Blood neurofilament light chain and total tau levels at admission predict death in COVID-19 patients

Lorenzo, Rebecca De; Lorè, Nicola Ivan; Finardi, Annamaria; Mandelli, Alessandra; Cirillo, Daniela María; Tresoldi, Cristina; Benedetti, Francesco; Ciceri, Fabio; Rovere‐Querini, Patrizia; Comı, Gıancarlo; Filippi, Massimo; Manfredi, Angelo A.; Furlan, Roberto

doi:10.1007/s00415-021-10595-6

Cited by 71 publications

(96 citation statements)

References 29 publications

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“…The results obtained from the analysis of GFAP and GFAP-DBP levels may suggest that patients with SARS-CoV-2 infection are at increased risk of astrocytic damage and neural dysfunction, especially among those with severe or critical COVID-19. These findings have also been suggested in other studies [19] , [42] , [43] and reinforce the capacity for neural damage caused by the infection. There is growing evidence of the role of astrocytes in the brain response to SARS-CoV-2-triggered neuroinflammation.…”

Section: Discussionsupporting

confidence: 89%

Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity

Passos

Heimfarth

Monteiro

et al. 2022

International Immunopharmacology

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Background SARS-CoV-2 infection can lead to the abnormal induction of cytokines and a dysregulated hyperinflammatory state that is implicated in disease severity and risk of death. There are several molecules present in blood associated with immune cellular response, inflammation, and oxidative stress that could be used as severity markers in respiratory viral infections such as COVID-19. However, there is a lack of clinical studies evaluating the role of oxidative stress-related molecules including glial fibrillary acidic protein (GFAP), the receptor for advanced glycation end products (RAGE), high mobility group box-1 protein (HMGB1) and cyclo-oxygenase-2 (COX-2) in COVID-19 pathogenesis. Aim To evaluate the role of oxidative stress-related molecules in COVID-19. Method An observational study with 93 Brazilian participants from September 2020 to April 2021, comprising 23 patients with COVID-19 admitted to intensive care unit (ICU), 19 outpatients with COVID-19 with mild to moderate symptoms, 17 individuals reporting a COVID-19 history, and 34 healthy controls. Blood samples were taken from all participants and western blot assay was used to determine the RAGE, HMGB1, GFAP, and COX-2 immunocontent. Results We found that GFAP levels were higher in patients with severe or critical COVID-19 compared to outpatients (p = 0.030) and controls (p < 0.001). A significant increase in immunocontents of RAGE (p < 0.001) and HMGB1 (p < 0.001) were also found among patients admitted to the ICU compared to healthy controls, as well as an overexpression of the inducible COX-2 (p < 0.001). In addition, we found a moderate to strong correlation between RAGE, GFAP and HMGB1 proteins. Conclusion SARS-CoV-2 infection induces the upregulation of GFAP, RAGE, HMGB1, and COX-2 in patients with the most severe forms of COVID-19.

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Section: Discussionsupporting

confidence: 89%

Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity

Passos

Heimfarth

Monteiro

et al. 2022

International Immunopharmacology

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“…Using cerebrospinal fluid may have had a higher predictive value [ 57 , 116 , 117 , 118 ]. Elevations in serum NF-L levels were reported inconsistently in studies plagued with small fibers, unadjusted for comorbidities, or limited to the most sick patients [ 12 , 32 , 35 , 94 , 119 , 120 , 121 ]. Gisslen et al reported the normalization of GFAP and NF-L six months after the resolution of COVID-19, but their patients continued to exhibit neurological symptoms and their study was limited to these markers [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…A lack of correlation between viral protein load and increases in any of the neurodegeneration markers is consistent with observations linking the ongoing elevation of neurodegeneration markers in the cerebrospinal fluid without cytokine storms [ 120 ]. Alternatively, the smoldering of neuroinflammation may be the underlying cause of the persistent elevation of neurodegeneration markers, which is not severe enough to be reflected in the serum level of an acute neuro-injury [ 33 , 35 ]. The predominance of tissue inflammation in olfactory structures during COVID-19 suggests that generalized, or regional, inflammation is the culprit despite direct viral neurotoxicity [ 18 , 66 , 124 ].…”

