Tag: long covid neurology

Microstructural alterations in brain tissue of ME/CFS and long COVID using diffusion tensor imaging and diffusion kurtosis imaging

Abstract:

Introduction: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and long COVID have overlapping symptoms, such as profound fatigue, cognitive impairment, post-exertional malaise, pain and sleep disturbances that are debilitating and reduce quality of life. While Magnetic Resonance Imaging (MRI) techniques, specifically Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI), have been used to investigate brain tissue microstructure in ME/CFS or long COVID, no study has yet combined these modalities to directly compare tissue microstructural differences between people living with ME/CFS and long COVID.

Methods: We recruited 37 ME/CFS participants (Age: 43.56 ± 12.5), 19 long COVID participants (Age: 47.92 ± 13.3), and 27 healthy controls (Age: 37.9 ± 10.4). Data were acquired using a 3 Tesla (3T) Prisma MRI scanner. DTI and DKI metrics were determined using MRtrix v3.0.7 and Designer V2.0 software, respectively. Voxel-based statistical analysis of cohort differences was performed using the Statistical Parametric Mapping (SPM12) toolbox in MATLAB. Correlation analysis was performed between DTI, DKI metrics and clinical measures such as duration of illness, fatigue severity, SF36 domains and WHODAS domains.

Results: Compared with healthy controls, individuals with ME/CFS showed microstructural alterations in the cingulum, supplementary motor areas, and parts of the corpus callosum (all p < 0.05). Long COVID participants demonstrated microstructural alterations in regions including the fusiform and precentral gyrus and in major white matter tracks (all p < 0.05). Direct comparisons between ME/CFS and long COVID revealed difference in the left corona radiata (p = 0.001).

Conclusion: This study identifies distinct tissue microstructural alterations in ME/CFS and long COVID and offers a vital insight into the neuropathological basis of shared symptoms in both conditions.

Source: Singh TB, Marshall-Gradisnik S, Barnden L, Eaton-Fitch N, Huynh TH, Inderyas M, Thapaliya K. Microstructural alterations in brain tissue of ME/CFS and long COVID using diffusion tensor imaging and diffusion kurtosis imaging. Front Med (Lausanne). 2026 Jul 17;13:1824498. doi: 10.3389/fmed.2026.1824498. PMID: 42539798; PMCID: PMC13424405. https://pmc.ncbi.nlm.nih.gov/articles/PMC13424405/ (Full text)

Inflammatory and neuroinjury blood biomarkers across COVID-19 severity groups in individuals with persistent neurological symptoms

Abstract:

Persistent neurological symptoms such as cognitive impairment, fatigue, and neuropsychiatric disturbances are increasingly reported in patients with long COVID, with chronic neuroinflammation and neuronal injury proposed as potential contributors. To characterize inflammatory and neuroinjury-related biomarker patterns, we conducted a case-control study including 325 participants recruited at King Chulalongkorn Memorial Hospital between January 2022 and December 2023, comprising 265 individuals with persistent neurological symptoms following COVID-19 infection and 60 asymptomatic COVID-19 participants who did not develop long COVID symptoms.

Blood samples were analysed for inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α, IFN-α, IL-4) using multiplex immunoassays, and for neuroinflammatory and neurodegenerative biomarkers, including neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), phosphorylated tau181, and beta-amyloid peptides (Aβ40, Aβ42) using SIMOA and ELISA platforms. Among 265 participants with complete data (critical = 7, severe = 22, moderate = 79, mild = 157), patients with severe and critical COVID-19 exhibited significantly higher concentrations of IL-6, IL-1β, TNF-α, and IL-8, together with elevated NfL, GFAP, and phosphorylated tau181 levels, and reduced Aβ42/40 ratios.

Strong positive correlations between neurodegenerative biomarkers and pro-inflammatory cytokines were observed in critically ill patients, whereas these associations were weak or absent in mild and moderate cases. Older age was also associated with greater disease severity and increased risk of persistent neurological complications.

