While many different combinations of genetic traits can cause autism, brains affected by autism share a pattern of ramped-up immune responses, an analysis of data from autopsied human brains reveals. The study, a collaborative effort between Johns Hopkins and the University of Alabama at Birmingham, included data from 72 autism and control brains. It was published online in the journal Nature Communications.“There are many different ways of getting autism, but we found that they all have the same downstream effect,” said Dan Arking, Ph.D., an associate professor in the McKusick-Nathans Institute for Genetic Medicine at the Johns Hopkins University School of Medicine. “What we don’t know is whether this immune response is making things better in the short term and worse in the long term.”

The causes of autism, also known as autistic spectrum disorder, remain largely unknown and are a frequent research topic for geneticists and neuroscientists. But Arking noticed that studies of whether and how much genes were being used — known as gene expression — involved too little data to draw many useful conclusions about autism. Unlike a genetic test, which can be done using nearly any cells in the body, gene-expression testing has to be performed on the specific tissue of interest — in this case, brains that could be obtained only through autopsies.

To combat this problem, Arking and his colleagues analyzed gene expression in samples from two different tissue banks, comparing gene expression in people with autism to that in controls without the condition. All told, they analyzed data from 104 brain samples from 72 individuals — the largest data set so far for a study of gene expression in autism.

Previous studies identified autism-associated abnormalities in cells that support neurons in the brain and spinal cord. In this study the research team was able to narrow in on a specific type of support cell known as a microglial cell, which polices the brain for pathogens and other threats. In the autism brains, the microglia appeared to be perpetually activated — and the genes for inflammation responses turned on.

“This type of inflammation is not understood well, but it highlights the lack of current understanding about how innate immunity controls neural circuits,” said Andrew West, Ph.D., an associate professor in the UAB Department of Neurology and co-author of the study.

“Given the known genetic contributors to autism, inflammation is unlikely to be its root cause,” Arking said. “Rather, this is a downstream consequence of upstream gene mutation.”

The next step, he says, would be to find out whether treating the inflammation could ameliorate symptoms of autism.

Other authors on the study are Simone Gupta, Shannon E. Ellis, Foram N. Ashar, Anna Moes, Joel S. Bader and Jianan Zhan, all of The Johns Hopkins University.

The study was funded by the Simons Foundation and the National Institute of Mental Health.

By Bob Shepard
UAB Media Relations
Neurologist David Geldmacher, M.D., who leads the University of Alabama at BirminghamDivision of Memory Disorders, sees many older patients with memory loss, dementia or Alzheimer’s disease. He also sees their caregivers, who often are spouses or adult children.

“I recognized the need for a dementia risk-assessment clinic because a lot of my time in the care of people with memory loss is spent advising people without memory loss how to protect themselves,” Geldmacher said.

Building on international studies that examined risk factors for dementia, Geldmacher created the UAB Alzheimer’s Risk Assessment and Intervention Clinic, the first such clinical service in the nation. Patients receive a detailed, personalized risk assessment, which includes family history, a detailed memory history for the patient, cognitive testing and a baseline MRI scan. That information is incorporated into existing risk-predictor models, which have been validated by research studies that followed thousands of patients for as many as 20 years to produce an accurate risk assessment.

“It’s about an hour-and-a-half process of collecting a detailed risk-factor history, and we focus on the reversible risk factors,” Geldmacher said. “So many people facing dementia focus on the irreversible risk factors, such as ‘I’m getting older’ or ‘my dad or mom had dementia.’ We can’t change those things, but we can change things like levels of physical activity and cholesterol counts and blood-pressure numbers.”

Geldmacher says the studies have shown that reducing one or more risk factors can have a significant effect on reducing one’s overall chances of developing Alzheimer’s disease.

“For most people, Alzheimer’s disease is an illness you live with, not an illness from which you die,” Geldmacher said. “With a better understanding of individual risk, there are steps that people can take to minimize the risk for serious memory loss. One of the common themes for both short-term and long-term risk is cardiovascular health, which is something that is more or less under our control through lifestyle changes or medications.”

He presents a hypothetical patient — a woman in her 50s with a family history of dementia who is mildly obese and has cardiovascular issues.

