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ARRA Investments in Parkinson’s Disease
Public Health Burden
Parkinson’s disease (PD) is a progressive, neurodegenerative disorder that affects voluntary movement and can cause a broad range of non-motor symptoms. Individuals with PD lose the brain cells that produce dopamine, which plays a role in transmitting nerve signals. Over time, PD causes tremors, stiffness in the limbs and trunk, and impaired balance and coordination. As these symptoms become more pronounced, patients may have difficulty walking, talking, or completing other simple tasks. Other symptoms may include depression and other emotional changes; difficulty in swallowing, chewing, and speaking; urinary problems or constipation; and sleep disruptions. Approximately 60,000 new cases of Parkinson’s disease (PD) are diagnosed each year. By some estimates, at least one million people in the United States have PD.
Current treatments for PD are far from adequate. PD is treated first with the drug levodopa, to replenish dopamine. Some PD patients go on to receive a brain pacemaker that provides deep brain stimulation (DBS). Both levodopa and DBS cause significant side effects and lose their effectiveness as the disease progresses. The following are examples of ARRA projects that are pursuing improvements to current PD treatments or developing new treatment strategies.
Two ARRA studies are optimizing DBS. One is investigating the effects of different DBS stimulation parameters on motor control in PD patients
. Another is exploring why DBS sometimes alters cognition and testing whether localizing DBS to a particular region of the brain prevents these problems.
Two projects are investigating how dopamine affects cognition and determining whether specific cognitive functions are disrupted, unaffected, or improved by levodopa. These studies will lay the groundwork for developing better treatments for the cognitive effects of PD.
One team of researchers is developing a videogame-based training program with the Nintendo WiiFit electronic balance board to improve gait and balance in PD patients.
Several grantees are investigating ways to slow or stop the progression of PD. For example, a GO grant recipient is developing a drug that targets LRRK2 protein, which is mutated in more than 10% of inherited PD cases and 3.6% of sporadic cases.
Another group is exploring the feasibility of a therapeutic vaccine for PD. The strategy is to stimulate the immune systems of PD patients to target and degrade abnormal a-synuclein protein, which is a signature feature of PD and believed to be toxic to nerve cells.
Recent clinical studies have shown that high levels of uric acid in the blood correlate with a reduced risk of developing PD. This raises the intriguing possibility that uric acid may provide some degree of protection against PD. An ARRA-funded project is testing whether boosting the levels of uric acid and its precursors can reduce PD symptoms in a mouse model.
One of the challenges in developing new PD therapies is detecting small, but significant improvements in motor and cognitive functions. Two challenge grant recipients are establishing more sensitive and objective functional tests that can be used in future clinical trials.
One is developing and testing a novel tool for assessing balance and gait through wireless sensors worn on the wrists, ankles, and trunk.
Another is validating new instruments for measuring quality of life and cognitive functioning. This study will use a well-described cohort of 160 individuals with PD, some of whom have also been diagnosed with depression.
Many questions remain regarding the causes and risk factors for PD and how they ultimately contribute to nerve cell degeneration and clinical symptoms. The following are only a few examples of studies funded through ARRA on the basic biology of PD.
A GO grant recipient has formed a consortium to develop and characterize induced pluripotent stem (iPS) cells created from the skin of PD patients. If these iPS cells can be used to generate nerve cells that resemble those found in the brains of PD patients, they will serve as a valuable resource for studying PD biology and for drug discovery.
To understand how mutations in the LRKK2 gene contribute to the development of PD symptoms, a team of researchers is investigating structural defects in the nerve cells of mice with LRKK2 mutations.
Researchers are using functional and high resolution structural brain imaging to elucidate the effects of PD on the brain circuits that control movement.
-- Time Course of Parkinson’s Symptoms in Response to Deep Brain Stimulation -- Kuncel, Alexis Marie (NC)
-- Mechanisms of Deep Brain Stimulation -- Perlmutter, Joel Synes (MO)
-- Feedback Learning and L-Dopa in Parkinson’s Disease -- Gluck, Mark A (NJ)
-- Dopaminergic Modulation of Cognitive Aspects of Skill Acquisition in PD -- Hanna-Pladdy, Brenda (KS)
-- PD Wii: Computer-Based Training Phase II -- Dowling, Glenna A; Hone, Robert W (contact) (CA)
-- A Novel Monkey Model for Parkinson’s Drug Discovery -- Federoff, Howard J (DC)
-- Alpha-Synuclein Isomers as Novel Immunogens for Immunotherapy of Parkinson’s Disease -- Chang, Rowen JY (TX)
-- Uric Acid: Novel Therapeutic Target for Parkinson’s Disease -- Schwarzschild, Michael Alan (MA)
-- Development of an Instrumented System to Measure Mobility in Parkinson’s Disease -- Horak, Fay Bahling (OR)
-- Validating New NIH Clinical Tools in Parkinson’s Disease With/Without Depression -- Husain, Mustafa M (TX)
-- PD iPS Cell Line Research Consortium -- Isacson, Ole (MA)
-- Axonal Degeneration in LRRK2 Parkinson’s Disease -- Li, Chenjian (NY)
-- Scaling and Sequencing Motor Output in Humans: fMRI Study -- Vaillancourt, David E (IL)
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