Neuroscience

In Parkinson’s disease, the protein “alpha-synuclein” aggregates and accumulates within neurons. Specific areas of the brain become progressively affected as the disease develops and advances. The mechanism underlying this pathological progression is poorly understood but could result from spreading of the protein (or abnormal forms of it) along nerve projections connecting lower to upper brain regions. Scientists at the German Center for Neurodegenerative Diseases (DZNE) in Bonn have developed a novel experimental model that reproduces for the first time this pattern of alpha-synuclein brain spreading and provides important clues on the mechanisms underlying this pathological process. They triggered the production of human alpha-synuclein in the lower rat brain and were able to trace the spreading of this protein toward higher brain regions. The new experimental paradigm could promote the development of ways to halt or slow down disease development in humans. The research team headed by Prof. Donato Di Monte presents these results in the scientific journal “EMBO Molecular Medicine”.

Parkinson’s disease is a disorder of the nervous system. It typically manifests itself with motor disturbances, such as an uncontrollable trembling of the limbs, as well as non-motor symptoms, including sleep disorders and depression.

At the present, no cure exists for Parkinson’s disease, although symptomatic intervention, including treatment with dopamine agonists, can alleviate patients’ motor impairment. Parkinson’s is the second most common neurodegenerative disorder, after Alzheimer’s disease; it is estimated that 100,000 to 300,000 patients are affected by Parkinson’s disease in Germany alone.

In a small percentage of cases, Parkinson’s disease is due to genetic abnormalities carried within families. For the vast majority of patients, however, the cause of the disease remains unknown; the development of this sporadic form of the disease is likely promoted by both environmental and genetic risk factors. An intriguing characteristic of the brain of patients with sporadic Parkinson’s disease is the progressive accumulation of intraneuronal inclusions that were first described by a German neurologist, Friedrich Lewy, and are therefore called Lewy bodies.

“A major discovery in the late 90’s was that Lewy bodies are formed when the protein alpha-synuclein becomes aggregated,” says Di Monte. “Since then, it was also found that aggregates of alpha-synuclein are progressively accumulated within the patients’ brains during the course of the disease”.

Pathology studies from human brains show that the deposits usually start forming in the lower part of the brain, in an area named “medulla oblongata”. In subsequent disease stages, alpha-synuclein aggregates are observed in progressively higher (more rostral) brain regions, including the midbrain and cortical areas.

“This spreading appears to follow a typical pattern based on anatomical connections between regions of the brain,” says the neuroscientist. “For this reason, it has been hypothesized that alpha-synuclein or abnormal forms of it can be transferred between two interconnected neurons and hence migrate throughout the brain. But until now, there was no way of targeting the medulla oblongata to reproduce this spreading of alpha-synuclein in the laboratory. It is also unclear what conditions could trigger the inter-neuronal passage of the protein or its aggregates. We have now developed a new experimental paradigm which enables investigations on these fundamental issues.”

From the neck into the brain
The researchers’ concept is based on reproducing alpha-synuclein spreading in rats: for this, they transferred the blueprint of the human form of alpha-synuclein into the rat brain. The blueprint was transported by specifically engineered viral particles that the scientists injected into nerve fibres in the neck of the animals. The genetic code for the protein passed along these fibres into the medulla oblongata, where transfected rat neurons began producing high quantities of human alpha-synuclein.

“We have good reasons to believe that the medulla oblongata is a primary site of early disease development. This is why we wanted to activate production of alpha-synuclein specifically in this part of the brain. The medulla oblongata is difficult to reach via surgical procedures. For this reason, we injected the viral particles into the vagus nerve. This is a long nerve stretching from the abdomen via the neck to the medulla oblongata. The nerve consequently served as an entrance into the brain and, in particular, the medulla oblongata,” Di Monte explains.

A migrating protein
The researchers monitored the production and localization of human alpha-synuclein in rats’ brains over a period of four and a half months after injection of the viral particles. As predicted, the exogenous protein was synthesized only within neurons of the medulla oblongata connected to the vagus nerve. Starting at two months, however, human alpha-synuclein was observed also in brain areas more and more distant from the medulla oblongata. Caudo-rostral spreading involved inter-neuronal passage of the protein along specific nerve tracts and was accompanied by morphological alterations (such as swellings) of the neuronal projections taking up human alpha-synuclein.

The study, sponsored in part by the Blanche A. Paul Foundation, bears a number of critical implications. It reproduces a pattern of protein propagation that resembles the progressive spreading of pathological alpha-synuclein in Parkinson’s disease. As importantly, the process of protein transmission was triggered by overproduction of alpha-synuclein within a specific brain region.

“Overproduction of alpha-synuclein accompanies a variety of conditions, such as aging, neuronal injury or genetic polymorphisms, that could promote the development of Parkinson’s disease.” concludes Di Monte. “Thus, our results suggest a mechanistic link between disease risk factors, enhanced levels of alpha-synuclein, spreading of the protein and its pathological accumulation.”

Insight into the early stages of Parkinson’s
The new model mimics events that likely occur in the early stages of alpha-synuclein pathology in the absence of overt behavioural (in rats) or clinical (in patients) manifestations. “It will therefore become a valuable tool to investigate early mechanisms of disease pathogenesis that could be targeted for therapeutic intervention. Early intervention would have a greater probability to prevent or halt the spreading of pathology and progression of the disease,” says Di Monte.

The first symptoms of major depression may be behavioral, but the common mental illness is based in biology — and not limited to the brain.

In recent years, some studies have linked major, long-term depression with life-threatening chronic disease and with earlier death, even after lifestyle risk factors have been taken into account.

Now a research team led by Owen Wolkowitz, MD, professor of psychiatry at UC San Francisco, has found that within cells of the immune system, activity of an enzyme called telomerase is greater, on average, in untreated individuals with major depression. The preliminary findings from his latest, ongoing study was reported Wednesday at the annual meeting of the American Psychiatric Association in San Francisco.

