Drug Reduces Brain Changes, Motor Deficits Associated With Huntington’s Disease

A drug that acts like a growth-promoting protein in the brain reduces degeneration and motor deficits associated with Huntington’s disease in two mouse models of the disorder, according to a study appearing November 27 in The Journal of Neuroscience. The findings add to a growing body of evidence that protecting or boosting neurotrophins — the molecules that support the survival and function of nerve cells — may slow the progression of Huntington’s disease and other neurodegenerative disorders.

Huntington’s disease is a brain disorder characterized by the emergence of decreased motor, cognitive, and psychiatric abilities, most commonly appearing in the mid-30s and 40s. The disease is caused by a genetic mutation that leads to abnormal clumps of protein in the brain, eventually resulting in the atrophy and death of nerve cells. While there are drugs to alleviate some symptoms of the disease, there are currently no therapies to delay the onset or slow its progression.

Previous studies of people with Huntington’s disease point to a link between low levels of a neurotrophin called brain-derived neurotrophic factor (BDNF) and symptoms of the disorder. In the current study, Frank Longo, MD, PhD, and others at Stanford University, tested LM22A-4, a drug that specifically binds to and activates the BDNF receptor TrkB on nerve cells, in mice that model the disorder. They found LM22A-4 reduces abnormal protein accumulation, delays nerve cell degeneration, and improves motor skills in the animals. The findings support other recent rodent studies that showed drugs that enhance the action of BDNF can reduce brain changes and symptoms of Huntington’s disease.

“These results strongly suggest that drugs that act, in part, like BDNF could be effective therapeutics for treating Huntington’s disease and other neurodegenerative conditions,” Longo said. 

How quickly the symptoms of Huntington’s disease progress in people vary greatly. Longo’s group examined the effects of LM22A-4 treatment in mice that were predisposed to develop symptoms of Huntington’s disease rapidly (within weeks) or gradually (within months). LM22A-4 treatment reduced the accumulation of abnormal proteins in the striatum and cortex — brain regions affected in Huntington’s disease. Motor behaviors (downward climbing and grip strength) also improved in the mice that received LM22A-4 treatments daily. “The search for treatments that slow the progression of neurodegenerative diseases has gradually shifted from ameliorating symptoms to finding agents that reduce the progression of the disease,” said Gary Lynch, PhD, who studies neurodegeneration at the University of California, Irvine, and was not involved with this study. “Given that this drug is clinically plausible, these results open up exciting possibilities for treating a devastating neurodegenerative disease,” he added.

Memories Are ‘Geotagged’ With Spatial Information

Using a video game in which people navigate through a virtual town delivering objects to specific locations, a team of neuroscientists from the University of Pennsylvania and Freiburg University has discovered how brain cells that encode spatial information form “geotags” for specific memories and are activated immediately before those memories are recalled.

Their work shows how spatial information is incorporated into memories and why remembering an experience can quickly bring to mind other events that happened in the same place.

"These findings provide the first direct neural evidence for the idea that the human memory system tags memories with information about where and when they were formed and that the act of recall involves the reinstatement of these tags," said Michael Kahana, professor of psychology in Penn’s School of Arts and Sciences.

The study was led by Kahana and professor Andreas Schulze-Bonhage of Freiberg. Jonathan F. Miller, Alec Solway, Max Merkow and Sean M. Polyn, all members of Kahana’s lab, and Markus Neufang, Armin Brandt, Michael Trippel, Irina Mader and Stefan Hefft, all members of Schulze-Bonhage’s lab, contributed to the study. They also collaborated with Drexel University’s Joshua Jacobs.

Their study was published in the journal Science.

Kahana and his colleagues have long conducted research with epilepsy patients who have electrodes implanted in their brains as part of their treatment. The electrodes directly capture electrical activity from throughout the brain while the patients participate in experiments from their hospital beds.

