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.

(Source: dzne.de)

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.”

(Source: eurekalert.org)

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.

(Source: hopkinsmedicine.org)