This thread will represent my personal interest in Covid regardless of whether we're in a Pandemic or traversing into an Endemic. I will try to only use articles, research, studies by those that have included visual aid (e.g. images, videos) to make it easier for you to visualize the science. Notice to Trolls: Stay out of this thread because you're on ignore/block. Thus, you can not read this thread unless you log out of the forum to read the thread and then log back into the forum to post in this thread while knowing I have you on ignore/block. If someone on my ignore/block list does post in this thread...I will call you out for trolling...including showing an image of you (username) on my ignore/block list as verification. wrbtrader
Nervous system consequences of COVID-19 Serena Spudich and Avindra Nath Science • 20 Jan 2022 • Vol 375, Issue 6578 • pp. 267-269 • DOI: 10.1126/science.abm2052 Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is considered a respiratory pathogen, myriad neurologic complications—including confusion, stroke, and neuromuscular disorders—manifest during acute COVID-19. Furthermore, maladies such as impaired concentration, headache, sensory disturbances, depression, and even psychosis may persist for months after infection, as part of a constellation of symptoms now called Long Covid. Even young people with mild initial disease can develop acute COVID-19 and Long Covid neuropsychiatric syndromes. The pathophysiological mechanisms are not well understood, although evidence primarily implicates immune dysfunction, including nonspecific neuroinflammation and antineural autoimmune dysregulation. It is uncertain whether unforeseen neurological consequences may develop years after initial infection. With millions of individuals affected, nervous system complications pose public health challenges for rehabilitation and recovery and for disruptions in the workforce due to loss of functional capacity. There is an urgent need to understand the pathophysiology of these disorders and develop disease-modifying therapies. Initial reports of neurologic syndromes accompanying COVID-19 described changes in level of consciousness or cognitive dysfunction, weakness, and headache in hospitalized patients that might be attributable to any severe acute illness with respiratory and metabolic disturbances. Subsequently, reports of strokes and acute inflammation or demyelination of the central or peripheral nervous system highlighted specific cerebrovascular and neural tissue involvement. As the number of cases increased globally, it was recognized that SARS-CoV-2 not only induces respiratory symptoms but also can affect multiple organ systems, including the kidneys, gastrointestinal tract, heart, and brain. Clinical neurological and psychiatric syndromes in patients with acute COVID-19 have been delineated by surveillance studies of hospitalized patients. A UK-wide study of hospitalized patients identified the most common neurologic conditions as anosmia (loss of smell), stroke, delirium, brain inflammation, encephalopathy, primary psychiatric syndromes, and peripheral nerve syndromes (1). Varied timing of onset suggests that these conditions have diverse pathophysiological mechanisms. For example, cerebrovascular complications co-occur with or even predate the onset of respiratory symptoms, whereas central inflammatory and peripheral nerve conditions manifest on average 2 weeks later, suggesting that they may result from peri- or postinfectious processes (2). Despite early speculation that SARS-CoV-2 may enter the central nervous system (CNS) via migration through the nasal cavity and the olfactory pathway or trafficking across the blood-brain barrier, analysis of cerebrospinal fluid (CSF) from living patients with neuropsychiatric manifestations has almost uniformly failed to detect viral RNA by reverse transcription polymerase chain reaction. Instead, the preponderance of evidence from CSF and brain tissue suggests that immune activation and inflammation within the CNS is the primary driver of neurologic disease in acute COVID-19. Indeed, histopathological studies of brain tissue from patients who died with acute COVID-19 reveal only limited detection of SARS-CoV-2 nucleic acid or viral protein in the brain (3, 4), consistent with findings in CSF from live patients. Direct examination of autopsy brain tissue has caveats—those who died with acute COVID-19 had severe disease that may not be representative of the majority of those infected with SARS-CoV-2. Many had systemic or metabolic derangements prior to death that may contribute to pathology in a nonspecific way. However, when infrequently detected, infected cells in human brain lack surrounding clusters of inflammatory cells, suggesting that SARS-CoV-2 presence in the CNS does not incite classic viral encephalitis. Examination of CSF samples from living patients reveals neuroinflammation and aberrant neuroimmune responses during acute COVID-19. CSF shows up-regulation in the expression of interferon-regulated genes in dendritic cells, along with activated T cells and natural killer (NK) cells. This is accompanied with an increase in interleukin-1 (IL-1) and IL-12, which is not seen in blood plasma (5). Additionally, CSF-specific clonal expansion of T cells and antibodies that recognize epitopes of SARS-CoV-2 spike protein that cross-react with neural antigens suggest compartmentalization of the immune response (5, 6), although the possibility of a persistent infection with restricted viral replication cannot be entirely excluded. During this acute phase, other markers of monocyte activation and neuronal injury can also be detected in CSF (7). In the following subacute phase, patients with severe manifestations show diminished