For the first time in a progressive, age-related mouse model of Parkinson’s, researchers have shown that exercise on a running wheel can stop the accumulation of the neuronal protein alpha-synuclein in brain cells.
The work, published Friday in the journal PLOS ONE, was done by Wenbo Zhou, PhD, research associate professor of medicine, and Curt Freed, MD, professor of medicine and division head of the Division of Clinical Pharmacology and Toxicology at the CU School of Medicine.
Exercise in mice boosts protective gene
The researchers said clumps of alpha-synuclein are believed to play a central role in the brain cell death associated with Parkinson’s disease. The mice in the study, like humans, started to get Parkinson’s symptoms in mid-life. At 12 months of age, running wheels were put in their cages.
“After three months,” Zhou said, “the running animals showed much better movement and cognitive function compared to control transgenic animals, which had locked running wheels.”
Zhou and Freed found that in the running mice, exercise increased brain and muscle expression of a key protective gene called DJ-1. Those rare humans born with a mutation in their DJ-1 gene are guaranteed to get severe Parkinson’s at a relatively young age.
The researchers tested mice that were missing the DJ-1 gene and discovered that their ability to run had severely declined, suggesting that the DJ-1 protein is required for normal movement.
Study suggests positive human implications
“Our results indicate that exercise may slow the progression of Parkinson’s disease by turning on the protective gene DJ-1 and thereby preventing abnormal protein accumulation in brain,” Freed said.
He explained that his animal experiments had very real implications for humans.
“Our experiments show that exercise can get to the heart of the problem in Parkinson’s disease,” Freed said. “People with Parkinson’s who exercise are likely able to keep their brain cells from dying.”
Parkinson’s is a disease caused by the death of brain cells that make a critical chemical called dopamine. Without dopamine, voluntary movement is impossible. Most people with Parkinson’s disease take a drug called L-DOPA to treat their symptoms. The oral drug is converted into dopamine in the brain allowing patients to get up and move.
In 1988, Freed and his colleague Robert Breeze, MD, performed the first transplant of human fetal dopamine cells into a Parkinson’s patient in the United States. His lab is currently working to convert human embryonic stem cells to dopamine neurons. These techniques should make it possible to produce unlimited quantities of dopamine cells for transplant.
Researchers at the Colorado School of Public Health at the University of Colorado Anschutz Medical Campus and the Colorado School of Mines received a two-year grant to investigate contamination of the drinking water in the communities of Fountain, Security and Widefield. Residents of these areas were exposed to drinking water contaminated with pollutants originating from aqueous film-forming foams (AFFF) used in firefighting and training activities.
By measuring biological markers of exposure and health indicators in a sample of approximately 200 people who consumed contaminated water, this study will provide communities and scientists with an improved understanding of the biopersistence and potential health impacts of AFFF-derived poly- and perfluoroalkyl substances (PFASs). PFASs are a class of chemicals widely used in industrial and commercial applications since the 1950s.
In July, a nine-month U.S. Air Force study verified that firefighting foam used at Peterson Air Force Base contaminated groundwater and soil with PFASs at levels more than 1,000 times an Environmental Protection Agency health advisory limit for similar chemicals.
The grant is from the National Institute of Environmental Health Sciences, a program of the National Institutes of Health. This study is being funded because of the recent discovery of the source of contamination, which has impacted the water supplies of these communities for several years.
“This research will contribute to our understanding of the factors driving this unique exposure and how it may affect long-term health,” said Dr. John Adgate, chair of ColoradoSPH’s Department of Environmental and Occupational Health and principal investigator of the study. “We will collect the first systematic data on blood levels of these persistent compounds in this PFAS-impacted community. While exposure to PFASs has been significantly reduced due to work by the Colorado Department of Public Health and Environment and the local water utilities, our hope is that by gathering data on blood levels shortly after people’s peak exposure we can provide better answers on related health effects and potential next steps.”
Currently, little is known about the health effects of human exposure to PFASs in areas with drinking water contaminated by AFFF, and no systematic biomonitoring has been done in these communities.
“Because we suspect that any health effects are likely related to peak blood levels, it is important to collect the blood data and health effect information as soon as we can,” Dr. Adgate said.
Dr. Christopher Higgins, an associate professor of civil and environmental engineering at Mines and a co-investigator for the study, will be applying advanced analytical techniques to examine the potential that a much broader suite of PFASs is present in the impacted water supplies and possibly in people’s blood.
