New research at the University of Colorado Cancer Center shows how to stop both.

Specifically, cells signal themselves to survive, grow, reproduce, and migrate. Two years ago, researchers at the CU Cancer Center showed that turning off a family of signals made brain cancer cells less robust – it sensitized these previously resistant cells to chemotherapy.

But the second major problem – migration – potentially remained.

“I thought, aha, I have this great way to treat this cancer, but needed to check that we weren’t going to cause other problems. We wondered if turning off TAM family signaling would make brain cancer cells crawl away to a new spot where they might make new problems,” says Amy Keating, MD, investigator at the CU Cancer Center and senior author of the study, recently published in the journal Nature: Oncogene.

So Keating and colleagues went inside this TAM signaling family to explore how its members affect not only proliferation but migration. When they inhibited signaling through the other family member Axl, little changed (actually this was good: at least turning off this signaling pathway didn’t promote cancer cell migration).

But when Keating and colleagues turned off signaling through the Mer pathway, it was neither too hot nor too cold – it was just right, and these affected cancer cells were not only more sensitive to chemotherapy, but also unable to escape to safer areas of the brain.

Currently glioblastoma multiforme affects 45,000 people in the United States every year, the majority of whom will not survive 14 months after diagnosis.

“This represents a new targeted therapy, offering a potential new direction that nobody’s tried before,” says Keating, assistant professor of pediatrics at the University of Colorado School of Medicine.

After these extremely promising results with cell lines, Keating and colleagues are currently testing the technology in mice, after which all involved hope to move soon to human clinical trials.

The discovery by researchers at Washington University School of Medicine in St. Louis may lead doctors and researchers to change the way Alzheimer’s disease is classified.

They report their findings Feb. 1 in the online journal PLoS One (Public Library of Science).

“We probably shouldn’t think of early-onset disease as inherited and late-onset as sporadic because sporadic cases and familial clustering occur in both age groups,” says senior investigator Alison M. Goate, DPhil. “I think it’s reasonable to assume that at least some cases among both early- and late-onset disease have the same causes. Our findings suggest the disease mechanism can be the same, regardless of the age at which Alzheimer’s strikes. People who get the disease at younger ages probably have more risk factors and fewer protective ones, while those who develop the disease later in life may have more protective factors, but it appears the mechanism may be the same for both.”

The researchers used next-generation DNA sequencing to analyze genes linked to dementia. They sequenced the APP (amyloid precursor protein) gene, and the PSEN1 and PSEN2 (presenilin) genes. Mutations in those genes have been identified as causes of early-onset Alzheimer’s disease. They also sequenced the MAPT (microtubule associated protein tau) gene and GRN (progranulin) gene, which have been associated with inherited forms of another illness involving memory loss called frontotemporal dementia.

“We found an increase in rare variants in the Alzheimer’s genes in families where four or more members were affected with late-onset disease,” says Goate, the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry, professor of neurology, of genetics and co-director of the Hope Center Program on Protein Aggregation and Neurodegeneration. “Changes in these genes were more common in Alzheimer’s cases with a family history of dementia, compared to normal individuals. This suggests that some of these gene variants are likely contributing to Alzheimer’s disease risk.”

The study also found mutations in the MAPT and GRN genes in some Alzheimer’s patients, suggesting they had been incorrectly diagnosed as having Alzheimer’s disease when they instead had frontotemporal dementia.

Goate and her colleagues studied the five genes in members of 440 families in which at least four individuals per family had been diagnosed with Alzheimer’s disease. They found rare variants in key Alzheimer’s-related genes in 13 percent of the samples they analyzed.

“Of those rare gene variants, we think about 5 percent likely contribute to Alzheimer’s disease,” says first author Carlos Cruchaga, PhD, assistant professor of psychiatry. “That may not seem like a lot, but so many people have the late-onset form of Alzheimer’s that even a very small percentage of patients with changes in these genes could represent very large numbers of affected individuals.”

