SARS-CoV-2 Nucleocapsid Protein Induces Tau Pathological Changes That Can Be Counteracted by SUMO2.

Neurologic manifestations are an immediate consequence of SARS-CoV-2 infection, the etiologic agent of COVID-19, which, however, may also trigger long-term neurological effects. Notably, COVID-19 patients with neurological symptoms show elevated levels of biomarkers associated with brain injury, including Tau proteins linked to Alzheimer's pathology. Studies in brain organoids revealed that SARS-CoV-2 alters the phosphorylation and distribution of Tau in infected neurons, but the mechanisms are currently unknown. We hypothesize that these pathological changes are due to the recruitment of Tau into stress granules (SGs) operated by the nucleocapsid protein (NCAP) of SARS-CoV-2. To test this hypothesis, we investigated whether NCAP interacts with Tau and localizes to SGs in hippocampal neurons in vitro and in vivo. Mechanistically, we tested whether SUMOylation, a posttranslational modification of NCAP and Tau, modulates their distribution in SGs and their pathological interaction. We found that NCAP and Tau colocalize and physically interact. We also found that NCAP induces hyperphosphorylation of Tau and causes cognitive impairment in mice infected with NCAP in their hippocampus. Finally, we found that SUMOylation modulates NCAP SG formation in vitro and cognitive performance in infected mice. Our data demonstrate that NCAP induces Tau pathological changes both in vitro and in vivo. Moreover, we demonstrate that SUMO2 ameliorates NCAP-induced Tau pathology, highlighting the importance of the SUMOylation pathway as a target of intervention against neurotoxic insults, such as Tau oligomers and viral infection.

Profiles of objective and subjective cognitive function in Post-COVID Syndrome, COVID-19 recovered, and COVID-19 naïve individuals.

Post-COVID Syndrome has emerged as a significant public health concern worldwide with increasing evidence to suggest that individuals who have had an acute COVID-19 infection report lingering memory and attention difficulties, even in individuals who have fully recovered and no longer experiencing symptoms of COVID-19. The present study sought to investigate the profile of objective and subjective cognitive difficulties in people who have Post-COVID Syndrome, people who have fully recovered from an acute COVID infection and people who have never had COVID-19. We further sought to explore the extent to which self-reported fatigue and stress are related to subjective and objective cognitive difficulties. 162 participants including 50 people living with Post-COVID Syndrome, 59 people who have had COVID-19 but have fully recovered and 53 people who have never experienced symptoms of COVID-19 and had never tested positive for COVID-19 were recruited from Academic Prolific to complete a series of online questionnaires and neurocognitive tasks. Subjective cognitive function was measured using the Cognitive Failures Questionnaire and objective cognitive function was measured using the Cognitron cognitive test battery. We found that objective and subjective measures of cognitive function were not significantly related, suggesting that self-reports of "brain fog" are not reflecting objectively measured cognitive dysfunction. A MANOVA revealed that subjective cognitive deficits were driven by heightened perceived stress and fatigue and not significantly related to COVID-19 status. Objective cognitive function, however, was significantly related to perceived stress and COVID status whereby we observed significant objective cognitive deficits in people who have been exposed to an acute COVID-19 infection regardless of whether they had Post-COVID Syndrome or had fully recovered, as compared to people who had never had COVID-19. This suggests that an acute infection can have long term effects on cognitive function, even without persistent COVID-19 symptoms. Encouragingly, objective cognitive function was significantly associated with time since initial infection showing that cognitive deficits improved over time for people who had recovered from COVID-19. However, we did not observe the same improvement in individuals with Post-COVID Syndrome and observed that cognitive dysfunction was significantly related to the number of neurological symptoms presently experienced. These results add to the accumulating literature that COVID-19 is associated with significant cognitive difficulties following a COVID-19 infection, which appear to improve over time for those who have recovered from COVID-19 yet persist in people living with Post-COVID Syndrome.

EEG signatures of cognitive decline after mild SARS-CoV-2 infection: an age-dependent study.

