Category: Dementia

— Long term exposure to pesticides may be linked to the development of dementia, suggests research published online in Occupational and Environmental Medicine.

The authors base their findings on 614 vineyard workers in South West France whose intellectual capacity was monitored for up to six years as part of the PHYTONER study.

This aims to track the impact of pesticides on the cognitive abilities of people in their 40s and 50s who have worked for at least 20 years in the agricultural sector.

Levels of exposure to pesticides were based on job calendars and categorised as 'directly exposed' (mixing or applying pesticides, cleaning or repairing spraying equipment); 'certainly indirectly exposed' (contact with treated plants); 'possibly indirectly exposed' (work in buildings, offices, cellars); and 'not exposed' if they had done none of the above.

Just under 1000 workers enrolled in the study between 1997 and 1998, 614 of whom were monitored between 2001 and 2003. On both occasions they completed a questionnaire and nine "neurobehavioural" tests designed to measure memory and recall; language retrieval and verbal skills; and reaction time speeds.

One in five had never been exposed to pesticides as part of their job; over half had been directly exposed, and the remainder had been possibly or certainly indirectly exposed.

Not unexpectedly, lower scores in some or all of the cognitive tests were associated with older age, lower levels of education, excessive alcohol intake, depression, and drug-taking on both occasions.

Around a fifth to half of the workers obtained higher scores in some of the tests; 15% to half obtained lower test scores over time, depending on the test.

But with the exception of two of the nine tests, those who had been exposed to pesticides were the most likely to perform worse second time around.

These workers were up to five times as likely to obtain lower test scores on both occasions, and they were twice as likely to register a drop of two points in the mini mental state exam (MMSE) — the initial test frequently used to determine if a person has dementia.

This decline in MMSE score "is particularly striking in view of the short duration of follow up and the relatively young age of the participants," say the authors, who add that previous research has already reported an association between pesticide exposure and poor performance for several of the tests used in this study.

"The mild impairment we observed raises the question of the potentially higher risks of injury in this population and also of the possible evolution towards neurodegenerative diseases such as Alzheimer's disease or other dementias," they say.

And they add: "Numerous studies have shown that low cognitive performances are associated with risk of dementia."

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Journal Reference:

1. I. Baldi, A. Gruber, V. Rondeau, P. Lebailly, P. Brochard, C. Fabrigoule. Neurobehavioral effects of long-term exposure to pesticides: results from the 4-year follow-up of the PHYTONER Study. Occupational and Environmental Medicine, 2010; DOI: 10.1136/oem.2009.047811

— Walking may slow cognitive decline in adults with mild cognitive impairment (MCI) and Alzheimer's disease, as well as in healthy adults, according to a study presented November 29 at the annual meeting of the Radiological Society of North America (RSNA).

"We found that walking five miles per week protects the brain structure over 10 years in people with Alzheimer's and MCI, especially in areas of the brain's key memory and learning centers," said Cyrus Raji, Ph.D., from the Department of Radiology at the University of Pittsburgh in Pennsylvania. "We also found that these people had a slower decline in memory loss over five years."

Alzheimer's disease is an irreversible, progressive brain disease that slowly destroys memory and cognitive skills. According to the National Institute on Aging, between 2.4 million and 5.1 million Americans have Alzheimer's disease. Based on current population trends, that number is expected to increase significantly over the next decade.

In cases of MCI, a person has cognitive or memory problems exceeding typical age-related memory loss, but not yet as severe as those found in Alzheimer's disease. About half of the people with MCI progress to Alzheimer's disease.

"Because a cure for Alzheimer's is not yet a reality, we hope to find ways of alleviating disease progression or symptoms in people who are already cognitively impaired," Dr. Raji said.

For the ongoing 20-year study, Dr. Raji and colleagues analyzed the relationship between physical activity and brain structure in 426 people, including 299 healthy adults (mean age 78), and 127 cognitively impaired adults (mean age 81), including 83 adults with MCI and 44 adults with Alzheimer's dementia.

Patients were recruited from the Cardiovascular Health Study. The researchers monitored how far each of the patients walked in a week. After 10 years, all patients underwent 3-D MRI exams to identify changes in brain volume.

"Volume is a vital sign for the brain," Dr. Raji said. "When it decreases, that means brain cells are dying. But when it remains higher, brain health is being maintained."

In addition, patients were given the mini-mental state exam (MMSE) to track cognitive decline over five years. Physical activity levels were correlated with MRI and MMSE results. The analysis adjusted for age, gender, body fat composition, head size, education and other factors.

