Neurovascular coupling impairment as a mechanism for cognitive deficits in COVID-19.

Components that comprise our brain parenchymal and cerebrovascular structures provide a homeostatic environment for proper neuronal function to ensure normal cognition. Cerebral insults (e.g. ischaemia, microbleeds and infection) alter cellular structures and physiologic processes within the neurovascular unit and contribute to cognitive dysfunction. COVID-19 has posed significant complications during acute and convalescent stages in multiple organ systems, including the brain. Cognitive impairment is a prevalent complication in COVID-19 patients, irrespective of severity of acute SARS-CoV-2 infection. Moreover, overwhelming evidence from in vitro, preclinical and clinical studies has reported SARS-CoV-2-induced pathologies in components of the neurovascular unit that are associated with cognitive impairment. Neurovascular unit disruption alters the neurovascular coupling response, a critical mechanism that regulates cerebromicrovascular blood flow to meet the energetic demands of locally active neurons. Normal cognitive processing is achieved through the neurovascular coupling response and involves the coordinated action of brain parenchymal cells (i.e. neurons and glia) and cerebrovascular cell types (i.e. endothelia, smooth muscle cells and pericytes). However, current work on COVID-19-induced cognitive impairment has yet to investigate disruption of neurovascular coupling as a causal factor. Hence, in this review, we aim to describe SARS-CoV-2's effects on the neurovascular unit and how they can impact neurovascular coupling and contribute to cognitive decline in acute and convalescent stages of the disease. Additionally, we explore potential therapeutic interventions to mitigate COVID-19-induced cognitive impairment. Given the great impact of cognitive impairment associated with COVID-19 on both individuals and public health, the necessity for a coordinated effort from fundamental scientific research to clinical application becomes imperative. This integrated endeavour is crucial for mitigating the cognitive deficits induced by COVID-19 and its subsequent burden in this especially vulnerable population.

Impaired Neurovascular Coupling and Increased Functional Connectivity in the Frontal Cortex Predict Age-Related Cognitive Dysfunction.

Impaired cerebrovascular function contributes to the genesis of age-related cognitive decline. In this study, the hypothesis is tested that impairments in neurovascular coupling (NVC) responses and brain network function predict cognitive dysfunction in older adults. Cerebromicrovascular and working memory function of healthy young (n = 21, 33.2±7.0 years) and aged (n = 30, 75.9±6.9 years) participants are assessed. To determine NVC responses and functional connectivity (FC) during a working memory (n-back) paradigm, oxy- and deoxyhemoglobin concentration changes from the frontal cortex using functional near-infrared spectroscopy are recorded. NVC responses are significantly impaired during the 2-back task in aged participants, while the frontal networks are characterized by higher local and global connection strength, and dynamic FC (p < 0.05). Both impaired NVC and increased FC correlate with age-related decline in accuracy during the 2-back task. These findings suggest that task-related brain states in older adults require stronger functional connections to compensate for the attenuated NVC responses associated with working memory load.

Exposome and unhealthy aging: environmental drivers from air pollution to occupational exposures.

The aging population worldwide is facing a significant increase in age-related non-communicable diseases, including cardiovascular and brain pathologies. This comprehensive review paper delves into the impact of the exposome, which encompasses the totality of environmental exposures, on unhealthy aging. It explores how environmental factors contribute to the acceleration of aging processes, increase biological age, and facilitate the development and progression of a wide range of age-associated diseases. The impact of environmental factors on cognitive health and the development of chronic age-related diseases affecting the cardiovascular system and central nervous system is discussed, with a specific focus on Alzheimer's disease, Parkinson's disease, stroke, small vessel disease, and vascular cognitive impairment (VCI). Aging is a major risk factor for these diseases. Their pathogenesis involves cellular and molecular mechanisms of aging such as increased oxidative stress, impaired mitochondrial function, DNA damage, and inflammation and is influenced by environmental factors. Environmental toxicants, including ambient particulate matter, pesticides, heavy metals, and organic solvents, have been identified as significant contributors to cardiovascular and brain aging disorders. These toxicants can inflict both macro- and microvascular damage and many of them can also cross the blood-brain barrier, inducing neurotoxic effects, neuroinflammation, and neuronal dysfunction. In conclusion, environmental factors play a critical role in modulating cardiovascular and brain aging. A deeper understanding of how environmental toxicants exacerbate aging processes and contribute to the pathogenesis of neurodegenerative diseases, VCI, and dementia is crucial for the development of preventive strategies and interventions to promote cardiovascular, cerebrovascular, and brain health. By mitigating exposure to harmful environmental factors and promoting healthy aging, we can strive to reduce the burden of age-related cardiovascular and brain pathologies in the aging population.

