Cognitive impairment after Long COVID-19: Current Evidence and Perspectives

Abstract:

COVID-19 is a respiratory infectious disease caused by the SARS-CoV-2 virus. Most patients recover after treatment, but COVID-19 treatment may lead to cognitive impairment. Recent studies have found that some recoverers experience cognitive impairments such as decreased memory and attention, and sleep disorder, indicating that COVID-19 may have longerterm effects on cognitive function.

Studies have found that COVID-19 may cause cognitive decline by damaging key brain regions such as the hippocampus and anterior cingulate cortex. Studies have also found that COVID-19 patients have active neuroinflammation, mitochondrial dysfunction, and microglial activation, suggesting that neuroinflammation, mitochondrial stress, and neurodegenerative changes may be potential mechanisms leading to cognitive impairment.

In summary, the possibility of cognitive impairment after COVID-19 treatment deserves close attention. Large-scale follow-up studies will help further explore the impact of COVID-19 on cognitive function and provide evidence to support clinical treatment and rehabilitation practices. Neuropathological and biological studies can explore precise mechanisms in-depth and provide a theoretical basis for prevention, treatment, and intervention research.

Given the risks of long-term COVID-19 and reinfection, it is necessary to integrate basic and clinical research data to maximize the maintenance of patient’s cognitive function and life quality. This also provides important experience in responding to similar public health events. This article integrates clinical and basic evidence of cognitive impairment after COVID-19 and discusses potential mechanisms and future research directions.

Source: Zhi-Tao Li, ZHANG ZHEN, Zhuoya Zhang, Zhi-Yong Wang, Hao Li. Cognitive impairment after Long COVID-19: Current Evidence and Perspectives. Front. Neurol. Sec. Neuroinfectious Diseases. Volume 14 – 2023 | doi: 10.3389/fneur.2023.1239182 https://www.frontiersin.org/articles/10.3389/fneur.2023.1239182/abstract

Evaluation of Outpatients in the Post-COVID-19 Period in Terms of Autonomic Dysfunction and Silent Ischemia

Abstract:

Introduction and objective: In this context, the objective of this study is to evaluate the 24-hour ambulatory electrocardiography (ECG) recordings, autonomous function with heart rate variability (HRV), and silent ischemia (SI) attacks with ST depression burden (SDB) and ST depression time (SDT) of post-COVID-19 patients. Materials and methods: The 24-hour ambulatory ECG recordings obtained >12 weeks after the diagnosis of COVID-19 were compared between 55 consecutive asymptomatic and 73 symptomatic post-COVID-19 patients who applied to the cardiology outpatient clinic with complaints of palpitation and chest pain in comparison with asymptomatic post-COVID-19 patients in Kars Harakani state hospital. SDB, SDT, and HRV parameters were analyzed. Patients who had been on medication that might affect HRV, had comorbidities that might have caused coronary ischemia, and were hospitalized with severe COVID-19 were excluded from the study.

Results: There was no significant difference between symptomatic and asymptomatic post-COVID-19 patients in autonomic function. On the other hand, SDB and SDT parameters were significantly higher in symptomatic post-COVID-19 patients than in asymptomatic post-COVID-19 patients. Multivariate analysis indicated that creatine kinase-myoglobin binding (CK-MB) (OR:1.382, 95% CI:1.043-1.831; p=0.024) and HRV index (OR: 1.033, 95% CI:1.005-1.061; p=0.019) were found as independent predictors of palpitation and chest pain symptoms in post-COVID-19 patients.

Conclusion: The findings of this study revealed that parasympathetic overtone and increased HRV were significantly higher in symptomatic patients with a history of COVID-19 compared to asymptomatic patients with a history of COVID-19 in the post-COVID-19 period. Additionally, 24-hour ambulatory ECG recordings and ST depression analysis data indicated that patients who experienced chest pain in the post-COVID-19 period experienced silent ischemia (SI) attacks.

