Blood-based cerebral biomarkers in preeclampsia: Plasma concentrations of NfL, tau, S100B and NSE during pregnancy in women who later develop preeclampsia - A nested case control study

Bergman, Lina; Zetterberg, Henrik; Kaihola, Helena; Hagberg, Henrik; Blennow, Kaj; Åkerud, Helena

doi:10.1371/journal.pone.0196025

Cited by 32 publications

(24 citation statements)

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“…In our study, median CSF concentrations of tau protein and the phospho-tau/tau ratio were significantly lower in women with PE and HELLP syndrome than in healthy controls. This is in agreement with recently reported diminished CSF tau and phospho-tau-181 protein concentrations in patients with placental dysfunction 14,15 . During normal pregnancy there is an increase in tau protein concentrations 16 .…”

Section: Discussionsupporting

confidence: 93%

Cerebrospinal beta-amyloid peptides(1-40) and (1-42) in severe preeclampsia and HELLP syndrome – a pilot study

Lederer

Schaffenrath

Alomar-Dominguez

et al. 2020

Sci Rep

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During pregnancy, substantial alterations in cerebral plasticity, vascular remodeling and neuronal growth occur in the maternal brain. We investigated whether concentrations of selected neurodiagnostic biomarkers in the cerebrospinal fluid of women with preeclampsia/HELLP syndrome differ from those in healthy controls using enzyme-linked immunosorbent assay technique. We found that tau protein concentrations (p = 0.016) and phospho-tau/tau ratio (p < 0.001) in cerebrospinal fluid were significantly lower in 39 preeclamptic women compared to 44 healthy controls during third trimester of pregnancy. Beta-amyloid(1-40)/(1-42) ratio was significantly higher in HELLP syndrome than in severe preeclampsia (8.49 + 2.73 vs. 4.71 + 1.65; p = 0.007). We conclude that betaamyloid(1-40)/(1-42) ratio in cerebrospinal fluid can discriminate severe preeclampsia and HELLP syndrome. High beta-amyloid peptide and low tau protein concentrations are associated with impaired development of the materno-feto-placental unit and correlate with placental dysfunction. During pregnancy, the invasion of trophoblast cells into maternal tissue of the uterus and the conversion of spiral arteries into wide sinusoids with low resistance and high flow are paramount for normal placental development 1. In preeclampsia (PE) placental development is impaired by defective deep placentation, platelet and thrombin activation, intravascular inflammation, endothelial dysfunction and imbalanced angiogenesis 2. Altered expression of proteins comes along with excess of antiangiogenic substances such as soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) and decreased levels of proangiogenic substances like placental growth factor (PlGF) and vascular endothelial growth factor A (VEGF-A) 3. Ciampa et al. observed in 13 patients with PE altered concentrations of proteins related to signaling pathways important for vascular remodeling, inflammation, and neuronal growth 4. Recent studies have shown that PE shares pathophysiologic features with recognized misfolding disorders and aggregation of proteins 4-8. There are several dysregulated proteins in PE but it is not clear whether aggregated proteins induce defective trophoblast invasion 4. D'Souza et al. reported that neurotrophic factors influence the development of the materno-feto-placental unit during pregnancy 9. Altered blood-brain barrier and impaired cerebral autoregulation may affect erebral blood flow in the maternal brain 10. Aggregated beta-amyloid peptides were observed in PE as well as in Alzheimer's disease 7. The presence of beta-amyloid aggregates in placentas of women with PE and intrauterine growth restriction (IUGR) further supports the notion that this condition goes with protein conformational disorders 6,11. Moreover, it was observed that short peptides occupying the self-recognition sites of beta-amyloid inhibit beta-amyloid aggregation 8. The aim of this study was to determine whether CSF concentrations of beta-amyloid peptides and tau protein differ between women with PE...

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Section: Discussionsupporting

confidence: 93%

Cerebrospinal beta-amyloid peptides(1-40) and (1-42) in severe preeclampsia and HELLP syndrome – a pilot study

Lederer

Schaffenrath

Alomar-Dominguez

et al. 2020

Sci Rep

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“…The increased BBB permeability reported by both Warrington et al (2014) and Clayton et al (2018) , is partly supported by clinical studies which demonstrated that in women developing preeclampsia, blood levels of S100B, neuronal specific enolase (NSE) and neurofilament light chain (NfL), three markers of cerebral injury, were higher than those observed in women with normal pregnancies ( Bergman et al, 2018 ). Indeed, another report showed that in preeclamptic women, the levels of S100B and NSE were still high 1-year post-partum, suggesting that the alterations in the integrity of the BBB are manifest for a substantial period of time following delivery ( Bergman et al, 2016 ).…”

Section: Endothelial Dysfunction At the Brain In Pregnancy-related DImentioning

confidence: 88%

“…Preeclampsia is associated with impaired systemic endothelial function ( Roberts et al, 1989 ) and, in the brain of preeclamptic women, this endothelial dysfunction presents in the form of impaired integrity of the BBB ( Bergman et al, 2018 ), which is apparently maintained even post-partum ( Bergman et al, 2016 ). The influence of endothelial dysfunction on drug disposition in the brain has been studied in disease states, including stroke ( Huang et al, 2017 ) however there is a lack of studies investigating the effect of endothelial dysfunction on brain drug disposition in pregnancy-related disorders.…”

Section: Introductionmentioning

confidence: 99%

Drug Transport at the Brain and Endothelial Dysfunction in Preeclampsia: Implications and Perspectives

Torres-Vergara

Escudero²,

Penny

2018

Front. Physiol.