Vascular mechanisms leading to progression of mild cognitive impairment to dementia after COVID-19: Protocol and methodology of a prospective longitudinal observational study.

INTRODUCTION: Mild cognitive impairment (MCI) is a prodromal stage to dementia, affecting up to 20% of the aging population worldwide. Patients with MCI have an annual conversion rate to dementia of 15-20%. Thus, conditions that increase the conversion from MCI to dementia are of the utmost public health concern. The COVID-19 pandemic poses a significant impact on our aging population with cognitive decline as one of the leading complications following recovery from acute infection. Recent findings suggest that COVID-19 increases the conversion rate from MCI to dementia in older adults. Hence, we aim to uncover a mechanism for COVID-19 induced cognitive impairment and progression to dementia to pave the way for future therapeutic targets that may mitigate COVID-19 induced cognitive decline. METHODOLOGY: A prospective longitudinal study is conducted at the University of Oklahoma Health Sciences Center. Patients are screened in the Department of Neurology and must have a formal diagnosis of MCI, and MRI imaging prior to study enrollment. Patients who meet the inclusion criteria are enrolled and followed-up at 18-months after their first visit. Visit one and 18-month follow-up will include an integrated and cohesive battery of vascular and cognitive measurements, including peripheral endothelial function (flow-mediated dilation, laser speckle contrast imaging), retinal and cerebrovascular hemodynamics (dynamic vessel retinal analysis, functional near-infrared spectroscopy), and fluid and crystalized intelligence (NIH-Toolbox, n-back). Multiple logistic regression will be used for primary longitudinal data analysis to determine whether COVID-19 related impairment in neurovascular coupling and increases in white matter hyperintensity burden contribute to progression to dementia.

Cerebral small vessel disease pathology in COVID-19 patients: A systematic review.

Cerebral small vessel disease (CSVD) is the leading cause of vascular cognitive impairment and is associated with COVID-19. However, contributing factors that often accompany CSVD pathology in COVID-19 patients may influence the incidence of cerebrovascular complications. Thus, a mechanism linking COVID-19 and CSVD has yet to be uncovered and differentiated from age-related comorbidities (i.e., hypertension), and medical interventions during acute infection. We aimed to evaluate CSVD in acute and recovered COVID-19 patients and to differentiate COVID-19-related cerebrovascular pathology from the above-mentioned contributing factors by assessing the localization of microbleeds and ischemic lesions/infarctions in the cerebrum, cerebellum, and brainstem. A systematic search was performed in December 2022 on PubMed, Web of Science, and Embase using a pre-established search criterion related to history of, or active COVID-19 with CSVD pathology in adults. From a pool of 161 studies, 59 met eligibility criteria and were included. Microbleeds and ischemic lesions had a strong predilection for the corpus callosum and subcortical/deep white matter in COVID-19 patients, suggesting a distinct CSVD pathology. These findings have important implications for clinical practice and biomedical research as COVID-19 may independently, and through exacerbation of age-related mechanisms, contribute to increased incidence of CSVD.

Comparison of Efficacy and Safety of Commercially Available Fixed-Ratio Combinations of Insulin Degludec/Liraglutide and Insulin Glargine/Lixisenatide: A Network Meta-analysis.