“By using high resolution mass spectrometry to look at both water samples and a subset of human serum samples, we hope to improve our understanding of exactly which compounds bioaccumulate in humans and how long they stick around in the human body,” Higgins said. “We will also explore the links between drinking water exposure, PFAS blood levels, and the potentially related health effects.”
Researchers from the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, selected to estimate the cost-effectiveness of the newly approved CAR-T therapies, have found the clinical benefit may justify the expensive price.
The treatments involve removing immune cells known as T-cells from the patient, genetically engineering them to kill cancer cells and then putting them back in the body. The therapy is known as CAR-T or chimeric antigen receptor T-cell therapy and is FDA approved for some B-cell cancers, including acute lymphoblastic leukemia in pediatric and young adult patients and those with adult lymphoma.
The evidence suggests a potentially great benefit from these therapies, but the treatments are costly. The leukemia therapy, known as Kymriah, costs $475,000 while the lymphoma treatment, Yescarta, costs $373,000. So the non-profit Institute for Clinical and Economic Review (ICER) enlisted the help of pharmaceutical outcomes research faculty Melanie Whittington, R. Brett McQueen, and Jon Campbell from the CU Skaggs School of Pharmacy to generate evidence on whether the treatments, already approved by the FDA, are cost-effective.
The draft report of their findings was published Wednesday on the ICER website. After a public comment period, the researchers in collaboration with ICER, will finalize the report and present the findings at a public forum on March 2, 2018.
In the draft report, they compared CAR-T therapies to chemotherapy, taking into account patient survival, quality of life and health care costs from the health care system perspective over the lifetime of a patient receiving the therapies.
“We take into account the clinical evidence, quality of life data, and health system costs to generate cost-effectiveness evidence,” said Whittington, PhD, research instructor at the CU School of Pharmacy.
According to Jon Campbell, PhD, associate professor of pharmacy, the cost-effectiveness findings for both CAR-T therapies were `promising’ and suggested that they may be a good use of our health care resources toward improving health. They significantly extended the lives of some patients, much more on average, than traditional chemotherapy.
“The CAR-T science is beyond whether the therapies work for certain patients and is now questioning its value,” he said. “CAR-T is promising on the clinical side but there is some feeling of sticker shock related to the price. Is it worth it? Yes, it seems to be.”
Does the cost-effectiveness of therapies matter in the U.S.?
“The straightforward answer to that question is yes,” said McQueen, PhD, assistant professor of pharmacy. “Insurance companies have a higher likelihood of providing access and payment for therapies that are considered good value for money.”
Campbell, who is director of pharmaceutical outcomes research graduate track at the Center for Pharmaceutical Outcomes Research at CU Anschutz, noted that cost-effectiveness doesn’t mean cheapest and it doesn’t mean denying access.
“It’s about ensuring patients have access to high value care while sustaining our health system for future generations,” he said.
Why can a rhythmic tune halt the tremors and walking struggles in people with Parkinson’s disease, allowing them to dance with fluidity and box with precision? And why do some teenagers storm sobbing out of clinic doors when their providers broach the subject of weight control?
“We’ve been told that the half-life of medical information is approximately seven years, so something that we are taught at the beginning of our first year of medical school may or may not be relevant at the end of our residency,” said David Nguyen, a third-year medical student, explaining the importance of the event. “Especially if we want to go into academic medicine, research is our bread and butter, and we need to stay informed.”
While learning research skills, students also benefit from networking, connecting with mentors, honing presentation skills, boosting resumes and delving into something new by taking part in research forums, said Will Dewispelaere, a second-year medical student. “We all have this inherent scientific desire to find out new things,” he said.
Probing the Parkinson’s brain
Dewispelaere, whose undergraduate degree is in neuroscience, has had a long interest in disorders such as Parkinson’s disease (PD), a progressive neurodegenerative disease that leads to severe tremors, limb rigidity, slowness of movement and gait and balance problems.
“I’ve been involved with Parkinson’s research since my junior year in college,” he said. “For some time, we have known that if you ask some people with PD to walk, they’ll have trouble getting started. But if you ask them to snap their fingers or listen to music and then walk to the beat, they tend to have fewer problems.”
Research has linked the sound of rhythm to improvement of gait, velocity and postural stability, Dewispelaere said. “Preliminary findings showed music therapy could ease these common Parkinson’s symptoms, including depression and anxiety,” he said, noting the popularity of dancing and boxing classes for PD patients. “But no one really knew why.”
In his study, researchers compared the brains of 23 PD patients with 21 age-matched, healthy patients (HC), using a special imaging technique (magnetoencephalography). The participants tapped a button with their right fingers to rhythmic cues played in their left ears.
