Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more

Alzheimer’s Disease

Redirecting beta-amyloid production in Alzheimer’s

Pharmacologist Thomas Kukar is exploring a strategy to subtly redirect the enzyme that produces beta-amyloid, which makes up the plaques appearing in the brains of Alzheimer’s patients.

Thomas Kukar, PhD

Preventing beta-amyloid production could be an ideal way to head off Alzheimer’s, but the reason why a subtle approach is necessary was illustrated last year by disappointing results from a phase III clinical trial. The experimental drug semagacestat was designed to block the enzyme gamma-secretase, which “chomps” on the amyloid precursor protein (APP), usually producing an innocuous fragment but sometimes producing toxic beta-amyloid.

Gamma-secretase also is involved in processing a bunch of other vital proteins, such as Notch, central to an important developmental signaling pathway. Scientists suspect that this is one of the reasons why trial participants who received semagacestat did worse on cognitive/daily function measures than controls and saw an increase in skin cancer, leading watchdogs to halt the study.

While a postdoc at Mayo Clinic Jacksonville and working with Todd Golde and Edward Koo, Kukar identified compounds – gamma-secretase modulators or GSM’s — that may offer an alternative.

“We are looking at a strategy that’s different from global gamma-secretase inhibition,” he says. “The approach is: don’t inhibit the enzyme overall, but instead modify its activity so that it makes less toxic products.”

Gamma-secretase chomps on amyloid precursor protein, and how it does so determines whether toxic beta-amyloid is produced. It also processes several other proteins important for brain function.

This line of inquiry started when it was discovered that some anti-inflammatory drugs also could reduce beta-amyloid production. Then, the crosslinkable probes Kukar was using to identify which part of the gamma-secretase fish was doing the chomping ended up binding the bait (APP). This suggested that drugs might be able to change how the enzyme acts on one protein, APP, but not others.

Now an assistant professor at Emory, he is examining in greater detail how gamma-secretase modulators work. Two recent papers he co-authored in Journal of Biological Chemistry show 1) how the proteins that gamma-secretase chews up are “anchored” in the membrane and 2) how selective GSM’s can be on amyloid precursor protein.

Although clinical studies of a “first generation” GSM, tarenflurbil, were also stopped after negative results, Kukar says GSM’s still haven’t really been tested adequately, since researchers do not know if the drugs are really having an effect on beta-amyloid levels in the brain. Newer compounds coming through the pharmaceutical pipeline are more potent and more able to get into the brain. While looking for more potent GSM’s is critical, Kukar says it’s equally as important to understand how gamma-secretase works to understand its biology.

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Default daydreaming linked to Alzheimer’s amyloid

Cut the daydreaming, and you can lessen the neurodegenerative burden on your brain? Surprising new research suggests that how we use our brains may influence which parts of the brain are most vulnerable to amyloid-beta (Aβ), which forms plaques in the brain in Alzheimer’s disease.

Lary Walker, PhD, has been investigating why amyloid accumulation seems to lead to Alzheimer's in humans but not non-human primates

In the June issue of Nature Neuroscience, Yerkes National Primate Research Center scientist Lary Walker and Mathias Jucker from the Hertie Institute for Clinical Brain Research in Tübingen, Germany summarize intriguing recent research on regional brain activity and Aβ accumulation.

Neuroscientists have described a set of interconnected brain regions called the “default mode network,” which appear to be activated during activities such as introspection, memory retrieval, daydreaming and imagination. When a person engages in an externally directed task, such as reading, playing a musical instrument, or solving puzzles, activity in the default network decreases.

The Nature Neuroscience paper, from David Holtzman and colleagues at Washington University St. Louis, suggests prolonged metabolic activation of the default-mode network in mice can render that system vulnerable to Aβ by accelerating Aβ deposition and plaque growth.

This line of research turns the “use it or lose it” idea upside-down. Use the default network too much, and the effect may be harmful. Walker and Jucker suggest why education, for example, appears to head off Alzheimer’s in epidemiological studies: by getting the brain involved in non-default/externally directed mode activity.

This idea has additional consequences that can be tested in the clinic. For example, by increasing metabolism in default-mode regions of the brain, prolonged wakefulness caused by sleep disorders might increase Aβ burden.

Walker and Jucker conclude: “Meanwhile, perhaps the best strategy for lessening soluble Aβ in the default mode network may be simply to work diligently, play hard and sleep well.”