OBJECTIVES: Our aim in this study was to compare the efficacy and safety of commercially available fixed-ratio combinations (FRCs) of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and basal insulins by a network meta-analysis of randomized controlled trials (RCTs) of people with type 2 diabetes. METHODS: We present a systematic review and network meta-analyses of RCTs of individuals with type 2 diabetes randomized to FRCs or to their components for ≥24 weeks. All reports were obtained from PubMed or ClinicalTrials.gov up to February 28, 2022. The primary outcome was glycated hemoglobin (A1C) level attained. Secondary outcomes included fasting plasma glucose, change in body weight, and incident hypoglycemia. Treatment effects were estimated as mean difference (MD) and standard error (SE), or as odds ratio (OR) with 95% confidence interval (CI) using the fixed combination of insulin glargine 100 IU/mL and lixisenatide (iGlarLixi) as reference. RESULTS: We included 29 RCTs from among the 1,404 articles identified. No direct comparisons between FRCs were found. After excluding some insulin-capped trials to reach model consistency, both FRCs were more efficacious regarding A1C than their components, but no difference between FRCs was found (MD, -0.10%; SE, 0.10%). The effect of the fixed combination of insulin degludec and liraglutide (IDegLira) (MD, -0.47 mmol/L; SE, 0.24 mmol/L) and basal insulins was similar to that of iGlarLixi (reference) on fasting glucose, whereas GLP-1RAs had lower efficacy than iGlarLixi. Weight gain was lower with GLP-1RAs and IDegLira (MD, -0.72 kg; SE, 0.32 kg) than with iGlarLixi (reference) and higher with basal insulins. Incident hypoglycemia (based on different definitions) was least frequent with GLP-1RAs, followed by IDegLira (OR, 0.78; 95% CI, 0.39 to 1.57), iGlarLixi (reference), and basal insulins. CONCLUSIONS: For A1C, both FRCs were more efficacious over their individual components, with similar efficacies of the 2 FRCs.

Decreased lifespan in female "Munchkin" actors from the cast of the 1939 film version of The Wizard of Oz does not support the hypothesis linking hypopituitary dwarfism to longevity.

In laboratory mice, pituitary dwarfism caused by genetic reduction or elimination of the activity of growth hormone (GH) significantly extends lifespan. The effects of congenital pituitary dwarfism on human longevity are not well documented. To analyse the effects of untreated pituitary dwarfism on human lifespan, the longevity of a diverse group of widely known little people, the 124 adults who played "Munchkins" in the 1939 movie The Wizard of Oz was investigated. Survival of "Munchkin" actors with those of controls defined as cast members of The Wizard of Oz and those of other contemporary Academy Award winning Hollywood movies was compared. According to the Kaplan-Meier survival curves, survival of female and male "Munchkin" actors was shorter than cast controls and Hollywood controls of respective sexes. Cox regression analyses showed that female "Munchkin" actors had significantly higher risk ratios compared to both female cast controls (RR, 1.70; 95% CI, 1.05 to 2.77) and female Hollywood controls (RR, 1.52; 95% CI, 1.03 to 2.24). Similar trends were also discernible for men, albeit point estimates were not significant. The lack of lifespan extension in "Munchkin" actors does not support the hypothesis that hereditary GH deficiency regulates longevity in humans.

Different patterns of excess all-cause mortality by age and sex in Hungary during the 2nd and 3rd waves of the COVID-19 pandemic.

It is well accepted that COVID-19-related mortality shows a strong age dependency. However, temporal changes in the age distribution of excess relative mortality between waves of the pandemic are less frequently investigated. We aimed to assess excess absolute mortality and the age-distribution of all-cause mortality during the second and third waves of the COVID-19 pandemic in Hungary compared to the same periods of non-pandemic years. Rate ratios for excess all-cause mortality with 95% confidence intervals and the number of excess deaths for the second (week 41 of 2020 through week 4 of 2021) and third waves (weeks 7-21 of 2021) of the COVID pandemic for the whole of Hungary compared to the same periods of the pre-pandemic years were estimated for 10-year age strata using Poisson regression. Altogether, 9771 (95% CI: 9554-9988) excess deaths were recorded during the second wave of the pandemic, while it was lower, 8143 (95% CI: 7953-8333) during the third wave. During the second wave, relative mortality peaked for ages 65-74 and 75-84 (RR 1.37, 95%CI 1.33-1.41, RR 1.38, 95%CI 1.34-1.42). Conversely, during the third wave, relative mortality peaked for ages 35-44 (RR 1.43, 95%CI 1.33-1.55), while those ≥65 had substantially lower relative risks compared to the second wave. The reduced relative mortality among the elderly during the third wave is likely a consequence of the rapidly increasing vaccination coverage of the elderly coinciding with the third wave. The hugely increased relative mortality of those 35-44 could point to non-biological causes, such as less stringent adherence to non-pharmaceutical measures in this population.

Comorbidities and increased mortality of COVID-19 among the elderly: A systematic review.