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Transport of drugs across biological barriers has been a subject of study for decades. The discovery and characterization of proteins that confer the barrier properties of endothelia and epithelia, including tight junction proteins and membrane transporters belonging to the ATP-binding cassette (ABC) and Solute Carrier (SLC) families, represented a significant step forward into understanding the mechanisms that govern drug disposition. Subsequently, numerous studies, including both pre-clinical approaches and clinical investigations, have been carried out to determine the influence of physiological and pathological states on drug disposition. Importantly, there has been increasing interest in gaining a better understanding of drug disposition during pregnancy, since epidemiological and clinical studies have demonstrated that the use of medications by pregnant women is significant and this condition embodies a series of significant anatomical and physiological modifications, particularly at excretory organs and barrier sites (e.g., placenta, breast) expressing transporter proteins which influence pharmacokinetics. Currently, most of the research in this field has focused on the expression profiling of transporter proteins in trophoblasts and endothelial cells of the placenta, regulation of drug-resistance mechanisms in disease states and pharmacokinetic studies. However, little attention has been placed on the influence that the cerebrovascular dysfunction present in pregnancy-related disorders, such as preeclampsia, might exert on drug disposition in the mother’s brain. This issue is particularly important since recent findings have demonstrated that preeclamptic women suffer from long-term alterations in the integrity of the blood-brain barrier (BBB). In this review we aim to analyze the available evidence regarding the influence of pregnancy on the expression of transporters and TJ proteins in brain endothelial cells, as well the mechanisms that govern the pathophysiological alterations in the BBB of women who experience preeclampsia. Future research efforts should be focused not only on achieving a better understanding of the influence of preeclampsia-associated endothelial dysfunction on drug disposition, but also in optimizing the pharmacological treatments of women suffering pregnancy-related disorders, its comorbidities and to develop new therapies aiming to restore the integrity of the BBB.

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“…Serum concentrations of tau have been proven to predict 6 months cerebral outcome after cardiac arrest in a pilot study [100]. Two studies have shown that concentrations of NfL are increased at the end of pregnancy but before onset of disease in women developing preeclampsia [101,102] and one of these studies also showed that tau was increased before onset of disease [102]…”

Section: Nfl and Tau In Preeclampsiamentioning

confidence: 99%

Investigating Maternal Brain Alterations in Preeclampsia: the Need for a Multidisciplinary Effort

et al. 2019

Self Cite

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Porpuose of Review: To provide insight into the mechanisms underlying cerebral pathophysiology in preeclampsia and to highlight possible methods for evaluation, screening and surveillance of cerebral complications in the condition. Recent Findings: Every 12 minutes, a woman dies as a consequence of preeclampsia with cerebral complications, such as eclampsia, among the most common causes. The incidence of eclampsia has been estimated to vary from one in 100 to one in 2000 deliveries, with the highest incidences in low-income countries. The pathophysiology of eclampsia remains enigmatic. The increased blood pressure cannot be the only underlying cause, since some cases of eclampsia arise without simultaneous hypertension. Evaluation of brain alterations in preeclampsia and eclampsia is challenging and demands a multidisciplinary collaboration, since no single method can accurately and fully describe how preeclampsia affects the brain. Summary: Cerebral complications of preeclampsia are a significant factor in maternal morbidity and mortality worldwide. No single method can accurately describe the full picture of how preeclampsia affects the brain vasculature and parenchyma. We recommend a multinational effort to overcome, not only the issue of limited sample availability, but also, to optimize the quality of research.

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Blood-based cerebral biomarkers in preeclampsia: Plasma concentrations of NfL, tau, S100B and NSE during pregnancy in women who later develop preeclampsia - A nested case control study

Cited by 32 publications

References 28 publications

Cerebrospinal beta-amyloid peptides(1-40) and (1-42) in severe preeclampsia and HELLP syndrome – a pilot study

Cerebrospinal beta-amyloid peptides(1-40) and (1-42) in severe preeclampsia and HELLP syndrome – a pilot study

Drug Transport at the Brain and Endothelial Dysfunction in Preeclampsia: Implications and Perspectives

Investigating Maternal Brain Alterations in Preeclampsia: the Need for a Multidisciplinary Effort

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