The findings showed across the board that greater amounts of physical activity were associated with greater brain volume. Cognitively impaired people needed to walk at least 58 city blocks, or approximately five miles, per week to maintain brain volume and slow cognitive decline. The healthy adults needed to walk at least 72 city blocks, or six miles, per week to maintain brain volume and significantly reduce their risk for cognitive decline.

Over five years, MMSE scores decreased by an average of five points in cognitively impaired patients who did not engage in a sufficient level of physical activity, compared with a decrease of only one point in patients who met the physical activity requirement.

"Alzheimer's is a devastating illness, and unfortunately, walking is not a cure," Dr. Raji said. "But walking can improve your brain's resistance to the disease and reduce memory loss over time."

Coauthors are Kirk Erickson, Ph.D., Oscar Lopez, M.D., James Becker, Ph.D., Caterina Rosano, M.D., Anne Newman, M.D., M.P.H., H. Michael Gach, Ph.D., Paul Thompson, Ph.D., April Ho, B.S., and Lewis Kuller, M.D.

— Scientists at the Gladstone Institute of Neurological Disease (GIND) in San Francisco have discovered a new strategy to prevent memory deficits in a mouse model of Alzheimer's disease (AD). Humans with AD and mice genetically engineered to simulate the disease have abnormally low levels of an enzyme called EphB2 in memory centers of the brain. Improving EphB2 levels in such mice by gene therapy completely fixed their memory problems.

The findings will be published in the Nov. 28 issue of the journal Nature.

In both humans and mice, learning and memory requires effective communication between brain cells called neurons. This communication involves the release of chemicals from neurons that stimulate cell surface receptors on other neurons. This important process, called neurotransmission, is impaired by amyloid proteins, which build up to abnormally high levels in brains of AD patients and are widely thought to cause the disease. But how exactly these poisonous proteins disrupt neurotransmission is unknown.

"EphB2 is a really cool molecule that acts as both a receptor and an enzyme," said Moustapha Cisse, PhD, lead author of the study. "We thought it might be involved in memory problems of AD because it is a master regulator of neurotransmission and its brain levels are decreased in the disease."

To determine if low EphB2 levels actually contribute to the development of memory problems, the investigators used gene therapy to experimentally alter EphB2 levels in memory centers of mice. Reducing EphB2 levels in normal healthy mice disrupted neurotransmission and gave them memory problems similar to those seen in AD. This finding suggests that the reduced EphB2 levels in AD brains contribute to the memory problems that characterize this condition.

"What we were most curious about, of course, was whether normalizing EphB2 levels could fix memory problems caused by amyloid proteins," said Lennart Mucke, MD, director of the GIND and senior author of the study. "We were absolutely thrilled to discover that it did."

Increasing EphB2 levels in neurons of mice engineered to produce high levels of human amyloid proteins in the brain prevented their neurotransmission deficits, memory problems and behavioral abnormalities. The scientists also discovered that amyloid proteins directly bind to EphB2 and cause its degradation, which helps explain why EphB2 levels are reduced in AD and related mouse models.

"Based on our results, we think that blocking amyloid proteins from binding to EphB2 and enhancing EphB2 levels or functions with drugs might be of benefit in AD." said Mucke. "We are excited about these possibilities and look forward to pursuing them in future studies."

Also contributing to this study were Gladstone scientists Brian Halabisky, Julie Harris, Nino Devidze, Dena Dubal, Bin-Gui Sun, Anna Orr, Gregor Lotz, Daniel H. Kim, Patricia Hamto, Kaitlyn Ho, and Gui-Qiu Yu.

The study was supported by grants from the National Institutes of Health and a fellowship from the McBean Foundation.

Lennart Mucke's primary affiliation is with the Gladstone Institute of Neurological Disease, where he is Director/Senior Investigator and where his laboratory is located and his research is conducted. He is also the Joseph B. Martin Distinguished Professor of Neuroscience and Professor of Neurology at UCSF.

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Journal Reference:

1. Moustapha Cissé, Brian Halabisky, Julie Harris, Nino Devidze, Dena B. Dubal, Binggui Sun, Anna Orr, Gregor Lotz, Daniel H. Kim, Patricia Hamto, Kaitlyn Ho, Gui-Qiu Yu, Lennart Mucke. Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature, 2010; DOI: 10.1038/nature09635

— Metformin, a drug used in type 2-diabetes might have the potential to also act against Alzheimer's disease. This has been shown in a study from scientists of the German Center for Neurodegenerative Diseases (DZNE), the University of Dundee and the Max-Planck-Institute for Molecular Genetics.

