Tag: long covid neurology

Blood Markers Show Neural Consequences of LongCOVID-19

Abstract:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists throughout the world with over 65 million registered cases of survivors with post-COVID-19 sequelae, also known as LongCOVID-19 (LongC). LongC survivors exhibit various symptoms that span multiple organ systems, including the nervous system.
To search for neurological markers of LongC, we investigated the soluble biomolecules present in the plasma and the proteins associated with plasma neuronal-enriched extracellular vesicles (nEVs) in 33 LongC patients with neurological impairment (nLongC), 12 COVID-19 survivors without any LongC symptoms (Cov), and 28 pre-COVID-19 healthy controls (HC). COVID-19 positive participants were infected between 2020 and 2022, not hospitalized, and were vaccinated or unvaccinated before infection.
IL-1β was significantly increased in both nLongC and Cov and IL-8 was elevated in only nLongC. Both brain-derived neurotrophic factor and cortisol were significantly elevated in nLongC and Cov compared to HC. nEVs from people with nLongC had significantly elevated protein markers of neuronal dysfunction, including amyloid beta 42, pTau181 and TDP-43.
This study shows chronic peripheral inflammation with increased stress after COVID-19 infection. Additionally, differentially expressed nEV neurodegenerative proteins were identified in people recovering from COVID-19 regardless of persistent symptoms.
Source: Tang N, Kido T, Shi J, McCafferty E, Ford JM, Dal Bon K, Pulliam L. Blood Markers Show Neural Consequences of LongCOVID-19. Cells. 2024; 13(6):478. https://doi.org/10.3390/cells13060478 https://www.mdpi.com/2073-4409/13/6/478 (Full text)

SARS-CoV2 evokes structural brain changes resulting in declined executive function

Abstract:

Background: Several research has underlined the multi-system character of COVID-19. Though effects on the Central Nervous System are mainly discussed as disease-specific affections due to the virus’ neurotropism, no comprehensive disease model of COVID-19 exists on a neurofunctional base by now. We aimed to investigate neuroplastic grey- and white matter changes related to COVID-19 and to link these changes to neurocognitive testings leading towards a multi-dimensional disease model.

Methods: Groups of acutely ill COVID-19 patients (n = 16), recovered COVID-19 patients (n = 21) and healthy controls (n = 13) were prospectively included into this study. MR-imaging included T1-weighted sequences for analysis of grey matter using voxel-based morphometry and diffusion-weighted sequences to investigate white matter tracts using probabilistic tractography. Comprehensive neurocognitive testing for verbal and non-verbal domains was performed.

Results: Alterations strongly focused on grey matter of the frontal-basal ganglia-thalamus network and temporal areas, as well as fiber tracts connecting these areas. In acute COVID-19 patients, a decline of grey matter volume was found with an accompanying diminution of white matter tracts. A decline in executive function and especially verbal fluency was found in acute patients, partially persisting in recovered.

Conclusion: Changes in gray matter volume and white matter tracts included mainly areas involved in networks of executive control and language. Deeper understanding of these alterations is necessary especially with respect to long-term impairments, often referred to as ‘Post-COVID’.

Source: Deuter D, Hense K, Kunkel K, Vollmayr J, Schachinger S, Wendl C, Schicho A, Fellner C, Salzberger B, Hitzenbichler F, Zeller J, Vielsmeier V, Dodoo-Schittko F, Schmidt NO, Rosengarth K. SARS-CoV2 evokes structural brain changes resulting in declined executive function. PLoS One. 2024 Mar 12;19(3):e0298837. doi: 10.1371/journal.pone.0298837. PMID: 38470899; PMCID: PMC10931481. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10931481/ (Full text)

Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment

Abstract:

Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood–brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog.

Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog.

Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers.

Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.

Source: Greene C, Connolly R, Brennan D, Laffan A, O’Keeffe E, Zaporojan L, O’Callaghan J, Thomson B, Connolly E, Argue R, Martin-Loeches I, Long A, Cheallaigh CN, Conlon N, Doherty CP, Campbell M. Blood-brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci. 2024 Mar;27(3):421-432. doi: 10.1038/s41593-024-01576-9. Epub 2024 Feb 22. PMID: 38388736; PMCID: PMC10917679. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917679/ (Full text)

Cognition and Memory after Covid-19 in a Large Community Sample

Abstract:

Background: Cognitive symptoms after coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are well-recognized. Whether objectively measurable cognitive deficits exist and how long they persist are unclear.

Methods: We invited 800,000 adults in a study in England to complete an online assessment of cognitive function. We estimated a global cognitive score across eight tasks. We hypothesized that participants with persistent symptoms (lasting ≥12 weeks) after infection onset would have objectively measurable global cognitive deficits and that impairments in executive functioning and memory would be observed in such participants, especially in those who reported recent poor memory or difficulty thinking or concentrating (“brain fog”).

