Figure
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Biomarkers classically studied in Alzheimer’s disease have been analyzed in numerous central nervous system infections in adults, but there are scarce data on these biomarkers in children. Enteroviruses appear to be the most common cause of aseptic meningitis throughout the world. The aim of the study was to investigate neuroinflammatory properties...
Citations
... In children with CNS infections including EV infection, studies on biomarker levels in CSF have shown inconclusive results. No changes in beta-amyloid concentrations were reported in one study, in contrast to another, where CSF-Ab42 was significantly decreased in 42 children diagnosed with EV meningitis [15,16]. ...
... The decrease of Ab40 and Ab42 in the CSF of the patients with EV meningitis in our study is in line with the results from other studies including children with EV meningitis [16] and in patients with other CNS infections such as HSV-1 encephalitis, CNS opportunistic infections and patients with acute bacterial meningitis [28]. In addition, we found no changes in the Ab42/Ab40 ratio when comparing patients with controls. ...
Purpose:
Enteroviruses (EV) comprises many different types and are the most common cause of aseptic meningitis. How the virus affects the brain including potential differences between types are largely unknown. Measuring biomarkers in CSF is a tool to estimate brain damage caused by CNS infections.
Methods:
A retrospective study was performed in samples from 38 patients with acute neurological manifestations and positive CSF-EV RNA (n = 37) or serum-IgM (n = 1). The EV in 17 samples were typed by sequencing. The biomarkers neurofilament light (NFL), glial fibrillary acidic protein (GFAP), S-100B protein, amyloid-β (Aβ) 40 and Aβ42, total-tau (T-tau) and phosphorylated tau (P-tau) were measured and compared with data derived from a control group (n = 19).
Results:
There were no increased levels of GFAP (p ≤ 0.1) nor NFL (p ≤ 0.1) in the CSF of patients with EV meningitis (n = 38) compared with controls. However, we found decreased levels of Aβ42 (p < 0.001), Aβ40 (p < 0.001), T-tau (p ≥ 0.01), P-tau (p ≤ 0.001) and S-100B (p ≤ 0.001). E30 (n = 9) and CVB5 (n = 6) were the most frequent EV-types identified, but no differences in biomarker levels or other clinical parameters were found between the infecting virus type. Seven patients who were followed for longer than one month reported remaining cognitive impairment, although no correlations with biomarker concentrations were observed.
Conclusion:
There are no indication of neuronal or astrocyte damage in patients with EV meningitis. Yet, decreased concentrations of Aβ40, Aβ42, P-tau and T-tau were shown, a finding of unknown importance. Cognitive impairment after acute disease occurs, but with only a limited number of patients analysed, no conclusion can be drawn concerning any association with biomarker levels or EV types.
... As shown in Figure 1 above, there are several other viruses, including human herpesvirus-6 (HHV-6), -7 (HHV-7) [43,[128][129][130][131][132], Epstein-Barr virus (EBV) [133][134][135][136][137][138][139], cytomegalovirus (CMV) [33,[140][141][142][143], varicella zoster virus (VZV) [144][145][146][147], human immunodeficiency virus [148][149][150][151][152][153][154][155][156][157][158][159][160][161][162], hepatitis C virus (HCV) [163], enterovirus [164][165][166], influenza A virus (IAV) [167][168][169][170][171], and measles [172][173][174][175], which have also been suggested to have a role in AD onset and development (see reference listed). Particularly, we wanted to briefly highlight the unique study by Levine et al. [176], where viral encephalitis and meningitis had the strongest risk association with an AD diagnosis, indicated through the mining of medical records of at least 300,000 individuals stored in FinnGen, a nationwide Finnish biobank. ...
... It must also be noted that the viral encephalitis diagnoses were described based on hospital billing codes, such as ICD-10 codes like A85 (which could be associated with enterovirus, adenovirus, and even arthropod-borne viral encephalitis [176]), but not on direct viral detection assays. Therefore, this begs for exploration of enterovirus encephalitis and its suggestive contribution to the development of AD (among other viruses listed above), especially since the majority of enteroviruses are strongly neurotropic and ubiquitouswith most individuals becoming infected with at least one of these viruses at some point in their life [166,177]. ...