“If she reverses one of three things — loses weight, brings her cholesterol under control or brings her blood pressure into the normal range — she can cut her risk in half,” Geldmacher said. “And if she manages all three of those reversible risk factors and brings them all into the desirable range, she can cut her dementia risk in half again.”

Jon Kling is a nonhypothetical patient. His mother had dementia, as did all four of her sisters. The 72-year-old, semiretired financial planner is reasonably healthy, but worries about his risk of dementia. He was one of the first patients to see Geldmacher at the new clinic.

“I really wanted to be able to establish a baseline of where I am today,” Kling said. “I didn’t feel like I was at particular risk right now, but down the road I didn’t know. I just wanted to see where I stood.”

Kling got good news: His dementia risk is relatively low. Geldmacher’s assessment included recommendations on how to keep that risk low, including increased physical activity and proper diet. Kling was already practicing some of those recommendations.

“The physical activity of walking and working with light weights — those were things I’ve been doing for years,” Kling said. “The assessment was really a reinforcement that I was doing the right things and that I need to continue to do so.” 

Geldmacher says the research models offer a long-term risk assessment of 20 years for people in their late 40s and 50s and a six-year assessment for older patients. Kling believes the assessment also helps with awareness and education.

“If I asked you what your ideal weight was, you could probably tell me exactly what that weight should be,” he said. “If I asked you to name three or four risk factors for dementia or Alzheimer’s, could you do it? Most people really don’t know, and this will provide a great deal of needed awareness.”

For Geldmacher, preventing or slowing the progression of dementia is key.

“At this point in 2014 and for the foreseeable future, we don’t have any medications that meaningfully attack the processes in the brain that lead to Alzheimer’s disease,” he said. “We still don’t understand the cause of Alzheimer’s disease, so prevention by medication is a distant goal for us. It’s something we work on every day in our research labs and our clinical testing, but it’s not something that will emerge tomorrow or next week.”

For Kling, having the assessment and a baseline of where he stands today is comforting.

“There’s peace of mind with knowing my risk,” he said. “And knowing that we have this type of help in our own backyard right here in Birmingham, Alabama, is fantastic. It’s great to have the type of professional risk assessment that Dr. Geldmacher and his program provide. I think it’s invaluable.”

Patients will have two clinical visits with Geldmacher and his staff. The first will be to compile histories and conduct testing. The second will be to review the personalized treatment plan, including how to access resources to help achieve lifestyle changes, and where to find supportive and educational materials. The clinic will also suggest coping strategies that can be employed to ease the burden of dementia on the individual and his or her family. The two-visit assessment is fee-for-service and will cost about $1,000, which includes the MRI scan.

Geldmacher anticipates that the risk-assessment clinic will ultimately serve as a gateway to research projects aimed at finding medications or other treatments designed to lower risk of memory disorders.

Call 205-975-7575 for more information or to make an appointment for a personalized dementia risk assessment.

By Bob Shepard
UAB Media Relations

Published on December 12, 2014

CCTS KL2 Awardee Granted American Cancer Society Mentored Research Scholars Grant

Kristen Triebel, PsyD, will start her new year off right by beginning a five-year, $728,000 American Cancer Society Mentored Research Scholars grant on January 1, 2015.

Triebel’s research is on “Decisional Capacity Evaluation in Metastatic Brain Cancer,” looking at long-term decision-making abilities in patients with advanced cancers, including lung and breast cancer that has metastasized to the brain, and pancreatic cancer. It also examines issues in these patients’ treatment, cognitive function and quality of life.

“These patients are seriously ill and have to make a lot of important medical decisions,” Triebel says. “We are looking to see if our initial findings from metastatic cancer patients can generalize to other cancer populations who have comparable levels of illness—even those who don’t get tumors that spread to the brain.” The goal, she says, is to be able to improve decision-making capacity. “We hope this research leads to better understanding of patients at risk, so we can advise on best practices for assessment and interventions to support patients in this capacity, ultimately improving their quality of life.”

Triebel, who received a KL2 award from the CCTS in 2012, leveraged that research into this five-year grant from the American Cancer Society (ACS). She is an assistant professor of Neurology and Director, Neuropsychology Fellowship Training Program in the Department of Neurology. The award provides opportunities to conduct grow a research program by fostering collaboration with other cancer investigators in the Comprehensive Cancer Center, she says. It also allows her to pursue career development opportunities in coursework, plus participate in research conferences.

