Tag: cognitive impairment

Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease after COVID-19 hospitalisation

Abstract:

One in ten SARS-CoV-2 infections result in prolonged symptoms termed long COVID, yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 previously hospitalised adults with long COVID grouped by symptoms. Elevated markers of myeloid inflammation and complement activation were associated with long COVID; elevated IL1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while MATN2 and DPP10 were elevated in gastrointestinal (GI) symptoms, and C1QA in cognitive impairment.
Proteins suggestive of neurodegeneration were elevated in cognitive impairment, whilst SCG3 (indicative of brain-gut axis disturbance) was specific to GI symptoms. Nasal inflammation was apparent after COVID-19 but did not associate with symptoms. Although SARS-CoV-2 specific IgG was elevated with some long COVID symptoms, virus was not detected from sputum. Thus, systemic inflammation is evident in long COVID and could be targeted in therapeutic trials tailored to pathophysiological differences between symptom groups.

Source: Peter Openshaw, Felicity Liew, Claudia Efstathiou et al. Large scale phenotyping of long COVID inflammation reveals mechanistic subtypes of disease after COVID-19 hospitalisation, 04 December 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3427282/v1] https://www.researchsquare.com/article/rs-3427282/v1 (Full text)

A systematic review of quantitative EEG findings in Long COVID, Fibromyalgia and Chronic Fatigue Syndrome

Abstract:

Long COVID (LC) is a multisymptom clinical syndrome with similarities to Fibromyalgia Syndrome (FMS) and Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). All these conditions are believed to be associated with centrally driven mechanisms such as central sensitisation.

There is a lack of consensus on quantitative EEG (qEEG) changes observed in these conditions. This review aims to synthesise and appraise the literature on resting-state qEEG in LC, FMS and CFS/ME, to help uncover possible mechanisms of central sensitisation in these similar clinical syndromes.

A systematic search of MEDLINE, Embase, CINHAL, PsycINFO and Web of Science databases for articles published between December 1994 and September 2023 was performed. Following screening for predetermined selection criteria and out of the initial 2510 studies identified, 17 articles were retrieved that met all the inclusion criteria, particularly of assessing qEEG changes in one of the three conditions compared to healthy controls. All studies scored moderate to high quality on the Newcastle-Ottawa scale.

There was a general trend for decreased low frequency EEG band activity (delta, theta, and alpha) and increased high-frequency EEG beta activity in FMS, whereas an opposite trend was found in CFS/ME. The limited LC studies included in this review focused mainly on cognitive impairments and showed mixed findings not consistent with patterns seen in FMS and CFS/ME.

Further research is required to explore whether there are phenotypes within LC that have EEG signatures similar to FMS or CFS/ME. This could inform identification of reliable diagnostic markers and possible targets for neuromodulation therapies.

Source: Bárbara Silva-Passadouro, Arnas Tamasauskas, Omar Khoja, Alexander J. Casson, Ioannis Delis, Christopher Brown, Manoj Sivan. A systematic review of quantitative EEG findings in Long COVID, Fibromyalgia and Chronic Fatigue Syndrome. medRxiv [Preprint] https://www.medrxiv.org/content/10.1101/2023.11.06.23298171v1.full-text (Full text)

Altered functional brain connectivity, efficiency, and information flow associated with brain fog after mild to moderate COVID-19 infection

Abstract:

COVID-19 is associated with increased risk for cognitive decline but very little is known regarding the neural mechanisms of this risk. We enrolled 49 adults (55% female, mean age = 30.7 +/- 8.7), 25 with and 24 without a history of COVID-19 infection. We administered standardized tests of cognitive function and acquired brain connectivity data using MRI.

The COVID-19 group demonstrated significantly lower cognitive function (W = 475, p < 0.001, effect size r = 0.58) and lower functional connectivity in multiple brain regions (mean t = 3.47 +/- 0.36, p = 0.03, corrected, effect size d = 0.92 to 1.5). Hypo-connectivity of these regions was inversely correlated with subjective cognitive function and directly correlated with fatigue (p < 0.05, corrected). These regions demonstrated significantly reduced local efficiency (p < 0.026, corrected) and altered effective connectivity (p < 0.001, corrected).

