Tag: cognitive impairment

Long COVID: Plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms

Abstract:

It is well known the potential of severe acute respiratory coronavirus type 2 (SARS-CoV-2) infection to induce post-acute sequelae, a condition called Long COVID. This syndrome includes several symptoms, but the central nervous system (CNS) main one is neurocognitive dysfunction. Recently it has been demonstrated the relevance of plasma levels of neurofilament light chain (pNfL), as a biomarker of early involvement of the CNS in COVID-19.

The aim of this study was to investigate the relationship between pNfL in patients with post-acute neurocognitive symptoms and the potential of NfL as a prognostic biomarker in these cases. A group of 63 long COVID patients ranging from 18 to 59 years-old were evaluated, submitted to a neurocognitive battery assessment, and subdivided in different groups, according to results. Plasma samples were collected during the long COVID assessment and used for measurement of pNfL with the Single molecule array (SIMOA) assays. Levels of pNfL were significantly higher in long COVID patients with neurocognitive symptoms when compared to HC (p = 0.0031).

Long COVID patients with cognitive impairment and fatigue symptoms presented higher pNfL levels when compared to long COVID patients without these symptoms, individually and combined (p = 0.0263, p = 0.0480, and 0.0142, respectively). Correlation analysis showed that levels of cognitive lost and exacerbation of fatigue in the neurocognitive evaluation had a significative correlation with higher pNfL levels (p = 0.0219 and 0.0255, respectively). Previous reports suggested that pNfL levels are related with higher risk of severity and predict lethality of COVID-19.

Our findings demonstrate that SARS-CoV-2 infection seems to have a long-term impact on the brain, even in patients who presented mild acute disease. NfL measurements might be useful to identify CNS involvement in long COVID associated with neurocognitive symptoms and to identify who will need continuous monitoring and treatment support.

Source: Gutman E, Salvio A, Fernandes R, et al. Long COVID: Plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms. Research Square; 2023. DOI: 10.21203/rs.3.rs-2921879/v1. https://www.researchsquare.com/article/rs-2921879/v1 (Full text)

Mouse Adapted SARS-CoV-2 Model Induces “Long-COVID” Neuropathology in BALB/c Mice

Abstract:

The novel coronavirus SARS-CoV-2 has caused significant global morbidity and mortality and continues to burden patients with persisting neurological dysfunction. COVID-19 survivors develop debilitating symptoms to include neuro-psychological dysfunction, termed “Long COVID”, which can cause significant reduction of quality of life. Despite vigorous model development, the possible cause of these symptoms and the underlying pathophysiology of this devastating disease remains elusive.

Mouse adapted (MA10) SARS-CoV-2 is a novel mouse-based model of COVID-19 which simulates the clinical symptoms of respiratory distress associated with SARS-CoV-2 infection in mice. In this study, we evaluated the long-term effects of MA10 infection on brain pathology and neuroinflammation. 10-week and 1-year old female BALB/cAnNHsd mice were infected intranasally with 10 4 plaque-forming units (PFU) and 10 3 PFU of SARS-CoV-2 MA10, respectively, and the brain was examined 60 days post-infection (dpi).

Immunohistochemical analysis showed a decrease in the neuronal nuclear protein NeuN and an increase in Iba-1 positive amoeboid microglia in the hippocampus after MA10 infection, indicating long-term neurological changes in a brain area which is critical for long-term memory consolidation and processing. Importantly, these changes were seen in 40-50% of infected mice, which correlates to prevalence of LC seen clinically.

Our data shows for the first time that MA10 infection induces neuropathological outcomes several weeks after infection at similar rates of observed clinical prevalence of “Long COVID”. These observations strengthen the MA10 model as a viable model for study of the long-term effects of SARS-CoV-2 in humans. Establishing the viability of this model is a key step towards the rapid development of novel therapeutic strategies to ameliorate neuroinflammation and restore brain function in those suffering from the persistent cognitive dysfunction of “Long-COVID”.