Telomerase is an enzyme that lengthens protective end caps on the chromosomes’ DNA, called telomeres. Shortened telomeres have been associated with earlier death and with chronic diseases in population studies.

The heightened telomerase activity in untreated major depression might represent the body’s attempt to fight back against the progression of disease, in order to prevent biological damage in long-depressed individuals, Wolkowitz said.

The researchers made another discovery that may suggest a protective role for telomerase. Using magnetic resonance imaging (MRI), they found that, in untreated, depressed study participants, the size of the hippocampus, a brain structure that is critical for learning and memory, was associated with the amount of telomerase activity measured in the white blood cells. Such an association at a single point in time cannot be used to conclude that there is a cause-and-effect relationship with telomerase helping to protect the hippocampus, but it is plausible, Wolkowitz said.

Telomerase Activity and Antidepressants

Remarkably, the researchers also found that the enzyme’s activity went up when some patients began taking an antidepressant. In fact, depressed participants with lower telomerase activity at baseline — as well as those in whom enzyme activity increased the most with treatment — were the most likely to become less depressed with treatment.

“Our results are consistent with the beneficial effect of telomerase when it is boosted in animal studies, where it has been associated with the growth of new nerve cells in the hippocampus and with antidepressant-like effects, evidenced by increased exploratory behavior,” Wolkowitz said. He cautions that his new findings are preliminary due to the small size of the study and must be confirmed through further research.

The researchers also measured telomere length in the same immune cells. Only very chronically depressed individuals showed telomere shortening, Wolkowitz said.

“The longer people had been depressed, the shorter their telomeres were,” he said. “Shortened telomere length has been previously demonstrated in major depression in most, but not all, studies that have examined it. The duration of depression may be a critical factor.”

Ongoing Study

The 20 depressed participants enrolled in the study had been untreated for at least six weeks and had an average lifetime duration of depression of about 13 years. After baseline evaluation and laboratory measures, 16 of the depressed participants were treated with sertraline, a member of the most popular class of antidepressants, the serotonin-selective-reuptake-inhibitors (SSRIs), and then evaluated again after eight weeks. There were 20 healthy participants who served as controls.

The ongoing study still is accepting depressed participants who are not now taking antidepressants.

Wolkowitz’s team also studies chronic inflammation and the biochemical phenomenon of oxidative stress, which he said have often been reported in major depression. Wolkowitz is exploring the hypothesis that inflammation and oxidative stress play a role in telomere shortening and accelerated aging in depression.

“New insights into the mechanisms of these processes may well lead to new treatments — both pharmacological and behavioral — that will be distinctly different from the current generation of drugs prescribed to treat depression,” he said. “Additional studies might lead to simple blood tests that can measure accelerated immune-cell aging.”

Researchers at Lund University have succeeded in preventing very early symptoms of Huntington’s disease, depression and anxiety, by deactivating the mutated huntingtin protein in the brains of mice.

“We are the first to show that it is possible to prevent the depression symptoms of Huntington’s disease by deactivating the diseased protein in nerve cell populations in the hypothalamus in the brain. This is hugely exciting and bears out our previous hypotheses”, explains Åsa Petersén, Associate Professor of Neuroscience at Lund University.

Huntington’s is a debilitating disease for which there is still neither cure nor sufficient treatment. The dance-like movements that characterise the disease have long been the focus for researchers, but the emotional problems affect the patient earlier than the motor symptoms. These are now believed to stem from a different part of the brain – the small emotional centre called the hypothalamus.

“Now that we have been able to show in animal experiments that depression and anxiety occur very early in Huntington’s disease, we want to identify more specifically which nerve cells in the hypothalamus are critical in the development of these symptoms. In the long run, this gives us better opportunities to develop more accurate treatments that can attack the mutated huntingtin where it does the most damage”, says Åsa Petersén.

As the role of the hypothalamus in Huntington’s disease is gradually mapped, knowledge might be gained from drug research for other psychiatric diseases. It is likely that similar mechanisms control different types of depression, according to Åsa Petersén.

Publication:
Hypothalamic expression of mutant huntingtin contributes to the development of depressive-like behavior in the BAC transgenic mouse model of Huntington’s disease
Human Molecular Genetics
Sofia Hult Lundh, Nathalie Nilsson, Rana Soylu, Deniz Kirik and Åsa Petersén

An anti-cancer drug about to be tested in a clinical trial by a biomedical company in Ohio as a possible treatment for Alzheimer’s disease has failed to work with the same type of brain plaques that plague Alzheimer’s patients, according to results of a study by University of Florida researchers.

David Borchelt, Ph.D., a professor of neuroscience affiliated with the Evelyn F. and William L. McKnight Brain Institute of the University of Florida, emphasized the importance of verifying promising research results before investing in clinical studies or testing potential therapies in people. Bexarotene has known side effects that include effects on the liver, blood and other metabolic systems.

“We wanted to repeat the study to see if we could build on it, and we couldn’t,” he said. “We thought it was important that something like this, which got a lot of publicity and patients were immediately looking to try to get access to this drug, that it was important to publish the fact that we couldn’t reproduce the most exciting part of the study. Maybe there should be some caution going forward in regard to patients.”

Borchelt and Kevin Felsenstein, Ph.D., an associate professor of neuroscience, said a drug called bexarotene that their team orally administered to mice did not reduce amyloid plaques, waxy buildups on the brain that are a key culprit in Alzheimer’s disease. Their findings will be published in the May 24, 2013 issue of the journal Science magazine, with two additional articles (1, 2) detailing similar results from other researchers.

The research follows up on a 2012 Science article that claimed bexarotene had reversed Alzheimer’s-like symptoms in mice afflicted with the plaques. Authors of that study also administered the drug orally.

The paper “indicated that with as little as three days of treatment, they basically cleared the amyloid deposits from these animals, as well as restored cognitive abilities,” Felsenstein said of the 2012 paper.He said the results of the original study were surprising, given decades of research that had failed to find a therapy successful in dismantling amyloid plaques.

