Clinopodium tomentosum (Kunth) Govaerts Leaf Extract Influences in vitro Cell Proliferation and Angiogenesis on Primary Cultures of Porcine Aortic Endothelial Cells

Clinopodium tomentosum (Kunth) Govaerts is an endemic species in Ecuador, where it is used as an anti-inflammatory plant to treat respiratory and digestive affections. In this work, effects of a Clinopodium tomentosum ethanolic extract (CTEE), prepared from aerial parts of the plant, were investigated on vascular endothelium functions. In particularly, angiogenesis activity was evaluated, using primary cultures of porcine aortic endothelial cells (pAECs). Cells were cultured for 24 h in the presence of CTEE different concentrations (10, 25, 50, and 100 \u3bcg/ml); no viability alterations were found in the 10-50 \u3bcg/ml range, while a slight, but significant, proliferative effect was observed at the highest dose. In addition, treatment with CTEE was able to rescue LPS-induced injury in terms of cell viability. The CTEE ability to affect angiogenesis was evaluated by scratch test analysis and by an in vitro capillary-like network assay. Treatment with 25-50\u3bcg/ml of extract caused a significant increase in pAEC\u2019s migration and tube formation capabilities compared to untreated cells, as results from the increased master junctions\u2019 number. On the other hand, CTEE at 100 \u3bcg/ml did not induce the same effects. Quantitative PCR data demonstrated that FLK-1 mRNA expression significantly increased at a CTEE dose of 25\u3bcg/ml. The CTEE phytochemical composition was assessed through HPLC-DAD; rosmarinic acid among phenolic acids and hesperidin among flavonoids were found as major phenolic components. Total phenolic content and total flavonoid content assays showed that flavonoids are the most abundant class of polyphenols. The CTEE antioxidant activity was also showed by means of the DPPH and ORAC assays. Results indicate that CTEE possesses an angiogenic capacity in a dose-dependent manner; this represents an initial step in elucidating the mechanism of the therapeutic use of the plant

Cognitive sequealae of COVID-19 is not predicted by SARS-CoV-2 variants

Background: The long term sequelae of COVID-19 in older adults are only beginning to be clarified, and its predictors and underlying molecular mechanisms may shed light on the relationship between viral infections and Alzheimer\u27s disease and related dementia. Method: A prospective cohort of 874 older adult Amerindians from Argentina with COVID-19 illness confirmed by PCR of nasal swabs as well as controls, was established during the first year of the COVID-19 pandemic. We obtained data on the severity of the acute illness, as well as extensive neuropsychiatric and cognitive assessments, neurological exams (including quantitative hyposmia/anosmia), plasma for biomarkers and preliminary brain MRI images using the ADNI-3 protoco (n=300)l,and whole genome sequencing (n=300). Isolates from SARS-CoV-2 were obtained by the provincial Direction of Epidemiology and sequenced by the national Ministry of Health. Variants of interest/concern were allocated to each case on the basis of the prevalent community isolate at the time of confirmed positive PCR. A deep learning strategy was used to identify predictive factors of cognitive and clinical outcomes. Result: Four distinctive cognitive profiles were identified. Greater cognitive impairment was associated with older age (p = E-9), worse acute COVID-19 illness (p=0.008), unvaccinated status (p = E-7), and severity of anosmia (p = E-5). SARS-CoV-2 variant was associated with severity of acute illness ((p = E-6) but notably not with cognitive impairment. Preliminary analysis of genomic and brain imaging data will be presented. Conclusion: Our data strongly suggest that all SARS-CoV-2 variants of interest up to the omicron wave seem equally likely to result in cognitive impairment in older adults, modulated by the severity of the acute illness

Olfactory dysfunction but not COVID-19 severity predicts severity of cognitive sequelae following SARS-CoV-2 infection in Amerindian older adults

