Project Summary Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a highly debilitating disease affecting millions of people in the United States, yet very little is known about its underlying pathophysiology. The disease itself is exceedingly complex and characterized by variable clusters of incapacitating symptoms, including extreme fatigue, unrefreshing sleep, muscle pain, joint pain, headaches, and loss of memory or concentration. Preliminary theories suggest that an initial trigger, possibly viral, results in inflammation that chronically affects several parts the body, including the muscles, joints, lymphatic system, and central nervous system (CNS). Unfortunately, current standard of care techniques for diagnosing suspected ME/CFS (i.e., blood tests and structural brain imaging) do not provide direct measures of inflammation in the CNS or other organs and often afford results within normal range. Hence, there is a critical unmet need to develop more sensitive and specific tests that not only improve the accuracy of diagnosis but also provide a means to investigate specific immune responses and their role in the initiation and progression of ME/CFS in the brain and periphery of ME/CFS.
Here, we propose for the first time to perform whole body position emission tomography (PET) imaging of ME/CFS patients using [11C]DPA-713, a highly sensitive and specific radiotracer for the translocator protein 18 kDa (TSPO). TSPO is an established imaging biomarker of inflammation that is predominately upregulated in activated innate immune cells including microglia in the CNS and other myeloid lineage cells (e.g., macrophages) in the periphery.
We hypothesize that chronic, unresolved inflammation driven by innate immune cells underlies the central clinical problems of fatigue, pain, and cognitive dysfunction observed in ME/CFS. Our encouraging preliminary data shows increased [11C]DPA-713-PET signal in multiple brain regions of severe ME/CFS patients compared to healthy controls. We also demonstrate the feasibility of whole body PET/magnetic resonance (PET/MR) imaging using [11C]DPA-713.
In this proposal, we will expand on this data by investigating the relationship between peripheral and central markers of inflammation, through the following aims: 1) Quantify [11C]DPA-713 uptake in the CNS and whole body of ME/CFS patients compared to healthy asymptomatic controls using PET/MRI, and 2) Correlate the extent and location of [11C]DPA-713-PET signal to clinical measures of disease severity and peripheral fluid-based biomarkers of inflammation and infection. Additionally, we will correlate PET findings with advanced multimodal MRI, including quantitative brain volumetry, diffusion tensor imaging, and quantitative susceptibility mapping (QSM). Completing these experiments will provide invaluable insights into the correspondence between myeloid cell activation in the CNS and whole body, with that of plasma cytokine signatures, herpesvirus shedding, blood brain barrier disruption, white matter changes, and disease severity in ME/CFS. Since [11C]DPA-713 is available for clinical use, this imaging tool has potential to immediately impact the way we study, monitor, and treat ME/CFS.
