The two-way route between delirium disorder and dementia: insights from Covid-19.

BACKGROUND: Delirium disorder is a frequent neurological complication of SARS-CoV-2 infection and associated with an increased disease severity and mortality. Cognitive impairment is a major risk factor for developing delirium disorder during Covid-19, which, in turn, increases the risk of subsequent neurological complications and cognitive decline. SUMMARY: The bidirectional connection between delirium disorder and dementia likely resides at multiple levels, and its pathophysiological mechanisms during Covid-19 include endothelial damage, blood-brain barrier dysfunction and local inflammation, with activation of microglia and astrocytes. Here, we describe the putative pathogenic pathways underlying delirium disorder during Covid-19 and highlight how they cross with the ones leading to neurodegenerative dementia. KEY MESSAGES: The analysis of the two-sided link can offer useful insights for confronting with long-term neurological consequences of Covid-19 and framing future prevention and early treatment strategies.

Brain functional connectivity alterations associated with neuropsychological performance 6-9 months following SARS-CoV-2 infection.

Neuropsychological deficits and brain damage following SARS-CoV-2 infection are not well understood. Then, 116 patients, with either severe, moderate, or mild disease in the acute phase underwent neuropsychological and olfactory tests, as well as completed psychiatric and respiratory questionnaires at 223 ± 42 days postinfection. Additionally, a subgroup of 50 patients underwent functional magnetic resonance imaging. Patients in the severe group displayed poorer verbal episodic memory performances, and moderate patients had reduced mental flexibility. Neuroimaging revealed patterns of hypofunctional and hyperfunctional connectivities in severe patients, while only hyperconnectivity patterns were observed for moderate. The default mode, somatosensory, dorsal attention, subcortical, and cerebellar networks were implicated. Partial least squares correlations analysis confirmed specific association between memory, executive functions performances and brain functional connectivity. The severity of the infection in the acute phase is a predictor of neuropsychological performance 6-9 months following SARS-CoV-2 infection. SARS-CoV-2 infection causes long-term memory and executive dysfunctions, related to large-scale functional brain connectivity alterations.

Functional connectivity underlying cognitive and psychiatric symptoms in post-COVID-19 syndrome: is anosognosia a key determinant?

Lack of awareness of cognitive impairment (i.e. anosognosia) could be a key factor for distinguishing between neuropsychological post-COVID-19 condition phenotypes. In this context, the 2-fold aim of the present study was to (i) establish the prevalence of anosognosia for memory impairment, according to the severity of the infection in the acute phase and (ii) determine whether anosognosic patients with post-COVID syndrome have a different cognitive and psychiatric profile from nosognosic patients, with associated differences in brain functional connectivity. A battery of neuropsychological, psychiatric, olfactory, dyspnoea, fatigue and quality-of-life tests was administered 227.07 ± 42.69 days post-SARS-CoV-2 infection to 102 patients (mean age: 56.35 years, 65 men, no history of neurological, psychiatric, neuro-oncological or neurodevelopmental disorder prior to infection) who had experienced either a mild (not hospitalized; n = 45), moderate (conventional hospitalization; n = 34) or severe (hospitalization with intensive care unit stay and mechanical ventilation; n = 23) presentation in the acute phase. Patients were first divided into two groups according to the presence or absence of anosognosia for memory deficits (26 anosognosic patients and 76 nosognosic patients). Of these, 49 patients underwent an MRI. Structural images were visually analysed, and statistical intergroup analyses were then performed on behavioural and functional connectivity measures. Only 15.6% of patients who presented mild disease displayed anosognosia for memory dysfunction, compared with 32.4% of patients with moderate presentation and 34.8% of patients with severe disease. Compared with nosognosic patients, those with anosognosia for memory dysfunction performed significantly more poorly on objective cognitive and olfactory measures. By contrast, they gave significantly more positive subjective assessments of their quality of life, psychiatric status and fatigue. Interestingly, the proportion of patients exhibiting a lack of consciousness of olfactory deficits was significantly higher in the anosognosic group. Functional connectivity analyses revealed a significant decrease in connectivity, in the anosognosic group as compared with the nosognosic group, within and between the following networks: the left default mode, the bilateral somatosensory motor, the right executive control, the right salient ventral attention and the bilateral dorsal attention networks, as well as the right Lobules IV and V of the cerebellum. Lack of awareness of cognitive disorders and, to a broader extent, impairment of the self-monitoring brain system, may be a key factor for distinguishing between the clinical phenotypes of post-COVID syndrome with neuropsychological deficits.

