Tag: neuroinflammation

Postural Orthostatic Tachycardia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID as Neuroimmune Disorders

Abstract:

Postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID are heterogeneous disorders with overlapping complex, multi-factorial and multi-systemic pathophysiology. POTS and ME/CFS are the most common phenotypes of Long COVID that can lead to significant disability and functional impairment.

The exact pathophysiologic mechanisms of these disorders alone or in combination are still being investigated, but important mechanistic factors have been identified, such as autonomic dysfunction, immune dysregulation, autoimmunity, mitochondrial dysfunction, cerebral hypoperfusion, and neuroinflammation.

To this end, we believe that these conditions should be viewed as neuroimmune disorders and should be included in the field of neuroimmunology, with its educational curriculum, training, and clinical care pathways. Including these disorders as part of neuroimmunology subspecialty is the key to advancing the science and clinical care of this underserved patient population with these complex and disabling conditions.

Source: Blitshteyn S, Doherty TA, Steinman L. Postural Orthostatic Tachycardia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID as Neuroimmune Disorders. Immunotargets Ther. 2026 Feb 2;15:581262. doi: 10.2147/ITT.S581262. PMID: 41859298; PMCID: PMC12998959. https://pmc.ncbi.nlm.nih.gov/articles/PMC12998959/ (Full text)

Evidence of White Matter Neuroinflammation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Diffusion-Based Neuroinflammation Imaging Study

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder with suspected neuroinflammatory pathophysiology. However, previous diffusion tensor imaging (DTI) studies have reported inconsistent white matter abnormalities in ME/CFS, and specific white matter inflammatory changes remain poorly characterised. This study employed an advanced diffusion-based neuroinflammation imaging (NII) model to investigate white matter neuroinflammation in ME/CFS.

Diffusion MRI data from 67 ME/CFS patients (median age, 38; and 54 women) and 67 rigorously matched healthy controls (HCs) (median age 38; and 52 women) were analysed. Seven NII-derived metrics were computed: hindered water ratio (NII-HR), restricted fraction (NII-RF), fibre fraction (NII-FF), axial diffusivity (NII-AD), radial diffusivity (NII-RD), mean diffusivity (NII-MD) and fractional anisotropy (NII-FA). Conventional DTI metrics were also calculated. Tract-based spatial statistics were used to perform voxel-wise group comparisons, and multiple regression analysis was conducted to examine the relationship between NII/DTI metrics and clinical measures of mental health, physical health, sleep quality, disability, disease severity and disease duration.

Compared to HCs, ME/CFS patients exhibited widespread white matter abnormalities, including significantly lower NII-HR and NII-RF, and significantly higher NII-FF, NII-AD, NII-MD and NII-FA across association, commissural and projection fibres. Additionally, some regions showed decreased NII-AD and NII-MD in ME/CFS. Lower NII-RF, NII-AD and NII-MD in ME/CFS were significantly associated with worse mental health, while lower NII-RF was also associated with a higher level of disability. Among ME/CFS patients, higher NII-FF was associated with lower disease severity. Conventional DTI showed minimal group differences and no significant clinical associations.

This study provides in vivo evidence of white matter neuroinflammation in ME/CFS, characterised by cerebral edema (reduced NII-HR), cellular infiltration (reduced NII-RF) and axonal reorganisation (increased NII-FF). This suggests NII-derived indices may serve as sensitive biomarkers for neuroinflammation in ME/CFS.

Source: Yu, Q., K.Kothe, R. A.Kwiatek, et al. 2026. “Evidence of White Matter Neuroinflammation in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Diffusion-Based Neuroinflammation Imaging Study.” Human Brain Mapping47, no. 4: e70505. https://doi.org/10.1002/hbm.70505. https://onlinelibrary.wiley.com/doi/full/10.1002/hbm.70505 (Full text)

Potential application of brain-gut axis-based treatments in Long COVID and ME/CFS: a case-based systematic review

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID share clinical features including persistent fatigue, post-exertional malaise (PEM), and gastrointestinal (GI) dysfunction. Growing evidence implicates brain-gut axis dysregulation, characterized by dysbiosis, neuroinflammation within the central nervous system (CNS), increased intestinal permeability, and microbial translocation in their pathophysiology. However, therapeutic strategies targeting these pathways remain poorly defined.

