Posts tagged dementia

A study published in the American Journal of Geriatric Psychiatry indicates that middle-aged adults with a history of problem drinking are more than twice as likely to suffer from severe memory impairment in later life.

The study highlights the hitherto largely unknown link between harmful patterns of alcohol consumption and problems with memory later in life – problems which may place people at a high risk of developing dementia.

The study was carried out by researchers from the University of Exeter Medical School with support from the NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula (NIHR PenCLAHRC).

The research team studied the association between a history of alcohol use disorders (AUDs) and the onset of severe cognitive and memory impairment in 6542 middle-aged adults born between 1931 and 1941. These individuals participated in the Health and Retirement Study in the US.

Participants were first assessed in 1992 and follow-up assessments took place every other year from 1996 to 2010.

A history of AUDs was identified using the CAGE* questionnaire (short for Cut down, Annoyed, Guilty, Eye-opener). Where participants registered a history of AUDs their chances of developing severe memory impairment more than doubled.

The study was led by Dr Iain Lang. He commented: “We already know there is an association between dementia risk and levels of current alcohol consumption – that understanding is based on asking older people how much they drink and then observing whether they develop problems. But this is only one part of the puzzle and we know little about the consequences of alcohol consumption earlier in life. What we did here is investigate the relatively unknown association between having a drinking problem at any point in life and experiencing problems with memory later in life.”

He added: “This finding – that middle-aged people with a history of problem drinking more than double their chances of memory impairment when they are older – suggests three things: that this is a public health issue that needs to be addressed; that more research is required to investigate the potential harms associated with alcohol consumption throughout life; and that the CAGE questionnaire may offer doctors a practical way to identify those at risk of memory/cognitive impairment and who may benefit from help to tackle their relationship with alcohol.”

Dr Doug Brown, Director of Research and Development at Alzheimer’s Society said: “When we talk about drinking too much, the media often focuses on young people ending up in A&E after a night out. However, there’s also a hidden cost of alcohol abuse given the mounting evidence that alcohol abuse can also impact on cognition later in life. This small study shows that people who admitted to alcohol abuse at some point in their lives were twice as likely to have severe memory problems, and as the research relied on self-reporting that number may be even higher.

"This isn’t to say that people need to abstain from alcohol altogether. As well as eating a healthy diet, not smoking and maintaining a healthy weight, the odd glass of red wine could even help reduce your risk of developing dementia."

* The CAGE asks four questions (and the acronym comes from words in each question: Cut down, Annoyed, Guilty, Eye-opener):

1. Have you ever felt you should cut down on your drinking?
2. Have people annoyed you by criticising your drinking?
3. Have you ever felt bad or guilty about your drinking?
4. Have you ever had a drink first thing in the morning to steady your nerves or get rid of a hangover (eye-opener)?

(Source: exeter.ac.uk)

A study involving nearly 27,000 older adults on five continents found that nearly 1 in 10 met criteria for pre-dementia based on a simple test that measures how fast people walk and whether they have cognitive complaints. People who tested positive for pre-dementia were twice as likely as others to develop dementia within 12 years. The study, led by scientists at Albert Einstein College of Medicine of Yeshiva University and Montefiore Medical Center, was published online on July 16, 2014 in Neurology®, the medical journal of the American Academy of Neurology.

The new test diagnoses motoric cognitive risk syndrome (MCR). Testing for the newly described syndrome relies on measuring gait speed (our manner of walking) and asking a few simple questions about a patient’s cognitive abilities, both of which take just seconds. The test is not reliant on the latest medical technology and can be done in a clinical setting, diagnosing people in the early stages of the dementia process. Early diagnosis is critical because it allows time to identify and possibly treat the underlying causes of the disease, which may delay or even prevent the onset of dementia in some cases.

“In many clinical and community settings, people don’t have access to the sophisticated tests—biomarker assays, cognitive tests or neuroimaging studies—used to diagnose people at risk for developing dementia,” said Joe Verghese, M.B.B.S., professor in the Saul R. Korey Department of Neurology and of medicine at Einstein, chief of geriatrics at Einstein and Montefiore, and senior author of the Neurology paper. “Our assessment method could enable many more people to learn if they’re at risk for dementia, since it avoids the need for complex testing and doesn’t require that the test be administered by a neurologist. The potential payoff could be tremendous—not only for individuals and their families, but also in terms of healthcare savings for society. All that’s needed to assess MCR is a stopwatch and a few questions, so primary care physicians could easily incorporate it into examinations of their older patients.”

