Tag: cognitive impairment

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)

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)

Impact of sleep disruption on cognitive function in patients with post-acute 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 post-acute 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 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 post-acute sequelae of SARS-CoV-2 infection: Initial findings from a Neuro-COVID-19 clinic, SLEEP Advances, 2024;, zpae002, https://doi.org/10.1093/sleepadvances/zpae002 https://academic.oup.com/sleepadvances/advance-article/doi/10.1093/sleepadvances/zpae002/7517273 (Full text available as PDF file)

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)