SARS-CoV-2-Induced Type I Interferon Signaling Dysregulation in Olfactory Networks Implications for Alzheimer's Disease.

Type I interferon signaling (IFN-I) perturbations are major drivers of COVID-19. Dysregulated IFN-I in the brain, however, has been linked to both reduced cognitive resilience and neurodegenerative diseases such as Alzheimer's. Previous works from our group have proposed a model where peripheral induction of IFN-I may be relayed to the CNS, even in the absence of fulminant infection. The aim of our study was to identify significantly enriched IFN-I signatures and genes along the transolfactory route, utilizing published datasets of the nasal mucosa and olfactory bulb amygdala transcriptomes of COVID-19 patients. We furthermore sought to identify these IFN-I signature gene networks associated with Alzheimer's disease pathology and risk. Gene expression data involving the nasal epithelium, olfactory bulb, and amygdala of COVID-19 patients and transcriptomic data from Alzheimer's disease patients were scrutinized for enriched Type I interferon pathways. Gene set enrichment analyses and gene-Venn approaches were used to determine genes in IFN-I enriched signatures. The Agora web resource was used to identify genes in IFN-I signatures associated with Alzheimer's disease risk based on its aggregated multi-omic data. For all analyses, false discovery rates (FDR) <0.05 were considered statistically significant. Pathways associated with type I interferon signaling were found in all samples tested. Each type I interferon signature was enriched by IFITM and OAS family genes. A 14-gene signature was associated with COVID-19 CNS and the response to Alzheimer's disease pathology, whereas nine genes were associated with increased risk for Alzheimer's disease based on Agora. Our study provides further support to a type I interferon signaling dysregulation along the extended olfactory network as reconstructed herein, ranging from the nasal epithelium and extending to the amygdala. We furthermore identify the 14 genes implicated in this dysregulated pathway with Alzheimer's disease pathology, among which HLA-C, HLA-B, HLA-A, PSMB8, IFITM3, HLA-E, IFITM1, OAS2, and MX1 as genes with associated conferring increased risk for the latter. Further research into its druggability by IFNb therapeutics may be warranted.

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.

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.

Sleep Quality in Greek Adolescent Swimmers.

The aim of our study was to investigate the relationship between sleep quality and functional indices, swimming distance and gender in adolescent competitive swimmers. Forty-eight adolescent swimmers (boys, n = 22, 15.7 ± 1.0 years and girls, n = 26, 15.1 ± 0.8 years) were included in our study. They were assessed for handgrip strength, respiratory muscle strength and pulmonary function, answered a Pittsburg Sleep Quality Index questionnaire (PSQI), and recorded their anthropometric and morphological characteristics and training load for the last four weeks. The results showed differences between swimming distance and chest circumference difference, between maximal inhalation and exhalation (Δchest) (p = 0.033), PSQI score (p < 0.001), and sleep quality domains for "cannot breathe comfortably" (p = 0.037) and "have pain" (p = 0.003). Binary logistic regression (chi-square = 37.457, p = 0.001) showed that the variables Δchest (p = 0.038, 95% CI: 1.05-6.07) and PSQI score (p = 0.048, 95% CI: 0.1-1.07) remained independent predictors of the swim distance groups. Girls had a lower percentage of predicted values for the maximal inspiratory pressure (p < 0.001), maximal expiratory pressure (p = 0.027), forced expiratory volume within the first second (p = 0.026), forced vital capacity (p = 0.008) and sleep quality domains for "cough or snore loudly" (p = 0.032) compared to boys. A regression analysis showed that the sleep quality score was explained by the six independent variables: respiratory muscle strength (t = 2.177, ß = 0.164, p = 0.035), Δchest (t = -2.353, ß = -0.17, p = 0.023), distance (t = -5.962, ß = -0.475, p < 0.001), total body water (t = -7.466, ß = -0.687, p < 0.001), lean body mass (t = -3.120, ß = -0.434, p = 0.003), and handgrip (t = 7.752, ß = 1.136, p < 0.001). Our findings demonstrate that sleep quality in adolescent swimmers is a multifactorial result of morphometric characteristics, strength and respiratory function.

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.

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.

The Impact of Different Exercise Modes in Fitness and Cognitive Indicators: Hybrid versus Tele-Exercise in Patients with Long Post-COVID-19 Syndrome.

The purpose of our study was to obtain evidence that an unsupervised tele-exercise program (TEgroup) via an online platform is a feasible alternative to a hybrid mode of supervised and unsupervised exercise (HEgroup) sessions for improving fitness indexes, respiratory and cognitive functions, and biomarkers of oxidative stress in patients recovering from COVID-19. Forty-nine patients with long post-COVID-19 were randomly divided into two groups (HEgroup: n = 24, age 60.0 ± 9.5 years versus TEgroup: n = 25, age 58.7 ± 9.5 years). For each patient, we collected data from body composition, oxidative stress, pulmonary function, physical fitness, and cognitive function before and after the 12-week exercise rehabilitation program (ERP). Our data showed differences in both groups before and after 12-week ERP on fitness indicators, body composition, and pulmonary function indicators. Our findings demonstrated differences between groups after 12-week ERP on adjustment in the domains of cognitive function (HEgroup increased the "visuospatial" domain: 3.2 ± 1.1 versus 3.5 ± 0.8 score, p = 0.008 and TEgroup increased the "memory" domain: 3.3 ± 1.0 versus 3.8 ± 0.5 score, p = 0.003; after 12-week ERP showed differences between groups in domain "attention" TEgroup: 4.8 ± 1.5 versus HEgroup: 3.6 ± 1.8 score, p = 0.014) and the diffusing capacity for carbon monoxide (HEgroup increased the percent of predicted values at 0.5 ± 32.3% and TEgroup at 26.0 ± 33.1%, p < 0.001). These findings may be attributed to the different ways of learning exercise programs, resulting in the recruitment of different neural circuits.