While both groups had similar activation in some areas of the brain, the PD group had increased activation in two right areas, one responsible for sound recognition and processing (superior temporal gyri), and the other important to the integration of sensory information, including hearing and self-motion (supramarginal).
“Our conclusion was that increased activity in these two regions of the brain allows for those with Parkinson’s disease to bypass some of their abnormal neural circuitry to generate regular movements,” Dewispelaere said.
Closing a provider-teenager gap
Four-year medical student Paola Casillas and second-year medical student Nemanja Vukovic focused their project on improving provider and teenage patient communication regarding a top health issue of today: obesity.
“It started about six years ago with a medical student here who saw a lot of these conversations go downhill really quickly, with the teens leaving feeling very discouraged or crying or worse,” Vukovic said. “Feeling like these conversations were super counterproductive, she wanted to know what was turning these kids off,” he said.
With the help of a teenage advisory board, the students devised questions and formed focus groups, using 47 volunteers from Denver-area high schools. The most consistent finding revolved around providers’ use of the Body Mass Index (BMI) chart when initiating conversations about patients’ weight.
Most focus-group members said they disliked the tactic, Casillas said. “They said: ‘I’m not a dot on a screen. This isn’t getting to know me and finding out what I struggle with,” Casillas recounted.
Cultural and gender differences surrounding what family and peers considered appropriate weight also placed pressure on some teens. “The biggest thing we ultimately learned was that they really want the provider to get to know who they are, what their family is like, and their goals and motivations for wanting to lose weight,” Vukovic said.
The project also involved sending surveys to local providers who served teens. Nearly 70 percent of the providers reported almost always starting weight conversations with a BMI chart, with the majority also indicating that their weight-control counseling with teens was not very effective.
The good news: Both providers and teens want to see change. “I was surprised by how much they cared,” Casillas said of the high-school students. “They want to have these conversations with their providers, and they understand the importance of the issue.”
With most providers indicating interest in learning the results of the project and incorporating the findings into their practices, the student researchers aim to expand the study and develop a provider plan for tailoring weight conversations to individual patients, Vukovic said. “We found some areas of disconnect, and we are hoping to bridge those gaps.”
Researchers at the University of Colorado Anschutz Medical Campus have discovered that color vision in mice is far more complex than originally thought, opening the door to experiments that could potentially lead to new treatments for humans.
The study was published today in the journal `Neuron.’
The scientists, led by Maureen Stabio, PhD, assistant professor of anatomy and neurobiology at the University of Colorado School of Medicine, discovered a new property of a little understood cell called the M5.
They knew that mice possessed light-sensitive proteins called opsins that allowed them to detect a limited range of colors. But as they investigated the role M5 cells played in this, Stabio discovered that the mice also had neurons that could compare signals from the different opsins and then send those color signals to the brain for interpretation.
“We are the first to discover this particular color vision circuit in mice,” Stabio said. “We knew they had opsins but we didn’t know they possessed the other two requirements for color vision.”
Stabio’s work focuses primarily on the cells and circuits of the retina, including a group called intrinsically photosensitive retinal ganglion cells or ipRGCs which includes the M5. These cells are primarily involved in a kind of vision known as non-image forming vision.
IpRGCs typically don’t process contrast, color, faces or art. Instead, they react to ambient light levels and send that information to the brains internal clock to put the body in synch with the rising and setting of the sun (aka the circadian rhythms).
Stabio and her colleagues found that the M5 cell, the least understood of the group, might play a role in both image and non-image forming vision.
“This adds to growing evidence that image forming and non-image forming pigments, cell types, and circuits are not as distinct as once imagined,” she said. “The two appear to be intersecting.”
But the biggest surprise was discovering that the M5 cells also process color information in mice. Mice are nocturnal and generally have poor vision. They navigate chiefly by using their nose and whiskers.
“What exactly they are doing with this color information remains to be discovered, but we know now there is a circuit for it and it’s getting to the mouse’s brain,” Stabio said.
It’s a contribution neuroscience researchers hope will help further unravel the mystery of why some people develop Alzheimer’s disease symptoms while others do not.
Potter, whose groundbreaking research expanded knowledge of the genetic and molecular relationships between Alzheimer’s disease and Down syndrome, said the donation was made by a Denver-based family who felt that their sister would have been thrilled to know that she was making a significant contribution to science.
