Brainhack 2013

We are thrilled to draw your attention on the upcoming Brainhack 2013, which is being held from October 23-26 at the Centre International d’Études Pédagogiques, Sèvres, France (just outside of Paris).

Brainhack 2013 is a unique workshop with the goals of fostering interdisciplinary collaboration and open neuroscience. The structure builds from the concepts of an unconference and hackathon: The term “unconference” refers to the fact that most of the content will be dynamically created by the participants — a “hackathon” is an event where participants collaborate
intensively on projects.

Participants interested in neuroimaging from any discipline are welcome. Ideal participants span in range from graduate students to professors across any disciplines willing to contribute (e.g., mathematics, computer
science, engineering, neuroscience, psychology, psychiatry, neurology, medicine, art, etc…). The primary requirement is a desire to work in close collaborations with people outside of your specialization in order to
address neuroscience questions that are beyond the expertise of a single discipline.

One should come to brainhack ready to engage into collaborative projects, and with some material (slides, ideas, data, tools) ready to start a project or a discussion panel. Brainhack will build on the successful techniques used in other unconferences to keep the meeting focused and productive. It is possible to start a project and build a team as early as today. Please have a look at the website for information on the conference and a sample of projects (from Brainhack 2012).

The Preliminary Schedule for Brainhack 2013 is available here.

***NEW*** We will be accepting and publishing Brainhack 2013 abstracts. Abstracts should be submitted when you register.

Registration is now open here

Research Points to Promising Treatment for Macular Degeneration

Experiments show promising results for a drug that could lead to a lasting treatment for millions of Americans with macular degeneration.

Researchers at the University of North Carolina School of Medicine have published new findings in the hunt for a better treatment for macular degeneration. In studies using mice, a class of drugs known as MDM2 inhibitors proved highly effective at regressing the abnormal blood vessels responsible for the vision loss associated with the disease.

“We believe we may have found an optimized treatment for macular degeneration,” said senior study author Sai Chavala, MD, director of the Laboratory for Retinal Rehabilitation and assistant professor of Ophthalmology and Cell Biology & Physiology at the UNC School of Medicine. “Our hope is that MDM2 inhibitors would reduce the treatment burden on both patients and physicians.”

The research appeared Sept. 9, 2013 in the Journal of Clinical Investigation.

As many as 11 million Americans have some form of macular degeneration, which is the most common cause of central vision loss in the western world. Those with the disease find many daily activities such as driving, reading and watching TV increasingly difficult.

Currently, the best available treatment for macular degeneration is an antibody called anti-VEGF that is injected into the eye. Patients must visit their doctor for a new injection every 4-8 weeks, adding up to significant time and cost.

“The idea is we’d like to have a long-lasting treatment so patients wouldn’t have to receive as many injections,” said Chavala. “That would reduce their overall risk of eye infections, and also potentially lower the economic burden of this condition by reducing treatment costs.” Chavala practices at the Kittner Eye Center at UNC Health Care in Chapel Hill and New Bern.

All patients with age-related macular degeneration start out with the “dry” form of the disease, which can cause blurred vision or blind spots. In about 20 percent of patients, the disease progresses to its “wet” form, in which abnormal blood vessels form in the eye and begin to leak fluid or blood, causing vision loss.

While anti-VEGF works by targeting the growth factors that lead to leaky blood vessels, MDM2 inhibitors target the abnormal blood vessels themselves causing them to regress — potentially leading to a lasting effect.

Chavala and his colleagues investigated the effects of MDM2 inhibitors in cell culture and in a mouse model of macular degeneration. They found that the drug abolishes the problematic blood vessels associated with wet macular degeneration by activating a protein known as p53. “p53 is a master regulator that determines if a cell lives or dies. By activating p53, we can initiate the cell death process in these abnormal blood vessels,” said Chavala.

MDM2 inhibitors also have conceivable advantages over another treatment that is currently being investigated in several clinical trials: the use of low-dose radiation for wet macular degeneration. Radiation works by causing DNA damage in cells leading to an increase in p53 and cell death. MDM2 inhibitors activate p53 without causing DNA damage. Also, MDM2 inhibitors can be given by eye injection, which is advantageous over some forms of radiation treatment that require surgery to administer.

