ABSTRACT
In elderly patients with COVID-19 cognitive functions decline;it has been suggested that SARS-CoV-2 infection may lead to the development of Alzheimer's disease (AD) and other long-term neurological consequences. We review several parallels between AD and COVID-19 in terms of pathogenetic mechanisms and risk factors. Possible mechanisms through which COVID-19 can initiate AD are discussed. These include systemic inflammation, hyperactivation of the renin-angiotensin system, innate immune activation, oxidative stress, and direct viral damage. It has been shown that increased expression of angiotensin-renin receptors (ACE2) may be a risk factor for COVID-19 in patients with AD. When entering the central nervous system, the SARS-CoV-2 virus can directly activate glial cell-mediated immune responses, which in turn can lead to the accumulation of beta-amyloid and the subsequent onset or progression of current AD. The involvement of inflammatory biomarkers, including interleukins (IL): IL6, IL1, as well as galectin-3, as a link between COVID-19 and AD is discussed. The rationale for the use of memantine (akatinol memantine) in patients with COVID-19 in order to prevent the development of cognitive deficits is discussed. Memantine has been shown to have a positive effect on neuroinflammatory processes in the onset or exacerbation of cognitive deficits, in reducing cerebral vasospasm and endothelial dysfunction in viral infections. Memantine therapy may improve everyday activity and reduce the risk of severe SARS-CoV-2 infection.Copyright © 2022 Ima-Press Publishing House. All rights reserved.
ABSTRACT
In elderly patients with COVID-19 cognitive functions decline;it has been suggested that SARS-CoV-2 infection may lead to the development of Alzheimer's disease (AD) and other long-term neurological consequences. We review several parallels between AD and COVID-19 in terms of pathogenetic mechanisms and risk factors. Possible mechanisms through which COVID-19 can initiate AD are discussed. These include systemic inflammation, hyperactivation of the renin-angiotensin system, innate immune activation, oxidative stress, and direct viral damage. It has been shown that increased expression of angiotensin-renin receptors (ACE2) may be a risk factor for COVID-19 in patients with AD. When entering the central nervous system, the SARS-CoV-2 virus can directly activate glial cell-mediated immune responses, which in turn can lead to the accumulation of beta-amyloid and the subsequent onset or progression of current AD. The involvement of inflammatory biomarkers, including interleukins (IL): IL6, IL1, as well as galectin-3, as a link between COVID-19 and AD is discussed. The rationale for the use of memantine (akatinol memantine) in patients with COVID-19 in order to prevent the development of cognitive deficits is discussed. Memantine has been shown to have a positive effect on neuroinflammatory processes in the onset or exacerbation of cognitive deficits, in reducing cerebral vasospasm and endothelial dysfunction in viral infections. Memantine therapy may improve everyday activity and reduce the risk of severe SARS-CoV-2 infection.Copyright © 2022 Ima-Press Publishing House. All rights reserved.
ABSTRACT
Obesity is associated with several diseases, including mental health. Adipose tissue is distributed around the internal organs, acting in the regulation of metabolism by storing and releasing fatty acids and adipokine in the tissues. Excessive nutritional intake results in hypertrophy and proliferation of adipocytes, leading to local hypoxia in adipose tissue and changes in these adipokine releases. This leads to the recruitment of immune cells to adipose tissue and the release of pro-inflammatory cytokines. The presence of high levels of free fatty acids and inflammatory molecules interfere with intracellular insulin signaling, which can generate a neuroinflammatory process. In this review, we provide an up-to-date discussion of how excessive obesity can lead to possible cognitive dysfunction. We also address the idea that obesity-associated systemic inflammation leads to neuroinflammation in the brain, particularly the hypothalamus and hippocampus, and that this is partially responsible for these negative cognitive outcomes. In addition, we discuss some clinical models and animal studies for obesity and clarify the mechanism of action of anti-obesity drugs in the central nervous system.Copyright © 2023 Wolters Kluwer Medknow Publications. All rights reserved.