The researchers have found out that the diabetes drug metformin counteracts alterations of the cell structure protein Tau in mice nerve cells. These alterations are a main cause of the Alzheimer's disease. Moreover, they uncovered the molecular mechanism of metformin in this process.

"If we can confirm that metformin shows also an effect in humans, it is certainly a good candidate for an effective therapy on Alzheimer's diseases," says Sybille Krauß from DZNE.

Their results have been published in the Proceedings of the National Academy of Sciences (Nov. 22, 2010).

Alzheimer's disease is a form of dementia that affects almost exclusively elderly people. Today, about 700,000 people are suffering from Alzheimer's disease in Germany. Neurons in their brains die, leading to cognitive impairment. At the molecular level, the disease is characterized amongst others by the formation of Tau protein deposits in nerve cells. Tau is a molecule that usually binds to the supportive cytoskeleton and performs a function in the transport system of the cell. In Alzheimer's disease, Tau is tipped too strongly with phosphate groups. This phosphorylation causes removal of Tau from the cytoskeleton and aggregation.

To counteract this problem, researchers aimed at regulating the protein PP2A. This protein is normally responsible for removing phosphate groups from Tau protein. In Alzheimer's disease, PP2A is not active enough — leading to an increased phosphorylation and deposition of Tau. The scientists around Sybille Krauß and Susann Schweiger (University of Dundee) therefore looked for a drug that increases the activity of PP2A. "So far there is no drug on the market that targets the formation of tau aggregates," says Krauß.

In cell culture experiments with mouse nerve cells, the researchers showed that metformin directly protects PP2A against degradation by preventing the binding to special degradation proteins. This mechanism of metformin has been unknown so far. In addition, an increase in PP2A activity leads to a reduction in Tau phosphorylation. In a next step, the scientists added metformin to drinking water of healthy mice. This also led to a reduction of Tau-phoshorylation in brain cells. In further experiments, the researchers now intend to investigate, whether metformin prevents the deposition of tau proteins also in mouse models of Alzheimer's disease and improves cognitive performance of the animals. The effect in humans will then be tested in clinical studies. There is no risk of unexpected side effects, due to the fact that the drug is already used against diabetes.

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Journal Reference:

1. E. Kickstein, S. Krauss, P. Thornhill, D. Rutschow, R. Zeller, J. Sharkey, R. Williamson, M. Fuchs, A. Kohler, H. Glossmann, R. Schneider, C. Sutherland, S. Schweiger. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.0912793107

 In a study that included healthy 65- to 85-years-old who carried a high-risk gene for Alzheimer's disease, those who exercised showed greater brain activity in memory-related regions than those who were sedentary. The results suggest that physical activity promotes changes in the brain that may protect high-risk individuals against cognitive decline.

Physical activity promotes changes in the brain that may protect high-risk individuals against cognitive decline, including development of Alzheimer's disease, according to a new study done at the University of Wisconsin-Milwaukee (UWM).

J. Carson Smith, an assistant professor of health sciences, included in the study both people who carry a high-risk gene for Alzheimer's disease, and other healthy older adults without the gene.

"Our study suggests that if you are at genetic risk for Alzheimer's disease, the benefits of exercise to your brain function might be even greater than for those who do not have that genetic risk," says Smith.

While evidence already shows that physical activity is associated with maintenance of cognitive function across a life span, most of this research has been done with healthy people, without any consideration of their level of risk for Alzheimer's, says Smith.

A team of researchers compared brain activation during memory processing in four separate groups of healthy 65- to 85-years-olds. The level of risk was defined by whether an individual carried the apolipoprotein E-epsilon4 (APOE-ϵ4) allele. Physical activity status was defined by how much and how often the participants reported physical activity (PA). The study divided subjects into Low Risk/Low PA, Low Risk/High PA, High Risk/Low PA and High Risk/High PA.

Functional magnetic resonance imaging (fMRI) was used to measure brain activation of participants while they performed a mental task involving discriminating among famous people. This test is very useful, says Smith, because it engages a wide network called the semantic memory system, with activation occurring in 15 different functional regions of the brain.

"When a person thinks about people — for example, Frank Sinatra or Lady Gaga — that involves several lobes of the brain," explains Smith.

In the study groups of those carrying the gene, individuals who exercised showed greater brain activity in memory-related regions than those who were sedentary.

