Intercorrelation of Molecular Biomarkers and Clinical Phenotype Measures in Fragile X Syndrome.

This study contributes to a greater understanding of the utility of molecular biomarkers to identify clinical phenotypes of fragile X syndrome (FXS). Correlations of baseline clinical trial data (molecular measures-FMR1 mRNA, CYFIP1 mRNA, MMP9 and FMRP protein expression levels, nonverbal IQ, body mass index and weight, language level, NIH Toolbox, adaptive behavior rating, autism, and other mental health correlates) of 59 participants with FXS ages of 6-32 years are reported. FMR1 mRNA expression levels correlated positively with adaptive functioning levels, expressive language, and specific NIH Toolbox measures. The findings of a positive correlation of MMP-9 levels with obesity, CYFIP1 mRNA with mood and autistic symptoms, and FMR1 mRNA expression level with better cognitive, language, and adaptive functions indicate potential biomarkers for specific FXS phenotypes. These may be potential markers for future clinical trials for targeted treatments of FXS.

Harm Avoidance is Correlated with the Reward System in Adult Patients with Attention Deficit Hyperactivity Disorder: A Functional Magnetic Resonance Imaging Study.

Objective: Hypoactivity in the reward system among patients with attention deficit hyperactivity disorder (ADHD) is a well-known phenomenon. Whether the activity in the reward pathway is related to harm avoidance, such as in sensitivity to punishment, is unclear. Evidence regarding the potential difference between ADHD patients and controls in terms of this association is scarce. Methods: Event-related functional magnetic resonance imaging was conducted on subjects performing the Iowa gambling test. Fourteen adults with ADHD and 14 controls were enrolled in the study. Results: Harm avoidance was found to be positively correlated with the activities of the bilateral orbitofrontal cortex and right insula in individuals with ADHD. A group difference was also confirmed. Conclusion: Understanding the roles of harm avoidance and brain activation during risk tasks is important.

Sex differences in the diagnosis of autism spectrum disorder and effects of comorbid mental retardation and attention-deficit hyperactivity disorder.

BACKGROUND/PURPOSE: The association between sex and diagnostic behavior of autism spectrum disorder (ASD), and the effects of comorbid mental retardation (MR) and attention-deficit hyperactivity disorder (ADHD), were explored. METHODS: Based on the Taiwan Longitudinal Health Insurance Database (LHID)-2000 and data from 1996 through 2008, the cumulative incidence of ASD over time was compared between the sexes (both cohorts n = 38,117) using the log-rank test. The effects of comorbid MR and ADHD on the incidence of ASD were evaluated using Cox proportional hazard regression analysis. The age at first diagnosis of ASD in the two sexes was compared using the independent-sample t-test. RESULTS: The incidence was higher in males than in females (0.0007 vs. 0.0002) across ages. Comorbid MR or ADHD increased the incidence of ASD in both sexes; comorbid MR or ADHD also decreased the male to female hazard ratio of ASD, with no significant differences in the incidence density of ASD between sexes. ADHD delayed diagnosis in both sexes (males: 6.61 vs 5.10, p < 0.0001; females: 6.83 vs 4.69, p = 0.0037). CONCLUSION: The general concept of a higher incidence of ASD among males was noted in this study of a Taiwanese population, but disappeared in those with comorbid MR or ADHD, indicating unique vulnerabilities to MR/ADHD or under-identification of high-functioning females with ASD in childhood. Increasing the diagnostic sensitivity of ASD in those with comorbid ADHD is important due to a delayed diagnostic age in this group.

Cardiovascular and metabolic risk of antipsychotics in children and young adults: a multinational self-controlled case series study.

AIMS: The risk of antipsychotic-associated cardiovascular and metabolic events may differ among countries, and limited real-world evidence has been available comparing the corresponding risks among children and young adults. We, therefore, evaluated the risks of cardiovascular and metabolic events in children and young adults receiving antipsychotics. METHODS: We conducted a multinational self-controlled case series (SCCS) study and included patients aged 6-30 years old who had both exposure to antipsychotics and study outcomes from four nationwide databases of Taiwan (2004-2012), Korea (2010-2016), Hong Kong (2001-2014) and the UK (1997-2016) that covers a total of approximately 100 million individuals. We investigated three antipsychotics exposure windows (i.e., 90 days pre-exposure, 1-30 days, 30-90 days and 90 + days of exposure). The outcomes were cardiovascular events (stroke, ischaemic heart disease and acute myocardial infarction), or metabolic events (hypertension, type 2 diabetes mellitus and dyslipidaemia). RESULTS: We included a total of 48 515 individuals in the SCCS analysis. We found an increased risk of metabolic events only in the risk window with more than 90-day exposure, with a pooled IRR of 1.29 (95% CI 1.20-1.38). The pooled IRR was 0.98 (0.90-1.06) for 1-30 days and 0.88 (0.76-1.02) for 31-90 days. We found no association in any exposure window for cardiovascular events. The pooled IRR was 1.86 (0.74-4.64) for 1-30 days, 1.35 (0.74-2.47) for 31-90 days and 1.29 (0.98-1.70) for 90 + days. CONCLUSIONS: Long-term exposure to antipsychotics was associated with an increased risk of metabolic events but did not trigger cardiovascular events in children and young adults.

