Acute nicotine exposure blocks aromatase in the limbic brain of healthy women: A [11C]cetrozole PET study.

BACKGROUND: Of interest to women's mental health, a wealth of studies suggests sex differences in nicotine addiction and treatment response, but their psychoneuroendocrine underpinnings remain largely unknown. A pathway involving sex steroids could indeed be involved in the behavioural effects of nicotine, as it was found to inhibit aromatase in vitro and in vivo in rodents and non-human primates, respectively. Aromatase regulates the synthesis of oestrogens and, of relevance to addiction, is highly expressed in the limbic brain. METHODS: The present study sought to investigate in vivo aromatase availability in relation to exposure to nicotine in healthy women. Structural magnetic resonance imaging and two [11C]cetrozole positron emission tomography (PET) scans were performed to assess the availability of aromatase before and after administration of nicotine. Gonadal hormones and cotinine levels were measured. Given the region-specific expression of aromatase, a ROI-based approach was employed to assess changes in [11C]cetrozole non-displaceable binding potential. RESULTS: The highest availability of aromatase was found in the right and left thalamus. Upon nicotine exposure, [11C]cetrozole binding in the thalamus was acutely decreased bilaterally (Cohen's d = -0.99). In line, cotinine levels were negatively associated with aromatase availability in the thalamus, although as non-significant trend. CONCLUSIONS: These findings indicate acute blocking of aromatase availability by nicotine in the thalamic area. This suggests a new putative mechanism mediating the effects of nicotine on human behaviour, particularly relevant to sex differences in nicotine addiction.

Neural correlates of beneficial effects of young plasma treatment in aged mice: PET-SPM analyses and neuro-behavioural/molecular biological studies.

PURPOSE: To investigate the in vivo neurofunctional changes and therapeutic effects of young blood plasma (YBP) in aged mice, as well as the molecular mechanisms underlying the therapeutic effects of YBP ex vivo and in vitro. METHODS: Aged C57/BL6 mice received systemic administrations of phosphate-buffered saline (PBS) or YBP twice a week, for 4 weeks. In vivo 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) under conscious state and cognitive behavioural tests were performed after 4-week treatment. In addition, an in vitro senescent model was established, and the expressions of key cognition-associated proteins and/or the alterations of key neuronal pathways were analysed in both brain tissues and cultured cells. RESULTS: Aged mice treated with YBP demonstrated higher glucose metabolism in the right hippocampus and bilateral somatosensory cortices, and lower glucose metabolism in the right bed nucleus of stria terminalis and left cerebellum. YBP treatment exerted beneficial effects on the spatial and long-term social recognition memory, and significantly increased the expressions of several cognition-related proteins and altered the key neuronal signalling pathways in the hippocampus and somatosensory cortex. Further in vitro studies suggested that YBP but not aged blood plasma significantly upregulated the expressions of several cognition-associated proteins. CONCLUSION: Our results highlight the role of the hippocampus and somatosensory cortex in YBP-induced beneficial effects on recognition memory in aged mice. 18F-FDG PET imaging under conscious state provides a new avenue for exploring the mechanisms underlying YBP treatment against age-related cognitive decline.

PET imaging of neural activity, ß-amyloid, and tau in normal brain aging.

Normal brain aging is commonly associated with neural activity alteration, ß-amyloid (Aß) deposition, and tau aggregation, driving a progressive cognitive decline in normal elderly individuals. Positron emission tomography (PET) with radiotracers targeting these age-related changes has been increasingly employed to clarify the sequence of their occurrence and the evolution of clinically cognitive deficits. Herein, we reviewed recent literature on PET-based imaging of normal human brain aging in terms of neural activity, Aß, and tau. Neural hypoactivity reflected by decreased glucose utilization with PET imaging has been predominately reported in the frontal, cingulate, and temporal lobes of the normal aging brain. Aß PET imaging uncovers the pathophysiological association of Aß deposition with cognitive aging, as well as the potential mechanisms. Tau-associated cognitive changes in normal aging are likely independent of but facilitated by Aß as indicated by tau and Aß PET imaging. Future longitudinal studies using multi-radiotracer PET imaging combined with other neuroimaging modalities, such as magnetic resonance imaging (MRI) morphometry, functional MRI, and magnetoencephalography, are essential to elucidate the neuropathological underpinnings and interactions in normal brain aging.