Source: Gressett TE, Leist SR, Ismael S, Talkington G, Dinnon KH, Baric RS, Bix G. Mouse Adapted SARS-CoV-2 Model Induces “Long-COVID” Neuropathology in BALB/c Mice. bioRxiv [Preprint]. 2023 Mar 20:2023.03.18.533204. doi: 10.1101/2023.03.18.533204. PMID: 36993423; PMCID: PMC10055301. https://www.biorxiv.org/content/10.1101/2023.03.18.533204v1.full (Full text)

Case Study: COVID-19 Brain Fog or Auditory Processing Disorder?

A wide array of symptoms have been directly associated with COVID-19 following recovery, but they can also occur several weeks or months after the diagnosis. These include, but are not limited to, damage to the respiratory tract as well as decreased cognition and other brain functions. The nonmedical term used to describe these post-COVID-19 problems is “brain fog.”

The symptoms of brain fog are similar to mild cognitive impairment or, of interest to audiologists, an auditory processing disorder (APD). 2 COVID-19 has neurological consequences and affects specific areas of the brain, such as the cingulate cortex (i.e. emotions, memory, depression, and decision of action). 3 Brain fog is also associated with several symptoms related to hearing and communication, which can affect the accomplishment of routine daily tasks. Many of those can be mistaken for or coexist with APD symptoms. These include “difficulty attending or staying focused, difficulty concentrating, difficulty understanding or remembering instructions, language problems, short-term memory problems,” to mention a few. 2 However, what might appear as a brain fog case could be an undiagnosed or even a pre-existing APD issue. 2 Symptoms could include struggling to keep track of conversations, forgetfulness and memory issues, problems following directions, and several cognitive difficulties. 2

This report presents the case of a 31-year-old medical doctor who was diagnosed with COVID-19 in December 2020, and later identified with APD symptoms that are now commonly seen in post-COVID-19 brain fog patients. Auditory training following the Buffalo Model 4 resolved the patient’s chief complaints following 12 treatment sessions. This issue is one of many that could shed light on the great potential auditory training has in resolving brain fog complaints that overlap with what is commonly seen in APD patients, highlighting the concerns regarding COVID-19’s direct effects on auditory processing.

Source: Alexander, Angela Loucks AuD, MNZAS, CCC-A; DiSogra, Robert M. AuD; Abbas, Fatima BS; Braund, Stacey AuD, CCC-A; Spokes, Chelsea BSpHLSc, MClinAud. Case Study: COVID-19 Brain Fog or Auditory Processing Disorder?. The Hearing Journal 76(04):p 18,19,20,22,23,24, April 2023. | DOI: 10.1097/01.HJ.0000927332.17564.4e https://journals.lww.com/thehearingjournal/Fulltext/2023/04000/Case_Study__COVID_19_Brain_Fog_or_Auditory.2.aspx (Full text)

Effect of Repetitive Transcranial Magnetic Stimulation on Long Coronavirus Disease 2019 with Fatigue and Cognitive Dysfunction

Abstract:

Objectives: There is no established treatment for chronic fatigue and various cognitive dysfunctions (brain fog) caused by long coronavirus disease 2019 (COVID-19). We aimed to clarify the effectiveness of repetitive transcranial magnetic stimulation (rTMS) for treating these symptoms.

Methods: High-frequency rTMS was applied to occipital and frontal lobes in 12 patients with chronic fatigue and cognitive dysfunction 3 months after severe acute respiratory syndrome coronavirus 2 infection. Before and after ten sessions of rTMS, Brief Fatigue Inventory (BFI), Apathy Scale (AS), and Wechsler Adult Intelligence Scale-fourth edition (WAIS4) were determined and N-isopropyl-p-[123I]iodoamphetamine single photon emission computed tomography (SPECT) was performed.