The U.S. Centers for Disease Control and Prevention estimates that up to 5.3 million Americans—about 1 in 9 people age 65 and over—have Alzheimer’s disease, the most common type of dementia. That number is expected to more than double by 2050 due to population aging.

“As a young researcher, I examined hundreds of patients and noticed that if an older person was walking slowly, there was a good chance that his cognitive tests were also abnormal,” said Dr. Verghese, who is also the Murray D. Gross Memorial Faculty Scholar in Gerontology at Einstein. “This gave me the idea that perhaps we could use this simple clinical sign—how fast someone walks—to predict who would develop dementia. In a 2002 New England Journal of Medicine study, we reported that abnormal gait patterns accurately predict whether people will go on to develop dementia. MCR improves on the slow gait concept by evaluating not only patients’ gait speed but also whether they have cognitive complaints.”

The Neurology paper reported on the prevalence of MCR among 26,802 adults without dementia or disability aged 60 years and older enrolled in 22 studies in 17 countries. A significant number of adults—9.7 percent—met the criteria for MCR (i.e., abnormally slow gait and cognitive complaints). While the syndrome was equally common in men and women, highly educated people were less likely to test positive for MCR compared with less-educated individuals. A slow gait, said Dr. Verghese, is a walking speed slower than about one meter per second, which is about 2.2 miles per hour (m.p.h.). Less than 0.6 meters per second (or 1.3 m.p.h.) is “clearly abnormal.”

To test whether MCR predicts future dementia, the researchers focused on four of the 22 studies that tested a total of 4,812 people for MCR and then evaluated them annually over an average follow-up period of 12 years to see which ones developed dementia. Those who met the criteria for MCR were nearly twice as likely to develop dementia over the following 12 years compared with people who did not.

Dr. Verghese emphasized that a slow gait alone is not sufficient for a diagnosis of MCR. “Walking slowly could be due to conditions such as arthritis or an inner ear problem that affects balance, which would not increase risk for dementia. To meet the criteria for MCR requires having a slow gait and cognitive problems. An example would be answering ‘yes’ to the question, ‘Do you think you have more memory problems than other people?’”

For patients meeting MCR criteria, said Dr. Verghese, the next step is to look for the causes of their slow gait and cognitive complaints. The search may reveal underlying—and controllable—problems. “Evidence increasingly suggests that brain health is closely tied to cardiovascular health—meaning that treatable conditions such as hypertension, smoking, high cholesterol, obesity and diabetes can interfere with blood flow to the brain and thereby increase a person’s risk for developing Alzheimer’s and other dementias,” said Dr. Verghese.

What about people who meet MCR criteria but no treatable underlying problems can be found?

“Even in the absence of a specific cause, we know that most healthy lifestyle factors, such as exercising and eating healthier, have been shown to reduce the rate of cognitive decline,” said Dr. Verghese. “In addition, our group has shown that cognitively stimulating activities—playing board games, card games, reading, writing and also dancing—can delay dementia’s onset. Knowing they’re at high risk for dementia can also help people and their families make arrangements for the future, which is an aspect of MCR testing that I’ve found is very important in my own clinical practice.”

Scientists have identified a set of 10 proteins in the blood which can predict the onset of Alzheimer’s, marking a significant step towards developing a blood test for the disease. The study, led by King’s College London and UK proteomics company, Proteome Sciences plc,analysed over 1,000 individuals and is the largest of its kind to date.

There are currently no effective long-lasting drug treatments for Alzheimer’s, and it is believed that many new clinical trials fail because drugs are given too late in the disease process. A blood test could be used to identify patients in the early stages of memory loss for clinical trials to find drugs to halt the progression of the disease.

The study, published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, is the result of an international collaboration led by King’s College London and Proteome Sciences plc, funded by Alzheimer’s Research UK, the UK Medical Research Council, the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre and Proteome Sciences.