BACKGROUND: Current research on the neurological impact of SARS-CoV-2 primarily focuses on the elderly or severely ill individuals. This study aims to explore the diverse neurological consequences of SARS-CoV-2 infection, with a particular focus on mildly affected children and adolescents. METHODS: A cohort study was conducted to collect pre- and post-infection resting-state electroencephalogram (EEG) data from 185 participants and 181 structured questionnaires of long-term symptoms across four distinct age groups. The goal was to comprehensively evaluate the impact of SARS-CoV-2 infection on these different age demographics. The study analyzed EEG changes of SARS-CoV-2 by potential biomarkers across age groups using both spatial and temporal approaches. RESULTS: Spatial analysis indicated that children and adolescents exhibit smaller changes in brain network and microstate patterns post-infection, implying a milder cognitive impact. Sequential linear analyses showed that SARS-CoV-2 infection is associated with a marked rise in low-complexity, synchronized neural activity within low-frequency EEG bands. This is evidenced by a significant increase in Hjorth activity within the theta band and Hjorth mobility in the delta band. Sequential nonlinear analysis indicated a significant reduction in the Hurst exponent across all age groups, pointing to increased chaos and complexity within the cognitive system following infection. Furthermore, linear regression analysis based on questionnaires established a significant positive relationship between the magnitude of changes in these neural indicators and the persistence of long-term symptoms post-infection. CONCLUSIONS: The findings underscore the enduring neurological impacts of SARS-CoV-2 infection, marked by cognitive decline and increased EEG disarray. Although children and adolescents experienced milder effects, cognitive decline and heightened low-frequency electrical activity were evident. These observations might contribute to understanding potential anxiety, insomnia, and neurodevelopmental implications.

Cognitive impairment in long-COVID.

Background and purpose:

Long Covid is a complex con­dition characterised by symptoms that per­sist for weeks and months after the Co­vid infection, accompanied by cognitive im­pairment that negatively affects daily life. Understanding this complex condition is im­portant for the development of diagnostic and therapeutic strategies.

This article aims to provide a comprehensive overview of cognitive impairment in long-COVID, including its definition, symptoms, pathophysiology, risk factors, assessment tools, imaging abnormalities, potential biomarkers, management strategies, long-term outcomes, and future directions for research.

The search methodology used in this review aimed to include a wide range of research on cognitive impairment related to both COVID-19 and long-COVID. Systematic searches of PubMed and Google Scholar databases were conducted using a mixture of MeSH terms and keywords including ‘cognition’, ‘cognitive impairment’, ‘brain fog’, ‘COVID-19’ and ‘long-COVID’. The search was restricted to studies published in English between 1 January 2019 and 11 February 2024, which presented findings on neurological manifestations in human participants.

Long-COVID is characterized by persistent symptoms following COVID-19 infection, with cognitive impairment being a prominent feature. Symptoms include brain fog, difficulties with concentration, memory issues, and executive function deficits. Pa­tho­physiological mechanisms involve vi­ral persistence, immune responses, and vas­cular damage. Risk factors include age, pre-existing conditions, and disease seve­rity. Cognitive assessment tools such as the Montreal Cognitive Assessment (MoCA) are essential for diagnosis. Imaging studies, including MRI, PET, and SPECT, reveal structural and functional brain alterations. Potential biomarkers include C-reactive protein, interleukin-6, and neuron-specific enolase. Management strategies encompass cognitive rehabilitation, occupational therapy, medications, and lifestyle modifications.

Long-COVID poses a multifaceted challenge, and cognitive impairment significantly impacts patients’ lives. A multi­disciplinary approach, including cognitive rehabilitation and medication when appropriate, is essential for effective management. Future research should focus on validating biomarkers and understanding long-term cognitive outcomes.

Conclusion – Long-COVID is a global health concern, and cognitive impairment is a distressing symptom. While pharmacological interventions have potential, they require careful consideration. Continued research is crucial for improving the understanding and treatment of cognitive impairment in long-COVID.

Clinical and CSF single-cell profiling of post-COVID-19 cognitive impairment.

