Tag: cognitive impairment

Blood-brain barrier penetration of non-replicating SARS-CoV-2 and S1 variants of concern induce neuroinflammation which is accentuated in a mouse model of Alzheimer’s disease

Highlights:

• Two models of SARS-CoV-2 and all S1 protein Variants of Concern readily cross the BBB.
• The SARS-CoV-2 pseudovirus is taken up by microglia and induce neuroinflammation.
• The S1-induced neuroinflammation is exacerbated in a mouse model of Alzheimer’s disease.

Abstract:

COVID-19 and especially Long COVID are associated with severe CNS symptoms and may place persons at risk to develop long-term cognitive impairments. Here, we show that two non-infective models of SARS-CoV-2 can cross the blood–brain barrier (BBB) and induce neuroinflammation, a major mechanism underpinning CNS and cognitive impairments, even in the absence of productive infection. The viral models cross the BBB by the mechanism of adsorptive transcytosis with the sugar N-acetylglucosamine being key. The delta and omicron variants cross the BB B faster than the other variants of concern, with peripheral tissue uptake rates also differing for the variants. Neuroinflammation induced by icv injection of S1 protein was greatly enhanced in young and especially in aged SAMP8 mice, a model of Alzheimer’s disease, whereas sex and obesity had little effect.

Source: Erickson MA, Logsdon AF, Rhea EM, Hansen KM, Holden SJ, Banks WA, Smith JL, German C, Farr SA, Morley JE, Weaver RR, Hirsch AJ, Kovac A, Kontsekova E, Baumann KK, Omer MA, Raber J. Blood-brain barrier penetration of non-replicating SARS-CoV-2 and S1 variants of concern induce neuroinflammation which is accentuated in a mouse model of Alzheimer’s disease. Brain Behav Immun. 2023 Jan 20;109:251-268. doi: 10.1016/j.bbi.2023.01.010. Epub ahead of print. PMID: 36682515; PMCID: PMC9867649. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9867649/ (Full text)

Cognitive impairments among patients in a long-COVID clinic: Prevalence, pattern and relation to illness severity, work function and quality of life

Abstract:

Background: A considerable proportion of people experience lingering symptoms after Coronavirus Disease 2019 (COVID-19). The aim of this study was to investigate the frequency, pattern and functional implications of cognitive impairments in patients at a long-COVID clinic who were referred after hospitalisation with COVID-19 or by their general practitioner.

Methods: Patients underwent cognitive screening and completed questionnaires regarding subjective cognition, work function and quality of life. Patients’ cognitive performance was compared with that of 150 age-, sex-, and education-matched healthy controls (HC) and with their individually expected performance calculated based on their age, sex and education.

Results: In total, 194 patients were assessed, on average 7 months (standard deviation: 4) after acute COVID-19.44-53 % of the patients displayed clinically relevant cognitive impairments compared to HC and to their expected performance, respectively. Moderate to large impairments were seen in global cognition and in working memory and executive function, while mild to moderate impairments occurred in verbal fluency, verbal learning and memory. Hospitalised (n = 91) and non-hospitalised (n = 103) patients showed similar degree of cognitive impairments in analyses adjusted for age and time since illness. Patients in the cognitively impaired group were older, more often hospitalised, had a higher BMI and more frequent asthma, and were more often female. More objective cognitive impairment was associated with more subjective cognitive difficulties, poorer work function and lower quality of life.

Limitations: The study was cross-sectional, which precludes causality inferences.

Conclusions: These findings underscore the need to assess and treat cognitive impairments in patients at long-COVID clinics.

Source: Miskowiak KW, Pedersen JK, Gunnarsson DV, Roikjer TK, Podlekareva D, Hansen H, Dall CH, Johnsen S. Cognitive impairments among patients in a long-COVID clinic: Prevalence, pattern and relation to illness severity, work function and quality of life. J Affect Disord. 2022 Dec 28;324:162-169. doi: 10.1016/j.jad.2022.12.122. Epub ahead of print. PMID: 36586593; PMCID: PMC9795797. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9795797/ (Full text)

Cognitive Impairment after Post-Acute COVID-19 Infection: A Systematic Review of the Literature

Abstract:

The present study aims to provide a critical overview of the literature on the relationships between post-acute COVID-19 infection and cognitive impairment, highlighting the limitations and confounding factors. A systematic search of articles published from 1 January 2020 to 1 July 2022 was performed in PubMed/Medline. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only studies using validated instruments for the assessment of cognitive impairment were included. Out of 5515 screened records, 72 studies met the inclusion criteria.

