Diffusion Basis Spectrum Imaging for Measurement of Neuroinflammation in Parkinson Disease

Project Summary/Abstract Parkinson disease (PD) is an age-related neurodegenerative disease affecting a large number of U.S. veterans that causes significant motor symptoms such as slow movement and tremor, as well as non-motor symptoms such as cognitive decline and dementia. Development of therapies to slow PD progression requires validated biomarkers of pathologic processes that predict progression. The brain’s inflammatory response is increasingly recognized as an important source of pathology in PD, and imaging biomarkers of neuroinflammation in PD are needed. A novel Magnetic Resonance Imaging (MRI) technique, Diffusion Basis Spectrum Imaging (DBSI), is sensitive to intermingled changes in brain microstructure, and has the capacity to measure the component of inflammatory cells within a volume of tissue, and distinguish this component from neurodegenerative pathology or anatomic variation. DBSI MRI has been recently shown to quantify neuroinflammation in multiple sclerosis and Alzheimer’s disease. Here, we will develop and validate this measure in PD. We will determine how the DBSI measure of neuroinflammation compares to quantitative immunohistochemistry in already-collected antemortem MRI data with corresponding postmortem fixed brain tissues from people with PD (Aim 1). Prospectively, in PD and control participants we will compare DBSI measures to the positron emission tomography (PET) marker of neuroinflammation, PBR28 (Aim 2), and to the activation profile of T cells in blood and cerebrospinal fluid (Aim 3). We will correlate cross-sectional and longitudinal DBSI measures with clinical features of motor and cognitive disease progression (Aim 4). In this manner, we will develop a strong mechanistic understanding of changes in both neuroimaging and T cell biomarkers of inflammation, and how these relate to motor and cognitive decline in PD. This project holds great promise for identifying and validating biomarkers of neuroinflammation for prediction of PD progression, patient stratification for trials, and evaluation of new treatments targeting the immune system in PD. Because DBSI MRI only requires sequences that are already Food and Drug Administration approved and available on existing clinical MRI scanners, it could be quickly scaled to clinical applications and clinical trials.