These findings indicate that individuals with persistent neurological symptoms following COVID-19, particularly those with a history of severe or critical disease, exhibited higher inflammatory and neuroinjury-related biomarker levels, while blood-based biomarkers such as NfL, GFAP, and phosphorylated tau181 may serve as minimally invasive tools for characterizing neurological involvement and identifying patients at risk of long-term neurological sequelae.

Source: Ruchisrisarod C, Kaewpom T, Wanthong P, Luechaipanit W, Bunprakob S, Ampoot W, Yomrat S, Hemachudha P, Supharatpariyakorn T, Thanapornsangsuth P, Tammachote R, Saraya AW. Inflammatory and neuroinjury blood biomarkers across COVID-19 severity groups in individuals with persistent neurological symptoms. Int J Immunopathol Pharmacol. 2026 Jan-Dec;40:3946320261465568. doi: 10.1177/03946320261465568. Epub 2026 Jul 16. PMID: 42460883; PMCID: PMC13376473. https://pmc.ncbi.nlm.nih.gov/articles/PMC13376473/ (Full text)

Assessment of dynamic cerebral blood flow changes during cognitive tasks in patients with post-COVID-19 syndrome

Abstract:

The objective of this study was to quantify the variability of cortical blood flow during cognitive load as an indicator of disease-related changes in cerebral capillary blood flow intermittency in patients with post-COVID-19 syndrome. The regulation of cerebral blood flow in the dorsolateral prefrontal cortex under cognitive load was examined using high-resolution functional near-infrared spectroscopy in 36 subjects including 12 patients with post-COVID-19 syndrome and two control groups [12 coronary artery disease patients matched for age and 12 young healthy individuals (CTRL)].

To induce cognitive load, a Flanker task and an N-back task were employed. The structure of temporal variability of local blood flow regulation was assessed using sample entropy at 17 channels spanning both brain hemispheres. The spatial variability of the regional blood flow pattern was evaluated using the coefficient of variation (CV) from sample entropies across all channels.

Results revealed a notable discrepancy in that patients with post-COVID-19 syndrome exhibited reduced temporal variability (lower sample entropy) but elevated spatial variability (higher CV) in comparison to coronary artery disease patients during cognitive load (P = 0.02). In the N-back task, the spatial variability increased from healthy individuals to coronary artery disease patients to patients with post-COVID-19 syndrome and was associated with longer reaction time and with lower accuracy.

The results confirmed that dynamic cerebral blood flow is altered in patients with post-COVID-19 syndrome, which may be related to fatigue during cognitive tasks. Sample entropy and CV values represent different aspects of blood flow regulation fluctuation. Their simultaneous analysis enabled a meaningful distinction between groups suggesting disease-related changes in brain haemodynamic. The presented method is therefore suitable for describing current states of cortical blood flow regulation and for documenting intervention results in patients with post-COVID-19 syndrome or patients with similar symptoms (e.g. myalgic encephalomyelitis/chronic fatigue syndrome).

Source: Kutz DF, Garbsch R, Mooren FC, Schmitz B, Voelcker-Rehage C. Assessment of dynamic cerebral blood flow changes during cognitive tasks in patients with post-COVID-19 syndrome. Brain Commun. 2026 Feb 10;8(1):fcag036. doi: 10.1093/braincomms/fcag036. PMID: 41728261; PMCID: PMC12917544. https://pmc.ncbi.nlm.nih.gov/articles/PMC12917544/ (Full text)

Distinct functional connectivity patterns in myalgic encephalomyelitis and long COVID patients during cognitive fatigue: a 7 Tesla task-fMRI study

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and long COVID are chronic debilitating illnesses featuring fatigue, post-exertional malaise (PEM) and neurocognitive deficits. Temporal correlation of neural activity between distinct brain regions, also referred to as functional connectivity (FC), can provide insights into how brain networks coordinate, at rest or during task. Therefore, we explored intrinsic FC correlates of cognitive fatigue in ME/CFS and long COVID patients during two Stroop-colour-word paradigms on 7 Tesla fMRI.