And, Potter said, it’s a sentiment that goes beyond this one family. “People with Down syndrome and their families would very much like to help research to understand Alzheimer’s disease in them and in the rest of us, and so brain donations from people with Down syndrome are very important.”
“It’s a great contribution to humanity,” he added.
Potter plays multiple roles related to Alzheimer’s disease and Down syndrome research at the CU School of Medicine. In addition to being the Director of the Rocky Mountain Alzheimer’s Disease Center, he is also the Director of Alzheimer’s Disease Research at the Linda Crnic Institute for Down Syndrome.
The brain came from a 63-year-old woman named Gretchen Josephson, whose family has a long lineage in medicine and a connection to the CU School of Medicine. (See sidebar below).
Connection to Alzheimer’s disease
The direct link between Down syndrome and Alzheimer’s disease is on human Chromosome 21. People with Down syndrome are born with three copies of Chromosome 21 in every cell, a condition that occurs at conception.
Additionally, the main gene that produces the protein linked to Alzheimer’s disease resides on Chromosome 21. Because people with Down syndrome have this third copy of Chromosome 21 in all of their cells, Potter says that they all will develop the underlying Alzheimer’s disease pathology by the time they are 40 years old.
According to Potter, the mystery is that despite all people with Down syndrome having this predisposition to Alzheimer’s disease brain pathology, around 20 percent will not develop dementia symptoms.
“We’d like to study them to better understand how Alzheimer’s disease brain pathology and dementia develop,” he said. “That way, we could learn who is most likely to develop dementia and who isn’t. And we’d like to be able to initiate treatment for people who don’t have Down syndrome but who might be at risk, say, in their 40s or 50s, and prevent the cell death and the problems that accompany Alzheimer’s disease.”
Potter points out that Alzheimer’s disease is believed to start developing as many as 20 years before clinical symptoms appear. He says the main research goal is to develop treatments for people “on the steps” to Alzheimer’s disease, and also to develop early diagnoses.
The vast majority of people who are diagnosed with typical age-related Alzheimer’s disease, over 95 percent, do not have Down syndrome. However, Potter’s earlier research showed that they have Down syndrome-like cells with three copies of Chromosome 21 throughout their bodies, including in neurons in their brains.
Insights into the pathology
“What are the earliest signals in people with Down syndrome that they’re going to develop Alzheimer’s disease within five or 10 years? Can we use those same signals, whether it be a blood protein or a neuropsychological test, to help figure out when and whether the rest of us are at risk for Alzheimer’s disease?”
In recent years, Alzheimer’s disease research centers around the world have received many brain donations from typical people with Alzheimer’s disease, but not from people with Down syndrome. These donations are very rare, and “are very valuable,” said Potter, “because if we can understand more about the pathology that develops in people with Down syndrome, we will be better able to understand the pathology that happens in typical people. And that’s going to give us a hint of what’s going wrong, and of how we might be able to compare the brains and come up with an idea for fixing them.”
Potter also notes that receiving a brain for research from a person with Down syndrome who did not have dementia at death would be especially rare and would be extremely valuable for research.
Potter encourages adults with Down syndrome to be assessed by the neurology team in the Memory Disorders Clinic, part of the Neurology clinic in the Anschutz Outpatient Pavilion and the clinical arm of the Rocky Mountain Alzheimer’s Disease Center. “We recommend this regardless of whether they have memory problems, so that they can take full advantage of the consultation opportunities,” he said.
More information about the center is at www.medschool.ucdenver.edu/alzheimers.
Guest Contributor: Both of these stories were written by Helen Gray, MBA, Communications and Community Outreach Coordinator of the Rocky Mountain Alzheimer’s Disease Center.
GRETCHEN JOSEPHSON MADE A ‘LAST GREAT GIFT TO ALL OF US’
The Denver woman with Down syndrome whose brain is the first donated for Alzheimer’s disease and Down syndrome research had a reputation for making her own way in the world and for making friends wherever she went.
Gretchen Josephson, who was 63 when she died, was the daughter of two physicians, the fourth of four girls. Her mother, Lula Lubchenco Josephson, MD, was a professor in the Department of Pediatrics in the CU School of Medicine. Her father, Carl Josephson, MD, was a cardiologist in private practice.
Gretchen graduated from South High in Denver Public Schools and studied food service at the Emily Griffith Opportunity School. The training helped her land a job as a bus girl at the Tea Room at the old downtown Denver Dry Goods store before it closed. Gretchen was retrained to work with inventory on the retail side of Foley’s, and then Macy’s at the Cherry Creek Mall. By the time she retired, Gretchen had worked continuously for 37 years.
