Researchers Provide the First Comprehensive and Prospective Characterization of a Genetic Subtype of Autism

In the first prospective study of its kind, Seaver Autism Center researchers at the Icahn School of Medicine at Mount Sinai provide new evidence of the severity of intellectual, motor, and speech impairments in a subtype of autism called Phelan-McDermid Syndrome (PMS). The data are published online in the June 11 issue of the journal Molecular Autism.

Mutation or deletion of a gene known as SHANK3 is one of the more common single-gene causes of autism spectrum disorders and is critical to the development of PMS, a  severe type of autism. To date, clinicians have relied on case studies and retrospective reviews of medical records to understand  the features of this disorder and how the clinical presentation relates to the extent of the genetic changes in the SHANK3 region. In the first systematic and comprehensive prospective trial, researchers led by Alex Kolevzon, MD, Clinical Director of the Seaver Autism Center, under the direction of Joseph Buxbaum, PhD, Director of the Seaver Autism Center, enrolled 32 participants with SHANK3 deletions to comprehensively assess their clinical symptoms and examine how the size of the SHANK3 deletion correlated to those symptoms.

“Previous studies have not utilized prospective assessments to understand Phelan-McDermid Syndrome, and the prevalence of autism spectrum disorder has never been examined using gold-standard instruments” said Dr. Kolevzon. “There is no established standard for assessing  this type of autism, and our study provides important guidance in developing such a standard.”

Of the 32 patients enrolled, 84 percent met criteria for an autism spectrum disorder. Seventy-seven percent of patients exhibited severe to profound intellectual disability, with 19 percent using some form of verbal communication. Other common features included low muscle tone, gait disturbance, and seizures. The researchers also found that patients who had larger SHANK3 deletions had more severe disease.

“Our findings provide additional evidence of the significant impairment associated with SHANK3 deficiency,” said Dr. Kolevzon. “Also, knowing how large the deletion of the  SHANK3 gene is may have important implications for medical monitoring and individualizing treatment plans. Results  also provide much-needed guidance in developing a standardized methodology for evaluating the features of this disorder.”

Many of the patients who participated in this study were next enrolled in a clinical trial at Mount Sinai evaluating Insulin-Like Growth Factor-1 (IGF-1), a  commercially available compound for growth deficiency that is known to promote nerve cell survival as well as synaptic maturation and plasticity.  The primary aim of the study is to target core features of PMS, including social withdrawal and language impairment, which will be measured using both behavioral and objective assessments. The clinical studies with IGF-1 were supported by studies in a genetically modified mouse with a mutation in SHANK3. These studies, carried out by Dr. Ozlem Bozdagi of the Seaver Autism Center, carefully examined brain function in the mice when SHANK3 was mutated, and provided preclinical evidence for a beneficial effect of IGF-1. These studies were reported the April 27th issue of Molecular Autism (1, 2).

“The Seaver Autism Center has the unique capacity to evaluate autism spectrum disorders on both the molecular level and the clinical level,” said Dr. Buxbaum. “This capability puts us in a unique position to see the entire picture—the connection between genetics and behavior in these disorders—and to develop new treatments and better tailor existing ones for these children.”

Hope for Spinal Cord Injuries

Laura Wong has coaxed damaged nerve cells to grow and send messages to the brain again

“An ailment not to be treated,” read the prescription for a spinal cord injury on an Egyptian papyrus in 1,700 B.C. Not much has changed in the intervening millennia. Despite decades of research, modern medicine has made little headway in its quest to reverse damage to the central nervous system.

That is not to say, however, that there isn’t a glimmer of hope. Laura Wong, an M.D./Ph.D. student in Professor Eric Frank’s molecular physiology lab at the Sackler School, has been able to coax damaged nerve cells known as sensory neurons to regenerate, growing as much as 10 times longer than previously documented. What’s more, the new neurons make organized connections with their counterparts inside the spinal cord and brain stem, ensuring information from the outside world paints an accurate picture inside the brain.

“All the regeneration in the world isn’t going to make any difference if they don’t reconnect. You’re still not going to get any function,” says Wong, who has worked since 2010 in Frank’s lab, which is trying to develop therapies for spinal cord injuries.

