Family-environmental factors associated with attention deficit hyperactivity disorder in Chinese children: a case-control study.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders, affecting an estimated 5 to 12% of school-aged children worldwide. From 15 to 19 million Chinese children suffer from ADHD. The aim of this study was to investigate the association between family-environmental factors and ADHD in a sample of Chinese children. METHODS: A pair-matched, case-control study was conducted with 161 ADHD children and 161 non-ADHD children of matching age and sex, all from 5-18 years of age. The ADHD subjects and the normal controls were all evaluated via structured diagnostic interviews. We examined the association between family-environmental factors and ADHD using the conditional multiple logistic regression with backward stepwise selection to predict the associated factors of ADHD. RESULTS: Having experienced emotional abuse and being a single child were both significant factors associated with children diagnosed with ADHD. ADHD subjects were more likely to have suffered from emotional abuse (OR = 11.09, 95% CI = 2.15-57.29, P = 0.004) and have been a single child in the family (OR = 6.32, 95% CI = 2.09-19.14, P = 0.001) when compared to normal controls. The results were not modified by other confounding factors. CONCLUSION: Our findings provide evidence that family-environmental factors are associated with ADHD among children in China. These findings, if confirmed by future research, may help to decrease ADHD by increasing the awareness of the effects of childhood emotional abuse.

Sex differences in the relationship of regional dopamine release to affect and cognitive function in striatal and extrastriatal regions using positron emission tomography and [¹8F]fallypride.

The purpose of this study was to examine sex differences in the correlations of d-amphetamine (d-AMPH) induced displacements of [¹8F]fallypride in striatal and extrastriatal regions in relation to affect and cognition. Seven male and six female healthy subjects, whose mean age was 25.9 years, underwent positron emission tomography (PET) with [¹8F]fallypride at baseline and 3 h after a 0.43 mg/kg oral dose of d-AMPH. Percent displacements in striatal and extrastriatal regions were calculated using regions of interest (ROI) analysis and on a pixel-by-pixel basis. Subjects underwent neuropsychological testing prior to the baseline PET study and one hour after d-AMPH administration for the second PET. In order to examine the subjective effect of d-AMPH, subjects rated PANAS at baseline and after administration of amphetamine. Correlations of changes in cognition and affect with regional dopamine (DA) release revealed several significant sex related differences. The results of this study demonstrate in vivo sex related differences in the relationship of regional DA release to affect and cognitive function.

The interrelationship of dopamine D2-like receptor availability in striatal and extrastriatal brain regions in healthy humans: a principal component analysis of [18F]fallypride binding.

Individual differences in dopamine D2-like receptor availability arise across all brain regions expressing D2-like receptors. However, the interrelationships in receptor availability across brain regions are poorly understood. To address this issue, we examined the relationship between D2-like binding potential (BPND) across striatal and extrastriatal regions in a sample of healthy participants. PET imaging was performed with the high affinity D2/D3 ligand [18F]fallypride in 45 participants. BPND images were submitted to voxel-wise principal component analysis to determine the pattern of associations across brain regions. Individual differences in D2-like BPND were explained by three distinguishable components. A single component explained almost all of the variance within the striatum, indicating that individual differences in receptor availability vary in a homogenous manner across the caudate, putamen, and ventral striatum. Cortical BPND was only modestly related to striatal BPND and mostly loaded on a distinct component. After controlling for the general level of cortical D2-like BPND, an inverse relationship emerged between receptor availability in the striatum and the ventral temporal and ventromedial frontal cortices, suggesting possible cross-regulation of D2-like receptors in these regions. The analysis additionally revealed evidence of: (1) a distinct component involving the midbrain and limbic areas; (2) a dissociation between BPND in the medial and lateral temporal regions; and (3) a dissociation between BPND in the medial/midline and lateral thalamus. In summary, individual differences in D2-like receptor availability reflect several distinct patterns. This conclusion has significant implications for neuropsychiatric models that posit global or regionally specific relationships between dopaminergic tone and behavior.

Cerebral morphology and dopamine D2/D3 receptor distribution in humans: a combined [18F]fallypride and voxel-based morphometry study.