Sleep Better, Look Better? New Research Says Yes

First scientific look at how sleep apnea treatment affects appearance — alertness, youthfulness & attractiveness — may help patients stick with care

Getting treatment for a common sleep problem may do more than help you sleep better – it may help you look better over the long term, too, according to a new research study from the University of Michigan Health System and Michigan Technological University.

The findings aren’t just about “looking sleepy” after a late night, or being bright-eyed after a good night’s rest.

It’s the first time researchers have shown specific improvement in facial appearance after at-home treatment for sleep apnea, a condition marked by snoring and breathing interruptions. Sleep apnea affects millions of adults – most undiagnosed — and puts them at higher risk for heart-related problems and daytime accidents.

Using a sensitive “face mapping” technique usually used by surgeons, and a panel of independent appearance raters, the researchers detected changes in 20 middle-aged apnea patients just a few months after they began using a system called CPAP to help them breathe better during sleep and overcome chronic sleepiness.

While the research needs to be confirmed by larger studies, the findings may eventually give apnea patients even more reason to stick with CPAP treatment – a challenge for some because they must wear a breathing mask in bed. CPAP is known to stop snoring, improve daytime alertness and reduce blood pressure.

Sleep neurologist Ronald Chervin, M.D., M.S., director of the U-M Sleep Disorders Center, led the study, which was funded by the Covault Memorial Foundation for Sleep Disorders Research and published in the Journal of Clinical Sleep Medicine.

Putting anecdote to the test

Chervin says the study grew out of the anecdotal evidence that sleep center staff often saw in sleep apnea patients when they came for follow-up visits after using CPAP. The team, including research program manager Deborah Ruzicka, R.N., Ph.D., sought a more scientific way to assess appearance before and after sleep treatment.

“The common lore, that people ‘look sleepy’ because they are sleepy, and that they have puffy eyes with dark circles under them, drives people to spend untold dollars on home remedies,” notes Chervin, the Michael S. Aldrich Collegiate Professor of Sleep Medicine and professor of Neurology at the U-M Medical School. “We perceived that our CPAP patients often looked better, or reported that they’d been told they looked better, after treatment. But no one has ever actually studied this.”

They teamed with U-M plastic and reconstructive surgeon Steven Buchman, M.D., to use a precise face-measuring system called photogrammetry to take an array of images of the patients under identical conditions before CPAP and a few months after. Capable of measuring tiny differences in facial contours, the system helps surgeons plan operations and assess their impact.

“One of the breakthroughs in plastic surgery over the last decade has been our aim to get more objective in our outcomes,” says Buchman. “The technology used in this study demonstrates the real relationship between how you look and how you really are doing, from a health perspective.”

The research team also included longtime collaborators at the Michigan Tech Research Institute, led by signal analysis expert and engineer Joseph W. Burns, Ph.D., who developed a way to precisely map the colors of patients’ facial skin before and after CPAP treatment.

The researchers also used a subjective test of appearance: 22 independent raters were asked to look at the photos, without knowing which were the “before” pictures and which the “after” pictures of each patient. The raters were asked to rank attractiveness, alertness and youthfulness – and to pick which picture they thought showed the patient after sleep apnea treatment.

Results show improvement

About two-thirds of the time, the raters stated that the patients in the post-treatment photos looked more alert, more youthful and more attractive. The raters also correctly identified the post-treatment photo two-thirds of the time.

Meanwhile, the objective measures of facial appearance showed that patients’ foreheads were less puffy, and their faces were less red, after CPAP treatment. The redness reduction was especially visible in 16 patients who are Caucasian, and was associated with the independent raters’ tendency to say a patient looked more alert in the post-treatment photo. The researchers also perceived, but did not have a way to measure, a reduction in forehead wrinkles after treatment.

However, the researchers note, they didn’t see a big change in facial characteristics that popular lore associates with sleepiness. “We were surprised that our approach could not document any improvement, after treatment, in tendency to have dark blue circles or puffiness under the eyes,” says Chervin. “Further research is needed, to assess facial changes in more patients, and over a longer period of CPAP treatment.”

He notes that this initial study wouldn’t have been possible without the generosity of donors who have supported U-M sleep research as a way of honoring the memory of Jonathan Covault, a promising attorney who died young, and whose undertreated sleep apnea may have contributed to his premature death. The Covault family was aware of the research study, and of the importance of research that might encourage others to seek and stay with apnea treatment.

