ANN ARBOR, Mich. — Deep in the brains of the million Americans with Parkinson's disease, changes to their brain cells put them at high risk of dangerous falls -- a problem that resists even the most modern treatments.
Now, University of Michigan scientists and doctors have launched a five-year, $11.5 million effort to better understand the cause of these problems, and find new options based in the latest brain science.
With the new grant from the National Institute of Neurological Diseases and Stroke, part of the National Institutes of Health, U-M becomes home to one of only nine Morris K. Udall Centers of Excellence in Parkinson's Disease Research in the country. Named for a noted member of Congress who battled the disease, the Udall Centers bring together researchers from many fields to tackle big questions in Parkinson's, to educate the next generation of Parkinson's researchers, and to serve as a vital resource for patients with the disease.
The U-M investigators will focus on a brain chemical system that is rapidly emerging as a key player in the disease's effect on walking and balance – in large part due to advances made at U-M. Called the cholinergic system, it helps us focus our attention on tasks such as walking, and may be the next key target for Parkinson's treatments.
The U-M Udall Center team includes researchers in many units of the university. They include Medical School doctors who treat Parkinson's patients at the U-M Health System and the VA Ann Arbor Healthcare System, and study the disease in their labs, as well as a neuroscientist in the College of Literature, Science & the Arts, and biostatisticians from the schools of Nursing and Public Health.
"Understanding the role of the cholinergic system is a key unexplored frontier in Parkinson's disease, and will allow us to go beyond the limits of current practice, so we can create better therapies to suppress the terrible symptoms of the disease that affect balance, walking and overall independence," says William Dauer, M.D., who will be the center's director. Dauer directs the UMHS Movement Disorders program and is the Elinor Levine Professor of Neurology, and an associate professor of Cell and Molecular Biology, in the U-M Medical School.
Targeting the "double whammy" of Parkinson's brain cell loss
Most Parkinson's disease research and treatment focuses on the brain's dopamine system, which normally helps control movement. This control breaks down in Parkinson's patients, as more and more dopamine-producing brain cells called neurons are lost.
Medicines to replace lost dopamine help correct the slowness, stiffness and tremor typical of the disease, but over time patients lose the ability to walk or even stand safely – symptoms that are resistant to dopamine therapy. They become prone to serious falls, which can lead to disastrous medical and social consequences.
Pioneering work on patients with Parkinson's by U-M brain imaging researcher Nicolaas Bohnen, M.D., Ph.D., a professor of radiology and neurology, suggests that the spread of cell loss to the cholinergic system creates a previously unrecognized effect. That is, loss of cholinergic cells robs patients of the ability to pay close attention to their movements, even as they're already having trouble walking safely. The involvement of the cholinergic system likely explains why current treatments – focused on dopamine replacement – are ineffective.
The new center will conduct three interrelated projects to better understand the role of the cholinergic system in falls, focusing on the effect of lost cholinergic neurons in brain areas called the basal forebrain, which regulates attention, and the pedunculopontine nucleus (PPN), which controls balance.
In both rats and people, the team will work to study this effect, and to determine if it may be possible to increase cholinergic traffic in the brains of patients using an already-approved drug that targets acetylcholine receptors on the surface of brain cells. That drug, varenicline or Chantix, is already available by prescription to help people stop smoking.
Neurologist Roger Albin, M.D. will serve as the center's associate director, and co-lead with Dauer a project to develop "personalized medicine" approaches to Parkinson's disease using specialized brain scanning and varenicline. They'll use a new positron emission tomography ("PET") brain scanning method – developed by Bohnen, Albin and colleagues – that makes it possible to see cholinergic activity with greater detail than ever before possible. Albin, an internationally known Parkinson's researcher, is the Anne B. Young Collegiate Professor of Neurology at U-M and leads neuroscience research at the VA Ann Arbor Healthcare System's Geriatrics Research, Education and Clinical Center.
Another key leader of the center is U-M neuroscientist Martin Sarter, Ph.D., the Charles M. Butter Collegiate Professor of Psychology in the College of Literature, Science & the Arts and a professor in U-M's Neuroscience Program. He is a world leader in research on the cholinergic system and its role in controlling attention.
In groundbreaking work, Sarter and his team have already shown in rats that the cholinergic system plays a key role in balance and walking, and that reduced cholinergic activity is associated with worse balance and more falls. They'll continue to explore this issue, and the role of the PPN brain area, in their animal model even as the work in humans continues.
A team of biostatisticians and data management specialists led by Ivaylo Dinov, Ph.D., of the U-M School of Nursing and Cathie Spino, D.Sc., of the U-M School of Public Health, will help design and analyze the results of the center's experiments, using advanced digital tools to parse the massive amounts of data the work will produce.
An education and outreach effort will be led by Kelvin Chou, M.D., co-director of U-M's Surgical Therapies Improving Movement (STIM) deep brain stimulation program for Parkinson's disease.
Chou will work to educate caregivers about Parkinson's disease management, and especially the issue of falls. He is the Thomas H. and Susan C. Brown Early Career Professor in the Department of Neurology, and an associate professor in the Department of Neurosurgery.
The center will also partner with the Michigan Alzheimer's Disease Center in minority outreach efforts, and run a Udall Center Fellows program, co-funded by U-M Medical School and the Department of Neurology, which will allow physicians and physician-scientists interested in Parkinson's disease to receive two years of intensive training and participate in center research.
Note to patients: The new center's studies will involve patients being treated at U-M Health System clinics, and others. Though they are not recruiting yet, you can register to be contacted via http://www.umclinicalstudies.org. To see what other Parkinson's disease studies at U-M currently need participants, visit umhealth.me/PDresearch.