Type I interferon signaling, cognition and neurodegeneration following COVID-19: update on a mechanistic pathogenetic model with implications for Alzheimer's disease.

COVID-19's effects on the human brain reveal a multifactorial impact on cognition and the potential to inflict lasting neuronal damage. Type I interferon signaling, a pathway that represents our defense against pathogens, is primarily affected by COVID-19. Type I interferon signaling, however, is known to mediate cognitive dysfunction upon its dysregulation following synaptopathy, microgliosis and neuronal damage. In previous studies, we proposed a model of outside-in dysregulation of tonic IFN-I signaling in the brain following a COVID-19. This disruption would be mediated by the crosstalk between central and peripheral immunity, and could potentially establish feed-forward IFN-I dysregulation leading to neuroinflammation and potentially, neurodegeneration. We proposed that for the CNS, the second-order mediators would be intrinsic disease-associated molecular patterns (DAMPs) such as proteopathic seeds, without the requirement of neuroinvasion to sustain inflammation. Selective vulnerability of neurogenesis sites to IFN-I dysregulation would then lead to clinical manifestations such as anosmia and cognitive impairment. Since the inception of our model at the beginning of the pandemic, a growing body of studies has provided further evidence for the effects of SARS-CoV-2 infection on the human CNS and cognition. Several preclinical and clinical studies have displayed IFN-I dysregulation and tauopathy in gene expression and neuropathological data in new cases, correspondingly. Furthermore, neurodegeneration identified with a predilection for the extended olfactory network furthermore supports the neuroanatomical concept of our model, and its independence from fulminant neuroinvasion and encephalitis as a cause of CNS damage. In this perspective, we summarize the data on IFN-I as a plausible mechanism of cognitive impairment in this setting, and its potential contribution to Alzheimer's disease and its interplay with COVID-19.

Extracranial internal carotid aneurysm treated with a covered stent in an infant.

BACKGROUND: Extracranial internal carotid aneurysms consist a rare pathology with an overall incidence less than 1% in the general population, and warrant treatment due to their association with cerebrovascular events and neurological complications. The incidence is even lower in the pediatric population. CASE REPORT: A 14-month infant presented in our clinic with neck swelling of unknown origin, with subsequent MR imaging revealing an extracranial internal carotid aneurysm. Due to the patient's age and risk of surgical complications, the decision to proceed with endovascular repair with stent placement and complete exclusion of the aneurysm from the circulation was made, after multidisciplinary consultation. RESULTS: In the pediatric population, pediatric population, endovascular stent placement can be considered at least as a last resort treatment when surgical access harbors significant risks or is impossible.

Trained immunity in viral infections, Alzheimer's disease and multiple sclerosis: A convergence in type I interferon signalling and IFNß-1a.

Type I interferon (IFN-I) signalling represents a major target for modulation in a virus' bid for latency. IFN-I perturbations are also present in such as Alzheimer's disease (AD) and multiple sclerosis (MS), where viral infections are known to increase symptomatic burden. IFN-I modulation such as via IFNß-1a, an established MS treatment, has been researched to a limited extent to both AD and COVID-19. In this mini review, we present emerging research on trained immunity as a pathogenetic basis for Alzheimer's disease and the emerging context for IFNß-1a repositioning, via mechanisms shared with multiple sclerosis and induced by viral infections.

Acute but not sustained aromatase inhibition displays antidepressant properties.

Aromatase inhibitors block the conversion of androgens to oestrogens and are used for the treatment of hormone-responsive breast cancer in menopause and recently also in premenopausal women. We investigate whether decreased oestrogen synthesis following aromatase inhibition leads to a depressive-like behavioural response in cycling female rats. Using the forced swim test (FST) we estimate the response of acute (three injections in 24 h) and sustained (7 d) letrozole and fluoxetine administration. Acute aromatase inhibition decreases immobility duration in the FST, indicating its antidepressant potential. Instead, sustained aromatase inhibition did not show such antidepressant potential. Testosterone elevation associates with the decreased depressive behaviour in the FST following acute letrozole treatment, but interestingly progesterone explains the increased swimming behaviour. Present findings may have potential implications for women treated with aromatase inhibitors, especially before menopause, as well as for the role of gonadal hormones in the expression of depressive symptoms and antidepressant response.