Tag: long covid neurology

Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study

Abstract:

Cognitive impairment and function post-acute mild to moderate COVID-19 are poorly understood. We report findings of 128 prospectively studied SARS-CoV-2 positive patients. Cognition and olfaction were assessed at 2-, 4- and 12-months post-diagnosis. Lung function, physical and mental health were assessed at 2-month post diagnosis. Blood cytokines, neuro-biomarkers, and kynurenine pathway (KP) metabolites were measured at 2-, 4-, 8- and 12-months. Mild to moderate cognitive impairment (demographically corrected) was present in 16%, 23%, and 26%, at 2-, 4- and 12-months post diagnosis, respectively. Overall cognitive performance mildly, but significantly (p<.001) declined. Cognitive impairment was more common in those with anosmia (p=.05), but only at 2 months. KP metabolites quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine were significantly (p<.001) associated with cognitive decline. The KP as a unique biomarker offers a potential therapeutic target for COVID-19-related cognitive impairment.

Source: Lucette A. Cysique, David Jakabek, Sophia G. Bracken, Yasmin Allen-Davidian, Benjamin Heng, Sharron Chow, Mona Dehhaghi, Ananda Staats Pires, David R. Darley, Anthony Byrne, Chansavath Phetsouphanh, Anthony Kelleher, Gregory J. Dore, Gail V. Matthews, Gilles J Guillemin, Bruce J. Brew. Post-acute COVID-19 cognitive impairment and decline uniquely associate with kynurenine pathway activation: a longitudinal observational study. medRxiv 2022.06.07.22276020; doi: https://doi.org/10.1101/2022.06.07.22276020 https://www.medrxiv.org/content/10.1101/2022.06.07.22276020v1.full-text (Full text)

Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation

Summary:

COVID survivors frequently experience lingering neurological symptoms that resemble cancer therapy-related cognitive impairment, a syndrome for which white-matter microglial reactivity and consequent neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans.
Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared to SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis and elevated CCL11 at early timepoints, but after influenza only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
Source: Anthony Fernández-Castañeda, Peiwen Lu, Anna C. Geraghty, Eric Song, MyoungHwa Lee, Jamie Wood, Michael R. O’Dea, Selena Dutton, Kiarash Shamardani, Kamsi Nwangwu, Rebecca Mancusi, Belgin Yalçın, Kathryn R. Taylor, Lehi AcostaAlvarez, Karen Malacon, Michael B. Keough, Lijun Ni, Pamelyn J. Woo, Daniel Contreras-Esquivel, Angus Martin Shaw Toland, Jeff R. Gehlhausen, Jon Klein, Takehiro Takahashi, Julio Silva, Benjamin Israelow, Carolina Lucas, Tianyang Mao, Mario A. Peña-Hernández, Alexandra Tabachnikova, Robert J. Homer, Laura Tabacof, Jenna Tosto-Mancuso, Erica Breyman, Amy Kontorovich, Dayna McCarthy, Martha Quezado, Hannes Vogel, Marco M. Hefti, Daniel P. Perl, Shane Liddelow, Rebecca Folkerth, David Putrino, Avindra Nath, Akiko Iwasaki, Michelle Monje. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation.  Cell (2022). Published: June 12, 2022 DOI:https://doi.org/10.1016/j.cell.2022.06.008 https://www.sciencedirect.com/science/article/pii/S0092867422007139 (Full text available as PDF file)

Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19

Abstract:

COVID-19 is primarily known as a respiratory disease caused by SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, severe headaches, and even stroke are reported in up to 30% of cases and can persist even after the infection is over (long COVID). These neurological symptoms are thought to be produced by the virus infecting the central nervous system, however we don’t understand the molecular mechanisms triggering them. The neurological effects of COVID-19 share similarities to neurodegenerative diseases in which the presence of cytotoxic aggregated amyloid protein or peptides is a common feature. Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we identified two peptides from the SARS-CoV-2 proteome that self-assemble into amyloid assemblies. Furthermore, these amyloids were shown to be highly toxic to neuronal cells. We suggest that cytotoxic aggregates of SARS-CoV-2 proteins may trigger neurological symptoms in COVID-19.