Low placental growth factor levels and high soluble endoglin levels at 26-31 weeks of gestation precede light placenta with and without relatively heavy infant, respectively: A retrospective cohort study.

AIM: Our aim was to examine whether serum levels of placental growth factor (PlGF) and soluble endoglin (sEng) at 19-25 and 26-31 weeks of gestation were associated with the occurrence of the 9-block categorization of placenta weight (PW) and fetal/placenta ratio (F/P ratio). METHODS: We performed a retrospective cohort study in 1391 women with singleton pregnancy. Serum levels of PlGF and sEng were measured by enzyme immunosorbent assay. A light placenta was defined as PW ZS < -1.28 SD. Based on the PW (light, normal, and heavy) and F/P ratio (relatively heavy, balanced growth, and relatively small), 9-block categorization were performed. Multivariable logistic regression analyses were performed. RESULTS: Low PlGF at 26-31 weeks was an independent risk factor for the birth of infants belonging to Block A (light placenta and relatively heavy infant), after adjusting for prepregnancy body mass index and serum levels of sEng. High sEng at 26-31 weeks was an independent risk factor for the birth of infants belonging to Block D (light placenta and balanced growth of infant), after adjusting for past history of either preeclampsia or gestational hypertension, high pulsatility index of uterine artery flow velocity waveforms in the second trimester, and serum level of PlGF. CONCLUSIONS: Low PlGF levels at 26-31 weeks of gestation may precede a light placenta and relatively heavy infant (Block A), and high sEng levels at 26-31 weeks of gestation may precede a light placenta and balanced growth of infant (Block D).

Quantification of aromatase binding in the female human brain using [11 C]cetrozole positron emission tomography.

Aromatase, the enzyme that in the brain converts testosterone and androstenedione to estradiol and estrone, respectively, is a putative key factor in psychoneuroendocrinology. In vivo assessment of aromatase was performed to evaluate tracer kinetic models and optimal scan duration, for quantitative analysis of the aromatase positron emission tomography (PET) ligand [11 C]cetrozole. Anatomical magnetic resonance and 90-min dynamic [11 C]cetrozole PET-CT scans were performed on healthy women. Volume of interest (VOI)-based analyses with a plasma-input function were performed using the single-tissue and two-tissue (2TCM) reversible compartment models and plasma-input Logan analysis. Additionally, the simplified reference tissue model (SRTM), Logan reference tissue model (LRTM), and standardized uptake volume ratio model, with cerebellum as reference region, were evaluated. Parametric images were generated and regionally averaged voxel values were compared with VOI-based analyses of the reference tissue models. The optimal reference model was used for evaluation of a decreased scan duration. Differences between the plasma-input- and reference tissue-based methods and comparisons between scan durations were assessed by linear regression. The [11 C]cetrozole time-activity curves were best described by the 2TCM. SRTM nondisplaceable binding potential (BPND ), with cerebellum as reference region, can be used to estimate [11 C]cetrozole binding and generated robust and quantitatively accurate results for a reduced scan duration of 60 min. Receptor parametric mapping, a basis function implementation of SRTM, as well as LRTM, produced quantitatively accurate parametric images, showing BPND at the voxel level. As PET tracer, [11 C]cetrozole can be employed for relatively short brain scans to measure aromatase binding using a reference tissue-based approach.

Extremely high levels of multiple cytokines in the cord blood of neonates born to mothers with systemic autoimmune diseases.

