The journey of a marathon sleeper

A marathon sleeper who got away left some clues for Emory and University of Florida scientists to Read more

A push for reproducibility in biomedical research

At Emory, several scientists are making greater efforts to push forward to improve scientific research and combat what is being called “the reproducibility crisis.” Guest post from Erica Read more

Exosomes as potential biomarkers of radiation exposure

Exosomes = potential biomarkers of radiation in the Read more

Neuro

Blood biomarkers may help predict risk in stroke and TBI


Biomarkers circulating in the bloodstream may serve as a predictive window for recurrent stroke risk and also help doctors accurately assess what is happening in the brains of patients with acute traumatic brain injury (TBI).

Michael Frankel, MD

Researchers at Emory University School of Medicine, led by principal investigator Michael Frankel, MD, Emory professor of neurology and director of Grady Memorial Hospital’s Marcus Stroke & Neuroscience Center, are studying biomarkers as part of two ancillary studies of blood samples using two grants from the National Institutes of Health.

In the $1.47 million, four-year grant called “Biomarkers of Ischemic Outcomes in Intracranial Stenosis” (BIOSIS), Emory researchers are analyzing blood samples from 451 patients from around the country who were enrolled in a study known as SAMMPRIS (Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis), the first randomized, multicenter clinical trial designed to test whether stenting intracranial arteries would prevent recurrent stroke.

Researchers in the SAMMPRIS study recently published their results in the New England Journal of Medicine, showing that medical management was more effective than stenting in preventing recurrent strokes in these patients. Frankel’s BIOSIS research team is using blood samples from these same patients to continue learning more about the molecular biology of stroke to predict risk of a stroke occurring in the future.

“Our goal is to learn more about stroke by studying proteins and cells in the blood that reflect the severity of disease in arteries that leads to stroke. If we can test blood samples for proteins and cells that put patients at high risk for stroke, we can better tailor treatment for those patients,” says Frankel.

Patients with narrowed brain arteries, known as intracranial stenosis, have a particularly high risk of disease leading to stroke. At least one in four of the 795,000 Americans who have a stroke each year will have another stroke within their lifetime. Within five years of a first stroke, the risk for another stroke can increase more than 40 percent. Recurrent strokes often have a higher rate of death and disability because parts of the brain already injured by the original stroke may not be as resilient.

The other study, “Biomarkers of Injury and Outcome in ProTECT III” (BIO-ProTECT)” is a $2.6 million, five-year NIH grant in which Frankel’s team will use blood to determine what is happening in the brain of patients with acute TBI.  The blood samples are from patients enrolled in the multicenter clinical trial ProTECT III (Progesterone for Traumatic brain injury, Experimental Clinical Treatment), led by Emory Emergency Medicine Professor, David Wright, MD, to assesses the use of progesterone to treat TBI in 1,140 patients at 17 centers nationwide.

In the BIO-ProTECT study, Emory is collaborating with the Medical University of South Carolina, the University of Pittsburgh, the University of Michigan and Banyan Biomarkers.

TBI is the leading cause of death and disability among young adults in the US and worldwide. According to the Centers for Disease Control and Prevention, approximately 1.4 million Americans sustain a traumatic brain injury each year, leading to 275,000 hospitalizations, 80,000 disabilities, and 52,000 deaths.

Acute TBI leads to a cascade of cellular events set in motion by the initial injury that ultimately lead to cerebral edema (swelling of the brain), cellular disruption and sometimes death. Tissue breakdown leads to the release of proteins into the bloodstream. These proteins may serve as useful biomarkers of the severity of the injury and perhaps provide useful information about response to treatment.

Using the large patient group in the ProTECT III trial, the researchers hope to validate promising TBI biomarkers as predictors of clinical outcome and also evaluate the relationship between progesterone treatment, biomarker levels and outcome.

“If we can better determine the amount of brain injury with blood samples, we can use blood to help doctors better assess prognosis for recovery, and, hopefully whether a patient will respond to treatment with progesterone,” says Frankel.

Posted on by Juliette Merchant in Neuro Leave a comment

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.

Posted on by Quinn Eastman in Neuro Leave a comment

Blue pill or red pill? Brains need both for memory consolidation

In the 1999 film The Matrix, the character Neo is offered a choice between a blue pill (to forget) and a red pill (to remember). If only neuroscience was that simple! It may be that neurons need both red and blue, possibly an elaborate dance of molecules, for a fragile memory to lodge itself in the brain.

Neuroscientists Kimberly Maguschak and Kerry Ressler provide a glimpse into this process with their recent paper in the Journal of Neuroscience.

