Research Update

The Department of Defense Neurofibromatosis Research Program has awarded Barrow a one-year exploratory and developmental grant worth $105,600. Researchers will use the grant to investigate whether gene defects in neurofibromatosis 1 (NF1) disrupt the function of nerve cells and movement of molecules from the cell body to the terminals where they are needed.

“This grant will help us study a new area of research in neurofibromatosis and might help us find new targets for treatment of NF1,” says Vinodh Narayanan, MD, senior staff investigator and pediatric neurogeneticist at Barrow.

Neurofibromatosis is one of the most common genetic disorders. Usually diagnosed in childhood, it causes tumors to grow along nerves anywhere in the body. NF1 is a distinct type of the disease that causes tumors and developmental problems, including moderate to severe cognitive impairment. It is believed to be the most common neurological disorder caused by a single gene.

The Barrow research will focus on the potential functions of neurofibromin, the protein encoded by the NF1 gene. Initial research has shown that neurofibromin may play a role in the transport of other molecules throughout different parts of the cell, which could have important implications on learning and memory. The team will study a mouse model to learn more about the specific cellular processes that are impaired as a result of NF1 gene mutation, poten- tially leading to new targets for drug development.

Dr. Narayanan and his team at Barrow treat many children with neurofibromatosis at St. Joseph’s Children’s Rehabilitative Services.

His research receives funding from Barrow Neurological Foundation.

Pediatrician plays key role in new medication for autism

Ronald L. Lindsay, MD, a developmental and behavioral pediatrician at St. Joseph’s Arizona Child Study Center, played a key role in a pivotal research study that led to the recent FDA approval of the first medication for children with autism.

Dr. Lindsay was the senior pediatrician in a multisite study into the benefits of using risperidone (Risperdal) for children with autism. The National Institutes of Mental Health-sponsored study took place between 1999 and 2001, during which time Dr. Lindsay was serving as the medical director of the Nisonger Center at Ohio State University.

Initially used to treat adults with schizophrenia, risperidone had shown promise for treating the serious behavioral problems often associated with autism. The study found that the medication was, in fact, effective for reducing symptoms such as irritability, tantrums and aggression. Children who were considered responders to the medication showed at least a 25 percent decrease in parent-reported irritability. A child psychologist or psychiatrist also had to note significant improvement.

The initial study results were published in the New England Journal of Medicine in 2002. More recent articles have appeared in the July 2005 issue of the American Journal of Psychiatry and the December 2006 issue of the Journal of Intellectual and Developmental Disability. Dr. Lindsay was the lead author of the latter, which exam- ines weight gain in children taking the medication. While risperidone is not designed to eliminate the core symptoms or behaviors of autism, Dr. Lindsay and others believe that the medication’s approval is significant.

“Risperidone is not a cure for autism by any stretch, but it does deal effectively with irritability, which is one of the main complicating issues confronted by children with autism and their families,” says Dr. Lindsay.

Scientist studying natural anti-cancer treatments

While the use of natural substances for anti-cancer treatment is not new, research into the field—and at Barrow—is increasing. Adrienne C. Scheck, PhD, senior staff scientist in Neuro-Oncology and Neu- rosurgery Research, is currently pursuing two such complementary treatments.

One project involves studying the extract from a Chinese medicinal herb. Scutellaria baicalensis has long been used in oriental medicine for the treatment of a variety of conditions, including inflammation and allergies. Dr. Scheck’s study, however, marks the first time anyone has researched the herb’s effect on brain tumors.

Initial results have been promising: Extracts from the herb have been found to kill cells from brain tumors, including some cells resistant to normal chemotherapy agents. Additionally, scutellaria baicalensis is historically nontoxic and is relatively easy to obtain. The team’s initial findings were published in a recent online issue of BioMed Central’s BMC Complementary and Alternative Medicine.

Dr. Scheck is also working with Barrow pediatric neurologist Jong Rho, MD, to study the effects of a ketogenic—or high-fat, low-carb—diet as a complementary treatment for people with brain tumors. Dr. Rho is a clinician and scientist who specializes in studying the diet in children with epilepsy, particularly the biochemical and neurophysiologic effects of ketones. A talk he gave at Barrow stimulated Dr. Scheck’s interest, and the two rapidly found a sound scientific basis for collaboration.

The duo has found that treating tumor cells with ketones—and treating others with a combination of ketones and a chemotherapy agent—inhibits cell growth. They have submitted several grant proposals for further research into the mechanism behind their findings. Barrow Neurological Foundation supports Dr. Scheck’s research.

Barrow receives $450,000 to study spinal-cord injuries, brain tumors.

The Arizona Biomedical Research Commission (ABRC) recently awarded Barrow and Arizona State University (ASU) two grants worth $450,000 each to study spinal-cord injuries and brain tumors

Researchers at Barrow and ASU will use one of the grants to develop new hydrogels, or liquids that gel, to stimulate the ends of damaged fiber on the spinal cord to grow and bypass injured or scarred areas. Barrow’s grant application for spinal-cord injury research scored the highest of all submitted grants.

Surgically placed at the site of spinal-cord damage, hydrogels form into scaffolds, which will hopefully enable the cells and the ends of damaged fiber to cross to the other side of the spinal cord, avoiding additional damage to the injured area.

