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.

Neurocognitive Impairment and Social Cognition in Parkinson's Disease Patients.

In addition to motor symptoms, neurocognitive impairment (NCI) affects patients with prodromal Parkinson's disease (PD). NCI in PD ranges from subjective cognitive complaints to dementia. The purpose of this review is to present the available evidence of NCI in PD and highlight the heterogeneity of NCI phenotypes as well as the range of factors that contribute to NCI onset and progression. A review of publications related to NCI in PD up to March 2023 was performed using PubMed/Medline. There is an interconnection between the neurocognitive and motor symptoms of the disease, suggesting a common underlying pathophysiology as well as an interconnection between NCI and non-motor symptoms, such as mood disorders, which may contribute to confounding NCI. Motor and non-motor symptom evaluation could be used prognostically for NCI onset and progression in combination with imaging, laboratory, and genetic data. Additionally, the implications of NCI on the social cognition of afflicted patients warrant its prompt management. The etiology of NCI onset and its progression in PD is multifactorial and its effects are equally grave as the motor effects. This review highlights the importance of the prompt identification of subjective cognitive complaints in PD patients and NCI management.

Effects of High Efficacy Multiple Sclerosis Disease Modifying Drugs on the Immune Synapse: A Systematic Review.

BACKGROUND: Co-signaling and adhesion molecules are important elements for creating immune synapses between T lymphocytes and antigen-presenting cells; they positively or negatively regulate the interaction between a T cell receptor with its cognate antigen, presented by the major histocompatibility complex. OBJECTIVES: We conducted a systematic review on the effects of High Efficacy Disease Modifying Drugs (HEDMDs) for Multiple Sclerosis (MS) on the co-signaling and adhesion molecules that form the immune synapse. METHODS: We searched EMBASE, MEDLINE, and other sources to identify clinical or preclinical reports on the effects of HEDMDs on co-signaling and adhesion molecules that participate in the formation of immune synapses in patients with MS or other autoimmune disorders. We included reports on cladribine tablets, anti- CD20 monoclonal antibodies, S1P modulators, inhibitors of Bruton's Tyrosine Kinase, and natalizumab. RESULTS: In 56 eligible reports among 7340 total publications, limited relevant evidence was uncovered. Not all co-signaling and adhesion molecules have been studied in relation to every HEDMD, with more data being available on the anti-CD20 monoclonal antibodies (that affect CD80, CD86, GITR and TIGIT), cladribine tablets (affecting CD28, CD40, ICAM-1, LFA-1) and the S1P modulators (affecting CD86, ICAM-1 and LFA-1) and less on Natalizumab (affecting CD80, CD86, CD40, LFA-1, VLA-4) and Alemtuzumab (affecting GITR and CTLA-4). CONCLUSION: The puzzle of HEDMD effects on the immune synapse is far from complete. The available evidence suggests that distinguishing differences exist between drugs and are worth pursuing further.

Sleep disorders and Alzheimer's disease pathophysiology: The role of the Glymphatic System. A scoping review.

BACKGROUND: Alzheimer's disease (AD) is highly intertwined with sleep disturbances throughout its whole natural history. Sleep consists of a major compound of the functionality of the glymphatic system, as the synchronized slow-wave activity during NREM facilitates cerebrospinal and interstitial long-distance mixing. OBJECTIVE: The present study undertakes a scoping review of research on the involvement of the glymphatic system in AD-related sleep disturbances. DESIGN: we searched Medline, Embase, PsychInfo and HEAL-link databases, without limitations on date and language, along with reference lists of relevant reviews and all included studies. We included in vivo, in vitro and post-mortem studies examining glymphatic implications of sleep disturbances in human populations with AD spectrum pathology. A thematic synthesis of evidence based on the extracted content was applied and presented in a narrative way. RESULTS: In total, 70 original research articles were included and were grouped as following: a) Protein aggregation and toxicity, after sleep deprivation, along with its effects on sleep architecture, b) Glymphatic Sequalae in SDB, yielding potential glymphatic markers c) Circadian Dysregulation, d) Possible Interventions. CONCLUSIONS: this review sought to provide insight into the role of sleep disturbances in AD pathogenesis, in the context of the glymphatic disruption.

