Category: Dementia

Researchers at Georgetown University Medical Center appear to have solved the mystery of why some patients infected with HIV, who are using antiretroviral therapy and show no signs of AIDS, develop serious depression as well as profound problems with memory, learning, and motor function. The finding might also provide a way to test people with HIV to determine their risk for developing dementia.

They say the answer, published in the July 11 issue of the Journal of Neuroscience, may ultimately lead to a therapeutic solution that helps these patients as well as others suffering from brain ailments that appear to develop through the same pathway, including those that occur in the aged.

"We believe we have discovered a general mechanism of neuronal decline that even explains what happens in some elderly folks," says the study's lead investigator, Italo Mocchetti, Ph.D., professor and vice chair of the department of neuroscience at Georgetown University Medical Center. "The HIV-infected patients who develop this syndrome are usually quite young, but their brains act old."

The research team found that even though HIV does not infect neurons, it tries to stop the brain from producing a protein growth factor — mature brain derived neurotrophic factor (mature BDNF) — that Mocchetti says acts like "food" for brain neurons. Reduced mature BDNF results in the shortening of the axons and their branches that neurons use to connect to each other, and when they lose this communication, the neurons die.

"The loss of neurons and their connections is profound in these patients," Mocchetti says. HIV-associated dementia occurs in two to three percent of HIV-infected patients using retroviral therapies, all of who appear to be otherwise healthy, and in 30 percent of HIV-positive patients who are not on medication.

Mocchetti believes that HIV stops production of mature BDNF because that protein interferes with the ability of the virus to attack other brain cells. It does this through the potent gp120 envelope protein that sticks out from the viral shell — the same protein that hooks on to brain macrophages and microglial cells to infect them. "In earlier experiments, when we dumped gp120 into neuronal tissue culture, there was a 30-40 percent loss of neurons overnight. That makes gp120 a remarkable neurotoxin."

This study is the product of years of work that has resulted in a string of publications. It began when Mocchetti and his colleagues were given a grant from the National Institutes on Drug Abuse to determine whether there was a connection between the use of cocaine and morphine, and dementia. (A substantial number of HIV-positive patients have been or currently are intravenous drugs users.)

They found that it was the virus that was responsible for the dementia, not the drugs, and so they set out to discover how the virus was altering neuronal function.

Their scientific break came when the researchers were able to study the blood of 130 women who were enrolled in the 17 year-old, nationwide WIHS (Women's Interagency HIV Study, directed at Georgetown by Mary Young, M.D.), which has focused on the effects of HIV in infected females. In one seminal discovery, Mocchetti and colleagues found that when there was less BDNF in the blood, patients were at risk of developing brain abnormalities. He published this finding in 2011 in the May 15 issue of AIDS.

In this study, Mocchetti, Alessia Bachis, Ph.D., and their colleagues studied the brains of HIV-positive patients who had died, and who had developed HIV-associated dementia. They also found that neurons had shrunk, and that mature BDNF had substantially decreased.

He and his colleagues then worked out the mechanism responsible for this destruction of neurons.

Normally, neurons release a long form of BDNF known as proBDNF, and then certain enzymes, including one called furin, cleave proBDNF to produce mature BDNF, which then nurtures brain neurons. When uncut, proBDNF is toxic, leading to "synaptic simplification," or the shortening of axons. It does this by binding to a receptor, p75NTR, that contains a death domain.

"HIV interferes with that normal process of cleaving proBDNF, resulting in neurons primarily secreting a toxic form of BDNF," Mocchetti says. The same imbalance between mature BDNF and proBDNF occurs as we age, he says, although no one knows how that happens. "The link between depression and lack of mature BDNF is also known, as is the link to issues of learning and memory. That's why I say HIV-associated dementia resembles the aging brain."

Loss of mature BDNF has also been suggested to be a risk factor in chronic diseases such as Parkinson's and Huntington's diseases, Mocchetti says.

The findings suggest a possible therapeutic intervention, he adds. "One way would be to use a small molecule to block the p75NTR receptor that proBDNF uses to kill neurons. A small molecule like that could get through the blood-brain barrier.

