Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology DOI Creative Commons
Julio Aguado, Alberto A. Amarilla, Atefeh Taherian Fard

et al.

Nature Aging, Journal Year: 2023, Volume and Issue: 3(12), P. 1561 - 1575

Published: Nov. 13, 2023

Aging is a major risk factor for neurodegenerative diseases, and coronavirus disease 2019 (COVID-19) linked to severe neurological manifestations. Senescent cells contribute brain aging, but the impact of virus-induced senescence on neuropathologies unknown. Here we show that senescent accumulate in aged human organoids senolytics reduce age-related inflammation rejuvenate transcriptomic aging clocks. In postmortem brains patients with COVID-19 observed increased cell accumulation compared age-matched controls. Exposure acute respiratory syndrome 2 (SARS-CoV-2) induced cellular senescence, analysis revealed unique SARS-CoV-2 inflammatory signature. Senolytic treatment infected blocked viral replication prevented distinct neuronal populations. human-ACE2-overexpressing mice, improved clinical outcomes, promoted dopaminergic neuron survival alleviated proinflammatory gene expression. Collectively our results demonstrate an important role driving SARS-CoV-2-induced neuropathology, therapeutic benefit senolytic treatments.

Language: Английский

Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment DOI Creative Commons
Chris Greene, Ruairi Connolly,

Declan Brennan

et al.

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(3), P. 421 - 432

Published: Feb. 22, 2024

Abstract Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood–brain barrier (BBB) function affected these conditions. Here we show that BBB evident during acute infection patients COVID cognitive impairment, commonly referred as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, COVID-associated Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation coagulation system a dampened adaptive immune response individuals Accordingly, showed increased adhesion human endothelial vitro, while exposure serum from induced expression inflammatory markers. Together, our data suggest sustained systemic inflammation persistent localized dysfunction key feature

Language: Английский

Citations

168
Pathogenesis Underlying Neurological Manifestations of Long COVID Syndrome and Potential Therapeutics DOI Creative Commons
Albert Leng, Manuj Shah, Syed A. Ahmad

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(5), P. 816 - 816

Published: March 6, 2023

The development of long-term symptoms coronavirus disease 2019 (COVID-19) more than four weeks after primary infection, termed "long COVID" or post-acute sequela COVID-19 (PASC), can implicate persistent neurological complications in up to one third patients and present as fatigue, "brain fog", headaches, cognitive impairment, dysautonomia, neuropsychiatric symptoms, anosmia, hypogeusia, peripheral neuropathy. Pathogenic mechanisms these long COVID remain largely unclear; however, several hypotheses both nervous system systemic pathogenic such SARS-CoV2 viral persistence neuroinvasion, abnormal immunological response, autoimmunity, coagulopathies, endotheliopathy. Outside the CNS, SARS-CoV-2 invade support stem cells olfactory epithelium leading alterations function. infection may induce abnormalities innate adaptive immunity including monocyte expansion, T-cell exhaustion, prolonged cytokine release, which cause neuroinflammatory responses microglia activation, white matter abnormalities, microvascular changes. Additionally, clot formation occlude capillaries endotheliopathy, due protease activity complement contribute hypoxic neuronal injury blood-brain barrier dysfunction, respectively. Current therapeutics target pathological by employing antivirals, decreasing inflammation, promoting regeneration. Thus, from laboratory evidence clinical trials literature, we sought synthesize pathophysiological pathways underlying potential therapeutics.

Language: Английский

Citations

119
Long COVID science, research and policy DOI Creative Commons
Ziyad Al‐Aly, Hannah Davis, Lisa McCorkell

et al.

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(8), P. 2148 - 2164

Published: Aug. 1, 2024

Long COVID represents the constellation of post-acute and long-term health effects caused by SARS-CoV-2 infection; it is a complex, multisystem disorder that can affect nearly every organ system be severely disabling. The cumulative global incidence long around 400 million individuals, which estimated to have an annual economic impact approximately $1 trillion-equivalent about 1% economy. Several mechanistic pathways are implicated in COVID, including viral persistence, immune dysregulation, mitochondrial dysfunction, complement endothelial inflammation microbiome dysbiosis. devastating impacts on individual lives and, due its complexity prevalence, also has major ramifications for systems economies, even threatening progress toward achieving Sustainable Development Goals. Addressing challenge requires ambitious coordinated-but so far absent-global research policy response strategy. In this interdisciplinary review, we provide synthesis state scientific evidence assess human health, systems, economy metrics, forward-looking roadmap.

Language: Английский

Citations

109
SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice DOI Creative Commons
Fabrícia Lima Fontes-Dantas, Gabriel Gripp Fernandes,

Elisa Gouvea Gutman

et al.

Cell Reports, Journal Year: 2023, Volume and Issue: 42(3), P. 112189 - 112189

Published: Feb. 17, 2023

Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or fragments released from cells during infection, reaching different tissues, including the CNS, irrespective of presence viral RNA. Here, we demonstrate brain infusion mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show neuroinflammation and hippocampal microgliosis mediate Spike-induced memory via complement-dependent engulfment synapses. Genetic pharmacological blockage Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination induced by infusion. Accordingly, cohort 86 who recovered mild COVID-19, genotype GG TLR4-2604G>A (rs10759931) associated poor outcome. These results identify TLR4 as key target to investigate long-term after COVID-19 infection humans rodents.

Language: Английский

Citations

107
Prevalence and Characteristics Associated With Post–COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults DOI Creative Commons
Joel Selvakumar, Lise Beier Havdal,

Martin Drevvatne

et al.

