Neurological manifestations of COVID-19 in adults and children

Different neurological manifestations of coronavirus disease 2019 (COVID-19) in adults and children and their impact have not been well characterized. We aimed to determine the prevalence of neurological manifestations and in-hospital complications among hospitalized COVID-19 patients and ascertain differences between adults and children. We conducted a prospective multicentre observational study using the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) cohort across 1507 sites worldwide from 30 January 2020 to 25 May 2021. Analyses of neurological manifestations and neurological complications considered unadjusted prevalence estimates for predefined patient subgroups, and adjusted estimates as a function of patient age and time of hospitalization using generalized linear models. Overall, 161 239 patients (158 267 adults; 2972 children) hospitalized with COVID-19 and assessed for neurological manifestations and complications were included. In adults and children, the most frequent neurological manifestations at admission were fatigue (adults: 37.4%; children: 20.4%), altered consciousness (20.9%; 6.8%), myalgia (16.9%; 7.6%), dysgeusia (7.4%; 1.9%), anosmia (6.0%; 2.2%) and seizure (1.1%; 5.2%). In adults, the most frequent in-hospital neurological complications were stroke (1.5%), seizure (1%) and CNS infection (0.2%). Each occurred more frequently in intensive care unit (ICU) than in non-ICU patients. In children, seizure was the only neurological complication to occur more frequently in ICU versus non-ICU (7.1% versus 2.3%, P < 0.001). Stroke prevalence increased with increasing age, while CNS infection and seizure steadily decreased with age. There was a dramatic decrease in stroke over time during the pandemic. Hypertension, chronic neurological disease and the use of extracorporeal membrane oxygenation were associated with increased risk of stroke. Altered consciousness was associated with CNS infection, seizure and stroke. All in-hospital neurological complications were associated with increased odds of death. The likelihood of death rose with increasing age, especially after 25 years of age. In conclusion, adults and children have different neurological manifestations and in-hospital complications associated with COVID-19. Stroke risk increased with increasing age, while CNS infection and seizure risk decreased with age

<i>Toxoplasma</i> infection alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease

ABSTRACTToxoplasma gondii is a single celled parasite thought to infect 1 in 3 worldwide. During chronic infection, T. gondii can migrate to the brain where it promotes low-grade neuroinflammation with the capacity to induce changes in brain morphology and behavior. Consequently, infection with T. gondii has been linked with a number of neurocognitive disorders including schizophrenia (SZ), dementia, and Parkinson’s disease. Beyond neuroinflammation, infection with T. gondii can modulate the production of neurotransmitters, such as dopamine. To further dissect these pathways and examine the impact of altered dopaminergic sensitivity in T. gondii-infected mice on both behavior and gene expression, we developed a novel mouse model, based on stimulant-induced (cocaine) hyperactivity. Employing this model, we found that infection with T. gondii did not alter fear behavior but did impact motor activity and neuropsychiatric-related behaviurs. While both behaviors may help reduce predator avoidance, consistent with previous studies, the latter finding is reminiscent of neurocognitive disorders. Applying RNASeq to two relevant brain regions, striatum and hippocampus, we identified a broad upregulation of immune responses. However, we also noted significant associations with more meaningful neurologically relevant terms were masked due to the sheer number of terms incorporated in multiple testing correction. We therefore performed a more focused analysis using a curated set of neurologically relevant terms revealing significant associations across multiple pathways. We also found that T. gondii and cocaine treatments impacted the expression of similar functional pathways in the hippocampus and striatum although, as indicated by the low overlap among differentially expressed genes, largely via different proteins. Furthermore, while most differentially expressed genes reacted to a single condition and were mostly upregulated, we identified gene expression patterns indicating unexpected interactions between T. gondii infection and cocaine exposure. These include sets of genes which responded to cocaine exposure but not upon cocaine exposure in the context of T. gondii infection, suggestive of a neuroprotective effect advantageous to parasite persistence. Given its ability to uncover such complex relationships, we propose this novel model offers a new perspective to dissect the molecular pathways by which T. gondii infection contributes to neuropsychiatric disorders such as schizophrenia.</jats:p

Supplementary spreadsheet with curation of neurologically relevant functional terms.

(XLSX)</p

Zip archive of ontologies and annotations used in this study.

(ZIP)</p

Heatmap of gene expression defining DE gene responses by type and subtype.

Hippocampus, 364 genes with significant (FDRT. gondii and cocaine effects. (PDF)</p

Expression of differentially expressed genes responding to cocaine and <i>T</i>. <i>gondii</i> infection.

The upset plot shows the number of differentially expressed genes by response, with overlaps by treatment category and tissue. The horizontal bars to the left indicate the total number of differentially expressed genes associated with each of the four conditions. The filled in dots in the dot matrix, together with the corresponding vertical bars then show how these genes are distributed. For example, of the 1150 differentially expressed genes in the Hippocampus associated with “Toxo Up”, 837 are only associated with the “Toxo Up” dataset (1st column), while 287 are shared with the “Cocaine Down” dataset (5th column) and 26 are shared with the “Cocaine Up” dataset (7th column). Within categories, tissue overlaps are indicated (bracketed). Genes represented are mouse genes identified as being significantly differentially expressed (likelihood ratio test, FDR<0.1) across pairs of conditions within a tissue.</p

Supplementary spreadsheet with statistical analysis of genes in categories

(XLSX)</p

Functional characterization of mouse genes with interacting effects.

A. Frequency of mouse genes with statistically significant interactions by functional effect category (hippocampus and striatum). B. Network visualization of KEGG pathway enrichments for functional effect group b in striatum (largest category) providing insight into parent-child relationships of significantly enriched terms. For example, “spliceosome” and “chaperones and folding catalysts” can be seen to be most specifically as well as most significantly enriched. For context, all significantly enriched terms before correction for multiple testing are shown. Colors represent significant terms after multiple testing correction (hypergeometric test, FDR < 0.05).</p

Heatmap of gene expression defining DE gene responses by type and subtype.

Striatum, 173 genes with significant (FDRT. gondii and cocaine effects. (PDF)</p

Heatmap of gene expression defining DE gene responses by type and subtype.

Hippocampus– 40 genes with significant (FDRT. gondii by cocaine interactions. (PDF)</p