"If this works in HIV-dementia, it may also work in other brain issues caused by proBDNF, such as aging," Mocchetti adds.

The finding also suggests that measuring proBDNF in HIV-positive patients may provide a biomarker of risk for development of dementia, he adds.

"This finding is extremely important for both basic scientists and physicians, because it suggests a new avenue to understand, and treat, a fairly widespread cause of dementia," Mocchetti says.

 Preventing diabetes or delaying its onset has been thought to stave off cognitive decline — a connection strongly supported by the results of a 9-year study led by researchers at the University of California, San Francisco (UCSF) and the San Francisco VA Medical Center.

Earlier studies have looked at cognitive decline in people who already had diabetes. The new study is the first to demonstrate that the greater risk of cognitive decline is also present among people who develop diabetes later in life. It is also the first study to link the risk of cognitive decline to the severity of diabetes.

The result is the latest finding to emerge from the Health, Aging, and Body Composition (Health ABC) Study, which enrolled 3,069 adults over 70 at two community clinics in Memphis, TN and Pittsburgh, PA beginning in 1997. All the patients provided periodic blood samples and took regular cognitive tests over time.

When the study began, hundreds of those patients already had diabetes. A decade later, many more of them had developed diabetes, and many also suffered cognitive decline. As described this week in Archives of Neurology, those two health outcomes were closely linked.

People who had diabetes at the beginning of the study showed a faster cognitive decline than people who developed it during the course of the study — and these people, in turn, tended to be worse off than people who never developed diabetes at all. The study also showed that patients with more severe diabetes who did not control their blood sugar levels as well suffered faster cognitive declines.

"Both the duration and the severity of diabetes are very important factors," said Kristine Yaffe, MD, the lead author of the study. "It's another piece of the puzzle in terms of linking diabetes to accelerated cognitive aging."

An important question for future studies, she added, would be to ask if interventions that would effectively prevent, delay or better control diabetes would also lower people's risk of cognitive impairment later in life.

Yaffe is the Roy and Marie Scola Endowed Chair of Psychiatry; professor in the UCSF departments of Psychiatry, Neurology and Epidemiology and Biostatistics; and Chief of Geriatric Psychiatry and Director of the Memory Disorders Clinic at the San Francisco VA Medical Center.

Diabetes and Cognitive Decline

Diabetes is a chronic and complex disease marked by high levels of sugar in the blood that arise due to problems with the hormone insulin, which regulates blood sugar levels. It is caused by an inability to produce insulin (type 1) or an inability to respond correctly to insulin (type 2).

A major health concern in the United States, diabetes of all types affects an estimated 8.3 percent of the U.S. population — some 25.8 million Americans — and costs U.S. taxpayers more than $200 billion annually. In California alone, an estimated 4 million people (one out of every seven adults) has type 2 diabetes and millions more are at risk of developing it. These numbers are poised to explode in the next half century if more is not done to prevent the disease.

Over the last several decades, scientists have come to appreciate that diabetes affects many tissues and organs of the body, including the brain and central nervous system — particularly because diabetes places people at risk of cognitive decline later in life.

In their study the scientists looked at a blood marker known as "glycosylated hemoglobin," a standard measure of the severity of diabetes and the ability to control it over time. The marker shows evidence of high blood sugar because these sugar molecules become permanently attached to hemoglobin proteins in the blood. Yaffe and her colleagues found that greater levels of this biomarker were associated with more severe cognitive dysfunction.

While the underlying mechanism that accounts for the link between diabetes and risk of cognitive decline is not completely understood, Yaffe said, it may be related to a human protein known as insulin degrading enzyme, which plays an important role in regulating insulin, the key hormone linked to diabetes. This same enzyme also degrades a protein in the brain known as beta-amyloid, a brain protein linked to Alzheimer's disease.

In addition to UCSF, authors on this study were affiliated with University of Tennessee, the National Institute on Aging and the University of Pittsburgh.

Our attitude towards our age has a massive impact on the likelihood of being diagnosed with dementia. New research shows that when seniors see themselves as 'older' their performance on a standard dementia screening test declines dramatically; making them five times more likely to meet the criteria for dementia.