Natural history and mechanisms for persistent cognitive symptoms ("brain fog") following acute and often mild COVID-19 are unknown. In a large prospective cohort of people who underwent testing a median of 9 months after acute COVID-19 in the New York City/New Jersey area, we found that cognitive dysfunction is common; is not influenced by mood, fatigue, or sleepiness; and is correlated with MRI changes in very few people. In a subgroup that underwent cerebrospinal fluid analysis, there are no changes related to Alzheimer's disease or neurodegeneration. Single-cell gene expression analysis in the cerebrospinal fluid shows findings consistent with monocyte recruitment, chemokine signaling, cellular stress, and suppressed interferon response-especially in myeloid cells. Longitudinal analysis shows slow recovery accompanied by key alterations in inflammatory genes and increased protein levels of CXCL8, CCL3L1, and sTREM2. These findings suggest that the prognosis for brain fog following COVID-19 correlates with myeloid-related chemokine and interferon-responsive genes.

Cerebral microstructural alterations in Post-COVID-condition are related to cognitive impairment, olfactory dysfunction and fatigue.

After contracting COVID-19, a substantial number of individuals develop a Post-COVID-Condition, marked by neurologic symptoms such as cognitive deficits, olfactory dysfunction, and fatigue. Despite this, biomarkers and pathophysiological understandings of this condition remain limited. Employing magnetic resonance imaging, we conduct a comparative analysis of cerebral microstructure among patients with Post-COVID-Condition, healthy controls, and individuals that contracted COVID-19 without long-term symptoms. We reveal widespread alterations in cerebral microstructure, attributed to a shift in volume from neuronal compartments to free fluid, associated with the severity of the initial infection. Correlating these alterations with cognition, olfaction, and fatigue unveils distinct affected networks, which are in close anatomical-functional relationship with the respective symptoms.

HIV-1 subtype C Tat exon-1 amino acid residue 24K is a signature for neurocognitive impairment.

Variation and differential selection pressures on Tat genes have been shown to alter the biological function of the protein, resulting in pathological consequences in a number of organs including the brain. We evaluated the impact of genetic variation and selection pressure on 147 HIV-1 subtype C Tat exon 1 sequences from monocyte-depleted peripheral lymphocytes on clinical diagnosis of neurocognitive impairment. Genetic analyses identified two signature amino acid residues, lysine at codon 24 (24K) with a frequency of 43.4% and arginine at codon 29 (29R) with a frequency of 34.0% in individuals with HIV-associated neurocognitive impairment. The analyses also revealed two signature residues, asparagine, 24 N (31.9%), and histidine, 29H (21.3%), in individuals without neurocognitive impairment. Both codons, 24 and 29, were associated with high entropy but only codon 29 was under positive selection. The presence of signature K24 increased by 2.08 times the risk of neurocognitive impairment, 3.15 times higher proviral load, and 69% lower absolute CD4 T-cell count compared to those without the signature. The results support a linkage between HIV-1 C Tat N24K polymorphism, proviral load, immunosuppression, and neurocognitive impairment. The signature may induce more neurotoxic effects, which contributes to establishment and severity of HIV-associated neurocognitive impairment.

Cognitive decline following acute viral infections: literature review and projections for post-COVID-19.

Recently, much attention has been drawn to the importance of the impact of infectious disease on human cognition. Several theories have been proposed, to explain the cognitive decline following an infection as well as to understand better the pathogenesis of human dementia, especially Alzheimer's disease. This article aims to review the state of the art regarding the knowledge about the impact of acute viral infections on human cognition, laying a foundation to explore the possible cognitive decline followed coronavirus disease 2019 (COVID-19). To reach this goal, we conducted a narrative review systematizing six acute viral infections as well as the current knowledge about COVID-19 and its impact on human cognition. Recent findings suggest probable short- and long-term COVID-19 impacts in cognition, even in asymptomatic individuals, which could be accounted for by direct and indirect pathways to brain dysfunction. Understanding this scenario might help clinicians and health leaders to deal better with a wave of neuropsychiatric issues that may arise following COVID-19 pandemic as well as with other acute viral infections, to alleviate the cognitive sequelae of these infections around the world.

Cerebrospinal Fluid Analysis Post-COVID-19 Is Not Suggestive of Persistent Central Nervous System Infection.