Social Cognition Impairments in Association to Clinical, Cognitive, Mood, and Fatigue Features in Multiple Sclerosis: A Study Protocol.

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS), characterized by the diffuse grey and white matter damage. Cognitive impairment (CI) is a frequent clinical feature in patients with MS (PwMS) that can be prevalent even in early disease stages, affecting the physical activity and active social participation of PwMS. Limited information is available regarding the influence of MS in social cognition (SC), which may occur independently from the overall neurocognitive dysfunction. In addition, the available information regarding the factors that influence SC in PwMS is limited, e.g., factors such as a patient's physical disability, different cognitive phenotypes, mood status, fatigue. Considering that SC is an important domain of CI in MS and may contribute to subjects' social participation and quality of life, we herein conceptualize and present the methodological design of a cross-sectional study in 100 PwMS of different disease subtypes. The study aims (a) to characterize SC impairment in PwMS in the Greek population and (b) to unveil the relationship between clinical symptoms, phenotypes of CI, mood status and fatigue in PwMS and the potential underlying impairment on tasks of SC.

Pulmonary Function Test: Relationship Between Adolescent Swimmers and Finswimmers.

INTRODUCTION: The aim of our study was to investigate the effects of training on the static and dynamic respiratory parameters in adolescent female swimmers (SWs) and finswimmers (FSWs). METHODS:  Forty-six female adolescent SWs (n=24, age=17.6±0.7 years) and FSWs (n=22, age=17.0±1.2 years) volunteered for this study. All participants underwent standard spirometry and lung volume measurements and were collected anthropometrical and morphological characteristics. RESULTS: The results of the groups in the pulmonary function test parameters, namely, inspiratory capacity (IC), expiratory reserve volume (ERV), and peak expiratory flow (PEF), were significantly different. Higher values of IC, ERV, and PEF were observed in the FSW group than the SW group: IC = 116.5±13.2 (SWs) vs. 125.5±11.5 (FSWs) % of predicted, p = 0.019; ERV = 121.8±14.8 (SWs) vs. 130.6±12.5 (FSWs) % of predicted, p = 0.036; PEF = 111.6±7.5 (SWs) vs. 116.3±5.0 (FSWs) % of predicted, p = 0.018. CONCLUSION:  The differences between groups probably reflect the activation of different muscle groups.

A novel conceptual framework for the functionality of the glymphatic system.

The glymphatic system is responsible for the clearance of the potentially harmful metabolic waste of the central nervous system. The prevalent theory is that the cerebrospinal fluid (CSF) circulates in the perivascular space (PVS) and through the astrocytes' aquaporin-4 channels (AQ-4), and it is then drained by the lymphatic vessels after mixing with interstitial fluid (ISF). However, there is little evidence supporting this hypothesis. A deeper understanding of the physiology of the glymphatic system could transform the way we understand neuropathology and our approach to treating neurological and neuropsychiatric disorders. In this review, we introduce a new conceptual framework for the functionality of the glymphatic system, offering new directions for future research. We propose that CSF and ISF exchange flow depends on arterial pulsation, respiration, posture, and sleep. PVS changes due to disrupted cerebral autoregulation, alternations of intrathoracic pressure, venous flow, and body position can also influence the glymphatic flow. The role of respiration remains controversial due to the variety of parameters that interfere with glymphatic functionality. Slow-wave sleep is important for glymphatic clearance due to neuronal electromagnetic synchronization and expansion of the interstitial space. Therefore, sleep and vascular disorders, as well as aging, may hinder glymphatic flow and induce a noxious milieu of susceptibility to neurodegenerative disorders because of metabolic waste accumulation. We lastly introduce a new idea postulating that electromagnetic induction may constitute one of the propelling forces for the convectional current and mixing of CSF and ISF.

Breathlessness and exercise with virtual reality system in long-post-coronavirus disease 2019 patients.