Goate, who in 1991 was the first scientist to identify a mutation in the APP gene linked to inherited, early-onset Alzheimer’s disease, now wants to look closely at families with multiple cases of Alzheimer’s but no mutations in previously identified Alzheimer’s genes. She says it’s likely they carry mutations in genes that scientists don’t yet know about. And she believes that new sequencing techniques could speed the discovery of these genes. In fact, the researchers say a study like this would have been impossible only a few years ago.

“With next-generation sequencing technology, it’s now possible to sequence all of these genes at the same time,” Cruchaga says. “One reason we didn’t do this study until now is that 15 to 20 years ago when these genes were first identified, it would have taken years to sequence each gene individually.”

Cruchaga and Goate say the new technology and their new findings suggest that it may be worthwhile to sequence these genes in people with a strong family history of Alzheimer’s disease.

“We would like to see physicians who treat patients with late-onset disease ask detailed questions about family history,” Goate says. “I’m sure many probably do that already, but in those families with very strong histories, it’s not unreasonable to think about screening for genetic mutations.”

She says such screenings also may weed out people thought to have Alzheimer’s disease who actually have changes in genes related to frontotemperal dementia.

Both Goate and Cruchaga agree that one result of their discovery that the same genes can be connected with both early- and late-onset forms of Alzheimer’s disease may be changes in the way the disease is classified.

“It’s always been somewhat arbitrary, figuring out where early-onset ends and late-onset begins,” Goate says. “So I no longer look at early- and late-onset disease as being different illnesses. I think of them as stages along a continuum.”

A group of psychological scientists explore the relationship between silence and memories in a new paper published in Perspectives on Psychological Science, a journal of the Association for Psychological Science.

“There’s this idea, with silence, that if we don’t talk about something, it starts fading,” says Charles B. Stone of Université Catholique de Louvain in Belgium, an author of the paper. But that belief isn’t necessarily backed up by empirical psychological research—a lot of it comes from a Freudian belief that everyone has deep-seated issues we’re repressing and ought to talk about. The real relationship between silence and memory is much more complicated, Stone says.

“We are trying to understand how people remember the past in a very basic way,” Stone says. He cowrote the paper with Alin Coman of the University of Pittsburgh, Adam D. Brown of New York University, Jonathan Koppel of the University of Aarhus, and William Hirst of the New School for Social Research.

“Silence is everywhere,” Stone says. He and his coauthors divide silence about memories into several categories. You might not mention something you’re thinking about on purpose—or because it just doesn’t come up in conversation. And some memories aren’t talked about because they simply don’t come to mind. Sometimes people actively try not to remember something.

One well-studied example used by Stone and his colleagues to demonstrate how subtle the effects of silence can be, establishes that silences about the past occurring within a conversation do not uniformly promote forgetting.  Some silences are more likely to lead to forgetting than others.  People have more trouble remembering silenced memories related to what they or others talk about than silenced memories unrelated to the topic at hand.

If President Bush wanted the public to forget that weapons of mass destruction figured in the build-up to the Iraq War, he should not avoid talking about the war and its build-up.  Rather he should talk about the build-up and avoid any discussion of WMDs.  And at a more personal level, when people talk to each other about the events of their lives, talking about happy memories may leave the unhappy memories unmentioned, but in the future, people may have more trouble remembering the unmentioned happy memories than the unmentioned sad memories.

Or to supply another example of the subtle relation between memory and silence:  If your mother is asking you about your boyfriend and you tell her about yesterday’s date, while thinking—but not talking—about the exciting ending of the date, that romantic finish may linger longer in your memory than if you just answered her questions without thinking about the later part of the evening.

“Silence has important implications for how we remember the past beyond just forgetting,” Stone says. “In terms of memory, not all silence is equal.”

“Neurologists see patients with neurologic disorders that may make them more susceptible to abuse or neglect,” said lead author Elliott A. Schulman, MD, of Lankenau Medical Center in Wynnewood, Penn., and a Fellow of the American Academy of Neurology. “They also see patients with neurologic issues that may be either directly or indirectly related to mistreatment.”

