Long COVID: Plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms

doi:10.21203/rs.3.rs-2921879/v1

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Long COVID: Plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms

https://doi.org/10.21203/rs.3.rs-2921879/v1

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published 27 Apr, 2024

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It is well known the potential of severe acute respiratory coronavirus type 2 (SARS-CoV-2) infection to induce post-acute sequelae, a condition called Long COVID. This syndrome includes several symptoms, but the central nervous system (CNS) main one is neurocognitive dysfunction. Recently it has been demonstrated the relevance of plasma levels of neurofilament light chain (pNfL), as a biomarker of early involvement of the CNS in COVID-19. The aim of this study was to investigate the relationship between pNfL in patients with post-acute neurocognitive symptoms and the potential of NfL as a prognostic biomarker in these cases. A group of 63 long COVID patients ranging from 18 to 59 years-old were evaluated, submitted to a neurocognitive battery assessment, and subdivided in different groups, according to results. Plasma samples were collected during the long COVID assessment and used for measurement of pNfL with the Single molecule array (SIMOA) assays. Levels of pNfL were significantly higher in long COVID patients with neurocognitive symptoms when compared to HC (p = 0.0031). Long COVID patients with cognitive impairment and fatigue symptoms presented higher pNfL levels when compared to long COVID patients without these symptoms, individually and combined (p = 0.0263, p = 0.0480, and 0.0142, respectively). Correlation analysis showed that levels of cognitive lost and exacerbation of fatigue in the neurocognitive evaluation had a significative correlation with higher pNfL levels (p = 0.0219 and 0.0255, respectively). Previous reports suggested that pNfL levels are related with higher risk of severity and predict lethality of COVID-19. Our findings demonstrate that SARS-CoV-2 infection seems to have a long-term impact on the brain, even in patients who presented mild acute disease. NfL measurements might be useful to identify CNS involvement in long COVID associated with neurocognitive symptoms and to identify who will need continuous monitoring and treatment support.

Health sciences/Biomarkers/Prognostic markers

Biological sciences/Neuroscience

Biological sciences/Biological techniques

The SARS-CoV-2 pandemic had worldwide devastating effects, and the late consequences of the disease are still emerging as a public health concern. Besides several acute complications, COVID-19 patients may also experience persistent sequelae, collectively termed long COVID¹. According to WHO², long COVID can be defined as a condition that occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, with symptoms that last for at least 2 months, usually 3 months from the onset of COVID-19 and cannot be explained by an alternative diagnosis.

This syndrome includes various neurocognitive and other neurological signs and symptoms that could have a major impact on return to everyday activities and quality of life³. The symptoms may fluctuate or relapse over the time and have been registered immediately or soon after the recovery period from an acute COVID-19 episode or it can persist since the initial illness².

The occurrence of neurological complications is expected in hospitalized COVID-19 patients, and it includes high frequency of encephalopathy and other neurological manifestations in the acute disease phase, due to the multiorgan damage caused by SARS-CoV-2^4–6. However, those with mild initial COVID-19 disease who never required hospitalization also often develop long COVID⁷.

Long COVID evolves a series of not yet well-defined neurological symptoms. The most frequents has been a spectrum of cognitive symptoms, chronic fatigue, and neuropsychiatric complaints such as new-onset depression and anxiety. It also includes headaches, dizziness, disorders of smell and taste, among others^8,9. The prevalence of long COVID symptoms vary from 30–86% of post-COVID-19 individuals within 6 months of the acute phase of the SARS-CoV-2 infection, depending on disease severity^10–12.

Several mechanisms have been proposed to explain the neuropathogenesis of long COVID, including active viral infection on the central nervous system (CNS) immune activation secondary to systemic inflammatory responses, spike protein’s damage to the endothelium and perivascular inflammation microvascular injuries, or hypoxic consequences of severe disease^13,14. Nevertheless, there are many questions and dubiousness that remains unknown, related to long COVID, such as duration of symptoms, disease mechanism, phenotypes that are grouped under the term long COVID, and the most troubling for the patients, the risk of serious and prolonged sequelae¹⁵.

