numbers of people over age 75", says Professor Laura Fratiglioni, Director of the Aging Research Center. "This means that the societal burden of dementia and the need for medical and social services will continue to increase. Today there’s no way to cure patients who have dementia. Instead we must continue to improve health care and prevention in this area."

(Source: ki.se)

Filed under dementia dementia risk aging SNAC-K cardiovascular disease neuroscience science

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Family history of Alzheimer’s associated with abnormal brain pathology

Close family members of people with Alzheimer’s disease are more than twice as likely as those without a family history to develop silent buildup of brain plaques associated with Alzheimer’s disease, according to researchers at Duke Medicine.

The study, published online in the journal PLOS ONE on April 17, 2013, confirms earlier findings on a known genetic variation that increases one’s risk for Alzheimer’s, and raises new questions about other genetic factors involved in the disease that have yet to be identified.

An estimated 25 million people worldwide have Alzheimer’s disease, and the number is expected to triple by 2050. More than 95 percent of these individuals have late-onset Alzheimer’s, which usually occurs after the age of 65. Research has shown that Alzheimer’s begins years to decades before it is diagnosed, with changes to the brain measurable through a variety of tests.

Family history is a known risk factor and predictor of late-onset Alzheimer’s disease, and studies suggest a two- to four-fold greater risk for Alzheimer’s in individuals with a mother, father, brother or sister who develop the disease. These first-degree relatives share roughly 50 percent of their genes with another member of their family. Common genetic variations, including changes to the APOE gene, account for around 50 percent of the heritability of Alzheimer’s, but the disease’s other genetic roots are still unexplained.

“In this study, we sought to understand whether simply having a positive family history, in otherwise normal or mildly forgetful people, was enough to trigger silent buildup of Alzheimer’s plaques and shrinkage of memory centers,” said senior author P. Murali Doraiswamy, professor of psychiatry and medicine at Duke.

Duke neuroscience research trainee Erika J. Lampert, Doraiswamy and colleagues analyzed data from 257 adults, ages 55 to 89, both cognitively healthy and with varying levels of impairment. The participants were part of the Alzheimer’s Disease Neuroimaging Initiative, a national study working to define the progression of Alzheimer’s through biomarkers.

The researchers looked at participants’ age, gender and family history of the disease, with a positive family history defined as having a parent or sibling with Alzheimer’s. This information was compared with cognitive assessments and other biological tests, including APOE genotyping, MRI scans measuring hippocampal volume, and studies of three different pathologic markers (Aβ42, t-tau, and t-tau/Aβ42 ratio) found in cerebrospinal fluid.

As expected, the researchers found that a variation in the APOE gene associated with a greater risk and earlier onset of Alzheimer’s was overrepresented in participants with a family history of the disease. However, other biological differences were also seen in those with a family history, suggesting that unidentified genetic factors may influence the disease’s development before the onset of dementia.

Nearly half of all healthy people with a positive family history would have met the criteria for preclinical Alzheimer’s disease based on measurements of their cerebrospinal fluid, but only about 20 percent of those without a family history would have met such criteria.

“We already knew that family history increases one’s risk for developing Alzheimer’s, but we now are showing that people with a positive family history may also have higher levels of Alzheimer’s pathology earlier, which could be a reason why they experience a faster cognitive decline than those without a family history,” Lampert said.

The findings may influence the design of future studies developing new diagnostic tests for Alzheimer’s, as researchers may choose to exclude those with a positive family history – a group that has historically volunteered to participate in studies to better understand the disease – as healthy controls, given that they are more likely to develop Alzheimer’s pathology.

“Our study shows the power of a simple one-minute questionnaire about family history to predict silent brain changes,” Doraiswamy said. “In the absence of full understanding of all genetic risks for late-onset Alzheimer’s, family history information can serve as a risk stratification tool for prevention research and personalizing care.” He encouraged those with a known positive family history to seek out clinical trials specific to preventing the disease.