Ressler is both a psychiatrist and a Howard Hughes Medical Institute-supported researcher with a laboratory at Yerkes National Primate Research Center. Maguschak completed her doctorate at Emory and is now a postdoc with Guoping Feng at MIT.

The research is a follow-up on their work probing the role of beta-catenin in fear memory formation. We previously described this protein as acting “like a Velcro strap”, attaching cells’ internal skeletons to proteins on their external membranes that help them adhere to other cells. If brain cells need to change shape and form new connections for memories to be consolidated, we can see how this kind of molecule would be important.

Beta-catenin is also central to a signaling circuit that maintains stem cells and prods an embryo to separate into front and back or top and bottom. This circuit is called “Wnt” (the name is a fusion of the fruit fly gene wingless and a cancer-promoting gene discovered in mice, originally called Int-1).

Maguschak and Ressler wanted to assess the role Wnt signals play in learning and memory. The model system was the same as in their previous work: if mice are electrically shocked just after they hear a certain tone, they gradually learn to fear that tone, and they show that fear by freezing.

Kerry Ressler, MD, PhD

Maguschak saw that in the amygdala, a part of the brain important for fear responses, Wnt genes are turned down during the learning process temporarily but then come back on. If the mice only hear the tone or only get the shock, the genes’ activities don’t change significantly.

She then introduced proteins that perturb Wnt signaling directly into the amygdala. Extra Wnt injected before training, while it didn’t stop the mice from learning to fear the tone, made that training less likely to “stick.” Two days later, the mice that received Wnt didn’t seem to fear the tone as much.

Here’s the possibly confusing part: a Wnt inhibitor also impaired fear memory consolidation. In effect, both blue and red pills actually interfered with how well memories endured. The authors suggest this is because Wnt signals have to be turned down during fear memory formation but then turned back up so those memories can solidify. The Wnt signals seem to go along with the adhesive interactions of beta-catenin. It looks like beta-catenin’s stickiness also needs to be tuned down and then back up.

The off-then-on-again requirement Maguschak and Ressler observe is reminiscent of results from cell biologist James Zheng’s lab. He and his colleagues saw that the actin cytoskeleton needed to be weakened and then stabilized during long-term potentiation, an enhancement of connections between neurons thought to lie behind learning and memory.

Several laboratories have identified potential drugs that modify beta-catenin/Wnt. These new results suggest that the timing of when and how to use such drugs to enhance memory may critically important to consider, Ressler says.

“To interfere with memory formation after trauma or enhance memory formation in people with dementia, researchers will clearly need to attend to the full complexity of the dynamics of synaptic plasticity and memory,” he says.

A nifty link to an animation of Wnt signaling

 

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Neuroinflammation: a different way to look at Parkinson’s disease

Emory physiologist Malu Tansey and her colleagues are using recent insights into the role of inflammation in Parkinson’s disease to envision new treatments. One possible form this treatment strategy could take would be surprisingly simple, and comparable to medications that are approved for rheumatoid arthritis.

Malu Tansey, PhD

Understanding the role of inflammation in Parkinson’s requires a shift in focus. Many Parkinson’s researchers understandably emphasize the neurons that make the neurotransmitter dopamine. They’re the cells that are dying or already lost as the disease progresses, leading to tremors, motor difficulties and a variety of other symptoms.

But thinking about the role of inflammation in Parkinson’s means getting familiar with microglia, the immune system’s field reps within the brain. At first, it was thought that the profusion of microglia in the brains of Parkinson’s patients was just a side effect of neurodegeneration. The neurons die, and the microglia come in to try to clean up the debris.

Now it seems like microglia and inflammation might be one of the main events, if not the initiating event.

“Something about the neurons’ metabolic state, whether it’s toxins, oxidative stress, unfolded proteins, or a combination, makes them more sensitive. But inflammation, sustained by the presence of microglia, is what sends them over the edge,” Tansey says.

She says that several recent studies have led to renewed attention to this area:

  1. In vivo PET imaging using a probe for microglia has allowed scientists to see inflammation starting early in the progression of Parkinson’s (see figure below)
  2. Epidemiology studies show that taking ibuprofen regularly is linked to lower incidence of Parkinson’s
  3. Experiments with animal models of genetic susceptibility demonstrate that inflammatory agents like endotoxin can accelerate neurodegeneration
  4. Genomics screens have identified HLA-DR, an immune system gene, as a susceptibility marker for Parkinson’s (Emory’s Stewart Factor was a co-author on this paper)

Popping a few ibuprofen pills everyday for prevention and possibly damaging the stomach along the way is probably not going to work well, Tansey says. It should be possible to identify a more selective way to inhibit microglia, which may be able to inhibit disease progression after it has started.

