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NeuroinflammationBiomarkersImmune SystemLong COVID Overlap

Persistent fatigue in long-COVID is not associated with peripheral inflammatory or cellular stress biomarkers: A cross-sectional controlled study.

Omdal, Roald, Lenning, Ole Bernt, Jonsson, Grete et al.·Brain, behavior, & immunity - health·2026

A study of 48 people with long-COVID and 48 recovered controls found that fatigue was much more severe in the long-COVID group, but common blood markers of inflammation and cellular stress did not differ between the groups. This suggests that the fatigue in long-COVID may not be driven by the types of inflammation typically measured in blood tests, though the researchers note their findings are preliminary and limited to the biomarkers they tested.

NeuroinflammationEnergy MetabolismImmune System

Increased galanin-galanin receptor 1 signaling, inflammation, and insulin resistance are associated with affective symptoms and chronic fatigue syndrome due to long COVID.

Al Masoodi, Wasim Talib Mahdi, Radhi, Sami Waheed, Abdalsada, Habiba Khdair et al.·PloS one·2025

This study looked at 90 people, some with Long COVID and some without, to understand why Long COVID patients develop depression, anxiety, and chronic fatigue. Researchers measured several substances in the blood related to inflammation and metabolism. They found that people with Long COVID had higher levels of inflammatory markers and abnormal insulin function, and these changes were linked to their mood and fatigue symptoms.

E2 ModerateCohortPEM not requiredCase-Control

Affective and chronic fatigue symptoms are associated with serum neuronal damage markers in Parkinson's disease.

Al-Hakeim, Hussein Kadhem, Khudhair, Hayder Naji, Ranaei-Siadat, Sayed-Omid et al.·Scientific reports·2025

This study looked at people with Parkinson's disease who also experienced depression and extreme fatigue, similar to ME/CFS. Researchers found that certain proteins in the blood that signal brain cell damage were elevated in these patients, and these proteins were connected to inflammation, blood sugar problems, and the mood and fatigue symptoms they experienced.

E2 ModerateCohortPEM not requiredCase-Control

In transfusion-dependent thalassemia, neuronal damage biomarkers are associated with affective and chronic fatigue symptoms.

Ridhaa, Maha Abdul Saheb, Al-Hakeim, Hussein Kadhem, Kahlol, Mohammed K et al.·Scientific reports·2025

This study looked at children with thalassemia, a blood disorder requiring frequent transfusions, to see if brain damage and inflammation might cause depression, anxiety, and chronic fatigue. Researchers measured specific markers of brain injury and inflammation in the blood and found that children with thalassemia had higher levels of these markers and more fatigue and mood symptoms than healthy children. The study suggests that iron buildup from transfusions may damage nerve cells in the brain, leading to these symptoms.

Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms.

Almulla, Abbas F, Maes, Michael, Zhou, Bo et al.·Journal of advanced research·2025

This study found that people with Long COVID have unusual immune responses targeting the brain and nerve cells. Researchers measured antibodies (immune proteins) in people with Long COVID and healthy controls, discovering that Long COVID patients have significantly higher levels of antibodies attacking several brain proteins. These brain-targeted immune responses were strongly linked to fatigue severity and mood symptoms like depression and anxiety.

E2 ModerateCohortPEM requiredCase-Control

Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling.

Hunter, Ewan, Alshaker, Heba, Bundock, Oliver et al.·Journal of translational medicine·2025

Researchers developed a new blood test called EpiSwitch®CFS that may help diagnose ME/CFS by detecting specific patterns in how DNA is organized in blood cells. When tested on stored blood samples from 47 ME/CFS patients and 61 healthy people, the test correctly identified 92% of ME/CFS patients and correctly ruled out 98% of healthy controls. This could potentially help doctors diagnose ME/CFS more reliably, since there is currently no standard blood test for the condition.

NeuroinflammationBiomarkersImmune System

Imbalanced Brain Neurochemicals in Long COVID and ME/CFS: A Preliminary Study Using MRI.

Thapaliya, Kiran, Marshall-Gradisnik, Sonya, Eaton-Fitch, Natalie et al.·The American journal of medicine·2025

Researchers used advanced brain imaging to measure chemical imbalances in ME/CFS and long COVID patients compared to healthy people. They found that two important brain chemicals—glutamate and N-acetyl-aspartate—were significantly higher in patients with both conditions. These chemical imbalances were connected to how severe patients' symptoms were, suggesting that abnormal brain chemistry may play a role in the exhaustion and other symptoms these patients experience.

