Longitudinal studies in Parkinson's disease (PD), that document how changes in structure and function of the brain relate to changes in movement and cognition, represent a critical component to developing new therapies that will slow the rate of progression of PD. Unfortunately, longitudinal studies of brain structure and function in PD are very rare. In years 7-12 of this renewal R01, our laboratory is well-positioned to conduct a longitudinal study since we have already tested 40 patients with PD and 40 age and sex-matched control subjects at baseline. Our research team has used diffusion tensor imaging (DTI) to show that the structural integrity of the dorsal substantia nigra is reduced with age, and that the ventral substantia nigra is reduced in early stage, de novo PD. Further, our laboratory has used functional magnetic resonance imaging (fMRI) to show that the functional activity of all basal ganglia nuclei are reduced in PD during specific grip force switching tasks. We have shown that the functional activity of basal ganglia nuclei relates to specific motor signs in PD, such as bradykinesia and tremor. In this renewal, we will compare our baseline DTI and fMRI data in 40 de novo patients with PD and 40 control subjects longitudinally to a 4 year time point. In year 4, patients will be tested off and on antiparkinsonian medication. We test the hypothesis that alterations in the structural integrity of the substantia nigra and anterior thalamus are linked to disease progression changes in motor signs and cognitive signs. As a consequence, disease progression changes in motor signs and cognitive signs will be related to region-specific changes in functional activity of the basal ganglia, thalamus, motor cortex, and frontal cortex in PD.
Aim 1 a will use DTI to examine the structural integrity of the substantia nigra in relation to motor signs of PD.
Aim 1 B will use fMRI during a well-defined force switching task to examine the relation between functional activity of the basal ganglia, thalamus, and motor cortex to motor signs of PD.
Aim 2 a will use DTI to examine the structural integrity of the thalamus in relation to cognitive signs of PD.
Aim 2 b will use fMRI during a cognitive-motor task to examine the functional activity of the caudate and frontal cortex in relation to cognitive signs of PD. The proposed research is both significant and innovative because it will be the first comprehensive study to use structural and functional brain imaging at 3 Tesla to focus on how subcortical and cortical brain structures change in patients with PD after 4 years.

Public Health Relevance

Parkinson's disease affects over one and a half million people in the United States, and patients with Parkinson's disease have significant problems with both movement and cognition. These debilitating motor and cognitive problems become worse as the disease progresses. Unfortunately, very little is known about how the structural and functional brain mechanisms change as the disease progresses. The purpose of this grant is to compare baseline structural and functional magnetic resonance imaging data already collected in drug naive patients with Parkinson's disease longitudinally to a 4 year time point. The expected outcome of this grant is to identify structural and functional brain markers of disease progression related to both motor and cognitive deficits in Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052318-10
Application #
8515533
Study Section
Musculoskeletal Rehabilitation Sciences Study Section (MRS)
Program Officer
Chen, Daofen
Project Start
2005-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2013
Total Cost
$313,936
Indirect Cost
$99,645
Name
University of Florida
Department
Physiology
Type
Schools of Allied Health Profes
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Kurani, Ajay S; Seidler, Rachael D; Burciu, Roxana G et al. (2015) Subthalamic nucleus--sensorimotor cortex functional connectivity in de novo and moderate Parkinson's disease. Neurobiol Aging 36:462-9
Wagle Shukla, Aparna; Vaillancourt, David E (2014) Treatment and physiology in Parkinson's disease and dystonia: using transcranial magnetic stimulation to uncover the mechanisms of action. Curr Neurol Neurosci Rep 14:449
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Neely, Kristina A; Coombes, Stephen A; Planetta, Peggy J et al. (2013) Segregated and overlapping neural circuits exist for the production of static and dynamic precision grip force. Hum Brain Mapp 34:698-712
Fox, Emily J; Baweja, Harsimran S; Kim, Changki et al. (2013) Modulation of force below 1 Hz: age-associated differences and the effect of magnified visual feedback. PLoS One 8:e55970
Hess, Christopher W; Ofori, Edward; Akbar, Umer et al. (2013) The evolving role of diffusion magnetic resonance imaging in movement disorders. Curr Neurol Neurosci Rep 13:400
Poon, Cynthia; Coombes, Stephen A; Corcos, Daniel M et al. (2013) Transient shifts in frontal and parietal circuits scale with enhanced visual feedback and changes in force variability and error. J Neurophysiol 109:2205-15

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