 

Posted on by Quinn Eastman in Neuro 2 Comments

Internationally Recognized Violinist Raises Money for Alzheimer’s Research

Virtuoso Robert McDuffie Performs at the Schwartz Center November 19

On November 19, world famous virtuoso Robert McDuffie will dedicate the Atlanta premiere performance of Philip Glass’ “The American Four Seasons” to the Emory Alzheimer’s Disease Research Center (ADRC) and to his late father-in-law, Mack Taylor, who was a talented musician and business leader in the Atlanta community.

The event,  “A Family Affair” Dinner and Concert at Emory University, will honor Dr. Allan Levey, Director of the Emory ADRC and chair of the Neurology Department, and Dr. Stuart Zola, Associate Director of the ADRC and director of the Yerkes National Primate Research Center. Dinner guests will gather at the Carlos Museum and proceed to the Schwartz Center for Performing Arts for the concert featuring McDuffie.

The Taylor family, including Gretchen and Andrew Taylor, Camille and Robert McDuffie and Mary Rose Taylor, are serving as chairs of this inaugural event to acknowledge Alzheimer’s toll on the entire family.

Honorary Chairs Stuart Zola and Allan Levey, Directors of Emory ADRC

“I’m incredibly honored to dedicate my performance to Dr. Levey and his team of scientists at Emory’s Alzheimer’s Disease Research Center,” says McDuffie. “For 15 years, they took great care of my wonderful father-in-law Mack Taylor, who suffered from this dreadful disease.”

Alzheimer’s disease, the most common form of dementia among older adults, affects parts of the brain that control thinking, remembering and making decisions.

The incidence of Alzheimer’s is growing at an alarming rate. According to the CDC, it recently surpassed diabetes as the 6th leading cause of death among American adults. Funds raised will go toward education and collaboration so that others may learn and benefit from the work of Emory’s ADRC.

“Since millions of baby boomers are entering late adulthood, we expect the number of patients with Alzheimer’s disease to increase drastically over the next several decades,” says Levey. “We have an opportunity to build on the momentum of much exciting research progress in early identification of disease and development of many new treatment strategies that offer promise to slow its progression and lead to prevention.”

Emory’s ADRC is a National Institute on Aging funded center focused on clinical trials and research for Alzheimer’s disease. The only comprehensive program in Georgia and one of only 32 nationwide, the Emory ADRC is seeking cures through basic laboratory research, bringing new diagnostic methods and treatments into the clinic, and providing patients and their families with state-of-the-art care and access to cutting-edge advances.

The $150 tickets ($100 is tax deductible) are available at www.alumni.emory.edu/ADRC-AFamilyAffair or by calling 404-727-5713.

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Welcome to the heat: Alzheimer’s Breakthrough Ride

Thomas Kukar, a new Emory faculty member in pharmacology, is participating in a charity bicycle ride for Alzheimer’s disease research called the Alzheimer’s Breakthrough Ride. On Thursday and Friday, he will be riding from Oklahoma City, OK to Wichita, KS. Tomorrow’s ride is 100 miles, and it’s supposed to be 97°F in Wichita.

Thomas Kukar, PhD

Kukar’s willingness to take on this challenge indicates that he shouldn’t have too much trouble adjusting to Atlanta’s climate. He comes to Emory from the Mayo Clinic in Jacksonville. There, he investigated potential drugs that could change how the body produces and processes beta-amyloid, a toxic protein fragment that builds up in the brains of people with Alzheimer’s.

The money raised by the bicycle ride goes to the Alzheimer’s Association.

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Alzheimer’s expert weighs in on proposed guidelines

Scans can show beta amyloid, a protein associated with Alzheimer’s disease (right)

For the first time in 25 years, medical experts are proposing new diagnostic criteria aimed at better and earlier detection of Alzheimer’s disease (AD).

The guidelines, proposed by the National Institute on Aging (NIA) and the Alzheimer’s Association, update and revise the current Alzheimer’s criteria with modern technologies and the latest research advances.

According to the Alzheimer’s Association, an estimated 5.3 million Americans have AD, most of them 65 and older. The disease is thought to begin years, possibly even decades, before symptoms are noticeable. But there is no single, generally accepted way to identify the disease in its earliest stages before symptoms are evident.

The new diagnostic guidelines focus on advances in detecting biomarkers for the disease, such as substances found in spinal fluid or appearing on cutting-edge brain imaging scans conducted with PET or MRI.

Emphasis will be on diagnosing early stages of the disease as soon as possible so that patients can take measures to slow the progression or prevent further damage.