Methods: We report a case of post-COVID ME/CFS successfully treated with electroacupuncture (EA)-based deep peroneal nerve stimulation which was employed to potentiate the vagal reflex. Fatigue trajectories were assessed using the Multidimensional Fatigue Inventory over 12 weeks. Based on the case, a systematic review of randomized controlled trials (RCTs) evaluating brain-gut axis-modulating interventions in ME/CFS or Long COVID was conducted.

Results: The patient exhibited a significant reduction in total fatigue, with early improvements in motivation and mental fatigue, and delayed improvement in physical fatigue following transient systemic symptom flares. Across included RCTs (n = 8, 790 participants), four investigated gut microbiome-modulating therapies and four employed nerve stimulation. Synbiotic and herbal interventions demonstrated benefits for fatigue or PEM, accompanied by alterations in specific bacterial populations or CNS metabolisms. Regarding nerve stimulation, transcranial direct current stimulation (tDCS) combined with exercise program improved fatigue, whereas standalone tDCS, auricular or peripheral TENS showed limited efficacy.

Conclusion: Brain-gut axis-based interventions may alleviate fatigue in ME/CFS and Long COVID by potentially modulating neuroinflammation, restoring microbiome balance, and improving epithelial barrier function. EA-based vagal stimulation represents a feasible option for patients with severe or treatment-resistant symptoms. Larger mechanistic studies and rigorously designed RCTs are needed to establish therapeutic targets and optimize intervention strategies.

Source: Kim DY, Youn J, Kang N, Cho SI, Ha IH. Potential application of brain-gut axis-based treatments in Long COVID and ME/CFS: a case-based systematic review. J Transl Med. 2026 Feb 10. doi: 10.1186/s12967-026-07807-w. Epub ahead of print. PMID: 41668172. https://link.springer.com/article/10.1186/s12967-026-07807-w (Full text available as PDF file)

Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS

Abstract:

Long COVID (LC) manifests with sex-specific differences, particularly in those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Our study reveals that female LC patients (LCF) with ME/CFS show a shift toward myelopoiesis, reduced lymphocytes, increased neutrophils/monocytes, and depleted regulatory T cells-suggesting persistent immune activation. Elevated CD71+ erythroid cells and disrupted erythropoiesis contribute to fatigue and tissue damage in LCF.

Cytokine profiling indicates a stronger pro-inflammatory response in LCF compared to males (LCM), along with markers of gut barrier dysfunction. Hormonal analysis shows reduced testosterone in LCF and estradiol in LCM. Transcriptomic data reveal neuroinflammatory signatures in LCF, potentially explaining cognitive symptoms. We also identify biomarkers that distinguish LCF from LCM and correlate with sex-specific clinical symptoms.

Overall, LC with ME/CFS is characterized by sex-specific immune, hormonal, and transcriptional alterations, with females exhibiting more severe inflammation. These insights underscore the need for sex-tailored interventions, including consideration of hormone replacement therapy.

Source: Shahbaz S, Osman M, Syed H, Mason A, Rosychuk RJ, Cohen Tervaert JW, Elahi S. Integrated immune, hormonal, and transcriptomic profiling reveals sex-specific dysregulation in long COVID patients with ME/CFS. Cell Rep Med. 2025 Nov 7:102449. doi: 10.1016/j.xcrm.2025.102449. Epub ahead of print. PMID: 41205594. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00522-1 (Full text)

Metabolic neuroimaging of myalgic encephalomyelitis/chronic fatigue syndrome and Long-COVID

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID are complex, disabling conditions that have emerged as significant public health challenges, affecting millions worldwide. Despite their growing prevalence, effective diagnostics and treatments remain limited, largely due to an incomplete understanding of their underlying pathophysiology. Both conditions share hallmark symptoms of chronic fatigue, cognitive dysfunction, and postexertional malaise, but their biological underpinnings remain to be elucidated. Neuroimaging offers a promising, noninvasive window into the brain’s metabolic landscape and has the potential to uncover objective biomarkers for these conditions.