This study was undertaken to assess whether SARS-CoV-2 causes a persistent central nervous system infection. SARS-CoV-2-specific antibody index and SARS-CoV-2 RNA were studied in cerebrospinal fluid following COVID-19. Cerebrospinal fluid was assessed between days 1 and 30 (n = 12), between days 31 and 90 (n = 8), or later than 90 days (post-COVID-19, n = 20) after COVID-19 diagnosis. SARS-CoV-2 RNA was absent in all patients, and in none of the 20 patients with post-COVID-19 syndrome were intrathecally produced anti-SARS-CoV-2 antibodies detected. The absence of evidence of SARS-CoV-2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post-COVID-19 syndrome. ANN NEUROL 2022;91:150-157.

Cognitive Intra-individual Variability in HIV: an Integrative Review.

Nearly 30-50% of people living with HIV experience HIV-Associated Neurocognitive Disorder (HAND). HAND indicates performance at least one standard deviation below the normative mean on any two cognitive domains. This method for diagnosing or classifying cognitive impairment has utility, however, cognitive intraindividual variability provides a different way to understand cognitive impairment. Cognitive intraindividual variability refers to the scatter in cognitive performance within repeated measures of the same cognitive test (i.e., inconsistency) or across different cognitive tests (i.e., dispersion). Cognitive intraindividual variability is associated with cognitive impairment and cognitive decline in various clinical populations. This integrative review of 13 articles examined two types of cognitive intraindividual variability in people living with HIV, inconsistency and dispersion. Cognitive intraindividual variability appears to be a promising approach to detect subtle cognitive impairments that are not captured by traditional mean-based neuropsychological testing. Greater intraindividual variability in people living with HIV has been associated with: 1) poorer cognitive performance and cognitive decline, 2) cortical atrophy, both gray and white matter volume, 3) poorer everyday functioning (i.e., driving simulation performance), specifically medication adherence, and 4) even mortality. This inspires future directions for research. First, greater cognitive intraindividual variability may reflect a greater task demand on executive control to harness and regulate cognitive control over time. By improving executive functioning through cognitive training, it may reduce cognitive intraindividual variability which could slow down cognitive decline. Second, cognitive intraindividual variability may be reconsidered in prior cognitive intervention studies in which only mean-based cognitive outcomes were used. It is possible that such cognitive interventions may actually improve cognitive intraindividual variability, which could have clinical relevance.

Examination of the cognitive function of Japanese community-dwelling older adults in a class for preventing cognitive decline during the COVID-19 pandemic.

We examined the changes in cognitive function due to restrictions in daily life during the coronavirus disease 2019 (COVID-19) pandemic in community-dwelling older adults with mild cognitive decline. This was a retrospective, case-control study. The participants include 88 older adults with mild cognitive decline (mean age = 81.0 [standard deviation = 6.5] years) who participated in a class designed to help prevent cognitive decline. This class was suspended from early-March to end of May 2020 to prevent the spread of COVID-19, and resumed in June 2020. We collected demographic and cognitive function test data (Touch Panel-type Dementia Assessment Scale [TDAS]) before and after class suspension and questionnaire data on their lifestyle and thoughts during the suspension. Change in TDAS scores from before and after the suspension was used to divide the participants into decline (2 or more points worsening) and non-decline (all other participants) groups, with 16 (18.2%) and 72 (81.8%) participants in each group, respectively. A logistic regression model showed that the odds ratio (OR) for cognitive decline was lower in participants whose responses were "engaged in hobbies" (OR = 0.07, p = 0.015), "worked on a worksheet about cognitive training provided by the town hall" (OR = 0.19, p = 0.026), and "had conversations over the phone" (OR = 0.28, p = 0.0495). There was a significant improvement in TDAS scores after class was resumed (p < 0.01). A proactive approach to intellectual activities and social ties may be important for the prevention of cognitive decline during periods of restrictions due to COVID-19. We found that cognitive function test scores before class suspension significantly improved after resuming classes. We speculate that continued participation in this class led to positive behavioral changes in daily life during periods of restriction due to COVID-19.

Non-invasive brain microcurrent stimulation therapy of long-COVID-19 reduces vascular dysregulation and improves visual and cognitive impairment.