Perhaps even more intriguing, physically active people with the gene had greater brain activity than those who were physically active but not gene carriers.

There are many physiological reasons why this could be happening, Smith says. "For example, people with this increased activation might be compensating for some underlying neurological event that is involved in cognitive decline.." "Using more areas of their brain may serve as a protective function, even in the face of disease processes."

The study's collaborating institutions include the Cleveland Clinic, Marquette University, Wayne State University and Rosalind Franklin University of Medicine and Science. It was funded by the National Institutes of Health and the National Institute on Aging.

The study will be published in the journal NeuroImage.

Smith's current research builds on this study. He and his team are conducting a new study testing the before-and-after effects of a structured exercise program on brain function. The study includes patients diagnosed with mild cognitive impairment or early Alzheimer's disease, as well as a healthy control group.

For more information on this ongoing study, visit http://www.exerciseforbrainhealth.com/.

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Journal Reference:

1. J. Carson Smith, Kristy A. Nielson, John L. Woodard, Michael Seidenberg, Sally Durgerian, Piero Antuono, Alissa M. Butts, Nathan C. Hantke, Melissa A. Lancaster, Stephen M. Rao. Interactive effects of physical activity and APOE-ε4 on BOLD semantic memory activation in healthy elders. NeuroImage, 2011; 54 (1): 635 DOI: 10.1016/j.neuroimage.2010.07.070

A protein known to exist in the brain for more than 30 years, called 5-lipoxygenase, has been found to play a regulatory role in the formation of the amyloid beta in the brain, the major component of plaques implicated in the development of Alzheimer's disease, according to researchers at Temple University's School of Medicine.

The researchers also found that inhibitors of this protein currently used to control asthma could possibly be used to prevent or treat Alzheimer's disease.

The researchers published their findings in the Annals of Neurology.

According to Domenico Praticò, an associate professor of pharmacology in Temple's School of Medicine and the study's lead researcher, the 5-Lipoxygenase enzyme is found in abundance mainly in the region of the brain, the hippocampus, involved in memory.

Praticò and his team discovered that 5-lipoxygenase, which unlike most proteins in the brain increases its levels during the aging process. It also controls the activation state of another protein, called gamma secretase, a complex of four elements which are necessary and responsible for the final production of the amyloid beta, a peptide that when produced in excess deposits and forms plaques in the brain. Today the amount of these amyloid plaques in the brain is used as a measurement of the severity of Alzheimer's.

"What we found was 5-lipoxygenase regulates and controls the amount of total amyloid beta produced in the brain," said Praticò. "With aging, the more 5-lipoxygenase you have the more amyloid beta you're going to produce. This will translate into a higher risk to develop full Alzheimer's"

A previous study by Praticò, in which researchers crossed a mouse model of Alzheimer's with a mouse that did not genetically feature 5-lipoxygenase, demonstrated that a lack of this enzyme protein alone can reduce the amount of disease in the brain by up to half.

"It has been known for years that the 5-lipoxygenase is an important protein in other areas of the body, such as the lung, but nobody really cared about its role in the brain," he said. "Based on some previously know information, we questioned whether this enzyme was a primary or secondary player in the development of Alzheimer's. What we found was a new primary role for an old enzyme."

Praticò said that the key in the process was 5-lipoxygenase's direct control over the gamma secretase, the only source of amyloid beta in the brain. "If you can modulate this enzyme easily, then you can control the amount of total amyloid beta that is produced by the gamma secretase in the brain, thus controlling the amount of Alzheimer's disease."

Praticò said that armed with new information, new therapies could be developed to block the increase of 5-lipoxygenase levels in the aging brain, which would in turn prevent the formation of amyloid beta.

He said that there are several FDA-approved 5-lipoxygenase inhibitors currently being used for the treatment of asthma, and that the Temple researchers tested some of these inhibitors in the lab against the production of amyloid beat with initial positive results.

"These drugs are already on the market, they're inexpensive and, most importantly, they are already FDA-approved, so you wouldn't need to go through an intense drug discovery process," said Praticò. "So you could quickly begin a clinical trial to determine if there is a new application for an old drug against a disease where there is currently nothing."

The study was funded by the National Institutes of Health and the Alzheimer's Association Zenith Fellowship.

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Journal Reference:

1. Jin Chu, Domenico Pratic. 5-lipoxygenase as an endogenous modulator of amyloid beta formation in vivo. Annals of Neurology, 2010; DOI: 10.1002/ana.22234