And customers remembered Gretchen. Her eldest sister, Patty McFeeley, MD, said “you couldn’t walk with her through the Cherry Creek Mall without someone stopping her and saying, ‘Hi Gretchen.’”
Wrote a book of poetry
Gretchen wrote poetry. In 1997, with her mother’s encouragement, she published a book of poems called “Bus Girl,” and read and signed copies for a packed house at the Tattered Cover bookstore.
One of Gretchen’s passions was country music. She frequently traveled to Nashville and figured out how to go backstage at concerts. The walls of Gretchen’s apartment were covered with photos of her and the stars she adored so much.
Another passion was sports. In addition to skiing, Gretchen swam and competed in Special Olympics. Her family took her on scuba trips, and her sister said she especially loved the shipwreck dives.
Self-advocate for Down syndrome
Gretchen was a self-advocate for Down syndrome, and she spoke at numerous national and international conferences, telling large audiences about her personal experiences with independent living.
McFeeley, a pathologist, said it was natural for Gretchen’s sisters to consider making the brain donation for scientific research. She occasionally took Gretchen along when she performed post-mortem examinations on cadavers, and Gretchen was, according to McFeeley, “fascinated” with the procedure.
Although Gretchen’s Alzheimer’s disease had advanced so much that she wasn’t able to discuss her own brain donation before she died, her sisters firmly believe that would have been what Gretchen wanted. “It was her last great gift to all of us,” said McFeeley.
When Andy Winter talks about the prospect of continuing his education at the University of Colorado Anschutz Medical Campus, one word comes to mind: excitement. Although he has spent the last year and a half on the CU Anschutz campus, Winter wants nothing more than to stay put.
This fall, Winter will graduate from the Graduate School with a master of science degree in Biomedical Sciences and Biotechnology.
“I knew that graduate school was in my future,” he said. “But, I wasn’t sure about jumping right into a program. So I worked in industry microbiology after finishing my undergraduate degree in biotechnology and microbiology.”
After three years in the industry, Winter missed the thrill of research. So, in 2015, he moved from Minnesota to Colorado to completely dedicate himself to applying to graduate school.
Choosing CU Anschutz
CU Anschutz was an attractive choice for Winter because of the numerous areas of research expertise on campus.
He also found the master’s program in Biomedical Sciences and Biotechnology (BSBT) at CU Anschutz especially appealing because it afforded him a flexible curriculum. He was able to navigate and sample any of the scientific disciplines CU Anschutz has to offer.
Little did Winter know that he would get much more out of CU Anschutz than just an education. It also re-introduced him to one of his passions – immunology.
Winter joined the lab of Beth Tamburini, PhD over a year ago. Although challenging, he has enjoyed his time there. While working in the lab, he conducts impactful research involving the immune system. The Tamburini lab is currently working on three different projects involving immune function. This variety of work has given him the opportunity to collaborate with other labs and extend his professional network.
“First, we are working to better understand how the immune system enhances protection against a secondary infection,” said Winter. “Secondly, we’re working with Dr. Traci Lyons to understand the role of lymphatic vessels in the immune response in breast cancer. Finally, we are working with Dr. Hugo Rosen to study lymphatic vessels and their interaction with immune cells in the liver during chronic liver disease.”
Through this hands-on laboratory work, Winter has gained invaluable knowledge and experience.
“I’m glad to be a part of this lab,” said Winter. “I’ve found immunology to be so fascinating and intricate. My understanding of immunology was limited prior to joining the Tamburini lab. The research we’re conducting is important in understanding how to better combat diseases that impact millions.”
Winter hopes to continue his professional development at CU Anschutz not only because of the campus’s cutting-edge research, but also because of its supportive attitudes.
“I’ve grown comfortable with the community of researchers and students on campus,” he said. “It has given me a strong support network and I’m dedicated to continue growing as a professional with the support of that community.”
More than academics
Despite his busy study and lab schedule, Winter found time to be an active member of the Women in STEM organization at CU Anschutz. He also attends the bi-weekly tumor immunology seminar series.
“These organizations have further enriched my experience at CU Anschutz,” said Winter. “They’ve given me unique perspective, knowledge and networking opportunities I wouldn’t have found elsewhere.”
CU Anschutz has also given him the opportunity to attend seminars, conferences and other events led by outstanding scientists. “Through these events, I’ve heard from some of the most prestigious scientists in the world – some of which are a part of this campus,” said Winter.