Long-post-coronavirus disease-2019 (COVID-19) patients tend to claim residual symptomatology from various systems, most importantly the respiratory and central nervous systems. Breathlessness and brain fog are the main complaints. The pulmonary function pattern is consistent with restrictive defects, which, in most cases, are self-resolved, while the cognitive profile may be impaired. Rehabilitation is an ongoing field for holistic management of long-post-COVID-19 patients. Virtual reality (VR) applications may represent an innovative implementation of rehabilitation. We aimed to investigate the effect of exercise with and without the VR system and to assess further breathlessness and functional fitness indicators in long-post-COVID-19 patients with mild cognitive impairment after self-selected exercise duration using the VR system. Twenty long-post-COVID-19 patients were enrolled in our study (age: 53.9 ± 9.1 years, male: 80%, body mass index: 28.1 ± 3.1 kg/m2). Participants' anthropometric data were recorded, and they underwent pulmonary functional test evaluation as well as sleep quality and cognitive assessment. The participants randomly exercised with and without a VR system (VR vs. no-VR) and, later, self-selected the exercise duration using the VR system. The results showed that exercise with VR resulted in a lower dyspnea score than exercise without VR. In conclusion, VR applications seem to be an attractive and safe tool for implementing rehabilitation. They can enhance performance during exercise and benefit patients with both respiratory and cognitive symptoms.

Selenium, Stroke, and Infection: A Threefold Relationship; Where Do We Stand and Where Do We Go?

Stroke is currently the second most common cause of death worldwide and a major cause of serious long-term morbidity. Selenium is a trace element with pleotropic effects on human health. Selenium deficiency has been associated with a prothrombotic state and poor immune response, particularly during infection. Our aim was to synthesize current evidence on the tripartite interrelationship between selenium levels, stroke, and infection. Although evidence is contradictory, most studies support the association between lower serum selenium levels and stroke risk and outcomes. Conversely, limited evidence on the role of selenium supplementation in stroke indicates a potentially beneficial effect of selenium. Notably, the relationship between stroke risk and selenium levels is bimodal rather than linear, with higher levels of serum selenium linked to disturbances of glucose metabolism and high blood pressure, morbidities which are, in turn, substrates for stroke. Another such substrate is an infection, albeit forming a bidirectional relationship with both stroke and the consequences of impaired selenium metabolism. Perturbed selenium homeostasis leads to impaired immune fitness and antioxidant capacity, which both favor infection and inflammation; specific pathogens may also contend with the host for transcriptional control of the selenoproteome, adding a feed-forward loop to this described process. Broader consequences of infection such as endothelial dysfunction, hypercoagulation, and emergent cardiac dysfunction both provide stroke substrates and further feed-forward feedback to the consequences of deficient selenium metabolism. In this review, we provide a synthesis and interpretation of these outlined complex interrelationships that link selenium, stroke, and infection and attempt to decipher their potential impact on human health and disease. Selenium and the unique properties of its proteome could provide both biomarkers and treatment options in patients with stroke, infection, or both.

Athletes with mild post-COVID-19 symptoms experience increased respiratory and metabolic demands: Α cross-sectional study.

