Biomarkers of disease severity and progression in Parkinson's

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Background: Parkinson’s disease (PD) is the second most common neurodegenerative disorder, and it is even more prevalent in veterans, due to military-specific exposures that increase PD risk. There is great phenotypic variability: some PD patients present primarily with tremor and retain good quality of life for decades whereas others demonstrate a more malignant phenotype with more rapid progression to dementia and severe motor impairments. The ability to predict which patients will exhibit slow or fast disease progression would be invaluable for patient counseling and for clinical trial design. To date, no biomarkers have been identified which predict PD progression. Given that mitochondrial dysfunction is an early and consistent cellular hallmark of the disease that tracks with disease progression, measuring mitochondrial function could prove to be one such predictive biomarker. Two promising approaches, magnetic resonance spectroscopic imaging (MRSI) and measurement of Nrf2 activity in peripheral blood mononuclear cells (PBMCs), could close this knowledge gap. Significance: This work addresses two high-priority areas. It makes inroads into precision medicine through its potential for predicting disease progression and laying foundation for improving clinical trial design and expediting translation of promising preclinical work. It also focused on a neurocognitive disorder highly prevalent within the VA population. The VA has an older average age, males are more likely to acquire the disease, PD is recognized as a service-connected disease, and veterans with PD are more likely to rely solely on the VA for their health care than veterans without PD. Innovation: This proposal is innovative because we plan to be the first to apply ultrahigh field MRSI to measure mitochondrial function in real time in the brains of patients with PD. Extending beyond static measurements of phosphate-containing compounds, we will also be the first to apply magnetization transfer, giving us further insight into mitochondrial dynamics and increasing the sensitivity of our assessments. Our work will also assess whether imaging-based measures of mitochondrial dysfunction will be able to predict subsequent clinical changes in PD progression. If so, this would provide the first biomarker that is able to predict progression in individuals with PD. Specific Aims: 1) Quantify mitochondrial bioenergetics in the PD brain by applying 31P-MRSI. 2) Evaluate PBMC Nrf2 mRNA expression and its downstream effectors in PD patients compared to controls. 3) Assess longitudinal changes in peripheral Nrf2 levels and 31P-MRSI-based changes in brain bioenergetics in early PD patients, to determine whether differences in mitochondrial bioenergetics predict clinical disease progression. Methods: A cross-sectional study of early and mid-stage patients with PD and healthy controls will undergo MRSI and peripheral blood analysis. One year later, the controls and early PD group will repeat these measurements. Next Steps: By measuring mitochondrial function in vivo, this proposal will establish readouts of disease activity which can next be used to measure target engagement in trials with mitochondria-directed therapeutics.