COVID survivors frequently experience lingering neurological symptoms that resemble cancer-therapy-related cognitive impairment, a syndrome for which white matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes, and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared with SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white-matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis, and elevated CCL11 at early time points, but after influenza, only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
Impairments in certain cardiac genes confer risk for myocarditis in children. To determine the extent of this association, we performed genomic sequencing in predominantly adult patients with acute myocarditis and matched control subjects. Putatively deleterious variants in a broad set of cardiac genes were found in 19 of 117 acute myocarditis cases vs 34 of 468 control subjects (P = 0.003). Thirteen genes classically associated with cardiomyopathy or neuromuscular disorders with cardiac involvement were implicated, including >1 associated damaging variant in DYSF, DSP, and TTN. Phenotypes of subjects who have acute myocarditis with or without deleterious variants were similar, indicating that genetic testing is necessary to differentiate them.
Abstract Objectives To identify echocardiographic signatures featuring left ventricular longitudinal strain (LS) associated with genetic risk for cardiac amyloidosis (CA) due to the TTR Val142Ile (V142I) variant in African American (AA) and Hispanic/Latinx (H/L) individuals. Background Hereditary transthyretin amyloidosis (hATTR) can cause CA in ∼60-70% of older V142I carriers, but amyloid deposition progresses over many years. Disease-modifying therapy for CA is now available and early initiation is a priority for improving outcomes. Genomic screening programs and familial cascade genetic testing uncover pre-symptomatic V142I carriers, yet no guidelines exist for early CA detection. Methods Exome sequencing data linked to electronic health records (EHRs) of Bio Me biobank participants were queried for AA or H/L TTR - and TTR + (V142I) subjects without hATTR diagnoses and with prior echocardiograms suitable for retrospective LS analysis. Systemic “red flag” features of ATTR were extracted from EHRs of TTR + subjects. Speckle tracking echocardiography was retrospectively applied to determine global (GLS) and segmental LS. Relative apical sparing (RAS) was calculated. Results 57 TTR + and 46 TTR -age- and ancestry-matched subjects were included. GLS declined with age in females but not males, and was abnormal (<16%) in 18 (31.6%) TTR + and 7 (15.2%) TTR -subjects (p = 0.066). Apical sparing was observed in 13 (22.8%) TTR + and 11 (23.9%) TTR -subjects (p = 1.0). After adjusting for relevant demographic and echocardiographic covariates, neither GLS nor RAS was associated with TTR + V142I status. Red flag features were not associated with GLS or RAS in TTR + subjects. Conclusions Neither GLS nor RAS were significantly different between TTR + and TTR -subjects. Since >50% of TTR + subjects were ≥ 60 years old, penetrance of CA by echocardiography among unselected V142I carriers may be lower than previously estimated. These findings indicate that surveillance for CA in individuals at increased genetic risk due to V142I should not rely solely on echocardiography, even with LS.