interferon responses and markers of T cell exhaustion in CSF (8). Autopsy studies of patients with acute COVID-19 show infiltration of macrophages, CD8+ T lymphocytes in perivascular regions, and widespread microglial activation throughout the brain (3). Single-cell analysis of brain tissue has also confirmed CD8+ T lymphocyte infiltration and microglial activation without evidence of SARS-CoV-2 RNA detection in cells of the brain parenchyma (9). The robust, generalized, and SARS-CoV-2–specific immune responses observed in the CNS are puzzling in the absence of readily detectable virus and may suggest transient infection of the brain very early in infection or low concentrations of viral antigen in the CNS. Systemic activation of immune cells may additionally lead to up-regulated expression of cell surface markers that facilitate amplified trafficking into the nervous system, even in the absence of targeted CNS antigens (see the figure). Does widespread vascular dysfunction contribute to nervous system complications of COVID-19? Acute COVID-19 is associated with heightened risk of stroke compared with influenza illness of similar severity, even after correcting for stroke risk factors (10). Overt cerebrovascular events during acute COVID-19 often occur in those with vulnerabilities to vascular disease (such as advanced age and cardiac disease). Increases in blood markers of vascular inflammation as well as thrombosis and infarction in other tissues can also be found in patients with COVID-19 and stroke, suggesting that endothelial inflammation and coagulopathy contribute to these events (11). Indeed, system-wide vascular dysfunction can characterize severe acute COVID-19 and has the potential to contribute to manifestations of organ system failure and systemic inflammation in those most severely ill (12). It is plausible that subtle forms of generalized vascular dysfunction, including thrombotic microangiopathy (microscopic blood clots) in the brain, may lead to neurological symptoms even in the absence of clinically apparent stroke. Additionally, high-field magnetic resonance examination of brain tissue demonstrates microvascular damage in structures plausibly related to neurologic manifestations of COVID-19, consistent with endothelial activation and widespread vascular injury observed in other organs (4). Since early in the COVID-19 pandemic, patients have described lingering syndromes following acute infection, now called Long Covid. These syndromes often include predominant neurologic and psychiatric symptoms, such as difficulty with memory, concentration, and ability to accomplish everyday tasks, frequent headaches, alterations in skin sensation, autonomic dysfunction, intractable fatigue, and in severe cases, delusions and paranoia. Many people who experience neurologic symptoms that linger after acute COVID-19 are less than 50 years old and were healthy and active prior to infection. Notably, the majority were never hospitalized during their acute COVID-19 illness, reflecting mild initial disease. Many of the symptoms experienced by individuals with Long Covid are similar to those of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is also considered to be a postinfectious syndrome caused by a variety of infectious agents. Because the pathophysiology of ME/CFS is poorly understood and there are no effective disease-modifying therapies available, it is likely that the study of Long Covid may benefit ME/CFS patients as well. There is also overlap in symptoms of post–Lyme disease, suggesting that there may be common host susceptibility factors that underlie these illnesses. The heterogeneity of symptoms affecting individuals with Long Covid and the difficulties in ascertaining which symptoms may be a consequence of SARS-CoV-2 infection versus aggravation of preexisting or coincidental conditions pose enormous challenges for mechanistic understanding and approaches to treatment. Few studies have systematically categorized or examined the natural history of Long Covid symptoms, let alone studied their biology. Of 3762 respondents in an online study of people with persistent symptoms after documented or suspected COVID-19, many had ongoing symptoms up to 7 months after initial infection, including prominent neuropsychiatric syndromes (13). Serial imaging routinely captured in the UK Biobank cohort has revealed focal areas of brain atrophy in individuals after documented COVID-19 compared with a parallel group without COVID-19, suggesting a potential biomarker for brain effects of SARS-CoV-2 (14). Studies of positron emission tomography (PET) imaging also show decreased metabolic activity in the brain in people with Long Covid (15). However, the pathophysiology leading to these symptoms and cerebral changes is unknown. Potential etiologies are mainly extrapolated from current understanding of nervous system pathogenesis during acute COVID-19. These include residual immune activation or persistent autoimmune disturbance, ongoing endothelial activation or vascular dysfunction, or residua of injury accrued during acute disease. Systematic neurologic studies of carefully phenotyped individuals with neurological Long Covid symptoms are essential. These patients often also experience stigma, employment difficulties, and mental health challenges. Thus, diagnostic certainty and therapeutic interventions are needed to address this major public health concern. The full extent of the long-term neurological complications of COVID-19 has not been realized. Observations of neuroinflammation and neuronal injury in acute COVID-19 have raised the possibility that infection may accelerate or trigger future development of neurodegenerative diseases such as Alzheimer’s or Parkinson’s diseases. No