Coronavirus Disease 2019 (COVID-19) has significantly affected different physiological systems, with a potentially profound effect on athletic performance. However, to date, such an effect has been neither addressed nor investigated. Therefore, the aim of this study was to investigate fitness indicators, along with the respiratory and metabolic profile, in post-COVID-19 athletes. Forty male soccer players, were divided into two groups: non-hospitalized COVID-19 (n = 20, Age: [25.2 ±â€¯4.1] years, Body Surface Area [BSA]: [1.9 ±â€¯0.2] m2, body fat: 11.8% ±â€¯3.4%) versus [vs] healthy (n = 20, Age: [25.1 ±â€¯4.4] years, BSA: [2.0 ±â€¯0.3] m2, body fat: 10.8% ±â€¯4.5%). For each athlete, prior to cardiopulmonary exercise testing (CPET), body composition, spirometry, and lactate blood levels, were recorded. Differences between groups were assessed with the independent samples t-test (p < 0.05). Several differences were detected between the two groups: ventilation (V˙E: Resting: [14.7 ±â€¯3.1] L·min-1 vs. [11.5 ±â€¯2.6] L·min-1, p = 0.001; Maximal Effort: [137.1 ±â€¯15.5] L·min-1 vs. [109.1 ±â€¯18.4] L·min-1, p < 0.001), ratio VE/maximal voluntary ventilation (Resting: 7.9% ±â€¯1.8% vs. 5.7% ±â€¯1.7%, p < 0.001; Maximal Effort: 73.7% ±â€¯10.8% vs. 63.1% ±â€¯9.0%, p = 0.002), ratioVE/BSA (Resting: 7.9% ±â€¯2.0% vs. 5.9% ±â€¯1.4%, p = 0.001; Maximal Effort: 73.7% ±â€¯11.1% vs. 66.2% ±â€¯9.2%, p = 0.026), heart rate (Maximal Effort: [191.6 ±â€¯7.8] bpm vs. [196.6 ±â€¯8.6] bpm, p = 0.041), and lactate acid (Resting: [1.8 ±â€¯0.8] mmol·L-1 vs. [0.9 ±â€¯0.1] mmol·L-1, p < 0.001; Maximal Effort: [11.0 ±â€¯1.6] mmol·L-1 vs. [9.8 ±â€¯1.2] mmol·L-1, p = 0.009), during CPET. No significant differences were identified regarding maximal oxygen uptake ([55.7 ±â€¯4.4] ml·min-1·kg-1 vs. [55.4 ±â€¯4.6] ml·min-1·kg-1, p = 0.831). Our findings demonstrate a pattern of compromised respiratory function in post-COVID-19 athletes characterized by increased respiratory work at both rest and maximum effort as well as hyperventilation during exercise, which may explain the reported increased metabolic needs.

Stroke risk in multiple sclerosis: a critical appraisal of the literature.

Observational studies suggest that the occurrence of stroke on multiple sclerosis (MS) patients is higher compared to the general population. MS is a heterogeneous disease that involves an interplay of genetic, environmental and immune factors. The occurrence of stroke is subject to a wide range of both modifiable and non-modifiable, short- and long-term risk factors. Both MS and stroke share common risk factors. The immune mechanisms that underlie stroke are similar to neurodegenerative diseases and are attributed to neuroinflammation. The inflammation in autoimmune diseases may, therefore, predispose to an increased risk for stroke or potentiate the effect of conventional stroke risk factors. There are, however, additional determinants that contribute to a higher risk and incidence of stroke in MS. Due to the challenges that are associated with their differential diagnosis, the objective is to present an overview of the factors that may contribute to increased susceptibility or occurrence of stroke in MSpatients by performing a review of the available to date literature. As both MS and stroke can individually detrimentally affect the quality of life of afflicted patients, the identification of factors that contribute to an increased risk for stroke in MS is crucial for the prompt implementation of preventative therapeutic measures to limit the additive burden that stroke imposes.

Type I interferon signaling in SARS-CoV-2 associated neurocognitive disorder (SAND): Mapping host-virus interactions to an etiopathogenesis.

Epidemiological, clinical, and radiological studies have provided insights into the phenomenology and biological basis of cognitive impairment in COVID-19 survivors. Furthermore, its association with biomarkers associated with neuroinflammation and neurodegeneration supports the notion that it is a distinct aspect of LongCOVID syndrome with specific underlying biology. Accounting for the latter, translational studies on SARS-CoV-2's interactions with its hosts have provided evidence on type I interferon dysregulation, which is seen in neuroinflammatory and neurodegenerative diseases. To date, studies attempting to describe this overlap have only described common mechanisms. In this manuscript, we attempt to propose a mechanistic model based on the host-virus interaction hypothesis. We discuss the molecular basis for a SARS-CoV-2-associated neurocognitive disorder (SAND) focusing on specific genes and pathways with potential mechanistic implications, several of which have been predicted by Vavougios and their research group. Furthermore, our hypothesis links translational evidence on interferon-responsive gene perturbations introduced by SARS-CoV-2 and known dysregulated pathways in dementia. Discussion emphasizes the crosstalk between central and peripheral immunity via danger-associated molecular patterns in inducing SAND's emergence in the absence of neuroinfection. Finally, we outline approaches to identifying targets that are both testable and druggable, and could serve in the design of future clinical and translational studies.