E2 ModerateCohortPEM not requiredCase-Control

[Association of inflammation and chronic fatigue syndrome in patients with Parkinson's disease].

Nikitina, M A, Bragina, E Yu, Ivanova, S A et al.·Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova·2024

This study looked at severe tiredness (chronic fatigue syndrome) in people with Parkinson's disease. Researchers found that about two-thirds of Parkinson's patients experience this kind of fatigue, and it tends to occur alongside other symptoms like mood problems, memory difficulties, and pain. Blood tests showed that people with this fatigue had higher levels of inflammation markers, suggesting that inflammation may play a role in causing the tiredness.

Chronic Fatigue, Depression and Anxiety Symptoms in Long COVID Are Strongly Predicted by Neuroimmune and Neuro-Oxidative Pathways Which Are Caused by the Inflammation during Acute Infection.

Al-Hakeim, Hussein Kadhem, Al-Rubaye, Haneen Tahseen, Almulla, Abbas F et al.·Journal of clinical medicine·2023

This study examined whether severe COVID-19 infection—particularly high fever and low oxygen levels—can trigger lasting fatigue, depression, and anxiety through inflammation and oxidative stress in the body. Researchers compared 86 long COVID patients with 39 healthy controls and found that about one-third of long COVID patients had very high signs of immune activation and cellular damage. The study suggests that the severity of initial COVID infection may predict who develops long-term symptoms through measurable changes in inflammatory markers.

NeuroinflammationBiomarkers

The physio-affective phenome of major depression is strongly associated with biomarkers of astroglial and neuronal projection toxicity which in turn are associated with peripheral inflammation, insulin resistance and lowered calcium.

Al-Hakeim, Hussein Kadhem, Al-Naqeeb, Tabarek Hadi, Almulla, Abbas F et al.·Journal of affective disorders·2023

This study examined whether brain and nerve damage markers in the blood are connected to depression symptoms and other physical complaints. Researchers measured several proteins in the blood of people with depression and compared them to healthy controls, finding that markers of brain cell and nerve damage—along with inflammation and insulin resistance—together explained about 61% of the severity of depression, anxiety, fatigue, and physical symptoms.

Free-water-corrected diffusion and adrenergic/muscarinic antibodies in myalgic encephalomyelitis/chronic fatigue syndrome.

Kimura, Yukio, Sato, Wakiro, Maikusa, Norihide et al.·Journal of neuroimaging : official journal of the American Society of Neuroimaging·2023

Researchers used a specialized brain imaging technique to look for signs of inflammation in the brains of ME/CFS patients and compared these findings to levels of harmful antibodies (immune proteins) in their blood. They found that certain antibodies were linked to visible changes in a specific brain region called the right frontal operculum, and that longer disease duration was associated with more brain changes. These findings suggest that ME/CFS may involve both immune system dysfunction and measurable changes in brain structure.

In Schizophrenia, Chronic Fatigue Syndrome- and Fibromyalgia-Like Symptoms are Driven by Breakdown of the Paracellular Pathway with Increased Zonulin and Immune Activation-Associated Neurotoxicity.

Maes, Michael, Andrés-Rodríguez, Laura, Vojdani, Aristo et al.·CNS & neurological disorders drug targets·2023

This study looked at people with schizophrenia who also experience fatigue and pain symptoms similar to ME/CFS and fibromyalgia. Researchers found that these symptoms may be caused by a breakdown in the intestinal barrier (the paracellular pathway), which allows harmful substances into the bloodstream and triggers immune system activation. This immune activation then produces neurotoxic byproducts that may cause the fatigue and pain symptoms.

Lowered Quality of Life in Long COVID Is Predicted by Affective Symptoms, Chronic Fatigue Syndrome, Inflammation and Neuroimmunotoxic Pathways.

Maes, Michael, Al-Rubaye, Haneen Tahseen, Almulla, Abbas F et al.·International journal of environmental research and public health·2022

This study found that Long COVID patients have significantly lower quality of life compared to healthy people, and this decline is mostly explained by three factors: mood and pain-related symptoms (like depression, anxiety, and fatigue), signs of ongoing inflammation in the body, and problems with how the body processes calcium. The severity of the initial infection—measured by high fever and low oxygen levels—also plays a role by triggering these inflammatory and immune problems that persist afterward.

NeuroinflammationBiomarkersPost-Exertional Malaise

Exercise modifies glutamate and other metabolic biomarkers in cerebrospinal fluid from Gulf War Illness and Myalgic encephalomyelitis / Chronic Fatigue Syndrome.