BACKGROUND: An effective treatment is needed for long-COVID patients which suffer from symptoms of vision and/or cognition impairment such as impaired attention, memory, language comprehension, or fatigue. OBJECTIVE: Because COVID-19infection causes reduced blood flow which may cause neuronal inactivation, we explored if neuromodulation with non-invasive brain stimulation using microcurrent (NIBS), known to enhance blood flow and neuronal synchronization, can reduce these symptoms. METHODS: Two female long-COVID patients were treated for 10-13 days with alternating current stimulation of the eyes and brain. While one patient (age 40) was infected with the SARS CoV-2 virus, the other (age 72) developed symptoms following AstraZeneca vaccination. Before and after therapy, cognition was assessed subjectively by interview and visual fields quantified using perimetry. One patient was also tested with a cognitive test battery and with a retinal dynamic vascular analyser (DVA), a surrogate marker of vascular dysregulation in the brain. RESULTS: In both patients NIBS markedly improved cognition and partially reversed visual field loss within 3-4 days. Cognitive tests in one patient confirmed recovery of up to 40-60% in cognitive subfunctions with perimetry results showing stable and visual field recovery even during follow-up. DVA showed that NIBS reduced vascular dysregulation by normalizing vessel dynamics (dilation/constriction), with particularly noticeable changes in the peripheral veins and arteries. CONCLUSIONS: NIBS was effective in improving visual and cognitive deficits in two confirmed SARS-COV-2 patients. Because recovery of function was associated with restoration of vascular autoregulation, we propose that (i) hypometabolic, "silent" neurons are the likely biological cause of long-COVID associated visual and cognitive deficits, and (ii) reoxygenation of these "silent" neurons provides the basis for neural reactivation and neurological recovery. Controlled trials are now needed to confirm these observations.

Endolysosome iron restricts Tat-mediated HIV-1 LTR transactivation by increasing HIV-1 Tat oligomerization and ß-catenin expression.

HIV-1 transactivator of transcription (Tat) protein is required for HIV-1 replication, and it has been implicated in the pathogenesis of HIV-1-associated neurocognitive disorder (HAND). HIV-1 Tat can enter cells via receptor-mediated endocytosis where it can reside in endolysosomes; upon its escape from these acidic organelles, HIV-1 Tat can enter the cytosol and nucleus where it activates the HIV-1 LTR promoter. Although it is known that HIV-1 replication is affected by the iron status of people living with HIV-1 (PLWH), very little is known about how iron affects HIV-1 Tat activation of the HIV-1 LTR promoter. Because HIV-1 proteins de-acidify endolysosomes and endolysosome de-acidification affects subcellular levels and actions of iron, we tested the hypothesis that the endolysosome pool of iron is sufficient to affect Tat-induced HIV-1 LTR transactivation. Ferric (Fe3+) and ferrous (Fe2+) iron both restricted Tat-mediated HIV-1 LTR transactivation. Chelation of endolysosome iron with deferoxamine (DFO) and 2-2 bipyridyl, but not chelation of cytosolic iron with deferiprone and deferasirox, significantly enhanced Tat-mediated HIV-1 LTR transactivation. In the presence of iron, HIV-1 Tat increasingly oligomerized and DFO prevented the oligomerization. DFO also reduced protein expression levels of the HIV-1 restriction agent beta-catenin in the cytosol and nucleus. These findings suggest that DFO increases HIV-1 LTR transactivation by increasing levels of the more active dimeric form of Tat relative to the less active oligomerized form of Tat, increasing the escape of dimeric Tat from endolysosomes, and/or reducing beta-catenin protein expression levels. Thus, intracellular iron might play a significant role in regulating HIV-1 replication, and these findings raise cautionary notes for chelation therapies in PLWH.

Post-infection cognitive impairments in a cohort of elderly patients with COVID-19.