“I’ve learned so much in my time as a master’s student and research assistant,” said Winter. “As I near completion of my master’s degree in the BSBT program, I can look back at the previous year and say CU Anschutz was the right decision for me.”
High-intensity exercise three times a week is safe for individuals with early-stage Parkinson’s disease and decreases worsening of motor symptoms, according to a new phase 2, multi-site trial led by University of Colorado Anschutz Medical Campus and Northwestern Medicine scientists.
This is the first time scientists have tested the effects of high-intensity exercise on patients with Parkinson’s disease, the second most common neurodegenerative disorder and the most common movement disorder affecting more than 1 million people in the United States.
“If you have Parkinson’s disease and you want to delay the progression of your symptoms, just a stroll isn’t sufficient. You should exercise three times a week with your heart rate between 80 to 85 percent maximum. It is that simple,” said lead author Margaret Schenkman, Associate Dean for Physical Therapy Education and PT Program Director at the CU School of Medicine at CU Anschutz.
Previously, it was thought high-intensity exercise was too physically stressful for individuals with Parkinson’s disease. “High-Intensity Treadmill Exercise in Parkinson Disease: A Randomized, Controlled Phase II Trial” was published today in JAMA Neurology.
Parkinson’s symptoms include progressive loss of muscle control, trembling, stiffness, slowness and impaired balance. As the disease progresses, it may become difficult to walk, talk and complete simple tasks. Most people who develop Parkinson’s are 60 and older.
‘We catch people early in the disease and are slowing them from getting worse, which is significant, particularly for a disorder that is chronic and progressive.’ – Margaret Schenkman
Because medications for Parkinson’s have adverse side effects and reduced effectiveness over time, new treatments are needed.
The randomized clinical trial included 128 participants ages 40 to 80 from Rush University Medical Center, Northwestern University and the University of Pittsburgh in addition to the University of Colorado Anschutz in Aurora.
Participants enrolled in the Study in Parkinson Disease of Exercise (SPARX) were at an early stage of the disease and not taking Parkinson’s medication, ensuring the results of the study were related to the exercise and not affected by medication.
“The earlier in the disease you intervene, the more likely it is you can prevent the progression of the disease,” said co-lead author Daniel Corcos, professor of physical therapy and human movement sciences at the Northwestern University Feinberg School of Medicine. “We delayed worsening of symptoms for six months; whether we can prevent progression any longer than six months will require further study.”
Scientists examined the safety and effects of exercise three times weekly for six months at high intensity, 80 to 85 percent of maximum heart rate, and moderate intensity, 60 to 65 percent of maximum heart rate. They compared the results to a control group who did not exercise.
Phase 2 outcomes
Exercise needs to between 80 and 85 percent maximum heart rate for benefit
First time high-intensity exercise is tested in Parkinson’s patients
Moderate intensity had no effect
“Exercise is medicine,” says CU Anschutz Medical Campus scientist Margaret Schenkman
After six months, participants were rated by clinicians on a Parkinson’s disease scale ranging from 0 to 108. The higher the number, the more severe the symptoms.
Participants in the study had a score of about 20 before exercise. Those in the high intensity group stayed at 20. The group with moderate exercise got worse by 1.5 points. The group that did not exercise worsened by three points. Three points out of a score of 20 points is a 15 percent change in the primary signs of the disease and considered clinically important to patients. It makes a difference in their quality of life.
“We catch people early in the disease and are slowing them from getting worse, which is significant, particularly for a disorder that is chronic and progressive,” Schenkman said.
Schenkman and colleagues confirmed it was safe for the participants to do high-intensity exercise by giving them a cardiologist-supervised graded exercise test to evaluate the heart’s response to exercise.
“What sets this study apart from others is we enrolled a high number of participants who exercised on a treadmill for six months with a robust workout, Schenkman said. “Many exercise studies are only 12 weeks in length and often the focus is on low intensity exercise or stretching.”
Previous studies in humans suggest high-intensity exercise improves motor symptoms, but the evidence wasn’t sufficient to determine whether exercise intensity modifies symptoms or disease progression. In addition, most studies have not precisely measured or controlled exercise intensity and none have been conducted at 80 to 85 percent maximum heart rate.
“Several lines of evidence point to a beneficial effect of exercise in Parkinson’s disease,” said Dr. Codrin Lungu, program director at the National Institute of Neurological Disorders and Stroke. “Nevertheless, it’s not clear which kind of exercise is most effective. The SPARX trial tries to rigorously address this issue. The results are interesting and warrant further exploration of the optimal exercise regimes for Parkinson‘s.”