COVID-19 may have a widespread effect on the functional connectome characterized by lower functional connectivity and altered patterns of information processing efficiency and effective information flow. This may serve as an adaptation to the pathology of SARS-CoV-2 wherein the brain can continue functioning at near expected objective levels, but patients experience lowered efficiency as brain fog.

Source: Shelli R. Kesler, Oscar Y. Franco Rocha, Alexa De La Torre Schutz et al. Altered functional brain connectivity, efficiency, and information flow associated with brain fog after mild to moderate COVID-19 infection, 20 October 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3466991/v1] https://www.researchsquare.com/article/rs-3466991/v1 (Full text)

Brain fog in long COVID: A glutamatergic hypothesis with astrocyte dysfunction accounting for brain PET glucose hypometabolism

Abstract:

Brain [18F]FDG-PET scans have revealed a glucose hypometabolic pattern in patients with long COVID. This hypometabolism might reflect primary astrocyte dysfunction. Astrocytes play a key role in regulating energy metabolism to support neuronal and synaptic activity, especially activity involving glutamate as the main neurotransmitter.

Neuroinflammation is one of the purported mechanisms to explain brain damage caused by infection with SARS-CoV-2. Microglial activation can trigger reactive astrogliosis, contributing to neuroinflammatory changes. These changes can disturb glutamatergic homeostasis, ultimately leading to cognitive fatigue, which has been described in other clinical situations.

We hypothesize that glutamatergic dysregulation related to astrocyte dysfunction could be the substrate of brain PET hypometabolism in long COVID patients with brain fog. Based on these elements, we propose that therapeutics targeting astrocytic glutamate regulation could help mitigate long COVID neurological manifestations.

Source: Tatiana Horowitz, Luc Pellerin, Eduardo R. Zimmer, Eric Guedj. Brain fog in long COVID: A glutamatergic hypothesis with astrocyte dysfunction accounting for brain PET glucose hypometabolism. Medical Hypotheses, Volume 180, 2023, 111186, ISSN 0306-9877, https://doi.org/10.1016/j.mehy.2023.111186. https://www.sciencedirect.com/science/article/pii/S0306987723001822 (Full text)

Vitamin B12 as an epidrug for regulating peripheral blood biomarkers in long COVID-associated visuoconstructive deficit

Abstract:

Approximately four months after recovering from a mild COVID-19 infection, around 25% of individuals developed visuoconstructive deficit (VCD), which was found to be correlated with an increase in peripheral immune markers and alterations in structural and metabolic brain imaging. Recently, it has been demonstrated that supplemental vitamin B12 regulates hyperinflammation during moderate and severe COVID-19 through methyl-dependent epigenetic mechanisms.

Herein, whole peripheral blood cultures were produced using samples obtained from patients with confirmed persistent VCD, and controls without impairment, between 10 and 16 months after mild COVID-19. This experimental model was used to assess the leukocyte expression patterns of 11 biomarkers previously associated with VCD in long COVID and explore the potential of pharmacological B12 in regulating these genes. The results showed that patients with persistent VCD displayed continued upregulation of CCL11 and LIF compared to controls.

It is worth noting that elevated serum levels of CCL11 have been previously linked to age-related neurodegenerative diseases. Notably, the addition of 1 nM of vitamin B12 to blood cultures from individuals with VCD normalized the mRNA levels of CCL11, upregulated the neuroprotective HGF, and, to a lesser extent, downregulated CSF2 and CXCL10. There was an inverse correlation observed between CCL11 mRNA levels and methylation levels of specific cytosines in its promoter region.

These findings underscore the significance of systemic inflammation in persistent VCD associated with long COVID. Moreover, the study provides evidence suggesting that B12, acting as an epidrug, shows promise as a therapeutic approach for addressing this cognitive impairment.

Source: Larissa Cassiano, Jonas Paula, Daniela Rosa et al. Vitamin B12 as an epidrug for regulating peripheral blood biomarkers in long COVID-associated visuoconstructive deficit, 11 October 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3158180/v1] https://www.researchsquare.com/article/rs-3158180/v1 (Full text)

Cognitive-linguistic difficulties in adults with Long COVID: A follow-up study

Abstract:

As the emergency phase of the COVID-19 pandemic subsides, the long-term health problems caused by SARS-CoV-2 infection are becoming increasingly clear. So-called Long COVID, or post COVID-19 condition, is a debilitating illness that impacts functioning for months and even years after infection. Alongside physical symptoms, Long COVID has a particularly insidious effect on cognition and language. While many studies have documented non-linguistic cognitive impairments in people with Long COVID, what has not been documented to any significant extent is the presence and duration of language difficulties in Long COVID. This study addresses this lack of research by examining the cognitive-linguistic skills of 41 adults with Long COVID.