ABSTRACT
Introduction: (IFITM3) is an innate immune protein that has been identified as a novel gamma-secretase (gammas) modulator. FYN is a kinase that stabilizes IFITM3 on the membrane, primes APP for amyloidogenic gammas processing and mediates tau oligomerization. The purpose of this study is to explore the role of FYN and IFITM3 in AD and COVID-19, expanding on previous research from our group. Method(s): A 520 gene signature containing FYN and IFITM3 (termed Ia) was extracted from a previously published meta-analysis of Alzheimer's disease (AD) bulk- and single nuclei sequencing data. Exploratory analyses involved meta-analysis of bulk and single cell RNA data for IFITM3 and FYN differential expression per CNS site and cellular type. Confirmatory analyses, gene set enrichment analysis (GSEA) on Ia was performed to detect overlapping enriched biological networks between COVID-19 with AD. Result(s): Bulk RNA data analysis revealed that IFITM3 and FYN were overexpressed in two CNS regions in AD vs. Controls: the temporal cortex Wilcoxon p-value=1.3e-6) and the parahippocampal cortex Wilcoxon p-value=0.012). Correspondingly, single cell RNA analysis of IFITM3 and FYN revealed that it was differentially expressed in neurons, glial and endothelial cells donated b AD patients, when compared to controls. Discussion(s): IFITM3 and FYN were found as interactors within biological networks overlapping between AD and SARS-CoV-2 infection. Within the context of SARS-CoV-2 induced tau aggregation and interactions between tau and Ab1-42, the FYN - IFITM3 regulome may outline an important innate immunity element responsive to viral infection and IFN-I signaling in both AD and COVID-19.Copyright © 2021 The Authors
ABSTRACT
Purpose : Background: Despite being primarily a respiratory disease, COVID-19 can lead to non-respiratory complications, including myocardial infarction and acute ischemic stroke. Moreover, COVID-19 spike protein (SP) was reported in the retina of deceased patients with COVID-19. Retinal microvascular abnormalities as loss of microvasculature and distinct thinning of the microcapillaries were reported in patients who recovered from COVID-19. We are still in the midst of the COVID-19 pandemic, with more deaths and cases every day. Therefore investigating the impact of COVID-19 on the retinal neurovascular environment and the long-term effect of this virus on vision is of great interest. Purpose: To study the contribution of COVID-19 SP to retinal inflammation and vascular death. Methods : Methods: COVID-19 SP, a highly glycosylated protein that allows the virus to penetrate the cell and cause infection, was injected intravitreally in 6-8 weeks global h-ACE2 knock-in mice and wild-type mice. Mice were sacrificed after 14 days, then vascular cell death and inflammation were evaluated by the presence of acellular capillaries and the expression of inflammatory and apoptotic markers. To complement our in-vivo studies, Human Microvascular Endothelial Cells (HMEC) were treated with 100 nM COVID-19 SP for 48 hours. The expression of inflammatory and apoptotic markers was assessed by PCR western blot. Results : Results: Our results showed that HMEC exposed to COVID-19 SP for 48 hours displayed an increase in inflammatory and apoptotic markers expression including TNF-α, IL-1β, IL-6, and cleaved caspase-3 compared to control conditions. Additionally, COVID-19 SP enhanced the oxidative stress in HMEC, evident by the increase in nitro-tyrosine formation, superoxide dismutase, and NADPH oxidase complex 1 (NOX1 and NOX5) expression. The in-vivo findings came in agreement with our in-vitro studies. We found that intravitreal injection of the COVID-19 SP-induced 1) strong activation of the retinal glial cells, assessed by GFAP radial staining, and 2) increased vascular death, assessed by acellular capillaries formation 14 days after the injection. Conclusions : Conclusions: Our findings highlight the possible role of COVID-19 SP in inducing retinal inflammation and vascular death. Further studies are required to reveal the impact of COVID-19 SP on visual acuity and the possibility of causing visual impairment using various animal models.
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Rationale Delirium affects a majority of critically-ill patients, increasing mortality and dementia risk. The absence of effective therapy reversing neuronal changes in delirium emphasizes the need for greater understanding of delirium pathophysiology. Neuroinflammation represents a common pathway through which delirium-triggering diseases act. Glial cells sense systemic inflammation across the blood-brain barrier and become activated, releasing cytokines within the brain. In one disease model, systemic infection with neurovirulent coronaviruses caused delirium and specifically increased levels of TNF-α, IL-1β, IL-6, IL-12 and IL-15 in the mouse brain. Methods Here, we tested how neuronal function was affected in a coronavirus-induced neurovirulent cytokine (NVC) model of delirium. Using whole-cell patch clamp methods, we examined how single neuron excitability in murine primary neocortical cultures was impacted by 22-28 hour incubation in NVC. Results NVC treatment depolarized the resting membrane potential (RMP) compared to control (-65 ± 1.6 mV versus -73 ± 1 mV;P < 0.0001, n = 37 and 31 respectively) without affecting action potential characteristics. Delirium is often diagnosed due to altered responses to external stimuli. NVC exposure altered the sensitivity of neurons to changes in external Ca2+ and Mg2+ from physiological (1.1 mM, T1.1) to low (0.2 mM, T0.2) levels. The frequency of spontaneous firing was substantially increased following T0.2 application in control but not in NVC-treated neurons (p=0.026, ANOVA, control: 0.02 ± 0.01 Hz to 2.1 ± 1.2 Hz, n=16, p=0.046;NVC: 0.5 ± 0.4 Hz to 0.9 ± 0.3 Hz, n = 15, p=0.16). Consistent with this, evoked spiking following current injection was also observed in control but not NVC-treated neurons following the switch from T1.1 to T0.2 (P = 0.006, 2WRM ANOVA, Control: 3.9 ± 1.2 Hz vs. 8.5 ± 1.3 Hz n=37, p<0.0001;NVC: 4.8 ± 1.3 Hz vs. 4.5 ± 1.0 Hz, n=31, p=0.78). The attenuated excitability observed in NVC-treated neurons was reversed by hyperpolarization of the RMP. Evoked firing was substantially improved in NVC-treated cells after correcting the RMP (p =0.049, ANOVA, Control: 7.5 ± 1.8 Hz vs. 10 ± 2.5 Hz, n=15, p=0.25;NVC: 6.7 ± 2.2 Hz vs. 11.7 ± 2.8 Hz, n=16 p=0.01). Conclusion Our studies indicate that NVC-treated neurons have attenuated sensitivity to microenvironment changes. As these changes are reversible by correction of the RMP, further characterization of the underlying pathophysiological mechanism is essential to identify biologically plausible targets for delirium.