“We can shut down the production of amyloid in these animal models and the deposits in these animal models don’t disappear,” Felsenstein said. “These deposits have been described by some as cement, and it will take a lot to get rid of them. The fact that something could actually make them disappear in literally a couple of days is — again — very remarkable.”

Interested to see how bexarotene might work to break down amyloid plaques, Felsenstein and Borchelt selected mice approximately the same age as those used in the 2012 study and orally administered the drug to the mice. Tests confirmed the drug had reached its target genes in the mice, and that it elevated levels of a protein called apolipoprotein E. Some scientists believe one of the forms of this protein may prevent the buildup of amyloid brain plaques in people who don’t have Alzheimer’s disease.

But elevated levels of the protein in the mice studied by UF researchers seemed to have no effect on the animals’ amyloid plaques. Samples taken after seven days of treatment with bexarotene showed no significant difference in the number or size of plaques in the animals’ brains. Two teams of researchers from other institutions also were unable to replicate the breakdown of amyloid plaques.

Felsenstein emphasized that his team does not claim the previous study indicating bexarotene’s effectiveness is “totally wrong.”

“We’re just saying right now it’s extremely difficult to replicate and there may be little nuances, that there’s something that we don’t quite understand,” he added. Felsenstein and Borchelt both work at UF’s Center for Translational Research in Neurodegenerative Disease.

Until now, little was scientifically known about the human potential to cultivate compassion — the emotional state of caring for people who are suffering in a way that motivates altruistic behavior.

A new study by researchers at the Center for Investigating Healthy Minds at the Waisman Center of the University of Wisconsin-Madison shows that adults can be trained to be more compassionate. The report, recently published online in the journal Psychological Science, is the first to investigate whether training adults in compassion can result in greater altruistic behavior and related changes in neural systems underlying compassion.

"Our fundamental question was, ‘Can compassion be trained and learned in adults? Can we become more caring if we practice that mindset?’" says Helen Weng, a graduate student in clinical psychology and lead author of the paper. "Our evidence points to yes."

In the study, the investigators trained young adults to engage in compassion meditation, an ancient Buddhist technique to increase caring feelings for people who are suffering. In the meditation, participants envisioned a time when someone has suffered and then practiced wishing that his or her suffering was relieved. They repeated phrases to help them focus on compassion such as, “May you be free from suffering. May you have joy and ease.”

Participants practiced with different categories of people, first starting with a loved one, someone whom they easily felt compassion for like a friend or family member. Then, they practiced compassion for themselves and, then, a stranger. Finally, they practiced compassion for someone they actively had conflict with called the “difficult person,” such as a troublesome coworker or roommate.

"It’s kind of like weight training," Weng says. "Using this systematic approach, we found that people can actually build up their compassion ‘muscle’ and respond to others’ suffering with care and a desire to help."

Compassion training was compared to a control group that learned cognitive reappraisal, a technique where people learn to reframe their thoughts to feel less negative. Both groups listened to guided audio instructions over the Internet for 30 minutes per day for two weeks. “We wanted to investigate whether people could begin to change their emotional habits in a relatively short period of time,” says Weng.

The real test of whether compassion could be trained was to see if people would be willing to be more altruistic — even helping people they had never met. The research tested this by asking the participants to play a game in which they were given the opportunity to spend their own money to respond to someone in need (called the “Redistribution Game”). They played the game over the Internet with two anonymous players, the “Dictator” and the “Victim.” They watched as the Dictator shared an unfair amount of money (only $1 out of $10) with the Victim. They then decided how much of their own money to spend (out of $5) in order to equalize the unfair split and redistribute funds from the Dictator to the Victim.

"We found that people trained in compassion were more likely to spend their own money altruistically to help someone who was treated unfairly than those who were trained in cognitive reappraisal," Weng says.

"We wanted to see what changed inside the brains of people who gave more to someone in need. How are they responding to suffering differently now?" asks Weng. The study measured changes in brain responses using functional magnetic resonance imaging (fMRI) before and after training. In the MRI scanner, participants viewed images depicting human suffering, such as a crying child or a burn victim, and generated feelings of compassion towards the people using their practiced skills. The control group was exposed to the same images, and asked to recast them in a more positive light as in reappraisal.

The researchers measured how much brain activity had changed from the beginning to the end of the training, and found that the people who were the most altruistic after compassion training were the ones who showed the most brain changes when viewing human suffering. They found that activity was increased in the inferior parietal cortex, a region involved in empathy and understanding others. Compassion training also increased activity in the dorsolateral prefrontal cortex and the extent to which it communicated with the nucleus accumbens, brain regions involved in emotion regulation and positive emotions.

"People seem to become more sensitive to other people’s suffering, but this is challenging emotionally. They learn to regulate their emotions so that they approach people’s suffering with caring and wanting to help rather than turning away," explains Weng.

Compassion, like physical and academic skills, appears to be something that is not fixed, but rather can be enhanced with training and practice. “The fact that alterations in brain function were observed after just a total of seven hours of training is remarkable,” explains UW-Madison psychology and psychiatry professor Richard J. Davidson, founder and chair of the Center for Investigating Healthy Minds and senior author of the article.

"There are many possible applications of this type of training," Davidson says. "Compassion and kindness training in schools can help children learn to be attuned to their own emotions as well as those of others, which may decrease bullying. Compassion training also may benefit people who have social challenges such as social anxiety or antisocial behavior."

Weng is also excited about how compassion training can help the general population. “We studied the effects of this training with healthy participants, which demonstrated that this can help the average person. I would love for more people to access the training and try it for a week or two — what changes do they see in their own lives?”

Both compassion and reappraisal trainings are available on the Center for Investigating Healthy Minds’ website. “I think we are only scratching the surface of how compassion can transform people’s lives,” says Weng.