These adults were assessed at two time points using a test protocol of 12 language tasks. This paper describes the findings of the 6-month follow-up study. Results indicate that difficulties in immediate and delayed verbal recall persist long after the onset of COVID symptoms, even as improvements occur in verbal fluency and the informativeness of spoken discourse.

It is argued that these difficulties are a significant contributing factor in a lack of work return in these adults. Implications of these findings for the provision of speech-language pathology services to these adults and occupational health policies relating to Long COVID are discussed.

Source: Louise Cummings. Cognitive-linguistic difficulties in adults with Long COVID: A follow-up study. Language and Health. Available online 2 October 2023. https://www.sciencedirect.com/science/article/pii/S2949903823000325 (Full text)

Long-Term cognitive dysfunction after the COVID-19 pandemic: a narrative review

Abstract:

Introduction: SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has brought a conglomerate of novel chronic disabling conditions described as ‘Long COVID/Post-COVID-19 Syndrome’. Recent evidence suggests that the multifaceted nature of this syndrome results in both pulmonary and extrapulmonary sequelae, chronic dyspnoea, persistent fatigue, and cognitive dysfunction being the most common, debilitating symptoms. Several mechanisms engender or exacerbate cognitive impairment, including central nervous system (CNS) and extra-CNS causes, although the exact mechanism remains unclear. Both hospitalized and non-hospitalized patients may suffer varying degrees of cognitive impairment, ranging from fatigue and brain fog to prolonged deficits in memory and attention, detrimental to the quality-of-life years post-recovery. The aim of this review is to understand the underlying mechanisms, associations, and attempts for prevention with early intervention of long-term cognitive impairment post-COVID-19.

Methodology: A systematic search was conducted through multiple databases such as Medline, National Library of Medicine, Ovid, Scopus database to retrieve all the articles on the long term sequalae of cognitive dysfunction after Sars-Cov2 infection. The inclusion criteria included all articles pertinent to this specific topic and exclusion criteria subtracted studies pertaining to other aetiologies of cognitive dysfunction. This search was carefully screened for duplicates and the relevant information was extracted and analysed.

Results/discussion: To date, the exact pathogenesis, and underlying mechanisms behind cognitive dysfunction in COVID-19, remain unclear, hindering the development of adequate management strategies. However, the proposed mechanisms suggested by various studies include direct damage to the blood-brain barrier, systemic inflammation, prolonged hypoxia, and extended intensive care admissions. However, no clear-cut guidelines for management are apparent.

Conclusion: This review of the COVID-19 pandemic has elucidated a new global challenge which is affecting individuals’ quality of life by inducing long-term impaired cognitive function. We have found that comprehensive evaluations and interventions are crucial to address the cognitive sequelae in all COVID-19 patients, especially in patients with pre-existing cognitive impairment. Nevertheless, the authors recommend further research for the development of relevant, timely neurocognitive assessments and treatment plans.

Source: Shariff, Sanobar; Uwishema, Olivier; Mizero, Jocelyn; Devi Thambi, Vimala; Nazir, Abubakar; Mahmoud, Ashraf; Kaushik, Ikshwaki; Khayat, Saadeddine; Yusif Maigoro, Abdulkadir; Awde, Sara; Al Maaz, Zeina; Alwan, Iktimal; Hijazi, Mahdi; Wellington, Jack MSc (LSHTM) FGMS; Soojin, Lee. Long-Term cognitive dysfunction after the COVID-19 pandemic: a narrative review. Annals of Medicine & Surgery ():10.1097/MS9.0000000000001265, September 8, 2023. | DOI: 10.1097/MS9.0000000000001265 https://journals.lww.com/annals-of-medicine-and-surgery/abstract/9900/long_term_cognitive_dysfunction_after_the_covid_19.1011.aspx

Prevalence, pathogenesis and spectrum of neurological symptoms in COVID-19 and post-COVID-19 syndrome: a narrative review

