The COVID-19 pandemic has left an indelible mark on every facet of our existence. In this issue of Acta Neuropsychiatrica, we embark on a comprehensive exploration of the pandemic’s multifaceted impact, drawing on the insights gleaned from four recent research papers. These studies illuminate critical dimensions, including the pivotal role of inflammation management in shaping COVID-19 outcomes, the unexpected neurological manifestations it incites, the potential risk of obsessive-compulsive disorder (OCD), and the pandemic’s toll on the mental health of undergraduate students. Collectively, these findings offer a holistic perspective on the profound and far-reaching effects of COVID-19, providing essential guidance as we continue to navigate this global crisis.

Inflammation Management in COVID-19 Our evolving understanding of COVID-19 has brought the role of inflammation into sharp focus, as underscored by the work of Tang and coworkers (Tang et al., Reference Tang, Helmeste and Leonard2023). This research emphasises the intricate interplay of various factors in COVID-19, highlighting the host’s inflammatory response as a key determinant of disease severity, symptoms, and prognosis. Genetic factors, age, immune status, health, and disease stage all influence this inflammatory response. Effectively managing inflammation has emerged as a vital strategy for reducing morbidity and mortality across all stages of COVID-19.

OCD and Gender Disparities The pandemic’s impact extends to the realm of mental health, including a potential risk of OCD, as elucidated in a systematic review (Jalalifar et al., Reference Jalalifar, Arad, Rastkar and Beheshti2023). This analysis reveals that COVID-19 and its containment measures may heighten the risk of OCD, with females appearing particularly susceptible. Notably, under-18 students, hospital staff, and individuals in the Middle East are among the groups most affected. This insight can inform targeted support and resource allocation to address these vulnerabilities.

Psychological Suffering Among Undergraduate Students One poignant revelation is the psychological toll exacted on undergraduate students during remote learning (Silva et al., 2023). Despite a relatively low prevalence of COVID-19 fear, an alarming 83.0% of students reported symptoms of depression, and 76.1% experienced anxiety. These findings underscore the profound impact of the pandemic on the mental health of young individuals. Vulnerable groups, including female students, those in poor health, and those who lost family members to COVID-19, are particularly affected. Targeted interventions, such as physical activity programmes, hold promise for enhancing students’ well-being.

Surprising Neurological Manifestations in Post-COVID-19 Patients A fourth paper explores the unexpected neurological sequelae in post-COVID-19 patients, revealing marked impairments in fine motor skills, balance, memory, attention, and concentration (Chiminazzo and Kirsten, Reference Chiminazzo and Kirsten2023). This study challenges initial assumptions about COVID-19, which primarily targets the respiratory system. Instead, it unveils a range of neurological manifestations even among young and healthy individuals. These findings underscore the urgency of developing rehabilitation protocols to address the neurological deficits stemming from COVID-19 infection.

Collectively, these research papers offer a comprehensive view of the multifaceted and profound impact of COVID-19. From the critical role of inflammation management to potential OCD risk disparities, surprising neurological consequences, and the psychological toll on students, our understanding of this pandemic continues to evolve. As we navigate the ongoing challenges, these insights must guide our response, offering hope and evidence-based strategies to mitigate COVID-19’s extensive effects on individuals and society as a whole.

Wegener, G. (2023). Navigating the complexity of COVID-19: A multifaceted examination. Acta Neuropsychiatrica, 35(5), 247-247. doi:10.1017/neu.2023.50

https://www.cambridge.org/core/journals/acta-neuropsychiatrica/article/navigating-the-complexity-of-covid19-a-multifaceted-examination/CCD0997DDCA5E1B26DEB74D974112844

 

 

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https://www.nature.com/articles/d41586-023-03435

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Human herpesvirus 6A (HHV-6A) and human herpesvirus 6B (HHV-6B), collectively termed HHV-6A/B, are neurotropic viruses that permanently infect most humans from an early age. Although most people infected with these viruses appear to suffer no ill effects, the viruses are a well-established cause of encephalitis in immunocompromised patients. In this review, we summarize the evidence that the viruses may also be one trigger for febrile seizures (including febrile status epilepticus) in immunocompetent infants and children, mesial temporal lobe epilepsy, multiple sclerosis (MS), and, possibly, Alzheimer’s disease.