As with earlier spatial memory experiments conducted by Kahana’s group, this study involved playing a simple video game on a bedside computer. The game in this experiment involved making deliveries to stores in a virtual city. The participants were first given a period where they were allowed to freely explore the city and learn the stores’ locations. When the game began, participants were only instructed where their next stop was, without being told what they were delivering. After they reached their destination, the game would reveal the item that had been delivered, and then give the participant their next stop.

After 13 deliveries, the screen went blank and participants were asked to remember and name as many of the items they had delivered in the order they came to mind.

This allowed the researchers to correlate the neural activation associated with the formation of spatial memories (the locations of the stores) and the recall of episodic memories: (the list of items that had been delivered).

“A challenge in studying memory in naturalistic settings is that we cannot create a realistic experience where the experimenter retains control over and can measure every aspect of what the participant does and sees. Virtual reality solves that problem,” Kahana said. “Having these patients play our games allows us to record every action they take in the game and to measure the responses of neurons both during spatial navigation and then later during verbal recall.”

By asking participants to recall the items they delivered instead of the stores they visited, the researchers could test whether their spatial memory systems were being activated even when episodic memories were being accessed. The map-like nature of the neurons associated with spatial memory made this comparison possible.

"During navigation, neurons in the hippocampus and neighboring regions can often represent the patient’s virtual location within the town, kind of like a brain GPS device," Kahana said. "These so-called ‘place cells’ are perhaps the most striking example of a neuron that encodes an abstract cognitive representation."

Using the brain recordings generated while the participants navigated the city, the researchers were able to develop a neural map that corresponded to the city’s layout. As participants passed by a particular store, the researchers correlated their spatial memory of that location with the pattern of place cell activation recorded. To avoid confounding the episodic memories of the items delivered with the spatial memory of a store’s location, the researchers excluded trips that were directly to or from that store when placing it on the neural map.

With maps of place cell activations in hand, the researchers were able to cross- reference each participant’s spatial memories as they accessed their episodic memories of the delivered items. The researchers found that the neurons associated with a particular region of the map activated immediately before a participant named the item that was delivered to a store in that region.

“This means that if we were given just the place cell activations of a participant,” Kahana said, “we could predict, with better than chance accuracy, the item he or she was recalling. And while we cannot distinguish whether these spatial memories are actually helping the participants access their episodic memories or are just coming along for the ride, we’re seeing that this place cell activation plays a role in the memory retrieval processes.”

Earlier neuroscience research in both human and animal cognition had suggested the hippocampus has two distinct roles: the role of cartographer, tracking

location information for spatial memory, and the role of scribe, recording events for episodic memory. This experiment provides further evidence that these roles are intertwined.

“Our finding that spontaneous recall of a memory activates its neural geotag suggests that spatial and episodic memory functions of the hippocampus are intimately related and may reflect a common functional architecture,” Kahana said.

Eat crow if you think I’m a bird-brain

Scientists have long suspected that corvids – the family of birds including ravens, crows and magpies – are highly intelligent. Now, Tübingen neurobiologists Lena Veit und Professor Andreas Nieder have demonstrated how the brains of crows produce intelligent behavior when the birds have to make strategic decisions. Their results are published in the latest edition of Nature Communications.

Crows are no bird-brains. Behavioral biologists have even called them “feathered primates” because the birds make and use tools, are able to remember large numbers of feeding sites, and plan their social behavior according to what other members of their group do. This high level of intelligence might seem surprising because birds’ brains are constructed in a fundamentally different way from those of mammals, including primates – which are usually used to investigate these behaviors.

The Tübingen researchers are the first to investigate the brain physiology of crows’ intelligent behavior. They trained crows to carry out memory tests on a computer. The crows were shown an image and had to remember it. Shortly afterwards, they had to select one of two test images on a touchscreen with their beaks based on a switching behavioral rules. One of the test images was identical to the first image, the other different. Sometimes the rule of the game was to select the same image, and sometimes it was to select the different one. The crows were able to carry out both tasks and to switch between them as appropriate. That demonstrates a high level of concentration and mental flexibility which few animal species can manage – and which is an effort even for humans.