The research, conducted by the University of Exeter, highlights the significance of our age perceptions and its effect on our mental functioning. It was presented June 12 at the first International Conference on Social Identity and Health. Hosted by the University of Exeter, the conference will cover community and public health, health in India, stress and resilience, and aging and dementia.

The research involved 68 people aged between 60 and 70 years, who were primed to either feel older or younger than others taking part in the study. Those in the 'older' group were told the participants ranged in age from 40 to 70, encouraging them to think of themselves as being at the upper end of the age spectrum, while those in the 'younger' group were told that participants ages ranged from 60 to 90 years, encouraging them to think of themselves at the lower end of the age spectrum. All participants were then given one of two articles to read, which either focused on the effects of age on memory loss or on the impact of aging on general cognitive ability.

The participants then completed a series of standard clinical tests that included a standard dementia screening test, the Addenbrooke's Cognitive Examination-Revised. 70 per cent of people who were encouraged to see themselves as older and to believe that aging was associated with a general decline in ability, met the criterion for dementia. This was compared to an average of 14 per cent in the other groups.

The tests used in the study are the same as those used in memory clinics and GP surgeries to assist in dementia diagnosis. Therefore, the participants' sense of their own age had a major impact on widely-established clinical tools.

Lead author Dr Catherine Haslam of the University of Exeter said: "Our research shows that the effect of age perceptions on performance can be dramatic, and that seeing oneself as 'older' significantly increases a person's risk of being diagnosed with dementia on such tests. It highlights the importance of taking a person's attitude towards their age into account when assessing for dementia."

A new study shows that changes in walking speed in late life may signal the early stages of dementia known as mild cognitive impairment (MCI). The research is published in the June 12, 2012, print issue of Neurology®, the medical journal of the American Academy of Neurology.

"In our study, we used a new technique that included installing infrared sensors in the ceilings of homes, a system designed to detect walking movement in hallways," said study author Hiroko Dodge, PhD, with Oregon Health and Science University in Portland and a member of the American Academy of Neurology. "By using this new monitoring method, we were able to get a better idea of how even subtle changes in walking speed may correlate with the development of MCI."

The study involved 93 people age 70 or older who lived alone. Of those, 54 participants had no cognitive impairment, 31 had non-memory related MCI and eight had memory-related MCI. Participants were given memory and thinking tests and had their walking speed monitored at their homes unobtrusively over a three-year period. Participants were placed in groups of slow, moderate or fast based on their average weekly walking speed and how much their walking speed fluctuated at home.

The study found that people with non-memory related MCI were nine times more likely to be slow walkers than moderate or fast walkers and the amount of the fluctuation in walking speed was also associated with MCI.

"Further studies need to be done using larger groups of participants to determine whether walking speed and its fluctuations could be a predictor of future memory and thinking problems in the elderly," said Dodge. "If we can detect dementia at its earliest phases, then we can work to maintain people's independence, provide treatments and ultimately develop ways to prevent the disease from developing. Our in-home monitoring approach has a lot of potential to be used for sustaining independence of the elderly."

The study was supported by the National Institutes of Health and the Intel Corporation.

Older people who take omega-3 fish oil supplements are probably not reducing their chances of losing cognitive function, according to a new Cochrane systematic review. Based on the available data from studies lasting up to 3.5 years, the researchers concluded that the supplements offered no benefits for cognitive health over placebo capsules or margarines, but that longer term effects are worth investigating.

Omega-3 fatty acids are fats responsible for many important jobs in the body. We get these fats through our daily diets and the three major omega-3 fats are: alpha linolenic acid (ALA) from sources such as nuts and seeds and eicosapentoic acid (EPA) and docosahexaenoic acid (DHA) from sources including oily fish such as salmon and mackerel. A number of studies have hinted that omega-3 fatty acids and DHA in particular may be involved in keeping nerve cells in the brain healthy into old age. However, there is limited evidence for the role of these fats in preventing cognitive decline and dementia.