Komaroff AL, Pellett PE, Jacobson S. Human Herpesviruses 6A and 6B in Brain Diseases: Association versus Causation. Clin Microbiol Rev. 2020 Nov 11;34(1):e00143-20. doi: 10.1128/CMR.00143-20. PMID: 33177186; PMCID: PMC7667666.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667666/

 

 

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Abstract

Mitochondrial dysfunction has been suggested to contribute to Parkinson’s disease pathogenesis, though an understanding of the extent or exact mechanism of this contribution remains elusive. This has been complicated by challenging nature of pathway-based analysis and an inability simultaneously study multiple related proteins within human brain tissue. We used imaging mass cytometry (IMC) to overcome these challenges, measuring multiple protein targets, whilst retaining the spatial relationship between targets in post-mortem midbrain sections. We used IMC to simultaneously interrogate subunits of the mitochondrial oxidative phosphorylation complexes, and several key signalling pathways important for mitochondrial homoeostasis, in a large cohort of PD patient and control cases. We revealed a generalised and synergistic reduction in mitochondrial quality control proteins in dopaminergic neurons from Parkinson’s patients. Further, protein-protein abundance relationships appeared significantly different between PD and disease control tissue. Our data showed a significant reduction in the abundance of PINK1, Parkin and phosphorylated ubiquitinSer65, integral to the mitophagy machinery; two mitochondrial chaperones, HSP60 and PHB1; and regulators of mitochondrial protein synthesis and the unfolded protein response, SIRT3 and TFAM. Further, SIRT3 and PINK1 did not show an adaptive response to an ATP synthase defect in the Parkinson’s neurons. We also observed intraneuronal aggregates of phosphorylated ubiquitinSer65, alongside increased abundance of mitochondrial proteases, LONP1 and HTRA2, within the Parkinson’s neurons with Lewy body pathology, compared to those without. Taken together, these findings suggest an inability to turnover mitochondria and maintain mitochondrial proteostasis in Parkinson’s neurons. This may exacerbate the impact of oxidative phosphorylation defects and ageing related oxidative stress, leading to neuronal degeneration. Our data also suggest that that Lewy pathology may affect mitochondrial quality control regulation through the disturbance of mitophagy and intramitochondrial proteostasis.

 

Chen, C., McDonald, D., Blain, A. et al. Parkinson’s disease neurons exhibit alterations in mitochondrial quality control proteins. npj Parkinsons Dis. 9, 120 (2023). https://doi.org/10.1038/s41531-023-00564-3

https://www.nature.com/articles/s41531-023-00564-3


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Abstract

Background: Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have been associated with multiple sclerosis (MS). Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing forms of MS. In the preclinical Theiler’s murine encephalitis virus model of MS, the drug demonstrated an increased rate of viral clearance versus the vehicle placebo. Furthermore, teriflunomide inhibits lytic EBV infection in vitro.

Objective: 1. To evaluate the humoral response against EBV and HHV-6 prior to teriflunomide treatment and 6 months later. 2. To correlate the variation in the humoral response against EBV and HHV-6 with the clinical and radiological response after 24 months of treatment with teriflunomide. 3. To analyze the utility of different demographic, clinical, radiological, and environmental data to identify early biomarkers of response to teriflunomide.

Methods: A total of 101 MS patients (62 women; mean age: 43.4 years) with one serum prior to teriflunomide onset and another serum sample 6 months later were recruited. A total of 80 had been treated for at least 24 months, 13 had stopped teriflunomide before 24 months, and 8 were currently under teriflunomide therapy but with less than 24 months of follow-up. We analyzed the levels of the viral antibodies titers abovementioned in serum samples with ELISA commercial kits, and the levels of serum neurofilament light chain (Nf-L).

Results: Antiviral antibody titers decreased for EBNA-1 IgG (74.3%), VCA IgG (69%), HHV-6 IgG (60.4%), and HHV-6 IgM (73.3%) after 6 months of teriflunomide. VCA IgG titers at baseline correlated with Nf-L levels measured at the same time (r = 0.221; p = 0.028) and 6 months later (r = 0.240; p = 0.017). We found that higher EBNA-1 titers (p = 0.001) and a higher age (p = 0.04) at baseline were associated with NEDA-3 conditions. Thus, 77.8% of patients with EBNA-1 >23.0 AU and >42.8 years (P50 values) were NEDA-3.

Conclusion: Treatment with teriflunomide was associated with a reduction of the levels of IgG antibody titers against EBV and HHV-6. Furthermore, higher EBNA-1 IgG titers prior to teriflunomide initiation were associated with a better clinical response.

Domínguez-Mozo MI, González-Suárez I, Villar LM, Costa-Frossard L, Villarrubia N, Aladro Y, Pilo B, Montalbán X, Comabella M, Casanova-Peño I, Martínez-Ginés ML, García-Domínguez JM, García-Martínez MÁ, Arroyo R, Álvarez-Lafuente R. Teriflunomide and Epstein-Barr virus in a Spanish multiple sclerosis cohort: in vivo antiviral activity and clinical response. Front Immunol. 2023 Sep 29;14:1248182. doi: 10.3389/fimmu.2023.1248182. PMID: 37841253; PMCID: PMC10570817.

https://pubmed.ncbi.nlm.nih.gov/37841253/

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The underlying cause of sporadic Alzheimer disease (AD) remains enigmatic, but an increased risk among spouses of people with AD has led to speculation of transmissibility. A mouse study now suggests that the transfer of microbiota could underlie this potential transmissibility, but the findings leave many questions unanswered.

