Triple play in science communication

We are highlighting Emory BCDB graduate student Emma D’Agostino, who is a rare triple play in the realm of science communication. Emma has her own blog, where she talks about what it’s like to have cystic fibrosis. Recent posts have discussed the science of the disease and how she makes complicated treatment decisions together with her doctors. She’s an advisor to the Cystic Fibrosis Foundation on patient safety, communicating research and including the CF community Read more

Deep brain stimulation for narcolepsy: proof of concept in mouse model

Emory neurosurgeon Jon Willie and colleagues recently published a paper on deep brain stimulation in a mouse model of narcolepsy with cataplexy. Nobody has ever tried treating narcolepsy in humans with deep brain stimulation (DBS), and the approach is still at the “proof of concept” stage, Willie says. People with the “classic” type 1 form of narcolepsy have persistent daytime sleepiness and disrupted nighttime sleep, along with cataplexy (a loss of muscle tone in response Read more

In current vaccine research, adjuvants are no secret

Visionary immunologist Charlie Janeway was known for calling adjuvants – vaccine additives that enhance the immune response – a “dirty little secret.” Janeway’s point was that foreign antigens, by themselves, were unable to stimulate the components of the adaptive immune system (T and B cells) without signals from the innate immune system. Adjuvants facilitate that help. By now, adjuvants are hardly a secret, looking at some of the research that has been coming out of Emory Read more

ALS

‘Genetic doppelgangers:’ Emory research provides insight into two neurological puzzles

An international team led by Emory scientists has gained insight into the pathological mechanisms behind two devastating neurodegenerative diseases. The scientists compared the most common inherited form of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) with a rarer disease called spinocerebellar ataxia type 36 (SCA 36).

Both of the diseases are caused by abnormally expanded and strikingly similar DNA repeats. However, ALS progresses quickly, typically killing patients within a year or two, while the disease progression of SCA36 proceeds more slowly over the course of decades. In ALS/FTD it appears that protein products can poison cells in the nervous system. Whether similar protein products exist in SCA36 is not known.

What Zachary McEachin, PhD, and Gary Bassell, PhD, from Emory’s Department of Cell Biology, along with a team of collaborators at Emory, the Mayo Clinic in Jacksonville, Florida, and internationally from Spain and Japan, discovered have provided a new paradigm for thinking about how aberrant protein species are formed.  Regardless of the disparate clinical outcomes between these diseases, this research could broaden the avenue of research toward genetically targeted treatments for such related neurodegenerative diseases.

Their study, published Tuesday in Neuron, provides a guide to types of protein that build up in brain cells in both disorders, and which should be reduced if the new mode of treatment is working in clinical trials.

“We are thinking of these diseases as genetic doppelgängers,” says McEachin, a postdoctoral fellow in Bassell’s lab. “By that, I mean they are genetically similar, but the neurodegeneration progresses differently for each disease. We can use this research to understand each of the respective disorders much better — and hopefully help patients improve their quality of life down the road with better treatments.”

An estimated 16,000 people in the United States have ALS, a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. The most common inherited form of ALS/FTD occurs because there is an abnormally expanded repeat of six DNA “letters” stuck into a gene called c9orf72.

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Posted on by Wayne Drash in Neuro, Uncategorized Leave a comment

Setting the goalposts for ALS clinical trials

In the fight against a relentless neurodegenerative disease such as ALS (amyotrophic lateral sclerosis), a critical question for research is: what is the definition of success?

Emory neurologists, with advice from other experts, have created a new disability rating scale for ALS. This is a set of questions patients or their caregivers answer to gauge how much ALS is eroding someone’s ability to manage daily life. The researchers think it can become a resource for testing new treatments for ALS in clinical trials.

The research used to develop the new rating scale was published on December 30 in JAMA Neurology. The rating scale itself will be available on the Emory ALS Center web site.

ALS’s attack on motor neurons makes it progressively more difficult to accomplish tasks such as household chores, daily hygiene, and eventually speaking and eating. Some patients live a year or two after diagnosis, some live ten.

Christina Fournier, MD

“If our goal in clinical trials is to have that decline happen more slowly, how we measure it matters,” says lead author Christina Fournier, MD, assistant professor of neurology at Emory University School of Medicine and co-director of Emory’s ALS Center.

Update: see Fournier’s comments to Medscape/Reuters Health here.

The current standard outcome measure is the ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised). While widely accepted in the field, the ALSFRS-R has some uneven aspects, or nonlinear weighting, which become problems when it is used to determine drug approval.

One example: a patient’s score will decline 3 points if they change from climbing stairs normally to holding a handrail, and will decline the same amount if they change from normal dressing and hygiene to being unable to dress or perform hygiene tasks without assistance. So 3 points can represent small or large changes in their lives. Also, the ALSFRS-R can change depending on symptom management, rather than underlying biology.