Her findings, which she presented at the annual meeting of the Society for Neuroscience in 2011 and 2012, shed light on the complex processes behind nerve cell growth and regeneration. If those results can be replicated in patients, it could prevent certain types of nerve damage and improve quality of life for some.

Going the Distance

Unlike tissues such as skin and bone, the cells of the central nervous system in an adult are notoriously resistant to healing. Not only does the supply of natural growth stimulants decline as we age, but the body also produces chemicals that discourage nerve cells from regenerating. Worse, the scar tissue that starts to form immediately after a spinal cord injury also contains compounds that hinder nerve cell growth.

Researchers in Frank’s lab have been seeking ways to either stimulate growth or block the mechanisms that inhibit nerve cell growth—or both—since 2005. Wong’s predecessor in the lab, Pamela Harvey, a 2009 graduate of the Sackler School, tested a synthetic version of a nerve cell growth factor, called artemin, on crushed sensory neurons that relay information from the hands, arms and shoulders to the brain.

The damage mimics a common injury called Erb’s palsy, which can occur when a baby’s shoulder gets caught behind the mother’s pelvis during labor and delivery, creating undue strain on nerves in the newborn’s neck. Riders thrown head first off a motorcycle or snowmobile can suffer similar injuries.

“Anytime the shoulder goes one way and the head and neck go the other, that’s when you see these injuries,” Wong says.

In earlier experiments, Harvey and Frank found that treating with artemin did indeed stimulate the sensory nerve fibers to regenerate and grow back into the spinal cord over the course of about six weeks. In her follow-up experiments, Wong showed that artemin could induce those nerve fibers to grow the 3- to 4-centimeter distance from there up to the brainstem, where the brain and the spinal cord meet. That’s a little more than an inch—or roughly 10 times longer than any other researchers have been able to demonstrate with artemin or any other growth factor.

“A lot of other researchers just haven’t seen this length,” notes Wong, who saw the artemin-induced growth occur over a period of three to six months.

That’s important, because while axons only have to grow across microscopic distances in a developing embryo, they would have to bridge much wider gaps—depending on the site of the injury—to heal a neural injury in an adult, Wong says. Nerves that extend from the spine to the foot or toe can reach lengths of about 60 centimeters, she adds.

But Wong’s artemin-treated nerve fibers achieved more than unprecedented growth. They also reestablished connections with correct regions in the brain stem, just as Harvey had seen the nerve cells do in the spinal cord. That is, the axons essentially plugged themselves back in just as they were prior to the injury, and, like an old-fashioned telephone switchboard, they sent the right messages to the right parts of the brain.

That’s crucial because should the sensory nerves that relay pain signals become crossed, for example, it could result in a patient feeling phantom pain or the sensation of pain from something that shouldn’t cause discomfort at all.

“With some other growth-promoting compounds you get regeneration, but you see those axons growing kind of willy-nilly,” says Wong. “You can see where it would be just as detrimental to have things wired incorrectly as it would be to have things not wired at all.”

Just a Start

Artemin isn’t a panacea for spinal cord injuries, Wong and Frank stress. To work its cellular magic, the compound must be administered within a day or two, and the sooner the better. Also, artemin promotes growth only in sensory neurons—and so far, only in rats—which means such growth wouldn’t improve motor function for someone who had been paralyzed by a spinal cord injury, for example.

But if the findings, which Wong presented at the Society for Neuroscience meetings in 2011 and 2012, prove applicable to humans, restoring sensation alone could still improve quality of life, even for those living with paralysis. Giving these people the ability to sense heat, cold and pain could help them avoid other accidental injuries, says Frank.

Wong hopes her work with sensory neurons will help unlock the secrets to promoting regeneration of other, more obstinate types of neurons in the brainstem and spinal cord. While she demonstrated that the sensory nerves plugged themselves back into the spinal cord precisely where they should have, it’s not clear how they did that.

Frank speculates that chemical cues guided the cells back into place. Should researchers be able to identify those cues, they potentially could use that knowledge to spark regeneration of other classes of neurons, such as motor neurons.

“There is hope—not proof—that even in humans these guidance molecules will persist into adulthood,” says Frank. “That means if we are able to get neurons to regenerate in patients, we might be able to make them go back to the right place. These experiments suggest we have some reason to believe it may work.”