information is yet available regarding neurodevelopmental trajectories in children, who usually experience mild COVID-19 and manifest few neurologic or psychiatric symptoms during or after acute illness. Those who experience the rare multisystem-inflammatory syndrome in children (MIS-C) may be at particular risk for neurological sequelae owing to widespread endothelial activation, often involving the brain. What are the host factors that account for the wide variability in clinical manifestations such that some patients develop acute neurologic illness, and others develop persistent postinfectious complications? It will be critical to characterize the pattern(s) of immune dysregulation in Long Covid patients. Is it possible that persistent immune dysregulation underlies ongoing symptoms? If so, this may be driven by host antigens with autoimmune responses, or a persistent viral infection with restricted viral replication in tissue reservoirs. Whether antiviral or immunetargeted interventions early in the disease course or prophylactic vaccination against COVID-19 will alter the trajectory of neurologic complications of COVID-19 is also unknown. Investigations that include longitudinal studies with neurological and psychiatric assessments and rigorous host-pathogen studies of systemic and nervous system interactions have the potential to answer these questions. Ultimately, interventional trials based on these discoveries are needed to determine approaches to curtail or reverse nervous system effects of COVID-19 that are experienced by huge numbers of people globally. References and Notes 1 A. Varatharaj et al., Lancet Psychiatry 7, 875 (2020). Go to reference Crossref PubMed Google Scholar 2 A. L. Ross Russell et al., Brain Commun. 3, fcab168 (2021). Go to reference Crossref PubMed Google Scholar 3 J. Matschke et al., Lancet Neurol. 19, 919 (2020). Crossref PubMed Google Scholar 4 M. H. Lee et al., N. Engl. J. Med. 384, 481 (2021). Crossref PubMed Google Scholar 5 E. Song et al., Cell Rep. Med. 2, 100288 (2021). Crossref PubMed Google Scholar 6 C. Franke et al., Brain Behav. Immun. 93, 415 (2021). Go to reference Crossref PubMed Google Scholar 7 A. Edén et al., Neurology 96, e294 (2021). Go to reference PubMed Google Scholar 8 M. Heming et al., Immunity 54, 164 (2021). Go to reference Crossref PubMed Google Scholar 9 J. F. Fullard et al., Genome Med. 13, 118 (2021). Go to reference Crossref PubMed Google Scholar 10 A. E. Merkler et al., JAMA Neurol. 77, 1366 (2020). Go to reference Crossref Google Scholar 11 L. S. McAlpine et al., Stroke 52, e233 (2021). Go to reference Crossref PubMed Google Scholar 12 L. A. Teuwen et al., Nat. Rev. Immunol. 20, 389 (2020). Go to reference Crossref PubMed Google Scholar 13 H. E. Davis et al., EClinicalMedicine 38, 101019 (2021). Go to reference Crossref PubMed Google Scholar 14 G. Douaud et al., medRxiv2021). Go to reference Crossref Google Scholar 15 J. A. Hosp et al., Brain 144, 1263 (2021). Go to reference Crossref PubMed Google Scholar https://www.science.org/doi/10.1126/science.abm2052# wrbtrader
COVID-19 and dementia: Are scientists concerned? Written by Katharine Lang on February 25, 2022 — Fact checked by Harriet Pike, Ph.D. For most, COVID-19 causes a few days of mild to moderate symptoms, but others feel the effects for months. Some of these effects are neurological, leading scientists to ask whether COVID-19 could increase the risk of dementia. Medical News Today looked at the evidence and spoke with experts to find out the latest views. Does COVID increase dementia risk? Here is what the experts think. Since the start of the COVID-19 pandemic, more than 425 million SARS-CoV-2 infections have been confirmed worldwide. Globally, almost 6 million people have died from, or with, the infection. For most, when SARS-CoV-2 infection leads to COVID-19, the symptoms are mild to moderate. But for some, symptoms of the illness are prolonged. Experts have described this issue, long COVID, as “not recovering [for] several weeks or months following the start of symptoms that were suggestive of COVID, whether you were tested or not.” Symptoms of long COVID vary, but some are common COVID-19 symptoms, such as fatigue, shortness of breath, a cough, and joint pain. Other respiratory virus infections have been associated with neurological and psychiatric after-effects. The authors of one review observe that “Numerous respiratory viruses can infect the cells of the peripheral and central nervous systems, elicit inflammatory cascades, and directly and indirectly cause various neurologic manifestations.” And it seems that COVID-19 is no exception, with many people reporting neurological symptoms after SARS-CoV-2 infections. These symptoms may include: brain fog, a reduced ability to think clearly anxiety difficulties with memory and concentration difficulty sleeping changes in mood Experts are now investigating how COVID-19 might affect neurocognitive function and whether it may increase dementia risk. COVID-19 and the nervous system SARS-CoV-2 usually gains access to the body via droplets that enter the nose or mouth. From there, the virus moves to the throat. It can then travel to the lungs and other organs, and, various studies suggest, may enter the nervous system. The blood-brain barrier stops most viruses from entering the brain. So some studies have investigated whether the neurological effects of COVID-19 stem from either a viral invasion of the central nervous system or the systemic effects of the infection. One review suggests that both may occur in parallel. In severe infections, oxygen deprivation and a cytokine storm may damage the blood-brain barrier and allow SARS-CoV-2 to enter the brain. Another review backs this up, suggesting that SARS-CoV-2 