The relationship between cerebral morphology and the expression of dopamine receptors has not been extensively studied in humans. Elucidation of such relationships may have important methodological implications for clinical studies of dopamine receptor ligand binding differences between control and patient groups. The association between cerebral morphology and dopamine receptor distribution was examined in 45 healthy subjects who completed T1-weighted structural MRI and PET scanning with the D(2)/D(3) ligand [(18)F]fallypride. Optimized voxel-based morphometry was used to create grey matter volume and density images. Grey matter volume and density images were correlated with binding potential (BP(ND)) images on a voxel-by-voxel basis using the Biological Parametric Mapping toolbox. Associations between cerebral morphology and BP(ND) were also examined for selected regions-of-interest (ROIs) after spatial normalization. Voxel-wise analyses indicated that grey matter volume and density positively correlated with BP(ND) throughout the midbrain, including the substantia nigra. Positive correlations were observed in medial cortical areas, including anterior cingulate and medial prefrontal cortex, and circumscribed regions of the temporal, frontal, and parietal lobes. ROI analyses revealed significant positive correlations between BP(ND) and cerebral morphology in the caudate, thalamus, and amygdala. Few negative correlations between morphology and BP(ND) were observed. Overall, grey matter density appeared more strongly correlated with BP(ND) than grey matter volume. Cerebral morphology, particularly grey matter density, correlates with [(18)F]fallypride BP(ND) in a regionally specific manner. Clinical studies comparing dopamine receptor availability between clinical and control groups may benefit by accounting for potential differences in cerebral morphology that exist even after spatial normalization.

Dopamine D2 receptor levels in striatum, thalamus, substantia nigra, limbic regions, and cortex in schizophrenic subjects.

BACKGROUND: Studies in schizophrenic patients have reported dopaminergic abnormalities in striatum, substantia nigra, thalamus, anterior cingulate, hippocampus, and cortex that have been related to positive symptoms and cognitive impairments. METHODS: [(18)F]fallypride positron emission tomography studies were performed in off-medication or never-medicated schizophrenic subjects (n = 11, 6 men, 5 women; mean age of 30.5 +/- 8.0 [SD] years; 4 drug-naive) and age-matched healthy subjects (n = 11, 5 men, 6 women, mean age of 31.6 +/- 9.2 [SD]) to examine dopamine D(2) receptor (DA D(2)r) levels in the caudate, putamen, ventral striatum, medial thalamus, posterior thalamus, substantia nigra, amygdala, temporal cortex, anterior cingulate, and hippocampus. RESULTS: In schizophrenic subjects, increased DA D(2)r levels were seen in the substantia nigra bilaterally; decreased levels were seen in the left medial thalamus. Correlations of symptoms with ROI data demonstrated a significant correlation of disorganized thinking/nonparanoid delusions with the right temporal cortex ROI (r = .94, p = .0001), which remained significant after correction for multiple comparisons (p < .03). Correlations of symptoms with parametric images of DA D(2)r levels revealed no significant clusters of correlations with negative symptoms but significant clusters of positive correlations of total positive symptoms, delusions and bizarre behavior with the lateral and anterior temporal cortex, and hallucinations with the left ventral striatum. CONCLUSIONS: The results of this study demonstrate abnormal DA D(2)r-mediated neurotransmission in the substantia nigra consistent with nigral dysfunction in schizophrenia and suggest that both temporal cortical and ventral striatal DA D(2)r mediate positive symptoms.

Estimation of baseline dopamine D2 receptor occupancy in striatum and extrastriatal regions in humans with positron emission tomography with [18F] fallypride.

BACKGROUND: This study examined whether positron emission tomography (PET) studies with [18F] fallypride performed before and after alpha-methyl-para-tyrosine (AMPT) administration can be used to estimate baseline dopamine (DA) D2 receptor occupancy in striatal and extrastriatal regions. METHODS: Six normal subjects underwent PET with [18 F] fallypride before and after administration of AMPT. The DA D2 receptor binding potentials (bp) were calculated with the reference region method. Percent changes in bp in striatal and extrastriatal regions were calculated with both region-of-interest analysis and on a voxel by voxel basis with parametric images of DA D2 receptor levels. RESULTS: The results of the current study indicate that AMPT treatment significantly increased the bp in the caudate, putamen, ventral striatum, and substantia nigra. A trend level increase was seen in the medial thalamus. CONCLUSIONS: This study demonstrates that PET with [18F] fallypride can be used to estimate baseline DA D2 receptor occupancy in striatal and extrastriatal regions.

Midbrain dopamine receptor availability is inversely associated with novelty-seeking traits in humans.