Source: Karakayalı M, Artac I, Ilis D, Omar T, Rencuzogullari I, Karabag Y, Altunova M, Arslan A, Guzel E. Evaluation of Outpatients in the Post-COVID-19 Period in Terms of Autonomic Dysfunction and Silent Ischemia. Cureus. 2023 Jun 11;15(6):e40256. doi: 10.7759/cureus.40256. PMID: 37440812; PMCID: PMC10335598. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10335598/ (Full text)

The effect of nirmatrelvir-ritonavir on the long-term risk of neuropsychiatric sequelae following COVID-19

Abstract:

The retrospective cohort was conducted to assess the effect of nirmatrelvir-ritonavir (NMV-r) on the long-term risk of neuropsychiatric sequela following COVID-19. TriNetX research network was used to identify nonhospitalized adult patients who tested positive for severe acute respiratory syndrome coronavirus 2 infection or were diagnosed with COVID-19 between March 1, 2020 and July 1, 2022. Further propensity score matching method was used to create two matched cohorts with and without receiving NMV-r.

The primary outcome was the incidence of neuropsychiatric sequela within a 90-day to 1-year period following a diagnosis of COVID-19. After screening 119 494 527 electronic health records, two matched cohorts of each 27 194 patients were identified. During the follow-up period, the NMV-r group demonstrated a reduced risk of any neuropsychiatric sequelae compared to the control group (odds ratio [OR], 0.634; 95% confidence interval [CI], 0.604-0.667).

In comparison with the control group, the patient treated with NMV-r exhibited a markedly diminished risk of developing neurocognitive sequela (OR, 0.377; 95% CI, 0.325-0.439) and psychiatric sequela (OR, 0.629; 95% CI, 0.593-0.666). In addition, patients treated with NMV-r had a significantly reduced risk of developing dementia (OR, 0.365; 95% CI, 0.255-0.522), depression (OR, 0.555; 95% CI, 0.503-0.612), insomnia (OR, 0.582; 95% CI, 0.508-0.668) and anxiety disorder (OR, 0.645 95% CI, 0.600-0.692). Moreover, the beneficial effect of NMV-r on the neuropsychiatric sequelae was observed across further subgroup analyses.

Among nonhospitalized COVID-19 patients, who at risk of disease progression, the use of NMV-r is associated with a reduction in the long-term risk of neuropsychiatric sequela, including dementia, depression, insomnia and anxiety disorder. It may be necessary to re-evaluate the use of NMV-r, as a preventive measure to reduce the risk of severe acute disease and post-acute adverse mental health outcomes.

Source: Liu TH, Wu JY, Huang PY, Tsai YW, Lai CC. The effect of nirmatrelvir-ritonavir on the long-term risk of neuropsychiatric sequelae following COVID-19. J Med Virol. 2023 Jul;95(7):e28951. doi: 10.1002/jmv.28951. PMID: 37436873. https://pubmed.ncbi.nlm.nih.gov/37436873/

SARS-CoV-2 post-acute sequelae in previously hospitalised patients: systematic literature review and meta-analysis

Abstract:

Background: Many individuals hospitalised with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection experience post-acute sequelae of SARS-CoV-2 infection (PASC), sometimes referred to as “long COVID”. Our objective was to conduct a systematic literature review and meta-analysis to identify PASC-associated symptoms in previously hospitalised patients and determine the frequency and temporal nature of PASC.

Methods: Searches of MEDLINE, Embase, Cochrane Library (2019-2021), World Health Organization International Clinical Trials Registry Platform and reference lists were performed from November to December 2021. Articles were assessed by two reviewers against eligibility criteria and a risk of bias tool. Symptom data were synthesised by random effects meta-analyses.

Results: Of 6942 records, 52 studies with at least 100 patients were analysed; ∼70% were Europe-based studies. Most data were from the first wave of the pandemic. PASC symptoms were analysed from 28 days after hospital discharge. At 1-4 months post-acute SARS-CoV-2 infection, the most frequent individual symptoms were fatigue (29.3% (95% CI 20.1-40.6%)) and dyspnoea (19.6% (95% CI 12.8-28.7%)). Many patients experienced at least one symptom at 4-8 months (73.1% (95% CI 44.2-90.3%)) and 8-12 months (75.0% (95% CI 56.4-87.4%)).

Conclusions: A wide spectrum of persistent PASC-associated symptoms were reported over the 1-year follow-up period in a significant proportion of participants. Further research is needed to better define PASC duration and determine whether factors such as disease severity, vaccination and treatments have an impact on PASC.

