Neuroplasticity and the emergence of motor and cognitive deficits in prodromal synucleinopathy

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Abstract Parkinson’s disease, dementia with Lewy bodies, and related synucleinopathies have a long prodromal stage, lasting years to decades, during which neurodegeneration progresses insidiously across the nervous system. Compensatory neuroplastic changes in structural and functional connectivity are thought to occur during the prodromal stage that mask the expression of motor and non-motor signs, which could markedly delay diagnosis during a critical therapeutic window. Alternatively, neuroplastic changes in structure and function may contribute to the emergence and/or exacerbation of motor and non-motor signs. Currently, little is known about the temporal evolution of structural and functional adaptations, the state of cortical neuroplasticity, and how these factors contribute to the masking and/or emergence of motor and cognitive signs during prodromal disease. This project will study the progression of disease in people with isolated rapid eye movement (REM) behavior sleep disorder (iRBD), a sleep disturbance characterized by elevated muscle activity during REM sleep, in conjunction with dream enactment. IRBD is recognized as a prodromal stage of synucleinopathy since more than 70% of people with this disorder eventually develop Parkinson’s disease, dementia with Lewy bodies, or multiple system atrophy. The goal of this project is to characterize the temporal evolution of neuroplastic changes in the structure and function of the brain in people with iRBD and to identify factors contributing to the masking and/or emergence of motor and cognitive signs. Aim 1 will use ultra-high field MRI at 7T to obtain measures of structural (diffusion tensor) and functional (rest-state) connectivity of prefrontal and sensorimotor pathways, their progression over two years, and their relationships to measures of motor and cognitive function. Aim 2 will use paired associative stimulation (peripheral nerve stimulation paired with transcranial magnetic stimulation) to examine the state and progression of long-term potentiation (LTP)-like plasticity in motor cortical pathways and its relationship to measures of motor function. Similarly, Aim 3 will use paired associative stimulation to examine the state and progression of LTP-like plasticity in prefrontal cortex and its relationship to measures of cognitive function and gait. Aim 4 will look at the relationships between the level of REM sleep muscle activity, the state of structural and functional connectivity, and cortical neuroplasticity and the progression of motor and cognitive signs. This project will provide unique insight into the temporal evolution of neuroplastic changes in the brain during prodromal disease in people at high risk of developing parkinsonism, dementia with Lewy bodies, or related synucleinopathies.