Results: Of the 141,583 participants who started the online cognitive assessment, 112,964 completed it. In a multiple regression analysis, participants who had recovered from Covid-19 in whom symptoms had resolved in less than 4 weeks or at least 12 weeks had similar small deficits in global cognition as compared with those in the no-Covid-19 group, who had not been infected with SARS-CoV-2 or had unconfirmed infection (-0.23 SD [95% confidence interval {CI}, -0.33 to -0.13] and -0.24 SD [95% CI, -0.36 to -0.12], respectively); larger deficits as compared with the no-Covid-19 group were seen in participants with unresolved persistent symptoms (-0.42 SD; 95% CI, -0.53 to -0.31). Larger deficits were seen in participants who had SARS-CoV-2 infection during periods in which the original virus or the B.1.1.7 variant was predominant than in those infected with later variants (e.g., -0.17 SD for the B.1.1.7 variant vs. the B.1.1.529 variant; 95% CI, -0.20 to -0.13) and in participants who had been hospitalized than in those who had not been hospitalized (e.g., intensive care unit admission, -0.35 SD; 95% CI, -0.49 to -0.20). Results of the analyses were similar to those of propensity-score-matching analyses. In a comparison of the group that had unresolved persistent symptoms with the no-Covid-19 group, memory, reasoning, and executive function tasks were associated with the largest deficits (-0.33 to -0.20 SD); these tasks correlated weakly with recent symptoms, including poor memory and brain fog. No adverse events were reported.

Conclusions: Participants with resolved persistent symptoms after Covid-19 had objectively measured cognitive function similar to that in participants with shorter-duration symptoms, although short-duration Covid-19 was still associated with small cognitive deficits after recovery. Longer-term persistence of cognitive deficits and any clinical implications remain uncertain. (Funded by the National Institute for Health and Care Research and others.).

Source: Hampshire A, Azor A, Atchison C, Trender W, Hellyer PJ, Giunchiglia V, Husain M, Cooke GS, Cooper E, Lound A, Donnelly CA, Chadeau-Hyam M, Ward H, Elliott P. Cognition and Memory after Covid-19 in a Large Community Sample. N Engl J Med. 2024 Feb 29;390(9):806-818. doi: 10.1056/NEJMoa2311330. PMID: 38416429. https://www.nejm.org/doi/10.1056/NEJMoa2311330 (Full text)

Cognitive domains affected post-COVID-19; a systematic review and meta-analysis

Abstract:

Background and purpose: This review aims to characterize the pattern of post-COVID-19 cognitive impairment, allowing better prediction of impact on daily function to inform clinical management and rehabilitation.

Methods: A systematic review and meta-analysis of neurocognitive sequelae following COVID-19 was conducted, following PRISMA-S guidelines. Studies were included if they reported domain-specific cognitive assessment in patients with COVID-19 at >4 weeks post-infection. Studies were deemed high-quality if they had >40 participants, utilized healthy controls, had low attrition rates and mitigated for confounders.

Results: Five of the seven primary Diagnostic and Statistical Manual of Mental Disorders (DSM-5) cognitive domains were assessed by enough high-quality studies to facilitate meta-analysis. Medium effect sizes indicating impairment in patients post-COVID-19 versus controls were seen across executive function (standardised mean difference (SMD) -0.45), learning and memory (SMD -0.55), complex attention (SMD -0.54) and language (SMD -0.54), with perceptual motor function appearing to be impacted to a greater degree (SMD -0.70). A narrative synthesis of the 56 low-quality studies also suggested no obvious pattern of impairment.

Conclusions: This review found moderate impairments across multiple domains of cognition in patients post-COVID-19, with no specific pattern. The reported literature was significantly heterogeneous, with a wide variety of cognitive tasks, small sample sizes and disparate initial disease severities limiting interpretability. The finding of consistent impairment across a range of cognitive tasks suggests broad, as opposed to domain-specific, brain dysfunction. Future studies should utilize a harmonized test battery to facilitate inter-study comparisons, whilst also accounting for the interactions between COVID-19, neurological sequelae and mental health, the interplay between which might explain cognitive impairment.