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Objective: To describe the clinicopathological correlations of 141 confirmed postmortem cases of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome-coronavirus -2 (SARS-CoV-2). Background: Analysis of 50 cases of COVID-19 with available neuropathology revealed three CNS findings. First, hypoxia-ischemia does not account for all relevant neuropathological features. Second, elevated levels of circulating cytokines suggest activation of post-infectious immunity indicative of a cytokine storm, with increased hypercoagulability leading to a risk for thrombotic and hemorrhagic parenchymal tissue infarction. Third, a minority of cases have acute demyelinating encephalomyelitis-(ADEM) like features or indolent brainstem encephalitis. Such cases may present with early altered sensorium and brainstem signs. Fourth, SARS-CoV-2 staining could not be confirmed due to paucity of available tissue specimens. Design/Methods: Ninety-four additional cases with available postmortem CNS neuropathology showed four additional findings. Results: First, positive SARS-CoV-2 genome by PCR testing is present in brain tissues especially in olfactory bulb neurons and glial cells lending support to a route of entry into the CNS and the importance of early anosmia. Second, SARS-CoV-2-positive neurons appear to be TUNEL positive and caspase-positive, displaying reversible pT231 Tau localization in some cell soma that may be highly neurotoxic and a driver of tauopathy. Third, expression of ACE2 in oligodendrocytes is associated with viral entry, while TMPRSS2 and TMPRSS4 staining is implicated in pruning of viral-decorating spikes. Fourth, meningeal and interstitial brainstem inflammation by cytotoxic T-cells coincides with the localization of SARS-CoV-2 viral proteins in cranial nerves and interstitial areas of lower brainstem encephalitis. The detection of brain microglial activation and sparse perivascular and leptomeningeal T-cell infiltrates correlates with critical illness encephalopathy. Conclusions: Genetic diversity, recombination, and viral mutation carries the foreseeable risk of continued fatality due to the direct and indirect effects of SARS-CoV-2 that include inflammatory vasculopathy, encephalitis, silent infarctions, and critical illness encephalopathy.
ABSTRACT
Headache is one of the most prevalent disorders of the nervous system. Headache is also the most common symptom of a variety of diseases, including migraine, COVID-19. International Classification of Headache Disorders (ICHD) lists over a thousand different types of headaches. Migraine is a widely known type of primary headache. Much research supports that the enhancement in migraine intensity related to chronic migraine such as neurogenic neuroinflammation, possibly leading to increased cytokine expression via activation of protein kinases in neurons and glial cells of the trigeminovascular system like some of the other headache diseases. No currently drug class available, either specific (triptans, ergots) or non-specific (opioids, paracetamol, NSAIDs), is effective in all types of headaches, in all patients and all attacks of the same patient. However, non-steroidal anti-inflammatory drugs (NSAIDs) minimize prostaglandin synthesis by blocking cyclooxygenase, which is included in the pathophysiology of migraine headaches. We searched the employed source was The Journal of Headache and Pain database by using NSAIDs with Headache, Migraine, and COVID-19 keywords. The search was performed from April 2021 and included 2017-2018-2019-2020-2021 (last five years) the studies and reviews from the Journal of Headache and Face Pain Sites. Additionally, we noted the published or on-going studies, eight of these, about NSAIDs information contain searches that exist in the 12th European Headache Federation Congress (jointly with 32nd National Congress of the Italian Society) Study of Headaches’ book. Also, we included relationship migraine with COVID-19 studies to highlight the connection between the headache, which is one of the most common symptoms of both migraine and COVID-19, and the importance of managing migraine pain with NSAIDs during corona processing.