may disrupt the blood-brain barrier or infect the peripheral neurons, then enter the central nervous system. Prof. Harris Gelbard, director of the Center for Neurotherapeutics Discovery at the University of Rochester Medical Center, told Medical News Today: “A recent cerebrospinal fluid study suggests that patients with COVID-19 infection have blood-cerebrospinal fluid barrier dysfunction, with pathology occurring in endothelial cells that line blood vessels in the blood-brain barrier. While this study did not demonstrate evidence for the presence of SARS-CoV-2 in any of the cerebrospinal fluid samples, all patients in this study had PCR-proven COVID-19.” Evidence is growing that COVID-19 can cause neurological damage. One 2020 review observed that “COVID-19 is also anticipated to take a toll on the nervous system in the long term.” Another Source asserts that “Respiratory virus neurotropism and collateral injury due to concurrent inflammatory cascades result in various neurologic pathologies, including Guillain-Barré syndrome, encephalopathy, encephalitis, ischemic stroke, intracerebral hemorrhage, and seizures.” ACE2 receptors Some research has suggested that SARS-CoV-2 might invade the nervous system in the same way that it invades other cells, via agiotensin-converting enzyme 2 (ACE2) receptors. However, only certain cells in the nervous system have these receptors. Among them are excitatory and inhibitory neurons and other types of cells, such as astrocytes, oligodendrocytes, and endothelial cells. One review points out that ACE2 receptors are expressed in small blood vessels in the brain, which could provide a potential entry route for SARS-CoV-2 into the brain. Prof. Gelbard emphasized that the evidence so far of how SARS-CoV-2 might enter the central nervous system is not conclusive: “The pathologic evidence for direct infection of neural cell types, particularly neurons, remain equivocal at best. Despite survey studies of neuronal expression of ACE2 receptors from brain transcriptome databases, […] the correlative neuropathology from postmortem human cases is scant.” Whether or not the virus invades the central nervous system, it is clear that SARS-CoV-2 infection can lead to cognitive dysfunction that may last for months or even years after the acute phase of COVID-19. Inflammation Many people who are hospitalized with COVID-19 have inflammatory complications, which can affect the nervous system. One study has reported that these patients experience delirium, reduced consciousness, stroke, and other encephalopathiesTrusted Source following SARS-CoV-2 infection. In this study, the researchers found that the degree of inflammation was correlated with the severity of COVID-19 symptoms and an increase in pro-inflammatory cytokines. Prof. Gelbard, who was not involved in this study, explains how experts interpret the findings: “Our collective view of this is that SARS-CoV-2 infection/COVID-19 impacts elderly patients with underlying neurovascular disease, whether it is from cerebrovascular disease, subclinical Alzheimer’s disease, Parkinson’s disease or other neurodegenerative disease, by creating a pro-inflammatory central nervous system milieu that is permissive for cognitive impairment, either manifesting as acute delirium or delirium superimposed on dementia.” Dementia and COVID-19 Studies have shown that people with dementia have increased morbidity and mortality from COVID-19. Many have comorbidities associated with poor COVID-19 outcome, such as cardiovascular disease, diabetes, hypertension, and obesity. Dr. Heather Snyder, Alzheimer’s Association’s vice president of medical and scientific relations, told MNT: “The factors causing or contributing to dementia, including hypertension and diabetes, may be what make individuals with dementia more vulnerable to contracting COVID-19. […] Research published in February 2021 in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association found that risk of contracting COVID-19 was twice as high for people living with dementia than those without it.” People with dementia are more at risk of COVID-19 — but might the disease worsen existing dementia or cause the development of dementia? It may be that for people with dementia, SARS-CoV-2 can more easily enter the brain, as the blood-brain barrier is damaged. This might explain worsening symptoms reported in people with dementia after COVID-19. One study states: “There is evidence for a bidirectional relationship between viral infections and dementia: People with dementia have an increased risk for infection, while a poor immune response to infection places individuals at increased risk for dementia.” Another risk of COVID-19, and particularly severe forms of this disease, is thrombosis, a cause of strokes. According to one large study, a stroke can double the risk of developing dementia. Mitigating the risks People with severe COVID-19 are more likely to have neurological symptoms of the illness, both during its acute phase and afterwards. And severe COVID-19 is more common in those who are older or have comorbidities, such as overweight or obesity, diabetes, chronic lung disease, and cancers. Studies suggest that the best way to avoid neurological effects of COVID-19 is to optimize brain and body health in these ways: being physically active doing cognitively stimulating activities sleeping for 7 to 8 hours every night having a balanced diet with all the essential vitamins and minerals having regular social interactions. Drug treatments to combat inflammation are also an option. Prof. Gelbard, who is now working on developing such a treatment, commented, “What is sorely needed is an appropriate anti-neuroinflammatory intervention with a brain-penetrant therapy that can mitigate