The next step will be a Phase III clinical trial with more participants and additional sites.
Co-authors on the study from CU Anschutz are Drs. Wendy M. Kohrt, Cory L. Christiansen, Brian D. Berman, Benzi M. Kluger and Edward L. Melanson. Collaborating authors from other sites include co-lead author Dr. Daniel Corcos, Northwestern University; Drs. Anthony Delitto, Charity G. Moore, and Deborah A. Josbeno from the University of Pittsburgh; and Drs. Deborah A. Hall and Cynthia L. Comella from Rush Medical Center.
The study was funded by grants from the National Institutes of Health and the Parkinson’s Disease Foundation.
Diagnosed in 1991, David Dillon was sure his HIV-positive test was a death sentence. He’d watched friends die, struggling on the only drugs available at the time, medications that had intense side effects and were barely effective, with the rapidly evolving AIDS virus building resistance to them often within months.
But then the words of a social worker resonated in his mind. Experts, she had told him soon after hearing his diagnosis, were on the verge of turning the once always-deadly affliction into a chronic but manageable disease. “That’s what I grabbed on to right away,” Dillon said. “And that’s what I’ve hung on to ever since.”
Dillon was one of the first HIV-positive patients to volunteer for studies with the AIDS Clinical Trials Unit (ACTU) at the now University of Colorado Anschutz Medical Campus. Today, as the ACTU celebrates 25 years of major contributions in revolutionizing HIV/AIDS treatment, Dillon is still alive, grateful for CU and content knowing he helped make a difference.
Creating a top-notch program
The human-immunodeficiency virus (HIV), which spread fear and bias throughout the country in the ‘80s, killing people from actor Rock Hudson to writer Isaac Asimov, had no treatment until 1987, and no effective drugs until the mid-‘90s. CU eventually became one of the top research universities for HIV/AIDS research in the world, but not until netting a major new faculty recruitment.
“It was a big deal,” Thomas Campbell, MD, principal investigator of CU’s ACTU, said of the 1989 recruitment of Robert “Chip” Schooley. A Harvard Medical School professor and prominent, internationally-recognized HIV researcher, Schooley established CU as an AIDS Clinical Trials Center, bringing front-line drugs to the region.
“I remember sitting on my back porch and reading about his recruitment on the front page of The Denver Post,” said Campbell, who was an infectious disease fellow at the time. “Bringing him to Colorado was like recruiting John Elway to the Denver Broncos. It’s bringing a superstar to Colorado, which helps elevate the whole team.”
By 1991, when Dillon, a Housing Department employee at CU Boulder at the time, was learning of his infection, the National Institutes of Health was tapping Schooley to lead a new ACTU, injecting $4.8 million in adult AIDS research and $3 million in pediatric AIDS research into CU’s coffers. CU’s unit joined a growing number of national sites within the AIDS Clinical Trials Group (ACTG), formed in 1986 as the urgency for new drugs intensified.
“Schooley was the key person that made that happen, and so all of the great HIV/AIDS research capacity that we have today is largely possible because of the groundwork that he laid and the foundation that he built in the early ‘90s,” said Campbell, who had joined CU as an infectious disease fellow that year and is now medical director of the adult Clinical and Translational Research Center (CTRC) of the Colorado Clinical Translational Science Institute at CU, where clinical trials are conducted.
For many Colorado HIV patients, including Dillon, the move was a life-saving boon.
Road past resistance is long
Wearing a beeper, which interrupted him every four hours to take his arsenal of pills, Dillon, now 65, was one of the lucky ones in that the regimen’s side effects didn’t make him so sick he ditched the AZT (azidothymidine), choosing to accept HIV’s fate. But he knew the drug’s effects were waning.
‘It seemed like I was already at the cusp, so when a drug came into testing, I was ready for it. Dr. Steven Johnson saved my life more than once.’ – patient David Dillon
Dillon found Graham Ray, RN, still a study coordinator with CU’s ACTU, and signed up for one of the first of what would exceed 177 clinical trials in the unit’s 25 years, with more than 2,500 participants coming forward to help scientists in their search for a more effective treatment.
The study involved spending some nights in the hospital, and Dillon recalled a trial patient in a nearby bed. “He had pretty much run the gamut of drugs available. He’d run out of options, so this trial was one of his last hopes,” Dillon said. “I lost several friends that were in the same boat. There just wasn’t new treatment coming fast enough to help them.”
Few drugs and rapid resistance were major problems for patients in those days,” Campbell said. “We could only give one or two drugs at the most together, and drug resistance developed very rapidly. The medicines lost their effectiveness.”