Long COVID Neuropsychological Deficits after Severe, Moderate, or Mild Infection

There is growing awareness that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, even in its mild or moderate respiratory forms, can include long-term neuropsychological deficits. Standardized neuropsychological, psychiatric, neurological, and olfactory tests were administered to 45 patients 236.51 ±22.54 days after hospital discharge following severe, moderate, or mild respiratory severity from SARS-CoV-2 infection (severe = intensive care unit hospitalization, moderate = conventional hospitalization, mild = no hospitalization). Deficits were found in all domains of cognition, and the prevalence of psychiatric symptoms was relatively high in the three groups. The severe infection group performed more poorly on long-term episodic memory tests and exhibited greater anosognosia than did the other two groups. Those with moderate infection had poorer emotion recognition, which was positively correlated with persistent olfactory dysfunction. Individuals with mild infection were more stressed, anxious, and depressed. The data support the hypothesis that the virus targets the central nervous system (notably the limbic system) and the notion that there are different neuropsychological phenotypes.

Omicron-Specific Cytotoxic T-Cell Responses After a Third Dose of mRNA COVID-19 Vaccine Among Patients With Multiple Sclerosis Treated With Ocrelizumab.

IMPORTANCE: The SARS-CoV-2 variant B.1.1.529 (Omicron) escapes neutralizing antibodies elicited after COVID-19 vaccination, while T-cell responses might be better conserved. It is crucial to assess how a third vaccination modifies these responses, particularly for immunocompromised patients with readily impaired antibody responses. OBJECTIVE: To determine T-cell responses to the Omicron spike protein in anti-CD20-treated patients with multiple sclerosis (MS) before and after a third messenger RNA COVID-19 vaccination. DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study conducted from March 2021 to November 2021 at the University Hospital Geneva, adults with MS receiving anti-CD20 treatment (ocrelizumab) were identified by their treating neurologists and enrolled in the study. A total of 20 patients received their third dose of messenger RNA COVID-19 vaccine and were included in this analysis. INTERVENTIONS: Blood sampling before and 1 month after the third vaccine dose. MAIN OUTCOMES AND MEASURES: Quantification of CD4 and CD8 (cytotoxic) T cells specific for the SARS-CoV-2 spike proteins of the vaccine strain as well as the Delta and Omicron variants, comparing frequencies before and after the third vaccine dose. RESULTS: Of 20 included patients, 11 (55%) were male, and the median (IQR) age was 45.8 (37.8-53.3) years. Spike-specific CD4 and CD8 T-cell memory against all variants were maintained in 9 to 12 patients 6 months after their second vaccination, albeit at lower median frequencies against the Delta and Omicron variants compared with the vaccine strain (CD8 T cells: Delta, 83.0%; 95% CI, 73.6-114.5; Omicron, 78.9%; 95% CI, 59.4-100.0; CD4 T cells: Delta, 72.2%; 95% CI, 67.4-90.5; Omicron, 62.5%; 95% CI, 51.0-89.0). A third dose enhanced the number of responders to all variants (11 to 15 patients) and significantly increased CD8 T-cell responses, but the frequencies of Omicron-specific CD8 T cells remained 71.1% (95% CI, 41.6-96.2) of the responses specific to the vaccine strain. CONCLUSIONS AND RELEVANCE: In this cohort study of patients with MS treated with ocrelizumab, there were robust T-cell responses recognizing spike proteins from the Delta and Omicron variants, suggesting that COVID-19 vaccination in patients taking B-cell-depleting drugs may protect them against serious complications from COVID-19 infection. T-cell response rates increased after the third dose, demonstrating the importance of a booster dose for this population.

Robust T-Cell Responses in Anti-CD20-Treated Patients Following COVID-19 Vaccination: A Prospective Cohort Study.

BACKGROUND: Patients treated with anti-CD20 therapy are particularly at risk of developing severe coronavirus disease 2019 (COVID-19); however, little is known regarding COVID-19 vaccine effectiveness in this population. METHODS: This prospective observational cohort study assesses humoral and T-cell responses after vaccination with 2 doses of mRNA-based COVID-19 vaccines in patients treated with rituximab for rheumatic diseases or ocrelizumab for multiple sclerosis (n = 37), compared to immunocompetent individuals (n = 22). RESULTS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies were detectable in only 69.4% of patients and at levels that were significantly lower compared to controls who all seroconverted. In contrast to antibodies, Spike (S)-specific CD4 T cells were equally detected in immunocompetent and anti-CD20 treated patients (85-90%) and mostly of a Th1 phenotype. Response rates of S-specific CD8 T cells were higher in ocrelizumab (96.2%) and rituximab-treated patients (81.8%) as compared to controls (66.7%). S-specific CD4 and CD8 T cells were polyfunctional but expressed more effector molecules in patients than in controls. During follow-up, 3 MS patients without SARS-CoV-2-specific antibody response had a mild breakthrough infection. One of them had no detectable S-specific T cells after vaccination. CONCLUSIONS: Our study suggests that patients on anti-CD20 treatment are able to mount potent T-cell responses to mRNA COVID-19 vaccines, despite impaired humoral responses. This could play an important role in the reduction of complications of severe COVID-19.

Cerebrospinal Fluid Features in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Reverse Transcription Polymerase Chain Reaction (RT-PCR) Positive Patients.