It is known that signs of neurological disorders such as Alzheimer’s and Huntington’s disease can appear years before the disease becomes manifest; these signs take the form of subtle changes in the brain and behavior of individuals affected. For the first time, an international group of researchers led by the DZNE and the Bonn University Hospital has proven the existence of such signatures for motor disorders belonging to the group of “spinocerebellar ataxias”. The scientists report these findings in the current online edition of “The Lancet Neurology”. This pan-European study could open up new possibilities of early diagnosis and smooth the way for treatments which tackle diseases before the patient’s nervous system is irreparably damaged.

“Spinocerebellar ataxias” comprise a group of genetic diseases of the cerebellum and other parts of the brain. Persons affected only have limited control of their muscles. They also suffer from balance disorders and impaired speech. The symptoms originate from mutations in the patient’s genetic make-up. These cause nerve cells to become damaged and to die off. Such genetic defects are comparatively rare: it is estimated that about 3,000 people in Germany are affected.

It is known that there are various subtypes of these neurodegenerative diseases. The age at which the symptoms manifest consequently fluctuates between about 30 and 50. “Our aim was to find out whether specific signs can be recognized before a disease becomes obvious,” says project leader Prof. Thomas Klockgether, Director for Clinical Research at the DZNE and Director of the Clinic for Neurology at Bonn University Hospital.

Pan-European cooperation
The study, which involved 14 research centers in all, focused on the four most common forms of spinocerebellar ataxia. These account for more than half of all cases. More than 250 siblings and children of patients throughout Europe declared their willingness to participate in appropriate tests. These individuals had no obvious symptoms of ataxia. However, about half of them had inherited the genetic defects which invariably cause the disease to manifest in the long term.

With the aid of a mathematical model that considered the genetic mutations and their effects, the scientists were able to estimate the time remaining until the disease could be expected to manifest. In the test group, this “time to onset” varied from 2 to 24 years. These and all other test results remained anonymous: the data was not known to the test subjects, neither could the researchers assign it to specific participants. The same applied to individuals whose DNA turned out to be inconspicuous. “People in families with cases of ataxia usually have not taken a genetic test and they don’t want to know any results. This kind of information has to be treated very carefully for ethical reasons,” emphasizes Klockgether.

Extensive tests
The study participants made themselves available for various examinations including standardized tests of muscular coordination. These included measuring the time needed by the subjects to walk a specific distance. Another series of experiments involved inserting small pins into the holes of a board and taking them back out as quickly as possible. Yet another test measured how often the participants could repeat a certain sequence of syllables in ten seconds. “The tests were designed in such a way that they would provide significant information but still be easy to perform,” says Klockgether. “Tests like these can be performed anywhere without need for special technology.”

Technically complex methods were also used: all study participants were tested for the genetic defects relevant to ataxia. At some of the research centers involved in the study, it was also possible to examine the subjects with the aid of magnetic resonance imaging (MRI). This enabled researchers to measure the total brain volume as well as the dimensions of individual parts of the brain in about a third of the subjects.

Notable findings
In two of the four types of ataxia investigated, the scientists found signs of impending disease. “We found a loss in brain volume, particularly shrinkage in the area of the cerebellum and brain stem. These subjects also had subtle difficulties with coordination,” Klockgether summarizes the results. “This means that manifestations of this kind can be measured years before the disease is likely to become obvious.”

The findings for the other two types of ataxia were less conclusive. “I assume that there are indications also for these types of the disease. However, this subgroup of participants was relatively small. It is therefore difficult to make statistically reliable statements about these subjects,” says the Bonn-based researcher.

In his view, the study results testify to the modern-day view of neurodegenerative processes: “Neurodegeneration doesn’t begin when the symptoms surface. Rather, it is a stealthy disease which starts developing years or even decades beforehand.”

Klockgether believes that this gradual development offers certain opportunities: “If we intervened in this process by appropriate treatments and at a sufficiently early stage, it might be possible to slow down or even stop the disease process.”

More investigations planned
The current results will be the basis for long-term investigations. A new series of tests with the same group of individuals has already started; further tests are scheduled every two years. The scientists intend to monitor the study participants for as long as possible.

Researchers at Johns Hopkins have unraveled the molecular foundations of cocaine’s effects on the brain, and identified a compound that blocks cravings for the drug in cocaine-addicted mice. The compound, already proven safe for humans, is undergoing further animal testing in preparation for possible clinical trials in cocaine addicts, the researchers say.

“It was remarkably serendipitous that when we learned which brain pathway cocaine acts on, we already knew of a compound, CGP3466B, that blocks that specific pathway,” says Solomon Snyder, M.D., a professor of neuroscience in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine. “Not only did CGP3466B help confirm the details of cocaine’s action, but it also may become the first drug approved to treat cocaine addiction.” Details of the research appear May 22 on the website of the journal Neuron.

Snyder, who won a 1978 Lasker Award for identifying the brain’s own opiate receptors, and his team have been studying the brain for decades. Twenty years ago, they discovered that the gas nitric oxide (NO) is a major player in the complex signaling network that lets our neurons coordinate activity with one another. Snyder and his team have since studied many of the proteins in that network that interact with NO, including GAPDH, a protein best known for regulating how cells store and use sugars.

A few years ago, Snyder’s team and other researchers found that if NO reacts with GAPDH, GAPDH can then bind to another protein that whisks GAPDH away from its humdrum sugar metabolism tasks and into the nucleus, the cell’s control center. There, depending on what other chemical signals are present, the GAPDH can either stimulate the neuron’s growth or activate a self-destruct program — called apoptosis — that will kill the neuron.

In his research on GAPDH, Snyder came across a paper published in 1998 by scientists at Novartis. The company had identified a molecule, CGP3466B, that in laboratory tests protected neurons from degeneration by inhibiting apoptosis, and had tested it in clinical trials on patients with Parkinson’s disease and amyotrophic lateral sclerosis, or ALS. But while the drug had few side effects, it wasn’t an effective treatment for either of the diseases. Before Novartis gave up on the drug, however, its scientists investigated which molecules it interacted with in the brain, hoping to learn the reasons for its neuroprotective effects. Their only hit was GAPDH, a result that no doubt left the researchers scratching their heads, Snyder says. After all, CGP3466B seemed so promising partly because its effects were so specific — it appeared to do nothing except protect neurons from self-destructing. How would it accomplish that by acting on GAPDH, a signaling molecule with such a broad role in sugar metabolism? Though the study seemed like a dead end, the researchers published it anyway.