Purpose: The purpose of current review is to conduct a systematic overview of articles published between 2019 and 2021 on the relationship of comorbidities and mortality due to Coronavirus Disease 2019 (COVID-19) among the elderly population. Methods: We conducted a systematic search on PubMed for articles published between 2019 and 2021 to identify any cohort and case-control studies that investigated the relationship of comorbidities and COVID-19 mortality among the elderly, defined as 60 years of age and above. Databases were searched independently by two authors. Disagreements were resolved by the inclusion of a third investigator. Reviews, systematic reviews, and meta-analyses were excluded from our systematic review. Results: A total of 15 studies were selected for our systematic review. Of the included studies, 3 were case-control, 3 were prospective cohort studies and 9 were retrospective cohort studies. As for size, 10 studies were conducted on populations of <1000 participants, 3 ranging from 1001 to 10,000, and 2 on populations of >10,000 individuals. The included studies found that the presence of certain conditions, such as cardiovascular, respiratory, renal diseases, malignancies, diseases of the nervous system and diabetes are associated to increased mortality in populations that consisted of elderly patients. Conclusion: Results of our systematic review suggest that comorbidities contribute to increased COVID-19 mortality among the elderly. The detrimental effect of comorbidities and advanced age on the immune response could lead to a more frequent occurrence of symptomatic and severe infections with COVID-19.

Nutrition Strategies Promoting Healthy Aging: From Improvement of Cardiovascular and Brain Health to Prevention of Age-Associated Diseases.

BACKGROUND: An increasing number of studies suggest that diet plays an important role in regulating aging processes and modulates the development of the most important age-related diseases. OBJECTIVE: The aim of this review is to provide an overview of the relationship between nutrition and critical age-associated diseases. METHODS: A literature review was conducted to survey recent pre-clinical and clinical findings related to the role of nutritional factors in modulation of fundamental cellular and molecular mechanisms of aging and their role in prevention of the genesis of the diseases of aging. RESULTS: Studies show that the development of cardiovascular and cerebrovascular diseases, neurodegenerative diseases, cognitive impairment and dementia can be slowed down or prevented by certain diets with anti-aging action. The protective effects of diets, at least in part, may be mediated by their beneficial macro- (protein, fat, carbohydrate) and micronutrient (vitamins, minerals) composition. CONCLUSIONS: Certain diets, such as the Mediterranean diet, may play a significant role in healthy aging by preventing the onset of certain diseases and by improving the aging process itself. This latter can be strengthened by incorporating fasting elements into the diet. As dietary recommendations change with age, this should be taken into consideration as well, when developing a diet tailored to the needs of elderly individuals. Future and ongoing clinical studies on complex anti-aging dietary interventions translating the results of preclinical investigations are expected to lead to novel nutritional guidelines for older adults in the near future.

[Covid-19 associated neurological disorders]. / Covid-19-encephalitis-esetünk és a betegség egyéb neurológiai szövôdményei.

The clinical signs of SARS-CoV-2 infection has become more recognisable in recent times. In addition to common symptoms such as fever, cough, dyspnea, pneumonia and ageusia, less common complications can be identified, including many neurological manifestations. In this paper, we discuss three Covid-19 associated neurological disorders (Case 1: Covid-19 encephalitis, Case 2: Covid-19 organic headache, Case 3: SARS-CoV-2-infection and ischaemic stroke). We emphasize in our multiple case study that during the present pandemic, it is especially important for neurologists to be aware of the nervous system complications of the virus infection, thus saving unnecessary examinations and reducing the frequency of patients' contact with health care personnel.

Drug residues in syringes and other injecting paraphernalia in Hungary.