this type of neuroinflammatory response.” And, as several experts have noted, vaccination against COVID-19 is one of the most effective ways of minimizing the risk of both severe COVID and long COVID, a view Dr. Snyder reiterated: “While we work to further understand the lasting impacts of COVID-19 on the brain, the take-home message for protecting your cognition is simple: Don’t get COVID-19. The best way to not get COVID-19 is to get vaccinated.” No clear answer As yet, it is unclear whether COVID-19 may be a risk factor for dementia. Dr. Snyder told MNT that “The ongoing COVID-19 pandemic gives us an unwelcome opportunity to study the impact of viral infection on the brain in the short and long term.” She added: “Potential viral contributions to Alzheimer’s and dementia have been long debated within the research community. However, no research to date has shown definitively that a virus can cause Alzheimer’s disease. Because COVID-19 is still relatively new, we won’t know if infection will have an impact on dementia risk for some time.” Prof. Gelbard concurred: “Unfortunately, we believe this is the tip of the iceberg. Not to sound like an alarmist, but we echo the sentiments of public health experts: We may feel like we are done with COVID-19, but the virus is not done with us. We expect the aftershocks of this pandemic to continue amplifying the challenge of dealing with neurodegenerative disease in the elderly and immunocompromised.” “If you have had COVID-19, it doesn’t mean you’re going to get dementia. We’re still trying to understand this relationship.” – Dr. Heather Snyder While researchers have yet to arrive at conclusive evidence, it appears that the neurological and psychiatric effects of COVID-19 are likely to be with us for many years to come. https://www.medicalnewstoday.com/ar...-why-are-scientists-concerned#No-clear-answer References The neuroinvasive potential of SARS‐CoV2 may be at least partially responsible for the respiratory failure of COVID‐19 patients. Li, Y. et al. (2020), J. Med. Virol. jmv.25728. Insights into RNA synthesis, capping, and proofreading mechanisms of SARS-coronavirus. Sevajol, M. et al. (2014), Virus Res. 194, 90–99. COVID-19: what has been learned and to be learned about the novel coronavirus disease. Yi, Y. et al. 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(2004), Vet. Pathol. 41, 101–107. Dementia care during COVID-19. Wang, H. et al. (2020), Lancet 395, 1190–1191. Anticipating and Mitigating the Impact of the COVID-19 Pandemic on Alzheimer’s Disease and Related Dementias. Brown, E. E. et al. (2020), Am. J. Geriatr. Psychiatry. Outcome of Parkinson’s Disease patients affected by <scp>COVID</scp> ‐19. Antonini, A. et al. (2020), Mov. Disord. mds.28104. Impact of the <scp>COVID</scp> ‐19 Pandemic on Parkinson’s Disease and Movement Disorders. Papa, S. M. et al. (2020), Mov. Disord. 35, 711–715. The Invisible Hand — Medical Care during the Pandemic. Kittleson, M. M. (2020), N. Engl. J. Med. 382, 1586–1587. Management of Advanced Therapies in Parkinson’s Disease Patients in Times of Humanitarian Crisis: The <scp>COVID</scp> ‐19 Experience. Fasano, A. et al. (2020), Mov. Disord. Clin. Pract. 7, 361–372. Parkinson’s Disease and <scp>COVID</scp> ‐19: Perceptions and Implications in Patients and Caregivers. Prasad, S. et al. (2020), Mov. Disord. mds.28088. The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia. Cummings, J. L. et al. (1994), Neurology 44, 2308–2308. Facetime to reduce behavioral problems in a nursing home resident with Alzheimer’s dementia during COVID-19. Padala, S. P. et al. (2020), Psychiatry Res. 288, 113028. The Promise of Telemedicine for Movement Disorders: an Interdisciplinary Approach. Ben-Pazi, H. et al. (2018), Curr. Neurol. Neurosci. Rep. 18, 26. COVID-19: An Early Review of Its Global Impact and Considerations for Parkinson’s Disease Patient Care. Bhidayasiri, R. et al. (2020), J. Mov. Disord. 13, 105–114. COVID-19 is catalyzing the adoption of teleneurology. Klein, B. C. et al. (2020), Neurology 94, 903–904. Interactive video conferencing: A means of providing interim care to parkinson’s disease patients. Hubble, J. P. et al. (1993), Mov. Disord. 8, 380–382. Remotely Assessing Symptoms of Parkinson’s Disease Using Videoconferencing: A Feasibility Study. 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A faulty immune response may be behind lingering brain trouble after COVID-19 Headaches and trouble thinking plague some people after a coronavirus infection By Laura Sanders February 2, 2022 at 7:00 am A tussle with COVID-19 can leave people’s brains fuzzy. SARS-CoV-2, the virus behind COVID-19, doesn’t usually make it into the brain directly. But the immune system’s response to even mild cases can affect the brain, new preliminary studies suggest. These reverberating effects may lead to fatigue, trouble thinking, difficulty remembering and even pain, months after the infection is gone. It’s not a new idea. Immune systems gone awry have been implicated in cognitive problems that come with other viral infections such as HIV and influenza, with disorders such as myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS, and even from the damaging effects of chemotherapy. What’s different with COVID-19 is the scope of the problem. Millions of people have been infected, says neurologist Avindra Nath of the National Institutes of Health in Bethesda, Md. “We are now faced with a public health crisis,” he says. To figure out ways to treat people for the fuzzy thinking, headaches and fatigue that hang around after a bout with COVID-19, scientists are racing to figure out what’s causing these symptoms (SN: 4/27/21). Cognitive neurologist Joanna Hellmuth at the University of California, San Francisco had a head