When Snyder saw the paper, he connected it to his team’s findings, inferring that CGP3466B might work by preventing GAPDH from entering the nucleus to trigger cell death. In a study published in 2006, he and other Johns Hopkins researchers tested two compounds similar to CGP3466B to see if they would block GAPDH from triggering cell death under the types of highly stressful conditions that would normally cause apoptosis. The protective drugs worked, the team found, by disrupting with extraordinary potency the reaction between NO and GAPDH, which ultimately blocked GAPDH from binding to the protein that ferries it into the nucleus.

In the most recent study, M.D./Ph.D. student Risheng Xu worked with other members of Snyder’s team to investigate whether cocaine works through the NO signaling network, and if so, how. Using mice, they found that cocaine induces NO to react with GAPDH so that GAPDH moves into the nucleus. At low doses of cocaine, the GAPDH in the nucleus will stimulate the neuron, but at higher doses it activates the cell’s self-destruct pathway. “This explains why cocaine can have very different effects depending on the dosage,” Xu says.

The team then did experiments to see whether CGP3466B, which blocks the reaction between NO and GAPDH, would also block the effects of cocaine. In one experiment, they placed mice in a cage with two rooms, and trained them to expect occasional doses of cocaine in one of the rooms. When the mice began spending most of their time in that room, it showed they had become addicted to cocaine. But when treated with CGP3466B, the mice went back to spending roughly equal amounts of time in both rooms: Their cravings had abated, Xu says.

“What’s exciting is that this drug works at very low doses, and it also appears only to affect this specific pathway, making it unlikely to have unwanted side effects,” Xu notes. “We also know from Novartis’ early-stage clinical trials that the drug exhibits few documented side effects in people.”

CGP3466B is now owned by a different company. With the results of the current study in hand, Snyder has brokered a deal between that company and the National Institute on Drug Abuse (NIDA) for NIDA to test CGP3466B as a treatment for cocaine addiction. NIDA will first conduct more animal trials, and then, if all goes well, move on to clinical trials in addicts. “Our study’s results provide a direct demonstration that actions of a major psychotropic drug are mediated by the NO-GAPDH system and afford an unprecedented, straightforward approach to the treatment of cocaine abuse and neurotoxicity,” Snyder says.

Another member of the research team, Nilkanta Sen, Ph.D., cautions that more research is needed to see whether CGP3466B will fulfill its apparent promise. But, says Sen, now an assistant professor at Georgia Regents University, “what we cannot deny is that this study provides a new hope in the field of addiction research.”

New research shows that craving drugs such as nicotine can be visualized in specific regions of the brain that are implicated in determining the value of actions, in planning actions and in motivation. Dr. Alain Dagher, from McGill University, suggests abnormal interactions between these decision-making brain regions could underlie addiction. These results were presented at the 2013 Canadian Neuroscience Meeting, the annual meeting of the Canadian Association for Neuroscience - Association Canadienne des Neurosciences (CAN-ACN).

Neuroeconomics is a field of research which seeks to explain decision making in humans based on calculating costs and likely rewards or benefits of choices individuals make. Previous studies have suggested addicted individuals place greater value on immediate rewards (cigarette smoking) over delayed rewards (health benefits). Research done by Dr. Dagher and colleagues show how the value of the drug, which is indicated by the degree of craving, varies based on drug availability, decision to quit and other factors. He also shows that this perceived value of the drug at a given time can be visualized in the brains of addicted individuals by functional Magnetic Resonance Imaging (fMRI), and that imaging results can be used to predict subsequent consumption.

Dr. Dagher showed that a specific brain region called the dorsolateral prefrontal cortex (abbreviated DLPFC) regulates cigarette craving in response to drug cues - seeing people smoke, or smelling cigarettes - and that these induced cravings could be altered by inactivating the DLPFC by Transcranial Magnetic Stimulation (TMS). He suggests addiction may result from abberrant connections between the DLFPC and other brain region in susceptible individuals. These results could provide a rational basis for novel interventions to reduce cravings in addicted individuals, such as cognitive behavioral therapy or transcranial stimulation of the DLFPC.

Concluding quote from Dr. Dagher: “Policy debates have often centred on whether addictive behaviour is a choice or a brain disease. This research allows us to view addiction as a pathology of choice. Dysfunction in brain regions that assign value to possible options may lead to choosing harmful behaviours.”

Alteration of two genes, detectable by simple blood test during pregnancy, foretold illness with 85 percent certainty in small study

Johns Hopkins researchers say they have discovered specific chemical alterations in two genes that, when present during pregnancy, reliably predict whether a woman will develop postpartum depression.

The epigenetic modifications, which alter the way genes function without changing the underlying DNA sequence, can apparently be detected in the blood of pregnant women during any trimester, potentially providing a simple way to foretell depression in the weeks after giving birth, and an opportunity to intervene before symptoms become debilitating.

The findings of the small study involving 52 pregnant women are described online in the journal Molecular Psychiatry.

“Postpartum depression can be harmful to both mother and child,” says study leader Zachary Kaminsky, Ph.D., an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “But we don’t have a reliable way to screen for the condition before it causes harm, and a test like this could be that way.”

It is not clear what causes postpartum depression, a condition marked by persistent feelings of sadness, hopelessness, exhaustion and anxiety that begins within four weeks of childbirth and can last weeks, several months or up to a year. An estimated 10 to 18 percent of all new mothers develop the condition, and the rate rises to 30 to 35 percent among women with previously diagnosed mood disorders. Scientists long believed the symptoms were related to the large drop-off in the mother’s estrogen levels following childbirth, but studies have shown that both depressed and nondepressed women have similar estrogen levels.