Most infants born to mothers with autoimmune diseases are thought to be entirely healthy. However, the immunological conditions have not been examined thoroughly. Fourteen neonates born to mothers with systemic autoimmune diseases, namely systemic lupus erythematosus, mixed connective tissue disease, Sjögren's syndrome, rheumatoid arthritis, and systemic sclerosis, were included. Serum concentrations of 17 cytokines from the infants' umbilical artery (UA) and vein (UV) and from the mothers' peripheral blood were investigated by a bead array system. Cytokine expression in the placenta was investigated by immunohistochemical staining. The disease was controlled in all mothers, and none had chorioamnionitis. Hypercytokinemia was found in 11 neonates irrespective of their mothers' autoimmune diseases. In six neonates, serum cytokines were at extremely high levels. Four neonates were born by cesarean section because of a non-reassuring fetal status (NRFS) of unknown cause were all included in the hypercytokinemia group. However, all the subjects were discharged without any complications. The cytokine levels were almost the same between UA and UV, but the mothers' blood samples did not show elevation of serum cytokines. There were no differences in the expression of cytokines in the placenta among three patients with different serum cytokines levels. Hypercytokinemia frequently occurred and a cytokine storm state sometimes developed in neonates born to mothers with systemic autoimmune diseases. Growth restriction and NRFS may be related to hypercytokinemia in utero. It is plausible that the high level of cytokines in cord blood originate in neither the mother nor the placenta but in fetal immune tissues. It is important to investigate the immunological mechanisms, prevalence, and long-term influence of hypercytokinemia in a large sample size of neonates and mothers with systemic autoimmune diseases.

Markedly higher sFlt-1/PlGF ratio in a woman with acute fatty liver of pregnancy compared with HELLP syndrome.

AIM: To compare serum levels of angiogenesis-related factors between 14 women with HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome and a woman with acute fatty liver of pregnancy (AFLP). METHODS: Serum samples were collected in 2004-2008 and 2013-2016. The levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) were measured by an automated electrochemiluminescence immunoassay using Elecsys sFlt-1 and Elecsys PlGF. After logarithmic transformation, levels of sFlt-1, PlGF and the sFlt-1/PlGF ratio in a woman with AFLP were compared with those in women with HELLP syndrome, using the one-sample t-test. RESULTS: At 37 weeks of gestation, a patient was diagnosed with AFLP based on Swansea criteria (showing six features including elevated transaminases), and she also showed a duodenal ulcer with active bleeding, thrombocytopenia and hypertension. Her serum levels of sFlt-1 and sFlt-1/PlGF ratio were significantly higher than in those with HELLP syndrome (273 040 pg/mL vs 15 135 [mean], P < 0.001; 4236 vs 224, P < 0.001; respectively). However, her serum level of PlGF was not significantly different from those with HELLP syndrome. CONCLUSION: Serum levels of sFlt-1 and the sFlt-1/PlGF ratio, but not PlGF, in a woman with AFLP were markedly higher than those in women with HELLP syndrome. AFLP may be a different clinical entity from HELLP syndrome based on angiogenesis-related factors. Clinically, the sFlt-1/PlGF ratio may be used to rapidly distinguish AFLP from HELLP syndrome.

Quantification of receptor activation by oxytocin and vasopressin in endocytosis-coupled bioluminescence reduction assay using nanoKAZ.

Oxytocin (OXT) and arginine vasopressin (AVP) are structurally similar neuropeptide hormones that function as neurotransmitters in the brain, and have opposite key roles in social behaviors. These peptides bind to their G protein-coupled receptors (OXTR and AVPRs), inducing calcium ion-dependent signaling pathways and endocytosis of these receptors. Because selective agonists and antagonists for these receptors have been developed as therapeutic and diagnostic agents for diseases such as psychiatric disorders, facile methods are in demand for the evaluation of selectivity between these receptors. In this study, we developed a quantitative assay for OXT- and AVP-induced endocytosis of their receptors. The mutated Oplophorus luciferase, nanoKAZ, was fused to OXTR and AVPRs to enable rapid quantification of agonist-induced endocytosis by bioluminescence reduction. Agonist stimulation significantly decreases bioluminescence of nanoKAZ-fused receptors in living cells. Using this system, we evaluated clinically used OXTR antagonist atosiban and a reported pyrazinyltriazole derivative, hereby designated as PF13. Atosiban acted as an antagonist of AVPR1a, as well as an agonist for AVPR1b, whereas PF13 antagonized OXTR more selectively than atosiban, as reported previously. This paper shows a strategy for quantification of agonist-induced endocytosis of OXTR and AVPRs, and confirms its potent utility in the evaluation of agonists and antagonists.