Source: Charnley, M., Islam, S., Bindra, G.K. et al. Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19. Nat Commun 13, 3387 (2022). https://doi.org/10.1038/s41467-022-30932-1 https://www.nature.com/articles/s41467-022-30932-1 (Full text)

Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease now well-documented as having arisen commonly from a viral infection, but also from other external stressors, like exposure to agricultural chemicals, other types of infection, surgery, or other severe stress events. Research has shown these events produce a systemic molecular inflammatory response and chronic immune activation and dysregulation. What has been more difficult to establish is the hierarchy of the physiological responses that give rise to the myriad of symptoms that ME/CFS patients experience, and why they do not resolve and are generally life-long.

The severity of the symptoms frequently fluctuates through relapse recovery periods, with brain-centered symptoms of neuroinflammation, loss of homeostatic control, “brain fog” affecting cognitive ability, lack of refreshing sleep, and poor response to even small stresses. How these brain effects develop with ME/CFS from the initiating external effector, whether virus or other cause, is poorly understood and that is what our paper aims to address.

We propose the hypothesis that following the initial stressor event, the subsequent systemic pathology moves to the brain via neurovascular pathways or through a dysfunctional blood-brain barrier (BBB), resulting in chronic neuroinflammation and leading to a sustained illness with chronic relapse recovery cycles. Signaling through recognized pathways from the brain back to body physiology is likely part of the process by which the illness cycle in the peripheral system is sustained and why healing does not occur. By contrast, Long COVID (Post-COVID-19 condition) is a very recent ME/CFS-like illness arising from the single pandemic virus, SARS-CoV-2.

We believe the ME/CFS-like ongoing effects of Long COVID are arising by very similar mechanisms involving neuroinflammation, but likely with some unique signaling, resulting from the pathology of the initial SARS-CoV-2 infection. The fact that there are very similar symptoms in both ongoing diseases, despite the diversity in the nature of the initial stressors, supports the concept of a similar dysfunctional CNS component common to both.

Source: Tate W, Walker M, Sweetman E, Helliwell A, Peppercorn K, Edgar C, Blair A, Chatterjee A. Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote Relapses. Front Neurol. 2022 May 25;13:877772. doi: 10.3389/fneur.2022.877772. PMID: 35693009; PMCID: PMC9174654.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174654/ (Full text)

ACE2 and SCARF expression in human dorsal root ganglion nociceptors: implications for SARS-CoV-2 virus neurological effects

Abstract:

SARS-CoV-2 has created a global crisis. COVID-19, the disease caused by the virus, is characterized by pneumonia, respiratory distress, and hypercoagulation and can be fatal. An early sign of infection is loss of smell, taste, and chemesthesis-loss of chemical sensation. Other neurological effects of the disease have been described, but not explained. It is now apparent that many of these neurological effects (for instance joint pain and headache) can persist for at least months after infection, suggesting a sensory neuronal involvement in persistent disease.

We show that human dorsal root ganglion (DRG) neurons express the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 at the RNA and protein level. We also demonstrate that SARS-CoV-2 and coronavirus-associated factors and receptors are broadly expressed in human DRG at the lumbar and thoracic level as assessed by bulk RNA sequencing. ACE2 mRNA is expressed by a subset of nociceptors that express MRGPRD mRNA, suggesting that SARS-CoV-2 may gain access to the nervous system through entry into neurons that form free nerve endings at the outermost layers of skin and luminal organs. Therefore, DRG sensory neurons are a potential target for SARS-CoV-2 invasion of the peripheral nervous system, and viral infection of human nociceptors may cause some of the persistent neurological effects seen in COVID-19.

Source: Shiers S, Ray PR, Wangzhou A, Sankaranarayanan I, Tatsui CE, Rhines LD, Li Y, Uhelski ML, Dougherty PM, Price TJ. ACE2 and SCARF expression in human dorsal root ganglion nociceptors: implications for SARS-CoV-2 virus neurological effects. Pain. 2020 Nov;161(11):2494-2501. doi: 10.1097/j.pain.0000000000002051. PMID: 32826754; PMCID: PMC7572821. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572821/ (Full text)

Acute Neurologic Complications of COVID-19 and Postacute Sequelae of COVID-19

Abstract:

Neurologic complications can be seen in mild to severe COVID-19 with a higher risk in patients with severe COVID-19. These can occur as a direct consequence of viral infection or consequences of treatments. The spectrum ranges from non-life-threatening, like headache, fatigue, malaise, anosmia, dysgeusia, to life-threatening complications, like stroke, encephalitis, coma, Guillain-Barre syndrome. A high index of suspicion can aid in early recognition and treatment. Outcomes depend on severity of underlying COVID-19, patient age, comorbidities, and severity of the complication. Postacute sequelae of COVID-19 range from fatigue, headache, dysosmia, brain fog, anxiety, depression to an overlap with postintensive care syndrome.