More than 90 percent of all injuries from intimate partner violence occur to the head, face or neck region, and can lead to traumatic brain injury, according to the position statement. People with neurologic disorders such as Parkinson’s disease, Alzheimer’s disease or stroke may be at higher risk for abuse and neglect.

“By routinely asking about violence and abuse, the neurologist increases the opportunity for both identifying ongoing abuse and intervening when appropriate,” Schulman said. “In addition to further physical and emotional harm, consequences of not asking about abuse might include failure of treatments and, when children are exposed to abuse, perpetuation of the cycle of abuse from generation to generation.”

The position statement outlines 10 principles of intervention by the neurologist when meeting with patients, beginning with integrating questions about abuse into the medical history and routinely screening all patients for past and ongoing violence.

The Academy is also offering free training to members interested in seeking to help address domestic violence issues in their communities.

“Our work with mice demonstrates how genes play a role in developing and extinguishing pathological fear like Post Traumatic Stress Disorder,” says Gleb Shumyatsky, an associate professor in the Department of Genetics in the School of Arts and Sciences. “It is clear that previous life experiences are not the only cause of PTSD – genetic predispositions may make some people more sensitive and others more resilient to PTSD.”

Since humans and animals register fear in the brain similarly, the discovery being reported today in the journal PLoS ONE, is an important step to understanding how genes work in the brain to control learning and memory as well as reactions to fearful and traumatic experiences.

In the study, mice bred missing either one of the two fear memory-related genes were trained to be afraid of the cage and a tone associated with a mild shock. Next, by repeatedly putting the mice in the training cage or presenting them with the tone – but now without the shock – the scientists taught them not to be afraid, a process called fear memory extinction. When extinction was performed using the fearful context, a training cage, the knockout mice behaved normally, similar to wild type control mice.

These same mutant mice acted quite differently, however, when they heard a quiet, fear-evoking tone that had previously been followed by the same shock. Mice bred without the gastrin-related peptide receptor (GRPR) gene were more fearful of the tone and froze up more often than normal mice, despite no longer being in danger of receiving a shock. By contrast, mice bred without the stathmin gene forgot that they had been afraid of the dangerous tones and stopped freezing.

Next, the scientists analyzed the neural activities of portions of the brain that deal with fear and anxiety in humans – the amygdala, hippocampus, and medial prefrontal cortex. What they discovered: Genetic evidence of a connection between the amygdala – the portion of the brain where unconscious fears are stored – and the prefrontal cortex, the area that enables animals and humans to inhibit excessive fear to better react to potential danger.

The “fearless” stathmin-deficient mice exhibited an increase in brain activity in the prefrontal cortex and a decrease in the amygdala. The opposite occurred in the timid, GRPR deficient mice that were overly afraid in spite of the fact that they were no longer in danger.

Shumyatsky says scientists need to continue identifying molecules involved in the neural circuits of the brain responsible for specific memories and behaviors in order to develop psychotherapeutic, pharmacological and genetic therapies to treat disabling anxiety disorders like PTSD which is estimated to affect 30 percent of combat veterans.

“The research suggests that there are different types of PTSD and that different medical treatments could be applied to treat the cue-related versus the context-related PTSD symptoms, Shumyatsky says.

“In our study, we observed that even in adults with apparently good cognitive health, increasing amounts of beta-amyloid in the brain are related to subtle changes in memory and mental function,” said study author Denise C. Park, PhD, of the Center for Vital Longevity at the University of Texas at Dallas.

For the study, 137 people between the ages of 30 and 89 who were highly educated and free of dementia underwent brain scans. Participants were also tested for the APOE gene, which has been linked to a higher risk of Alzheimer’s disease.

The study found that the amount of beta-amyloid in people’s brains increased with age and that about 20 percent of adults age 60 and older had significantly elevated levels of beta-amyloid. Higher amounts of beta-amyloid detected on brain scans were linked with lower test scores related to working memory, reasoning and speed of processing information.

In the group with higher levels of beta-amyloid, 38 percent of people had the Alzheimer’s risk allele of the APOE gene compared to 15 percent of people who did not have higher levels of beta-amyloid.