Abstract Background: COVID-19 has affected more than 380 million people. Infections may result in long term sequelae, including neuropsychiatric symptoms. In older adults COVID-19 sequelae resemble early Alzheimer’s disease, and may share risk factors and blood biomarkers with it. The Alzheimer’s Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) established harmonized definitions, ascertainment and assessment methodologies to evaluate and longitudinally follow up cohorts of older adults with exposure to COVID-19. We present one year data in a prospective cohort from Argentina. Method: Participants (n = 766) are older adults (≥60 years) recruited from the provincial health registry containing all SARS-CoV-2 testing data. We randomly invite older adults stratified by PCR COVID-19 testing status regardless of symptom severity, between 3 and 6 months after recovery. Assessment includes interview with the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and Clinical Dementia Rating scale (CDR); neurocognitive assessment; emotional reactivity scale; and neurological assessment including semiquantitative olfactory function test, motor function, coordination and gait. Result: We assessed 88.4% infected participants and 11.6 % controls. Education is 10.36 ± 5.6 years and age is 66.9 ± 6.14 years. Level of care during COVID-19 is described in Figure 1. Normalized cognitive Z-scores categorize the cohort in 3 groups with decreased performance compared to normal cognition: memory only impairment (Single-domain,11.7%); impairment in attention+executive function without memory impairment (Two-domain, 8.3%); and multiple domain impairment (Multiple domain,11.6%). Logistic regression showed that severity of anosmia, but not clinical status, significantly predicts cognitive impairment. No controls had olfactory dysfunction. Cognitive impairment is defined as Z-scores below (- 2) (Table 1). Clinical assessment with SCAN revealed functional memory impairment in two thirds of infected patients (CDR ≥ 1), which was severe in half of them. Phone-based follow up at 1 year revealed high adherence (4 participants declined). Five were deceased at follow up. Rates of re-infection (between 10 and 23%) were not affected by the vaccination schedule (Table 2). Conclusion: The longitudinal cohort had very high adherence. Persistent cognitive and functional impairment after SARS-CoV-2 infection is predicted by persistent anosmia but not by the severity of the initial COVID-19 disease

Evolution of SARS-CoV-2 during the first year of the COVID-19 pandemic in Northwestern Argentina

Studies about the evolution of SARS-CoV-2 lineages in different backgrounds such as naive populations are still scarce, especially from South America. This work aimed to study the introduction and diversification pattern of SARS-CoV-2 during the first year of the COVID-19 pandemic in the Northwestern Argentina (NWA) region and to analyze the evolutionary dynamics of the main lineages found. In this study, we analyzed a total of 260 SARS-CoV-2 whole-genome sequences from Argentina, belonging to the Provinces of Jujuy, Salta, and Tucumán, from March 31st, 2020, to May 22nd, 2021, which covered the full first wave and the early second wave of the COVID-19 pandemic in Argentina. In the first wave, eight lineages were identified: B.1.499 (76.9%), followed by N.5 (10.2%), B.1.1.274 (3.7%), B.1.1.348 (3.7%), B.1 (2.8%), B.1.600 (0.9%), B.1.1.33 (0.9%) and N.3 (0.9%). During the early second wave, the first-wave lineages were displaced by the introduction of variants of concern (VOC) (Alpha, Gamma), or variants of interest (VOI) (Lambda, Zeta, Epsilon) and other lineages with more limited distribution. Phylodynamic analyses of the B.1.499 and N.5, the two most prevalent lineages in the NWA, revealed that the rate of evolution of lineage N.5 (7.9 × 10−4 substitutions per site per year, s/s/y) was a ∼40% faster than that of lineage B.1.499 (5.6 × 10−4 s/s/y), although both are in the same order of magnitude than other non-VOC lineages. No mutations associated with a biological characteristic of importance were observed as signatures markers of the phylogenetic groups established in Northwestern Argentina, however, single sequences in non-VOC lineages did present mutations of biological importance or associated with VOCs as sporadic events, showing that many of these mutations could emerge from circulation in the general population. This study contributed to the knowledge about the evolution of SARS-CoV-2 in a pre-vaccination and without post-exposure immunization period.Instituto de Patología VegetalFil: Zambrana Montaño, Romina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones en Bacteriología y Virología Molecular; ArgentinaFil: Zambrana Montaño, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Culasso, Andrés Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones en Bacteriología y Virología Molecular; ArgentinaFil: Culasso, Andrés Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fernandez, Franco Daniel. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Patología Vegetal; ArgentinaFil: Fernandez, Franco Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Unidad de Fitopatología y Modelización Agrícola (UFyMA); ArgentinaFil: Marquez, Nathalie. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Patología Vegetal; ArgentinaFil: Marquez, Nathalie. Consejo Nacional de Investigaciones Científicas y Técnicas. Unidad de Fitopatología y Modelización Agrícola (UFyMA); ArgentinaFil: Debat, Humberto Julio. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Patología Vegetal; ArgentinaFil: Debat, Humberto Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Unidad de Fitopatología y Modelización Agrícola (UFyMA); ArgentinaFil: Salmerón, Mariana. Laboratorio de Salud Pública; ArgentinaFil: Zamora, Ana María. Laboratorio de Salud Pública; ArgentinaFil: Ruíz de Huidobro, Gustavo. Laboratorio de Salud Pública; ArgentinaFil: Costas, Dardo. Laboratorio de Salud Pública; ArgentinaFil: Alabarse, Graciela. Laboratorio de Salud Pública; ArgentinaFil: Charre, Miguel Alejandro. Laboratorio Central de Salud Pública, San Salvador de Jujuy; ArgentinaFil: Fridman, Ariel David. Laboratorio Central de Salud Pública. San Salvador de Jujuy; ArgentinaFil: Mamani, Claudia. Laboratorio Central de Salud Pública. San Salvador de Jujuy; ArgentinaFil: Vaca, Fabiana. Laboratorio Central de Salud Pública. San Salvador de Jujuy; ArgentinaFil: Maza Diaz, Claudia. Laboratorio Central de Salud Pública. San Salvador de Jujuy; ArgentinaFil: Raskovsky, Viviana. Hospital Señor del Milagro. Laboratorio de Virus Respiratorios y Neurovirosis; ArgentinaFil: Lavaque, Esteban. Hospital Señor del Milagro. Laboratorio de Virus Respiratorios y Neurovirosis; ArgentinaFil: Lesser, Veronica. Hospital Señor del Milagro. Laboratorio de Virus Respiratorios y Neurovirosis; ArgentinaFil: Cajal, Pamela. Hospital Señor del Milagro. Laboratorio de Virus Respiratorios y Neurovirosis; ArgentinaFil: Agüero, Fernanda. Hospital Señor del Milagro. Laboratorio de Virus Respiratorios y Neurovirosis; ArgentinaFil: Calvente, Cintia. Hospital Señor del Milagro. Laboratorio de Virus Respiratorios y Neurovirosis; ArgentinaFil: Torres, Carolina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones en Bacteriología y Virología Molecular; ArgentinaFil: Torres, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Viegas, Mariana. Hospital de Niños Dr. Ricardo Gutiérrez. Laboratorio de Virología; Argentin