Association between methylphenidate and risk of myocardial infarction: A multinational self-controlled case series study.

PURPOSE: To investigate the association between use of methylphenidate and risk of myocardial infarction among Asians. METHODS: We conducted a multinational self-controlled case series study using nationwide healthcare databases of South Korea (2002-2018), Taiwan (2004-2015), and Hong Kong (2001-2016). Of patients with myocardial infarction who were also prescribed methylphenidate within the observation period, methylphenidate use was classified into four mutually exclusive periods by each person-day: exposed (exposed to methylphenidate), pre-exposure (prior to the first methylphenidate prescription), washout (after the end of methylphenidate treatment), and baseline (unexposed to methylphenidate). Risk of myocardial infarction among the three periods of methylphenidate use was compared to the baseline period using conditional Poisson regression analysis to estimate incidence rate ratios (IRRs) with 95% confidence intervals (CIs). RESULTS: We identified 2104, 484, and 30 patients from South Korea, Taiwan, and Hong Kong, respectively. Risk of myocardial infarction was the highest during the pre-exposure period in all three populations: South Korea, pre-exposure (IRR 3.17, 95% CI 3.04-3.32), exposed (1.05, 1.00-1.11), washout (1.92, 1.80-2.04); Taiwan, pre-exposure (1.97, 1.78-2.17), exposed (0.72, 0.65-0.80), washout (0.56, 0.46-0.68); Hong Kong, pre-exposure (18.09, 8.19-39.96), exposed (9.32, 3.44-25.28), washout (7.69, 1.72-34.41). Following stratification for age and sex, the trends remained analogous to the main findings across all three populations. CONCLUSIONS: Although a positive association between initiating methylphenidate and the onset of myocardial infarction was observed, the risk was the highest in the period before its initiation. Thus, this multinational study suggests there was no causal relationship between methylphenidate and myocardial infarction among Asians.

Positive Symptoms in Antipsychotic-naïve Schizophrenia are Associated with Increased Body Mass Index after Treatment.

OBJECTIVE: Weight gain is an important risk factor for morbidity and mortality among patients with schizophrenia. We speculated that positive symptoms, related to dopaminergic hyperactivity and altered mesolimbic function, are associated with weight gain. METHODS: Twenty-two antipsychotic-naïve, first-episode patients with schizophrenia were enrolled. The Positive and Negative Syndrome Scale was completed at enrollment and follow-up. Body mass index (BMI) was also measured. RESULTS: The increase in BMI, after 6.04 ± 2.16 years of follow-up, was associated with positive symptoms, but not negative symptoms, before treatment with antipsychotics in antipsychotic-naïve patients with schizophrenia. CONCLUSION: This finding implied that dopaminergic hyperactivity could be an important factor to predict the treatment outcome. Body weight control is important for the health management of patients with schizophrenia with more severe positive symptoms.

A pilot study on the association between the blood oxygen level-dependent signal in the reward system and dopamine transporter availability in adults with attention deficit hyperactivity disorder.

BACKGROUND: It is well-known that attention deficit hyperactivity disorder (ADHD) is associated with changes in the dopaminergic system. However, the relationship between central dopaminergic tone and the blood oxygen level-dependent (BOLD) signal during receipt of rewards and penalties in the corticostriatal pathway in adults with ADHD is unclear. METHODS: Single-photon emission computed tomography with [99mTC]TRODAT-1 was used to assess striatal dopamine transporter (DAT) availability. Event-related functional magnetic resonance imaging was conducted on subjects performing the Iowa Gambling Test. RESULT: DAT availability was found to be associated with the BOLD response, which was a covariate of monetary loss, in the medial prefrontal cortex (r = 0.55, P = .03), right ventral striatum (r = 0.69, P = .003), and right orbital frontal cortex (r = 0.53, P = .03) in adults with ADHD. However, a similar correlation was not found in the controls. CONCLUSIONS: The results confirmed that dopaminergic tone may play a different role in the penalty-elicited response of adults with ADHD. It is plausible that a lower neuro-threshold accompanied by insensitivity to punishment could be exacerbated by the hypodopaminergic tone in ADHD.

The Interaction of Oxytocin and Social Support, Loneliness, and Cortisol Level in Major Depression.

