Posts tagged dementia

ScienceDaily (July 10, 2012) — 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.

Source: Science Daily

ScienceDaily (June 22, 2012) — Some dementia patients show symptoms of a malfunctioning immune system and can receive appropriate treatment.

Scientists at Charité — Universitätsmedizin Berlin have succeeded in recommending a new type of therapeutic approach to dementia. The study published in the journal Neurology shows that immune reactions against the body’s own nerve cells can be the cause of advanced dementia and an appropriate immune suppressive therapy can develop with significant effectiveness.

Dementia burdens society with high costs, and those affected by it and their family members carry a tremendous psychosocial burden. Dementia is increasingly perceived as a sword of Damocles over an aging society due to its often unclear origin, difficult prevention and unsatisfactory therapies.

Together with a workgroup and cooperation partners in Germany and the US, Dr. Harald Prüß, physician at the Klinik für Neurologie of the Charité, was able to prove that dementia is also caused by the immune system. As an accessory symptom of an autoimmune disease, dementia can thus be treated. This approach to diagnostic criteria has been overlooked until now. It was proven that a number of patients in this study who suffered from advanced memory loss had developed an immune defense response with antibodies against an ion channel in the brain, a so-called NMDA-type glutamate channel. Particular proteins in the nerve cell membrane are reduced leading to the characteristic disruption in nerve function and synapsis loss. Those affected exhibit memory problems and abnormalities in mood and emotion. Eliminating these antibodies through hemodialysis improved the symptoms in cerebral metabolism in the hippocampus region — a part of the brain that is relevant for memory performance and particularly affected by dementia.

"Through the study results, a completely new approach to diagnosing dementia can possibly result. At the moment we are working on a follow-up study with larger test groups in order to verify our approach even further," explains Harald Prüß. He adds: "The potential promise of this new approach is that completely new perspectives could result for an entire group of people suffering from dementia for whom no specific therapeutic option exists."

Source: Science Daily

ScienceDaily (June 21, 2012) — 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.

Source: Science Daily

ScienceDaily (June 13, 2012) — 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.

Source: Science Daily