Preclinical Markers of Parkinsonism

SUMMARY We have known for some time that α-synuclein aggregates to form insoluble fibrils in pathological conditions characterized by Lewy bodies, such as Parkinson’s disease (PD), multiple system atrophy, and dementia with Lewy bodies. People with synucleinopathies desperately need disease modifying therapies, that either slow or stop neurodegeneration. In order to facilitate the development of new therapies, the fields of neurology, motor control, neuroimaging, and α-synuclein biomarkers need to join forces to identify disease far earlier, well before a neurologist currently makes a diagnosis. In Alzheimer’s disease, investigators have defined Mild Cognitive Impairment (MCI) before dementia and this has unleashed a series of preclinical behavioral, imaging, and pathologically-relevant markers that have revolutionized how clinical trials are conducted for dementia. This same type of revolution in early identification is sorely missing, but clearly needed, in the area of Parkinsonism. In this proposal, we will define a Mild Parkinson Impairment (MPI) using innovative markers that cut across imaging and physiology. We will study a preclinical model of Parkinsonism, known as rapid eye movement (REM) behavior disorder (RBD). The reason RBD is a preclinical model of Parkinsonism, is that 50-60% of patients with RBD go on to develop PD, and the remainder develop either dementia with Lewy bodies or multiple system atrophy. Individuals with RBD will eventually exhibit clinical Parkinsonism with varying degrees of severity. Here, we test the central hypothesis that we can identify early cross-sectional and longitudinal markers of Mild Parkinson Impairment in patients with RBD. Our goal in this proposal is to study patients with RBD prior to other diagnoses to identify early cross-sectional and longitudinal markers of preclinical Parkinsonism. Based on our strong preliminary data and our prior work we will: 1) evaluate innovative measures of brainstem functional magnetic resonance imaging and task-based striatal-cortical functional connectivity; 2) test our robust marker free-water in the substantia nigra in RBD for the first time; 3) measure a newly developed α-synuclein skin biomarker called real-time quaking-induced conversion (RT-QuIC) assay; 4) evaluate motor control assays to define a preclinical mild motor impairment; and 5) follow patients longitudinally after 24 months to determine if these imaging and physiology markers progress over time in people with RBD.