Cerebral Biomarkers and Blood-Brain Barrier Integrity in Preeclampsia

Abstract

Cerebral complications in preeclampsia contribute substantially to maternal mortality and morbidity. There is a lack of reliable and accessible predictors for preeclampsia-related cerebral complications. In this study, plasma from women with preeclampsia (n = 28), women with normal pregnancies (n = 28) and non-pregnant women (n = 16) was analyzed for concentrations of the cerebral biomarkers neurofilament light (NfL), tau, neuron-specific enolase (NSE) and S100B. Then, an in vitro blood−brain barrier (BBB) model, based on the human cerebral microvascular endothelial cell line (hCMEC/D3), was employed to assess the effect of plasma from the three study groups. Transendothelial electrical resistance (TEER) was used as an estimation of BBB integrity. NfL and tau are proteins expressed in axons, NSE in neurons and S100B in glial cells and are used as biomarkers for neurological injury in other diseases such as dementia, traumatic brain injury and hypoxic brain injury. Plasma concentrations of NfL, tau, NSE and S100B were all higher in women with preeclampsia compared with women with normal pregnancies (8.85 vs. 5.25 ng/L, p < 0.001; 2.90 vs. 2.40 ng/L, p < 0.05; 3.50 vs. 2.37 µg/L, p < 0.001 and 0.08 vs. 0.05 µg/L, p < 0.01, respectively). Plasma concentrations of NfL were also higher in women with preeclampsia compared with non-pregnant women (p < 0.001). Higher plasma concentrations of the cerebral biomarker NfL were associated with decreased TEER (p = 0.002) in an in vitro model of the BBB, a finding which indicates that NfL could be a promising biomarker for BBB alterations in preeclampsia.

Keywords: NSE; NfL; S100B; blood-brain barrier; cerebral biomarkers; in vitro studies; preeclampsia; pregnancy; tau.

Figure 1

Plasma concentrations of (a) NfL, (b) tau, (c) NSE and (d) S100B. Plasma concentrations of the cerebral biomarkers (a) neurofilament light (NfL), (b) tau, (c) neuron specific enolase (NSE) and (d) S100B in women with preeclampsia (PE), women with normal pregnancies (NP) and non-pregnant women (Non-P). Values are represented by medians with interquartile range (IQR). Pairwise comparisons by Mann-Whitney U-test, Bonferroni correction. * p < 0.05; ** p < 0.01; *** p < 0.001; n.s. = non-significant.

Figure 2

Re−confirmation analysis of TEER and permeability to 70 kDa Dextran. Plasma from a small, randomly chosen sample of the women with preeclampsia (PE, n = 12) and the women with normal pregnancies (NP, n = 13) was analyzed for re−confirmation of previously published data on (a) transendothelial electrical resistance (TEER) and (b) permeability to 70 kDa fluorescein isothiocyanate (FITC)−dextran [30]. ** p < 0.01; **** p < 0.0001.

Figure 3

Association of TEER with NfL, tau, NSE and S100B. Associations between transendothelial electrical resistance (TEER (Ωcm²)) and cerebral biomarkers neurofilament light (NfL (ng/L)), tau (ng/L), neuron-specific enolase (NSE (µg/L)) and S100B (µg/L) in plasma analyzed by a cumulative probability model stratified by group and adjusted for baseline TEER, body mass index, parity and maternal age. NfL p < 0.01, tau p = n.s., NSE p = n.s., S100B p = n.s.