Methods: 450 sagittal volumes were acquired from seventy-eight participants: 32 patients with MECFS (pwME/CFS); 19 long COVID (pwLC) and 27 healthy controls (HC) during performance of baseline or Pre (before/during fatigue build-up) and repeat Post (fatigue set-in) Stroop tasks. Structural and functional data were analysed using the CONN toolbox.

Results: Regions of interest (ROI-to-ROI) analysis revealed significantly increased FC in subcortical regions in HC for Pre vs Post. Relative to HC, pwLC showed significantly reduced FC between nucleus accumbens and vermis 3 (p = 0.02) in Pre and increased FC in the prefrontal cortex and hippocampus (p = 0.02) in Post. pwME/CFS showed a significantly increased FC between the left cuneiform nucleus and right medulla (p = 0.03). Compared to HC, reduced FC was significant in pwLC during Pre, and between medulla and hippocampus (p = 0.04) and between nucleus accumbens and vermis (p = 0.001) during Post. Aberrant FC was significant for pwME/CFS in core networks during Pre. Core network FC to the cerebellum, amygdala, caudate and red nucleus correlated with symptom scores for cognition in both pwME/CFS and pwLC. Hippocampus and cerebellar FC correlated with duration of illness in pwME/CFS.

Conclusions: Our findings of reduced dopaminergic hippocampal-nucleus-accumbens connectivity imply blunted motivation and cognition. Extensive FC differences in subcortical and core networks in patient cohorts were detected relative to an increased FC in HC. High regional communication indicative of greater task engagement by HC was distinctive while FC differences in ME/CFS and long COVID patients indicated reduced and dysregulated regional coordination that may serve as candidate biomarkers of symptomatology in long COVID and ME/CFS.

Source: Inderyas M, Thapaliya K, Marshall-Gradisnik S, Barnden L. Distinct functional connectivity patterns in myalgic encephalomyelitis and long COVID patients during cognitive fatigue: a 7 Tesla task-fMRI study. J Transl Med. 2026 Jan 20. doi: 10.1186/s12967-026-07708-y. Epub ahead of print. PMID: 41559785. https://link.springer.com/article/10.1186/s12967-026-07708-y (Full text)

Altered brain tissue microstructure and neurochemical profiles in long COVID and recovered COVID-19 individuals: A multimodal MRI study

Abstract:

Background: Diverse neurological symptoms are experienced by long COVID and COVID-19 recovered individuals. However, the long-term effects of SARS-CoV-2 in the brain of both groups are underexplored. This study aimed to investigate changes in tissue microstructural and brain neurochemical levels in long COVID and recovered COVID-19 patients compared to healthy controls.

Methods: We recruited 47 participants (long COVID = 19, COVID-recovered healthy controls = 12, and healthy controls without COVID-19 infection = 16) who underwent 3T MRI scans. We acquired T1 and T2 weighted images to assess myelin signal, diffusion weighted images to assess tissue microstructure, and magnetic resonance spectroscopy data to estimate brain neurochemical levels.

Findings: Our multimodal MRI study showed altered T1w/T2w signal between long COVID vs COVID-recovered-healthy controls, long COVID vs healthy controls, and COVID-recovered-healthy controls vs healthy controls. Furthermore, T1w/T2w signal intensity was significantly correlated with physical and cognitive function. Diffusion weighted imaging also showed altered tissue microstructure in these three group comparisons. However, brain neurochemicals were only significantly different between long COVID vs COVID-recovered-healthy controls.

Interpretation: This is one of the first studies to report different myelin signal and brain neurochemical changes between long COVID, COVID-recovered-healthy controls, and healthy controls without SARS-CoV-2 infection. These brain changes provide compelling evidence for the long-term effects of SARS-CoV-2 on brain function.