Results: Twelve subjects completed ten sessions of rTMS without adverse events. The mean age of the subjects was 44.3 ± 10.7 years, and the mean duration of illness was 202.4 ± 114.5 days. BFI, which was 5.7 ± 2.3 before the intervention, decreased significantly to 1.9 ± 1.8 after the intervention. The AS was significantly decreased after the intervention from 19.2 ± 8.7 to 10.3 ± 7.2. All WAIS4 sub-items were significantly improved after rTMS intervention, and the full-scale intelligence quotient increased from 94.6 ± 10.9 to 104.4 ± 13.0. Hypoperfusion in the bilateral occipital and frontal lobes observed on SPECT improved in extent and severity after ten sessions of rTMS.

Conclusions: Although we are still in the early stages of exploring the effects of rTMS, the procedure has the potential for use as a new non-invasive treatment for the symptoms of long COVID.

Source: Sasaki N, Yamatoku M, Tsuchida T, Sato H, Yamaguchi K. Effect of Repetitive Transcranial Magnetic Stimulation on Long Coronavirus Disease 2019 with Fatigue and Cognitive Dysfunction. Prog Rehabil Med. 2023 Feb 28;8:20230004. doi: 10.2490/prm.20230004. PMID: 36861061; PMCID: PMC9968785. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9968785/ (Full text)

Association of Post-COVID-19 Condition Symptoms and Employment Status

Abstract:

Importance: Little is known about the functional correlates of post-COVID-19 condition (PCC), also known as long COVID, particularly the relevance of neurocognitive symptoms.

Objective: To characterize prevalence of unemployment among individuals who did, or did not, develop PCC after acute infection.

Design, setting, and participants: This survey study used data from 8 waves of a 50-state US nonprobability internet population-based survey of respondents aged 18 to 69 years conducted between February 2021 and July 2022.

Main outcomes and measures: The primary outcomes were self-reported current employment status and the presence of PCC, defined as report of continued symptoms at least 2 months beyond initial month of symptoms confirmed by a positive COVID-19 test.

Results: The cohort included 15 308 survey respondents with test-confirmed COVID-19 at least 2 months prior, of whom 2236 (14.6%) reported PCC symptoms, including 1027 of 2236 (45.9%) reporting either brain fog or impaired memory. The mean (SD) age was 38.8 (13.5) years; 9679 respondents (63.2%) identified as women and 10 720 (70.0%) were White. Overall, 1418 of 15 308 respondents (9.3%) reported being unemployed, including 276 of 2236 (12.3%) of those with PCC and 1142 of 13 071 (8.7%) of those without PCC; 8229 respondents (53.8%) worked full-time, including 1017 (45.5%) of those with PCC and 7212 (55.2%) without PCC. In survey-weighted regression models excluding retired respondents, the presence of PCC was associated with a lower likelihood of working full-time (odds ratio [OR], 0.71 [95% CI, 0.63-0.80]; adjusted OR, 0.84 [95% CI, 0.74-0.96]) and with a higher likelihood of being unemployed (OR, 1.45 [95% CI, 1.22-1.73]; adjusted OR, 1.23 [95% CI, 1.02-1.48]). The presence of any cognitive symptom was associated with lower likelihood of working full time (OR, 0.70 [95% CI, 0.56-0.88]; adjusted OR, 0.75 [95% CI, 0.59-0.84]).

Conclusions and relevance: PCC was associated with a greater likelihood of unemployment and lesser likelihood of working full time in adjusted models. The presence of cognitive symptoms was associated with diminished likelihood of working full time. These results underscore the importance of developing strategies to treat and manage PCC symptoms.

Source: Perlis RH, Lunz Trujillo K, Safarpour A, Santillana M, Ognyanova K, Druckman J, Lazer D. Association of Post-COVID-19 Condition Symptoms and Employment Status. JAMA Netw Open. 2023 Feb 1;6(2):e2256152. doi: 10.1001/jamanetworkopen.2022.56152. PMID: 36790806; PMCID: PMC9932847. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9932847/(Full text)

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)