start. As someone who had studied the effects of HIV on the brain, she quickly noted similarities in the neurological symptoms of HIV and COVID-19. The infections paint “the same exact clinical picture,” she says. HIV-related cognitive symptoms have been linked to immune activation in the body, including the brain. “Maybe the same thing is happening in COVID,” Hellmuth says. She and her colleagues looked for differences in the fluid that surrounds the brain and spinal cord in 13 people who had lingering cognitive symptoms from COVID-19 and four people who had no cognitive symptoms. The four people without cognitive symptoms had normal cerebrospinal fluid. But 10 of the 13 people who did have lasting symptoms had abnormalities in their fluid, some of which point to immune system reactions. So far, the analyses can’t pinpoint the precise changes that may be important. Possible suspects are antibodies that can mistakenly attack key proteins in the brain, the researchers say. The results, published January 19 in Annals of Clinical and Translational Neurology, raise many more questions, but show that there’s a real difference in the cerebrospinal fluid, Hellmuth says. “This is a very small study, but the data suggest that there’s a real biological basis in these COVID-related cognitive changes,” she says. “These are not just people who are stressed out … we’re seeing abnormalities that are not typically seen in brain fluid.” More hints to the brain troubles come from an analysis of mice and people, posted January 10 at bioRxiv.org, that has not yet been reviewed by other scientists. By analyzing human tissue and mice infected with SARS-CoV-2, researchers showed that immune cells called microglia are overactive in the brain. When microglia shift into high gear, they can damage surrounding brain tissue. It turns out that microglia overactivity is similar to that caused by toxic chemotherapy treatments, says study coauthor Michelle Monje, a neurologist and researcher at Stanford University. “When the reports started coming out about the frequency of persistent cognitive symptoms associated with long COVID, I noted striking similarities between ’chemo-fog’ and ‘COVID-fog,’ and decided we needed to study this.” Microglia were more active in the brains of mice infected with SARS-CoV-2 than in uninfected mice. A similar pattern emerged when the researchers studied postmortem brain tissue from nine people who died with COVID-19. It’s not clear how well these samples represent the majority of people who experienced mild COVID and are living with the aftereffects. Infected mice also had higher levels of immune proteins in their cerebrospinal fluid. One in particular, called CCL11, has been tied to cognitive trouble in people that comes with age and in certain psychiatric conditions. People with lingering neurological symptoms of COVID also had more CCL11 in their plasma than people who didn’t have those symptoms, the researchers found. The new results come with caveats, says neurologist Svetlana Blitshteyn of the University at Buffalo Jacobs School of Medicine and Biomedical Sciences in New York, who also directs the Dysautonomia Clinic. “They’re small studies, and obviously they are not definitive,” she says, “but the preliminary evidence speaks for itself.” It’s becoming clearer now that the brain fog that comes after an infection may be “rooted in neuroinflammation.” Figuring out the cause of the neurological problems may reveal a treatment. Laboratory studies have pointed to potential therapies that can interrupt this immune system overreaction, particularly in brain inflammation caused by chemo, Monje says. She and colleagues are studying whether those same treatments might help with COVID-19. Tragic as the pandemic is, it may ultimately lead to something good, adds Nath, who is setting up a small clinical trial to study possible long COVID treatments. All these other syndromes such as ME/CFS that researchers have struggled to understand “might benefit from what we learn here from long COVID. We might be able to develop treatments for them all.” Citations S. Spudich and A. Nath. Nervous system consequences of COVID-19. Science. Vol. 375, January 21, 2022, p. 267. doi: 10.1126/science.abm2052. A.C. Apple et al. Risk factors and abnormal cerebrospinal fluid associate with cognitive symptoms after mild COVID-19. Annals of Clinical and Translational Neurology. Published January 19, 2022. doi: 10.1002/acn3.51498. A. Fernández-Castañeda et al. Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain. bioRxiv.org. Posted January 10, 2022. doi: 10.1101/2022.01.07.475453. https://www.sciencenews.org/article/covid-brain-fog-coronavirus-immune-response-fatigue ----------- wrbtrader
Ministrokes are different from regular strokes. Yet, ministrokes are very common and go undiagnosed in Covid-19 infected individuals that had just a mild illness but are usually discovered in hospitalized patients. The main reason why ministrokes go undiagnosed is due to the fact that they last a much shorter duration in which people have some "brain fog". Yet, there is a connection between ministrokes with those that later develop vascular cognitive impairment or vascular dementia. In fact, 20 - 30% of patients with dementia...had ministrokes earlier in their life from disease. Simply, when you hear someone say they had a Covid infection and that it was nothing or they barely had a cough or they only had a little fatigue...most likely its a person that didn't have a brain scan that would have discovered ministrokes that many Covid-19 infected people do have but go undiagnosed. In the research article below, they don't use the phrase ministroke. Instead, they use its more common name...transient ischemic attack (TIA). When people