Oxidative Stress and Neuroinflammation

Probing the Pathophysiology of ME/CFS through Neuroimaging

The discovery of ME/CFS-specific biomarkers that can advance our understanding of
the illness and its pathogenic mechanisms, differentiate the disorder from overlapping or comorbid diagnoses, and identify potential treatment targets is currently a pressing and unmet research and public health need. We plan to fill this knowledge gap by using advanced neuroimaging techniques to test and then validate a pathophysiological model of ME/CFS which posits that oxidative stress and neuroinflammation are intertwined mechanisms in the etiopathogenesis of the disorder.
We will use proton magnetic resonance spectroscopy (1H MRS) to measure in vivo brain levels of glutathione (GSH) -- the most abundant antioxidant in the central nervous system – as a marker of oxidative stress. The same method will be used to measure in vivo brain levels of lactate and N-acetylaspartate (NAA) as markers of mitochondrial dysfunction. To measure in vivo brain levels of ATP, creatine phosphate (PCr) and inorganic phosphate (Pi) as complementary indices of mitochondrial dysfunction, 31P MRS can be used. In vivo brain 11C-(R)-PK11195 positron emission tomography (PET) will measure the binding potential of the ligand as a marker of neuroinflammation. We will examine the levels of circulating markers of neuroinflammation and oxidative stress for corroborating the proposed neuroimaging biomarkers.
Our analyses will be performed before and following symptom provocation with cardiopulmonary exercise tests (CPET), known to trigger post-exertional malaise (PEM) in ME/CFS patients. This research has the potential to shed new light onto the neurobiological mechanisms and underpinnings of ME/CFS to advance our understanding of the illness, and establish ME/CFS-specific biomarkers for differentiating the disorder from overlapping or comorbid diagnoses, and identifying potential treatment targets.

The project will be led by Dr. Dikoma Shungu, an accomplished magnetic resonance spectroscopist/physicist and computer programmer. In addition to prior work on ME/CFS, he has previously used neuroimaging methods to study fibromyalgia, Gulf War Illness, schizophrenia, major depression, anxiety and obsessive-compulsive disorders, Parkinson’s disease, ALS, primary mitochondrial disorders, and brain tumors. He will be assisted by Xiangling Mao, a long-term associate and computer programmer skilled in analysis of spectroscopy data. Dr. Yi Wang, an internationally known theoretical physicist, will play a major role in assessing brain tissue iron content by MRS. Dr. Pascal Spincemaille, a long-term associate of Dr. Wang, will analyze structural and physiological imaging data. Experiments using PET will be overseen by Dr. John Babich, who is Chief of Radiochemistry at Weill Cornell Medicine. Dr. Yeona Kang will process the PET neuroimaging data to assess neuroinflammation.