Alzheimer's disease study links brain health, physical activity

People at risk for Alzheimer's disease who do more moderate-intensity physical activity, but not light-intensity physical activity, are more likely to have healthy patterns of glucose metabolism in their brain, according to a new UW-Madison study.

Results of the research were published online in Journal of Alzheimer's Disease. Senior author Dr. Ozioma Okonkwo, assistant professor of medicine, is a researcher at the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Alzheimer's Institute at the UW School of Medicine and Public Health. First author Ryan Dougherty is a graduate student studying under the direction of Dr. Dane B. Cook, professor of kinesiology and a co-author of the study, and Dr. Okonkwo. The research involved 93 members of the Wisconsin Registry for Alzheimer's Prevention (WRAP), which with more than 1,500 registrants is the largest parental history Alzheimer's risk study group in the world.

Researchers used accelerometers to measure the daily physical activity of participants, all of whom are in late middle-age and at high genetic risk for Alzheimer's disease, but presently show no cognitive impairment. Activity levels were measured for one week, quantified, and analyzed. This approach allowed scientists to determine the amount of time each subject spent engaged in light, moderate, and vigorous levels of physical activity. Light physical activity is equivalent to walking slowly, while moderate is equivalent to a brisk walk and vigorous a strenuous run. Data on the intensities of physical activity were then statistically analyzed to determine how they corresponded with glucose metabolism -- a measure of neuronal health and activity -- in areas of the brain known to have depressed glucose metabolism in people with Alzheimer's disease. To measure brain glucose metabolism, researchers used a specialized imaging technique called 18F-fluorodeoxyglucose positron emission tomography (FDG-PET).

Moderate physical activity was associated with healthier (greater levels of) glucose metabolism in all brain regions analyzed. Researchers noted a step-wise benefit: subjects who spent at least 68 minutes per day engaged in moderate physical activity showed better glucose metabolism profiles than those who spent less time.

"This study has implications for guiding exercise 'prescriptions' that could help protect the brain from Alzheimer's disease," said Dougherty. "While many people become discouraged about Alzheimer's disease because they feel there's little they can do to protect against it, these results suggest that engaging in moderate physical activity may slow down the progression of the disease."

"Seeing a quantifiable connection between moderate physical activity and brain health is an exciting first step," said Okonkwo. He explained that ongoing research is focusing on better elucidating the neuroprotective effect of exercise against Alzheimer's disease.

---

News Source:
IOS Press.

Anti-epilepsy drug restores normal brain activity in mild Alzheimer's disease

In the last decade, mounting evidence has linked seizure-like activity in the brain to some of the cognitive decline seen in patients with Alzheimer's disease. Patients with Alzheimer's disease have an increased risk of epilepsy and nearly half may experience subclinical epileptic activity -- disrupted electrical activity in the brain that doesn't result in a seizure but which can be measured by electroencephalogram (EEG) or other brain scan technology.

In a recent feasibility study, clinician-scientists at Beth Israel Deaconess Medical Center (BIDMC) tested an anti-epileptic drug for its potential impact on the brain activity of patients with mild Alzheimer's disease. The team, led by Daniel Z. Press, MD, of the Berenson-Allen Center for Non-invasive Brain Stimulation at BIDMC, documented changes in patients' EEGs that suggest the drug could have a beneficial effect. The research was published in the Journal of Alzheimer's Disease.

"In the field of Alzheimer's disease research, there has been a major search for drugs to slow its progression," said Press, an Instructor of Neurology in the Cognitive Neurology Unit at BIDMC and an Associate Professor of Neurology at Harvard Medical School. "If this abnormal electrical activity is leading to more damage, then suppressing it could potentially slow the progression of the disease."

In this double-blind within-subject study, a small group of patients with mild Alzheimer's disease visited BIDMC three times. At each visit, patients were given a baseline (EEG) to measure the electrical activity in the brain. Next, patients were given injections containing either inactive placebo or the anti-seizure drug levetiracetam, at either a low dose (2.5 mg/kg) or a higher dose (7.5 mg/kg). Neither patients nor medical professionals knew which injections patients were receiving, but each patient eventually got one of each type, in a random order.

After receiving the injection, patients underwent another EEG, then magnetic resonance imaging (MRI) -- which measures blood flow in the brain, another way to quantify brain activity and determine where in the brain it is taking place. Finally, patients took a standardized cognitive test, designed to measure memory, executive functioning, naming, visuospatial ability and semantic function -- capabilities all affected by Alzheimer's disease.