Source: Thapaliya K, Marshall-Gradisnik S, Inderyas M, Barnden L. Altered brain tissue microstructure and neurochemical profiles in long COVID and recovered COVID-19 individuals: A multimodal MRI study. Brain Behav Immun Health. 2025 Nov 25;50:101142. doi: 10.1016/j.bbih.2025.101142. PMID: 41404601; PMCID: PMC12704066. https://pmc.ncbi.nlm.nih.gov/articles/PMC12704066/ (Full text)

Association of Autonomic Dysfunction With Long COVID: Evaluation Using Quantitative Autonomic Testing

Abstract:

Background: Persistent symptoms (eg, heart palpitations, lightheadedness, fatigue) despite resolution of acute COVID-19 infection is termed “long COVID syndrome” or simply “long COVID.” Long COVID is believed to be associated with autonomic dysfunction, but the nature and severity of any autonomic disturbances are not well understood.

Objective: This study sought to compare autonomic function measures in patients with long COVID, control subjects, and individuals with pure autonomic failure.

Methods: Patients referred for autonomic testing were classified into 3 groups: long COVID (acute COVID-19 infection ≥12 weeks before testing), control subjects (COVID-19 negative, normal autonomic tests), and pure autonomic failure (COVID-19 negative, abnormal autonomic testing). Heart rate and blood pressure were recorded during active standing, Valsalva maneuver, respiratory sinus arrhythmia, and tilt-table testing.

Results: Compared with control subjects, patients with long COVID exhibited both a greater heart rate increase and blood pressure drop with active standing and tilt-table testing (all P < 0.05). They also had lower Valsalva ratios and respiratory sinus arrhythmia values than did control subjects (both P < 0.05). Compared with pure autonomic failure patients, patients with long COVID had a greater heart rate increase but a lower drop in blood pressure with active standing and tilt-table testing and lesser respiratory sinus arrhythmia values and Valsalva ratios (all P < 0.001). After age and sex adjustment, autonomic dysfunction measures in patients with long COVID were comparable with those in the pure autonomic failure group. Further, autonomic testing abnormalities were observed in patients referred up to 40 months after infection.

Conclusions: When adjusted for age and sex, patients with long COVID may demonstrate persistent autonomic dysfunction that is similar to patients with pure autonomic failure.

Source: Keller C, Mascarenhas L, Reyes JL, Duval S, Benditt DG. Association of Autonomic Dysfunction With Long COVID: Evaluation Using Quantitative Autonomic Testing. J Am Coll Cardiol. 2025 Nov 21:S0735-1097(25)09919-X. doi: 10.1016/j.jacc.2025.09.1608. Epub ahead of print. PMID: 41369621. https://pubmed.ncbi.nlm.nih.gov/41369621/

Brain MRI findings in patients with post COVID-19 condition: frequency and longitudinal changes in a nationwide cohort study

Abstract:

Background: Prolonged neurological symptoms following COVID-19 are common, yet few longitudinal studies describe brain MRI findings in this patient group. The use of contrast enhanced sequences is particularly lacking. We address this knowledge gap by reporting the frequency and longitudinal changes in brain MRI findings among patients with post COVID-19 condition exhibiting neurological symptoms.

Methods: This prospective multicenter study included 140 adult patients referred for persistent neurological symptoms following COVID-19. Brain MRI was performed at both 6 and 12 months after infection onset, reporting white matter hyperintensities, cerebral microbleeds, and additional pathological findings including contrast enhancement. White matter hyperintensities were compared with a healthy control group.

Results: The prevalence of white matter hyperintensities was comparable to healthy controls, and microbleeds were found at rates comparable to population studies, with longitudinal changes being infrequent. Lesions consistent with inflammation or demyelination were present in 4% (5/120) of patients at 6 months. Cranial nerve enhancement was found in 7% (7/94) of patients, persisting up to 12 months, predominantly affecting the oculomotor nerve. However, enhancement occurred without clinically detected ocular muscle paresis.

Conclusion: Our findings indicate that brain MRI primarily serves to exclude differential diagnoses in post COVID-19 condition, with limited clinical benefit of repeated imaging in the absence of new symptoms. However, signs of long-term inflammatory processes can be observed, and detection is improved by contrast enhanced sequences.

