Neuroimaging Biomarkers in Parkinsonism: Differentiating Subtypes and Tracking Disease Progression (U01)
There is an urgent need for biomarkers of diagnosis and progression of Parkinson’s disease (PD) and related disorders to improve clinical-trial ready biomarkers for PD, MSA, and PSP. Overlap of symptoms in early stages makes diagnosing these diseases challenging, yet accurate diagnosis is critical for effective targeting of disease-modifying therapies. Further, clinical-trials for a medication in PD may not apply to MSA and PSP. Thus, developing biomarkers to differentiate disease is a critical step to making sure that a clinical-trial is testing the medication on patients with the correct diagnosis. To develop disease differentiation and progression biomarkers for PD and related disorders, we will use two imaging modalities, free-water imaging and task-fMRI in two brain regions, the basal ganglia and cerebellum. Free-water imaging applies a two-compartment model of diffusion to estimate the fractional volume of unconstrained diffusion (free-water), and fractional anisotropy of the tissue corrected for the free-water compartment. Task-fMRI assesses the blood oxygenation level dependent (BOLD) activity in key regions of the brain involved in the production of grip force. The ability to use these imaging techniques for monitoring disease progression will be determined over a 12 month period and the utility of these imaging modalities for patient stratification will be studied in PD, PSP and MSA patient cohorts.
The goal of this application is to test and validate across two imaging sites a set of diagnostic and progression biomarkers we have recently published that differentiate and track disease progression in Parkinson's disease (PD), parkinsonian variant of multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Over the past 5 years our group has led the efforts in magnetic resonance imaging (MRI) for the Parkinson's Disease Biomarker Program (PDBP) and has developed 2 innovative biomarkers for differentiating PD, MSA, and PSP. Both free-water diffusion imaging and task-fMRI have uncovered clear patterns of degeneration and abnormal functional activation in the basal ganglia and cerebellum that can reliably differentiate PD, MSA, and PSP. In longitudinal studies we found that free-water diffusion imaging and task- fMRI track progression of PD, MSA, and PSP over one year with no changes in age and sex matched controls. Reproducible, reliable, objective and validated MRI-based progression markers are of great significance and would transform clinical trials in PD, MSA, and PSP. At our two imaging sites, we will acquire data on 100 PD, 50 MSA, 50 PSP, and 50 healthy age and sex matched controls. We will provide timely data sharing with the PDBP community.
1. Cohort Development: 100 PD, 50 PSP and 50 MSA patients and follow up after 12 months. Participants will be assessed using stand PDBP core clinical measures, biosamples (DNA, RNA and plasma) will be collected at the baseline and 12 month visit and deposited with the NINDS BioSEND Repository.
2. Imaging: Free water and task-fMRI imaging will be completed at the baseline and 12 month visit. Clinical and imaging data will be deposited with the PDBP data management resource