Plasma neurofilament light chain (pNfL) is a highly specific structural protein of neurons and it has been validated as a biomarker for neuroaxonal damage^16,17. The tight correlation between levels in cerebrospinal fluid (CSF) and blood samples, serum and plasma¹⁸, make it widely usable as a biomarker for neuroinflammation and degeneration in a series of neurological conditions, such as Multiple Sclerosis and Alzheimer’s Disease^16,19,20, and as a predictor for neurological outcome in the Intense Care Unity (ICU)^21,22,

Several studies were able to associate increase in levels of pNfL with CNS injury in the acute phase of both severe and mild-to-moderate COVID-19, indicating the possible neuroaxonal injury that occurs in acute SARS-CoV-2 infection ^23,24. Changes in these CNS damage biomarkers have been associated with neuropsychiatric complications, such as encephalopathy and delirium, severity of COVID-19, poor disease outcome, and even death^25–33. In this sense, it has been useful for clinicians worldwide, enabling a more guided approach, in the way precision medicine works.

In this study, we investigate whether there is evidence of CNS injury, here indicated by pNfL, in long COVID patients with chronic neurocognitive symptoms after mild disease, thereby measuring the importance of pNfL as a biomarker of brain injury in non-hospitalized long COVID patients.

Participants and study design

The study was conducted with a group of long COVID patients from Clementino Fraga Filho University Hospital and Gaffrée and Guinle University Hospital, in Rio de Janeiro, Brazil, between December 11, 2020, and December 20, 2022. It encompassed patients with mild acute COVID-19.

For the pNfL analysis, it included 32 matched health control (HC) subjects who have never been infected with SARS-CoV-2, from a blood bank of HC with samples collected before the pandemic.

Inclusion criteria involved: COVID-19 diagnosis was confirmed with Polymerase Chain Reaction; accordance with the WHO definition of post-COVID-19 syndrome (have the assessment at least three months after the end of acute symptoms, and duration of symptoms of at least two months)²; patient’s acute clinical status of mild illness, according to WHO definition of the clinical spectrum of SARS-CoV-2 infection³⁴; agreement to collect blood samples for analysis and to perform the neuropsychiatric evaluation.

Exclusion criteria encompassed: individuals with 18-years-old or younger, individuals with 60 years-old or more, moderate or severe acute COVID-19 course according to WHO definition of the clinical spectrum of SARS-CoV-2 infection³⁴, and/or previously known cognitive impairment or other neuropsychiatrist disorders that could interfere with the test results.

All of them were evaluated from a clinical point of view, with detailed clinical history, social and epidemiological information. The post-COVID-19 assessment included comorbidities, symptoms experienced during acute infection, date of symptom onset, and long COVID persistent symptoms, including fatigue, persistence of anosmia and dysgeusia, and neurocognitive symptoms.

Neurocognitive assessment

All participants infected by SARS-CoV-2 underwent neuropsychological testing, which included: Symbol Digit Modalities Test (SDMT), Fatigue Severity Scale (FSS) and Hospital Anxiety and Depression Scale (HADS).

The SDMT³⁵ is a validated test to identify cognitive impairment through a straightforward assignment that comprises attention, processing speed and motor skills. The test page presents a series of nine different symbols, each one paired with a single digit labeled 1–9 and a list of the same symbols below, with blank spaces instead of numbers. The patient must manually fill the blank space under each symbol with the corresponding number over a 90 s period, with the number of total items, correct pairings, and errors registered by the evaluator^36,37.

Demographically influenced T-scores for each participant were calculated based on multiple regression equations derived from the healthy group’s scores, described by Parmenter et al. 2010³⁸. The raw score of the SDMT is converted to scaled scores (M = 10, SD = 3) using the cumulative frequency distribution of the test. This served to normalize all the test score distributions. Then, the resulting scaled scores are regressed on age, age-squared, sex, and education.

Next, the participants’ raw test scores are converted to scaled scores using the raw-to-scale-score conversions, derived from the healthy controls. Multiple regression equations derived from the healthy controls are applied to compute demographically predicted scores for each participant. These predicted scores were then subtracted from each participant’s actual scores and the differences were divided by the standard deviation of the controls group’s raw residuals for each measure. Finally, the resulting values were converted to T scores. To increase clinical interpretation, the calculated cut-points are one standard deviation below the mean (T ≤ 40) to indicate impairment.

The FSS is a 9-item self-reported questionnaire developed to assess fatigue in patients with systemic lupus erythematosus and multiple sclerosis³⁹, by asking subjects to choose for each item the number from 1 to 7 which best applied to them^39,40. 1 indicates strongly disagree and 7 indicates strongly agree. Its use has expanded to several diseases that present with chronic fatigue, including long COVID^41–44. We employed the standard cut-off (FSS mean score ≥ 28) to determine clinically significant levels of fatigue³⁹.

