Cognitive Biomarker Targets for Treatment in Veterans with Parkinson's Disease

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 DESCRIPTION: More than 100,000 Veterans living with Parkinson's disease (PD) currently receive PD-related care and services from the VA. Management of PD includes treatment of both motor and non-motor symptoms. Mild cognitive impairment (PD-MCI) is a common non-motor symptom in PD that negatively impacts functioning, is a main determinant of quality of life, and is a risk factorfor developing dementia. In the civilian population, over a quarter of PD patients have PD-MCI; estimates are unknown in Veterans. It is also unknown if combat- related risk factors impact the nature PD-MCI (i.e., severity or types of cognitive domains), thus studying PD- MCI in Veterans may be particularly important. Limited treatment options for PD-MCI in the civilian population and the possible need to tailor treatments to Veterans with PD-MCI makes this an important research topic. Understanding PD-MCI can offer insight into the brain mechanisms at the earliest stage of cognitive decline. For example, cognitive function is supported by brain regions that comprise neural networks. These networks are functionally connected even when a cognitive task is not being performed (i.e., when a person is at rest). Changes in the resting state functional connectivity (rsFC) of cognitive networks are associated with changes in cognitive function. Understanding unique differences in the rsFC of cognitive networks associated with PD-MCI will aid in elucidating the neurobiology of this condition. Such information can be used to develop early rehabilitation interventions, such as repetitive transcranial magnetic stimulation (rTMS), that focus on preventing or delaying the onset of PD-D. rTMS is a non-pharmacological and non- invasive stimulation technique that can induce neuronal plasticity in targeted brain regions and networks. rTMS shows promise as a tool for cognitive enhancement in people with neurological conditions. The objectives of the current CDA2 proposal are to enhance our understanding of the mild cognitive deficits that most frequently occur in Veterans with PD and to determine the altered rsFC of critical brain regions that support cognitive function. Information gained about these brain and behavior relationships will be used to guide the development of a protocol for a cognitive rehabilitation intervention using rTMS. To carry out these objectives, Veterans with PD will be recruited and cognitive behavior will be characterized using neuropsychological tests. The underlying neurobiology of the behavior will be characterized using advanced functional magnetic resonance imaging (fMRI) techniques and rsFC analysis. Multiple approaches for functional connectivity analyses will be undertaken. Specifically, disruptions in functional connectivity of regions within or between cognitive networks that are correlated with cognitive impairment will be determined. These brain and behavior characterizations will be evaluated collectively to develop an rTMS protocol such that a cortical stimulation site as well as stimulation parameters will be determined. A pilot randomized control trial to determine safety, feasibility and efficacy of rTMS to improve cognitive function will be conducted. Participants will be treated with either active or sham rTMS for 10 daily sessions over the course of two weeks. It is expected that this innovative project will contribute a missing, fundamental element to our base knowledge, without which mild cognitive impairment in Veterans with PD cannot be understood. The acquisition of such knowledge is critical for developing and optimizing cognitive rehabilitation treatments for Veterans with PD-MCI, with an ultimate goal of improving quality of life. Findings related to this CDA2 proposal will potentially inform neurorehabilitation of other conditions in which MCI and dementia occur.