(Source: dukehealth.org)

Filed under alzheimer's disease family history APOE gene memory dementia neuroscience science

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Genetic markers ID second Alzheimer’s pathway

Researchers at Washington University School of Medicine in St. Louis have identified a new set of genetic markers for Alzheimer’s that point to a second pathway through which the disease develops.

image

Much of the genetic research on Alzheimer’s centers on amyloid-beta, a key component of brain plaques that build up in the brains of people with the disease.

In the new study, the scientists identified several genes linked to the tau protein, which is found in the tangles that develop in the brain as Alzheimer’s progresses and patients develop dementia. The findings may help provide targets for a different class of drugs that could be used for treatment.

The researchers report their findings online April 24 in the journal Neuron.

"We measured the tau protein in the cerebrospinal fluid and identified several genes that are related to high levels of tau and also affect risk for Alzheimer’s disease,” says senior investigator Alison M. Goate, DPhil, the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry. “As far as we’re aware, three of these genes have no effect on amyloid-beta, suggesting that they are operating through a completely different pathway.”

A fourth gene in the mix, APOE, had been identified long ago as a risk factor for Alzheimer’s. It has been linked to amyloid-beta, but in the new study, APOE appears to be connected to elevated levels of tau. Finding that APOE is influencing more than one pathway could help explain why the gene has such a big effect on Alzheimer’s disease risk, the researchers say.

“It appears APOE influences risk in more than one way,” says Goate, also a professor of genetics and co-director of the Hope Center for Neurological Disorders. “Some of the effects are mediated through amyloid-beta and others by tau. That suggests there are at least two ways in which the gene can influence our risk for Alzheimer’s disease.”

The new research by Goate and her colleagues is the largest genome-wide association study (GWAS) yet on tau in cerebrospinal fluid. The scientists analyzed points along the genomes of 1,269 individuals who had undergone spinal taps as part of ongoing Alzheimer’s research.

Whereas amyloid is known to collect in the brain and affect brain cells from the outside, the tau protein usually is stored inside cells. So tau usually moves into the spinal fluid when cells are damaged or die. Elevated tau has been linked to several forms of non-Alzheimer’s dementia, and first author Carlos Cruchaga, PhD, says that although amyloid plaques are a key feature of Alzheimer’s disease, it’s possible that excess tau has more to do with the dementia than plaques.

“We know there are some individuals with high levels of amyloid-beta who don’t develop Alzheimer’s disease,” says Cruchaga, an assistant professor of psychiatry. “We don’t know why that is, but perhaps it could be related to the fact that they don’t have elevated tau levels.”

In addition to APOE, the researchers found that a gene called GLIS3, and the genes TREM2 and TREML2 also affect both tau levels and Alzheimer’s risk.

Goate says she suspects changes in tau may be good predictors of advancing disease. As tau levels rise, she says people may be more likely to develop dementia. If drugs could be developed to target tau, they may prevent much of the neurodegeneration that characterizes Alzheimer’s disease and, in that way, help prevent or delay dementia.

The new research also suggests it may one day be possible to reduce Alzheimer’s risk by targeting both pathways.

“Since two mechanisms apparently exist, identifying potential drug targets along these pathways could be very useful,” she says. “If drugs that influence tau could be added to those that affect amyloid, we could potentially reduce risk through two different pathways.”

(Source: news.wustl.edu)

Filed under alzheimer's disease dementia tau protein genes APOE gene genomics genetics neuroscience science