BACKGROUND: Understanding the long-term effects of coronavirus disease 2019 (COVID-19) on cognitive function is essential for monitoring the cognitive decline in the elderly population. This study aims to assess the current cognitive status and the longitudinal cognitive decline in elderly patients recovered from COVID-19. METHODS: This cross-sectional study recruited 1539 COVID-19 inpatients aged over 60 years who were discharged from three COVID-19-designated hospitals in Wuhan, China, from February 10 to April 10, 2020. In total, 466 uninfected spouses of COVID-19 patients were selected as controls. The current cognitive status was assessed using a Chinese version of the Telephone Interview of Cognitive Status-40 (TICS-40) and the longitudinal cognitive decline was assessed using an Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Cognitive assessments were performed 6 months after patient discharge. RESULTS: Compared with controls, COVID-19 patients had lower TICS-40 scores and higher IQCODE scores [TICS-40 median (IQR): 29 (25 to 32) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR): 3.19 (3.00 to 3.63) vs. 3.06 (3.00 to 3.38), p < 0.001]. Severe COVID-19 patients had lower TICS-40 scores and higher IQCODE scores than non-severe COVID-19 patients [TICS-40 median (IQR): 24 (18 to 28) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR): 3.63 (3.13 to 4.31) vs. 3.13 (3.00 to 3.56), p < 0.001] and controls [TICS-40 median (IQR): 24 (18 to 28) vs. 30 (26 to 33), p < 0.001; IQCODE median (IQR) 3.63 (3.13 to 4.31) vs. 3.06 (3.00 to 3.38), p < 0.001]. Severe COVID-19 patients had a higher proportion of cases with current cognitive impairment and longitudinal cognitive decline than non-severe COVID-19 patients [dementia: 25 (10.50 %) vs. 9 (0.69 %), p < 0.001; Mild cognitive impairment (MCI): 60 (25.21 %) vs. 63 (4.84 %), p < 0.001] and controls [dementia: 25 (10.50 %) vs. 0 (0 %), p < 0.001; MCI: 60 (25.21 %) vs. 20 (4.29 %), p < 0.001)]. COVID-19 severity, delirium and COPD were risk factors of current cognitive impairment. Low education level, severe COVID-19, delirium, hypertension and COPD were risk factors of longitudinal cognitive decline. CONCLUSIONS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with an increased risk of long-term cognitive decline in elderly population. COVID-19 patients, especially severe patients, should be intensively monitored for post-infection cognitive decline.

Brain Stress Mapping in COVID-19 Survivors Using MR Spectroscopy: New Avenue of Mental Health Status Monitoring$.

Coronavirus (COVID-19) has emerged as a human catastrophe worldwide, and it has impacted human life more detrimentally than the combined effect of World Wars I and II. Various research studies reported that the disease is not confined to the respiratory system but also leads to neurological and neuropsychiatric disorders suggesting that the virus is potent to affect the central nervous system (CNS). Moreover, the damage to CNS may continue to rise even after the COVID-19 infection subsides which may further induce a long-term impact on the brain, resulting in cognitive impairment. Neuroimaging techniques is the ideal platform to detect and quantify pathological manifestations in the brain of COVID-19 survivors. In this context, a scheme based on structural, spectroscopic, and behavioral studies could be executed to monitor the gradual changes in the brain non-invasively due to COVID-19 which may further help in quantifying the impact of COVID-19 on the mental health of the survivors. Extensive research is required in this direction for identifying the mechanism and implications of COVID-19 in the brain. Cohort studies are urgently required for monitoring the effects of this pandemic on individuals of various subtypes longitudinally.

Long COVID in a prospective cohort of home-isolated patients.

Long-term complications after coronavirus disease 2019 (COVID-19) are common in hospitalized patients, but the spectrum of symptoms in milder cases needs further investigation. We conducted a long-term follow-up in a prospective cohort study of 312 patients-247 home-isolated and 65 hospitalized-comprising 82% of total cases in Bergen during the first pandemic wave in Norway. At 6 months, 61% (189/312) of all patients had persistent symptoms, which were independently associated with severity of initial illness, increased convalescent antibody titers and pre-existing chronic lung disease. We found that 52% (32/61) of home-isolated young adults, aged 16-30 years, had symptoms at 6 months, including loss of taste and/or smell (28%, 17/61), fatigue (21%, 13/61), dyspnea (13%, 8/61), impaired concentration (13%, 8/61) and memory problems (11%, 7/61). Our findings that young, home-isolated adults with mild COVID-19 are at risk of long-lasting dyspnea and cognitive symptoms highlight the importance of infection control measures, such as vaccination.