The researchers, led by Emma Sydenham at the London School of Hygiene & Tropical Medicine (LSHTM), London, UK, gathered together evidence from three high quality trials comparing the effects of omega-3 fatty acids taken in capsules or margarine spread to those of sunflower oil, olive oil or regular margarine. A total of 3,536 people over the age of 60 took part in the trials, which lasted between six and 40 months. None of the participants had any signs of poor cognitive health or dementia at the start of the trials.

The researchers found no benefit of taking the omega-3 capsules or spread over placebo capsules or spread. Participants given omega-3 did not score better in standard mental state examinations or in memory and verbal fluency tests than those given placebo.

"From these studies, there doesn't appear to be any benefit for cognitive health for older people of taking omega-3 supplements," said Alan Dangour, a nutritionist at LSHTM and co-author of the report. "However, these were relatively short-term studies, so we saw very little deterioration in cognitive function in either the intervention groups or the control groups. It may take much longer to see any effect of these supplements."

The researchers conclude that the longer term effects of omega-3 fatty acids on cognitive decline and dementia need to be explored in further studies, particularly in people with low intakes of omega-3 fatty acids in their diet. In the meantime, they stress other potential health benefits. "Fish is an important part of a healthy diet and we would still support the recommendation to eat two portions a week, including one portion of oily fish," said Dangour.

— Brains that maintain healthy nerve connections as we age help keep us sharp in later life, new research funded by the charity Age UK has found.

Older people with robust brain 'wiring' — that is, the nerve fibers that connect different, distant brain areas — can process information quickly and that this makes them generally smarter, the study suggests.

According to the findings, joining distant parts of the brain together with better wiring improves mental performance, suggesting that intelligence is not found in a single part of the brain.

However a loss of condition of this wiring or 'white matter' — the billions of nerve fibers that transmit signals around the brain — can negatively affect our intelligence by altering these networks and slowing down our processing speed.

The research by the University of Edinburgh shows for the first time that the deterioration of white matter with age is likely to be a significant cause of age-related cognitive decline.

The research team used three different brain imaging techniques in compiling the results, including two that have never been used before in the study of intelligence.

These techniques measure the amount of water in brain tissue, indicate structural loss in the brain, and show how well the nerve fibers are insulated.

The researchers examined scans and results of thinking and reaction time tests from 420 people in the Lothian Birth Cohort of 1936, a group of nearly 1100 people whose intelligence & general health have been tracked since they were 11

The research was part of the Disconnected Mind Project, a large study of the causes of people's differences in cognitive aging, led by Professor Ian Deary.

Study author Doctor Lars Penke said "Our results suggest a first plausible way how brain structure differences lead to higher intelligence. The results are exciting for our understanding of human intelligence differences at all ages."

"They also suggest a clear target for seeking treatment for mental difficulties, be they pathological or age-related. That the brain's nerve connections tend to stay the same throughout the brain means we can now look at factors that affect the overall condition of the brain, like its bloody supply."

Professor Deary said that uncovering the secrets of good thinking skills in old age is a high priority. "The research team is now looking at what keeps the brain's connections healthy. We value our thinking skills, and research should address how we might retain them or slow their decline with age."

Doctor Mark Bastin, who co-authored the study, said "These findings are exciting as they show how quantitative brain imaging can provide novel insights into the links between brain structure and cognitive ability. This is a key research area given the importance of identifying strategies for retaining good mental ability into older age."

Professor James Goodwin, Head of Research at Age UK, said: "This research is very exciting as it could have a real impact on tackling mental decline in later life, including dementia. With new understanding on how the brain functions we can work out why mental faculties decline with age in some people and not others and look at what can be done to improve our minds' chances of aging better."

Elderly people with pre-diabetes and type 2 diabetes suffer from an accelerated decline in brain size and mental capacity in as little as two years according to new research presented at the joint International Congress of Endocrinology/European Congress of Endocrinology in Florence, Italy.

An Australian research team led by Associate Professor Katherine Samaras (Garvan Institute of Medical Research) found that the aging brain is vulnerable to worsening blood sugar levels even before type 2 diabetes is diagnosable.

While some brain volume loss is a normal part of aging, the researchers found that elderly people with blood sugar levels in flux, as well as type 2 diabetes, lost almost two and a half times more brain volume than their peers over two years. The reduction in size of the frontal lobe — associated with higher mental functions like decision-making, emotional control, and long term memory — has a significant impact on cognitive function and quality of life.