use the term "ministroke," what they're really often referring to is a transient ischemic attack (TIA). A TIA is a brief interruption of blood flow to part of the brain, spinal cord, or retina...which may cause temporary stroke-like symptoms but does not damage brain cells or cause permanent disability. Below is a huge research article that I don't have time to post the entire article but I did include one graphical image out of many plus the scientific references. Yet, remember this statistic... Compare the neurological complications of COVID-19 directly to vaccination: Risk of neurological complications from COVID-19: between 40% and 80% of people who have symptomatic COVID-19. This means at least 400,000 per million people with symptomatic COVID-19 experience neurological issues Risk of TTS from vaccination: two per million people who receive the Johnson & Johnson vaccine. This means 0.0002% of people who get vaccinated with J&J experience TTS I'm not sure why the above stats only mentions J&J vaccine when similar stats occurs for all the other vaccines. ---------- Neutrophils predominate the immune signature of cerebral thrombi in COVID-19 stroke patients Abstract Coronavirus disease 2019 (COVID-19) is associated with an increased risk of thrombotic events. Ischemic stroke in COVID-19 patients entails high severity and mortality rates. Here we aimed to analyze cerebral thrombi of COVID-19 patients with large vessel occlusion (LVO) acute ischemic stroke to expose molecular evidence for SARS-CoV-2 in the thrombus and to unravel any peculiar immune-thrombotic features. We conducted a systematic pathological analysis of cerebral thrombi retrieved by endovascular thrombectomy in patients with LVO stroke infected with COVID-19 (n = 7 patients) and non-covid LVO controls (n = 23). In thrombi of COVID-19 patients, the SARS-CoV-2 docking receptor ACE2 was mainly expressed in monocytes/macrophages and showed higher expression levels compared to controls. Using polymerase chain reaction and sequencing, we detected SARS-CoV-2 Clade20A, in the thrombus of one COVID-19 patient. Comparing thrombus composition of COVID-19 and control patients, we noted no overt differences in terms of red blood cells, fibrin, neutrophil extracellular traps (NETs), von Willebrand Factor (vWF), platelets and complement complex C5b-9. However, thrombi of COVID-19 patients showed increased neutrophil density (MPO+ cells) and a three-fold higher Neutrophil-to-Lymphocyte Ratio (tNLR). In the ROC analysis both neutrophils and tNLR had a good discriminative ability to differentiate thrombi of COVID-19 patients from controls. In summary, cerebral thrombi of COVID-19 patients can harbor SARS-CoV2 and are characterized by an increased neutrophil number and tNLR and higher ACE2 expression. These findings suggest neutrophils as the possible culprit in COVID-19-related thrombosis. Graphical Abstract Introduction Coronavirus disease 2019 (COVID-19) is primarily characterized by pulmonary involvement but neurological manifestations [10, 11, 14, 30, 39] and thrombotic complications [17] are also frequent... Ischemic stroke is not uncommon in patients with COVID-19, especially those with severe infection and pre-existing vascular risk factors [25]. A meta-analysis showed that acute cerebrovascular disease occurs in about 1.4% of the hospitalized COVID-19 population, with a prevalence of acute ischemic stroke over intracerebral hemorrhage [25]. Although the true relationship between COVID-19 and stroke incidence remains to be clarified, multicenter and meta-data suggest that ischemic stroke in COVID-19 patients is more severe with a worse functional outcome and higher mortality [21, 27]... 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Hybrid is better A Swedish study concludes that the risk of SARS-CoV-2 reinfection and hospitalisation in previously infected individuals remained low for up to 20 months, although vaccination further decreased the risk of both outcomes. This study adds to the evidence that vaccination reinforces natural immunity. Similarly, an Omicron BA.1 infection in people who were not vaccinated elicits antibodies that can cross-neutralise BA.2 or BA.3 subvariants, but not previous variants of concern. In contrast, a BA.1 breakthrough infection in previously vaccinated people results in strong neutralising activity not only against Omicron subvariants but also against previously circulating variants)...now referred to as Super Immunity. (studies not yet peer-reviewed) Omicron BA.1 Infection In People Who Were Not Vaccinated (natural immunity against Omicron seen only in subvariants...not against prior Variants of Concern). It explains the reinfections...someone infected with Delta and then later infected with Omicron. https://www.biorxiv.org/content/10.1101/2022.03.30.486409v1.full.pdf BA.1 Breakthrough Infection In Previously Vaccinated (good against subvariants and good against other previous variants) https://www.biorxiv.org/content/10.1101/2022.04.01.486695v1.full wrbtrader
