PROJECT SUMMARY/ABSTRACT
In this R01 project, we will test a magnetic resonance spectroscopic imaging (MRSI) technique to assess
several markers of neuroinflammation across the entire brain. We will use the technique to investigate the
pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a condition of unknown
etiology that is characterized by profound fatigue not alleviated by rest. The lack of information on ME/CFS
pathophysiology has posed a substantial obstacle to the development of treatments that are specific and
effective for the disorder. We hypothesize that ME/CFS is the result of low-level inflammation in the brain.
Chronic activation of microglia and astrocytes provokes the release of proinflammatory agents that interact
with neurons to cause symptoms of fatigue, pain sensitivity, and cognitive and mood disruption. MRSI may be
able to detect that neuroinflammation by showing elevated myo-inositol, choline, lactate, brain temperature,
and lower N-acetylaspartate that have been associated with abnormal microglia activation. In this five-year
R01 study, we will conduct three separate studies. Study #1 examines 90 women with ME/CFS and 30 age-
and body mass index-matched healthy controls. Neuroinflammatory markers will be assessed on a voxel-by-
voxel basis throughout the entire brain, yielding approximately 4,000 assessments in gray matter, white
matter, and cerebrospinal fluid. We hypothesize that the neuroinflammatory markers will be elevated in
several brain regions in the ME/CFS group. Study #2 uses a “good-day, bad-day” longitudinal design to
examine correlation between neuroinflammatory markers and symptom severity fluctuations in 20 women with
ME/CFS. We hypothesize that the higher fatigue severity days will be associated with higher levels of
neuroinflammatory markers. In Study #3, we will validate the MRSI scan with positron emission tomography
(PET) analysis of 18F-DPA-714, a marker of activated microglia. We expect to see spatial overlap in MRSI
and PET indicators of neuroinflammation. Support for these three hypotheses would show that ME/CFS is
associated with brain inflammation. This test would allow for safe and inexpensive longitudinal assessment of
neuroinflammation that is not possible with positron emission tomography (PET) or lumbar puncture measures
of cerebrospinal fluid. Because we collect the entire available spectrum in each voxel, we will also have the
first whole-brain metabolic data in ME/CFS. The MRS data can be used to quantify other markers of interest
to ME/CFS researchers, such as glutamate and glutamine. We will therefore make the entire dataset available
to other researchers for secondary analyses. Ultimately, we hope this non-invasive scanning technique will aid
in ME/CFS diagnosis, treatment decisions, and the development of new treatments.