Source: Dangayach NS, Newcombe V, Sonnenville R. Acute Neurologic Complications of COVID-19 and Postacute Sequelae of COVID-19. Crit Care Clin. 2022 Jul;38(3):553-570. doi: 10.1016/j.ccc.2022.03.002. Epub 2022 Mar 23. PMID: 35667743; PMCID: PMC8940578. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8940578/ (Full text)

Preparing for the long-haul: Autonomic complications of COVID-19

Abstract:

As global numbers of COVID-19 grow, chronic neurological symptoms, including those of autonomic dysfunction, are being reported with increasing frequency. Mounting evidence suggests that many patients experience chronic and sometimes debilitating symptoms long after their acute infectious period, leading to the new diagnostic category of post-acute COVID syndrome. Many symptoms of post-acute COVID syndrome appear autonomic in nature, suggesting that autonomic impairment may play a central role in the underlying pathophysiology. In this review, we discuss the autonomic symptoms and manifestations of post-acute COVID syndrome, potential mechanisms involved, and future directions for a better understanding of this novel condition.

Source: Larsen NW, Stiles LE, Miglis MG. Preparing for the long-haul: Autonomic complications of COVID-19. Auton Neurosci. 2021;235:102841. doi:10.1016/j.autneu.2021.102841  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254396/ (Full text)

Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET

Abstract:

A significant number of COVID-19 patients develop ‘long COVID’, a condition defined by long-lasting debilitating, often neurological, symptoms. The pathophysiology of long COVID is unknown. Here we present in-vivo evidence of widespread neuroinflammation in long COVID, using a quantitative assessment, [18F]DPA-714 PET, in two long COVID patients. We reanalyzed historical data from three matched healthy control subjects, for comparison purposes. Both patients with long COVID had widespread increases in [18F]DPA-714 binding throughout the brain. Quantitative measures of binding (BPND values) were increased on average by 121% and 76%, respectively. This implicates profound neuroinflammation in the pathophysiology of long COVID.

Source: Denise Visser, Sandeep S.V. Golla, Sander C.J. Verfaillie, Emma M. Coomans, Roos M. Rikken, Elsmarieke M. van de Giessen, Marijke E. den Hollander, Anouk Verveen, Maqsood Yaqub, Frederik Barkhof, Janneke Horn, Bart Koopman, Patrick Schober, Dook W. Koch, Robert C. Schuit, Albert D. Windhorst, Michael Kassiou, Ronald Boellaard, Michele van Vugt, Hans Knoop, Nelleke Tolboom, Bart N.M. van Berckel. Long COVID is associated with extensive in-vivo neuroinflammation on [18F]DPA-714 PET. medRxiv 2022.06.02.22275916; doi: https://doi.org/10.1101/2022.06.02.22275916 https://www.medrxiv.org/content/10.1101/2022.06.02.22275916v1.full-text (Full text)

Neurological Sequelae of COVID-19

Abstract:

Background: Though primarily a pulmonary disease, Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus can generate devastating disease states that affect multiple organ systems including the central nervous system (CNS). The various neurological disorders associated with COVID-19 range in severity from mild symptoms such as headache, or myalgias to more severe symptoms such as stroke, psychosis, and anosmia. While some of the COVID-19 associated neurological complications are mild and reversible, a significant number of patients suffer from stroke. Studies have shown that COVID-19 infection triggers a wave of inflammatory cytokines that induce endothelial cell dysfunction and generate coagulopathy that increases the risk of stroke or thromboses. Inflammation of the endothelium following infection may also destabilize atherosclerotic plaque and induce thrombotic stroke. Although uncommon, there have also been reports of hemorrhagic stroke associated with COVID-19.

The proposed mechanisms include a blood pressure increase caused by infection leading to a reduction in angiotensin converting enzyme-2 (ACE-2) levels that results in an imbalance of the renin-angiotensin system ultimately manifesting inflammation and vasoconstriction. Coagulopathy, as demonstrated by elevated prothrombin time (PT), has also been posited as a factor contributing to hemorrhagics stroke in patients with COVID-19. Other neurological conditions associated with COVID-19 include encephalopathy, anosmia, encephalitis, psychosis, brain fog, headache, depression, and anxiety. Though there are several hypotheses reported in the literature, a unifying pathophysiological mechanism of many of these disorders remains unclear. Pulmonary dysfunction leading to poor oxygenation of the brain may explain encephalopathy and other disorders in COVID-19 patients. Alternatively, a direct invasion of the CNS by the virus or breach of the blood-brain barrier by the systemic cytokines released during infection may be responsible for these conditions. Notwithstanding, the relationship between the inflammatory cytokine levels and conditions such as depression and anxiety is contradictory and perhaps the social isolation during the pandemic may in part be a contributing factor to some of the reported CNS disorders.