This study analyzed the cerebrospinal fluid features of 31 coronavirus disease 2019 (COVID-19) patients with neurological complications. We observed neither severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in the cerebrospinal fluid, nor intrathecal immunoglobulin G (IgG) synthesis but did observe signs of blood-brain barrier disruption. These results might serve as a basis for a better understanding of SARS-CoV-2 related neuropathogenesis.

C-reactive protein and white matter microstructural changes in COVID-19 patients with encephalopathy.

Encephalopathy is a neurological complication of COVID-19. The objective of this exploratory study is to investigate the link between systemic inflammation and brain microstructural changes (measured by diffusion-weighted imaging) in patients with COVID-19 encephalopathy. 20 patients with COVID-19 encephalopathy (age: 67.3 [Formula: see text] 10.0 years; 90% men) hospitalized in the Geneva University Hospitals for a SARS-CoV-2 infection between March and May 2020 were included in this retrospective cohort study. COVID-19 encephalopathy was diagnosed following a comprehensive neurobiological evaluation, excluding common causes of delirium, such as hypoxemic or metabolic encephalopathy. We investigated the correlation between systemic inflammation (measured by systemic C-reactive protein (CRP)) and brain microstructural changes in radiologically normal white matter (measured by apparent diffusion coefficient (ADC)) in nine spatially widespread regions of the white matter previously associated with delirium. Systemic inflammation (CRP = 60.8 ± 50.0 mg/L) was positively correlated with ADC values in the anterior corona radiata (p = 0.0089), genu of the corpus callosum (p = 0.0064) and external capsule (p = 0.0086) after adjusting for patients' age. No statistically significant association between CRP and ADC was found in the other six white matter regions. Our findings indicate high risk of white matter abnormalities in COVID-19 encephalopathy patients with high peripheral inflammatory markers, suggesting aggressive imaging monitoring may be warranted in these patients. Future studies should clarify a possible specificity of the spatial patterns of CRP-white matter microstructure association in COVID-19 encephalopathy patients and disentangle the role of individual cytokines on brain inflammatory mechanisms.

COVID-19 encephalopathy: Clinical and neurobiological features.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) has been associated with neurological complications, including acute encephalopathy. To better understand the neuropathogenesis of this acute encephalopathy, we describe a series of patients with coronavirus disease 2019 (COVID-19) encephalopathy, highlighting its phenomenology and its neurobiological features. On May 10, 2020, 707 patients infected by SARS-CoV-2 were hospitalized at the Geneva University Hospitals; 31 (4.4%) consecutive patients with an acute encephalopathy (64.6 ± 12.1 years; 6.5% female) were included in this series, after exclusion of comorbid neurological conditions, such as stroke or meningitis. The severity of the COVID-19 encephalopathy was divided into severe and mild based on the Richmond Agitation Sedation Scale (RASS): severe cases (n = 14, 45.2%) were defined on a RASS < -3 at worst presentation. The severe form of this so-called COVID-19 encephalopathy presented more often a headache. The severity of the pneumonia was not associated with the severity of the COVID-19 encephalopathy: 28 of 31 (90%) patients did develop an acute respiratory distress syndrome, without any difference between groups (p = .665). Magnetic resonance imaging abnormalities were found in 92.0% (23 of 25 patients) with an intracranial vessel gadolinium enhancement in 85.0% (17 of 20 patients), while an increased cerebrospinal fluid/serum quotient of albumin suggestive of blood-brain barrier disruption was reported in 85.7% (6 of 7 patients). Reverse transcription-polymerase chain reaction for SARS-CoV-2 was negative for all patients in the cerebrospinal fluid. Although different pathophysiological mechanisms may contribute to this acute encephalopathy, our findings suggest the hypothesis of disturbed brain homeostasis and vascular dysfunction consistent with a SARS-CoV-2-induced endotheliitis.

Cerebrovascular Complications and Vessel Wall Imaging in COVID-19 Encephalopathy-A Pilot Study.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with several complications of the central nervous system (CNS), including acute encephalopathy. METHODS: In this pilot study, we report a series of 39 patients (66.5 ± 9.2 years; 10.3% female) with acute encephalopathy, who underwent a standard brain magnetic resonance imaging (MRI) at 1.5 T during the acute symptomatic phase. In addition to diffusion-weighted imaging, MR angiography and susceptibility-weighted images, high-resolution vascular black blood sequences (in 34 cases) were used to investigate the vasculature of the brain. RESULTS: In 29 out of 34 patients with COVID-19 encephalopathy (85%) with high-resolution vessel wall imaging, we found a circular enhancement and thickening of the basilar and vertebral arteries, without any correlation with ischemia or microbleeds (reported in 21% and 59%, respectively). CONCLUSION: We report a high prevalence of vascular changes suggestive of endotheliitis as reported in other organs. This could suggest an inflammatory mechanism underlying this encephalopathy.