The crows were quickly able to carry out these tasks even when given new sets of images. The researchers observed neuronal activity in the nidopallium caudolaterale, a brain region associated with the highest levels of cognition in birds. One group of nerve cells responded exclusively when the crows had to choose the same image – while another group of cells always responded when they were operating on the “different image” rule. By observing this cell activity, the researchers were often able to predict which rule the crow was following even before it made its choice.

The study published in Nature Communications provides valuable insights into the parallel evolution of intelligent behavior. “Many functions are realized differently in birds because a long evolutionary history separates us from these direct descendants of the dinosaurs,” says Lena Veit. “This means that bird brains can show us an alternative solution out of how intelligent behavior is produced with a different anatomy.” Crows and primates have different brains, but the cells regulating decision-making are very similar. They represent a general principle which has re-emerged throughout the history of evolution. “Just as we can draw valid conclusions on aerodynamics from a comparison of the very differently constructed wings of birds and bats, here we are able to draw conclusions about how the brain works by investigating the functional similarities and differences of the relevant brain areas in avian and mammalian brains,” says Professor Andreas Nieder.

Polymer Foam Expands Potential to Treat Aneurysms

Thirty thousand Americans suffer severe neurological damage or death from brain aneurysms each year and the existing treatments eventually fail in nearly half of patients. Currently, these “bubbles” in the blood vessel are either clamped off, which requires invasive brain surgery, or filled with platinum coils to induce clotting in the aneurysm. Both treatments, although somewhat effective, can have subsequent problems, including inflammation, incomplete healing, and the development of secondary aneurysms adjacent to the initial site. These complications result in approximately 40 percent of patients needing additional treatment to attempt to re-repair the aneurysm.

NIBIB-funded researchers in Texas A&M’s bioengineering department are moving rapidly to provide a better treatment for this serious disorder. The group specializes in using the unique properties of foam shape memory polymers (SMPs) to solve clinical conditions lacking satisfactory treatments.

The group, led by Associate Professor Duncan Maitland, is using SMPs in a pig model of brain aneurysm to develop a minimally-invasive procedure that fills and stabilizes the aneurysm. Because the system induces only minimal inflammation, it successfully allows natural healing of the border between the aneurysm and the blood vessel. As reported in the May 22 issue of the Journal of Biomedical Materials Research, partial healing was observed at 30 days post-procedure and almost complete healing had occurred at 90 days in the pig model.

How it Works

Two of the properties of SMP are critical to the success seen in the animal experiments:

• the foam’s ability to be compressed into a very thin sheath and then induced to expand to 100 times its compressed volume when heated, and
• its rigid, yet porous structure when fully expanded.

The rigid uniform structure of the expanded foam is a significant improvement over the current practice of filling an aneurysm with a platinum coil. Because a coil is threaded into the aneurysm until it fills the space, pressure is exerted on the aneurysm during the process, which can damage the vessel wall. In addition, the platinum coils do not uniformly fill the space, leaving large gaps that can allow shifting of the coils as well as the formation of unstable, large clots. The platinum coil approach can also result in inflammation which destabilizes the aneurysm, resulting in incomplete healing and failure to completely wall-off from the blood vessel.

The minimally-invasive procedure involves inserting the slim, compressed foam into the aneurysm using a microcatheter. The microcatheter is inserted into an artery through a small cut in the groin and then threaded through the blood vessels to the location of the aneurysm in the brain. Once in position, a laser optical fiber heats the foam to induce expansion and complete filling of the fragile pouch of the aneurysm. In contrast to the platinum coils currently in use, the foam exerts a firm, uniform pressure on the walls of the aneurysm, which reduces chances of rupture.

The foam contains tiny compartments that result in the development of a matrix of blood clots that further stabilize the structure. The investigators found that unlike the aneurysms filled with metal coils, the foam structure produced little inflammation and allowed natural healing, defined by the growth of new cells at the border between the foam and the wall of the damaged blood vessel.