Source: Fanshawe JB, Sargent BF, Badenoch JB, Saini A, Watson CJ, Pokrovskaya A, Aniwattanapong D, Conti I, Nye C, Burchill E, Hussain ZU, Said K, Kuhoga E, Tharmaratnam K, Pendered S, Mbwele B, Taquet M, Wood GK, Rogers JP, Hampshire A, Carson A, David AS, Michael BD, Nicholson TR, Paddick SM, Leek CE. Cognitive domains affected post-COVID-19; a systematic review and meta-analysis. Eur J Neurol. 2024 Feb 20:e16181. doi: 10.1111/ene.16181. Epub ahead of print. PMID: 38375608. https://onlinelibrary.wiley.com/doi/10.1111/ene.16181 (Full text)

Impact of sleep disruption on cognitive function in patients with postacute sequelae of SARS-CoV-2 infection: initial findings from a Neuro-COVID-19 clinic

Abstract:

Introduction: Fatigue, brain fog, and sleep disturbance are among the most common symptoms of postacute sequelae of SARS-CoV-2 infection (PASC). We sought to determine the impact of sleep disruption on cognition and quality of life in patients with neurologic manifestations of PASC (Neuro-PASC).
Methods: Thirty-nine patients were recruited from Neuro-COVID-19 clinic. Mean age was 48.1 years, 71.8% were female, and 82% were never hospitalized for COVID-19. Patients were evaluated via clinical assessment, quality-of-life measures in domains of cognitive function, fatigue, sleep disturbance, anxiety, and depression, NIH Toolbox cognitive tests, and 7 days of wrist actigraphy.
Results: The median number of neurologic symptoms attributed to PASC was 6, with brain fog being the most common in 89.7%. Regarding non-neurologic symptoms, 94.9% complained of fatigue and 74.4% of insomnia. Patients reported significant impairment in all quality-of-life domains and performed worse in a task of attention compared to a normative US population. Actigraphy showed Neuro-PASC patients had lower sleep efficiency, longer sleep latency (both p < 0.001), and later sleep midpoint (p = 0.039) compared to 71 age-matched healthy controls with no PASC history. Self-reported cognitive symptoms correlated with the severity of fatigue (p < 0.001), anxiety (p = 0.05), and depression (p < 0.01). Objective evidence of sleep disruption measured by wakefulness after sleep onset, sleep efficiency, and latency were associated with decreased performance in attention and processing speed.
Conclusion: Prospective studies including larger populations of patients are needed to fully determine the interplay of sleep disruption on the cognitive function and quality of life of patients with PASC.

Source: Kathryn J Reid, Louis T Ingram, Millenia Jimenez, Zachary S Orban, Sabra M Abbott, Daniela Grimaldi, Kristen L Knutson, Phyllis C Zee, Igor J Koralnik, Mathew B Maas, Impact of sleep disruption on cognitive function in patients with postacute sequelae of SARS-CoV-2 infection: initial findings from a Neuro-COVID-19 clinic, SLEEP Advances, Volume 5, Issue 1, 2024, zpae002, https://doi.org/10.1093/sleepadvances/zpae002 https://academic.oup.com/sleepadvances/article/5/1/zpae002/7517273 (Full text)

Cluster Analysis to Identify Long COVID Phenotypes Using 129Xe Magnetic Resonance Imaging: A Multi-centre Evaluation

Abstract:

Background Long COVID impacts ∼10% of people diagnosed with COVID-19, yet the pathophysiology driving ongoing symptoms is poorly understood. We hypothesised that 129Xe magnetic resonance imaging (MRI) could identify unique pulmonary phenotypic subgroups of long COVID, therefore we evaluated ventilation and gas exchange measurements with cluster analysis to generate imaging-based phenotypes.

Methods COVID-negative controls and participants who previously tested positive for COVID-19 underwent 129XeMRI ∼14-months post-acute infection across three centres. Long COVID was defined as persistent dyspnea, chest tightness, cough, fatigue, nausea and/or loss of taste/smell at MRI; participants reporting no symptoms were considered fully-recovered. 129XeMRI ventilation defect percent (VDP) and membrane (Mem)/Gas, red blood cell (RBC)/Mem and RBC/Gas ratios were used in k-means clustering for long COVID, and measurements were compared using ANOVA with post-hoc Bonferroni correction.

Results We evaluated 135 participants across three centres: 28 COVID-negative (40±16yrs), 34 fully-recovered (42±14yrs) and 73 long COVID (49±13yrs). RBC/Mem (p=0.03) and FEV1 (p=0.04) were different between long- and COVID-negative; FEV1 and all other pulmonary function tests (PFTs) were within normal ranges. Four unique long COVID clusters were identified compared with recovered and COVID-negative. Cluster1 was the youngest with normal MRI and mild gas-trapping; Cluster2 was the oldest, characterised by reduced RBC/Mem but normal PFTs; Cluster3 had mildly increased Mem/Gas with normal PFTs; and Cluster4 had markedly increased Mem/Gas with concomitant reduction in RBC/Mem and restrictive PFT pattern.

Conclusion We identified four 129XeMRI long COVID phenotypes with distinct characteristics. 129XeMRI can dissect pathophysiologic heterogeneity of long COVID to enable personalised patient care.

