Our long-term goal is to develop effective rehabilitation to improve balance and gait in patients with Parkinson's disease (PD). To reach this goal, the purpose of this proposal is to develop a valid, objective measure of 'freezing of gait', relate it to abnormal brain connectivity and [determine the feasibility of using these freezing and brain biomarkers for rehabilitation of gait disorders in PD.] Freezing of gait is the intermittent inability to step and is a common cause of falls in patients with PD and other degenerative neurological diseases in the elderly. The [three] aims of this study are: 1) To objectively characterize freezing in PD with body-worn sensors, 2) To explore how these objective measures of freezing are associated with abnormal functional connectivity in the brain using resting state functional imaging (fMRI), and [3) To determine the number of subjects needed for a future randomized, controlled trial of the ABC rehabilitation intervention on FoG.] We hypothesize that valid, instrumented measures of severity of freezing can be developed from portable, wireless inertial sensors practical for clinical trials and clinica practice. We also hypothesize that freezing severity will be related to abnormal functional connectivity of the medial frontal cortex with the basal ganglia and the brainstem locomotor region. [We predict that use of objective gait and brain connectivity biomarkers will be useful to evaluate how rehabilitation intervention reduces freezing and improves gait and balance in patients with PD.] An observational study will relate quantitative measures of coordination of balance and gait during turning and walking to frontal-subcortical functional connectivity from state-of-the art, resting state fMRI in three matched groups of 30 subjects: PD with freezing, PD without freezing, and elderly control subjects. To evaluate freezing of gait, subjects with idiopathic PD will be tested in the OFF levodopa state after withholding their antiparkinson medication for 12 hours. To develop a 'freezing index', all subjects will turn in place and walk through narrow doorways with auditory tones in their left or right ears to indicate change in direction. Wireless, synchronized inertial sensors on the two shanks, low back and sternum will record angular velocity and linear accelerations. Resting-state (task free) fMRI connectivity will be obtained on the same day and analyzed based on synchronization of low frequency activity in a functional network involving the medial frontal cortex, brainstem locomotor region, the striatum and subthalamic nucleus of the basal ganglia, and the cerebellum. [In addition, a pilot, interventional study will randomize 20 of these PD subjects with freezing of gait into either an 8- week ABC rehabilitation program or usual care. A blinded examiner will conduct objective FoG assessment, rsfMRI, and cognitive tests before and after the 8-week period in both groups as pilot data for a clinical trial in the competing renewal of this proposal.] The results of this stdy will identify the best mobility and brain outcome measures for our long- term goal of a rehabilitation intervention study for FoG in Veterans with PD. Clarifying the relationships between gait deficits and frontal lobe deficits will lead to more effective rehabilitation interventions that can improve both mobility and cognitive function not only in Veterans with PD, but also in many elderly Veterans at high risk of falling due to neurological deficits that affect the frontal lobe of the brain.)

Public Health Relevance

Parkinson's disease (PD) imposes a heavy burden on over 3% of US veterans in the VHA health care system. PD is responsible for major mobility disability as well as cognitive disabilit, resulting in worse quality of life than most other chronic diseases. Freezing of gait is a major reason for mobility disability and associated with cognitive disability, leading to falls and mortality in PD and many other degenerative neurological disorders in the elderly. Over 80% of patients with PD develop this intermittent failure to initiate or maintain walking. The results of this study will identify the best mobility and brain outcome measures for our long-term goal of a rehabilitation intervention study for FoG in Veterans with PD. Clarifying the relationships between gait deficits and frontal lobe deficits will lead to more effective rehabilitation interventions that can improve both mobility and cognitive function not only in Veterans with PD, but also in many elderly Veterans at high risk of falling due to neurological deficits that affect the frontal lobe of the brain.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01RX001075-04
Application #
9210554
Study Section
Blank (RRD6)
Project Start
2014-01-01
Project End
2017-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Portland VA Medical Center
Department
Type
DUNS #
089461255
City
Portland
State
OR
Country
United States
Zip Code
97239
Bonora, Gianluca; Mancini, Martina; Carpinella, Ilaria et al. (2017) Investigation of Anticipatory Postural Adjustments during One-Leg Stance Using Inertial Sensors: Evidence from Subjects with Parkinsonism. Front Neurol 8:361
de Souza Fortaleza, Ana Claudia; Mancini, Martina; Carlson-Kuhta, Patty et al. (2017) Dual task interference on postural sway, postural transitions and gait in people with Parkinson's disease and freezing of gait. Gait Posture 56:76-81
Schlenstedt, Christian; Mancini, Martina; Horak, Fay et al. (2017) Anticipatory Postural Adjustment During Self-Initiated, Cued, and Compensatory Stepping in Healthy Older Adults and Patients With Parkinson Disease. Arch Phys Med Rehabil 98:1316-1324.e1
Mancini, Martina; Smulders, Katrijn; Cohen, Rajal G et al. (2017) The clinical significance of freezing while turning in Parkinson's disease. Neuroscience 343:222-228
Peterson, Daniel S; Gera, Geetanjali; Horak, Fay B et al. (2017) Corpus Callosum Structural Integrity Is Associated With Postural Control Improvement in Persons With Multiple Sclerosis Who Have Minimal Disability. Neurorehabil Neural Repair 31:343-353
Smith, Beth A; Carlson-Kuhta, Patricia; Horak, Fay B (2016) Consistency in Administration and Response for the Backward Push and Release Test: A Clinical Assessment of Postural Responses. Physiother Res Int 21:36-46
Mancini, Martina; Horak, Fay B (2016) Letter to the Editor: On ""Advantages and disadvantages of stiffness instructions when studying postural control"" by C.T. Bonnet: Comments on ""Advantages and disadvantages of stiffness instructions when studying postural control"". Gait Posture 46:214
Horak, Fay B; Mancini, Martina; Carlson-Kuhta, Patricia et al. (2016) Balance and Gait Represent Independent Domains of Mobility in Parkinson Disease. Phys Ther 96:1364-71
Peterson, D S; Horak, F B (2016) Effects of freezing of gait on postural motor learning in people with Parkinson's disease. Neuroscience 334:283-289
Peterson, Daniel S; King, Laurie A; Cohen, Rajal G et al. (2016) Cognitive Contributions to Freezing of Gait in Parkinson Disease: Implications for Physical Rehabilitation. Phys Ther 96:659-70

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