Chervin and his colleagues hope to continue to study the effect of sleep apnea treatment on many aspects of a person’s life, including further research on appearance. “We want sleep to be on people’s minds, and to educate them about the importance of getting enough sleep and getting attention for sleep disorders,” he says.

Research yields first detailed view of morphing Parkinson’s protein

Researchers have taken detailed images and measurements of the morphing structure of a brain protein thought to play a role in Parkinson’s disease, information that could aid the development of medications to treat the condition.

The protein, called alpha synuclein (pronounced sine-yoo-cline), ordinarily exists in a globular shape. However, the protein morphs into harmful structures known as amyloid fibrils, which are linked to protein molecules that form in the brains of patients with neurodegenerative diseases.

"The abnormal protein formation characterizes a considerable number of human diseases, such as Alzheimer’s, Parkinson’s and Huntington’s diseases and type II diabetes," said Lia Stanciu, an associate professor of materials engineering at Purdue University.

Until now, the transition from globular to fibrils had not been captured and measured.

Researchers incubated the protein in a laboratory and then used an electron microscope and a technique called cryoelectron microscopy to snap thousands of pictures over 24 hours, capturing its changing shape. The protein was frozen at specific time intervals with liquid nitrogen.

Findings reveal that the protein morphs from its globular shape into “protofibril” strands that assemble into pore-like rings. These rings then open up, forming pairs of protofibrils that assemble into fibrils through hydrogen bonds.

"We found a correlation between protofibrils in these rings and the fibrils, for the first time to our knowledge, by measuring their true sizes and visualizing the aggregation steps," Stanciu said. "A better understanding of the mechanism yields fresh insight into the pathogenesis of amyloid-related diseases and may provide us the opportunity to develop additional therapeutic strategies."

Parkinson’s disease affects 1 percent to 2 percent of people older than 60, and an increase in its prevalence is anticipated in coming decades.

The findings were detailed in a research paper appearing in the June issue of the Biophysical Journal. The paper was authored by doctoral student Hangyu Zhang; former postdoctoral research associate Amy Griggs; Jean-Christophe Rochet, an associate professor of medicinal chemistry and molecular pharmacology; and Stanciu.

The researchers caused the protein to morph into fibrils by exposing it to copper, mimicking what happens when people are exposed to lead and other heavy metals. The contaminants interfere with the protein, changing the oxidation states of ions in its structure.

Reference:

Hangyu Zhang, Amy Griggs, Jean-Christophe Rochet, and Lia A. Stanciu. In Vitro Study of a-Synuclein Protofibrils by Cryo-EM Suggests a Cu2D-Dependent Aggregation Pathway. Biophysical Journal, 2013 (in press)

Alzheimer’s missing link found: Is a promising target for new drugs

Yale School of Medicine researchers have discovered a protein that is the missing link in the complicated chain of events that lead to Alzheimer’s disease, they report in the Sept. 4 issue of the journal Neuron. Researchers also found that blocking the protein with an existing drug can restore memory in mice with brain damage that mimics the disease.

“What is very exciting is that of all the links in this molecular chain, this is the protein that may be most easily targeted by drugs,” said Stephen Strittmatter, the Vincent Coates Professor of Neurology and senior author of the study. “This gives us strong hope that we can find a drug that will work to lessen the burden of Alzheimer’s.”

Scientists have already provided a partial molecular map of how Alzheimer’s disease destroys brain cells. In earlier work, Strittmatter’s lab showed that the amyloid-beta peptides, which are a hallmark of Alzheimer’s, couple with prion proteins on the surface of neurons. By an unknown process, the coupling activates a molecular messenger within the cell called Fyn.

In the Neuron paper, the Yale team reveals the missing link in the chain, a protein within the cell membrane called metabotropic glutamate receptor 5 or mGluR5. When the protein is blocked by a drug similar to one being developed for Fragile X syndrome, the deficits in memory, learning, and synapse density were restored in a mouse model of Alzheimer’s.

Strittmatter stressed that new drugs may have to be designed to precisely target the amyloid-prion disruption of mGluR5 in human cases of Alzheimer’s and said his lab is exploring new ways to achieve this.