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Study examines change in cognitive function following physical, mental activity in older adults A randomized controlled trial finds that 12 weeks of physical plus mental activity in inactive older adults with cognitive complaints was associated with significant improvement in cognitive function but there was no difference between intervention and control groups, according to a report published Online First by JAMA Internal Medicine, a JAMA Network publication. An epidemic of dementia worldwide is anticipated during the next 40 years because of longer life expectancies and demographic changes. Behavioral interventions are a potential strategy to prevent or delay dementia in asymptomatic individuals, but few randomized controlled trials have studied the effects of physical and mental activity together, according to the study background. "We found that cognitive scores improved significantly over the course of 12 weeks, but there were no significant differences between the intervention and active control groups. These results may suggest that in this study population, the amount of activity is more important than the type of activity, because all groups participated in both mental activity and exercise for [60 minutes/per day, three days/per week] for 12 weeks. Alternatively, the cognitive improvements observed may be due to practice effects," the authors note. The study by Deborah E. Barnes, Ph.D., M.P.H., of the University of California, San Francisco, and colleagues included 126 inactive, community-dwelling older adults with cognitive complaints. All the individuals engaged in home-based mental activity (1 hour/per day, 3 days/per week) plus class-based physical activity (1 hour/per day, 3 days/per week) for 12 weeks and were assigned to either mental activity intervention (MA-I, intensive computer work); or mental activity control (MA-C, educational DVDs) plus exercise intervention (EX-1, aerobic) or exercise control (EX-C, stretching and toning). The study design meant there were four groups: MA-I/EX-I, MA-I/EX-C, MA-C/EX-1 and MA-C/EX-C. Global cognitive scores improved significantly over time but did not differ between groups in the comparison between MA-I and MA-C (ignoring exercise), the comparison between EX-I and EX-C (ignoring mental activity), or across all four randomization groups, according to the study results. "The prevalence of cognitive impairment and dementia are projected to rise dramatically during the next 40 years, and strategies for maintaining cognitive function with age are critically needed. Physical or mental activity alone result in small, domain-specific improvements in cognitive function in older adults; combined interventions may have more global effects," the study concludes. (Image: Getty Images)

Study examines change in cognitive function following physical, mental activity in older adults

A randomized controlled trial finds that 12 weeks of physical plus mental activity in inactive older adults with cognitive complaints was associated with significant improvement in cognitive function but there was no difference between intervention and control groups, according to a report published Online First by JAMA Internal Medicine, a JAMA Network publication.

An epidemic of dementia worldwide is anticipated during the next 40 years because of longer life expectancies and demographic changes. Behavioral interventions are a potential strategy to prevent or delay dementia in asymptomatic individuals, but few randomized controlled trials have studied the effects of physical and mental activity together, according to the study background.

"We found that cognitive scores improved significantly over the course of 12 weeks, but there were no significant differences between the intervention and active control groups. These results may suggest that in this study population, the amount of activity is more important than the type of activity, because all groups participated in both mental activity and exercise for [60 minutes/per day, three days/per week] for 12 weeks. Alternatively, the cognitive improvements observed may be due to practice effects," the authors note.

The study by Deborah E. Barnes, Ph.D., M.P.H., of the University of California, San Francisco, and colleagues included 126 inactive, community-dwelling older adults with cognitive complaints. All the individuals engaged in home-based mental activity (1 hour/per day, 3 days/per week) plus class-based physical activity (1 hour/per day, 3 days/per week) for 12 weeks and were assigned to either mental activity intervention (MA-I, intensive computer work); or mental activity control (MA-C, educational DVDs) plus exercise intervention (EX-1, aerobic) or exercise control (EX-C, stretching and toning). The study design meant there were four groups: MA-I/EX-I, MA-I/EX-C, MA-C/EX-1 and MA-C/EX-C.

Global cognitive scores improved significantly over time but did not differ between groups in the comparison between MA-I and MA-C (ignoring exercise), the comparison between EX-I and EX-C (ignoring mental activity), or across all four randomization groups, according to the study results.

"The prevalence of cognitive impairment and dementia are projected to rise dramatically during the next 40 years, and strategies for maintaining cognitive function with age are critically needed. Physical or mental activity alone result in small, domain-specific improvements in cognitive function in older adults; combined interventions may have more global effects," the study concludes.

