Project Summary Many patients who have recovered from SARS-CoV-2, the virus that causes COVID-19, continue to experience a constellation of symptoms long after the initial illness. Known as “long-COVID”, or Post- Acute Sequelae of SARS-Cov-2 infection (PASC), the most frequently reported symptoms are fatigue, post exertional malaise and cognitive dysfunction, which are also the primary symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Many of the PASC patients fulfill diagnostic criteria for ME/CFS, but differ from non-PASC ME/CFS patients in that they share a common infectious trigger and have a shorter duration of illness, which reduces heterogeneity. Understanding whether PASC ME/CFS shares overlapping mechanisms with non-PASC ME/CFS is critical, as this could provide insights into the mechanisms and inform treatment strategies of ME/CFS in general. To address this question, we propose a comparison study of PASC ME/CFS patients with sudden onset illness to non-PASC ME/CFS patients who reported a sudden flu-like illness onset. Limited studies have shown reductions in cerebral blood flow and increased cerebroventricular lactate in ME/CFS patients suggesting alterations in perfusion and metabolic properties. Our recent preliminary results show that the oxygen extraction fraction was elevated in PASC ME/CFS patients, which may be attributed to reduced cerebral blood flow and mitochondrial dysfunction. In this project, we aim to conduct non- invasive brain magnetic resonance imaging (MRI) to compare the similarities and differences in cerebral oxygen and glucose metabolism between the two patient groups as well as healthy controls. We will measure and compare the oxygen extraction fraction, cerebral blood flow, and cerebral metabolic rate of oxygen and glucose uptake and metabolic rate in the patient groups and healthy controls. The MRI derived parameters will then be correlated to the disease symptom burden. Additional, since many PASC patients recover over one year, we aim to perform a follow-up study on the PASC and non-PASC ME/CFS groups. Completion of this timely and important study will provide comparison of PASC and non-PASC ME/CSF in terms of changes in glucose and oxygen metabolic properties, as well as how these imaging parameters are related to the disease burden. Through analysis of the longitudinal data, we will be able to determine whether the changes in metabolic properties are associated with changes of patient reported outcome measures. The knowledge learned will deepen our understanding of the ME/CFS/PASC (long-COVID) disease mechanisms, aid in ME/CFS diagnosis, inform treatment decisions, and inspire new treatment targets.

Narrative Many patients suffering from Post-Acute Sequelae (PASC) fulfill the clinical diagnostic criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Understanding whether PASC ME/CFS shares overlapping mechanisms with non-PASC ME/CFS is critical, as this could provide insights into the mechanisms and inform treatment strategies of ME/CFS in general. In this project, we aim to conduct non-invasive brain magnetic resonance imaging (MRI) to compare the similarities and differences in cerebral oxygen and glucose metabolism between the two patient groups as well as healthy controls, correlating these MRI derived parameters with patient reported outcome measures and study the effects over time.