Disease in a Dish

Scientists use latest stem cell and gene-editing techniques to generate neurons in a dish, and reveal new clues behind deadly diseases of the brain

There is no easy way to study diseases of the brain. Extracting neurons from a living patient is both difficult and risky, while examining a patient’s brain post-mortem usually only reveals the disease’s final stages. And animal models, while incredibly informative, have frequently fallen short during the crucial drug-development stage of research. The result: we are woefully unprepared to fight—and win—the war against this class of diseases.

But scientists at the Gladstone Institutes and the University of California, San Francisco (UCSF) are taking a potentially more powerful approach: an advanced stem-cell technique that creates a human model of degenerative disease in a dish.

Using this model, the team uncovered a molecular process that causes neurons to degenerate, a hallmark sign of conditions such as Alzheimer’s disease and frontotemporal dementia (FTD). The results, published in the latest issue of Stem Cell Reports, offer fresh ammunition in the continued battle against these and other deadly neurodegenerative disorders.

The research team, led by Gladstone Investigator Yadong Huang, MD, PhD, identified an important mechanism behind tauopathies. A group of disorders that includes both Alzheimer’s and FTD, tauopathies are characterized by the abnormal accumulation of the protein Tau in neurons. This buildup is thought to contribute to the degeneration of these neurons over time, leading to debilitating symptoms such as dementia and memory loss. But while this notion has been around for a long time, the underlying processes have largely remained unclear.

“So much about the mechanisms that cause tauopathies is a mystery, in part because traditional approaches—such as post-mortem brain analysis and animal models—give an incomplete picture,” explained Dr. Huang. “But by using the latest stem-cell technology, we generated human neurons in a dish that exhibited the same pattern of cell degeneration and death that occurs inside a patient’s brain. Studying these models allowed us to see for the first time how a specific genetic mutation may kick start the tauopathy process.”

Other scientists recently discovered that the Tau mutation in question could increase a person’s risk of developing different tauopathies, including Alzheimer’s or FTD. So the research team, in collaboration with Bruce Miller, MD, who directs the UCSF Memory and Aging Center and who provided skin cells from a patient with this mutation, transformed these cells into induced pluripotent stem cells, or iPS cells. This technique, pioneered by Gladstone Investigator and 2012 Nobel Laureate Shinya Yamanaka, MD, PhD, allows scientists to reprogram adult skin cells into cells that are virtually identical to stem cells. These stem cells can then develop into almost any cell in the body.

The team combined this method with a cutting-edge gene-editing technique that essentially eliminated the Tau mutation in some of the iPS cells. The result was a system that allowed the team to compare neurons that had the mutation to those that did not.

“Our approach allowed us to grow human neurons in a dish that contained the exact same mutation as the neurons in the brain of the patient,” explained first author Helen Fong, PhD, who is also a California Institute for Regenerative Medicine postdoctoral scholar. “By comparing these diseased neurons with the ‘genetically corrected’ healthy neurons, we could see—cell by cell—how the Tau mutation leads to the abnormal build up of Tau and, over time, neuronal degeneration and death.”

“Tau’s main functions include keeping the skeletal structure of individual neurons intact and regulating neuronal activity,” said Dr. Huang. “But our research showed that the Tau produced by neurons from people with the Tau mutation is different; so it is red-flagged by the cell and targeted for destruction. However, instead of being flushed out, Tau gets chopped into pieces. These potentially toxic fragments accumulate over time and may in fact cause the neuron to degenerate and die.”

But by correcting the Tau mutation, the team effectively removed Tau’s red flag. The protein remained in one piece, the abnormal buildup ceased and the neurons remained healthy. Ongoing studies aim to determine whether the abnormal fragmentation and buildup of mutant tau is really the main cause of the neuronal death and, if so, how to block it.

Finding a way to block this toxic buildup of tau fragments has been a key focus of drug development—but has thus far been unsuccessful. But Dr. Huang and his colleagues are optimistic that their approach could be exactly what researchers need to fight back against deadly tauopathies.

“These findings not only offer a glimpse into how these powerful new models can shed light on mechanisms of disease” said Dr. Miller, “They may also prove invaluable for screening potential drugs that could be developed into better treatments for Alzheimer’s disease, FTD and related conditions.”