The HADS is a self-reported scale developed to identify the presence of anxiety disorders and depressive symptoms in people in nonpsychiatric hospital clinics⁴⁵, however it has good psychometric properties of both the anxiety and depression scales for assessing anxiety and depressive symptoms within the general population and in other disorders, including COVID-19 patients^46–49. It is composed of 14 items, subdivided into HADS-A and HADS-D. HADS-A consists of 7 items assessing anxiety symptoms whereas HADS-D consists of 7 items evaluating depressive symptoms. Each item is scored on a 4-point scale (0–3) providing a maximum of 21 points for each subscale⁴⁶. It employed a cut-off score of ≥ 8 points for each scale since this value has shown good sensitivity and specificity to determine the presence of anxiety or depressive symptoms^49,50.

Based on the neurocognitive tests results, study subjects were subdivided into the following groups, according to each test classification:

SDMT: Long COVID patients with cognitive impairment and long COVID without cognitive impairment.

FSS: Long COVID patients with fatigue and long COVID patients without fatigue.

HADS-A: Long COVID patients with anxiety and long COVID patients without anxiety.

HADS-D: Long COVID patients with depression and long COVID patients without depression.

Ethics

This work was approved by the Brazilian Ethics Committee (CONEP, CAAE 33659620.1.1001.5258). All subjects signed the informed consent term, agreeing to participate in this research.

Procedures

Blood samples were collected in EDTA tubes at the moment of the post-COVID-19 assessment, the same day as the neuropsychologic test. The samples were processed by centrifugation at 2,880 g and 4°C for 15 min to separate the buffy coat from plasma. Both plasma and buffy coat were frozen in aliquots at − 80 ◦C. For NfL analysis, it was used the plasma from the samples.

Plasma NfL measurement was performed at the Translational Neuroscience Laboratory of the Federal University of the State of Rio de Janeiro, Brazil, using commercially available Single molecule array (SIMOA) assays on an SR-X Analyzer, with the plasma NfL kit, as described by the manufacturer (Quanterix, Billerica, MA). Calibrators were run in duplicates, while samples were diluted four-fold and run in singlicates. Two quality control (QC) samples with different levels were run in duplicates at the beginning and the end of each run. Repeatability and intermediate precision were both 8.7% for the QC sample with an pNfL concentration of 8.4 pg/mL and 5.9% for the 79.6 pg/mL sample.

First, we compared the levels of pNfL of all patients that had at least one of the four tests altered with the HC group control, to assess the relationship between CNS damage and long COVID symptoms. It is well established that pNfL concentration is correlated with aging, and therefore, it was determined that the HC had a similar age distribution from the patients’ groups. The mean (IQR) and median age of HC were, respectively, 34.79 (25–41) and 35. All patients and controls with less than 18 years and more than 59 were excluded.

Then, we compared the levels of pNfL of the subgroups of each test to understand their influence on the possible CNS damage individually. At last, we investigated the correlation between each test result and the pNfL levels.

Statistical analyses

Statistical analysis data were summarized as number of patients (percentage/ frequency), normally distributed variables as mean (SD), or median (interquartile range) for non-normally distributed variables. Each of these groups was compared with control group using One-way ANOVA followed by the Kruskal–Wallis test by for data without Gaussian distribution. Followed by Dunn's multiple comparison test to find out which means are significantly different. The non-parametric Mann-Whitney U test was applied to determine whether two groups of symptomatic long COVID patients and without symptoms and or healthy controls were statistically different for non-parametric variables. Associations between quantitative variables were assessed using the Pearson correlation test. A p-value < 0·05 was considered statistically significant. Graphs and corresponding statistical analyses were generated using Prism (GraphPad Software version 9.5.1, La Jolla, CA, USA).

Post-COVID-19 Patients: Demographics and Study Groups

A total of 63 post-COVID-19 volunteers with mild acute COVID-19 were recruited for inclusion in this study. The sociodemographic characteristics are summarized in Table 1. The mean (IQR) age in the COVID-19 cohort was 39.21 (19-57); 49 (77.8%) were female. Most of the patients (37; 58.7%) didn’t have any known comorbidity. Among the comorbidities, the most prevalent was hypertension (14; 22.2%), followed by obesity (9; 14.3%).