By studying mice, the Johns Hopkins researchers suspected that estrogen induced epigenetic changes in cells in the hippocampus, a part of the brain that governs mood. Kaminsky and his team then created a complicated statistical model to find the candidate genes most likely undergoing those epigenetic changes, which could be potential predictors for postpartum depression. That process resulted in the identification of two genes, known as TTC9B and HP1BP3, about which little is known save for their involvement in hippocampal activity.

Kaminsky says the genes in question may have something to do with the creation of new cells in the hippocampus and the ability of the brain to reorganize and adapt in the face of new environments — two elements important in mood. In some ways, he says, estrogen can behave like an antidepressant, so that when inhibited, it adversely affects mood.

The researchers later confirmed their findings in humans by looking for epigenetic changes to thousands of genes in blood samples from 52 pregnant women with mood disorders. Jennifer L. Payne, M.D., director of the Johns Hopkins Women’s Mood Disorders Center, collected the blood samples. The women were followed both during and after pregnancy to see who developed postpartum depression.

The researchers noticed that women who developed postpartum depression exhibited stronger epigenetic changes in those genes that are most responsive to estrogen, suggesting that these women are more sensitive to the hormone’s effects. Specifically, two genes were most highly correlated with the development of postpartum depression. TTC9B and HP1BP3 predicted with 85 percent certainty which women became ill.

“We were pretty surprised by how well the genes were correlated with postpartum depression,” Kaminsky says. “With more research, this could prove to be a powerful tool.”

Kaminsky says the next step in research would be to collect blood samples from a larger group of pregnant women and follow them for a longer period of time. He also says it would be useful to examine whether the same epigenetic changes are present in the offspring of women who develop postpartum depression.

Evidence suggests that early identification and treatment of postpartum depression can limit or prevent debilitating effects. Alerting women to the condition’s risk factors — as well as determining whether they have a previous history of the disorder, other mental illness and unusual stress — is key to preventing long-term problems.

Research also shows, Kaminsky says, that postpartum depression not only affects the health and safety of the mother, but also her child’s mental, physical and behavioral health.

Kaminsky says that if his preliminary work pans out, he hopes a blood test for the epigenetic biomarkers could be added to the battery of tests women undergo during pregnancy, and inform decisions about the use of antidepressants during pregnancy. There are concerns, he says, about the effects of these drugs on the fetus and their use must be weighed against the potentially debilitating consequences to both the mother and child of foregoing them.

“If you knew you were likely to develop postpartum depression, your decisions about managing your care could be made more clearly,” he says.

Nutritional supplement delays advancement of Parkinson’s and Familial Dysautonomia, TAU researchers discover

Widely available in pharmacies and health stores, phosphatidylserine is a natural food supplement produced from beef, oysters, and soy. Proven to improve cognition and slow memory loss, it’s a popular treatment for older people experiencing memory impairment. Now a team headed by Prof. Gil Ast and Dr. Ron Bochner of Tel Aviv University’s Department of Human Molecular Genetics has discovered that the same supplement improves the functioning of genes involved in degenerative brain disorders, including Parkinson’s disease and Familial Dysautonomia (FD).

In FD, a rare genetic disorder that impacts the nervous system and appears almost exclusively in the Ashkenazi Jewish population, a genetic mutation prevents the brain from manufacturing healthy IKAP proteins — which likely have a hand in cell migration and aiding connections between nerves — leading to the early degeneration of neurons. When the supplement was applied to cells taken from FD patients, the gene function improved and an elevation in the level of IKAP protein was observed, reports Prof. Ast. These results were replicated in a second experiment which involved administering the supplement orally to mouse populations with FD.

The findings, which have been published in the journal Human Molecular Genetics, are very encouraging, says Prof. Ast. “That we see such an effect on the brain — the most important organ in relation to this disease — shows that the supplement can pass through the blood-brain barrier even when administered orally, and accumulate in sufficient amounts in the brain.”

Slowing the death of nerve cells

Already approved for use as a supplement by the FDA, phosphatidylserine contains a molecule essential for transmitting signals between nerve cells in the brain. Prof. Ast and his fellow researchers decided to test whether the same chemical, which is naturally synthesized in the body and known to boost memory capability, could impact the genetic mutation which leads to FD.

Researchers applied a supplement derived from oysters, provided by the Israeli company Enzymotec, to cells collected from FD patients. Noticing a robust effect on the gene, including a jump in the production of healthy IKAP proteins, they then tested the same supplement on mouse models of FD, engineered with the same genetic mutation that causes the disease in humans.

The mice received the supplement orally, every two days for a period of three months. Researchers then conducted extensive genetic testing to assess the results of the treatment. “We found a significant increase of the protein in all the tissues of the body,” reports Prof. Ast, including an eight-fold increase in the liver and 1.5-fold increase in the brain. “While the food supplement does not manufacture new nerve cells, it probably delays the death of existing ones,” he adds.

Therapeutic potential for Parkinson’s

That the supplement is able to improve conditions in the brain, even when given orally, is a significant finding, notes Prof. Ast. Most medications enter the body through the blood stream, but are incapable of breaking through the barrier between the blood and the brain.

In addition, the researchers say the supplement’s positive effects extend beyond the production of IKAP. Not only did phosphatidylserine impact the gene associated with FD, but it also altered the level of a total of 2400 other genes — hundreds of which have been connected to Parkinson’s disease in previous studies.

The researchers believe that the supplement may have a beneficial impact on a number of degenerative diseases of the brain, concludes Prof. Ast, including a major potential for the development of new medications which would help tens of millions of people worldwide suffering from these devastating diseases.

Salamanders’ immune systems are key to their remarkable ability to regrow limbs, and could also underpin their ability to regenerate spinal cords, brain tissue and even parts of their hearts, scientists have found.

In research published today in the Proceedings of the National Academy of Sciences researchers from the Australian Regenerative Medicine Institute (ARMI) at Monash University found that when immune cells known as macrophages were systemically removed, salamanders lost their ability to regenerate a limb and instead formed scar tissue.