Alzheimer’s Disease (AD), a progressive and debilitating condition, is reported to be the most common type of dementia, with at least 55 million people believed to be currently affected. Many causation hypotheses of AD exist, yet the intriguing link between viral infection and its possible contribution to the known etiology of AD has become an attractive focal point of research for the field and a challenging study task. In this review, we will explore the historical perspective and milestones that led the field to investigate the viral connection to AD. Specifically, several viruses such as Herpes Simplex Virus 1 (HSV-1), Zika virus (ZIKV), and severe cute respiratory syndrome coronavirus 2 (SARS-CoV-2), along with several others mentioned, include the various viruses presently considered within the field. We delve into the strong evidence implicating these viruses in the development of AD such as the lytic replication and axonal transport of HSV-1, the various mechanisms of ZIKV neurotropism through the human protein Musashi-1 (MSI1), and the spread of SARS-CoV-2 through the transfer of the virus through the BBB endothelial cells to glial cells and then to neurons via transsynaptic transfer. We will also explore beyond these mere associations by carefully analyzing the potential mechanisms by which these viruses may contribute to AD pathology. This includes but is not limited to direct neuronal infections, the dysregulation of immune responses, and the impact on protein processing (Aβ42 and hyperphosphorylated tau). Controversies and challenges of the virus–AD relationship emerge as we tease out these potential mechanisms. Looking forward, we emphasize future directions, such as distinct questions and proposed experimentations to explore, that the field should take to tackle the remaining unanswered questions and the glaring research gaps that persist. Overall, this review aims to provide a comprehensive survey of the past, present, and future of the potential link between viral infections and their association with AD development while encouraging further discussion.
... The CSF concentration of Aβ1-42 was decreased when compared with the control group without CNS infection. In contrast, other biomarker concentrations are unchanged [32]. Thus, an enteroviral infection may lead to a specific impact on Aβ1-42 production. ...
Background
β-Amyloid (Aβ) protein is a pivotal pathogenetic factor in Alzheimer’s disease (AD). However, increasing evidence suggests that the brain has to continuously produce excessive Aβ to efficaciously prevent pathogenic micro-organism infections, which induces and accelerates the disease process of AD. Meanwhile, Aβ exhibits activity against herpes simplex virus type 1 (HSV-1) and influenza A virus (IAV) replication, but not against other neurotropic viruses. Enterovirus A71 (EV-A71) is the most important neurotropic enterovirus in the post-polio era. Given the limitation of existing research on the relationship between Aβ and other virus infections, this study aimed to investigate the potent activity of Aβ on EV-A71 infection and extended the potential function of Aβ in other unenveloped viruses may be linked to Alzheimer's disease or infectious neurological diseases.
Methods
Aβ peptides 1–42 are a major pathological factor of senile plaques in Alzheimer’s disease (AD). Thus, we utilized Aβ1–42 as a test subject to perform our study. The production of monomer Aβ1–42 and their high-molecular oligomer accumulations in neural cells were detected by immunofluorescence assay, ELISA, or Western blot assay. The inhibitory activity of Aβ1–42 peptides against EV-A71 in vitro was detected by Western blot analysis or qRT-PCR. The mechanism of Aβ1–42 against EV-A71 replication was analyzed by time-of-addition assay, attachment inhibition assay, pre-attachment inhibition analysis, viral-penetration inhibition assay, TEM analysis of virus agglutination, and pull-down assay.
Results
We found that EV-A71 infection induced Aβ production and accumulation in SH-SY5Y cells. We also revealed for the first time that Aβ1–42 efficiently inhibited the RNA level of EV-A71 VP1, and the protein levels of VP1, VP2, and nonstructural protein 3AB in SH-SY5Y, Vero, and human rhabdomyosarcoma (RD) cells. Mechanistically, we demonstrated that Aβ1–42 primarily targeted the early stage of EV-A71 entry to inhibit virus replication by binding virus capsid protein VP1 or scavenger receptor class B member 2. Moreover, Aβ1–42 formed non-enveloped EV-A71 particle aggregates within a certain period and bound to the capsid protein VP1, which partially caused Aβ1–42 to prevent viruses from infecting cells.
Conclusions
Our findings unveiled that Aβ1–42 effectively inhibited nonenveloped EV-A71 by targeting the early phase of an EV-A71 life cycle, thereby extending the potential function of Aβ in other non-envelope viruses linked to infectious neurological diseases.
... Studies have found decreased Aβ 1-42 levels in bacterial meningitis, multiple sclerosis, and HIV with cerebral engagement [22][23][24]. Studies of viral meningitis have exhibited conflicting results [22,25,26]. Additionally, low levels of Aβ 1-42 were associated with worse outcomes of CNS infections [26,27]. ...
Alzheimer’s disease (AD) has emerged as a growing threat to human health. It is a multifactorial disorder, in which abnormal amyloid beta metabolism and neuroinflammation have been demonstrated to play a key role. Intrathecal inflammation can be triggered by infections and precede brain damage for years. We analyzed the influence of infections of the central nervous system on biomarkers that are crucially involved in AD pathology. Analyses of the cerebrospinal fluid (CSF) levels of Aβ1–42, Aβ1–40, Tau, and pTau proteins were performed in 53 children with neuroinfections of viral (n = 26) and bacterial origin (n = 19), and in controls (n = 8). We found no changes in CSF amyloid Aβ1–42 concentrations, regardless of etiology. We showed an increase in tau and phosphorylated tau concentrations in purulent CNS infections of the brain, compared to other etiologies. Moreover, the total concentrations of tau in the CSF correlated with the CSF absolute number of neutrophils. These findings and the Aβ 42/40 concentration quotient discrepancies in CFS between meningitis and encephalitis suggest that infections may affect the metabolism of AD biomarkers.