Novelty-seeking personality traits are a major risk factor for the development of drug abuse and other unsafe behaviors. Rodent models of temperament indicate that high novelty responding is associated with decreased inhibitory autoreceptor control of midbrain dopamine neurons. It has been speculated that individual differences in dopamine functioning also underlie the personality trait of novelty seeking in humans. However, differences in the dopamine system of rodents and humans, as well as the methods for assessing novelty responding/seeking across species leave unclear to what extent the animal models inform our understanding of human personality. In the present study we examined the correlation between novelty-seeking traits in humans and D(2)-like (D(2)/D(3)) receptor availability in the substantia nigra/ventral tegmental area. Based on the rodent literature we predicted that novelty seeking would be characterized by lowered levels of D(2)-like (auto)receptor availability in the midbrain. Thirty-four healthy adults (18 men, 16 women) completed the Tridimensional Personality Questionnaire-Novelty-Seeking Scale and PET scanning with the D(2)/D(3) ligand [(18)F]fallypride. Novelty-Seeking personality traits were inversely associated with D(2)-like receptor availability in the ventral midbrain, an effect that remained significant after controlling for age. We speculate that the lower midbrain (auto)receptor availability seen in high novelty seekers leads to accentuated dopaminergic responses to novelty and other conditions that induce dopamine release.

Effects of antiretroviral therapy on tube-like network formation of human endothelial cells.

New guidelines suggest that HIV-infected pregnant women should be offered combination antiretroviral therapy (zidovudine and protease inhibitors) to prevent fetal HIV infection but concerns remain about potential adverse effects for the infant. Prior small case series have suggested an increased risk for hemangioma. In this study we used zidovudine and indinavir, alone or in combination, to assess the effect on an in vitro angiogenesis system for endothelial cells. The increase in capillary tube formation, was associated with a significant increase in vascular endothelial growth factor (VEGF) production. Zidovudine and indinavir used in combination do not further strengthen both endothelial cell tubes formation and VEGF secretion. We conclude that zidovudine and indinavir may induce angiogenesis in an in vitro model.

Sex differences in amphetamine-induced displacement of [(18)F]fallypride in striatal and extrastriatal regions: a PET study.

OBJECTIVE: The authors examined gender differences in d-amphetamine-induced displacements of [(18)F]fallypride in the striatal and extrastriatal brain regions and the correlations of these displacements with cognition and sensation seeking. METHOD: Six women and seven men underwent positron emission tomography (PET) with [(18)F]fallypride before and after an oral dose of d-amphetamine. Percent displacements were calculated using regions of interest and parametric images of dopamine 2 (D(2)) receptor binding potential. RESULTS: Parametric images of dopamine release suggest that the female subjects had greater dopamine release than the male subjects in the right globus pallidus and right inferior frontal gyrus. Gender differences were observed in correlations of changes in cognition and sensation seeking with regional dopamine release. CONCLUSION: Findings revealed a greater dopamine release in women as well as gender differences in the relationship between regional dopamine release and sensation seeking and cognition.

Non-invasive detection of fetal rhesus D status: a comparison between polymerase chain reaction and flow cytometry.

OBJECTIVE: A non-invasive prenatal determination of the fetal RhD status might be useful for the management of pregnancies in RhD-negative women whose partners are RhD positive. METHODS: Maternal peripheral blood of 32 RhD-negative women (17-24 weeks of gestation) was collected, and circulating fetal cells were enriched by CD71 mini-magnetic activated cell sorting. The RhD status of the fetuses was assessed using multiparametric flow cytometry, and results were compared to those of reverse transcriptase (RT)-polymerase chain reaction (PCR), or PCR, which acted as control. Flow-cytometric study of fetal cells employed monoclonal antibodies directed against CD71, glycophorin A (GPA) and RhD antigens. RESULTS: The median percentage of CD71- and RhD-positive cells was 0.83% (range 0.14-6.44%), and that of CD71 and GPA-positive cells was 10.07% (range 0.52-45.84%). Flow-cytometric analysis correlated with RT-PCR results of RNA obtained from whole maternal blood. In 1 case, an incorrect result was due to the failure of the amplification of the specific RhD band on RNA extracted from the CD71-positive fraction. In two instances, we observed false-positive results for RhD in PCR of DNA obtained from maternal plasma. CONCLUSION: Based on our results, flow-cytometric analysis might be proposed as a clinical tool for the non-invasive prenatal determination of the fetal RhD status independently of fetal gender.

Occupancy of striatal and extrastriatal dopamine D2 receptors by clozapine and quetiapine.