Lead researcher, Dr James Godwin, a Fellow in the laboratory of ARMI Director Professor Nadia Rosenthal, said the findings brought researchers a step closer to understanding what conditions were needed for regeneration. 

"Previously, we thought that macrophages were negative for regeneration, and this research shows that that’s not the case - if the macrophages are not present in the early phases of healing, regeneration does not occur," Dr Godwin said. 

"Now, we need to find out exactly how these macrophages are contributing to regeneration. Down the road, this could lead to therapies that tweak the human immune system down a more regenerative pathway."

Salamanders deal with injury in a remarkable way. The end result is the complete functional restoration of any tissue, on any part of the body including organs. The regenerated tissue is scar free and almost perfectly replicates the injury site before damage occurred.

"We can look to salamanders as a template of what perfect regeneration looks like," Dr Godwin said. 

Aside from “holy grail” applications, such as healing spinal cord and brain injuries, Dr Godwin believes that studying the healing processes of salamanders could lead to new treatments for a number of common conditions, such as heart and liver diseases, which are linked to fibrosis or scarring. Promotion of scar-free healing would also dramatically improve patients’ recovery following surgery.

There are indications that there is the capacity for regeneration in a range of animal species, but it has, in most cases been turned off by evolution. 

"Some of these regenerative pathways may still be open to us. We may be able to turn up the volume on some of these processes," Dr Godwin said. 

"We need to know exactly what salamanders do and how they do it well, so we can reverse-engineer that into human therapies."

A new study conducted by researchers at the Child Study Center at NYU Langone Medical Center found men diagnosed as children with attention-deficit/hyperactivity disorder (ADHD) were twice as likely to be obese in a 33-year follow-up study compared to men who were not diagnosed with the condition. The study appears in the May 20 online edition of Pediatrics.

“Few studies have focused on long-term outcomes for patients diagnosed with ADHD in childhood. In this study, we wanted to assess the health outcomes of children diagnosed with ADHD, focusing on obesity rates and Body Mass Index,” said lead author Francisco Xavier Castellanos, MD, Brooke and Daniel Neidich Professor of Child and Adolescent Psychiatry, Child Study Center at NYU Langone. “Our results found that even when you control for other factors often associated with increased obesity rates such as socioeconomic status, men diagnosed with ADHD were at a significantly higher risk to suffer from high BMI and obesity as adults.”

According to the Centers for Disease Control and Prevention, ADHD is one of the most common neurobehavioral disorders, often diagnosed in childhood and lasting into adulthood. People with ADHD typically have trouble paying attention, controlling impulsive behaviors and tend to be overly active. ADHD has an estimated worldwide prevalence of five percent, with men more likely to be diagnosed than women.

The prospective study included 207 white men diagnosed with ADHD at an average age of 8 and a comparison group of 178 men not diagnosed with childhood ADHD, who were matched for race, age, residence and social class. The average age at follow up was 41 years old. The study was designed to compare Body Mass Index (BMI) and obesity rates in grown men with and without childhood ADHD.

Results showed that, on average, men with childhood ADHD had significantly higher BMI (30.1 vs. 27.6) and obesity rates (41.1 percent vs. 21.6 percent) than men without childhood ADHD.

“The results of the study are concerning but not surprising to those who treat patients with ADHD. Lack of impulse control and poor planning skills are symptoms often associated with the condition and can lead to poor food choices and irregular eating habits,” noted Dr. Castellanos. “This study emphasizes that children diagnosed with ADHD need to be monitored for long-term risk of obesity and taught healthy eating habits as they become teenagers and adults.”

Imaging technique shows premature birth interrupts vital brain development processes, leading to reduced cognitive abilities in infants

Researchers from King’s College London have for the first time used a novel form of MRI to identify crucial developmental processes in the brain that are vulnerable to the effects of premature birth. This new study, published today in the Proceedings of the National Academy of Sciences (PNAS), shows that disruption of these specific processes can have an impact on cognitive function.

The researchers say the new techniques developed here will enable them to explore how the disruption of key processes can also cause conditions such as autism, and will be used in future studies to test possible treatments to prevent brain damage.

Scientists from King’s College London and Imperial College London used diffusion MRI – a type of imaging which looks at the natural diffusion of water – to observe the maturation of the cerebral cortex where much of the brain’s computing power resides. By analysing the diffusion of water in the cerebral cortex of 55 premature infants and 10 babies born at full term they mapped the growing complexity and density of nerve cells across the whole of the cortex in the months before the normal time of birth.

They found that during this period maturation was most rapid in areas of the brain relating to social and emotional processing, decision making, working memory and visual-spatial processing. These functions are often impaired after premature birth, and the researchers found that cortical development was reduced in preterm compared to full term infants, with the greatest effect in the most premature infants. When they re-examined the infants at two years of age, the preterm infants with the slowest cortical development performed less well on neurodevelopmental testing, demonstrating the longer-term impact of prematurity on cortical maturation.

Professor David Edwards, Director of the Centre for the Developing Brain at King’s, based at the Evelina Children’s Hospital, said: ‘The number of babies born prematurely is increasing, so it has never been more important to improve our understanding of how preterm birth affects brain development and causes brain damage. We know that prematurity is extremely stressful for an infant, but by using a new technique we are able to track brain maturation in babies to pinpoint the exact processes that might be affected by premature birth. Here we have used innovative ways to understand how the development of the cerebral cortex is affected.

‘These findings highlight a key stage of brain development where the neurons branch out to create a complex, mature structure. We can now see that this happens in the latter stages of development that would usually take place in healthy babies when they are still in the womb. This suggests that premature birth can interrupt this vital developmental process. It may explain why we sometimes see adverse effects on brain development in those born only slightly prematurely as we now know that this process is happening right up to the normal time of birth. With this study we found that the earlier a baby is born, the less mature the cortex structure. The weeks a baby loses in the womb really matter.