Noninvasive Evaluation of Cellular Proliferative Activity in Brain Neurogenic Regions in Rats under Depression and Treatment by Enhanced [18F]FLT-PET Imaging.

UNLABELLED: Neural stem cells in two neurogenic regions, the subventricular zone and the subgranular zone (SGZ) of the hippocampal dentate gyrus, can divide and produce new neurons throughout life. Hippocampal neurogenesis is related to emotions, including depression/anxiety, and the therapeutic effects of antidepressants, as well as learning and memory. The establishment of in vivo imaging for proliferative activity of neural stem cells in the SGZ might be used to diagnose depression and to monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging with 3'-deoxy-3'-[(18)F]fluoro-l-thymidine ([(18)F]FLT) has been studied to allow visualization of proliferative activity in two neurogenic regions of adult mammals; however, the PET imaging has not been widely used because of lower accumulation of [(18)F]FLT, which does not allow quantitative assessment of the decline in cellular proliferative activity in the SGZ under the condition of depression. We report the establishment of an enhanced PET imaging method with [(18)F]FLT combined with probenecid, an inhibitor of drug transporters at the blood-brain barrier, which can allow the quantitative visualization of neurogenic activity in rats. Enhanced PET imaging allowed us to evaluate reduced cell proliferation in the SGZ of rats with corticosterone-induced depression, and further the recovery of proliferative activity in rats under treatment with antidepressants. This enhanced [(18)F]FLT-PET imaging technique with probenecid can be used to assess the dynamic alteration of neurogenic activity in the adult mammalian brain and may also provide a means for objective diagnosis of depression and monitoring of the therapeutic effect of antidepressant treatment. SIGNIFICANCE STATEMENT: Adult hippocampal neurogenesis may play a role in major depression and antidepressant therapy. Establishment of in vivo imaging for hippocampal neurogenic activity may be useful to diagnose depression and monitor the therapeutic efficacy of antidepressants. Positron emission tomography (PET) imaging has been studied to allow visualization of neurogenic activity; however, PET imaging has not been widely used due to the lower accumulation of the PET tracer in the neurogenic regions. Here, we succeeded in establishing highly quantitative PET imaging for neurogenic activity in adult brain with an inhibitor for drug transporter. This enhanced PET imaging allowed evaluation of the decline of neurogenic activity in the hippocampus of rats with depression and the recovery of neurogenic activity by antidepressant treatment.

Independent risk factors for a small placenta and a small-for-gestational-age infant at 35-41 weeks of gestation: An association with circulating angiogenesis-related factor levels at 19-31 weeks of gestation.

AIM: Our aim was to investigate the effects of angiogenesis-related factor levels at 19-25 and 26-31 weeks of gestation (WG) on the later occurrence of a small-for-gestational-age (SGA) placenta (small placenta) or an SGA infant delivered at 35-41 WG. METHODS: We measured plasma levels of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), and the serum level of soluble endoglin (sEng) in 679 pregnant women with blood sampling at both 19-25 and 26-31 WG in a prospective study. A small placenta and an SGA infant were defined as <10th percentile, respectively. Multivariate logistic regression analyses were performed using maternal factors, a high mean pulsatility index (high mPI) of the uterine artery in the second trimester, and angiogenesis-related factor levels. RESULTS: Regarding the occurrence of a small placenta, low PlGF at 19-25 WG (adjusted odds ratio [95% confidence interval]: 2.4 [1.01-5.7]) and a high mPI (2.5 [1.4-4.3]) were independent risk factors. Moreover, low PlGF at 26-31 WG (3.3 [1.5-7.0]) was also an independent risk factor after adjusting for the effect of mPI. Concerning the occurrence of an SGA infant, a high mPI (2.8 [1.6-5.2]) and high sEng at 26-31 WG (2.3 [1.2-4.5]) were independent risk factors. CONCLUSION: Low levels of PlGF at 19-25 and 26-31 WG were independent risk factors for a small placenta at ≥35 WG; and a high sEng at 26-31 WG was an independent risk factor for an SGA infant at ≥35 WG.