Source: Kelly JD, Curteis T, Rawal A, Murton M, Clark LJ, Jafry Z, Shah-Gupta R, Berry M, Espinueva A, Chen L, Abdelghany M, Sweeney DA, Quint JK. SARS-CoV-2 post-acute sequelae in previously hospitalised patients: systematic literature review and meta-analysis. Eur Respir Rev. 2023 Jul 12;32(169):220254. doi: 10.1183/16000617.0254-2022. PMID: 37437914; PMCID: PMC10336551. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10336551/ (Full text)

People with Long Covid and ME/CFS Exhibit Similarly Impaired Balance and Physical Capacity: A Case-Case-Control Study

Abstract:

Purpose: Postural sway and physical capacity had not previously been compared between people with long COVID and people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Therefore, this study determined postural sway and physical capacity in people with long COVID (∼16 month illness duration; n=21) and ME/CFS (∼16 year illness duration; n=20), versus age-matched healthy controls (n=20).

Methods: Postural sway was during a 30 s static stand test. Physical capacity was determined using the timed up and go test and five times sit to stand test. Throughout, participants wore isoinertial measurement units.

Results: Postural sway was worse (i.e. greater) in people with long COVID and ME/CFS than controls, but not different between long COVID and ME/CFS. Performance of the timed up and go test and five times sit to stand test were worse in long COVID and ME/CFS than controls, but not different between long COVID and ME/CFS. 87% and 13% of long COVID and ME/CFS participants exceeded the threshold for muscle weakness in the five times sit to stand test and timed up and go test, respectively.

Conclusions: These data suggest that both people with long COVID and people with ME/CFS have similarly impaired balance and physical capacity. Therefore, there is an urgent need for interventions to target postural sway and physical capacity in people with ME/CFS, and given the current pandemic, people with long COVID.

Source: Lawrence D. Hayes, PhD, Nilihan E.M. Sanal-Hayes, PhD, Marie Mclaughlin, PhD, Ethan C.J. Berry, BSc (Hons), Nicholas F. Sculthorpe, PhD. People with Long Covid and ME/CFS Exhibit Similarly Impaired Balance and Physical Capacity: A Case-Case-Control Study. The American Journal of Medicine. Published: July 23, 2023 DOI: https://doi.org/10.1016/j.amjmed.2023.06.028 https://www.amjmed.com/article/S0002-9343(23)00465-5/fulltext#%20

A Cross-Sectional Study of Symptom Prevalence, Frequency, Severity, and Impact of Long-COVID in Scotland: Part II

Abstract:

Background: There has been some effort to map the prevalence, frequency, and severity of symptoms of long-COVID at local and national levels. However, what is frequently absent from such accounts is details of the impact the disease and its symptoms have had on those living with the condition. In this manuscript, we present details of impact to work, caring, and mental health gathered using a cross-sectional survey.

Methods: Data were collected using an online survey which was available from 21st April 2022 to 5th August 2022. Included participants had either self-diagnosed or confirmed long-COVID, were living in Scotland, and were ≥18 years old. Hospitalisation during initial COVID-19 infection was an exclusion criterion. Participants were asked to report on the impact of their illness on everyday activities such as working, studying, or caring. They also completed an assessment of their current mood.

Results: People with long-COVID were often severely impacted in their ability to work and study. Severe impact on work and study were predicted by more severe and more frequent fatigue, more severe pain, and more severe cognitive impairment. Respondents’ ability to care for child dependants was also associated with more severe and more frequent fatigue, as well as more severe cognitive impairments. More severe pain associated with greater impact on adult care. Negative mood correlated most strongly with frequency and severity of neurological symptoms, including lack of attention, loss of smell, impaired sense of smell, loss of taste, impaired sense of taste, and loss of appetite.

Conclusions: Long-COVID has a significant impact on ability to work, study, and care for dependants. The severity of this impact is associated with specific symptom burden, including fatigue, pain, and cognitive impairment.

Source: Mclaughlin M, Cerexhe L, Macdonald E, Ingram J, Sanal-Hayes NEM, Hayes LD, Meach R, Carless D, Sculthorpe N. A Cross-Sectional Study of Symptom Prevalence, Frequency, Severity, and Impact of Long-COVID in Scotland: Part II. Am J Med. 2023 Jul 19:S0002-9343(23)00461-8. doi: 10.1016/j.amjmed.2023.07.009. Epub ahead of print. PMID: 37478960. https://www.amjmed.com/article/S0002-9343(23)00461-8/fulltext (Full text)

A Cross-Sectional Study of Symptom Prevalence, Frequency, Severity, and Impact of Long-COVID in Scotland: Part I

Abstract:

Background: Commonly reported symptoms of long-COVID may have different patterns of prevalence and presentation across different countries. While some limited data has been reported for the UK, national specificity for Scotland is less clear. We present a cross-sectional survey to examine the symptom prevalence, frequency and severity of long-COVID for people living with the condition in Scotland.

Methods: An online survey was created in the English language and was available between 21st April 2022 and 5th August 2022. Participants were included if they were ≥18 years old, living in Scotland, and had self-diagnosed or confirmed Long-COVID; and excluded if they were hospitalised during their initial infection. Within this article we quantify symptom prevalence, frequency, severity, and duration.

Results: Participants (n=253) reported the most prevalent long-COVID symptoms to be post-exertional malaise (95%), fatigue/tiredness (85%), and cognitive impairment (68%). Fatigue/tiredness, problems with activities of daily living (ADL), and general pain were most frequently occurring, whilst sleep difficulties, problems with ADL, and nausea were the most severe. Scottish Index of Multiple Deprivation associated with symptom number, severity and frequency, while vaccine status, age, sex, and smoking status had limited or no association.

Conclusions: These findings outline the challenges faced for those living with long COVID and highlight the need for longitudinal research to ascertain a better understanding of the condition and its longer-term societal impact.

Source: Mclaughlin M, Cerexhe L, Macdonald E, Ingram J, Sanal-Hayes NEM, Hayes LD, Meach R, Carless D, Sculthorpe N. A Cross-Sectional Study of Symptom Prevalence, Frequency, Severity, and Impact of Long-COVID in Scotland: Part I. Am J Med. 2023 Jul 20:S0002-9343(23)00460-6. doi: 10.1016/j.amjmed.2023.07.004. Epub ahead of print. PMID: 37481021. https://www.amjmed.com/article/S0002-9343(23)00460-6/fulltext (Full text)

Cortical thickness alterations and systemic inflammation define long-COVID patients with cognitive impairment

Abstract:

As the heterogeneity of symptoms is increasingly recognized among long-COVID patients, it appears highly relevant to study potential pathophysiological differences along the different subtypes. Preliminary evidence suggests distinct alterations in brain structure and systemic inflammatory patterns in specific groups of long-COVID patients.

To this end, we analyzed differences in cortical thickness and peripheral immune signature between clinical subgroups based on 3T-MRI scans and signature inflammatory markers in n=120 participants comprising healthy never-infected controls, healthy COVID-19 survivors, and subgroups of long-COVID patients with and without cognitive impairment according to screening with Montreal Cognitive Assessment.

Whole-brain comparison of cortical thickness between the 4 groups was conducted by surface-based morphometry. We identified distinct cortical areas showing a progressive increase in cortical thickness across different groups, starting from healthy individuals who had never been infected with COVID-19, followed by healthy COVID-19 survivors, long-COVID patients without cognitive deficits (MoCA ≥ 26), and finally, long-COVID patients exhibiting significant cognitive deficits (MoCA < 26). These findings highlight the continuum of cortical thickness alterations associated with COVID-19, with more pronounced changes observed in individuals experiencing cognitive impairment (p<0.05, FWE-corrected).

Affected cortical regions covered prefrontal and temporal gyri, insula, posterior cingulate, parahippocampal gyrus, and parietal areas. Additionally, we discovered a distinct immunophenotype, with elevated levels of IL-10, IFNg, and sTREM2 in long-COVID patients, especially in the group suffering from cognitive impairment.

We demonstrate lingering cortical and immunological alterations in healthy and impaired subgroups of COVID-19 survivors. This implies a complex underlying pathomechanism in long-COVID and emphasizes the necessity to investigate the whole spectrum of post-COVID biology to determine targeted treatment strategies targeting specific sub-groups.