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https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.20230631

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Abstract:  Gastrointestinal fungal dysbiosis is a hallmark of several diseases marked by systemic immune activation. Whether persistent pathobiont colonization during immune alterations and impaired gut barrier function has a durable impact on host immunity is unknown. We found that elevated levels of Candida albicans immunoglobulin G (IgG) antibodies marked patients with severe COVID-19 (sCOVID-19) who had intestinal Candidaovergrowth, mycobiota dysbiosis and systemic neutrophilia. Analysis of hematopoietic stem cell progenitors in sCOVID-19 revealed transcriptional changes in antifungal immunity pathways and reprogramming of granulocyte myeloid progenitors (GMPs) for up to a year. Mice colonized with C. albicans patient isolates experienced increased lung neutrophilia and pulmonary NETosis during severe acute respiratory syndrome coronavirus-2 infection, which were partially resolved with antifungal treatment or by interleukin-6 receptor blockade. sCOVID-19 patients treated with tocilizumab experienced sustained reductions in C. albicans IgG antibodies titers and GMP transcriptional changes. These findings suggest that gut fungal pathobionts may contribute to immune activation during inflammatory diseases, offering potential mycobiota-immune therapeutic strategies for sCOVID-19 with prolonged symptoms.

Kusakabe, T., Lin, WY., Cheong, JG. et al. Fungal microbiota sustains lasting immune activation of neutrophils and their progenitors in severe COVID-19. Nat Immunol (2023). https://doi.org/10.1038/s41590-023-01637-4

https://www.nature.com/articles/s41590-023-01637-4

 

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Highlights

  • Infants and young children mount antibody responses that are durable for up to 300 days
  • Atypical innate response in blood: no inflammatory markers; high IFNα and chemokines
  • Robust upper respiratory tract antiviral and inflammatory responses
  • Single-cell transcriptomics and epigenomics in the first weeks and months of life

Summary

The dynamics of immunity to infection in infants remain obscure. Here, we used a multi-omics approach to perform a longitudinal analysis of immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in infants and young children by analyzing blood samples and weekly nasal swabs collected before, during, and after infection with Omicron and non-Omicron variants. Infection stimulated robust antibody titers that, unlike in adults, showed no sign of decay for up to 300 days. Infants mounted a robust mucosal immune response characterized by inflammatory cytokines, interferon (IFN) α, and T helper (Th) 17 and neutrophil markers (interleukin [IL]-17, IL-8, and CXCL1). The immune response in blood was characterized by upregulation of activation markers on innate cells, no inflammatory cytokines, but several chemokines and IFNα. The latter correlated with viral load and expression of interferon-stimulated genes (ISGs) in myeloid cells measured by single-cell multi-omics. Together, these data provide a snapshot of immunity to infection during the initial weeks and months of life.

https://www.cell.com/cell/fulltext/S0092-8674%2823%2900978-9

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Abstract

Objective: To identify data-driven subgroups in Major Depressive Disorder (MDD) in order to elucidate underlying neural correlates and determine if these subgroups have utility in predicting response to antidepressant versus placebo.

Methods: Using 27 clinical measures at baseline of Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study, participants with MDD (n=244) were sub grouped using principal component (PC) analysis. Baseline-to-week-8 changes in depression severity with sertraline versus placebo were compared in these subgroups. Resting-state functional connectivity of these subgroups were compared to those of healthy controls (n=38).

Results: Eight subgroups were identified from four PCs: (PC1) severity of depression-associated symptoms, (PC2) sub-threshold mania and anhedonia, (PC3) childhood trauma, medical comorbidities, and sexual dysfunction, and (PC4) personality traits of openness and agreeableness. Participants with high childhood trauma experienced greater improvement with sertraline (Cohen’s d=0.87), whereas those with either higher levels of subthreshold hypomanic symptoms (Cohen’s d=0.67) or with lower levels of agreeableness and openness experienced greater improvement with placebo (Cohen’s d=0.71). Participants with high childhood trauma had greater connectivity between salience and dorsal attention networks, whereas those with higher levels of subthreshold hypomanic symptoms and lower levels of agreeableness and openness had greater connectivity within limbic network and that of visual network with hippocampus and dorsal attention network.

Conclusion: Assessing history of childhood trauma, presence of subthreshold hypomanic symptoms and personality traits may help to identify subgroups of patients with MDD who respond differentially to sertraline or placebo and have distinct neural signatures.

Chin Fatt CR, Cooper CM, Jha MK, Minhajuddin A, Rush AJ, Trombello JM, Fava M, McInnis M, Weissman M, Trivedi MH. Differential response to SSRI versus Placebo and distinct neural signatures among data-driven subgroups of patients with major depressive disorder. J Affect Disord. 2021 Mar 1;282:602-610. doi: 10.1016/j.jad.2020.12.102. Epub 2020 Dec 28. PMID: 33445082.

https://pubmed.ncbi.nlm.nih.gov/33445082/

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