Baraniuk, James N, Kern, Grant, Narayan, Vaishnavi et al.·PloS one·2021

Researchers studied the fluid around the brain and spinal cord in people with ME/CFS and Gulf War Illness to see how exercise affects certain chemicals in the body. They found that glutamate (a brain chemical) levels changed differently depending on whether someone had exercised and how their body responded, and that some fat-related molecules were different between the two conditions. This suggests that ME/CFS and Gulf War Illness may involve different problems with how the body uses energy and processes fats.

NeuroinflammationEnergy Metabolism

Kynurenine metabolites and ratios differ between Chronic Fatigue Syndrome, Fibromyalgia, and healthy controls.

Groven, Nina, Reitan, Solveig Klæbo, Fors, Egil Andreas et al.·Psychoneuroendocrinology·2021

This study examined a specific metabolic pathway in the blood called the kynurenine pathway, which affects how the brain functions. Researchers compared blood samples from people with ME/CFS, people with fibromyalgia, and healthy people to see if the chemical breakdown products in this pathway differed. They found that the balance of certain chemicals was different in people with these conditions, and these differences may relate to fatigue and pain symptoms.

E2 ModerateCohortPEM unclearObservational

Oral Minocycline Therapy Improves Symptoms of Myalgic Encephalomyelitis, Especially in the Initial Disease Stage.

Miwa, Kunihisa·Internal medicine (Tokyo, Japan)·2021

Researchers tested whether minocycline, an antibiotic that may reduce brain inflammation, could help ME/CFS patients. About 27% of 100 patients taking minocycline for 6 weeks experienced meaningful symptom improvement, particularly those who had been sick for less than 3 years. However, 38% of patients had to stop taking it early due to side effects like nausea and dizziness.

Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy.

Mueller, Christina, Lin, Joanne C, Sheriff, Sulaiman et al.·Brain imaging and behavior·2020

Researchers used advanced brain imaging to measure chemical substances in the brains of ME/CFS patients and compared them to healthy people. They found several differences in brain chemistry and temperature in ME/CFS patients, particularly in areas involved in processing pain and regulating energy. These changes suggest that inflammation in the brain may contribute to ME/CFS symptoms.

E2 ModerateCohortPEM unclearCase-Control

Using Plasma Autoantibodies of Central Nervous System Proteins to Distinguish Veterans with Gulf War Illness from Healthy and Symptomatic Controls.

Abou-Donia, Mohamed B, Lapadula, Elizabeth S, Krengel, Maxine H et al.·Brain sciences·2020

Researchers tested blood samples from Gulf War veterans with Gulf War Illness (GWI) and compared them to healthy veterans and people with ME/CFS or irritable bowel syndrome. They found that GWI veterans had higher levels of autoantibodies—proteins the immune system makes that mistakenly attack the brain and nervous system—compared to all three control groups. This suggests that a blood test measuring these autoantibodies could potentially help doctors diagnose Gulf War Illness objectively.

NeuroinflammationBiomarkers

In Schizophrenia, Depression, Anxiety, and Physiosomatic Symptoms Are Strongly Related to Psychotic Symptoms and Excitation, Impairments in Episodic Memory, and Increased Production of Neurotoxic Tryptophan Catabolites: a Multivariate and Machine Learning Study.

Kanchanatawan, Buranee, Thika, Supaksorn, Sirivichayakul, Sunee et al.·Neurotoxicity research·2018

This study examined 80 people with schizophrenia and 40 healthy controls to understand why schizophrenia patients often experience depression, anxiety, and physical symptoms like those seen in chronic fatigue. The researchers found that these symptoms were linked to changes in how the body breaks down tryptophan (an amino acid), problems with memory, and the severity of psychotic symptoms. The findings suggest that toxic byproducts from tryptophan metabolism may contribute to depression, anxiety, and physical symptoms in schizophrenia.

Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndrome.

Barnden, Leighton R, Shan, Zack Y, Staines, Donald R et al.·NeuroImage. Clinical·2018

Researchers used advanced MRI scans to compare the brains of 43 people with ME/CFS and 27 healthy people. They found that people with ME/CFS had different patterns in their brainstem (the base of the brain that controls basic functions) and in the sensorimotor areas (parts that control movement and sensation). The study suggests that the body may be compensating for problems in the brainstem by increasing protective coating around nerve fibers in motor control areas.