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.