Diabetes is a very common disorder caused by high levels of sugar in the bloodstream. It affects 6.4% (285 million) of the worldwide population and is associated with an increased risk of heart attacks, stroke and damage to the eyes, feet and kidneys. In type 2 diabetes, which accounts for 90% of all cases, insulin — a hormone that allows cells to take sugar from the bloodstream and store it as energy — does not work properly. 344 million people also have pre-diabetes, a condition with mildly elevated blood sugar levels that gives them a 50% risk of developing the disease over ten years.

This research — a follow-up of 312 participants from the Sydney Memory and Ageing Study — compared MRI scans taken from the beginning and end of a two-year period. The participants were elderly community-dwelling Australians aged between 70 and 90 years old (average age 78, 54% male) and free from dementia. At the start of the study 41% had pre-diabetes and 13% had type 2 diabetes.

At the end of the study the participants were divided into four groups: (1) those with normal, stable glucose levels (102 people); (2) those with stable pre-diabetes (120 people); (3) those whose glucose levels had worsened (57 people); and finally, (4) those with type 2 diabetes from the start (33 people).

The MRI scans showed that the normal group lost an average of 18.4 cm3 total brain volume over two years. In comparison, the stable pre-diabetic group lost 1.4 times more brain volume (26.6 cm3). Both the third group (worsening glucose levels) and fourth group (type 2 diabetes) lost 2.3 times the stable group's brain volume loss (41.7 cm3 and 42.3 cm3, respectively).

The researchers — using statistical models that accounted for other variables — concluded that a person's blood sugar status after two years can significantly predict their decline in brain volume.

Associate Professor Katherine Samaras, from the Garvan Institute of Medical Research, said:

"These findings highlight the importance of prevention of diabetes. They also emphasise that, in the elderly, clinicians and allied health professionals need to understand that the complexity of diabetes care needs to accommodate expected declines in cognitive function.

"We need to understand why these changes in cognition and brain size occur. Is it due merely to higher blood sugars? Is the brain subject to the toxic effects of glucose, just as peripheral nerves are? To what extent do other factors associated with diabetes also contribute to the decline in brain size and function, for example inflammation or blood fat levels?

"We also need to learn how we can prevent or deter the negative effects of diabetes on the brain."

— Aging may seem unavoidable, but that's not necessarily so when it comes to the brain. So say researchers in the April 27th issue of the Cell Press journal Trends in Cognitive Sciences based on counterintuitive evidence that it is what you do in old age that matters when it comes to maintaining a youthful brain rather than what you did earlier in life.

"Although some memory functions do tend to decline as we get older, several elderly show well-preserved functioning and this is related to a well-preserved, youth-like brain," says Lars Nyberg, Professor of Neuroscience at Umeå University in Sweden.

Education won't save your brain — PhDs are as likely as high school dropouts to experience memory loss with old age, the researchers say. Don't count on your job either. Those with a complex or demanding career may enjoy a limited advantage, but those benefits quickly dwindle after retirement. Engagement is the secret to success. Those who are socially, mentally and physically stimulated reliably show greater cognitive performance with a brain that appears younger than its years.

"There is quite solid evidence that staying physically and mentally active is a way towards brain maintenance," Nyberg says.

The researchers say this new take on successful aging represents an important shift in focus for the field. Much attention in the past has gone instead to understanding ways in which the brain copes with or compensates for cognitive decline in aging. The research team now argues for the importance of avoiding those age-related brain changes in the first place. Genes play a role, but life choices and other environmental factors, especially in old age, are critical.

Elderly people generally do have more trouble remembering meetings or names, Nyberg says. But those memory losses often happen later than many often think, after the age of 60. Older people also continue to accumulate knowledge and to use what they know effectively, often to very old ages.

"Taken together, a wide range of findings provides converging evidence for marked heterogeneity in brain aging," the scientists write. "Critically, some older adults show little or no brain changes relative to younger adults, along with intact cognitive performance, which supports the notion of brain maintenance. In other words, maintaining a youthful brain, rather than responding to and compensating for changes, may be the key to successful memory aging."

