学会抄録

Canonical pathways enrichment calculated by Ingenuity Pathway Analysis. A total of 46 pathways were detected as significantly enriched with genes differentially expressed in the pairwise comparisons indicated in the first row of the table (P < 0.05). First column on the left indicates Gene Ontology name associated with the canonical pathway. Log10P values are reported for each pathway. (XLS 38 kb

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

<div><p>Objective</p><p>To evaluate if concentrations of the neuronal proteins neurofilament light chain and tau are changed in women developing preeclampsia and to evaluate the ability of a combination of neurofilament light chain, tau, S100B and neuron specific enolase in identifying neurologic impairment before diagnosis of preeclampsia.</p><p>Methods</p><p>A nested case-control study within a longitudinal study cohort was performed. 469 healthy pregnant women were enrolled between 2004–2007 and plasma samples were collected at gestational weeks 10, 25, 28, 33 and 37. Plasma concentrations of tau and neurofilament light chain were analyzed in 16 women who eventually developed preeclampsia and 36 controls throughout pregnancy with single molecule array (Simoa) method and compared within and between groups. S100B and NSE had been analyzed previously in the same study population. A statistical model with receiving characteristic operation curve was constructed with the four biomarkers combined.</p><p>Results</p><p>Plasma concentrations of neurofilament light chain were significantly increased in women who developed preeclampsia in gestational week 33 (11.85 ng/L, IQR 7.48–39.93 <i>vs</i> 6.80 ng/L, IQR 5.65–11.40) and 37 (22.15 ng/L, IQR 10.93–35.30 <i>vs</i> 8.40 ng/L, IQR 6.40–14.30) and for tau in gestational week 37 (4.33 ng/L, IQR 3.97–12.83 <i>vs</i> 3.77 ng/L, IQR 1.91–5.25) in contrast to healthy controls. A combined model for preeclampsia with tau, neurofilament light chain, S100B and neuron specific enolase in gestational week 25 displayed an area under the curve of 0.77, in week 28 it was 0.75, in week 33 it was 0.89 and in week 37 it was 0.83. Median week for diagnosis of preeclampsia was at 38 weeks of gestation.</p><p>Conclusion</p><p>Concentrations of both tau and neurofilament light chain are increased in the end of pregnancy in women developing preeclampsia in contrast to healthy pregnancies. Cerebral biomarkers might reflect cerebral involvement before onset of disease.</p></div

Plasma levels of tau during pregnancy in normal pregnancies and those developing preeclampsia.

<p>Line diagram showing median concentrations with interquartile range (IQR) of tau during pregnancy in women developing preeclampsia (red line) and in women with normal pregnancies (blue line). In women developing preeclampsia, concentrations of tau remained unchanged throughout pregnancy. In healthy pregnancies, concentrations of tau decreased in gestational week 25, 28 and 33 (p<0.05) and showed a borderline significant reduction in gestational week 37 compared to gestational week 10 (p = 0.06). Women developing preeclampsia had increased levels of tau in gestational week 37 in contrast to women with healthy pregnancies (p<0.05).</p

Plasma levels of neurofilament light chain (NfL) during pregnancy in normal pregnancies and those developing preeclampsia.

<p>Line diagram showing median concentrations with interquartile range (IQR) of NfL during pregnancy in women developing preeclampsia (red line) and in women with normal pregnancies (blue line). In women developing preeclampsia, concentrations of NfL were increased in gestational week 28, 33 and 37 compared to gestational week 10 (p<0.05). In healthy pregnancies, concentrations of NfL increased in gestational week 37 compared to gestational week 10 (p<0.05). Women developing preeclampsia had increased concentrations of NfL in gestational weeks 33 and 37 in contrast to women with healthy pregnancies (p<0.05).</p

Concentrations of NfL in plasma during pregnancy in women developing preeclampsia compared to women with normal pregnancies.

<p>Concentrations of NfL in plasma during pregnancy in women developing preeclampsia compared to women with normal pregnancies.</p

Concentrations of tau in plasma during pregnancy in women developing preeclampsia compared to women with normal pregnancies.