For Dillon, who estimates he tried upwards of 20 single experimental drugs, the trials always came right in time, with Ray and his CU doctor, Steven Johnson, MD, of the Division of Infectious Diseases, regularly alerting him to new studies.
“It just seemed like I was already right at the cusp, so when a drug came into testing, I was ready for it,” said Dillon, who still travels to CU Anschutz from his Loveland home, indebted to his caregivers. “Dr. Johnson saved my life more than once,” said Dillon, who has AIDS, the end-stage disease of an HIV infection.
HIV attacks patients’ immune systems by binding to and killing CD4 cells, which are largely responsible for fighting infections. Doctors monitor CD4-cell counts, assessing the progression of the disease. If a patient’s count falls below 200, then they are diagnosed with AIDS, and their risk of deadly infections rises. Dillon’s counts were once as low as five.
Trial volunteers join mission
For Patrick Terry, a former Colorado rodeo staple and Denver-area native, who has done “probably a dozen” trials with CU since 2000, taking part in trials is about staving off AIDS (his CD4 count has never fallen below 500), and putting an end to the epidemic. “To me, it’s so important that we find out more about it, and if there’s any chance that there could be a cure, then I’d like to be a part of it.”
Helping science isn’t always easy, said Dillon and Terry, 60, who calls himself a go-to volunteer for ACTU research nurse Cathi Basler, RN, because of his dedication to the trial process. Although he said he’s “lucky” to have apparently always received the active drug in the double-blind studies, Dillon recalled a nearly five-year trial that required injecting a drug in his abdominal muscles twice a day. “It just hurt, and you had to just keep doing it.”
“You know when you are on the real drug,” said Terry, who has volunteered for clinical trials with Basler for years after being diagnosed with HIV in 1995. “I’ve had some very difficult studies,” he said, noting one in which the drug was so strong, it caused hallucinations, and another in which he had to have lymph nodes removed.
But the pair’s dedication has paid off, for them, and for many of the more than 30 million people worldwide living with HIV.
Treatment only works with adherence
In 1996, a CU ACTU-led research study played a key role in the development and widespread use of what was commonly termed “drug cocktails.” That was a major turning point in HIV/AIDS treatment, Campbell said.
“When we first really had the ability to put three drugs together to make an effective combination, it greatly reduced the risk of drug resistance. It did so by having much more effective suppression of viral replication,” he said. “We suddenly had a way to effectively treat HIV and prevent all the damage it does to the body.”
Part of a two-drug combination trial today, Terry’s CD4 counts hover around 1,000, and his viral load is undetectable. For, Dillon, although his CD4 counts aren’t quite so high, and his “cocktail” includes five drugs, his viral load is also undetectable.
But Terry, emphasizing that the effective drugs are still not a cure, advocates for medication adherence. “I’ve never missed a dose, and that’s probably one of the most important things,” said Terry, , who watched his “little brother” die in 2005, after living in denial with an HIV infection for years and succumbing to AIDS within 18 days of hospitalization.
“Take it seriously,” Terry said. “Don’t skip your medicine. That’s a problem with so many people. The medicine doesn’t work if you don’t take it. And take care of yourself,” he said, adding that he stopped drinking at diagnosis and keeps an eye on fitness.
Workload for researchers still great
While noting the great scientific achievements, which would not have been possible without dedicated volunteers, Campbell, too, emphasized that HIV remains a serious virus with no cure. “Yes, a person diagnosed today who seeks treatment early and adheres to it should live a near-normal lifespan,” Campbell said. “But near normal is not normal. There’s still a lot of work that needs to be done.”
The to-do list for HIV/AIDS researchers remains long, with vaccine trials still underway, and development of a cure feasible but probably not within close reach, Campbell said. Continuing efforts to treat HIV patients in developing countries remains a priority, as does boosting prevention education.
For instance, use of an antiretroviral drug combination called PrEP in high-risk individuals who are not yet infected can reduce their chances of contracting HIV, and early treatment in patients already infected can not only boost their chances of success; it reduces the virus’s spread, Campbell said. “So we not only help them, but we help the rest of the community.”
Dillon said he’s grateful for that first social worker’s hopeful words and for finding the ACTU at CU at the right time. “It saved my life, and it saved a lot of other lives.”
Photo at top: Constance Benson, MD, Robert “Chip” Schooley, MD, and Thomas Campbell, MD, attended a recent Zimbabwe Art and Sculpture Auction in the Fulginiti Pavilion.