(Image: Getty Images)

Filed under cognitive function physical activity mental activity dementia cognitive impairment neuroscience science

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New Research on the Effects of Traumatic Brain Injury (TBI) Considerable opportunity exists to improve interventions and outcomes of traumatic brain injury (TBI) in older adults, according to three studies published in the recent online issue of NeuroRehabilitation by researchers from the Icahn School of Medicine at Mount Sinai. An Exploration of Clinical Dementia Phenotypes Among Individuals With and Without Traumatic Brain Injury Some evidence suggests that a history of TBI is associated with an increased risk of dementia later in life, but the clinical features of dementia associated with TBI have not been well investigated.  Researchers at the Icahn School of Medicine as well as other institutions analyzed data from elderly individuals with dementia with and without a history of TBI to characterize the clinical profiles of patients with post-TBI dementia. The results of the study indicate that compared to older adults with dementia with no history of TBI, those with a history of TBI had higher fluency and verbal memory scores and later onset of decline. However, their general health was worse, they were more likely to have received medical attention for depression, and were more likely to have a gait disorder, falls, and motor slowness.  These findings suggest that dementia among individuals with a history of TBI may represent a unique clinical phenotype that is distinct from that seen among elderly individuals who develop dementia without a history of TBI. "Our study indicates that individuals with dementia and without a history of TBI may present clinical characteristics that differ in subtle but meaningful ways," said Kristen Dams-O’Connor, PhD, first author of the study and an Assistant Professor of Rehabilitation Medicine at the Icahn School of Medicine at Mount Sinai. "It is imperative that clinicians take a history of TBI into account when making dementia diagnoses." For this study, researchers used data from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) collected between September 2005 and May 2012 to analyze 332 elderly individuals with dementia and a history of TBI and 664 elderly individuals without dementia who do have a history of TBI. Statistical analyses focused on evaluating differences in the areas of neurocognitive functioning, psychiatric functioning, medical history and health, clinical characteristics of dementia, and dementia diagnosis using data collected at the baseline (first) NACC study visit. Mortality of Elderly Individuals with TBI in the First 5 Years Following Injury After observing a high rate of mortality among patients over the age of 55 in the first five years after sustaining a TBI, researchers at the Icahn School of Medicine at Mount Sinai were interested in learning more about the precise causes for what may be considered a premature death. The results of this study indicate that for approximately a third of the patients, death one to five years after TBI resulted from health conditions that were present at the time of injury before the onset of TBI, suggesting a continuation of an already ongoing process. The remainder of patients died from conditions that appeared to unfold in the years after injury. According to the authors, each cause of death in this sample would have required pro-active medical management, medical intervention and medication compliance. "Like those with other chronic health conditions, individuals with TBI could benefit from the development of a disease management model of primary care," said one of the study authors, Wayne Gordon, PhD, Jack Nash Professor and Vice Chair of the Department of Rehabilitation Medicine at the Icahn School of Medicine at Mount Sinai and Chief of the Rehabilitation Psychology and Neuropsychology service. "This study suggests that close medical management and lifestyle interventions may help to prevent premature death among elderly survivors of TBI in the future." Researchers reviewed the charts of 30 individuals over the age of 55 who completed inpatient acute rehabilitation during the period from 2003-2009 and who died one to four years after TBI, and then compared that data to a matched sample of 30 patients who did not die. They found that 53 percent of deceased subjects had been diagnosed with gait abnormalities, 32 percent were taking respiratory medications at admission, and 17 percent were taking respiratory medications at discharge. Compared to patients who survived several years after injury, deceased patients were discharged from the hospital with significantly more medications. Inpatient Rehabilitation for Traumatic Brain Injury: The Influence of Age on Treatments and Outcomes For this study, researchers analyzed the difference in treatment and outcomes between elderly and younger patients with TBI. They found that patients over 65 had lower brain injury severity and a shorter length of stay in acute care. Elderly patients also received fewer hours of rehabilitation therapy, due to a shorter length of stay, and fewer hours of treatment per day, especially from psychology and therapeutic recreation. They gained less functional ability during and after rehabilitation, and had a very high mortality rate. "We know significantly more about the treatment received by adolescents and young adults with TBI than we do about those over 65," said Marcel Dijkers, PhD, lead author and Research Professor in the Department of Rehabilitation Medicine at Mount Sinai.  "Our data indicates that elderly people can be rehabilitated successfully, but it raises a number of questions. For instance: is the high mortality due to the TBI or is it the result of the continuation of a condition that began pre-TBI?" The researchers analyzed data on 1,419 patients with TBI admitted to nine TBI rehabilitation inpatient programs across the country between 2009 and 2011. They collected data through abstracting of medical records, point-of-care forms completed by therapists, and interviews conducted three and nine months after discharge.