Activated microglia in the midbrain and striatum of a Parkinson's patient

Targeting TNF (tumor necrosis factor), an important inflammatory signaling molecule, may be one way to go. Anti-TNF agents are already used to treat rheumatoid arthritis and inflammatory bowel disease. This January, Tansey and her co-workers published a paper showing that a gene therapy approach using decoy TNF can reduce neuronal loss in a rat model of Parkinson’s. More recently, her lab has also shown that targeting the gene RGS10 is another way to inhibit microglia and reduce neurodegeneration in the same models.

It is important to note that in the rat studies, they do surgery and put the gene therapy viral vector straight into the brain. She says it might possible to perform peripheral gene therapy with the microglia, or even anti-TNF medical therapy. In terms of mechanism, decoy (technically, dominant negative) TNF is more selective and may avoid the side effects, such as opportunistic infections, of existing anti-TNF agents.

Posted on by Quinn Eastman in Neuro 1 Comment

Autism linked to hundreds of spontaneous genetic mutations

Emory genetic researchers Daniel Moreno De Luca, Christa Lese Martin and David Ledbetter were part of a team that produced a landmark result in autism genetics. The team identified hundreds of regions of the genome where spontaneous mutations are implicated in autism. Spontaneous mutations are those that arise for the first time in an individual, rather than being inherited from parents.

Christa Lese Martin, PhD

The team was led by Matthew State at Yale, and their results were published in the journal Neuron. Moreno De Luca discussed the topic in Spanish on a recent edition of the NPR program Science Friday. The June 10 segment was focused on autism genetics.

The team made an intriguing finding on a segment of chromosome 7. Deletion of the region is associated with Williams syndrome, where individuals can exhibit “striking verbal abilities, highly social personalities and an affinity for music.” Duplication of the same region, they found, is associated with autism.

Daniel Moreno De Luca, MD MSc

Companion studies also shed light on the question of why boys are more likely to develop autism than girls, and begin to outline a network of genes whose activity is altered in the brains of individuals with autism.

Ledbetter is now chief scientific officer at Geisinger Health in Pennsylvania.

 

 

 

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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

Brain enhancement: can and should we do it?

The Emory Center for Ethics and Emory’s Neuroscience Graduate Program recently co-hosted a symposium discussing the ethics of brain-enhancing technologies, both electronic and pharmacological.

Georgia Tech biomedical engineer Steve Potter explained his work harnessing the behavior of neurons grown on a grid of electrodes. The neurons, isolated from rats, produce bursts of electrical signals in various patterns, which can be “tuned” by the inputs they receive.

“The cells want to form circuits and wire themselves up,” he said.

As for future opportunities, he cited the technique of deep brain stimulation as well as clinical trials in progress, including one testing technology developed by the company Neuropace that monitors the brain’s electrical activity for the purpose of suppressing epileptic seizures. Similar technology is being developed to help control prosthetic limbs and could also promote recovery from brain injury or stroke, he said. Eventually, electrical stimulation that is not modulated according to feedback from the brain will be seen as an overly blunt instrument, even “barbaric,” he said.

Mike Kuhar, a neuroscientist at Yerkes National Primate Research Center, introduced the topic of cognitive enhancers or “smart drugs.” He described one particular class of proposed cognitive enhancers, called ampakines, which appear to improve functioning on certain tasks without stimulating signals throughout the brain. Kuhar questioned whether “smart drugs” pose unique challenges, compared to other types of drugs. From a pharmacology perspective, he said there is less distinction between therapy and enhancement, compared to a perspective imposed by regulators or insurance companies. He described three basic concerns: safety (avoiding toxicity or unacceptable side effects), freedom (lack of coercion from governments or employers) and fairness.

“Every drug has side effects,” he said. “There has to be a balance between the benefits versus the risks, and regulation plays an important role in that.”

He identified antidepressants and treatments for attention deficit-hyperactivity disorder or the symptoms of Alzheimer’s disease as already raising similar issues. The FDA has designated mild cognitive impairment associated with aging as an open area for pharmaceutical development, he noted.

James Hughes, a sociologist from Trinity College and executive director of the Institute for Ethics and Emerging Technologies, welcomed new technologies that he said could not only treat disease, but also enhance human capabilities and address social challenges such as criminal rehabilitation. However, he did identify potential “Ulysses problems”, where users of new technologies would need to exercise control and judgment.