The available evidence revealed the presence of impairment in executive functions, speed of processing, attention and memory in subjects recovered from COVID-19. However, several limitations of the literature reviewed should be highlighted: most studies were performed on small samples, not stratified by severity of disease and age, used as a cross-sectional or a short-term longitudinal design and provided a limited assessment of the different cognitive domains. Few studies investigated the neurobiological correlates of cognitive deficits in individuals recovered from COVID-19. Further studies with an adequate methodological design are needed for an in-depth characterization of cognitive impairment in individuals recovered from COVID-19.

Source: Perrottelli A, Sansone N, Giordano GM, Caporusso E, Giuliani L, Melillo A, Pezzella P, Bucci P, Mucci A, Galderisi S. Cognitive Impairment after Post-Acute COVID-19 Infection: A Systematic Review of the Literature. J Pers Med. 2022 Dec 15;12(12):2070. doi: 10.3390/jpm12122070. PMID: 36556290; PMCID: PMC9781311. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9781311/ (Full text)

Brain fog as a Long-term Sequela of COVID-19

Abstract:

Increasing data indicate that people infected with COVID-19 are at high risk for developing long-term neurological complications, such as “brain fog” or cognitive impairment. However, little is known about the long-term outcomes of COVID-19 survivors. This also applies to the prevalence, risk factors, and pathobiological findings associated with these consequences. Although cognitive complications are anticipated in patients who require a long-lasting hospital stay or intubation, milder cases of COVID-19 with no record of hospitalization have also been shown to experience assessable cognitive challenges. Cognitive impairment can have a devastating impact on daily functioning. Understanding the long-term effect of COVID-19 on cognitive function is vital for applying specific schemes to those who wish to return to their jobs productively.

Source: Nouraeinejad A. Brain fog as a Long-term Sequela of COVID-19. SN Compr Clin Med. 2023;5(1):9. doi: 10.1007/s42399-022-01352-5. Epub 2022 Nov 24. PMID: 36466122; PMCID: PMC9685075. https://link.springer.com/article/10.1007/s42399-022-01352-5 (Full text)

SARS-CoV-2 promotes microglial synapse elimination in human brain organoids

Abstract:

Neuropsychiatric manifestations are common in both the acute and post-acute phase of SARS-CoV-2 infection, but the mechanisms of these effects are unknown. In a newly established brain organoid model with innately developing microglia, we demonstrate that SARS-CoV-2 infection initiate neuronal cell death and cause a loss of post-synaptic termini. Despite limited neurotropism and a decelerating viral replication, we observe a threefold increase in microglial engulfment of postsynaptic termini after SARS-CoV-2 exposure.

We define the microglial responses to SARS-CoV-2 infection by single cell transcriptomic profiling and observe an upregulation of interferon-responsive genes as well as genes promoting migration and synapse engulfment. To a large extent, SARS-CoV-2 exposed microglia adopt a transcriptomic profile overlapping with neurodegenerative disorders that display an early synapse loss as well as an increased incident risk after a SARS-CoV-2 infection. Our results reveal that brain organoids infected with SARS-CoV-2 display disruption in circuit integrity via microglia-mediated synapse elimination and identifies a potential novel mechanism contributing to cognitive impairments in patients recovering from COVID-19.

Source: Samudyata, Oliveira AO, Malwade S, Rufino de Sousa N, Goparaju SK, Gracias J, Orhan F, Steponaviciute L, Schalling M, Sheridan SD, Perlis RH, Rothfuchs AG, Sellgren CM. SARS-CoV-2 promotes microglial synapse elimination in human brain organoids. Mol Psychiatry. 2022 Oct 5:1–12. doi: 10.1038/s41380-022-01786-2. Epub ahead of print. PMID: 36198765; PMCID: PMC9533278.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9533278/ (Full text)

Cognitive Complications of COVID-19 Infection

Abstract:

SARS-CoV-2 is associated with a post-infectious neurocognitive syndrome characterized by fatigue and deficits in attention, memory, and executive function. As screening cognitive testing generally remains normal, the pathophysiologic basis of these symptoms remains controversial and there is no standardized treatment paradigm.

We present a clinical case demonstrative of typical neurocognitive sequelae of SARS-CoV-2 infection, highlighting medical and social factors that may have contributed to the severity of symptoms. We discuss the pathophysiologic evidence for cognitive “brain fog” following COVID-19 infection as well as lifestyle changes and rehabilitation strategies that may improve recovery. As the benefits of pharmacologic therapy remain unproven, we close with a brief discussion of medication options that might be appropriate targets for future clinical trials in the context of rehabilitative treatment.