The appearance and spread of new psychoactive substances (NPS) is a phenomenon seen throughout Europe since 2008. Synthetic cathinones, a group of NPS, have been self-reported as the drug injected by the vast majority of people who inject drugs (PWID) in Hungary. This study aims at updating our knowledge of what exactly are the compounds injected by PWID. This multi-site study analysed residues from used injecting drug paraphernalia collected from PWID via low-threshold services and from public places in Budapest, Debrecen, Miskolc, Szeged, Békéscsaba and Pécs between March 2015 and February 2016. The paper describes the results of the chemical analysis of 2985 analytical samples created out of the 22 005 objects collected in this period. Active agents and their occurrences (compound cases) were identified using GC-MS. The study detected 161 different compounds, mostly synthetic cathinones (29%), non-psychoactive compounds (14%), amines (12%), non-psychoactive medications (12%) and other substances (32%). Of the 12 762 compound cases, 50% were cathinones, 18% substitution medications, 9% non-controlled psychoactive substances and 24% other substances. Among compound cases, the most frequent cathinones were pentedrone (21%) and α-PHP (12%). Among substitution medications, most were methadone (93%), and non-controlled psychoactive substances were caffeine (74%) and nicotine (21%). Overall, the most prevalent substances were methadone (16%), pentedrone (10%) and caffeine (7%) with considerable variation detected among participating cities. Our results are consistent with previous self-reported data showing a high prevalence of synthetic cathinone injection among PWID in Hungary. We also detected a large-scale misuse of methadone by PWID.

Diverted medications and new psychoactive substances-A chemical network analysis of discarded injecting paraphernalia in Hungary.

BACKGROUND: Until about 2010, people who inject drugs (PWIDs) injected almost exclusively heroin and amphetamines in Hungary. After 2010, self-reported studies have indicated a dominance of new psychoactive substances on the drug market for injectable drugs. METHODS: Between March 2015 and February 2016, we collected used and discarded injecting paraphernalia. We utilized chemical analysis to assess and UCINet to visualize the connections between the most prevalent main substances and their respective co-occurring additional components at 7 locations in Hungary. RESULTS: The samples (n=2977) contained a mean of 4.5 components (SD=3.1, range: 1-18); 422 contained only one component. We found that the most common main components were the diverted substitution medication methadone (32%) and cathinones: pentedrone (18%), mephedrone (13%), alpha-PHP (8%), and alpha-PEP (5%). While these main substances also occurred among the top co-occurring additional components, caffeine and benzoic acid (a preservative) also frequently co-occurred. CONCLUSION: A large number of co-occurring additional components indicate either common reuse of injecting paraphernalia or the common addition of additives or both. While caffeine may indeed be an adulterant, the high prevalence of benzoic acid may be difficult to explain. The preference of methadone despite the availability of a wide array of drugs may indicate a preference for opioids during the current heroin drought and/or a true demand for opioid substitution therapy.

Changes in patterns of injecting drug use in Hungary: a shift to synthetic cathinones.

The spread of synthetic cathinone injecting is a new phenomenon observed in recent years in Hungary. Until 2010, when the first anecdotal reports on cathinone injecting appeared, injecting was associated with the use of heroin and amphetamine. In this paper we review available evidence of the changes in the drug market and a concurrent shift in patterns of injecting drug use that have been taking place in Hungary since 2010. Remarkable changes have been observed in police seizures data since 2010. While new psychoactive substances have appeared, the availability of heroin has dropped significantly. A qualitative study in 2011 revealed that these market changes correlate with changes in patterns of injecting drug use: decreasing heroin use and the appearance of mephedrone injecting were reported by treatment and needle and syringe programme (NSP) personnel. These changes are detectable in other routine epidemiological data collection systems in the following years as well (i.e. treatment, drug-related deaths, NSP clientele). Heroin-related treatment demand dropped, as did heroin-related mortality. Parallel to this, a growing number of clients appeared in treatment and in NSPs who were primarily injecting cathinones. The shift to cathinones can be observed in amphetamine and heroin injectors as well. Monitoring changes in patterns of injecting drug use are especially important because of the vulnerability of this drug-user population and the consequences of this high-risk route of drug administration. The realignment observed in Hungary is to be further investigated with regard to its determinants, changes in risk behaviour, and in treatment needs.

[Tolosa-Hunt syndrome]. / A Tolosa-Hunt-szindróma.

Both men and women are affected by the rare disease called Tolosa-Hunt syndrome. We don't know exactly what causes it to evolve. It is usually put into the categories of either idiopathic inflammation or pseudotumor. Its pathological feature is a non-specific inflammatory process with fibroblastic, lymphocytic, plasmocytic infiltration, which can be found, for the most part, in the wall of the sinus cavernosus. Granulocytic and giant-cell infiltrations have been described too. The possibility of autoimmune disease has also come up. In our current study we describe the case of a female patient who recovered with the help of a steroid therapy. Through examining her, we also found immunological alterations, which should urge us to thoroughly examine the further observations of this kind.