In the seven patients able to complete the study protocol successfully, Press and colleagues analyzed changes in their EEGs. (Blood flow analysis from the MRI data is still underway.) Overall, higher doses of the anti-seizure drug appeared to normalize abnormalities seen in the patients' EEG profiles. That is, researchers saw overall increases in brain wave frequencies that had been abnormally low in Alzheimer's disease patients prior to receiving the higher dose of levetiracetam, and, likewise, saw decreases in those that had been abnormally high.

"It's worth noting, we did not demonstrate any improvement in cognitive function after a single dose of medication in this study," said Press. "It's too early to use the drug widely, but we're preparing for a larger, longer study."

The risk of developing Alzheimer's disease increases sharply with age. Today, it affects more than 5 million Americans, a figure that is projected to reach 16 million by 2050 as the population ages. In recent years, researchers have focused on developing techniques to clear the brain of amyloid and tau protein plaques that build up and wreak havoc in the brains of patients with Alzheimer's disease.

"These strategies have not led to new therapies to date," said Press. "There have been a lot of disappointments. So our findings represent an interesting new avenue."

---

News Source:
Beth Israel Deaconess Medical Center.

Drug discovery: Alzheimer's and Parkinson's spurred by same enzyme

Alzheimer's disease and Parkinson's disease are not the same. They affect different regions of the brain and have distinct genetic and environmental risk factors.

But at the biochemical level, these two neurodegenerative diseases start to look similar. That's how Emory scientists led by Keqiang Ye, PhD, landed on a potential drug target for Parkinson's.

In both Alzheimer's (AD) and Parkinson's (PD), a sticky protein forms toxic clumps in brain cells. In AD, the troublemaker inside cells is called tau, making up neurofibrillary tangles. In PD, the sticky protein is alpha-synuclein, forming Lewy bodies.

Ye and his colleagues had previously identified an enzyme (asparagine endopeptidase or AEP) that trims tau in a way that makes it more sticky and toxic. Drugs that inhibit AEP have beneficial effects in Alzheimer's animal models.

In a new Nature Structural and Molecular Biology paper, Emory researchers show that AEP acts in the same way toward alpha-synuclein.

"In Parkinson's, alpha-synuclein behaves much like Tau in Alzheimer's," Ye says. "We reasoned that if AEP cuts Tau, it's very likely that it will cut alpha-synuclein too."

A particular chunk of alpha-synuclein produced by AEP's scissors can be found in samples of brain tissue from patients with PD, but not in control samples, Ye's team found.

In control brain samples AEP was confined to lysosomes, parts of the cell with a garbage disposal function. But in PD samples, AEP was leaking out of the lysosomes to the rest of the cell.

The researchers also observed that the chunk of alpha-synuclein generated by AEP is more likely to aggregate into clumps than the full length protein, and is more toxic when introduced into cells or mouse brains. In addition, alpha-synuclein mutated so that AEP can't cut it is less toxic.

Ye cautions that AEP is not the only enzyme that cuts alpha-synuclein into various toxic pieces, and the full-length alpha-synuclein protein is still able to aggregate and cause harm. Nevertheless, he says his team is moving on to testing drugs that inhibit AEP in Parkinson's animal models.

---

News Source:
Emory Health Sciences.

Extra-virgin olive oil preserves memory, protects brain against Alzheimer's

The Mediterranean diet, rich in plant-based foods, is associated with a variety of health benefits, including a lower incidence of dementia. Now, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) have identified a specific ingredient that protects against cognitive decline: extra-virgin olive oil, a major component of the Mediterranean diet. In a study published online June 21 in the Annals of Clinical and Translational Neurology, the researchers show that the consumption of extra-virgin olive oil protects memory and learning ability and reduces the formation of amyloid-beta plaques and neurofibrillary tangles in the brain -- classic markers of Alzheimer's disease.

The Temple team also identified the mechanisms underlying the protective effects of extra-virgin olive oil. "We found that olive oil reduces brain inflammation but most importantly activates a process known as autophagy," explained senior investigator Domenico Praticò, MD, Professor in the Departments of Pharmacology and Microbiology and the Center for Translational Medicine at LKSOM. Autophagy is the process by which cells break down and clear out intracellular debris and toxins, such as amyloid plaques and tau tangles.

"Brain cells from mice fed diets enriched with extra-virgin olive oil had higher levels of autophagy and reduced levels of amyloid plaques and phosphorylated tau," Dr. Praticò said. The latter substance, phosphorylated tau, is responsible for neurofibrillary tangles, which are suspected of contributing to the nerve cell dysfunction in the brain that is responsible for Alzheimer's memory symptoms.