... Kacper T et al. studied the neuroinlammatory characteristics of non-polio enteroviruses by evaluating the concentration of biomarkers in CSF associated to the neuropathological pathway of neurodegenerative diseases, the concentrations of Aβ42, t-tau and S100B in 42 children with enteroviral meningitis (EM) were measured and compared with those without central nervous system infection. The results documented that EM could reduce the content of Aβ42 in CSF, while the concentrations of t-tau and S100B in CSF were not afected by EM, and the absolute number of mononuclear cells in CSFwas related with t-tau (Toczylowski K,et al., 2019). ...
At present, data independent acquisition (DIA) protein spectrum detection technology is one of the most attractive mass spectrometry acquisition techniques, which once led the new development of quantitative proteomics. Its application fields include the screening of clinical disease markers, the study of action mechanism, the study of drug targets and so on. DIA has been wide‐ranging used in clinic because of its high throughput, high resolution and high reproducibility. The occurrence of mental disorders in encephalitis is common, and such neurocognitive impairment has a dramatically impact on the disease progression and prognosis of patients, which undoubtedly increases the economic burden of sufferers' families and society. Under the circumstance that the mechanism of mental disorder of encephalitis is still unknown, this paper summarizes a large number of literatures of encephalitis, originates the possibility of the application of cerebrospinal fluid detection by DIA in the occurrence of mental disorder of encephalitis, seeks for biomarkers for the occurrence of mental disorder of encephalitis, and provides clinical guidance.
... Photophobia; n (%) 42 Blood monocytes (%) 9 (7-12) 9 (8-11) 9 (7-12) 8 (6-9) 10 (7-12) ...
... It was hypothesized that lymphocytes play a central role in the immunopathology of those infections. We have previously shown that in children with enteroviral meningitis, lymphocytes in the CSF correlate with CSF concentrations of total tau protein, which is a marker of brain parenchymal damage [42]. However, the detrimental role of lymphocytes has been questioned, as these lymphocytes now are suggested to be protective. ...
Enteroviruses are common causes of infections of the central nervous system (CNS) that in temperate climates tend to peak in the summer. The aim of the study was to describe epidemiology, drivers of seasonality, and types of enteroviruses causing infections of the CNS in children in Northeastern Poland. We prospectively collected data on children hospitalized with infection of the CNS attributed to enteroviruses in Bialystok, Poland, from January 2015 to December 2019. In total, 224 children were included. Nineteen different enterovirus types were identified in isolates collected from 188 children. Coxsackie B5 (32%), echovirus 30 (20%), and echovirus 6 (14%) were the three most common types. Enteroviruses were more prevalent during the summer–fall season. Infections caused by echovirus 30 peaked early in June and coxsackievirus B5 in July, whereas echovirus 6 peaked late in October. Phylogenetic analyses of these three enterovirus types showed multiple lineages co-circulating in this region. Mean air temperatures and precipitation rates were independently associated with monthly number of cases. Considering lack of effective treatment or vaccine, easy transmission of enteroviruses between susceptible individuals, their high mutation rate and prolonged time of viral shedding, continued monitoring and surveillance are imperative to recognize enteroviral infections of the CNS and the changes in circulation of enteroviruses in Poland.
Human enteroviruses are the most prevalent causes of aseptic meningitis worldwide. However, despite such predominancy, defining the enteroviral etiology of aseptic meningitis remains a diagnostic dilemma for the clinician in Iran. Therefore, this study was conducted to characterize the prevalence and clinical significance of enteroviral aseptic meningitis as well as the predominant enterovirus serotypes among patients with aseptic meningitis in the South of Iran.Cerebrospinal fluid (CSF) specimens were obtained from 73 patients with aseptic meningitis (52.1% males and 47.9% females), ages ranging from 1 month to 88 years. Following the extraction of nucleic acid, the detection of enteroviruses was performed by RT-PCR, targeting the 5′ untranslated region of the genome, and sequencing. Enteroviruses were found in 46.6% of samples (34/73). The most predominant serotype was echovirus 30, followed by coxsackievirus B5 and poliovirus type 1 Sabin strain. The enterovirus infections were more prevalent among female patients (58.8%) and those below 5 years of age (52.9%). Although enterovirus infections were observed throughout the year, the infections were more prevalent during autumn with fever as the predominant clinical symptom. The outcomes revealed that enteroviruses are significant causes of aseptic meningitis in the South of Iran, while suspected cases of aseptic meningitis are usually monitored by bacterial culture and biochemical testing of CSF samples. Therefore, the etiology remains unknown in most cases. Molecular detection of viral pathogens should be included as a common approach in the screening of patients with aseptic meningitis to prevent unnecessary treatment and to improve clinical management.