“A key question for future research is whether some adults with high levels of beta-amyloid will maintain good mental function for a long period of time and whether higher beta-amyloid deposits in healthy adults always predetermines cognitive decline,” said Park.

However people with aMCI are at a greater risk of developing Alzheimer’s disease (AD), and identification of these people would mean that they could begin treatment as early as possible.

New research published in BioMed Central’s open access journal BMC Geriatrics shows that specific questions, included as part of a questionnaire designed to help diagnose AD, are also able to discriminate between normal memory loss and aMCI.

Loss of memory can be distressing for the person affected and their families and both the patient and people who know them may complain about their memory as well as difficulties in their daily lives. However memory problems can be a part of normal aging and not necessarily an indicator of incipient dementia. A pilot study had indicated that a simple, short, questionnaire (AQ), designed to identify people with AD by using informant-reported symptoms, was also able to recognize people with aMCI.

The AQ consists of 21 yes/no questions designed to be answered by a relative or carer in a primary care setting. The questions fall into five categories: memory, orientation, functional ability, visuospatial ability, and language. Six of these questions are known to be predictive of AD and are given extra weighting, resulting in a score out of 27. A score above 15 was indicative of AD, and between 5 and 14 of aMCI. Scores of 4 or lower indicate that the person does not have significant memory problems.

While validating the AQ researchers from Banner Sun Health Research Institute discovered that four of the questions were strong indicators of aMCI.

Psychometrist Michael Malek-Ahmadi, who led the study, explained, “People with aMCI were more often reported as repeating questions and statements, having trouble knowing the date or time, having difficulties managing their finances and a decreased sense of direction.” He continued, “While the AQ cannot be used as a definitive guide to diagnosing AD or aMCI, it is a quick and simple-to-use indicator that may help physicians determine which individuals should be referred for more extensive testing.”

The findings are now published in the scientific journal Diabetes Care.

The main hormonal function of insulin is to support the uptake and use of glucose in muscles and fat tissues.

However, in an earlier article recently published in Molecular Neurobiology, Christian Benedict from the Department of Neuroscience at Uppsala University has reported that when insulin reaches the brain, it enhances memory function in humans.

As insulin’s capacity to stimulate glucose metabolism generally declines with age, it may also be that it affects the rate of cognitive aging in seniors.

In a new study, Christian Benedict, together with colleagues from Uppsala University (Samantha Brooks, Håkan Ahlström, Lars Lind, and Helgi Schiöth), the UK, and the US, have systematically studied 331 men and women at the age of 75 years. The researchers examined whether insulin sensitivity is tied to brain health.

The brain structure of each participant was measured using magnetic imaging technology, so-called MRT, and their language skills were tested by asking them to name as many animals as possible in one minute (so-called verbal fluency).

“We found that in elderly whose insulin sensitivity was still high, the brains were larger, and they had more grey matter in regions that are important for language skills, compared with those who had diminished insulin sensitivity. We also observed that higher insulin sensitivity was associated with better scores on the language test. Our findings offer a possible explanation for why methods that improve insulin sensitivity, such as exercise, are promising strategies for counteracting cognitive aging late in life,” says Christian Benedict.

The study, conducted by researchers at the Center for Infection and Immunity at Columbia University’s Mailman School of Public Health and collaborators at seven other institutions in the U.S, Germany and Australia, can be found online at Molecular Psychiatry.

The scientists evaluated 198 patients in California with schizophrenia, bipolar disorder and major depressive disorder, carefully matched each one of them with a healthy control of the same sex, age, region and socio-economic status, and tested blood of patients and controls for the presence of BDV genetic material and antibodies to BDV. The investigators hypothesized that if the virus was, in fact, associated with a psychiatric disorder, genetic evidence of infection would be apparent in blood samples taken at the onset and/or at the peak of a psychiatric episode, and antibody evidence would be detectable several weeks afterward.