JAMA Network Open, Journal Year: 2023, Volume and Issue: 6(3), P. e235763 - e235763

Published: March 30, 2023

The prevalence and baseline risk factors of post-COVID-19 condition (PCC) remain unresolved among the large number young people who experienced mild COVID-19.To determine point PCC 6 months after acute infection, to development adjusted for possible confounders, explore a broad range potential factors.This cohort study included nonhospitalized individuals from 2 counties in Norway between ages 12 25 years underwent reverse transcription-polymerase chain reaction (RT-PCR) testing. At early convalescent stage at 6-month follow-up, participants clinical examination; pulmonary, cardiac, cognitive functional testing; immunological organ injury biomarker analyses; completion questionnaire. Participants were classified according World Health Organization case definition follow-up. Association analyses 78 performed.SARS-CoV-2 infection.The RT-PCR testing SARS-CoV-2-positive SARS-CoV-2-negative groups, difference with corresponding 95% CIs.A total 404 positive SARS-CoV-2 105 negative enrolled (194 male [38.1%]; 102 non-European [20.0%] ethnicity). A 22 4 lost 16 excluded due infection observational period. Hence, 382 (mean [SD] age, 18.0 [3.7] years; 152 [39.8%]) 85 17.7 [3.2] 31 [36.5%]) could be evaluated. was 48.5% group 47.1% control (risk difference, 1.5%; CI, -10.2% 13.1%). positivity not associated (relative [RR], 1.06; 0.83 1.37; final multivariable model utilizing modified Poisson regression). main factor symptom severity (RR, 1.41; 1.27-1.56). Low physical activity 0.96; 0.92-1.00) loneliness 1.01; 1.00-1.02) also associated, while biological markers not. Symptom correlated personality traits.The persistent symptoms disability that characterize are other than including psychosocial factors. This finding raises questions about utility has implications planning health care services as well further research on PCC.

Language: Английский

Citations

85
Post-COVID cognitive dysfunction: current status and research recommendations for high risk population DOI Creative Commons
Meina Quan,

Xuechu Wang,

Min Gong

et al.

The Lancet Regional Health - Western Pacific, Journal Year: 2023, Volume and Issue: 38, P. 100836 - 100836

Published: July 5, 2023

Summary

Post-COVID cognitive dysfunction (PCCD) is a condition in which patients with history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, usually three months from the onset, exhibit subsequent impairment various domains, and cannot be explained by an alternative diagnosis. While our knowledge risk factors management strategy PCCD still incomplete, it necessary to integrate current epidemiology, diagnosis treatment evidence, form consensus criteria better understand this disease improve management. Identifying vulnerable population providing reliable strategies for effective prevention urgently needed. In paper, we reviewed diagnostic markers, available treatments on disease, formed research recommendation framework population, under background post-COVID period.

Language: Английский

Citations

65
Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization DOI Creative Commons
Maxime Taquet,

Zuzanna Skórniewska,

Adam Hampshire

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(10), P. 2498 - 2508

Published: Aug. 31, 2023

Post-COVID cognitive deficits, including 'brain fog', are clinically complex, with both objective and subjective components. They common debilitating, can affect the ability to work, yet their biological underpinnings remain unknown. In this prospective cohort study of 1,837 adults hospitalized COVID-19, we identified two distinct biomarker profiles measured during acute admission, which predict outcomes 6 12 months after COVID-19. A first profile links elevated fibrinogen relative C-reactive protein deficits. second D-dimer deficits occupational impact. This was mediated by fatigue shortness breath. Neither significantly depression or anxiety. Results were robust across secondary analyses. replicated, specificity COVID-19 tested, in a large-scale electronic health records dataset. These findings provide insights into heterogeneous biology post-COVID

Language: Английский

Citations

65
Epidemiology, clinical presentation, pathophysiology, and management of long COVID: an update DOI

Sizhen Su,

Yi‐Miao Zhao, Na Zeng

et al.

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(10), P. 4056 - 4069

Published: July 25, 2023

Language: Английский

Citations

62
Mechanisms of long COVID and the path toward therapeutics DOI Creative Commons

Michael J. Peluso,

Steven G. Deeks

Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

Citations

33
Fibrin drives thromboinflammation and neuropathology in COVID-19 DOI Creative Commons
Jae Kyu Ryu, Zhaoqi Yan, Mauricio Montaño

et al.

Nature, Journal Year: 2024, Volume and Issue: 633(8031), P. 905 - 913

Published: Aug. 28, 2024

Abstract Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 persistent patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection 1–4 . Despite the clinical evidence 1,5–7 , underlying mechanisms coagulopathy its consequences inflammation neuropathology remain poorly understood treatment options insufficient. Fibrinogen, central structural component blood clots, is abundantly deposited lungs brains COVID-19, correlates disease severity a predictive biomarker for post-COVID-19 cognitive deficits 1,5,8–10 Here we show that fibrin binds to spike protein, forming proinflammatory clots drive systemic thromboinflammation COVID-19. Fibrin, acting through inflammatory domain, required oxidative stress macrophage activation lungs, whereas it suppresses natural killer cells, after infection. Fibrin promotes neuroinflammation neuronal loss infection, as well innate immune brain independently active A monoclonal antibody targeting domain provides protection from microglial injury, lung Thus, drives fibrin-targeting immunotherapy may represent therapeutic intervention acute COVID.

Language: Английский

Citations

25