Source: Furevik LL, Lapina O, Lindland ES, Høgestøl EA, Geier OM, Devik K, Farmen AH, Flemmen HØ, Harbo HF, Morsund ÅH, Novotny V, Ofte HK, Pedersen KO, Popperud TH, Ratajczak-Tretel B, Samsonsen C, Selnes P, Torkildsen Ø, Undseth RM, Aamodt AH, Beyer MK, Boldingh MI. Brain MRI findings in patients with post COVID-19 condition: frequency and longitudinal changes in a nationwide cohort study. Front Neurol. 2025 Nov 13;16:1662263. doi: 10.3389/fneur.2025.1662263. PMID: 41323230; PMCID: PMC12658414. https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1662263/full (Full text)

Systemic increase of AMPA receptors associated with cognitive impairment of Long COVID

Abstract:

Long COVID primarily presents with persistent cognitive impairment (Cog-LC), imposing a substantial and lasting global burden. Even after the pandemic, there remains a critical global need for diagnostic and therapeutic strategies targeting Cog-LC. Nevertheless, the underlying neural mechanisms remain poorly understood. Given the central role of synapses in brain function, investigation of synaptic molecular changes may provide vital insights into Cog-LC pathophysiology.

In this study, we used [11C]K-2 PET to characterize the density of AMPA receptors (AMPARs) on the post-synaptic cell surface, which are crucial synaptic components in brain signalling. Statistical parametrical mapping was used to spatially normalize and apply independent t-test for a voxel-based comparison.

We selected patients with Cog-LC (n = 30) based on Repeatable Battery for the Assessment of Neuropsychological Status assessed persistent cognitive impairment and healthy controls (n = 80) with no diagnosed neuropsychiatric disorders. The primary objective was to compare [11C]K-2 standardized uptake value ratio with white matter (SUVRWM) as a reference region between patients with Cog-LC and healthy controls, and to define the regional extent of differences. The secondary objective was to examine associations between [11C]K-2 SUVRWM and plasma concentrations of cytokines or chemokines.

As an exploratory objective, we tested whether [11C]K-2 PET data could distinguish Cog-LC from healthy controls using a partial least squares based classification algorithm. A voxel-based comparison (P < 0.05, T > 1.66, one-tailed, false discovery rate control) and a volume of interests analysis (P < 0.05, Bonferroni multiple comparison) demonstrated that increased index of AMPAR density in large parts of the brains of patients with Cog-LC compared with that in healthy controls.

A voxel-based correlation analysis also showed the brain regions where [11C]K-2 SUVRWM correlated positively with plasma TNFSF12 and negatively with plasma CCL2 concentrations.

A partial least squares model trained on the index of AMPAR density data demonstrated high diagnostic accuracy, achieving 100% sensitivity and 91.2% specificity. [11C]K-2 PET signal represents the index of AMPAR density on the post-synaptic neural cell surface, not on the glial cell surface.

A systemic increase in synaptic AMPARs across the brain may drive abnormal information processing in Cog-LC and, through excessive excitatory signalling, pose a risk of excitotoxic neuronal damage.

We derived the hypothesis that [11C]K-2 PET would be helpful in establishing a diagnostic framework for Cog-LC and that antagonists for cell surface AMPARs, such as perampanel, would be a potential therapeutic target. These hypotheses should be investigated in future large-scale clinical studies.

Source: Fujimoto Y, Abe H, Eiro T, Tsugawa S, Tanaka M, Hatano M, Nakajima W, Ichijo S, Arisawa T, Takada Y, Kimura K, Sano A, Hirahata K, Sasaki N, Kimura Y, Takahashi T. Systemic increase of AMPA receptors associated with cognitive impairment of long COVID. Brain Commun. 2025 Oct 1;7(5):fcaf337. doi: 10.1093/braincomms/fcaf337. PMID: 41036177; PMCID: PMC12483584. https://pmc.ncbi.nlm.nih.gov/articles/PMC12483584/ (Full text)

Evidence of clinical and brain recovery in post-COVID-19 condition: a three-year follow-up study

Abstract:

Fatigue and cognitive dysfunction linked to persistent brain changes have been reported for up to two years after COVID-19. In this study, we followed the clinical, neuroimaging and fluid biomarker trajectories over three years post SARS-CoV-2 infection to evaluate potential signs and underlying factors of brain recovery.