Source: Warren S, Drake J, Wu CK. Cognitive Complications of COVID-19 Infection. R I Med J (2013). 2022 Sep 1;105(7):27-30. PMID: 35930487. https://pubmed.ncbi.nlm.nih.gov/35930487/ http://rimed.org/rimedicaljournal/2022/09/2022-09-27-covid-warren.pdf  (Full text available as PDF file)

Cognitive task performance and subjective cognitive symptoms in individuals with Chronic Fatigue Syndrome or Fibromyalgia: A cross-sectional analysis of the Lifelines cohort study

Abstract:

Objective: This study examined cognitive task performance and self-reported cognitive functioning in individuals with chronic fatigue syndrome (CFS) and fibromyalgia (FM) in a population-based sample and investigated the role of mood and anxiety disorders as well as severity of the physical symptoms.

Methods: This study was performed in 79,966 participants (Mean age: 52.9, SD = ±12.6 years, 59.2% women) from the Lifelines general-population. Symptoms consistent with the diagnostic criteria for CFS and FM were assessed using questionnaires. Two comparison groups were used: participants with self-reported medical disorders with well-defined pathophysiology (i.e., multiple sclerosis and rheumatic arthritis) and controls without these diseases. Objective task-performance was based on the computerized CogState cognitive battery and subjective cognitive symptoms using the concentration subscale of the Checklist Individual Strength.

Results: Cognitive task performance was poorer in individuals with CFS vs. controls without disease and controls with a medical disorder, although the severity of cognitive dysfunction was mild. Participants meeting criteria for CFS (n = 2,461) or FM (n = 4,295) reported more subjective cognitive symptoms compared to controls without a medical disorder (d = 1.53, 95%CI = 1.49-1.57 for CFS; d = 1.25, 95%CI = 1.22-1.29 for FM) and participants with a medical disease (d = 0.62, 95%CI = 0.46-0.79 for CFS; d = 0.75, 95%CI = 0.70-0.80 for FM). These differences remained essentially the same when excluding participants with comorbid mood or anxiety disorders or adjusting for physical symptom severity.

Conclusions: Subjective cognitive symptoms and to a lesser extent suboptimal cognitive task performance are more prevalent in individuals with CFS or FM compared to controls without these conditions.

Source: Joustra ML, Hartman CA, Bakker SJL, Rosmalen JGM. Cognitive task performance and subjective cognitive symptoms in individuals with Chronic Fatigue Syndrome or Fibromyalgia: A cross-sectional analysis of the Lifelines cohort study. Psychosom Med. 2022 Aug 2. doi: 10.1097/PSY.0000000000001117. Epub ahead of print. PMID: 35980775.  https://pubmed.ncbi.nlm.nih.gov/35980775/

High-density EEG sleep correlates of cognitive and affective impairment at 12-month follow-up after COVID-19

Abstract:

Objective: To disentangle the pathophysiology of cognitive/affective impairment in Coronavirus Disease-2019 (COVID-19), we studied long-term cognitive and affective sequelae and sleep high-density electroencephalography (EEG) at 12-month follow-up in people with a previous hospital admission for acute COVID-19.

Methods: People discharged from an intensive care unit (ICU) and a sub-intensive ward (nonICU) between March and May 2020 were contacted between March and June 2021. Participants underwent cognitive, psychological, and sleep assessment. High-density EEG recording was acquired during a nap. Slow and fast spindles density/amplitude/frequency and source reconstruction in brain gray matter were extracted. The relationship between psychological and cognitive findings was explored with Pearson correlation.

Results: We enrolled 33 participants ( 17 nonICU) and 12 controls. We observed a lower Physical Quality of Life index, higher post-traumatic stress disorder (PTSD) score, and a worse executive function performance in nonICU participants. Higher PTSD and Beck Depression Inventory scores correlated with lower executive performance. The same group showed a reorganization of spindle cortical generators.

Conclusions: Our results show executive and psycho-affective deficits and spindle alterations in COVID-19 survivors – especially in nonICU participants – after 12 months from discharge.

Significance: These findings may be suggestive of a crucial contribution of stress experienced during hospital admission on long-term cognitive functioning.

Source: Rubega M, Ciringione L, Bertuccelli M, Paramento M, Sparacino G, Vianello A, Masiero S, Vallesi A, Formaggio E, Del Felice A. High-density EEG sleep correlates of cognitive and affective impairment at 12-month follow-up after COVID-19. Clin Neurophysiol. 2022 Jun 15;140:126-135. doi: 10.1016/j.clinph.2022.05.017. Epub ahead of print. PMID: 35763985; PMCID: PMC9292469. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9292469/ (Full text)

Study on the active components and mechanism of Suanzaoren decoction in improving cognitive impairment caused by sleep deprivation

Abstract:

Ethnopharmacological relevance: Suanzaoren Decoction (SZRD) is a traditional and classic prescription for the treatment of insomnia, with a history of more than 1,000 years. It replenishes blood components, calms the nerves, reduces fever and irritability. It is commonly used in the clinical treatment of chronic fatigue syndrome, cardiac neurosis, and menopausal syndromes. Modern pharmacological studies have shown that it improves cognitive impairment; however, its mechanism of action remains unclear.