High Sugar Intake Linked to Low Dopamine Release in Insulin Resistant Patients

PET study led by Stony Brook Professor indicates that overeating and weight gain contributing to onset of diabetes could be related to a deficit in reward circuits in the brain

Using positron emission tomography (PET) imaging of the brain, researchers have identified a sweet spot that operates in a disorderly way when simple sugars are introduced to people with insulin resistance, a precursor to type 2 diabetes. For those who have the metabolic syndrome, a sugar drink resulted in a lower-than-normal release of the chemical dopamine in a major pleasure center of the brain. This chemical response may be indicative of a deficient reward system, which could potentially be setting the stage for insulin resistance. This research could revolutionize the medical community’s understanding of how food-reward signaling contributes to obesity, according to a study presented at the Society of Nuclear Medicine and Molecular Imaging’s 2013 Annual Meeting.

"Insulin resistance is a significant contributor to obesity and diabetes," said Gene-Jack Wang, MD, lead author of the study and Professor of Radiology at Stony Brook University and researcher at the U.S. Department of Energy’s Brookhaven National Laboratory in Upton, N.Y. "A better understanding of the cerebral mechanisms underlying abnormal eating behaviors with insulin resistance would help in the development of interventions to counteract the deterioration caused by overeating and subsequent obesity. We suggest that insulin resistance and its association with less dopamine release in a central brain reward region might promote overeating to compensate for this deficit."

An estimated one-third of Americans are obese, according to the U.S. Centers for Disease Control and Prevention. The American Diabetes Association estimates that about 26 million Americans are living with diabetes and another 79 million are thought to be prediabetic, including those with insulin resistance.

The tendency to overeat may be caused by a complex biochemical relationship, as evidenced by preliminary research with rodents. Dr. Wang’s research marks the first clinical study of its kind with human subjects.

"Animal studies indicated that increased insulin resistance precedes the lack of control associated with pathological overeating," said Wang. "They also showed that sugar ingestion releases dopamine in brain regions associated with reward. However, the central mechanism that contributes to insulin resistance, pathological eating and weight gain is unknown."

He continued, “In this study we were able to confirm an abnormal dopamine response to glucose ingestion in the nucleus accumbens, where much of the brain’s reward circuitry is located. This may be the link we have been looking for between insulin resistance and obesity. To test this, we gave a glucose drink to an insulin-sensitive control group and an insulin-resistant group of individuals and we compared the release of dopamine in the brain reward center using PET.”

In this study, a total of 19 participants-including 11 healthy controls and eight insulin-resistant subjects-consumed a glucose drink and, on a separate day, an artificially sweetened drink containing sucralose. After each drink, PET imaging with C-11 raclopride-which binds to dopamine receptors-was performed. Researchers mapped lit-up areas of the brain and then gauged striatal dopamine receptor availability (which is inversely related to the amount of natural dopamine present in the brain). These results were matched with an evaluation in which patients were asked to document their eating behavior to assess any abnormal patterns in their day-to-day lives. Results showed agreement in receptor availability between insulin-resistant and healthy controls after ingestion of sucralose. However, after patients drank the sugary glucose, those who were insulin-resistant and had signs of disorderly eating were found to have remarkably lower natural dopamine release in response to glucose ingestion when compared with the insulin-sensitive control subjects.

"This study could help develop interventions, i.e., medication and lifestyle modification, for early-stage insulin-resistant subjects to counteract the deterioration that leads to obesity and/or diabetes," said Wang. "The findings set a path for future clinical studies using molecular imaging methods to assess the link of peripheral hormones with brain neurotransmitter systems and their association with eating behaviors."

Alzheimer’s and Low Blood Sugar in Diabetes May Trigger a Vicious Cycle

A new UC San Francisco-led study looks at the close link between diabetes and dementia, which can create a vicious cycle.

Diabetes-associated episodes of low blood sugar may increase the risk of developing dementia, while having dementia or even milder forms of cognitive impairment may increase the risk of experiencing low blood sugar, according to the study published online Monday in JAMA Internal Medicine.