We conducted a monocentric, longitudinal study using resting-state functional and structural T1-weighted magnetic resonance imaging data from 51 patients with Post-COVID-19 Condition (mean age 50 years, 33 female) collected at a mean time of 6, 23 and 38 months after COVID-19 infection. The trajectory of brain changes was compared to 23 age- and sex-matched healthy controls (mean age 37 years, 13 female) with similar time intervals between brain scans and analysed in relation to clinical, neuropsychological and fluid biomarkers including interleukins and neurodestruction markers at all timepoints. In addition, hand grip strength to evaluate muscular fatigue, was assessed at the final follow-up visit.

Self-reported fatigue improved over time but was still moderate on average three years after COVID-19 infection, while measures of hand grip strength and cognitive performance were largely unaffected. We found a significant increase of both lateral ventricles (∼8%) and the third (∼6%) ventricle accompanied by a structural volume reduction in adjacent areas including the thalamus, pallidum, caudate nucleus and putamen. An increased neuronal activation pattern was widespread and pronounced in these areas. The brainstem no longer exhibited volume loss as reported in our pervious study, but enhanced functional connectivity. Laboratory markers including interleukins and neuronal injury markers remained within the normal reference ranges across all study timepoints.

Our study revealed an overall slow but evident clinical improvement, including improved fatigue, regular muscular strength and recovery as well as normal cognitive function without signs of systemic inflammation three years after COVID-19. Clinical improvement is reflected by a pattern of brain recovery along periventricular regions. This pattern is characterized by structural stabilization and increased connectivity starting in the brainstem as well as efficient neuronal recruitment and increased activation in the basal ganglia, with no evidence of neuronal injury. These results highlight the positive long-term recovery trajectory in post-COVID patients.

Source: Ravi Dadsena, Sophie Wetz, Anna Hofmann, Ana Sofia Costa, Sandro Romanzetti, Stella Andrea Lischewski, Christina Krockauer, Carolin Balloff, Ferdinand Binkofski, Jörg B Schulz, Kathrin Reetz, Julia Walders, Evidence of clinical and brain recovery in post-COVID-19 condition: a three-year follow-up study, Brain Communications, 2025;, fcaf366, https://doi.org/10.1093/braincomms/fcaf366 https://academic.oup.com/braincomms/advance-article/doi/10.1093/braincomms/fcaf366/8262587 (Full study available as PDF file)

Abnormal Brain Activation Patterns in Patients With Post-Acute Sequelae of COVID-19 (PASC) During Recovery: A fNIRS Study

Abstract:

COVID-19 has increased the likelihood of cognitive impairment in patients with post-acute sequelae of COVID-19 (PASC). There is a lack of direct evidence regarding the working memory performance of mild patients during the recovery period. This study employed functional near-infrared spectroscopy (fNIRS) to construct a mixed effects model for PASC patients performing the N-back task, assessing brain activation levels and brain connectivity.

PASC patients exhibited abnormally low activation in the parietal lobe (β = −0.21) and abnormally high activation in the occipital lobe (β = 0.40). There was a significant reduction in brain connectivity within the frontal–parietal and frontal–occipital networks.

These findings suggest that PASC patients experience impaired fronto-parietal network connectivity, rely more on the visual cortex to compensate for executive function deficits, and use this as a compensatory mechanism to reduce overall cerebral blood oxygenation. This study provides evidence of altered brain activation patterns in PASC patients during the recovery period due to cognitive impairment.

Source: Y. Ran, S. Wu, S. Liu, et al., “ Abnormal Brain Activation Patterns in Patients With Post-Acute Sequelae of COVID-19 (PASC) During Recovery: A fNIRS Study,” Journal of Biophotonics (2025): e202500206, https://doi.org/10.1002/jbio.202500206. https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbio.202500206