The researchers used data from three international studies. Blood samples from a total of 1,148 individuals (476 with Alzheimer’s disease; 220 with ‘Mild Cognitive Impairment’ (MCI) and 452 elderly controls without dementia) were analysed for 26 proteins previously shown to be associated with Alzheimer’s disease. A sub-group of 476 individuals across all three groups also had an MRI brain scan.  

Researchers identified 16 of these 26 proteins to be strongly associated with brain shrinkage in either MCI or Alzheimer’s. They then ran a second series of tests to establish which of these proteins could predict the progression from MCI to Alzheimer’s. They identified a combination of 10 proteins capable of predicting whether individuals with MCI would develop Alzheimer’s disease within a year, with an accuracy of 87 percent.

Dr Abdul Hye, lead author of the study from the Institute of Psychiatry at King’s College London, said: “Memory problems are very common, but the challenge is identifying who is likely to develop dementia. There are thousands of proteins in the blood, and this study is the culmination of many years’ work identifying which ones are clinically relevant. We now have a set of 10 proteins that can predict whether someone with early symptoms of memory loss, or mild cognitive impairment, will develop Alzheimer’s disease within a year, with a high level of accuracy.”

Professor Simon Lovestone, senior author of the study from the University of Oxford, who led the work whilst at King’s, said: “Alzheimer’s begins to affect the brain many years before patients are diagnosed with the disease. Many of our drug trials fail because by the time patients are given the drugs, the brain has already been too severely affected. A simple blood test could help us identify patients at a much earlier stage to take part in new trials and hopefully develop treatments which could prevent the progression of the disease. The next step will be to validate our findings in further sample sets, to see if we can improve accuracy and reduce the risk of misdiagnosis, and to develop a reliable test suitable to be used by doctors.”

Dr Eric Karran, Director of Research at Alzheimer’s Research UK, the UK’s leading dementia research charity, said: “As the onset of Alzheimer’s is often slow and subtle, a blood test to identify those at high risk of the disease at an early stage would be of real value. Detecting the first signs of Alzheimer’s could improve clinical trials for new treatments and help those already concerned about their memory, but we’re not currently in a position to use such a test to screen the general population.

“With an ageing population, and age the biggest risk factor for Alzheimer’s, we are expecting rising numbers of people to be affected over the coming years. It’s important to develop new ways to intervene early in the disease to help people maintain their quality of life for as long as possible.”

Dr Ian Pike, co-author of the paper from Proteome Sciences, said: “By linking the best British academic and commercial research, this landmark study in Alzheimer’s disease is a major advance in the development of a simple blood test to identify the disease before clinical symptoms appear. This is the window that will offer the best chance of successful treatment. Equally important, a blood test will be considerably easier and less expensive than using brain imaging or cerebrospinal spinal fluid.

“We are in the process of selecting commercial partners to combine the protein biomarkers in a blood test for the global market, a key step forward to deliver effective and early treatment for this crippling disease.”

Alzheimer’s disease is the most common form of dementia. Globally, it is estimated that 135 million people will have dementia by 2050. In 2010, the annual global cost of dementia was estimated at$604 billion. MCI includes problems with day-to-day memory, language and attention,and can be an early sign of dementia, or a symptom of stress or anxiety. Approximately 10% of people diagnosed with MCI develop dementia within a year but apart from regular assessments to measure memory decline, there is currently no accurate way of predicting who will, or won’t, develop dementia.

Previous studies have also shown that PET brain scans and plasma in lumbar fluid can be used to predict the onset of dementia from MCI. However, PET imaging is highly expensive and lumbar punctures invasive.

(Source: kcl.ac.uk)

Deep inside the brains of people with dementia and Lou Gehrig’s disease, globs of abnormal protein gum up the inner workings of brain cells – dooming them to an early death.

But boosting those cells’ natural ability to clean up those clogs might hold the key to better treatment for such conditions.

That’s the key finding of new research from a University of Michigan Medical School physician scientist and his colleagues in California and the United Kingdom. They reported their latest findings this week in the journal Nature Chemical Biology.