Clozapine and quetiapine have a low incidence of extrapyramidal side effects at clinically effective doses, which appears to be related to their significantly lower occupancy of striatal dopamine D2 receptors (DA D2r) compared to typical antipsychotic drugs (APDs). Animal studies have indicated that clozapine and quetiapine produce selective effects on cortical and limbic regions of the brain and in particular on dopaminergic neurotransmission in these regions. Previous PET and SPECT studies have reported conflicting results regarding whether clozapine produces preferential occupancy of cortical DA D2r. To examine whether clozapine and/or quetiapine produce preferential occupancy of DA D2r in cortex and limbic regions, we studied the occupancy of putamenal, ventral striatal, thalamic, amygdala, substantia nigra, and temporal cortical DA D2r using PET with [18F]fallypride in six schizophrenic subjects receiving clozapine monotherapy and in seven schizophrenic subjects receiving quetiapine monotherapy. Doses were chosen clinically to minimize psychopathology at tolerable levels of side effects such as drowsiness. All had minimal positive symptoms at the time of the study. Regional receptor occupancies were estimated using mean regional DA D2r levels calculated for 10 off-medication schizophrenic subjects. Both clozapine and quetiapine produced lower levels of putamenal DA D2r occupancy than those reported for typical APDs, 47.8 and 33.5%, respectively. Clozapine produced preferential occupancy of temporal cortical vs putamenal DA D2r, 59.8% (p=0.05, corrected for multiple comparisons), and significantly lower levels of occupancy in the substantia nigra, 18.4% (p=0.0015, corrected for multiple comparisons). Quetiapine also produced preferential occupancy of temporal cortical DA D2r, 46.9% (p=0.03, corrected for multiple comparisons), but did not spare occupancy of substantia nigra DA D2r. The therapeutic effects of clozapine and quetiapine appear to be achieved at less than the 65% threshold for occupancy seen with typical APDs, consistent with the involvement of non-DA D2r mechanisms in at least partially mediating the therapeutic effects of these drugs. Preferential occupancy of cortical DA D2r, sparing occupancy of substantia nigra receptors, and non-DA D2r-mediated actions may contribute to the antipsychotic actions of these and other atypical APDs.

Amphetamine-induced displacement of [18F] fallypride in striatum and extrastriatal regions in humans.

This study examined D-amphetamine (D-AMPH)-induced displacements of [18F] fallypride in striatal and extrastriatal regions and the correlations of these displacements with cognition, affect, and sensation-seeking behavior. In all, 14 normal subjects, six females and eight males (ages 21-32, mean age 25.9 years), underwent positron emission tomography (PET) with [18F]fallypride before and 3 h after a 0.43 mg/kg oral dose of D-AMPH. Levels of dopamine (DA) D2 receptor density were calculated with the reference region method of Lammerstma. Percent displacements in striatal and extrastriatal regions were calculated for the caudate, putamen, ventral striatum, medial thalamus, amygdala, substantia nigra, and temporal cortex. Correlations of changes in cognition, affect, and sensation seeking with parametric images of D-AMPH-induced DA release were computed. Significant displacements were seen in the caudate, putamen, ventral striatum substantia nigra, and temporal cortex with a trend level change in the amygdala. Greatest displacements were seen in striatal subdivisions-5.6% in caudate, 11.2% in putamen, 7.2% in ventral striatum, and 6.6% in substantia nigra. Lesser decrements were seen in amygdala-4.4%, temporal cortex-3.7%, and thalamus-2.8%. Significant clusters of correlations of regional DA release with cognition and sensation-seeking behavior were observed. The current study demonstrates that [18F]fallypride PET studies using oral D-AMPH (0.43 mg/kg) can be used to study D-AMPH-induced DA release in the striatal and extrastriatal regions in humans, and their relationship with cognition and sensation-seeking behavior.

123I-5-IA-85380 SPECT measurement of nicotinic acetylcholine receptors in human brain by the constant infusion paradigm: feasibility and reproducibility.