In this mini review, we highlight recent advancements in metabolic neuroimaging, particularly positron emission tomography and magnetic resonance imaging/magnetic resonance spectroscopy, that reveal alterations in glucose and oxygen metabolism, neurotransmitter balance, and oxidative stress. These insights point toward shared disruptions in brain energy metabolism and neuroinflammatory processes, which may underlie the persistent symptoms in both ME/CFS and Long-COVID.

Importantly, while some findings overlap, inconsistencies in metabolite profiles between ME/CFS and Long-COVID underscore the need for further stratification and longitudinal research. Standardizing definitions, such as identifying Long-COVID patients who meet ME/CFS diagnostic criteria, could help improve study comparability.

By summarizing current imaging evidence, this review underscores the potential of neuroimaging to identify imaging biomarkers to advance the clinical diagnosis of Long-COVID and identify therapeutic targets for treatment development. As we continue to face the growing burden of Long-COVID and ME/CFS, metabolic imaging may serve as a powerful tool to bridge gaps in knowledge and accelerate progress toward effective care.

Source: Zhu Y, Quan P, Yamazaki T, Norweg A, Natelson B, Xu X. Metabolic neuroimaging of myalgic encephalomyelitis/chronic fatigue syndrome and Long-COVID. Immunometabolism (Cobham). 2025 Sep 12;7(4):e00068. doi: 10.1097/IN9.0000000000000068. PMID: 40958852; PMCID: PMC12435251. https://pmc.ncbi.nlm.nih.gov/articles/PMC12435251/ (Full text)

Mechanistic Insights Into Long Covid: Viral Persistence, Immune Dysregulation, and Multi-Organ Dysfunction

Abstract:

Long Covid is a post-viral syndrome characterized by persistent symptoms targeting multiple organ systems after initial SARS-CoV-2 infection. Current literature suggests that the mechanisms causing Long Covid involve viral persistence, immune dysregulation, systemic inflammation, endothelial dysfunction, and metabolic disturbances.

By forming reservoirs in the tissues of various organs, SARS-CoV-2 may evade immunological clearances while triggering immune responses and contributing to chronic symptoms through cytokine imbalances, T-cell exhaustion, and systemic inflammation. These symptoms parallel other post-viral syndromes such as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), suggesting similar mechanisms of pathology.

The coronavirus has also been linked to neuroinflammation and endothelial dysfunction causing cognitive symptoms and cardiovascular complications. Furthermore, its ability to lower energy production links it to post-exertion malaise (PEM) and muscle pain. These symptoms may result from iron dysregulation and persistent oxidative stress due to Covid-impaired mitochondrial function.

This review synthesizes current data on the mechanisms that drive Long Covid pathogenesis and explores potential therapeutic strategies to mitigate viral persistence, immune dysfunction, and metabolic disturbances. It is critical to understand these interactions to develop targeted interventions that address the long-term sequelae of SARS-CoV-2 infection and improve patient outcomes.

Source: Gupta G, Buonsenso D, Wood J, Mohandas S, Warburton D. Mechanistic Insights Into Long Covid: Viral Persistence, Immune Dysregulation, and Multi-Organ Dysfunction. Compr Physiol. 2025 Jun;15(3):e70019. doi: 10.1002/cph4.70019. PMID: 40474772. https://pubmed.ncbi.nlm.nih.gov/40474772/

Brainstem Reduction and Deformation in the 4th Ventricle Cerebellar Peduncles in Long COVID Patients: Insights into Neuroinflammatory Sequelae and “Broken Bridge Syndrome”

Abstract:

Post-COVID Syndrome (PCS), also known as Long COVID, is characterized by persistent and often debilitating neurological sequelae, including fatigue, cognitive dysfunction, motor deficits, and autonomic dysregulation (Dani et al., 2021). This study investigates structural and functional alterations in the brainstem and cerebellar peduncles of individuals with PCS using diffusion tensor imaging (DTI) and volumetric analysis. Forty-four PCS patients (15 bedridden) and 14 healthy controls underwent neuroimaging. Volumetric analysis focused on 22 brainstem regions, including the superior cerebellar peduncle (SCP), middle cerebellar peduncle (MCP), periaqueductal gray (PAG), and midbrain reticular formation (mRt).