Chronic neuropsychiatric sequelae of SARS‐CoV‐2: Protocol and methods from the Alzheimer's Association Global Consortium

Introduction: Coronavirus disease 2019 (COVID‐19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID‐19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID‐19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID‐19 to neurologic illness, both short and long term. Methods: This article describes what is known so far in terms of links among COVID‐19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS‐CoV‐2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions. Results: Successful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe. Discussion: The Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long‐term neurocognitive sequelae of SARS‐CoV‐2 infection. Key Points: The following review describes what is known so far in terms of molecular and epidemiological links among COVID‐19, the brain, neurological symptoms, and AD and related dementias (ADRD) The primary objective of this large‐scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long‐term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS‐CoV‐2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS‐CoV‐2 triggers ADRD‐like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility. The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under‐represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long‐term consequences, and trends in cognitive aging, ADRD, and vascular disease. We provide a framework for current and future studies to be carried out within the Consortium. and offers a “green paper” to the research community with a very broad, global base of support, on tools suitable for low‐ and middle‐income countries aimed to compare and combine future longitudinal data on the topic. The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID‐19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high‐quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations

Chronic neuropsychiatric sequelae of SARS‐CoV‐2: Protocol and methods from the Alzheimer's Association Global Consortium

Abstract Introduction Coronavirus disease 2019 (COVID‐19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID‐19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID‐19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID‐19 to neurologic illness, both short and long term. Methods This article describes what is known so far in terms of links among COVID‐19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS‐CoV‐2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions. Results Successful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe. Discussion The Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long‐term neurocognitive sequelae of SARS‐CoV‐2 infection. Key Points The following review describes what is known so far in terms of molecular and epidemiological links among COVID‐19, the brain, neurological symptoms, and AD and related dementias (ADRD) The primary objective of this large‐scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long‐term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS‐CoV‐2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS‐CoV‐2 triggers ADRD‐like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility. The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under‐represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long‐term consequences, and trends in cognitive aging, ADRD, and vascular disease. We provide a framework for current and future studies to be carried out within the Consortium. and offers a “green paper” to the research community with a very broad, global base of support, on tools suitable for low‐ and middle‐income countries aimed to compare and combine future longitudinal data on the topic. The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID‐19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high‐quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations

Chronic neuropsychiatric sequelae of SARS-CoV-2: Protocol and methods from the Alzheimer's Association Global Consortium.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID-19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID-19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID-19 to neurologic illness, both short and long term. METHODS: This article describes what is known so far in terms of links among COVID-19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions. RESULTS: Successful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe. DISCUSSION: The Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long-term neurocognitive sequelae of SARS-CoV-2 infection. KEY POINTS: The following review describes what is known so far in terms of molecular and epidemiological links among COVID-19, the brain, neurological symptoms, and AD and related dementias (ADRD)The primary objective of this large-scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long-term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS-CoV-2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS-CoV-2 triggers ADRD-like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility.The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under-represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long-term consequences, and trends in cognitive aging, ADRD, and vascular disease.We provide a framework for current and future studies to be carried out within the Consortium. and offers a "green paper" to the research community with a very broad, global base of support, on tools suitable for low- and middle-income countries aimed to compare and combine future longitudinal data on the topic.The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID-19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high-quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations