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)

COVID-19 induces CNS cytokine expression and loss of hippocampal neurogenesis

Abstract:

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with acute and postacute cognitive and neuropsychiatric symptoms including impaired memory, concentration, attention, sleep and affect. Mechanisms underlying these brain symptoms remain understudied.

Here we report that SARS-CoV-2-infected hamsters exhibit a lack of viral neuroinvasion despite aberrant blood-brain barrier permeability. Hamsters and patients deceased from coronavirus disease 2019 (COVID-19) also exhibit microglial activation and expression of interleukin (IL)-1β and IL-6, especially within the hippocampus and the medulla oblongata, when compared with non-COVID control hamsters and humans who died from other infections, cardiovascular disease, uraemia or trauma. In the hippocampal dentate gyrus of both COVID-19 hamsters and humans, we observed fewer neuroblasts and immature neurons.

Protracted inflammation, blood-brain barrier disruption and microglia activation may result in altered neurotransmission, neurogenesis and neuronal damage, explaining neuropsychiatric presentations of COVID-19. The involvement of the hippocampus may explain learning, memory and executive dysfunctions in COVID-19 patients.

Source: Soung AL, Vanderheiden A, Nordvig AS, Sissoko CA, Canoll P, Mariani MB, Jiang X, Bricker T, Rosoklija GB, Arango V, Underwood M, Mann JJ, Dwork AJ, Goldman JE, Boon ACM, Boldrini M, Klein RS. COVID-19 induces CNS cytokine expression and loss of hippocampal neurogenesis. Brain. 2022 Aug 25:awac270. doi: 10.1093/brain/awac270. Epub ahead of print. PMID: 36004663. https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awac270/6672950?login=false  (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)

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)

Associations Between Psychological and Immunological Variables in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Systematic Review

Abstract:

Background: Little emphasis has been given to the fact that various psychological processes and behaviors in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) have neural correlates that affect-and are affected by-the immune system. The aim of this paper is to provide a systematic review of the literature on cross-sectional and longitudinal associations between psychological and immunological variables/changes in CFS/ME.

Methods: The systematic literature search was conducted on Dec 10, 2020 using PubMed. Original research studies investigating associations between a predefined set of psychological and immunological variables in CFS/ME were included. Specifically, the review was focused on studies examining the following psychological variables: executive function, emotion regulation, interpersonal function, sleep, mental health, anxiety, depression, and/or other psychiatric symptoms. In terms of immunological variables, studies investigating interleukin (IL)-1, IL-2, IL-4, IL-6, tumor necrosis factor (TNF), CD4+, and/or CD8+ were included. Besides original research papers, other potentially relevant papers (e.g., literature reviews) were carefully read and reference lists were checked in order to identify any additional relevant studies. Available data was summarized in text and tables.

Results: The literature search identified 897 potentially relevant papers. Ultimately, 14 studies (807 participants in total) were included in the review of which only two were longitudinal in nature. The review indicated that executive function is associated with IL-1 and IL-6, and interpersonal function is associated with IL-6 and TNF-α. Further, the available data suggested that emotion regulation is associated with IL-2 and sleep is associated with IL-1, IL-6, TNF-α, and IL-2. Interestingly, poorer emotion regulation, interpersonal function, and sleep have all been found to be associated with higher cytokine levels. Executive function has shown both positive and negative relationships with cytokines and among these psychological constructs, it is also the only one that has been found to be associated with CD4+ and CD8+ counts/percentages.

Conclusions: Correlations exist between psychological and immunological variables in CFS/ME. However, there are few consistent findings and there is almost a complete lack of longitudinal studies. This review points to a gap in existing CFS/ME research and hopefully, it will inspire to the generation of innovative, psychoneuroimmunological hypotheses within the CFS/ME research field.

Source: Raanes EFW, Stiles TC. Associations Between Psychological and Immunological Variables in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Systematic Review. Front Psychiatry. 2021 Nov 23;12:716320. doi: 10.3389/fpsyt.2021.716320. PMID: 34887782; PMCID: PMC8650213.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8650213/  (Full text)

Working memory deficits associated with chronic fatigue syndrome

Abstract:

Cognitive impairments are among the most frequently reported and least investigated components of the chronic fatigue syndrome (CFS). As part of a multifaceted study of the CFS, the present study investigated the cognitive functioning of chronic fatigue patients.

The performance of 20 CFS patients was compared to that of controls (N = 20) on 4 tests of working memory (WM). Digit Span Forward was used to assess the storage capacity of WM. Multiple aspects of central executive functioning were assessed using several standard measures: Digit Span Backward, and Trails A and Trails B. More recently developed measures of WM were used to assess control of processing under temporal demands (working memory task) and resistance to interference (a sustained attention task).

Deficits were restricted to more demanding tasks, requiring resistance to interference and efficient switching between processing routines. The overall results clearly implicate deficits in the control aspects of central executive function in CFS.

 

Source: Dobbs BM, Dobbs AR, Kiss I. Working memory deficits associated with chronic fatigue syndrome. J Int Neuropsychol Soc. 2001 Mar;7(3):285-93. http://www.ncbi.nlm.nih.gov/pubmed/11311029

 

Memory, attention, and executive function in chronic fatigue syndrome

Abstract:

OBJECTIVES: To examine cognitive function in chronic fatigue syndrome.

METHODS: Twenty patients with chronic fatigue syndrome recruited from primary care and 20 matched normal controls were given CANTAB computerised tests of visuospatial memory, attention, and executive function, and verbal tests of letter and category fluency and word association learning.

RESULTS: Patients with chronic fatigue syndrome were impaired, predominantly in the domain of memory but their pattern of performance was unlike that of patients with amnesic syndrome or dementia. They were normal on tests of spatial pattern recognition memory, simultaneous and delayed matching to sample, and pattern-location association learning. They were impaired on tests of spatial span, spatial working memory, and a selective reminding condition of the pattern-location association learning test. An executive test of planning was normal. In an attentional test, eight subjects with chronic fatigue syndrome were unable to learn a response set; the remainder exhibited no impairment in the executive set shifting phase of the test. Patients with chronic fatigue syndrome were also impaired on verbal tests of unrelated word association learning and letter fluency.

CONCLUSION: Patients with chronic fatigue syndrome have reduced attentional capacity resulting in impaired performance on effortful tasks requiring planned or self ordered generation of responses from memory.

Source: Joyce E, Blumenthal S, Wessely S. Memory, attention, and executive function in chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 1996 May;60(5):495-503. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC486360/ (Full article)