Significant volume reductions were observed in the SCP (p < .001, Hedges’ g = 3.31) and MCP (p < .001, Hedges’ g = 1.77), alongside decreased fractional anisotropy (FA) in the MCP, indicative of impaired white matter integrity. FA_Avg fractional anisotropy average tested by FreeSurfer Tracula, is an index of white matter integrity, reflecting axonal fiber density, axonal diameter and myelination. These neuroimaging findings correlated with clinical manifestations of motor incoordination, proprioceptive deficits, and autonomic instability. Furthermore, volume loss in the dorsal raphe (DR) and midbrain reticular formation suggests disruption of pain modulation and sleep-wake cycles, consistent with patient-reported symptoms.

Post-mortem studies provide supporting evidence for brainstem involvement in COVID-19. Radtke et al. (2024) reported activation of intracellular signaling pathways and release of immune mediators in brainstem regions of deceased COVID-19 patients, suggesting an attempt to inhibit viral spread. While viral genetic material was detectable, infected neurons were not observed. Matschke et al. (2020) found that microglial activation and cytotoxic T lymphocyte infiltration were predominantly localized to the brainstem and cerebellum, with limited involvement of the frontal lobe. This aligns with clinical observations implicating the brainstem in PCS pathophysiology. Cell-specific expression analysis of genes contributing to viral entry (ACE2, TMPRSS2, TPCN2, TMPRSS4, NRP1, CTSL) in the cerebral cortex showed their presence in neurons, glial cells, and endothelial cells, indicating the potential for SARS-CoV-2 infection of these cell types. Associations with autoimmune diseases with specific autoantibodies, including beta-2 and M-2 against G-protein coupled alpha-1, beta-1, beta-2 adrenoceptors against angiotensin II type 1 receptor or M1,2,3-mAChR, among others, voltage-gated calcium channels (VGCC) are known (Blitshteyn et al. 2015 and Wallukat and Schminke et al. 2014).

These findings support the “Broken Bridge Syndrome” hypothesis, positing that structural disconnections between the brainstem and cerebellum contribute to PCS symptomatology. Furthermore, we propose that chronic activation of the Extended Autonomic System (EAS), encompassing the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system, may perpetuate these symptoms (Goldstein, 2020). Perturbations in this system may relate to the elevation of toxic autoantibodies AABs (Beta-2 and M-2), specific epitopes of the COVID virus’s SPIKE protein and Cytokine storm of IL-1, IL-6, and IL-8 in their increased numbers (1,000->10,000)

Further research is warranted to elucidate the underlying neuroinflammatory mechanisms, EAS dysregulation, and potential therapeutic interventions for PCS

Source: Ziaja Peter Christof, Young Yvette Susanne, Stark Sadre-Chirazi Michael, Lindner Thomas, Zurék Grzegorz, Sedlacik Jan. Brainstem Reduction and Deformation in the 4th Ventricle Cerebellar Peduncles in Long COVID Patients: Insights into Neuroinflammatory Sequelae and “Broken Bridge Syndrome” medRxiv 2025.04.08.25325108; doi: https://doi.org/10.1101/2025.04.08.25325108 https://www.medrxiv.org/content/10.1101/2025.04.08.25325108v1.full-text (Full text)

Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses

Abstract:

Long-term symptoms such as pain, fatigue, and cognitive impairments are commonly observed in individuals affected by coronavirus disease 2019 (COVID-19). Metabolites of the kynurenine pathway have been proposed to account for cognitive impairment in COVID-19 patients.

Here, cerebrospinal fluid (CSF) and plasma levels of kynurenine pathway metabolites in 53 COVID-19 patients and 12 non-inflammatory neurological disease controls in Sweden were measured with an ultra-performance liquid chromatography-tandem mass spectrometry system (UPLC-MS/MS) and correlated with immunological markers and neurological markers. Single cell transcriptomic data from a previous study of 130 COVID-19 patients was used to investigate the expression of key genes in the kynurenine pathway.

The present study reveals that the neuroactive kynurenine pathway metabolites quinolinic acid (QUIN) and kynurenic acid (KYNA) are increased in CSF in patients with acute COVID-19. In addition, CSF levels of kynurenine, ratio of kynurenine/tryptophan (rKT) and QUIN correlate with neurodegenerative markers.