Objective: In this article, we review the current literature pertaining to some of the most significant and common neurological disorders such as ischemic and hemorrhagic stroke, encephalopathy, encephalitis, brain fog, Long COVID, headache, Guillain-Barre syndrome, depression, anxiety, and sleep disorders in the setting of COVID-19. We summarize some of the most relevant literature to provide a better understanding of the mechanistic details regarding these disorders in order to help physicians monitor and treat patients for significant COVID-19 associated neurologic impairments.

Methods: A literature review was carried out by the authors using PubMed with the search terms “COVID-19” and “Neurology”, “Neurological Manifestations”, “Neuropsychiatric Manifestations”, “Stroke”, “Encephalopathy”, “Headache”, “Guillain-Barre syndrome”, “Depression”, “Anxiety”, “Encephalitis”, “Seizure”, “Spasm”, and “ICUAW”. Another search was carried out for “Long-COVID” and “Post-Acute COVID-19” and “Neurological Manifestations” or “Neuropsychiatric Manifestations”. Articles such as case reports, case series, and cohort studies were included as references. No language restrictions were enforced. In the case of anxiety and depression, attempts were made to focus mainly on articles describing these conditions in infected patients.

Results: A total of 112 articles were reviewed. The incidence, clinical outcomes, and pathophysiology of selected neurological disorders are discussed below. Given the recent advent of this disease, the incidence of certain neurologic sequelae was not always available. Putative mechanisms for each condition in the setting of COVID-19 are outlined.

Source: Ahmad SJ, Feigen CM, Vazquez JP, Kobets AJ, Altschul DJ. Neurological Sequelae of COVID-19. J Integr Neurosci. 2022 Apr 6;21(3):77. doi: 10.31083/j.jin2103077. PMID: 35633158. https://www.imrpress.com/journal/JIN/21/3/10.31083/j.jin2103077/htm (Full text)

Antioxidant Genetic Profile Modifies Probability of Developing Neurological Sequelae in Long-COVID

Abstract:

Understanding the sequelae of COVID-19 is of utmost importance. Neuroinflammation and disturbed redox homeostasis are suggested as prevailing underlying mechanisms in neurological sequelae propagation in long-COVID. We aimed to investigate whether variations in antioxidant genetic profile might be associated with neurological sequelae in long-COVID. Neurological examination and antioxidant genetic profile (SOD2, GPXs and GSTs) determination, as well as, genotype analysis of Nrf2 and ACE2, were conducted on 167 COVID-19 patients. Polymorphisms were determined by the appropriate PCR methods.
Only polymorphisms in GSTP1AB and GSTO1 were independently associated with long-COVID manifestations. Indeed, individuals carrying GSTP1 Val or GSTO1 Asp allele exhibited lower odds of long-COVID myalgia development, both independently and in combination. Furthermore, the combined presence of GSTP1 Ile and GSTO1 Ala alleles exhibited cumulative risk regarding long-COVID myalgia in carriers of the combined GPX1 LeuLeu/GPX3 CC genotype. Moreover, individuals carrying combined GSTM1-null/GPX1LeuLeu genotype were more prone to developing long-COVID “brain fog”, while this probability further enlarged if the Nrf2 A allele was also present.
The fact that certain genetic variants of antioxidant enzymes, independently or in combination, affect the probability of long-COVID manifestations, further emphasizes the involvement of genetic susceptibility when SARS-CoV-2 infection is initiated in the host cells, and also months after.
Source: Ercegovac M, Asanin M, Savic-Radojevic A, Ranin J, Matic M, Djukic T, Coric V, Jerotic D, Todorovic N, Milosevic I, Stevanovic G, Simic T, Bukumiric Z, Pljesa-Ercegovac M. Antioxidant Genetic Profile Modifies Probability of Developing Neurological Sequelae in Long-COVID. Antioxidants. 2022; 11(5):954. https://doi.org/10.3390/antiox11050954  https://www.mdpi.com/2076-3921/11/5/954/htm (Full text)