UNLABELLED: (123)I-5-IA-85380 ((123)I-5-IA; [(123)I]-5-iodo-3-[2(S)-azetidinylmethoxy]pyridine) is a promising SPECT radiotracer for imaging beta(2)-containing nicotinic acetylcholine receptors (beta(2)-nAChRs) in brain. Beta(2)-nAChRs are the initial site of action of nicotine and are implicated in various neuropsychiatric disorders. The feasibility and reproducibility of the bolus-plus-constant-infusion paradigm for equilibrium modeling of (123)I-5-IA using SPECT in healthy nonsmokers was studied. METHODS: Ten healthy nonsmokers (mean age +/- SD, 43.7 +/- 9.9 y) underwent two (123)I-5-IA SPECT scans within 4 wk. (123)I-5-IA was administered as a bolus (125.8 +/- 14.6 MBq) plus constant infusion (18.1 +/- 1.5 MBq/h). SPECT acquisitions (30 min) and venous blood sampling were performed every 60 min throughout the infusion (10-14 h). The test-retest variability and reliability of plasma activity (kBq/mL), the regional brain activity reflected by units of kBq/mL and %ID/mL (injected dose/mL brain tissue), and the equilibrium outcome measures V(T)' (ratio of total uptake to total plasma parent concentration) and V(T) (ratio of total uptake to free plasma parent concentration) were evaluated in 4 brain areas, including thalamus, striatum, cortex, and cerebellum. RESULTS: Linear regression analysis revealed that time-activity curves for both plasma and brain (123)I-5-IA activity stabilized by 5 h, with an average change of [2.5%/h between 6 and 8 h of infusion, permitting equilibrium modeling. The plasma free fraction (f(1)), total parent, and clearance demonstrated good test-retest variability (mean, 10.9%-12.5%), whereas the variability of free parent was greater (mean, 24.3%). Regional brain activity (kBq/mL) demonstrated good test-retest variability (11.1%-16.4%) that improved when corrected for infusion rate (mean, 8.2%-9.9%) or for injected dose (mean, 9.5%-13.3%). V(T)' demonstrated better test-retest variability (mean, 7.0%-8.9%) than V(T) (mean, 12.9%-14.6%). Reliability assessed by the intraclass correlation coefficient (ICC) was superior for kBq/mL (ICC = 0.83-0.90) and %ID/mL (ICC = 0.93-0.96) compared with V(T)' (ICC = 0.30-0.64) and V(T) (ICC = 0.28-0.60). The lower reliability of V(T) was attributed to the poor reliability of the free fraction (ICC = 0.35) and free parent (ICC = 0.68). CONCLUSION: These results support the feasibility and reproducibility of equilibrium imaging with (123)I-5-IA for measurement of beta(2)-nAChRs in human brain.

Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol.

There have been conflicting reports as to whether olanzapine produces lower occupancy of striatal dopamine D(2)/D(3) receptor than typical antipsychotic drugs and preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors. We performed [(18)F] fallypride PET studies in six schizophrenic subjects treated with olanzapine and six schizophrenic subjects treated with haloperidol to examine the occupancy of striatal and extrastriatal dopamine receptors by these antipsychotic drugs. [(18)F] setoperone PET studies were performed in seven olanzapine-treated subjects to determine 5-HT(2A) receptor occupancy. Occupancy of dopamine D(2)/D(3) receptors by olanzapine was not significantly different from that seen with haloperidol in the putamen, ventral striatum, medial thalamus, amygdala, or temporal cortex, that is, 67.5-78.2% occupancy; olanzapine produced no preferential occupancy of dopamine D(2)/D(3) receptors in the ventral striatum, medial thalamus, amygdala, or temporal cortex. There was, however, significantly lower occupancy of substantia nigra/VTA dopamine D(2)/D(3) receptors in olanzapine-treated compared to haloperidol-treated subjects, that is, 40.2 vs 59.3% (p=0.0014, corrected for multiple comparisons); in olanzapine-treated subjects, the substantia nigra/VTA was the only region with significantly lower dopamine D(2)/D(3) receptor occupancy than the putamen, that is, 40.2 vs 69.2% (p<0.001, corrected for multiple comparison). Occupancy of 5-HT(2A) receptors was 85-93% in the olanzapine- treated subjects. The results of this study demonstrated that olanzapine does not produce preferential occupancy of extrastriatal dopamine D(2)/D(3) receptors but does spare substantia nigra/VTA receptors. Sparing of substantia nigra/VTA dopamine D(2)/D(3) receptor occupancy may contribute to the low incidence of extrapyramidal side effects in olanzapine-treated patients.

Homocysteine induces trophoblast cell death with apoptotic features.

Hyperhomocysteinemia has been suggested as a possible risk factor in women suffering from habitual abortions, placental abruption or infarcts, preeclampsia, and/or intrauterine growth retardation. However, little is known about the pathogenic mechanisms underlying the action of homocysteine. The present study investigated the in vitro ability of homocysteine to affect trophoblast gonadotropin secretion and to induce cell death. In primary human trophoblast cells, homocysteine treatment (20 micromol/L) resulted in cellular flattening and enlargement, extension of pseudopodia, and cellular vacuolization. Cellular detachment, apoptosis, and necrosis were favored. With in situ nick end labeling, we investigated DNA degradation, and we used M30 CytoDEATH to selectively stain the cytoplasm of apoptotic cells. Cytochrome c release from mitochondria to the cytosol and DNA cleavage in agarose gel have been investigated. Homocysteine, but not cysteine, induced trophoblast apoptosis and significantly reduced human chorionic gonadotropin secretion. These findings suggest that trophoblast cell death might represent a pathogenic mechanism by which homocysteine may cause pregnancy complications related to placental diseases.