<p>Concentrations of tau in plasma during pregnancy in women developing preeclampsia compared to women with normal pregnancies.</p

Receiver Operating Characteristic (ROC) curves using S100B, Neuron Specific Enolase (NSE), Nerofilament Light chain (NfL) and tau combined for determining preeclampsia at specific gestational weeks.

<p>a) 10, Area Under the Curve (AUC) = 0.67 (0.47–0.88), p = 0.103, 11 cases and 26 controls. AUC for NfL 0.33 (0.00–0.67), for tau 0.24 (0.00–0.58), for S100B 0.71 (0.39–1.00) and for NSE 0.24 (0.00–0.54). b) 25, AUC = 0.77 (0.61–0.93), p<0.05, 7 cases, 29 controls. AUC for NfL 0.29 (0.00–0.61), for tau 0.38 (0.00–0.78), for S100B 0.38 /0.02–0.74) and for NSE 0.48 (0.12–0.84). c) 28, AUC = 0.75 (0.56–0.95), p<0.05, 7 cases, 27 controls. AUC for NfL 0.29 (0.00–0.64), for tau 0.05 (0.00–0.18), for S100B 0.45 (0.06–0.85) and for NSE 0.43 (0.05–0.81). d) 33, AUC = 0.89 (0.73–1.00), p<0.01, 6 cases, 28 controls. AUC for NfL 0.62 (0.17–1.00), for tau 0.57 (0.19–0.95), for S100B 0.95 (0.82–1.00) and for NSE 0.71 (0.37–1.00). e) 37, AUC = 0.83 (0.66–1.00), p<0.01, 8 cases, 24 controls. AUC for NfL 0.71 (0.24–1.00), for tau 0.31 (0.00–0.65), for S100B 0.69 (0.31–1.00) and for NSE 0.48 (0.06–0.89).</p

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<p>Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine member of the TNF family. TWEAK binds to its only known receptor, Fn14, enabling it to activate downstream signaling processes in response to tissue injury. The aim of this study was to investigate the role of TWEAK signaling in neonatal hypoxia–ischemia (HI). We found that after neonatal HI, both TWEAK and Fn14 expression were increased to a greater extent in male compared with female mice. To assess the role of TWEAK signaling after HI, the size of the injury was measured in neonatal mice genetically deficient in Fn14 and compared with their wild-type and heterozygote littermates. A significant sex difference in the Fn14 knockout (KO) animals was observed. Fn14 gene KO was beneficial in females; conversely, reducing Fn14 expression exacerbated the brain injury in male mice. Our findings indicate that the TWEAK/Fn14 pathway is critical for development of hypoxic–ischemic brain injury in immature animals. However, as the responses are different in males and females, clinical implementation depends on development of sex-specific therapies.</p

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<p>Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine member of the TNF family. TWEAK binds to its only known receptor, Fn14, enabling it to activate downstream signaling processes in response to tissue injury. The aim of this study was to investigate the role of TWEAK signaling in neonatal hypoxia–ischemia (HI). We found that after neonatal HI, both TWEAK and Fn14 expression were increased to a greater extent in male compared with female mice. To assess the role of TWEAK signaling after HI, the size of the injury was measured in neonatal mice genetically deficient in Fn14 and compared with their wild-type and heterozygote littermates. A significant sex difference in the Fn14 knockout (KO) animals was observed. Fn14 gene KO was beneficial in females; conversely, reducing Fn14 expression exacerbated the brain injury in male mice. Our findings indicate that the TWEAK/Fn14 pathway is critical for development of hypoxic–ischemic brain injury in immature animals. However, as the responses are different in males and females, clinical implementation depends on development of sex-specific therapies.</p

Pam3CSK4 decreases cerebellar molecular layer volume.

<p>Representative microphotograph of the cerebellar lobe (A) with arrow indicating Purkinje cell under higher magnification. Quantitative analysis of the total volume of molecular cell layer (B), granule cell layer (C), and Purkinje cell counts (D) in cerebellum at PND 12 after Pam₃CSK₄ administration from PND 3 to PND 11 in while type mice. Arrow indicates Purkinje cell with higher magnification. *p<0.05.</p