Symptoms associated with acute COVID-19

The mean interval between the onset of COVID-19 and the long COVID assessment was 8.01 (3-30) months. All patients had some symptoms in the acute phase of the disease, however none of them were hospitalized, since it’s a sample composed of mild COVID-19 patients. The most frequent symptoms during the acute phase were fatigue (49; 77.8%), headache (38; 60.3%), anosmia (33; 52.4%) and ageusia (33; 52.4%). Acute COVID-19 symptoms frequency is also described in Table 1.

Long COVID symptoms and neurocognitive assessment

The most frequently reported post-COVID-19 symptoms were fatigue (44; 69.8%), cognitive impairment (41; 65.1%), anxiety (33; 52.4%) and depression (25; 39.7%). As to objectify these symptoms, it was only considered patients with subjective complaints that started after COVID-19 and corresponding alterations on the neurocognitive assessment. Cognitive performance, fatigue, anxiety and depression were analyzed using, respectively SDMT, FSS, HADS-A and HADS-D. Others long COVID symptoms are described in Table 1.

NfL levels according to neurocognitive assessment

Long COVID patients with at least one of the four tests altered had significantly higher levels of pNfL when compared to the HC group (p = 0.0031) (Figure 1). On the individual symptom’s evaluation, long COVID patients with cognitive impairment in the SDMT had significantly higher levels of pNfL when compared to long COVID patients without cognitive impairment (p = 0.0256) (Figure 2A). Long COVID patients with fatigue in the FSS had significantly higher levels of pNfL when compared to long COVID patients without fatigue (p = 0.0480) (Figure 2B).

Long COVID patients with anxiety in the HADS-A didn’t have significantly higher levels of pNfL when compared to long COVID patients without fatigue (p = 0.3608) (Figure 2C). Similarly, long COVID patients with depression in the HADS-D didn’t have significantly higher levels of pNfL when compared to long COVID patients without depression (p = 0.5232) (Figure 2D).

Since both cognitive and fatigue results were significant, it was made a second analysis, which included the comparison of pNfL levels between a group of long COVID patients with cognitive impairment and fatigue, and a group of long COVID patients without cognitive impairment and fatigue. The first group had significantly higher levels of pNfL (p = 0.0031) (Figure 3).

On the correlation analysis, it was shown a significantly negative correlation between pNfL levels and the SDMT results (p = 0.0219) (Figure 4A) and a significantly positive correlation between pNfL levels and the FSS results (p = 0.0255) (Figure 4B). Thus, it can be inferred that lower SDMT results, namely, worse cognitive impairment, associate with greater CNS damage, manifested by higher pNfL levels. Likewise, higher FSS results, videlicet, worse fatigue, also associate with more CNS damage.

Conversely, pNfL levels did not correlate with HADS-A (p = 0.6646) or HADS-D (p = 0.1643) results (Figure 4C and figure 4D, respectively). This goes accordingly with the test t results, that presented no difference between long COVID patients with anxiety and depression, and long COVID patients without anxiety and depression. These findings draw the inference that these symptoms, unlike cognitive impairment and fatigue, not interfere with ongoing CNS damage.

Despite the high frequency of neurologic involvement in hospitalized COVID-19 patients, there is a large amount of asymptomatic and mild symptomatic COVID-19 individuals who developed long COVID symptoms after the SARS-CoV-2 infection¹.

These neurological manifestations could reflect a nonspecific effect of respiratory viral infections on the CNS⁵¹. The underlying mechanism common to these different disease conditions might be represented by hypoxic damage due to respiratory insufficiency, thus resembling NfL increase following hypoxic-ischemic injury after cardiac arrest²². This theory is supported by the “happy hypoxia” seen in some COVID-19 patients, in which patient’s symptoms of dyspnea and signs of respiratory distress are absent⁵². Another plausible determinant might be the systemic hyperinflammatory state that promotes sepsis-associated encephalopathy⁵³.

The increased pNfL levels in long COVID could be compatible with both hypoxic and inflammatory injury, but there’s probably other mechanisms of COVID-19-induced neuronal impairment. Namely, a direct damage to the nervous tissue by SARS-CoV-2^54,55 or the entry of the Spike protein of the SARS-CoV-2 virus in the CNS, disrupting the blood-brain barrier (BBB), and its ligation with TLR4, leading to neuro-inflammation and contributing to long COVID¹⁴. We recently demonstrated that the genotype GG TLR4 -2604G > A (rs10759931) is associated with poor cognitive outcome in the post-acute phase of patients with mild COVID-19⁵⁶. Also, the blockage of TLR4 signaling protects rodents against memory dysfunction induced by Spike brain infusion⁵⁶.