Summary:

  • Neurological symptoms are not uncommon during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and reflect a broad spectrum of neurological disorders of which clinicians should be aware.
  • The underlying pathogenesis of neurological disease in coronavirus disease 2019 (COVID-19) may be due to four mechanisms of nervous system dysfunction and injury: i) direct viral neurological invasion; ii) immune dysregulation; iii) endothelial dysfunction and coagulopathy; and iv) severe systemic COVID-19 disease.
  • Neurological manifestations of acute COVID-19 include headache, peripheral neuropathies, seizures, encephalitis, Guillain–Barré syndrome, and cerebrovascular disease.
  • Commonly reported long term neurological sequelae of COVID-19 are cognitive dysfunction and dysautonomia, which despite being associated with severe acute disease are also seen in people with mild disease.
  • Assessment of cognitive dysfunction after COVID-19 is confounded by a high prevalence of comorbid fatigue, anxiety, and mood disorders. However, other markers of neuroaxonal breakdown suggest no significant neuronal injury apart from during severe acute COVID-19.
  • The long term impact of COVID-19 on neurological diseases remains uncertain and requires ongoing vigilance.

Source: Wesselingh, R. (2023), Prevalence, pathogenesis and spectrum of neurological symptoms in COVID-19 and post-COVID-19 syndrome: a narrative review. Med J Aust. https://doi.org/10.5694/mja2.52063 https://onlinelibrary.wiley.com/doi/10.5694/mja2.52063 (Full text available as PDF file)

 

Evaluation of Post–COVID-19 Cognitive Dysfunction: Recommendations for Researchers

Opinion:

SARS-CoV-2 infection is associated with increased rates of postillness cognitive dysfunction, colloquially referred to as “brain fog,”1 that may portend significant consequences for patient functioning and quality of life. Post–COVID-19 cognitive dysfunction is 1 of approximately 200 symptoms of post–COVID-19 condition (PCC), defined by the World Health Organization as developing within 3 months of an initial SARS-CoV-2 infection, lasting at least 2 months, and cannot be explained by an alternative diagnosis. A pooled analysis of 54 studies and 1.2 million individuals found that 3.2% of patients’ self-reported cognitive problems 3 months after symptomatic infection,1 while other studies have shown objective evidence of cognitive dysfunction in approximately 24% of patients nearly 1 year later.2 Accumulating evidence also supports the hypothesis that COVID-19 may increase risk for later neurodegeneration3 and exacerbate preexisting cognitive dysfunction.4 As one of the most common symptoms of PCC and one for which affected individuals may seek accommodations and disability benefits in accordance with the Americans With Disabilities Act, it is imperative that we use more rigorous studies of cognitive outcomes. Accordingly, the following recommendations have been generated by members of the NeuroCOVID International Neuropsychology Taskforce based on initial guidelines.5

Source: Jaqueline H. Becker, PhD; Tracy D. Vannorsdall, PhD; Sara L. Weisenbach, PhD. JAMA Psychiatry. Published online August 16, 2023. doi:10.1001/jamapsychiatry.2023.2820 https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2808155

Post-COVID cognitive dysfunction: current status and research recommendations for high risk population

Abstract:

Post-COVID cognitive dysfunction (PCCD) is a condition in which patients with a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, usually three months from the onset, exhibit subsequent cognitive impairment in various cognitive domains, and cannot be explained by an alternative diagnosis.

While our knowledge of the risk factors and management strategy of PCCD is still incomplete, it is necessary to integrate current epidemiology, diagnosis and treatment evidence, and form consensus criteria to better understand this disease to improve disease management. Identifying the risk factors and vulnerable population of PCCD and providing reliable strategies for effective prevention and management is urgently needed.

In this paper, we reviewed epidemiology, diagnostic markers, risk factors and available treatments on the disease, formed research recommendation framework for vulnerable population, under the background of post-COVID period.

Source: Quan M, Wang X, Gong M, Wang Q, Li Y, Jia J. Post-COVID cognitive dysfunction: current status and research recommendations for high risk population. Lancet Reg Health West Pac. 2023 Jul 5;38:100836. doi: 10.1016/j.lanwpc.2023.100836. PMID: 37457901; PMCID: PMC10344681. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344681/ (Full text)