“This study uses the latest in bioengineering materials against one of our most pressing problems in neurosurgery,” says Mark Preul, MD, Barrow Newsome Endowed Chair of Neurosurgery Research, who heads the grant along with bioengineer, Alyssa Panitch, PhD. “Our team is composed of some of the best minds from Barrow and ASU in a practical attempt to help reconnect the damaged spinal cord. Those with spinal-cord injuries are often young or in the prime of their lives. Helping to repair the damage is daunting.”

The brain tumor immunotherapy grant, a partnership between Dr. Preul, Adrienne C. Scheck, PhD, and researchers at ASU, will be used to develop proteins that stimulate the immune system to attack malignant brain tumors. An additional grant from the Wallace Foundation will allow researchers to investigate if the proteins work with malignant melanoma, which has a high tendency to metastasize to the brain.

“The fusion of expertise in neurosurgery research, neurooncology, and some really novel applications of peptides driving the immune system is the key to this work,” says Dr. Preul. “We’re focused on translating new ideas into therapies that will give brain-tumor patients some extra time—the most valuable commodity there is.”

Barrow scientist contributes to new research into addiction

For nearly 30 years, A.D. “Bud” Craig, PhD, has been studying the pathways that carry sensations from the spinal cord to the brain. On Feb. 6, his work made national headlines as the New York Times reported on new findings that people with damage to a part of the brain called the insula were able to stop smoking instantly.

Although Dr. Craig was not directly involved in the smoking research, his research paved the way for the scientists who were. In his research at Barrow, Dr. Craig has tracked sensations like itch, pain, cold, taste, hunger, thirst and muscle soreness from receptors in the skin and internal organs to the insula. What Dr. Craig has learnedis that the insula processes sensations from throughout the body and generates subjective feelings that bring about actions designed to keep the body in a state of internal balance, or homeostasis.

“Let's say you're in a cold room, and it starts to feel uncomfortable,” Dr. Craig says. “You are motivated to do something about being cold because if you're cold too long, you die. So you put on a sweater or turn up the heat or go to a warm room. Those are all behavioral responses to the condition of your body.”

In humans, information from the insula goes to other parts of the brain involved in making decisions, says Dr. Craig, and is the source of emotions. The insula may also interpret body states like hunger and crav ing, and motivate people to buy a candy bar or smoke a cigarette. Thus, research into the insula may lead to new strategies for treating addiction, anxiety and eating disorders.

Dr. Craig holds the Atkinson Research Chair at Barrow, an endowed chair made possible by donors.

Barrow neurologist conducts Alzheimer’s research

Wrapping up his second year as medical director of Barrow’s Alzheimer’s and Cognitive Disease Program, Patricio Reyes, MD, continues to work toward the goals he envisioned upon his arrival. Collaborations among neurology, neurosurgery, neuropsychology and neu ropathology have helped initiate programs that benefit patients, caregivers and medical professionals alike.

Most recently, Dr. Reyes instituted a bimonthly Clinico-Pathologic Conference. “We discuss interesting and challenging neurological and neurosurgical cases, including symptoms, diagnosis and outcome,” he says.

This year, the Alzheimer’s program also hosted its second annual diversity and caregivers conferences, both of which drew record numbers of participants from across the country.

On the research front, the program is involved in several cutting-edge projects. Clinicians recently completed a clinical trial using an acetylcholinesterase inhibitor to treat Hispanic patients. The trial marked the first time researchers studied the effects of an approved medication for Alzheimer’s on a specific ethnic group, which is significant because medications may be processed differently by different ethnicities.

Barrow was one of the first sites to test a new skin patch for Alzheimer’s disease, and it is also participating in a study to verify the efficacy and safety of treating Alzheimer’s patients with a combination of two new drugs. In collaboration with neurosurgery, the team has received funding to develop diagnostic pro- tocol and determine clinical and biomedical markers for normal-pressure hydrocephalus.

In the lab, researchers are studying the metabolic and neuropathologic features of a genetically engineered mouse as an animal model for Alzheimer’s disease.

Dr. Reyes receives support from Barrow Neurological Foundation.

Brain Proteomics Lab studies biological basis of disease.

There’s an emerging field that has the potential to provide even more detailed knowledge about the human body than genomics. Proteomics, the study of proteins and how they interact, takes genomics to another level. To stay on the leading edge of brain disease, Barrow has established a Brain Proteomics Laboratory.

While the human genome (the collective genes in the body) is static, the human proteome (the collective proteins in the body) changes in response to factors such as environmental stress and disease. The goal of proteomics is to analyze the more than 300,000 proteins in the body and use them as biomarkers for diagnosis, disease progression and treatment.

“Proteomics holds the promise of unraveling the biological basis of disease and leading to the discovery of new diagnostic and prognostic markers and the development of new clinical tests,” says Richard S. Burns, MD, director of Barrow’s Movement Disorders Program and co-director of the Proteomics Laboratory.

With generous support from Barrow Neurological Foundation, the lab was established in 2005 in the Parkinson’s research area. Additional donor support has provided more equipment, software and staffing, including co-director Peter L. Pingerelli, PhD.

The primary equipment used in the lab includes two mass spectrometers. These instruments can measure the masses and relative concentrations of atoms and molecules. The lab also offers a molecular modeling program that produces high-quality, three-dimensional images of proteins.

“This type of sophisticated instrumentation is most often found in the chemistry department of a university,” says Dr. Burns. “But at Barrow, we’re driven by the clinical aspect—diagnosis and treatment—as opposed to the theoretical.”