‘These new techniques we’ve developed to identify these crucial processes will allow us to examine how disruption caused by premature birth can lead to conditions such as autism and learning difficulties. We will also use the technique in future studies to test new treatments to prevent brain damage. It’s an extremely exciting step forward.’

While Huntington’s disease (HD) is currently incurable, the HD research community anticipates that new disease-modifying therapies in development may slow or minimize disease progression. The success of HD research depends upon the identification of reliable and sensitive biomarkers to track disease and evaluate therapies, and these biomarkers may eventually be used as outcome measures in clinical trials. Biomarkers could be especially helpful to monitor changes during the time prior to diagnosis and appearance of overt symptomatology. Three reports in the current issue of the Journal of Huntington’s Disease explore the potential of neuroimaging, proteomic analysis of brain tissue, and plasma inflammatory markers as biomarkers for Huntington’s disease.

"Characteristics of an ideal biomarker include quantification which is reliable, reproducible across sites, minimally invasive and widely available. The biomarker should show low variability in the normal population and change linearly with disease progression, ideally over short time intervals. Finally, the biomarker should respond predictably to an intervention which modifies the disease," says Elin Rees, researcher at UCL Institute of Neurology, London.

In the first report, Rees and colleagues explore the use of neuroimaging biomarkers. She says they are strong candidates as outcome measures in future clinical trials because of their clear relevance to the neuropathology of disease and their increased precision and sensitivity compared with some standard functional measures. This review looks at results from longitudinal imaging studies, focusing on the most widely available imaging modalities: structural MRI (volumetric and diffusion), functional MRI, and PET.

"All imaging modalities are logistically complicated and expensive compared with standard clinical or cognitive end-points and their sensitivity is generally reduced in individuals with later stage HD due to movement," says Rees. "Nevertheless, imaging has several advantages including the ability to track progression in the pre-manifest stage before any detectable clinical or cognitive change."

Current evidence suggests that the best neuroimaging biomarkers are structural MRI and PET using [11C] raclopride (RACLO-PET) as the tracer, in order to assess changes in the basal ganglia, especially the caudate.

A study led by Garth J.S. Cooper, PhD, professor of Biochemistry and Clinical Biochemistry at the School of Biological Sciences and the Department of Medicine at the University of Auckland, used comparative proteome analysis to identify how protein expression might correlate with Huntington’s neurodegeneration in two regions of human brain: the middle frontal gyrus (MFG) and the visual cortex (VC). The investigators studied post mortem human brain tissue from seven HD brains and eight matched controls. They found that the MFG of HD brains differentially expressed 22 proteins compared to controls, while only seven were different in the VC. Several of these proteins had not been linked to HD previous. Investigators categorized these proteins into six general functional categories: stress response, apoptosis, glycolysis, vesicular trafficking, and endocytosis. They determined that there is a common thread in the degenerative processes associated with HD, Alzheimer’s disease, and diabetes.

The third report explores the possibility that inflammatory markers in plasma can be used to track HD, noting that immune changes are apparent even during the preclinical stage. “The innate immune system orchestrates an inflammatory response involving complex interactions between cytokines, chemokines and acute phase proteins and is thus a rich source of potential biomarkers,” says Maria Björkqvist, PhD, head of the Brain Disease Biomarker Unit, Department of Experimental Science of Lund University, Sweden.

The authors compare plasma levels of several markers involved in inflammation and innate immunity of healthy controls and HD patients at different stages of disease. Two methods were used to analyze plasma: antibody-based technologies and multiple reaction monitoring (MRM).

None of the measures were significantly altered in both HD cohorts tested and none correlated with HD disease stage. Only one substance, C-reactive protein (CRP), was decreased in early HD – but this was found in only one of the two cohorts, so the finding may not be reliable. The investigators were unable to confirm other studies that had found HD-related changes in other inflammatory markers, including components of the complement system.

Some markers correlated with clinical measures. For instance, ApoE was positively correlated with depression and irritability scores, suggesting an association between ApoE and mood changes.

Even though recent data suggest that the immune system is likely to be a modifier of HD disease, inflammatory proteins do not seem to be likely candidates to be biomarkers for HD. “Many proteomic studies designed to provide potential biomarkers of disease have generated significant findings, however, often these biomarkers fail to replicate during the validation process,” says Björkqvist.

In 1979 China instituted the one-child policy, which limited every family to just one offspring in a controversial attempt to reduce the country’s burgeoning population. The strictly enforced law had the desired effects: in 2011 researchers estimated that the policy prevented 400 million births. In a new study in Science, researchers find that it has also caused China’s so-called little emperors to be more pessimistic, neurotic and selfish than their peers who have siblings.

Psychologist Xin Meng of the Australian National University in Canberra and her colleagues recruited 421 Chinese young adults born between 1975 and 1983 from around Beijing for a series of surveys and tests that evaluated a variety of psychological traits, such as trustworthiness and optimism. Almost all the participants born after 1979 were only children compared with about one fifth of those born before 1979. The study participants born after the policy went into effect were found to be both less trusting and less trustworthy, less inclined to take risks, less conscientious and optimistic, and less competitive than those born a few years earlier.

“Because of the one-child policy, parents are less likely to teach their child to be imaginative, trusting and unselfish,” Meng says. Without siblings, she notes, the need to share may not be emphasized, which could help explain these findings.

Only children in other parts of the world, however, do not show such striking differences from their peers. Toni Falbo, a social psychologist at the University of Texas at Austin, who was not involved in the study, suggests that larger social forces in China also probably contributed to these results. “There’s a lot of pressure being placed on [Chinese] parents to make their kid the best possible because they only had one,” Falbo says. These types of pressures could harm anyone, even if they had siblings, she says.

Whatever its cause, the personality profile of China’s little emperors may be troubling to a nation hoping to continue its ascent in economic prosperity. The traits marred by the one-child policy, the study authors point out, are exactly those needed in leaders and entrepreneurs.