To put this in perspective, the most recent drug to be approved by the FDA (edaravone) displayed an effect size of 2.5 points – and the same drug faced resistance from European regulators. According to the Wall Street Journal, about 20 drugs are in clinical testing for ALS and 5 are in the late stages of development. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

Rethinking the role of an aggregation-prone protein in ALS

Anyone studying neuroscience will notice that many neurodegenerative diseases seem to have their own sticky, possibly toxic protein. This protein tends to aggregate, or clump together, in or near the cells affected by the disease.

Picture a glass of milk left in a warm place for several days. Yuck. That is the macro version of the microscopic clumps scientists believe are bothering the brain. For many diseases, there is a debate: are the clumps by themselves toxic to neurons, or a byproduct of something else killing the cells?

Parkinson’s disease has one of the pesky proteins: alpha-synuclein. Alzheimer’s disease has two: beta-amyloid outside cells and tau inside. ALS (amyotrophic lateral sclerosis) has at least three.*

One of them, TDP-43, is found in protein aggregates in most forms of ALS, both familial and sporadic. Mutations in the TDP-43 gene also account for a small fraction of both familial and sporadic forms of ALS. This suggests that even the normal protein can create problems, but a mutated version can accelerate the disease. In addition, TDP-43 aggregates have been connected with other diseases such as frontotemporal dementia.

Again, it’s not clear whether the aggregates themselves are toxic, or whether it’s more a matter of TDP-43, which appears to regulate RNA processing, is not doing what it’s supposed to in the cell.

TDP-43 protein is mobile within motor neurons.

Emory cell biologists Claudia Fallini and Wilfried Rossoll have been probing the effects of tweaking TDP-43 levels in motor neurons, the cell type vulnerable to degeneration in ALS. They find that motor neurons may be more sensitive to changes in TDP-43 levels than other neurons, which may explain why ALS selectively affects motor neurons.

The results were published in Human Molecular Genetics.

Fallini was able to obtain a movie of fluorescently-tagged TDP-43 “granules” moving around in live motor neurons. Importantly: this is healthy/functional, not aggregated/ toxic protein. The finding that TDP-43 is mobile implies that it has something to do with transporting RNAs around the cell, rather than only functioning in the nucleus.

“Our data point to the hypothesis that TDP-43 increased localization in the cytoplasm is the early trigger of toxicity, followed by protein aggregation,” Fallini says. “Because motor neurons are unique neurons due to their high degree of polarization, we believe they might be more sensitive to alterations in TDP-43 functions in the cytoplasm or the axon.”

In particular, the researchers found that elevated levels of TDP-43 provoke motor neurons to shut down axon outgrowth. They focused on a role for the C-terminal end of TDP-43 in this effect.

“Nobody had looked at TDP-43 specifically in motor neurons before,” she says. “Our paper for the first time shows the localization and axonal transport of TDP-43, and the effects of TDP-43 altered levels on motor neuron morphology.”

*Another ALS protein, SOD1 (superoxide dismutase), apparently forms toxic aggregates when mutated in some cases of familial ALS. At Emory, Terrell Brotherton and Jonathan Glass have been investigating these forms of SOD. The third protein, FUS, has similar properties to TDP-43.

 

Posted on by Quinn Eastman in Neuro Leave a comment

A concussion is more than just a headache

 

Ken Mautner, MD

To ensure better management of sports concussions, physicians at Emory Sports Medicine Center have incorporated Immediate Post-concussion Assessment and Cognitive Testing (ImPACT) into their program for high school athletes.

 

Concussions occur in about 10 percent of all athletes in contact sports.

They are caused by sudden and violent rocking of the brain inside the skull from a traumatic blow to the head or upper body.

Symptoms vary in length of time and may include amnesia, disorientation, confusion, fogginess, headache, blurred vision, nausea, fatigue and sometimes loss of consciousness.

Ken Mautner, MD, sports medicine physician and assistant professor in the Department of Orthopaedics at Emory University School of Medicine, says that most athletes recover completely from concussions as long as they are not returned back to play too soon.

Repeated concussions are cumulative and may cause critical damage to the brain.  Studies have indicated a possible association with frequent or untreated concussions and development of dementia, depression and, most recently, ALS (Lou Gehrig’s Disease).  Going back to the sport too soon, before the brain recovers, leaves athletes vulnerable to repeat concussions.

Athletes in the ImPACT program take a 20-minuted baseline test on a computer that measures brain processing such as speed, memory, and visual motor skills.

Each individual’s data are stored in a computer file. In the event of injury, the athlete will take the ImPACT test in the days following concussion.  Post-concussion data are then compared to baseline data to help determine the severity and effects of the injury.

Mautner says that data from ImPACT combined with a thorough history and physical exam is the best way to prevent athletes from getting “back in the game” too soon.

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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

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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