Making a Difference through Innovative Technologies

Dr. Maitland describes his work, broadly, as developing technologies to solve clinical problems that lack satisfactory solutions. He has formed a company called Shape Memory Therapeutics to assist with moving the encouraging results obtained with the SMP system from animal models into testing and, potentially, eventual use in humans. Maitland’s desire to make a difference is clear. “There are people walking around with aneurysms that are untreatable. My hope is to develop a game-changing therapy that reduces the risk of aneurysm ruptures, increases patient safety, and has a real impact on human health care.”

Speech recovery after stroke

With right-handed people, it is positioned in the left side of the brain; left-handed people have it (usually) in the right side: the location of speech production has been known for quite some time. But it is not that simple, states psychologist Gesa Hartwigsen, Professor at Kiel University. In her current scientific publication, published in the magazine Proceedings of the National Academy of Science of the USA (PNAS), she investigates which areas in the brain really are in charge of speech, and how these interact. Her findings are supposed to help patients who have speech production problems or aphasia following a stroke.

Comprehending & Speaking

Gesa Hartwigsen and her team started by analysing speech production. They let healthy right-handed test persons listen to words, which they should then repeat. “These were pseudo words such as `beudo`. In German, they don’t have any associated meaning. Therefore, when hearing and repeating these words, no areas of the brain that had a connection to the meaning of what had been heard were activated”, said Hartwigsen.

The psychologist applies a combination of non-invasive methods (fMRI– functional magnetic resonance imaging and TMS – transcranial magnetic stimulation) to deduce what happens in the brain during the test. “We thus proved that the left hemisphere, as expected, was activated during speech production, while the right hemisphere did not actively contribute to language function”, explains Hartwigsen. This is the regular functionality within a healthy brain. From these results as well as others, scientists had up to now deduced that the right hemisphere did not contribute to speech production in the healthy system and was therefore suppressed.

Interfering & Measuring

With a second test, the Kiel University scientists simulated a dysfunction in the brain comparable to a stroke. A magnetic coil transmits a current pulse that interrupts the function of the area responsible for producing speech (Broca’s Area) in the left hemisphere. This completely harmless method influences the speech production of the volunteers for about 30 to 45 minutes. “During this period, the ability to listen and repeat was tested again. While we observed a suppressed activity in the left hemisphere during repeating, with some test persons taking longer to repeat the pseudo words, we also found unexpected activities in the right hemisphere”, reports Hartwigsen.

The right hemisphere showed increased activity during pseudo word repetition. The more the activity in the right Borca’s Area increased, the faster the volunteers were able to solve their speech tests. The right hemisphere also increased its facilitatory influence on the right hemisphere, a finding that was not observed prior to the TMS-induced lesion. “This reaction lends further support to the notion that the right hemisphere area reacts to the dysfunction of the left hemisphere and tries to compensate for the lesion.” Does the right hemisphere have a supporting influence and does it play an active role in speech production? So far, the common opinion was that it does not.

Result & Outlook

The findings of Gesa Hartwigsen and her team show an interaction of both hemispheres during speech repetition. When the left hemisphere is suppressed for example by a stroke, the right hemisphere could actively facilitate speech production. “By stimulating the right hemisphere, it could be possible to support speech recovery”, speculates the scientist. Here, timing would be very important. “Right after a stroke, we could support the right hemisphere. But when the remaining areas of the left hemisphere are ready to do their work again, it might be more helpful if the right hemisphere was suppressed. During this phase, we could stimulate the left hemisphere instead. The correct timing can therefore be crucial for recovery of speech after a stroke.”

In collaboration with the Department of Neurology at Kiel University, a stroke specialist from Leipzig and doctoral students of Medicine and Psychology, Gesa Hartwigsen has started a follow-up study on the recent publication. “We would like to find out more about the collaboration of the hemispheres and the right timing in helping stroke patients to recover”, says Hartwigsen. Her field of research is fairly new within the cognitive neuroscience. Nevertheless, she is positive that it will offer practical help in the form of concrete therapies within the next ten to fifteen years.