Source: Bianca BesteherTonia RocktaeschelAlejandra Patricia GarzaMarlene MachnikJohanna BallezDario Lucas HelbingKatrhin FinkePhilipp ReukenDaniel GuellmarChristian GaserMartin WalterNils OpelIldiko Rita Dunay. Cortical thickness alterations and systemic inflammation define long-COVID patients with cognitive impairment. (Full text available as PDF file)

Post COVID-19 symptoms are common, also among young adults in the general population

Abstract:

Post coronavirus disease-19 (post COVID-19) is mainly studied in clinical populations and less is known about post COVID-19 in a young general population. The aim of the study is to investigate the prevalence and symptoms of post COVID-19 and its potential risk factors in young adults.

Participants from the Swedish population-based birth cohort BAMSE were included (n = 2022, mean age 26.5 years). Post COVID-19 was assessed through a questionnaire and defined as symptoms after confirmed COVID-19 (registry-based or self-reported positive test) lasting for ≥ 2 months. In total, 681 participants had had confirmed COVID-19. Among them, 112 (16.5%) fulfilled the definition of post COVID-19 (17.8% in females, 14.5% in males, p = 0.26).

The most common post COVID-19 symptoms were altered smell and taste (68.8%), dyspnea (33.7%) and fatigue (30.4%). Overall, no major risk factors for post COVID-19 were identified except for being bedbound during COVID-19. However, asthma and rhinitis were associated with the post COVID-19 symptom dyspnea, migraine with altered smell and taste, and lower self-rated health with fatigue. In conclusion, post COVID-19 symptoms are common, also among young adults in the general population. Although not life-threatening, it could have a considerable impact on public health due to the high prevalence and long-term symptoms.

Source: Mogensen I, Ekström S, Hallberg J, Georgelis A, Melén E, Bergström A, Kull I. Post COVID-19 symptoms are common, also among young adults in the general population. Sci Rep. 2023 Jul 12;13(1):11300. doi: 10.1038/s41598-023-38315-2. PMID: 37438424; PMCID: PMC10338459. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10338459/ (Full text)

Fatigue presentation, severity, and related outcomes in a prospective cohort following post-COVID-19 hospitalization in British Columbia, Canada

Abstract:

Introduction: Increasing evidence on long-term health outcomes following SARS CoV-2 infection shows post-viral symptoms can persist for months. These symptoms are often consistent with those of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (ME/CFS). The aim of the present study was to examine the prevalence and outcome predictors of post-viral fatigue and related symptoms 3- and 6-months following symptom onset.

Methods: A prospective cohort of patients hospitalized with Coronavirus disease (COVID-19) (n = 88) were recruited from a Post-COVID-19 Respiratory Clinic (PCRC) in Vancouver, Canada to examine predictors of long-term fatigue and substantial fatigue. Multivariable mixed effects analyses examined the relationship between patient predictors, including pre-existing comorbidities, patient reported outcome measures, and fatigue and substantial fatigue at follow-up.

Results: The number of patients experiencing fatigue or substantial fatigue at 3 months post-infection were 58 (67%) and 14 (16%) respectively. At 6 months these numbers declined to 47 (60%) patients experiencing fatigue and 6 (6%) experiencing substantial fatigue. Adjusted analysis, for sex, age, and time, revealed the number of pre-existing comorbidities to be associated with fatigue (OR 2.21; 95% CI 1.09-4.49; 0.028) and substantial fatigue (OR 1.73; 95% CI 1.06-2.95; 0.033) at 3 months follow-up. Except for shortness of breath, self-care, and follow-up time, all follow-up variables were found to be associated with fatigue and substantial fatigue at 3 months.

Conclusion: Fatigue and substantial fatigue are common after COVID-19 infection but often diminish over time. A significant number of patients continue to exhibit long-term fatigue at 6 months follow-up. Further research is needed to clarify the causality of viral infections in the development and severity of fatigue as a symptom and in meeting post-viral fatigue syndrome or ME/CFS diagnostic criteria.

Source: Magel T, Meagher E, Boulter T, Albert A, Tsai M, Muñoz C, Carlsten C, Johnston J, Wong AW, Shah A, Ryerson C, Mckay RJ, Nacul L. Fatigue presentation, severity, and related outcomes in a prospective cohort following post-COVID-19 hospitalization in British Columbia, Canada. Front Med (Lausanne). 2023 Jun 29;10:1179783. doi: 10.3389/fmed.2023.1179783. PMID: 37457578; PMCID: PMC10344448. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10344448/ (Full text)