Though the team showed the effect worked in animals and human neurons from stem cells, not patients, their discoveries point the way to find new medicines that boost the protein-clearing cleanup process.

The work also shows how an innovative microscope technique can help researchers see what’s going on inside brain cells, as they labor to clear out the protein buildup.

The researchers focused on a crucial cell-cleaning process called autophagy – a hot topic in basic medical research these days, as scientists discover its important role in many conditions. In autophagy, cells bundle unwanted materials up, break them down and push the waste products out.

In the newly published research, the team showed how the self-cleaning capacity of some brain cells gets overwhelmed if the cells make too much of an abnormal protein called TDP43. They found that cells vary greatly in how quickly their autophagy capacity gets swamped.

In brain cells that were made from stem cells derived from ALS patients, treatment with two drugs that stimulate autophagy led to longer cell survival (middle two lines).

But they also showed how three drugs that boost autophagy – speeding up the clean-out process – could keep the brain cells alive longer.

Longer-living, TDP43-clearing brain cells are theoretically what people with Lou Gehrig’s disease (amyotrophic lateral sclerosis or ALS) and certain forms of dementia (called frontotemporal) need. But only further research will show for sure.

Sami Barmada, M.D., Ph.D., the U-M neurologist and scientist who is first author of the new study, says the new findings are encouraging – and so is the success of a microscope technique used in the research. His new lab, in the U-M Department of Neurology, is continuing to refine ways to view the inner workings of nerve cells.

“Using this new visualization technique, we could truly see how the protein was being cleared, and therefore which compounds could enhance the pace of clearance and shorten the half-life of TDP43 inside cells,” he says. “This allowed us to see that increased autophagy was directly related to improved cell survival.”

Barmada worked on the team at the Gladstone Institutes and the University of California San Francisco headed by Steven Finkbeiner, M.D., Ph.D., that published the new findings. The team used stem cells derived from the cells of people who have ALS to grow neurons and astrocytes – the two types of brain cell most crucial to normal brain function.

Because he both sees patients in clinic and studies neurological disease in the laboratory, Barmada brings a special perspective to the research.

At U-M, he specializes in treating patients who have neurological diseases that affect both thinking and muscle control. About a third of ALS patients develop signs of frontotemporal dementia, also called FTD – and about 10 percent of people with FTD also have a motor neuron disease that affects their brain’s ability to control muscle movement. 

One of the drugs tested in the study, an antipsychotic drug developed in the 1960s to treat people with schizophrenia, had actually shown some anti-dementia promise in human ALS patients, but comes with many side effects. Barmada notes that Finkbeiner’s team at the Gladstone Institute is already working to identify other compounds that could produce the effect with fewer side effects.

Interestingly, small studies have suggested that people with schizophrenia who take antipsychotic drugs are much less likely to develop ALS.

Barmada’s work at U-M now focuses on the connection between brain cells’ ability to clear abnormal proteins. He also studies the cells’ regulation of RNA molecules created as part of expressing protein-encoding genes. Looking further upstream in the protein-producing process could yield further clues to why disease develops and what can be done about it, he says.

(Source: uofmhealth.org)

Researchers at Duke-NUS Graduate Medical School Singapore (Duke-NUS) have found evidence that the less older adults sleep, the faster their brains age. These findings, relevant in the context of Singapore’s rapidly ageing society, pave the way for future work on sleep loss and its contribution to cognitive decline, including dementia.

Past research has examined the impact of sleep duration on cognitive functions in older adults. Though faster brain ventricle enlargement is a marker for cognitive decline and the development of neurodegenerative diseases such as Alzheimer’s, the effects of sleep on this marker have never been measured.

The Duke-NUS study examined the data of 66 older Chinese adults, from the Singapore-Longitudinal Aging Brain Study(1). Participants underwent structural MRI brain scans measuring brain volume and neuropsychological assessments testing cognitive function every two years. Additionally, their sleep duration was recorded through a questionnaire. Those who slept fewer hours showed evidence of faster ventricle enlargement and decline in cognitive performance.