New Research on the Effects of Traumatic Brain Injury (TBI)

Considerable opportunity exists to improve interventions and outcomes of traumatic brain injury (TBI) in older adults, according to three studies published in the recent online issue of NeuroRehabilitation by researchers from the Icahn School of Medicine at Mount Sinai.

An Exploration of Clinical Dementia Phenotypes Among Individuals With and Without Traumatic Brain Injury

Some evidence suggests that a history of TBI is associated with an increased risk of dementia later in life, but the clinical features of dementia associated with TBI have not been well investigated.  Researchers at the Icahn School of Medicine as well as other institutions analyzed data from elderly individuals with dementia with and without a history of TBI to characterize the clinical profiles of patients with post-TBI dementia.

The results of the study indicate that compared to older adults with dementia with no history of TBI, those with a history of TBI had higher fluency and verbal memory scores and later onset of decline. However, their general health was worse, they were more likely to have received medical attention for depression, and were more likely to have a gait disorder, falls, and motor slowness.  These findings suggest that dementia among individuals with a history of TBI may represent a unique clinical phenotype that is distinct from that seen among elderly individuals who develop dementia without a history of TBI.

"Our study indicates that individuals with dementia and without a history of TBI may present clinical characteristics that differ in subtle but meaningful ways," said Kristen Dams-O’Connor, PhD, first author of the study and an Assistant Professor of Rehabilitation Medicine at the Icahn School of Medicine at Mount Sinai. "It is imperative that clinicians take a history of TBI into account when making dementia diagnoses."

For this study, researchers used data from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) collected between September 2005 and May 2012 to analyze 332 elderly individuals with dementia and a history of TBI and 664 elderly individuals without dementia who do have a history of TBI. Statistical analyses focused on evaluating differences in the areas of neurocognitive functioning, psychiatric functioning, medical history and health, clinical characteristics of dementia, and dementia diagnosis using data collected at the baseline (first) NACC study visit.

Mortality of Elderly Individuals with TBI in the First 5 Years Following Injury

After observing a high rate of mortality among patients over the age of 55 in the first five years after sustaining a TBI, researchers at the Icahn School of Medicine at Mount Sinai were interested in learning more about the precise causes for what may be considered a premature death.

The results of this study indicate that for approximately a third of the patients, death one to five years after TBI resulted from health conditions that were present at the time of injury before the onset of TBI, suggesting a continuation of an already ongoing process. The remainder of patients died from conditions that appeared to unfold in the years after injury. According to the authors, each cause of death in this sample would have required pro-active medical management, medical intervention and medication compliance.

"Like those with other chronic health conditions, individuals with TBI could benefit from the development of a disease management model of primary care," said one of the study authors, Wayne Gordon, PhD, Jack Nash Professor and Vice Chair of the Department of Rehabilitation Medicine at the Icahn School of Medicine at Mount Sinai and Chief of the Rehabilitation Psychology and Neuropsychology service. "This study suggests that close medical management and lifestyle interventions may help to prevent premature death among elderly survivors of TBI in the future."

Researchers reviewed the charts of 30 individuals over the age of 55 who completed inpatient acute rehabilitation during the period from 2003-2009 and who died one to four years after TBI, and then compared that data to a matched sample of 30 patients who did not die. They found that 53 percent of deceased subjects had been diagnosed with gait abnormalities, 32 percent were taking respiratory medications at admission, and 17 percent were taking respiratory medications at discharge. Compared to patients who survived several years after injury, deceased patients were discharged from the hospital with significantly more medications.