Triebel’s primary mentor on the award is Karen Meneses, PhD, RN, FAAN, Professor and Associate Dean for Research, UAB School of Nursing. Her primary mentor on the KL2 award is Burt Nabors, MD, Department of Neurology, UAB School of Medicine. She learned of the award through her affiliation with UAB’s Comprehensive Cancer Center, she says.

"Kristen’s research is an extremely important area of study for which we have little data, specifically decision-making and quality of life among a seriously ill population," says Meneses.  "She is a remarkable young scientist with the requisite strength, tenacity, and clinical experience to conduct and complete this vital work. I consider it a great honor to serve as her mentor along with Dr. Burt Nabors and our interdisciplinary mentoring team."

An article on Triebel’s research entitled, “Cognition in patients with newly diagnosed brain metastasis: profiles and implications,” was published in 2014 in the Journal of Neuro-Oncology. (Gerstenecker, A., Nabors, L. B., Meneses, K., Fiveash, J., Marson, D. C., Cutter, G., Martin, R., Meyers, C. A., & Triebel, K. L. Cognition in patients with newly diagnosed brain metastasis: profiles and implications. Journal of Neuro-Oncology 2014; 120(1): 179-185.[PMCID in process])  Two other UAB researchers are currently conducting research funded by an ACS Mentored Research Scholars grant: Dori Peckmezi, PhD, assistant professor in the Department of Health Behavior, School of Public Health; and Elizabeth Kvale, MD, associate professor, School of Medicine and director of the UAB Supportive Care and Survivorship outpatient clinic.

In her research career, Triebel says, “the CCTS has been and continues to be critical, providing research support in terms of my time and effort, and a lot of resources. The resources of the Training Academy have been wonderful in helping me come up with a road map for what would be competitive for the KL2.”

Triebel emphasizes the protected time and money to conduct the research that the KL2 allowed, as well as “access to successful researchers who taught me how to conduct research and write grants,” she says. “That grant was great, providing two years of support that allowed me to do the research, which in turn helped me secure this larger grant.”

Triebel says she also benefited from CCTS activities such as the Training Interdisciplinary and Emerging Research Scholars (TIERS) program. She attended the Association for Clinical and Translational Science annual Translational Science conference in Spring 2014 where she presented this research. “It was an excellent opportunity to see people advocating for NIH funding and getting to present the research.”

“I’m a huge advocate of the CCTS, I couldn’t have done this work without it,” Triebel says. “For people starting out there’s really nothing else like it, for mentoring, for networking.” In addition to the CCTS, she acknowledges “incredible support” received from the UAB Department of Neurology, including Dr. David Standaert and Dr. Daniel Marson, UAB President Dr. Ray Watts, the Comprehensive Cancer Center, and her research team, including Amanda Eakin, program coordinator.


Compliments of US News & World Report - Health News - By Robert Preidt, HealthDay Reporter

WEDNESDAY, Dec. 10, 2014 (HealthDay News) -- Brain inflammation, triggered by an overactive immune system, is common among people with autism, a new study finds.

However, this inflammation does not cause the developmental disorder. Rather, it's a response to the different factors that can trigger autism, the researchers stressed.

Their findings are based on autopsies performed on 72 brains of people with and without autism. In the brains of those who had autism when they were alive, a certain type of cell had its genes for inflammation permanently turned on.

"There are many different ways of getting autism, but we found that they all have the same downstream effect," study author Dan Arking, an associate professor at the Institute for Genetic Medicine at Johns Hopkins University School of Medicine in Baltimore, said in a university news release.

"What we don't know is whether this immune response is making things better in the short term and worse in the long term," he added.

The next step is to find out whether treating this inflammation would reduce symptoms of autism, Arking said.

The study was published online Dec. 10 in the journal Nature Communications.

"This type of inflammation is not well understood, but it highlights the lack of current understanding about how innate immunity controls neural circuits," study co-author Andrew West, an associate professor of neurology at the University of Alabama at Birmingham, said in the news release.

More information

The U.S. National Institute of Neurological Disorders and Stroke has more about autism.

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