The Comparative Superiority of SARS-CoV-2 Antibody Response in Different Immunization Scenarios.

Background: Both SARS-CoV-2 infection and/or vaccination result in the production of SARS-CoV-2 antibodies. We aimed to compare the antibody titers against SARS-CoV-2 in different scenarios for antibody production. Methods: A surveillance program was conducted in the municipality of Deskati in January 2022. Antibody titers were obtained from 145 participants while parallel recording their infection and/or vaccination history. The SARS-CoV-2 IgG II Quant method (Architect, Abbott, IL, USA) was used for antibody testing. Results: Advanced age (>56 years old) was associated with higher antibody titers. No significant differences were detected in antibody titers among genders, BMI, smoking status, comorbidities, vaccine brands, and months after the last dose. Hospitalization length and re-infection were predictors of antibody titers. The individuals who were fully or partially vaccinated and were also double infected had the highest antibody levels (25,017 ± 1500 AU/mL), followed by people who were fully vaccinated (20,647 ± 500 AU/mL) or/partially (15,808 ± 1800 AU/mL) vaccinated and were infected once. People who were only vaccinated had lower levels of antibodies (9946 ± 300 AU/mL), while the lowest levels among all groups were found in individuals who had only been infected (1124 ± 200 AU/mL). Conclusions: Every hit (infection or vaccination) gives an additional boost to immunization status.

Evaluation of Sirtuin 1 Levels in Peripheral Blood Mononuclear Cells of Patients With Idiopathic Pulmonary Fibrosis.

AIM: Idiopathic pulmonary fibrosis (IPF) is a devastating lung disorder that is characterized by aggressive and dysbalanced wound healing. IPF is mainly a disease of the elderly and thus is likely to share common pathophysiologic mechanisms with other more age-related diseases. Emerging evidence has linked disturbance of sirtuin-1 (SIRT1) expression and activity with aging and diseases of the elderly. In the present study, we aimed to evaluate SIRT1 expression in the peripheral blood mononuclear cells (PBMCs) of patients with IPF given the lack of studies in the literature. METHODS: We enrolled 34 IPF patients and 22 healthy volunteers (age and sex-matched). In both groups, SIRT1 levels were assessed in plasma, cell pellets of PBMCs, and supernatant from PBMCs' culture with and without the addition of 10% human serum. We also measured transforming growth factor ß1 (TGF-ß1) concentration in plasma from IPF patients and controls. RESULTS: The mean (SD) age (years) of the healthy volunteers was 68.57±6.97 and of the IPF patients was 71.28±5.39 years (p>0.05). The mean SIRT1 concentration was found significantly decreased in the supernatant of PBMCs culture (without the addition of serum) in IPF subjects versus controls (1.97±0.59 ng/ml versus 2.40±0.74 ng/ml, respectively, p=0.047). No significant differences were observed between the two groups in the SIRT1 concentration of all the other materials. TGFß1 concentration of IPF subjects was significantly increased when compared to controls (1281.38±2742.74 versus 131.11±156.06 ng/ml, respectively, p=0.032). Decreased SIRT1 levels in no-serum supernatant were predictive of IPF, after adjustment for age and sex (p=0.014, OR=0.124 [95%CI: 0.023-0.653]). CONCLUSION: The findings of decreased concentration of SIRT1 in PBMCs supernatant and increased concentration of TGFß1 in plasma in IPF patients versus controls provide important insights into the role of SIRT1 in IPF and could serve as a tool for the diagnosis and evaluation of patients with IPF.

Tele-Exercise in Non-Hospitalized versus Hospitalized Post-COVID-19 Patients.