Cell senescence, characterized by a permanently arrested cell cycle that is no longer responsive to differentiation and apoptotic signaling processes, is also a possible contributor to SARS-CoV-2 CNS damage^57,58. Although mal-functioning, senescent cells continue to be metabolically active and are responsible for causing a hyperinflammatory state in the body, due to its senescence-associated secretory phenotype, accelerating age-related neurodegenerative processes⁵⁹.

The neuroinvasive potential of SARS-CoV-2 may result in senescence of several different CNS cell types, such as oligodendrocytes and astrocytes, which may compromise remyelination of axons and the BBB integrity, just as limit the distribution of metabolic substrates of neuronal networks⁵⁷. Besides, the senescence of neural stem cells may prevent neurogenesis in hippocampus, critical to memory consolidation⁶⁰. The pNfL might be able to express this process, as it has been associated with other demyelinating and neurodegenerative diseases^16,17,19,61, as well as cell senescence due to aging⁶² and cancer treatment⁶³.

NfL has been found to be significantly increased in acute COVID-19 patients when compared to HC, regardless of the severeness of the disease, and the presence of major neurological symptoms, such as encephalopathy^24,64,65. However, some studies observed the normalization of these NfL levels in the long-term long COVID evaluation⁶⁶. The mechanism regarding acute COVID-19 pNfL levels evolves systemic hyperinflammation, hypoxia and BBB disruption, and may differ from post COVID-19 mechanism. Despite the difference, short-term longitudinal pNfL levels of post COVID-19 were nominally, but not significantly, higher in COVID-19 patients than corresponding baseline ones in HC^64,67. The present study aim to investigate the relationship between the plasma levels of neurofilament light chain (pNfL) in patients with post-acute neurological symptoms (fatigue, cognitive dysfunction, and anxiety) and matched control who presented mild acute COVID-19 and provide information about the potential of NFL as a prognostic biomarker in those cases

In time, results in studies about the correlation between NfL and long COVID are controversial. One study with hundred patients with mild, moderate, and severe COVID-19 showed that, after six months, NfL concentrations had normalized, with no persisting group differences, and they found no correlation between persistent neurological symptoms and CNS injury biomarkers in the acute phase⁶⁶. Nonetheless, the mentioned study has some limitations, such as: they didn’t try to correlate NfL levels in the follow-up with neurological symptoms, only with acute levels; their form of classification of post-COVID-19 was based solely in self-reported symptoms questionnaires, without a more objective approach; and HC were from after SARS-CoV-2 pandemic, making it hard to exclude the possibility of the HC being infected. Also, they didn’t individualize the long COVID neurological symptoms, that demonstrated an important difference in our study.

In this study, it was exhibited that pNfL levels are significantly higher in long COVID patients with mild acute COVID-19 with neurocognitive symptoms when compared to HC (p = 0.0031), what could indicate the ongoing CNS damage caused by SARS-CoV-2, directly or indirectly, even in patients acutely with mild disease.

Nonetheless, it was demonstrated a divergence among the neurocognitive symptoms and their respective influence on the CNS injury. Levels of pNfL were significantly higher in long COVID patients with cognitive impairment and fatigue when compared to long COVID patients without these symptoms, individually and combined (p = 0.0263; p = 0.0480; and p = 0.0031, respectively). The combined analysis of the cognitive impairment and fatigue symptoms with significant higher levels of pNfL indicated the synergism between symptoms in the influence of pNfL levels, increasing the statistical power of the results.

Fatigue and cognitive complains are considered the most common and debilitating symptoms of long-COVID, directly affecting the quality of life of these patients⁶⁸. The FSS has been widely used in post COVID-19 fatigue assessment^{40–44, 69–71}. Besides, primary findings in neurocognitive profile of post COVID-19 patients exhibit deficits in attention and processing speed, and aspects of executive function⁴⁴. The SDMT is a neuropsychiatric test used to evaluate the above-mentioned cognitive aspects, thus, resulting in a more reliable assessment. In this study, 69.8% of patients presented chronic fatigue after SARS-CoV-2 infection according to FSS, while 65.1% of patients presented cognitive impairment in SDMT. Indeed, when compared cognitive test results in adults recovering from COVID-19 with non-COVID-19 cases, it was found to be significantly reduced the cognitive performance in the COVID-19 group⁷².

Both fatigue and cognitive impairment has been shown to be prevalent, as well as to persist and potentially worsen over time, in contrast to other persistent symptoms which may be self-limiting, such as anosmia^73,74. In this sense, these symptoms could reflect ongoing neuro-damage, demonstrated by pNfL.