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Untangling the mysteries of Alzheimer’s disease

Lary Walker, PhD

Consider this: Alzheimer’s is a uniquely human disorder. But why? Why don’t nonhuman primates, such as monkeys, get Alzheimer’s disease. Monkeys form the senile plaques that are identical to the plaques found in humans. So do other animals.

“Yet, despite the fact that nonhuman primates make this protein that we know is very important in the pathogenesis of Alzheimer’s disease, they don’t develop the full disease,” says Lary Walker, PhD. Walker is an associate professor at Yerkes National Primate Research Center.

“They don’t develop the tangles we associate with Alzheimer’s disease, the neuronal loss, the shrinkage of the brain, and they don’t get demented in the sense that humans do,” says Walker.

When our bodies make a protein, the protein tends to fold into a functional form. But when it comes to Alzheimer’s disease, some proteins misfold, becoming sticky and then combining with one another. In their collective form, the proteins can then form plaques or tangles, the two types of lesions associated with Alzheimer’s disease.

And for some unknown reason, people who have plaques usually go on to form tangles. But people who have tangles don’t always go on to form plaques. No one is sure why. But that’s what researcher Walker wants to find out.

To listen to Walker’s own words about Alzheimer’s disease, access Emory’s new Sound Science podcast.

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A new class of brain-protecting drugs

Pathologist Keqiang Ye has made a series of discoveries recently, arising from his investigations of substances that can mimic the growth factor BDNF (brain-derived neurotrophic factor).

BDNF is a protein produced by the brain that pushes neurons to withstand stress and make new connections. Some neuroscientists have described BDNF as “Miracle Gro for brain cells.”

“BDNF has been studied extensively for its ability to protect neurons vulnerable to degeneration in several diseases, such as ALS, Parkinson’s and Alzheimer’s disease,” Ye says. “The trouble with BDNF is one of delivery. It’s a protein, so it can’t cross the blood-brain barrier and degrades quickly.”

Working with Ye, postdoctoral fellow Sung-Wuk Jang identified a compound called 7,8-dihydroxyflavone that can duplicate BDNF’s effects on neurons and can protect them against damage in animal models of seizure, stroke and Parkinson’s disease. The compound’s selective effects suggest that it could be the founder of a new class of brain-protecting drugs. The results were published in Proceedings of the National Academy of Sciences.

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Posted on by Quinn Eastman in Neuro 1 Comment

World Alzheimer’s Day – brain health tips from Emory

Today is World Alzheimer’s Day 2009 and Emory’s Alzheimer’s Disease Research Center is part of an effort nationwide to address this disease through research and state-of-the-art care for patients.

Allan Levey, MD, PhD, chair of Emory’s Department of Neurology and an Alzheimer’s researcher and clinician, says millions of baby boomers are entering late adulthood and experts expect the number of patients with Alzheimer’s disease to increase drastically over the next several decades. Prevention and early detection are extremely important, he says.

Emory’s Center is a National Institute on Aging funded center focused on clinical trials and research for Alzheimer’s disease. It is the only comprehensive program in Georgia and one of only 32 nationwide.

Levey, who directs the Center, offers the tips for good brain health:

Stay socially active
Remaining socially engaged in activities that stimulate the mind and body can reduce stress levels and help maintain healthy connections among brain cells.

Stay active, say experts

Stay active, say experts

Be physically active
Exercising your body regularly is vital for maintaining good blood flow to the brain and encouraging the growth of new brain cells.

Stay mentally active
Your brain needs mental stimulation to allow it to function at its peak. Research shows that keeping the brain active helps increase its vigor and may strengthen brain cells and the connections between them, and may even generate new ones.

Protect your head
Injury to the head can increase your risk of dementia as you get older. Make sure you wear a helmet when you ride a bike, skate, ski or engage in any activity where you may injure yourself.

Eat brain healthy foods
The brain, like the heart, needs the proper balance of nutrients, including protein and sugar, to optimally function. According to current research, certain foods appear to protect brain cells so increase your intake of these protective foods.

Levey says scientists are finding more clues that high blood pressure, high cholesterol and diabetes may increase a person’s risk of getting Alzheimer’s disease. He says to keep your weight in a healthy range, lower your cholesterol if it is high and maintain control of your blood glucose and blood pressure.

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Discerning a prelude to Alzheimer’s

Imagine that an elderly relative has been having difficulty remembering appointments and acquaintances’ names, or even what happened yesterday. Memory problems can be signs of mild cognitive impairment (MCI), a prelude to Alzheimer’s disease.