Inpatient Rehabilitation for Traumatic Brain Injury: The Influence of Age on Treatments and Outcomes

For this study, researchers analyzed the difference in treatment and outcomes between elderly and younger patients with TBI. They found that patients over 65 had lower brain injury severity and a shorter length of stay in acute care. Elderly patients also received fewer hours of rehabilitation therapy, due to a shorter length of stay, and fewer hours of treatment per day, especially from psychology and therapeutic recreation. They gained less functional ability during and after rehabilitation, and had a very high mortality rate.

"We know significantly more about the treatment received by adolescents and young adults with TBI than we do about those over 65," said Marcel Dijkers, PhD, lead author and Research Professor in the Department of Rehabilitation Medicine at Mount Sinai.  "Our data indicates that elderly people can be rehabilitated successfully, but it raises a number of questions. For instance: is the high mortality due to the TBI or is it the result of the continuation of a condition that began pre-TBI?"

The researchers analyzed data on 1,419 patients with TBI admitted to nine TBI rehabilitation inpatient programs across the country between 2009 and 2011. They collected data through abstracting of medical records, point-of-care forms completed by therapists, and interviews conducted three and nine months after discharge.

Filed under TBI brain injury dementia brain rehabilitation neuroscience neurobiology medicine science

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Surgical menopause may prime brain for stroke, Alzheimer’s

Women who abruptly and prematurely lose estrogen from surgical menopause have a two-fold increase in cognitive decline and dementia.

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"This is what the clinical studies indicate and our animal studies looking at the underlying mechanisms back this up," said Brann, corresponding author of the study in the journal Brain. “We wanted to find out why that is occurring. We suspect it’s due to the premature loss of estrogen.”

In an effort to mimic what occurs in women, Brann and his colleagues looked at rats 10 weeks after removal of their estrogen-producing ovaries that were either immediately started on low-dose estrogen therapy, started therapy 10 weeks later or never given estrogen.

When the researchers caused a stroke-like event in the brain’s hippocampus, a center of learning and memory, they found the rodents treated late or not at all experienced more brain damage, specifically to a region of the hippocampus called CA3 that is normally stroke-resistant.

To make matters worse, untreated or late-treated rats also began an abnormal, robust production of Alzheimer’s disease-related proteins in the CA3 region, even becoming hypersensitive to one of the most toxic of the beta amyloid proteins that are a hallmark of Alzheimer’s.

Both problems appear associated with the increased production of free radicals in the brain. In fact, when the researchers blocked the excessive production, heightened stroke sensitivity and brain cell death in the CA3 region were reduced.

Interestingly the brain’s increased sensitivity to stressors such as inadequate oxygen was gender specific, Brann said. Removing testes in male rats, didn’t affect stroke size or damage.

Although exactly how it works is unknown, estrogen appears to help protect younger females from problems such as stroke and heart attack. Their risks of the maladies increase after menopause to about the same as males. Follow up studies are needed to see if estrogen therapy also reduces sensitivity to the beta amyloid protein in the CA3 region, as they expect, Brann noted.

Brann earlier showed that prolonged estrogen deprivation in aging rats dramatically reduces the number of brain receptors for the hormone as well as its ability to prevent strokes. Damage was forestalled if estrogen replacement was started shortly after hormone levels drop, according to the 2011 study in the journal Proceedings of the National Academy of Sciences.

The surprising results of the much-publicized Women’s Health Initiative – a 12-year study of 161,808 women ages 50-79 – found hormone therapy generally increased rather than decreased stroke risk as well as other health problems. Critics said one problem with the study was that many of the women, like Brann’s aged rats, had gone years without hormone replacement, bolstering the case that timing is everything.

(Source: eurekalert.org)

Filed under beta amyloid brain damage cognitive decline dementia alzheimer's disease neuroscience science

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