Scientists have discovered a compound that restores the capacity to form new memories in aging rats, likely by improving the survival of newborn neurons in the brain’s memory hub. The research, funded in part by the National Institutes of Health, has turned up clues to a neuroprotective mechanism that could lead to a treatment for Alzheimer’s disease.

“This neuroprotective compound, called P7C3, holds special promise because of its medication-friendly properties,” explained Steven McKnight, Ph.D., who co-led the research with Andrew Pieper, M.D., Ph.D., both of University of Texas Southwestern Medical Center, Dallas. “It can be taken orally, crosses the blood-brain barrier with long-lasting effects, and is safely tolerated by mice during many stages of development.”

The researchers report on their findings July 9, 2010 in the journal Cell. Their work was funded, in part, by the NIH’s National Institute of Mental Health (NIMH), a NIH Director’s Pioneer Award funded through the Common Fund and managed by the National Institute of General Medical Sciences, and National Cancer Institute.

“This striking demonstration of a treatment that stems age-related cognitive decline in living animals points the way to potential development of the first cures that will address the core illness process in Alzheimer’s disease,” said NIMH Director Thomas Insel, M.D.

Physical activity, social, or other enriching experiences promote neurogenesis — the birth and maturation of new neurons. This growth takes place in the dentate gyrus, a key area of the brain’s memory hub, the hippocampus. But even in the normal adult brain, most of these newborn neurons die during the month it takes to develop and get wired into brain circuitry. To survive, the cells must run a gauntlet of challenges. Newborn hippocampus neurons fare much worse in aging-related disorders like Alzheimer’s, marked by runaway cell death.

In hopes of finding compounds that might protect such vulnerable neurons during this process, Pieper, McKnight and colleagues tested more than 1000 small molecules in living mice. One of the compounds, designated P7C3, corrected deficits in the brains of adult mice engineered to lack a gene required for the survival of newborn neurons in the hippocampus. Giving P7C3 to the mice reduced programmed death of newborn cells — normalizing stunted growth of branch-like neuronal extensions and thickening an abnormally thin layer of cells by 40 percent. Among clues to the mechanism by which P7C3 works, the researchers discovered that it protects the integrity of machinery for maintaining a cell’s energy level.

To find out if P7C3 could similarly stem aging-associated neuronal death and cognitive decline, the researchers gave the compound to aged rats. Rodents treated with P7C3 for two months significantly outperformed their placebo-treated peers on a water maze task, a standard assay of hippocampus-dependent learning. This was traced to a threefold higher-than-normal level of newborn neurons in the dentate gyrus of the treated animals. Rats were used instead of mice for this phase of the study because the genetically engineered mice could not swim.

The researchers pinpointed a derivative of P7C3, called A20, which is even more protective than the parent compound. They also produced evidence suggesting that two other neuroprotective compounds eyed as possible Alzheimer’s cures may work through the same mechanism as P7C3. The A20 derivative proved 300 times more potent than one of these compounds currently in clinical trials for Alzheimer’s disease. This suggested that even more potent neuroprotective agents could potentially be discovered using the same methods. Following up on these leads, the researchers are now searching for the molecular target of P7C3 – key to discovering the underlying neuroprotective mechanism.

The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit the NIMH website.

The NIH Common Fund encourages collaboration and supports a series of exceptionally high impact, trans-NIH programs. These new programs are funded through the Common Fund, and managed by the NIH Office of the Director in partnership with the various NIH Institutes, Centers and Offices. Common Fund programs are designed to pursue major opportunities and gaps in biomedical research that no single NIH Institute could tackle alone, but that the agency as a whole can address to make the biggest impact possible on the progress of medical research. Additional information about the NIH Common Fund can be found at http://commonfund.nih.gov.

NIGMS is a part of NIH that supports basic research to increase our understanding of life processes and lay the foundation for advances in disease diagnosis, treatment and prevention. For more information on the Institute’s research and training programs, see http://www.nigms.nih.gov.

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The National Institutes of Health (NIH) — The Nation’s Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit the NIH website.

(CNN) — Every Friday morning, students walk into an art class in Atlanta, Georgia. Some look dazed, uncertain in their environment, as if it’s vaguely familiar but they can’t fully recognize where they are — until they sit down and begin to draw.

The moment their brushes hit the paper, their faces light up. Using bright colors — yellows, oranges, greens, purples — they begin to transfer the images from their minds. Sometimes they paint what they want and sometimes they draw the highlighted centerpiece of the day. One week it’s vegetables, another week it’s hats. As their artworks progress, they look happy, smiling and glancing at their teachers for approval. They’re not the only ones who are pleased.

Tania Becker, president of the board of the Spruill Center in Atlanta, developed the Arts 4 Alzheimer’s program with the help of the Museum of Modern Art in New York and the Alzheimer’s Association. This program helps Alzheimer’s patients and their caregivers escape the disease, even if only for a few hours.

“One of the ways to get to people with Alzheimer’s is to engage them through art, because art is so creative,” says Becker. “It’s the one thing, of course, you learn as a child, so those memories are still there and we can get into their memory bank through art. It’s just amazing to see how this works.”

An estimated 5.3 million Americans of all ages have Alzheimer’s disease, according to the Alzheimer’s Association. The number could be as high as 13.4 million by 2050, the U.S. Centers for Disease Control and Prevention projects. There is no cure.

As the world waits for a cure, Becker and her volunteers are reaching their students in a creative way. The class cuts through the isolation Alzheimer’s patients can experience and gives them a chance to express emotion through their art.

Bill and Carole Bates benefit from Arts 4 Alzheimer’s. They have been happily married since they were teenagers. After 57 years, they remain resilient partners.

After they learned Carole had Alzheimer’s, Bill wanted to read and learn everything he could about the disease. Then one day, he picked up the Spruill Center newsletter and found a class that he thought might help Carole: Arts 4 Alzheimer’s.

“I immediately wanted to become a part of it,” Bill says.

So they did. Every week Bill and Carole come to the class and sit down with others who share an understanding and circumstance. Instead of falling victim to this disease, people are celebrating their lives through their art.

Bill sometimes sits in the corner reading his newspaper. Every now and then Carole will gently grab her husband’s hand and look up at him with love and generosity. This class brings people away from the isolation they may experience and gives them a chance to be expressive through their art.

Carole loved the class so much, she asked her husband to take her to the Spruill Center on a day when class wasn’t in session just to be certain she wouldn’t miss.

In 2009, almost 11 million family members and friends provided unpaid care for a person with Alzheimer’s and other dementias; this resulted in an estimated 12.5 billion hours of care, according to the Alzheimer’s Association. This disease takes both victims and caregivers away from their lives and memories.

“One of the things about people with Alzheimer’s is that they have no yesterday and they have no tomorrow,” says Becker. “All they have is the now. So what we give them is a very special now here with their art.”

Some guys sound tough – and according to a new study, that may a good way of predicting whether they really are.

Results  in the current Proceedings of the Royal Society B found that people can accurately evaluate the upper-body strength based on men’s voices from four different populations and language groups. The voice samples came from the Tsimane of Bolivia, Andean herder-horticulturalists from Argentina, and college students from the United States and Romania.

Researchers recorded body size and strength measurements from women and men in each of these groups. These participants also reported how many fights they had been involved in during the last four years.

Then, undergraduates from the University of California, Santa Barbara, rated the voices on physical strength, height and weight. For the sample of male voices from the United States, raters assessed “how tough he would be in a physical fight.”

The study found that, for the sample where data were available, the higher the perceived fighting ability, the more fights the man in the voice sample had reported being involved in during the last four years. It is not known how many fights these men won, but previous research suggests that “more formidable individuals are those more likely to engage in fights,” the authors wrote.]

For the rest of the samples, regardless of language spoken in the speech samples, participants rating the voices reported mostly accurate predictions for physical strength for men, but not for women. There was no significant difference between how good men and women were at evaluating the voices.

The results support the idea that the human voice, especially the male voice, has cues of physical strength, and that humans have evolved to be able to predict fighting ability based on those cues. This would have had great benefit to human ancestors, who may have used this information to their survival benefit – for instance, in choosing whom to fight with and whom not to confront.

Update: The study did not determine specifically what qualities in the voices were associated with greater strength. Researchers found, however, that pitch and timbre were not explanatory factors. In other words, contrary to what you might expect, lower pitch was not associated with greater perceived strength.

WASHINGTON – Playing violent video games can make some adolescents more hostile, particularly those who are less agreeable, less conscientious and easily angered. But for others, it may offer opportunities to learn new skills and improve social networking.

In a special issue of the journal Review of General Psychology, published in June by the American Psychological Association, researchers looked at several studies that examined the potential uses of video games as a way to improve visual/spatial skills, as a health aid to help manage diabetes or pain and as a tool to complement psychotherapy. One study examined the negative effects of violent video games on some people.

“Much of the attention to video game research has been negative, focusing on potential harm related to addiction, aggression and lowered school performance,” said Christopher J. Ferguson, PhD, of Texas A&M International University and guest editor of the issue. “Recent research has shown that as video games have become more popular, children in the United States and Europe are having fewer behavior problems, are less violent and score better on standardized tests. Violent video games have not created the generation of problem youth so often feared.”

In contrast, one study in the special issue shows that video game violence can increase aggression in some individuals, depending on their personalities.

In his research, Patrick Markey, PhD, determined that a certain combination of personality traits can help predict which young people will be more adversely affected by violent video games. “Previous research has shown us that personality traits like psychoticism and aggressiveness intensify the negative effects of violent video games and we wanted to find out why,” said Markey.

Markey used the most popular psychological model of personality traits, called the Five-Factor Model, to examine these effects. The model scientifically classifies five personality traits: neuroticism, extraversion, openness to experience, agreeableness and conscientiousness.

Analysis of the model showed a “perfect storm” of traits for children who are most likely to become hostile after playing violent video games, according to Markey. Those traits are: high neuroticism (e.g., easily upset, angry, depressed, emotional, etc.), low agreeableness (e.g., little concern for others, indifferent to others feelings, cold, etc.) and low conscientiousness (e.g., break rules, don’t keep promises, act without thinking, etc.).

Markey then created his own model, focusing on these three traits, and used it to help predict the effects of violent video games in a sample of 118 teenagers. Each participant played a violent or a non-violent video game and had his or her hostility levels assessed. The teenagers who were highly neurotic, less agreeable and less conscientious tended to be most adversely affected by violent video games, whereas participants who did not possess these personality characteristics were either unaffected or only slightly negatively affected by violent video games.

“These results suggest that it is the simultaneous combination of these personality traits which yield a more powerful predictor of violent video games,” said Markey. “Those who are negatively affected have pre-existing dispositions, which make them susceptible to such violent media.”

“Violent video games are like peanut butter,” said Ferguson. “They are harmless for the vast majority of kids but are harmful to a small minority with pre-existing personality or mental health problems.”

The special issue also features articles on the positives of video game play, including as a learning tool. For example:

• Video games serve a wide range of emotional, social and intellectual needs, according to a survey of 1,254 seventh and eighth graders. The study’s author, Cheryl Olson, PhD, also offers tips to parents on how to minimize potential harm from video games (i.e., supervised play, asking kids why they play certain games, playing video games with their children).
• Commercial video games have been shown to help engage and treat patients, especially children, in healthcare settings, according to a research review by Pamela Kato, PhD. For example, some specially tailored video games can help patients with pain management, diabetes treatment and prevention of asthma attacks.
• Video games in mental health care settings may help young patients become more cooperative and enthusiastic about psychotherapy. T. Atilla Ceranoglu, M.D., found in his research review that video games can complement the psychological assessment of youth by evaluating cognitive skills and help clarify conflicts during the therapy process.

Contact Dr. Christopher Ferguson by e-mail or by phone at (956) 326-2636 or (407) 384-8874 during June 1 – June 15.

Contact Dr. Patrick Markey by e-mail or by phone at (610) 519-4743.

Background

In addition to its association with intellectual disability, FXS is the most common known specific genetic risk factor for autism spectrum disorders (ASD). FXS results from mutations on a gene that creates a protein called FMRP. The mutations, in effect, turn off the gene. Relatively little is known about how these mutations affect brain development in early childhood.

Allan Reiss, M.D., of Stanford University, in collaboration with colleagues from Stanford and the University of North Carolina, used magnetic resonance imaging (MRI) to examine changes in brain volumes in 69 boys, first assessed at ages 1-3 and then again an average of two years later at ages 3-5. Of the participants, 41 had FXS, 21 had typical development, and seven had some form of developmental delay.

Results of the Study

The researchers found that some brain regions were similar between the boys with FXS and those without FXS at both times they underwent MRI. Other regions were abnormal among those with FXS at the first time point and remained that way at the second time point, suggesting that the gene mutations responsible for FXS begin to alter brain development early in life, possibly even before birth.

Furthermore, some brain regions were similar among all the participants at the start of the study but showed major differences by the second MRI at ages 3-5.

“This third category is the most interesting because it suggests that we have captured a critical development window of brain development that is significantly affected by fragile X,” said Reiss.

Significance

The same mutations that cause FXS are also strongly linked to ASD. Thus, FXS is considered a model condition for informing research on ASD.

This study provides greater insight into how FXS mutations affect early brain development, which may one day serve as targets for the development and evaluation of new interventions for FXS and related disorders.

What’s Next

The researchers note that their study provides only preliminary information and that it will be crucial to follow the study participants as they enter their school age years, a time when the greatest number and severity of ASD behaviors tend to appear.

Future studies should include larger control samples, track development from an earlier age, and follow participants for a longer period of time. Studies comparing FXS population with those affected by other specific genetic risk factors, such as those occurring in Williams syndrome, may be useful as well.

Reference

Hoeft F, Carter JC, Lightbody AA, Cody Hazlett H, Piven J, Reiss AL. Region-specific alterations in brain development in one- to three-year-old boys with fragile X syndrome. Proc Natl Acad Sci U S A. 2010 2010 May 18;107(20):9335-9. Epub 2010 May 3. PubMed PMID: 20439717.

“These results suggest that early treatment decisions are probably the most crucial to the recovery of teens with hard-to-treat depression,” said NIMH Director Thomas R. Insel, M.D.

In the Treatment of Resistant Depression in Adolescents (TORDIA) study, teens whose depression had not improved after an initial course of selective serotonin reuptake inhibitor (SSRI) antidepressant treatment were randomly assigned to one of four interventions for 12 weeks:

• Switch to another SSRI-paroxetine (Paxil), citalopram (Celexa) or fluoxetine (Prozac)
• Switch to a different SSRI plus cognitive behavioral therapy (CBT), a type of psychotherapy that emphasizes problem-solving and behavior change
• Switch to venlafaxine (Effexor), another type of antidepressant called a serotonin and norepinephrine reuptake inhibitor (SNRI)
• Switch to venlafaxine plus CBT

As reported in February 2008, after 12 weeks, about 55 percent of those who switched to either type of medication and added CBT responded, while 41 percent of those who switched to another medication alone responded.

For the most recent findings, Graham Emslie, M.D., of the University of Texas Southwestern Medical Center at Dallas, and colleagues measured the teens’ rate of remission after 24 weeks of treatment. Among the 334 TORDIA participants, 78 percent completed the 24-week assessment. The researchers found that nearly 40 percent of those who completed 24 weeks of treatment achieved remission, regardless of which treatment to which they had initially been assigned. However, those who achieved remission were more likely to have responded to treatment early—during the first 12 weeks.

Those who had very severe depression at baseline, a sense of hopelessness, anxiety and family conflict were less likely to achieve remission. Those who were taking an additional mood stabilizing medication, such as an antipsychotic or anti-anxiety medication, or who were receiving CBT, were more likely to achieve remission, but ONLY if the teens received these additional treatments in the first 12 weeks.

Moreover, those who achieved remission tended to have responded to treatment by six weeks into treatment compared to those who had not achieved remission by 24 weeks, underscoring the importance of early treatment decisions.

The authors suggest that the current clinical guidelines, which recommend staying with a treatment for at least eight to twelve weeks before trying another, may need to be revisited. More research is needed to clarify when is the optimal time to change a treatment strategy among treatment-resistant teens with depression, they concluded.

Reference

Emslie GJ, Mayes T, Porta G, Vitiello B, Clarke G, Wagner KD,Asarnow JR, Spirito A, Birmaher B, Ryan N, Kennard B, DeBar L, McCracken J, Strober M, Onorato M, Zalazny J, Keller M, Iyengar S, Brent D. Treatment of resistant depression in adolescents (TORDIA): week 24 outcomes. American Journal of Psychiatry. Online ahead of print May 17, 2010.