Researchers analyzed data from 783 diabetic participants and found that hospitalization for severe hypoglycemia among the diabetic, elderly participants in the study was associated with a doubled risk of developing dementia later. Similarly, study participants with dementia were twice as likely to experience a severe hypoglycemic event.

The study results suggest some patients risk entering a downward spiral in which hypoglycemia and cognitive impairment fuel one another, leading to worse health, said Kristine Yaffe, MD, senior author and principal investigator for the study, and a UCSF professor of psychiatry, neurology and epidemiology based at the San Francisco Veterans Affair Medical Center.

“Older patients with diabetes may be especially vulnerable to a vicious cycle in which poor diabetes management may lead to cognitive decline and then to even worse diabetes management,” she said.

Cognitive Function a Factor in Managing Diabetes

The researchers analyzed hospital records of patients from Memphis and Pittsburgh, ages 70 to 79 at the time of enrollment, who participated in the federally funded Health, Aging and Body Composition (Health ABC) study, begun in 1997. The UCSF results are based on an average of 12 years of follow-up study. Participants in the Health ABC study periodically underwent tests to measure cognitive function.

Nearly half of participants included in the newly published analysis were black, and the rest were white. None had dementia at the start of the study, and all either had diabetes at the beginning of the study or were diagnosed during the course of the study.

“Individuals with dementia or even those with milder forms of cognitive impairment may be less able to effectively manage complex treatment regimens for diabetes and less able to recognize the symptoms of hypoglycemia and to respond appropriately, increasing their risk of severe hypoglycemia,” Yaffe said. “Physicians should take cognitive function into account in managing diabetes in elderly individuals.”

Certain medications known to carry a higher risk for hypoglycemia — such as insulin secretagogues and certain sulfonylureas — may be inappropriate for older adults with dementia or who are at risk for cognitive impairment, according to Yaffe.

Previous studies in which researchers investigated hypoglycemia and cognitive function have had inconsistent findings. A strength of the current study is that individuals were tracked from baseline over a relatively long time, and the older age of participants may also have been a factor in the highly statistically significant outcome, Yaffe said.

Mice Give New Clues to Origins of OCD

Columbia Psychiatry researchers have identified what they think may be a mechanism underlying the development of compulsive behaviors. The finding suggests possible approaches to treating or preventing certain characteristics of OCD.

OCD consists of obsessions, which are recurrent intrusive thoughts, and compulsions, which are repetitive behaviors that patients perform to reduce the severe anxiety associated with the obsessions. The disorder affects 2–3 percent of people worldwide and is an important cause of illness-related disability, according to the World Health Organization.

Using a new technology in a mouse model, the researchers found that repeated stimulation of specific circuits linking the brain’s cortex and striatum produces progressive repetitive behavior. By targeting this region, it may be possible to stop abnormal circuit changes before they become pathological behaviors in people at risk for obsessive-compulsive disorder (OCD). The study, which was led by Susanne Ahmari, MD, PhD, assistant professor of clinical psychiatry at Columbia Psychiatry and the New York State Psychiatric Institute, was published in the June 7 issue of Science.

While the obsessions and compulsions that are the hallmarks of OCD are thought to be centered in the cortex, which controls thoughts, and the striatum, which controls movements, little is known about how abnormalities in these brain regions lead to compulsive behaviors in patients.

To simulate the increased activity that takes place in the brains of OCD patients, Dr. Ahmari and her colleagues used a new technology called optogenetics, in which light-activated ion channels are expressed in subsets of neurons in mice, and neural circuits are then selectively activated using light delivered through fiberoptic probes.

“What we found was really surprising,” said Dr. Ahmari. “That activation of cortico-striatal circuits did not lead directly to repetitive behaviors in the mice. But if we repeatedly stimulated for multiple days in a row for only five minutes a day, we saw a progressive development of repetitive behaviors—in this case, repetitive grooming behavior—that persisted up to two weeks after the stimulation was stopped.”

She added, “And not only that, when we treated the mice with fluoxetine, one of the most common medications used for OCD, their behavior went back to normal.” The current study, as well as others currently being performed by Dr. Ahmari and her team, may ultimately provide clues for new treatment targets in terms of both novel drug development and direct stimulation techniques, including deep brain stimulation (DBS).