Genetic mutation increases risk of Parkinson’s disease from pesticides

A team of researchers has brought new clarity to the picture of how gene-environmental interactions can kill nerve cells that make dopamine. Dopamine is the neurotransmitter that sends messages to the part of the brain that controls movement and coordination. Their discoveries, described in a paper published online in Cell today, include identification of a molecule that protects neurons from pesticide damage.

"For the first time, we have used human stem cells derived from Parkinson’s disease patients to show that a genetic mutation combined with exposure to pesticides creates a ‘double hit’ scenario, producing free radicals in neurons that disable specific molecular pathways that cause nerve-cell death," said Stuart Lipton, M.D., Ph.D., professor and director of Sanford-Burnham Medical Research Institute’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research and senior author of the study.

Until now, the link between pesticides and Parkinson’s disease was based mainly on animal studies and epidemiological research that demonstrated an increased risk of disease among farmers, rural populations, and others exposed to agricultural chemicals.

In the new study, Lipton, along with Rajesh Ambasudhan, Ph.D., research assistant professor in the Del E. Webb Center, and Rudolf Jaenisch, M.D., founding member of Whitehead Institute for Biomedical Research and professor of biology at the Massachusetts Institute of Technology, used skin cells from Parkinson’s patients that had a mutation in the gene encoding a protein called alpha-synuclein. Alpha-synuclein is the primary protein found in Lewy bodies—protein clumps that are the pathological hallmark of Parkinson’s disease.

Using patient skin cells, the researchers created human induced pluripotent stem cells (hiPSCs) containing the mutation, and then “corrected” the alpha-synuclein mutation in other cells. Next, they reprogrammed all of these cells to become the specific type of nerve cell that is damaged in Parkinson’s disease, called A9 dopamine-containing neurons—thus creating two sets of neurons—identical in every respect except for the alpha-synuclein mutation.

"Exposing both normal and mutant neurons to pesticides—including paraquat, maneb, and rotenone—created excessive free radicals in cells with the mutation, causing damage to dopamine-containing neurons that led to cell death," said Frank Soldner, M.D., research scientist in Jaenisch’s lab and co-author of the study.

"In fact, we observed the detrimental effects of these pesticides with short exposures to doses well below EPA-accepted levels," said Scott Ryan, Ph.D., researcher in the Del E. Webb Center and lead author of the paper.

Having access to genetically matched neurons with the exception of a single mutation simplified the interpretation of the genetic contribution to pesticide-induced neuronal death. In this case, the researchers were able to pinpoint how cells with the mutation, when exposed to pesticides, disrupt a key mitochondrial pathway—called MEF2C-PGC1alpha—that normally protects neurons that contain dopamine. The free radicals attacked the MEF2C protein, leading to the loss of function of this pathway that would otherwise have protected the nerve cells from the pesticides.

"Once we understood the pathway and the molecules that were altered by the pesticides, we used high-throughput screening to identify molecules that could inhibit the effect of free radicals on the pathway," said Lipton. "One molecule we identified was isoxazole, which protected mutant neurons from cell death induced by the tested pesticides. Since several FDA-approved drugs contain derivatives of isoxazole, our findings may have potential clinical implications for repurposing these drugs to treat Parkinson’s."

While the study clearly shows the relationship between a mutation, the environment, and the damage done to dopamine-containing neurons, it does not exclude other mutations and pathways from being important as well. The team plans to explore additional molecular mechanisms that demonstrate how genes and the environment interact to contribute to Parkinson’s and other neurodegenerative diseases, such as Alzheimer’s and ALS.

"In the future, we anticipate using the knowledge of mutations that predispose an individual to these diseases in order to predict who should avoid a particular environmental exposure. Moreover, we will be able to screen for patients who may benefit from a specific therapy that can prevent, treat, or possibly cure these diseases," Lipton said.