"Our findings relate short sleep to a marker of brain aging," said Dr June Lo, the lead author and a Duke-NUS Research Fellow. "Work done elsewhere suggests that seven hours a day(2) for adults seems to be the sweet spot for optimal performance on computer based cognitive tests. In coming years we hope to determine what’s good for cardio-metabolic and long term brain health too," added Professor Michael Chee, senior author and Director of the Centre for Cognitive Neuroscience at Duke-NUS.

(Source: eurekalert.org)

Scientists at NYU Langone Medical Center have identified a compound, called 2-PMAP, in animal studies that reduced by more than half levels of amyloid proteins in the brain associated with Alzheimer’s disease. The researchers hope that someday a treatment based on the molecule could be used to ward off the neurodegenerative disease since it may be safe enough to be taken daily over many years.  

“What we want in an Alzheimer’s preventive is a drug that modestly lowers amyloid beta and is also safe for long term use,” says Martin J. Sadowski, MD, PhD, associate professor of neurology, psychiatry, and biochemistry and molecular pharmacology, who led the research to be published online June 3 in the journal Annals of Neurology. “Statin drugs that lower cholesterol appear to have those properties and have made a big impact in preventing coronary artery disease. That’s essentially what many of us envision for the future of Alzheimer’s medicine.”

The 2-PMAP molecule that Dr. Sadowski’s team identified is non-toxic in mice, gets easily into the brain, and lowers the production of amyloid beta and associated amyloid deposits.

The prime target for Alzheimer’s prevention is amyloid beta. Decades before dementia begins, this small protein accumulates in clumps in the brain. Modestly lowering the production of amyloid beta in late middle age, and thus removing some of the burden from the brain’s natural clearance mechanisms, is believed to be a good prevention strategy. Researchers two years ago reported that something like this happens naturally in about 0.5 percent of Icelanders, due to a mutation they carry that approximately halves amyloid beta production throughout life. These fortunate people show a slower cognitive decline in old age, live longer, and almost never get Alzheimer’s.

Prevention of Alzheimer’s dementia is now considered more feasible than stopping it after it has begun, when brain damage is already severe. Every prospective Alzheimer’s drug in clinical trials has failed even to slow the disease process at that late stage. “The key is to prevent the disease process from going that far,” Dr. Sadowski says.

Dr. Sadowski and colleagues screened a library of compounds and found that 2-PMAP reduced the production of amyloid beta’s mother protein, known as amyloid precursor protein (APP). The APP protein normally is cut by enzymes in a way that leaves amyloid beta as one of the fragments. Dr. Sadowski’s team found that 2-PMAP, even at low, non-toxic concentrations, significantly reduced APP production in test cells, lowering amyloid beta levels by 50 percent or more.

The scientists subsequently found that 2-PMAP had essentially the same impact on APP and amyloid beta in the brains of living mice. The mice were engineered to have the same genetic mutations found in Alzheimer’s patients with a hereditary form of the disease, causing overproduction of APP and Alzheimer’s-like amyloid deposits. A five-day treatment with 2-PMAP lowered brain levels of APP and, even more so, levels of amyloid beta. Four months of treatment sharply reduced the amyloid deposits and prevented the cognitive deficits that are normally seen in these transgenic mice as they get older.

Dr. Sadowski and his laboratory are now working to make chemical modifications to the compound to improve its effectiveness. But 2-PMAP already seems to have advantages over other amyloid-lowering compounds, he says. One is that it can cross efficiently from the bloodstream to the brain, and thus doesn’t require complex modifications that might compromise its effects on APP.

The compound also appears to have a highly selective effect on APP production, by interfering with the translation of APP’s gene transcript into the APP protein itself. The best known candidates for Alzheimer’s preventives lower amyloid by inhibiting the secretase enzymes that cleave amyloid beta from APP, tending to cause unwanted side-effects via their off target interference with the processing of other client proteins cleaved by these enzymes. A clinical trial of one secretase inhibitor was halted in 2010 after it was found to worsen dementia and cause a higher incidence of skin cancer.

Alzheimer’s disease, the most common form of dementia, currently afflicts more than five million Americans, according to the Alzheimer’s Association. Unless preventive drugs or treatments are developed, the prevalence of Alzheimer’s is expected to triple by 2050.

(Source: communications.med.nyu.edu)