Aim of the study: This study preliminarily investigated the potential bioactive components and mechanism of SZRD in improving cognitive impairment by exploring network pharmacology, molecular docking, and conducting in vivo experiments.

Materials and methods: The components of various Chinese herbs in SZRD and their disease-related targets were identified through network pharmacology and literature. Gene ontology (GO) function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of intersection targets were performed using the relevant database. Next, the “Components-Targets-Pathways” (C-T-P) and “Protein-Protein interaction” networks were constructed using the enrichment analysis results to further identify potential pathways, bioactive components, and hub genes. At the same time, molecular docking was used to further distinguish the key bioactive components and genes of SZRD responsible for improving cognitive impairment. Finally, the potential mechanism of action was further analysed and verified using in vivo experiments.

Results: A total of 117 potential active components and 138 intersection targets were identified by network pharmacology screening. The key bioactive components, including calycosin, 5-Prenylbutein, licochalcone G, glypallichalcone, and ZINC189892, were identified by analysing the networks and molecular docking results. Hub genes included ACHE, CYP19A1, EGFR, ESR1, and ESR2. The oestrogen signalling pathway was the most important in the enrichment analysis. In vivo experiments further proved that SZRD could improve cognitive impairment by affecting the oestrogen signalling pathway and the expression of ACHE and CYP19A1.

Conclusions: Network pharmacology and in vivo experiments demonstrate that SZRD improves cognitive impairment caused by sleep disturbance through estrogen receptor pathway, which provides a basis for its clinical application.

Source: Cheng L, Wang F, Li ZH, Wen C, Ding L, Zhang SB, You QY. Study on the active components and mechanism of Suanzaoren decoction in improving cognitive impairment caused by sleep deprivation. J Ethnopharmacol. 2022 Jun 28:115502. doi: 10.1016/j.jep.2022.115502. Epub ahead of print. PMID: 35777606. https://www.sciencedirect.com/science/article/abs/pii/S0378874122005414 (Full text)

Comprehensive clinical assessment identifies specific neurocognitive deficits in working-age patients with long-COVID

Abstract:

Introduction: There have been more than 425 million COVID-19 infections worldwide. Post-COVID illness has become a common, disabling complication of this infection. Therefore, it presents a significant challenge to global public health and economic activity.

Methods: Comprehensive clinical assessment (symptoms, WHO performance status, cognitive testing, CPET, lung function, high-resolution CT chest, CT pulmonary angiogram and cardiac MRI) of previously well, working-age adults in full-time employment was conducted to identify physical and neurocognitive deficits in those with severe or prolonged COVID-19 illness.

Results: 205 consecutive patients, age 39 (IQR30.0-46.7) years, 84% male, were assessed 24 (IQR17.1-34.0) weeks after acute illness. 69% reported ≥3 ongoing symptoms. Shortness of breath (61%), fatigue (54%) and cognitive problems (47%) were the most frequent symptoms, 17% met criteria for anxiety and 24% depression. 67% remained below pre-COVID performance status at 24 weeks. One third of lung function tests were abnormal, (reduced lung volume and transfer factor, and obstructive spirometry). HRCT lung was clinically indicated in <50% of patients, with COVID-associated pathology found in 25% of these. In all but three HRCTs, changes were graded ‘mild’. There was an extremely low incidence of pulmonary thromboembolic disease or significant cardiac pathology. A specific, focal cognitive deficit was identified in those with ongoing symptoms of fatigue, poor concentration, poor memory, low mood, and anxiety. This was notably more common in patients managed in the community during their acute illness.

Conclusion: Despite low rates of residual cardiopulmonary pathology, in this cohort, with low rates of premorbid illness, there is a high burden of symptoms and failure to regain pre-COVID performance 6-months after acute illness. Cognitive assessment identified a specific deficit of the same magnitude as intoxication at the UK drink driving limit or the deterioration expected with 10 years ageing, which appears to contribute significantly to the symptomatology of long-COVID.

Source: Holdsworth DA, Chamley R, Barker-Davies R, O’Sullivan O, Ladlow P, Mitchell JL, Dewson D, Mills D, May SLJ, Cranley M, Xie C, Sellon E, Mulae J, Naylor J, Raman B, Talbot NP, Rider OJ, Bennett AN, Nicol ED. Comprehensive clinical assessment identifies specific neurocognitive deficits in working-age patients with long-COVID. PLoS One. 2022 Jun 10;17(6):e0267392. doi: 10.1371/journal.pone.0267392. PMID: 35687603; PMCID: PMC9187094. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187094/ (Full text)