Furthermore, tryptophan is significantly decreased in plasma but not in the CSF. In addition, the kynurenine pathway is strongly activated in the plasma and correlates with the peripheral immunological marker neopterin. Single-cell transcriptomics revealed upregulated gene expressions of the rate-limiting enzyme indoleamine 2,3- dioxygenase1 (IDO1) in CD14+ and CD16+ monocytes that correlated with type II-interferon response exclusively in COVID-19 patients.

In summary, our study confirms significant activation of the peripheral kynurenine pathway in patients with acute COVID-19 and, notably, this is the first study to identify elevated levels of kynurenine metabolites in the central nervous system associated with the disease. Our findings suggest that peripheral inflammation, potentially linked to overexpression of IDO1 in monocytes, activates the kynurenine pathway. Increased plasma kynurenine, crossing the blood-brain barrier, serves as a source for elevated brain KYNA and neurotoxic QUIN.

We conclude that blocking peripheral-to-central kynurenine transport could be a promising strategy to protect against neurotoxic effects of QUIN in COVID-19 patients.

Source: Li X, Edén A, Malwade S, Cunningham JL, Bergquist J, Weidenfors JA, Sellgren CM, Engberg G, Piehl F, Gisslen M, Kumlien E, Virhammar J, Orhan F, Rostami E, Schwieler L, Erhardt S. Central and peripheral kynurenine pathway metabolites in COVID-19: Implications for neurological and immunological responses. Brain Behav Immun. 2024 Nov 28:S0889-1591(24)00720-7. doi: 10.1016/j.bbi.2024.11.031. Epub ahead of print. PMID: 39615604. https://www.sciencedirect.com/science/article/abs/pii/S0889159124007207

Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients

Abstract:

A substantial portion of patients infected with SARS-CoV-2 experience prolonged complications, known as Long COVID (LC). A subset of these patients exhibits the most debilitating symptoms, similar to those defined in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We performed bulk RNA sequencing (RNAseq) on the whole blood of LC with ME/CFS, at least 12 months post-onset of the acute disease, and compared them with controls.

We found that LC patients had a distinct transcriptional profile compared to controls. Key findings include the upregulation of genes involved in immune dysregulation and neuronal development, such as Fezf2, BRINP2, HOXC12, MEIS2, ZFHX3, and RELN. These genes are linked to neuroinflammatory responses, cognitive impairments, and hematopoietic disturbances, suggesting ongoing neurological and immune disturbances in LC patients. RELN, encoding the Reelin protein, was notably elevated in LC patients, potentially serving as a biomarker for LC pathogenesis due to its role in inflammation and neuronal function.

Immune cell analysis showed altered profiles in LC patients, with increased activated memory CD4 + T cells and neutrophils, and decreased regulatory T cells and NK cells, reflecting immune dysregulation. Changes in cytokine and chemokine expression further underscore the chronic inflammatory state in LC patients. Notably, a unique upregulation of olfactory receptors (ORs) suggest alternative roles for ORs in non-olfactory tissues. Pathway analysis revealed upregulation in ribosomal RNA processing, amino acid metabolism, protein synthesis, cell proliferation, DNA repair, and mitochondrial pathways, indicating heightened metabolic and immune demands. Conversely, downregulated pathways, such as VEGF signaling and TP53 activity, point to impaired tissue repair and cellular stress responses.

Overall, our study underscores the complex interplay between immune and neuronal dysfunction in LC patients, providing insights into potential diagnostic biomarkers and therapeutic targets. Future research is needed to fully understand the roles and interactions of these genes in LC pathophysiology.

Source: Shahbaz S, Rezaeifar M, Syed H, Redmond D, Terveart JWC, Osman M, Elahi S. Upregulation of olfactory receptors and neuronal-associated genes highlights complex immune and neuronal dysregulation in Long COVID patients. Brain Behav Immun. 2024 Nov 28:S0889-1591(24)00721-9. doi: 10.1016/j.bbi.2024.11.032. Epub ahead of print. PMID: 39615603. https://www.sciencedirect.com/science/article/pii/S0889159124007219 (Full text)