Scientists believe that the outward effects of the slow damage that comes from Alzheimer’s only show up after the damage has been accumulating for years. However, memory difficulties can also be the result of stress or another health problem. Patients thought to have MCI at an initial doctor’s visit sometimes improve later.

That’s why researchers at Emory’s Alzheimer’s Disease Research Center have been testing noninvasive imaging approaches to distinguishing MCI from healthy aging and Alzheimer’s. Their goal is to identify individuals at risk of developing Alzheimer’s, at a time when intervention can make a difference in how the disease progresses.

“We believe that imaging technology may help us find the signature changes in brain structure that are specific to MCI,” says Felicia Goldstein, PhD, associate professor of neurology.

Color coded diffusion tensor image (DTI) of a brain section from a healthy individual (A) showed a thick and intact corpus callosum (orange color), a white matter fiber bundle connecting left and right hemisphere as illustrated in the 3D rendering of the tractograph derived from DTI (B). However, a thin and narrow corpus callosum is seen in an AD patient (C) due to the degeneration of this white matter structure

Color coded diffusion tensor image (DTI) of a brain section from a healthy individual (A) showed a thick and intact corpus callosum (orange color). However, a thin and narrow corpus callosum is seen in an AD patient (C) due to the degeneration of this white matter structure. Courtesy of Hui Mao.

Two recent papers highlight the use of diffusion tensor imaging, an advanced form of magnetic resonance imaging.

The first paper was published by Brain Imaging and Behavior with Goldstein as first author, in collaboration with Hui Mao, PhD, associate professor of radiology, and ADRC colleagues.

It examines diffusion tensor imaging as a way to probe the integrity of the brain’s white matter, and compares it with tests of memory and behavior traditionally used to diagnose MCI and Alzheimer’s.

White matter appears white because of the density of axons, the signal-carrying cables allowing communication between different brain regions responsible for complicated tasks such as language and memory.

Diffusion tensor imaging allows researchers to see white matter by gauging the ability of water to diffuse in different directions, because a bundle of axons tends to restrict the movement of water in the brain.

Goldstein and her colleagues found that patients diagnosed with “amnestic” MCI showed greater loss of white matter integrity in a certain part of the brain — the medial temporal lobe – than cognitively normal controls of similar age. This loss of white matter was linked with poor recall of words and stories.

The second paper, with Liya Wang, PhD, a senior research associate in Mao’s laboratory as first author, was published by the American Journal of Neuroradiology in April. Here the authors try combining probing white matter integrity with a MRI measure of whether the brain has shrunk as a result of disease.

Combining the two methods improves the accuracy of MCI diagnosis with respect to either alone, the authors found.

Mao notes that Emory has been participating in a multi-center study called ADNI (Alzheimer’s Disease Neuroimaging Initiative). Diffusion tensor imaging is a relatively new technique and could add information to future large-scale Alzheimer’s imaging studies, he says.

The Dana Foundation’s BrainWorks newsletter had an article recently on Alzheimer’s and brain imaging.

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Emory and Georgia Tech

Over the past twenty years, the research partnership between Emory University and the Georgia Institute of Technology has developed into one of the leading bioengineering and biomedical research and educational programs in the nation. In recent years this partnership has resulted in the development of several pieces of diagnostic and medical-assistant technology, with medical experts on the Emory side working with engineers on the Georgia Tech side.

An example of this collaboration is the El-E robot, designed to perform simple tasks such as opening drawers and retrieving objects. Clinicians at Emory’s School of Medicine and engineers at Georgia Tech created the 5½-foot-tall machine, which glides across the floor on wheels and takes direction from a laser pointer that users can control in a variety of ways, depending on their preferences and capabilities. El-E is no mere toy, however: The machine could help patients with significant motor impairments, such as sufferers of ALS, maintain their independence and help relieve physical and financial burdens faced by caregivers.

 

Another result of the Emory-Georgia Tech collaboration is DETECT, a portable device capable of detecting the earliest stage of Alzheimer’s disease, mild cognitive impairment, in any environment. DETECT has a helmet device that includes an LCD display in a visor, along with a computer and noise-reduction headphones. DETECT gives the patient a battery of words and pictures to assess cognitive abilities—reaction time and memory capabilities. The low-cost test takes approximately 10 minutes. The device was co-developed by emergency medicine physician David Wright, and Michelle LaPlaca, a scientist in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory.

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