The purpose of our study was to investigate the effect of tele-exercise (TE) performed for 4 consecutive weeks on fitness indicators in hospitalized post-COVID-19 patients versus non-hospitalized patients. Forty COVID-19 survivors were included, and divided into two groups: non-hospitalized versus hospitalized. Body composition, anthropometric characteristics, pulmonary function tests, single-breath diffusing capacity for carbon monoxide, 6-min walk tests (6MWT) and handgrip strength tests were recorded before and after a TE regimen (3 sessions per week, 60 min each session, warm-up and cool-down with mobility exercises, aerobic exercise such as walking outdoors, and multi-joint strength exercises). Following TE, the 6-min walk distance and handgrip were increased in both groups, with a greater observed response in the non-hospitalized group (6MWT: 32.9 ± 46.6% vs. 18.5 ± 14.3%, p < 0.001; handgrip: 15.9 ± 12.3% vs. 8.9 ± 7.6%, p < 0.001). Self-assessed dyspnea and leg fatigue were reduced in both groups, while a higher percentage of reduction was observed in the non-hospitalized group (dyspnea: 62.9 ± 42.5% vs. 37.5 ± 49.0%, p < 0.05; leg fatigue: 50.4 ± 42.2% vs. 31.7 ± 45.1%, p < 0.05). Post- vs. pre-TE arterial blood pressure decreased significantly in both groups, with the hospitalized group exhibiting more prominent reduction (p < 0.001). Both groups benefited from the TE program, and regardless of the severity of the disease the non-hospitalized group exhibited a potentially diminished adaptative response to exercise, compared to the hospitalized group.

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.

Restless legs syndrome due to brainstem stroke: A systematic review.

Restless Legs Syndrome (RLS) is a sleep-related movement disorder, which can also result from brainstem pathology. A systematic review of articles published in the electronic databases PubMed and Web of Science was conducted to summarize the existent literature on RLS associated with a brainstem stroke. We identified eight articles including 19 subjects with RLS due to brainstem ischemic lesion. The symptoms occurred simultaneously with the infarction (66.7%) or few days after (33.3%). The most common location of infarction was pons and less commonly medulla. In most cases (68.4%), symptoms were unilateral. In the majority of those cases (92.3%), the contralateral limb was affected due to a lateral pons infarction. RLS symptoms after infarction improved or resolved in almost 90% of cases within a few days up to 3 months. In almost all patients who received dopaminergic treatment (11 out of 13, 91.7%), the symptoms improved significantly or resolved completely. Screening for RLS has to be considered in patients suffering a brainstem stroke, particularly anteromedial pontine infarction. The appearance of acute unilateral RLS symptoms, usually in association with other sensorimotor deficits, should prompt the clinician to consider a vascular event in the brainstem. RLS in these cases seem to have a favorable outcome and respond well to dopaminergic treatment.

Post-COVID-19 Parkinsonism and Parkinson's Disease Pathogenesis: The Exosomal Cargo Hypothesis.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease, globally. Dopaminergic neuron degeneration in substantia nigra pars compacta and aggregation of misfolded alpha-synuclein are the PD hallmarks, accompanied by motor and non-motor symptoms. Several viruses have been linked to the appearance of a post-infection parkinsonian phenotype. Coronavirus disease 2019 (COVID-19), caused by emerging severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, has evolved from a novel pneumonia to a multifaceted syndrome with multiple clinical manifestations, among which neurological sequalae appear insidious and potentially long-lasting. Exosomes are extracellular nanovesicles bearing a complex cargo of active biomolecules and playing crucial roles in intercellular communication under pathophysiological conditions. Exosomes constitute a reliable route for misfolded protein transmission, contributing to PD pathogenesis and diagnosis. Herein, we summarize recent evidence suggesting that SARS-CoV-2 infection shares numerous clinical manifestations and inflammatory and molecular pathways with PD. We carry on hypothesizing that these similarities may be reflected in exosomal cargo modulated by the virus in correlation with disease severity. Travelling from the periphery to the brain, SARS-CoV-2-related exosomal cargo contains SARS-CoV-2 RNA, viral proteins, inflammatory mediators, and modified host proteins that could operate as promoters of neurodegenerative and neuroinflammatory cascades, potentially leading to a future parkinsonism and PD development.

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.