Blood samples were therefore collected within six weeks of the onset of an acute episode or clinically significant worsening of symptoms and six weeks later to allow for changes in viral load or antibody levels. Not only did the researchers find no relationship between mental illness and bornavirus, they found no evidence of active or historical infection with BDV in any of the subjects.

“Our study provides compelling evidence that bornaviruses do not play a role in schizophrenia or mood disorders,” says Mady Hornig, MD, director of translational research at the Center for Infection and Immunity.

In a commentary in the same issue of the journal, Michael B.A. Oldstone, MD, an expert in molecular virology and central nervous system infections at the Scripps Research Institute, observes that the design and experimental procedures carried out in the Hornig study provide a gold standard for investigating links between persistent viral infection and human disease.

CII director, W. Ian Lipkin, MD, senior author of the paper, notes that “it was concern over the potential role of BDV in mental illness and the inability to identify it using classical techniques that led us to develop molecular methods for pathogen discovery. Ultimately these new techniques enabled us to refute a role for BDV in human disease. But the fact remains that we gained strategies for the discovery of hundreds of other pathogens that have important implications for medicine, agriculture and environmental health.”

Among key findings of the study by National Institutes of Health scientists: genes implicated in schizophrenia and autism turn out to be members of a select club of genes in which regulatory activity peaks during an environmentally-sensitive critical period in development. The mechanism, called DNA methylation, abruptly switches from off to on within the human brain’s prefrontal cortex during this pivotal transition from fetal to postnatal life. As methylation increases, gene expression slows down after birth.

Epigenetic mechanisms like methylation leave chemical instructions that tell genes what proteins to make –what kind of tissue to produce or what functions to activate. Although not part of our DNA, these instructions are inherited from our parents. But they are also influenced by environmental factors, allowing for change throughout the lifespan.

“Developmental brain disorders may be traceable to altered methylation of genes early in life,” explained Barbara Lipska, Ph.D., a scientist in the NIH’s National Institute of Mental Health (NIMH) and lead author of the study. “For example, genes that code for the enzymes that carry out methylation have been implicated in schizophrenia. In the prenatal brain, these genes help to shape developing circuitry for learning, memory and other executive functions which become disturbed in the disorders. Our study reveals that methylation in a family of these genes changes dramatically during the transition from fetal to postnatal life – and that this process is influenced by methylation itself, as well as genetic variability. Regulation of these genes may be particularly sensitive to environmental influences during this critical early life period.”

Lipska and colleagues report on the ebb and flow of the human prefrontal cortex’s (PFC) epigenome across the lifespan, February 2, 2012, online in the American Journal of Human Genetics.

“This new study reminds us that genetic sequence is only part of the story of development. Epigenetics links nurture and nature, showing us when and where the environment can influence how the genetic sequence is read,” said NIMH director Thomas R. Insel, M.D.

In a companion study published last October, the NIMH researchers traced expression of gene products in the PFC across the lifespan. The current study instead examined methylation at 27,000 sites within PFC genes that regulate such expression. Both studies examined post-mortem brains of non-psychiatrically impaired individuals ranging in age from two weeks after conception to 80 years old.

In most cases, when chemicals called methyl groups attach to regulatory regions of genes, they silence them. Usually, the more methylation, the less gene expression. Lipska’s team found that the overall level of PFC methylation is low prenatally when gene expression is highest and then switches direction at birth, increasing as gene expression plummets in early childhood. It then levels off as we grow older. But methylation in some genes shows an opposite trajectory. The study found that methylation is strongly influenced by gender, age and genetic variation.

For example, methylation levels differed between males and females in 85 percent of X chromosome sites examined, which may help to explain sex differences in disorders like autism and schizophrenia.

Different genes – and subsets of genes – methylate at different ages. Some of the suspect genes found to peak in methylation around birth code for enzymes, called methytransferases, that are over-expressed in people with schizophrenia and bipolar disorder. This process is influenced, in turn, by methylation in other genes, as well as by genetic variation. So genes associated with risk for such psychiatric disorders may influence gene expression through methylation in addition to inherited DNA.