Previous studies have suggested that the widespread use of extra-virgin olive oil in the diets of people living in the Mediterranean areas is largely responsible for the many health benefits linked to the Mediterranean diet. "The thinking is that extra-virgin olive oil is better than fruits and vegetables alone, and as a monounsaturated vegetable fat it is healthier than saturated animal fats," according to Dr. Praticò.

In order to investigate the relationship between extra-virgin olive oil and dementia, Dr. Praticò and colleagues used a well-established Alzheimer's disease mouse model. Known as a triple transgenic model, the animals develop three key characteristics of the disease: memory impairment, amyloid plagues, and neurofibrillary tangles.

The researchers divided the animals into two groups, one that received a chow diet enriched with extra-virgin olive oil and one that received the regular chow diet without it. The olive oil was introduced into the diet when the mice were six months old, before symptoms of Alzheimer's disease begin to emerge in the animal model.

In overall appearance, there was no difference between the two groups of animals. However, at age 9 months and 12 months, mice on the extra virgin olive oil-enriched diet performed significantly better on tests designed to evaluate working memory, spatial memory, and learning abilities.

Studies of brain tissue from both groups of mice revealed dramatic differences in nerve cell appearance and function.

"One thing that stood out immediately was synaptic integrity," Dr. Praticò said. The integrity of the connections between neurons, known as synapses, were preserved in animals on the extra-virgin olive oil diet. In addition, compared to mice on a regular diet, brain cells from animals in the olive oil group showed a dramatic increase in nerve cell autophagy activation, which was ultimately responsible for the reduction in levels of amyloid plaques and phosphorylated tau.

"This is an exciting finding for us," explained Dr. Praticò. "Thanks to the autophagy activation, memory and synaptic integrity were preserved, and the pathological effects in animals otherwise destined to develop Alzheimer's disease were significantly reduced. This is a very important discovery, since we suspect that a reduction in autophagy marks the beginning of Alzheimer's disease."

Dr. Praticò and colleagues plan next to investigate the effects of introducing extra-virgin olive oil into the diet of the same mice at 12 months of age, when they have already developed plaques and tangles. "Usually when a patient sees a doctor for suspected symptoms of dementia, the disease is already present," Dr. Praticò added. "We want to know whether olive oil added at a later time point in the diet can stop or reverse the disease."

---

News Source:
Temple University Health System

Eyewitness recollection easily distorted by the views of others

IT is human nature to give added credence to the views of family and friends. But this could lead to inaccurate eyewitness statements in court cases and therefore potential miscarriages of justice, argues a University of Huddersfield lecturer, who is calling on police and the courts to take this factor into account.

Dara Mojtahedi -- who lectures in forensic psychology -- has been carrying out innovative research into the reliability of eyewitness statements and has been disseminating his findings at conferences and during talks with police.

During an earlier phase of research he screened footage of an actual violent incident to groups of "witnesses" -- specially recruited volunteers. Some of them were allowed to confer, and it was found that many people's recollection of what they saw was readily distorted by comments from others, including dummy eyewitnesses who purposely suggested that the wrong man had started the fight.

This resulted in many inaccurate and misleading statements from people susceptible to being influenced by others.

Now Dara has developed the project, in order to discover the extent of what he describes as "co-witness familiarity on statement similarity."

He recruited 420 participants. They were placed in groups that included relations or people who had known each other for at least three months. They then watched the fight footage and held a discussion before giving individual statements privately. It was found that the post-event discussions significantly increased the level of statement similarity when the co-witnesses had a pre-existing relationship.

One reason the findings are important is that studies have shown that 86 per cent of eyewitnesses are known to each other, meaning there is enormous scope for misleading statements to be made.

As a psychologist, Dara Mojtahedi -- who is completing his PhD on eyewitness reliability -- was unsurprised by the findings of his latest experiment.

"When we encounter information from a stranger, we have no background knowledge of them to help us decide on whether they are more likely to be correct than we are. But with friends and family members, we have known them for a long time and it is a natural process that when we like someone we spend less time questioning and criticising their reliability and accuracy."

Dara has presented his research at academic events, such as the recent Forensic Psychology in Canada Conference, held in Ottawa, and at the British Psychological Society in Bristol. Also, he is supervising Master's students who are writing dissertations in the subject area.

But he is particularly determined that his findings about eyewitness reliability and especially co-witness familiarity should make an impact on police investigation and court procedures.

"A big question that police officers, lawyers and indeed jurors should be asking is, did you witness this incident with friends or did you witness it with strangers?" said Dara.

He has recently presented his work to West Yorkshire Police and his ideas were well-received. "This research is really aimed at officers and at jurors rather than an academic audience," he said.

---

News Source:
University of Huddersfield.