In contrast, historian and Judaic scholar Hava Tirosh-Samuelson, from Arizona State University, decried an “overly mechanistic and not culturally-based understanding of what it means to be human.” She described transhumanism as a utopian extension of 19th century utilitarianism as expounded by thinkers such as Jeremy Bentham.

“Is the brain simply a computational machine?” she asked.

The use of military metaphors – such as “the war on cancer” – in the context of mental illness creates the false impression that everything is correctable or even perfectable, she said.

Emory neuroscience program director Yoland Smith said he wants ethics to become a strong component of Emory’s neuroscience program, with similar discussions and debates to come in future years.

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Links between autism and epilepsy

An article in the April 2011 issue of Nature Medicine highlights the mechanistic overlap between autism and epilepsy.

By studying how rare genetic conditions known to coincide with both epilepsy and autism—such as Rett syndrome, fragile X syndrome and tuberous sclerosis—unfold at an early age, neuroscientists are finding that both disorders may alter some of the same neural receptors, signaling molecules and proteins involved in the development of brain cell synapses.

Gary Bassell, PhD

Emory cell biologist Gary Bassell and his colleagues have been taking exactly this approach. Recently they published a paper in Journal of Neuroscience, showing that the protein missing in fragile X syndrome, FMRP, regulates expression of an ion channel linked to epilepsy. This could provide a partial explanation for the link between fragile X syndrome and epilepsy.

The Nature Medicine article also mentions a drug strategy, targeting the mTOR pathway, which Bassell’s group has been exploring with fragile X syndrome.

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New Biological Pathway Identified for PTSD

Emory MedicalHorizon

High blood levels of a hormone produced in response to stress are linked to post-traumatic stress disorder in women but not men, a study from researchers at Emory University and the University of Vermont has found.

The results were published in the Feb. 24 issue of Nature.

The hormone, called PACAP (pituitary adenylate cyclase-activating polypeptide), is known to act throughout the body and the brain, modulating central nervous system activity, metabolism, blood pressure, pain sensitivity and immune function. The identification of PACAP as an indicator of PTSD may lead to new diagnostic tools and eventually, to new treatments for anxiety disorders.


Video on YouTube

“Few biological markers have been available for PTSD or for psychiatric diseases in general,” says first author Kerry Ressler, MD, PhD, associate professor of psychiatry and behavioral sciences at Emory University School of Medicine and a researcher at Yerkes National Primate Research Center. “These results give us a new window into the biology of PTSD.”

Read more @ emoryhealthsciences.org.

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BPH, Inflammation and Depression: Chicken or the Egg

Data collected during a recent study by researchers at Emory University School of Medicine and published in the journal Urology, show a significant link between benign prostatic hyperplasia (BPH) and depression.

Researchers have been aware for a long time that depression is a common illness that accompanies inflammatory diseases such as heart disease, diabetes and cancer.  Recent evidence has suggested that depression also might be associated with BPH, another disease with inflammatory components.

Studies have not directly examined the relationship between depression and BPH explains study investigator, Viraj A. Master, MD, associate director in the Department of Urology at Emory. “BPH and depression both affect a significant number of men worldwide. This is the first study to show a direct association between the two illnesses.”

Study data showed that almost three-quarters of the participants without depression presented with mild or moderate symptoms, while more than two thirds of the depressed patients had moderate or severe symptoms.

The data raises questions about whether the severity of symptoms is due to depression, or if the depression is causing the symptoms to worsen, says lead author, Timothy V. Johnson, MD. He points out that several studies have demonstrated depression in the setting of cardiovascular disease and cancer actually worsens these chronic disease states.

The study also raises the question of whether or not the depression simply causes patients to perceive their symptoms to be much worse than patients with the same degree of illness.

The researchers stress that further studies are imperative to address comorbid depression in the presence of BPH so that treatment can be appropriately managed.

Timothy V. Johnson, lead author, was an Emory School of Medicine student when the trial was conducted. Johnson is currently a resident at Columbus Regional Hospital in Columbus, Ga.

Other investigators include Ammara Abbasi, Samantha S. Ehrlich, Renee S. Kleris, Siri L. Chirumamilla, Evan D. Schoenberg, Ashli Owen-Smith, Charles L. Raison and Virag A. Master from the Departments of Urology and Psychiatry and Behavioral Sciences at Emory University School of Medicine, and the Department of Behavioral Sciences and Health Education at Emory University Rollins School of Public Health.

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