Not only the presence of cognitive impairment and fatigue in long COVID associated with higher pNfL levels, but also the levels of cognitive lost and exacerbation of fatigue in the neurocognitive evaluation had a significative correlation with pNfL levels. SDMT score T results correlated negatively with higher pNfL levels (p = 0.0219), and, comparably, FSS results correlated positively with higher pNfL levels (p = 0.0255). Therefore, a poorer cognitive performance and worse fatigue status indicates greater CNS injury. Furthermore, this authenticates both SDMT and FSS as powerful tools for the investigation of the degree of ongoing neuro-damage in long COVID patients.

In a follow-up study prior to the COVID-19 pandemic, elevated levels of NfL in cognitively healthy adults showed an association with the development of mild cognitive impairment⁷⁵. Moreover, protein markers of neuronal dysfunction including NfL were shown to be significantly increased in neuronal-enriched extracellular vesicle of participants recovering from COVID-19 compared to historic controls, suggesting ongoing peripheral and neuroinflammation after COVID-19 infection that may influence neurological sequelae⁷⁶.

Other coronaviruses are known for causing demyelination, neurodegeneration, and cellular senescence, all of which accelerate brain aging and potentially exacerbate underlying neurodegenerative pathology^77,78. Thus, they can cause chronic fatigue and cognitive impairment symptoms after the acute infection^79–82.

Anxiety and depression symptoms in long COVID patients were also evaluated in this study. A meta-analysis with 4318 COVID-19 patients presented a prevalence of depression and anxiety symptoms in 38% of the sample⁴⁹. HADS is the most used self-reported scale in COVID-19 research for evaluating anxiety and depressive symptoms^46,48,49. In this sample, anxiety had a prevalence of 52.4%, while depression was presented in 39.7% of the individuals. Nonetheless, despite the high frequency, this study provided an absence of association and correlation between the presence of anxiety and depression symptoms in long COVID patients with higher pNfL levels.

This study has some limitations, such as: the absence of neurocognitive evaluation and pNfL levels from before the SARS-CoV-2 infection; Limited sample, although the results were already promising despite the number of patients; Majority of female sample, since it is a voluntary sample, composed by patients of the long COVID ambulatory of both university hospitals.

In this study, it was exhibited that pNfL levels are significantly higher in long COVID patients with mild acute COVID-19 and neurocognitive symptoms when compared to HC, besides the dissimilarity among the neurocognitive symptoms and their respective influence on pNfL levels. Levels of pNfL were significantly higher in long COVID patients with cognitive impairment and fatigue when compared to long COVID patients without these symptoms, individually and combined. Additionally, poorer cognitive performance and worse fatigue status correlated with higher pNfL levels. These results demonstrate the potential of pNfL as a biomarker of the CNS ongoing injury in long COVID patients with cognitive impairment and fatigue. This can contribute to a better understanding of the mechanism of long COVID and to identify who will need continuous monitoring and treatment support. Further studies are needed to elucidate the extension of the CNS damage and possible neurodegenerating consequences.

Acknowledgements

This study was supported by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (E-26/210.254/2020–Edital Segunda Chamada Emergencial de Projetos para Combater os Efeitos da COVID-19–2020, E-26/210.657/2021, E-26/210.273/2018 and E-26/201.040/2021) and Financiadora de Estudos e Projetos (FINEP).

S.V.A-L. is supported by FAPERJ (E-26/210.254/2020–Edital Segunda Chamada Emergencial de Projetos para Combater os Efeitos da COVID-19–2020, E-26/210.657/2021, E-26/210.273/2018 and E-26/201.040/2021) and FINEP.

L.A.A.L. is supported by FAPERJ (E-26/201.406/2021), MS/Programa Inova FIOCRUZ – Edital Geração de Conhecimento – Enfrentamento da Pandemia e Pós-pandemia Covid-19: Encomendas Estratégicas” / processo VPPCB-005-FIO-20-2-56).

C.P.F. is supported by the FAPERJ, the Instituto Nacional de Ciência e Tecnologia – Inovação em Medicamentos e Identificação de Novos Alvos Terapêuticos – (INCT-INOVAMED) 465430/2014-7, Brazil and the Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq, Brazil.

Conflicts of Interest

The authors declare there are no conflicts of interest or competing financial interests in relation to the work described above.

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Long COVID: Plasma levels of neurofilament light chain in mild COVID-19 patients with neurocognitive symptoms

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