New findings, led by neuroscientists at the University of Bristol and recently published in the journal Neurobiology of Aging, reveal a novel mechanism through which the brain may become more reluctant to function as we grow older.

It is not fully understood why the brain's cognitive functions such as memory and speech decline as we age. Although work published this year suggests cognitive decline can be detectable before 50 years of age. The research, led by Professor Andy Randall and Dr Jon Brown from the University's School of Physiology and Pharmacology, identified a novel cellular mechanism underpinning changes to the activity of neurons which may underlie cognitive decline during normal healthy aging.

The brain largely uses electrical signals to encode and convey information. Modifications to this electrical activity are likely to underpin age-dependent changes to cognitive abilities.

The researchers examined the brain's electrical activity by making recordings of electrical signals in single cells of the hippocampus, a structure with a crucial role in cognitive function. In this way they characterised what is known as "neuronal excitability" — this is a descriptor of how easy it is to produce brief, but very large, electrical signals called action potentials; these occur in practically all nerve cells and are absolutely essential for communication within all the circuits of the nervous system.

Action potentials are triggered near the neuron's cell body and once produced travel rapidly through the massively branching structure of the nerve cell, along the way activating the synapses the nerve cell makes with the numerous other nerve cells to which it is connected.

The Bristol group identified that in the aged brain it is more difficult to make hippocampal neurons generate action potentials. Furthermore they demonstrated that this relative reluctance to produce action potential arises from changes to the activation properties of membrane proteins called sodium channels, which mediate the rapid upstroke of the action potential by allowing a flow of sodium ions into neurons.

Professor Randall, Professor in Applied Neurophysiology said: "Much of our work is about understanding dysfunctional electrical signalling in the diseased brain, in particular Alzheimer's disease. We began to question, however, why even the healthy brain can slow down once you reach my age. Previous investigations elsewhere have described age-related changes in processes that are triggered by action potentials, but our findings are significant because they show that generating the action potential in the first place is harder work in aged brain cells.

"Also by identifying sodium channels as the likely culprit for this reluctance to produce action potentials, our work even points to ways in which we might be able modify age-related changes to neuronal excitability, and by inference cognitive ability."

This research is funded by Pfizer.

— In low- and middle-income countries, mild cognitive impairment — an intermediate state between normal signs of cognitive aging, such as becoming increasingly forgetful, and dementia, which may or may not progress — is consistently associated with higher disability and with neuropsychiatric symptoms but not with most socio-demographic factors, according to a large study published in this week's PLoS Medicine.

The established 10/66 Dementia Research Group interviewed approximately 15 000 people over 65 years of age who did not have dementia in eight low- and middle-incomes countries: Cuba, Dominican Republic, Peru, Mexico, Venezuela, Puerto Rico, China, and India.

Participants also completed standardized assessments of their mental and physical health and cognitive function and the researchers also interviewed relatives and carers for further details about any memory loss or other declines in cognitive function or the presence of any neuropsychiatric symptoms.

Then, using a clinical framework and a statistical model, the authors found that mild cognitive impairment with related memory problems was associated with disability, anxiety, apathy, and irritability but not with depression.

Increasing age or former education level did not seem to be linked but the authors found that men had a slightly higher prevalence of mild cognitive impairment than women. Furthermore, the prevalence of this type of mild cognitive impairment ranged from 0.8% in China to 4.3% in India.

The authors say: "This is one of the first studies, to our knowledge, to investigate the prevalence of [mild cognitive impairment with related memory problems] in [low- and middle-income countries], where the large majority of older people and people with dementia currently live."

They continue: "Differences in prevalence between countries were marked and ranged from 0.8% (China) to 4.3% (India), that is, greater than fivefold variation. After direct standardization for age, gender, and education, using the whole population as the reference, these differences were not markedly attenuated."

The authors conclude: "Further evaluation is needed of the associations with disability and neuropsychiatric symptoms since our findings do suggest higher than expected comorbidity and there are large absolute numbers of older people with [mild cognitive impairment with related memory problems] in these rapidly ageing and populous world regions."