Section: Discussionmentioning

confidence: 99%

“…These interactions can trigger the aggregation of the brain’s proteins when protective anti-folding mechanisms are impaired, potentially exacerbating ongoing neurodegeneration processes and effects of the non-specific inflammatory response [ 26 , 27 , 28 , 29 , 30 ]. Several case reports, case series, and research projects provided conflicting data regarding the levels of τ, Amyloid β1-42, and Amyloid β2-41 in COVID-19 [ 6 , 31 , 32 , 33 , 34 , 35 ]. In silica, analyses suggested molecular mimicry between the compromising of SARS-CoV-2 and nervous system proteins, but clinical correlations are not described [ 3 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

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Dynamic Changes in Central and Peripheral Neuro-Injury vs. Neuroprotective Serum Markers in COVID-19 Are Modulated by Different Types of Anti-Viral Treatments but Do Not Affect the Incidence of Late and Early Strokes

et al. 2021

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The balance between neurodegeneration, neuroinflammation, neuroprotection, and COVID-19-directed therapy may underly the heterogeneity of SARS-CoV-2′s neurological outcomes. A total of 105 patients hospitalized with a diagnosis of COVID-19 had serum collected over a 6 month period to assess neuroinflammatory (MIF, CCL23, MCP-1), neuro-injury (NFL, NCAM-1), neurodegenerative (KLK6, τ, phospho τ, amyloids, TDP43, YKL40), and neuroprotective (clusterin, fetuin, TREM-2) proteins. These were compared to markers of nonspecific inflammatory responses (IL-6, D-dimer, CRP) and of the overall viral burden (spike protein). Data regarding treatment (steroids, convalescent plasma, remdasavir), pre-existing conditions, and incidences of strokes were collected. Amyloid β42, TDP43, NF-L, and KLK6 serum levels declined 2–3 days post-admission, yet recovered to admission baseline levels by 7 days. YKL-40 and NCAM-1 levels remained elevated over time, with clusters of differential responses identified among TREM-2, TDP43, and YKL40. Fetuin was elevated after the onset of COVID-19 while TREM-2 initially declined before significantly increasing over time. MIF serum level was increased 3–7 days after admission. Ferritin correlated with TDP-43 and KLK6. No treatment with remdesivir coincided with elevations in Amyloid-β40. A lack of convalescent plasma resulted in increased NCAM-1 and total tau, and steroidal treatments did not significantly affect any markers. A total of 11 incidences of stroke were registered up to six months after initial admission for COVID-19. Elevated D-dimer, platelet counts, IL-6, and leukopenia were observed. Variable MIF serum levels differentiated patients with CVA from those who did not have a stroke during the acute phase of COVID-19. This study demonstrated concomitant and opposite changes in neurodegenerative and neuroprotective markers persisting well into recovery.

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“… 7 NFL was also shown to be significantly increased in the blood of COVID-19 patients requiring ICU admission and in those who died from it. 8 …”

Section: Main Textmentioning

confidence: 99%

Potential role of neurofilament in COVID-19 and preeclampsia

Samara

Herlenius

Brien

et al. 2022

Cell Reports Medicine

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Blood neurofilament light chain and total tau levels at admission predict death in COVID-19 patients

Cited by 71 publications

References 29 publications

Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity

Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity

Dynamic Changes in Central and Peripheral Neuro-Injury vs. Neuroprotective Serum Markers in COVID-19 Are Modulated by Different Types of Anti-Viral Treatments but Do Not Affect the Incidence of Late and Early Strokes

Potential role of neurofilament in COVID-19 and preeclampsia

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