Dementia and COVID-19, a Bidirectional Liaison: Risk Factors, Biomarkers, and Optimal Health Care.

Cognitive impairment following SARS-CoV-2 infection is being increasingly recognized as an acute and possibly also long-term sequela of the disease. Direct viral entry as well as systemic mechanisms such as cytokine storm are thought to contribute to neuroinflammation in these patients. Biomarkers of COVID-19-induced cognitive impairment are currently lacking, but there is some limited evidence that SARS-CoV-2 could preferentially target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET. Possible confounders include cognitive impairment due to hypoxia and mechanical ventilation and post-traumatic stress disorder. Conversely, patients already suffering from dementia, as well as their caregivers, have been greatly impacted by the disruption of their care caused by COVID-19. Patients with dementia have experienced worsening of cognitive, behavioral, and psychological symptoms, and the rate of COVID-19-related deaths is disproportionately high among cognitively impaired people. Multiple factors, such as difficulties in remembering and executing safeguarding procedures, age, comorbidities, residing in care homes, and poorer access to hospital standard of care play a role in the increased morbidity and mortality. Non-pharmacological interventions and new technologies have shown a potential for the management of patients with dementia, and for the support of their caregivers.

[The "Fourth Wave"? COVID-19 and consecutive cognitive impairment]. / Die "vierte Welle"? COVID-19 und konsekutive kognitive Störungen.

The COVID-19 pandemic poses new challenges for the healthcare systems world-wide which will go beyond prevention, acute and intensive care treatment of patients with severe illness. A large proportion of "COVID-survivors" - and not only elderly patients - suffers from "post-COVID-syndrome". Risk factors are preexisting somatic multimorbidity, cognitive and cerebral changes together with pneumonia and hypoxemia, intensive care treatment and confusional states during the acute phase of illness. Post-COVID cognitive deficits usually manifest as a frontal dysexecutive syndrome combined with fatigue and dysphoria and/or with attentional and memory deficits. Several pathogenetic mechanisms of COVID encephalopathy are understood, but no specific treatment strategies have been established so far. We assume that general practitioners, psychiatrists, neurologists and social workers will need to take care of the activation, reintegration and expert appraisals of patients with post-COVID fatigue and cognitive deficits during the years to come.

Long-COVID syndrome-associated brain fog and chemofog: Luteolin to the rescue.

COVID-19 leads to severe respiratory problems, but also to long-COVID syndrome associated primarily with cognitive dysfunction and fatigue. Long-COVID syndrome symptoms, especially brain fog, are similar to those experienced by patients undertaking or following chemotherapy for cancer (chemofog or chemobrain), as well in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or mast cell activation syndrome (MCAS). The pathogenesis of brain fog in these illnesses is presently unknown but may involve neuroinflammation via mast cells stimulated by pathogenic and stress stimuli to release mediators that activate microglia and lead to inflammation in the hypothalamus. These processes could be mitigated by phytosomal formulation (in olive pomace oil) of the natural flavonoid luteolin.

TCA cycle metabolic compromise due to an aberrant S-nitrosoproteome in HIV-associated neurocognitive disorder with methamphetamine use.

In the brain, both HIV-1 and methamphetamine (meth) use result in increases in oxidative and nitrosative stress. This redox stress is thought to contribute to the pathogenesis of HIV-associated neurocognitive disorder (HAND) and further worsening cognitive activity in the setting of drug abuse. One consequence of such redox stress is aberrant protein S-nitrosylation, derived from nitric oxide, which may disrupt normal protein activity. Here, we report an improved, mass spectrometry-based technique to assess S-nitrosylated protein in human postmortem brains using selective enrichment of S-nitrosocysteine residues with an organomercury resin. The data show increasing S-nitrosylation of tricarboxylic acid (TCA) enzymes in the setting of HAND and HAND/meth use compared with HIV+ control brains without CNS pathology. The consequence is systematic inhibition of multiple TCA cycle enzymes, resulting in energy collapse that can contribute to the neuronal and synaptic damage observed in HAND and meth use.