Source: Rachel L Eddy, David Mummy, Shuo Zhang, Haoran Dai, Aryil Bechtel, Alexandra Schmidt, Bradie Frizzell, Firoozeh V Gerayeli, Jonathon A Leipsic, Janice M Leung, Bastiaan Driehuys, Loretta G Que, Mario Castro, Don D Sin, Peter J Niedbalski. Cluster Analysis to Identify Long COVID Phenotypes Using 129Xe Magnetic Resonance Imaging: A Multi-centre Evaluation. European Respiratory Journal Jan 2024, 2302301; DOI: 10.1183/13993003.02301-2023 https://erj.ersjournals.com/content/early/2024/02/02/13993003.02301-2023 (Full text)

Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment

Abstract:

Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood–brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog.

Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog.

Source: Greene, C., Connolly, R., Brennan, D. et al. Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nat Neurosci (2024). https://doi.org/10.1038/s41593-024-01576-9 https://www.nature.com/articles/s41593-024-01576-9 (Full text)

Cognitive and Mental Health Trajectories of COVID-19: Role of Hospitalisation and Long-COVID Symptoms

Abstract:

Background: There is considerable evidence of cognitive impairment post COVID-19, especially in individuals with long-COVID symptoms, but limited research objectively evaluating whether such impairment attenuates or resolves over time, especially in young and middle-aged adults.

Methods: Follow-up assessments (T2) of cognitive function (processing speed, attention, working memory, executive function, memory) and mental health were conducted in 138 adults (18-69 years) who had been assessed six months earlier (T1). Of these, 88 had a confirmed history of COVID-19 at T1 assessment (≥20 days post-diagnosis) and were also followed-up on COVID-19 related symptoms (acute and long-COVID); 50 adults had no known COVID-19 history at any point up to their T2 assessment.

Results: From T1 to T2, a trend-level improvement occurred in intra-individual variability in processing speed in the COVID, relative to the non-COVID group. However, longer response/task completion times persisted in participants with COVID-19 related hospitalisation relative to those without COVID-19 related hospitalisation and non-COVID controls. There was a significant reduction in long-COVID symptom load, which correlated with improved executive function in non-hospitalised COVID-19 participants. The COVID group continued to self-report poorer mental health, irrespective of hospitalisation history, relative to non-COVID group.

Conclusions: Although some cognitive improvement has occurred over a six-month period in young and middle-aged COVID-19 survivors, cognitive impairment persists in those with a history of COVID-19 related hospitalisation and/or long-COVID symptoms. Continuous follow-up assessments are required to determine whether cognitive function improves or possibly worsens, over time in hospitalised and long-COVID participants.

Source: Vakani K, Ratto M, Sandford-James A, Antonova E, Kumari V. Cognitive and Mental Health Trajectories of COVID-19: Role of Hospitalisation and Long-COVID Symptoms. Eur Psychiatry. 2024 Feb 5:1-40. doi: 10.1192/j.eurpsy.2024.7. Epub ahead of print. PMID: 38312039. https://www.researchgate.net/publication/377977040_Cognitive_and_Mental_Health_Trajectories_of_COVID-19_Role_of_Hospitalisation_and_Long-COVID_Symptoms (Full text)

Neuroinflammatory imaging markers in white matter: insights into the cerebral consequences of post-acute sequelae of COVID-19 (PASC)

Abstract:

Symptoms of coronavirus disease 2019 (COVID-19) can persist for months or years after infection, a condition called Post-Acute Sequelae of COVID-19 (PASC). Whole-brain white matter and cortical gray matter health were assessed using multi-shell diffusion tensor imaging. Correlational tractography was utilized to dissect the nature and extent of white matter changes.

In this study of 42 male essential workers, the most common symptoms of Neurological PASC (n = 24) included fatigue (n = 19) and headache (n = 17). Participants with neurological PASC demonstrated alterations to whole-brain white matter health when compared to controls made up of uninfected, asymptomatic, or mildly infected controls (n = 18). Large differences were evident between PASC and controls in measures of fractional anisotropy (Cohen’s D=-0.54, P = 0.001) and cortical isotropic diffusion (Cohen’s D = 0.50, P = 0.002).

Symptoms were associated with white matter fractional anisotropy (fatigue: rho = -0.62, P < 0.001; headache: rho = -0.66, P < 0.001), as well as nine other measures of white and gray matter health. Brain fog was associated with improved cerebral functioning including improved white matter isotropic diffusion and quantitative anisotropy.

This study identified changes across measures of white and gray matter connectivity, neuroinflammation, and cerebral atrophy that were interrelated and associated with differences in symptoms of PASC. These results provide insights into the long-term cerebral implications of COVID-19.

Source: Sean Clouston, Chuan Huang, Jia Ying et al. Neuroinflammatory imaging markers in white matter: insights into the cerebral consequences of post-acute sequelae of COVID-19 (PASC), 19 January 2024, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3760289/v1] https://www.researchsquare.com/article/rs-3760289/v1 (Full text)