Homologous boosters are defined as boosters matching the primary vaccination series and Heterologous boosters are defined as boosters that differ from the primary vaccination series. ---------- Effectiveness of Homologous or Heterologous Covid-19 Boosters in Veterans April 7, 2022 N Engl J Med 2022; 386:1375-1377 DOI: 10.1056/NEJMc2200415 Metrics Vaccine effectiveness against coronavirus disease 2019 (Covid-19) wanes over time, and boosters are now recommended for residents of the United States starting at the age of 12 years. 1 Clinical trials have shown that receipt of a booster that does not match the primary vaccination (heterologous booster) may result in a higher neutralizing-antibody response than the receipt of a matching (homologous) booster, particularly after primary vaccination with an adenoviral-vector vaccine.2-5 Whether the choice of booster affects real-world vaccine effectiveness is poorly understood. We performed a study involving 4,806,026 veterans and linked their information to the Veterans Affairs Covid-19 Shared Data Resource, a database that was created in response to the Covid-19 pandemic and that contains information on all veterans with a confirmed laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We created two analysis cohorts based on the primary vaccine that each veteran received (adenoviral-vector or messenger RNA [mRNA]) to compare the effectiveness of heterologous and homologous boosters. (Details regarding the study participants are provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org.) For each participant who had received a heterologous booster, we identified a matched control who had received a homologous booster. Matching was based on age, sex, race, Charlson Comorbidity Index, geographic location, primary vaccine type, week of booster administration, and interval between the primary vaccination and the booster. We calculated adjusted rate ratios and used robust error estimates to derive 95% confidence intervals using Poisson regression. The primary outcome was the incidence of documented SARS-CoV-2 infection after a booster dose. Additional outcomes included the incidence of moderate disease (defined as Covid-19–related hospitalization within 14 days after documented infection) and severe or critical disease (defined as admission to an intensive care unit or death within 28 days after documented infection). Among the veterans in the database who had at least two primary care visits before vaccine rollout, 43,394 had received a booster after vaccination with the Ad26.COV2.S vaccine (Johnson & Johnson–Janssen). Similarly, we identified 965,063 veterans who had received a booster after primary vaccination with either the BNT162b2 vaccine (Pfizer–BioNTech) or the mRNA-1273 vaccine (Moderna). The matched analysis cohorts contained 25,972 veterans with Ad26.COV2.S primed boosters (Ad26.COV2.S vaccine cohort: 12,986 homologous and 12,986 heterologous boosters) and 35,850 veterans with mRNA-primed boosters (mRNA vaccine cohort: 17,925 homologous and 17,925 heterologous boosters) (Table S1 in the Supplementary Appendix). In the Ad26.COV2.S-primed vaccine cohort, we observed 415 documented infections, including 34 participants with moderate disease and 12 with severe or critical disease (Table 1). Of these infections, 278 occurred in participants who had received a homologous booster and 137 in those who had received a heterologous booster. The incidence of infection after heterologous boosting was approximately 50% lower than that after homologous boosting (adjusted rate ratio, 0.49; 95 confidence interval [CI], 0.40 to 0.60). Similarly, adjusted rate ratios for moderate and severe or critical disease were lower after heterologous boosting. In the mRNA-primed cohort (which included recipients of either the BNT162b2 or mRNA-1273 vaccine), we observed 362 documented infections, including 23 participants with moderate disease and 8 with severe or critical disease. No material difference was noted in the incidence of SARS-CoV-2 infection, including moderate and severe or critical disease, among participants who had received heterologous or homologous boosting after primary mRNA vaccination (adjusted rate ratio, 1.10; 95% CI, 0.90 to 1.35). Outcomes for the individual mRNA vaccines were similar to those in the combined mRNA category. (Additional data regarding individual vaccines are provided in Table S2.) Recent clinical trials examining the safety and immunogenicity of SARS-CoV-2 boosters in healthy adults have shown greater increases in antibody titers after heterologous boosting than after homologous boosting.2,5 In particular, neutralizing immunoglobulin G antibodies were lowest after homologous Ad26.COV2.S boosting and remained below the predicted efficacy threshold for preventing symptomatic Covid-19.2 Our findings support the results of these clinical trials since we observed the largest number of documented breakthrough infections in participants who had received a homologous Ad26.COV2.S booster. Our analysis provides further evidence that the infection rate is lower in persons who are boosted with a heterologous mRNA vaccine. Overall, documented infections, including moderate and severe or critical disease, were uncommon among veterans who had received either homologous or heterologous boosters. Heterologous mRNA boosting may better protect against incident infection in persons who were initially vaccinated with an adenoviral-vector vaccine. Florian B. Mayr, M.D., M.P.H. Victor B. Talisa, Ph.D. Obaid Shaikh, M.D. Sachin Yende, M.D. Adeel A. Butt, M.B., B.S. Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA florian@pitt.edu Supported by the facilities of the Veterans Affairs Shared Data Resource; by the resources and facilities of the Department of Veterans Affairs Informatics and Computing Infrastructure (VA HSR RES 13-457); and by the resources and facilities of the Veterans Affairs Pittsburgh Healthcare System and the central data repositories maintained by the Veterans Affairs Information Resource Center, including the Corporate Data Warehouse. Dr. Mayr is supported by a grant (K23GM132688) from the National Institutes of Health. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. The views expressed in this letter are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government. This letter was published on February 9, 2022, at NEJM.org. Drs. Yende and Butt contributed equally to this letter. https://www.nejm.org/doi/full/10.1056/NEJMc2200415 wrbtrader