OBJECTIVE: Loneliness is a specific risk factor for depressive symptoms and suicidal behavior. The present study examined whether the serum oxytocin level would interact with social support and buffers loneliness and hypothalamic-pituitary-adrenal (HPA)-axis activity in drug-naïve patients with major depressive disorder (MDD). METHODS: Twenty-six patients with MDD (male:female = 3:23; mean age, 45.54 ± 12.97 years) were recruited. The 17-item Hamilton Depression Rating Scale, UCLA Loneliness Scale and self-reported Measurement of Support Function Questionnaire were administered. Serum oxytocin and cortisol levels were assessed using a commercial immunoassay kits. RESULTS: In MDD patients, a negative association was found between degrees of social support and loneliness (ß= -0.39, p = 0.04). The interaction between social support and serum oxytocin level was negatively associated with loneliness (ß= -0.50, p = 0.017) and serum cortisol level (ß= -0.55, p = 0.020) after adjusting for age. Follow-up analyses showed that the association between higher social support and lower loneliness was observed only in the higher-oxytocin group (r = -0.75, p = 0.003) but not in the lower group (r = -0.19, p = 0.53). The significance remained after further adjusting for sex and depression severity. CONCLUSION: Low oxytocin level is a vulnerability factor for the buffering effect of social support for loneliness and aberrant HPA-axis activity in MDD patients.

Altered Auditory P300 Performance in Parents with Attention Deficit Hyperactivity Disorder Offspring.

OBJECTIVE: Altered event-related potential (ERP) performances have been noted in attention deficit hyperactivity disorder (ADHD) patients and reflect neurocognitive dysfunction. Whether these ERP alterations and correlated dysfunctions exist in healthy parents with ADHD offspring is worth exploring. METHODS: Thirteen healthy parents with ADHD offspring and thirteen healthy controls matched for age, sex and years of education were recruited. The auditory oddball paradigm was used to evaluate the P300 wave complex of the ERP, and the Wechsler Adult Intelligence Scale-Revised, Wisconsin Card Sorting Test, and continuous performance test were used to measure neurocognitive performance. RESULTS: Healthy parents with ADHD offspring had significantly longer auditory P300 latency at Fz than control group. However, no significant differences were found in cognitive performance. CONCLUSION: The presence of a subtle alteration in electro-neurophysiological activity without explicit neurocognitive dysfunction suggests potential candidate of biological marker for parents with ADHD offspring.

The association between plasma cholesterol and the effect of tryptophan depletion on heart rate variability.

Studies on the cholesterol-serotonin hypothesis and its link to mood disorders are scarce. In addition, little is known about the association between cholesterol and the effects of tryptophan depletion (TD). The aim of the present study was to investigate the association between plasma cholesterol and changes in heart rate variability (HRV), an important marker of depression and anxiety, after TD. The plasma cholesterol levels of 28 healthy participants were noted, and their HRVs were measured by spectrum analysis. TD was carried out on testing day, and participants provided blood samples just before and 5 hours for tryptophan level after TD. HRV was measured again after TD. An association was found between plasma cholesterol levels and the change in HRV. Decreased high frequency HRV was marginally associated with lower levels of high-density lipoprotein cholesterol, while increased low frequency HRV was significantly associated with lower levels of total and low-density lipoprotein cholesterol. Our findings indicate that low cholesterol levels may play parts of role in the mechanism of the deactivation of parasympathetic, and activation of sympathetic, functions induced by altered serotonergic function.

Orbitofrontal dysfunction during the reward process in adults with ADHD: An fMRI study.

OBJECTIVE: The present study aimed to detect differences in the reward response between adults with attention deficit hyperactivity disorder (ADHD) and healthy controls (HCs) using functional magnetic resonance imaging (fMRI). METHODS: The Iowa gambling task (IGT) was designed to explore participants' reward-related decision-making in relation to selections during risky behaviors. Twenty adults with ADHD and 20 HCs were enrolled. fMRI with a modified IGT was performed. RESULTS: The adults with ADHD showed a poorer performance in terms of avoidance during risky behaviors. The fMRI results indicated that the adults with ADHD had significantly lower orbitofrontal cortex (OFC) activation. A positive correlation between performance in the IGT and brain activation in the OFC was detected. CONCLUSIONS: The results suggested that the adults with ADHD exhibited abnormal OFC responses during decision-making. SIGNIFICANCE: To the best of our knowledge, this is the first study to use fMRI to collect brain activation data while performing the IGT in adults with ADHD. Our findings suggest that deficits in reward processing in ADHD are still present during adulthood.

The OXTR Polymorphism Stratified the Correlation of Oxytocin and Glucose Homeostasis in Non-Diabetic Subjects.

OBJECTIVE: Previous animal studies have shown that the oxytocin system might affect glucose homeostasis through the hypothalamus-pituitary-adrenal (HPA) axis and peripheral organs. Moreover, whether the effect is stratified by the polymorphism of oxytocin receptor gene (OXTR) remains unclear. METHODS: In this study, we recruited 89 non-diabetic participants. Their plasma oxytocin and serum insulin profiles were obtained, and the polymorphism of OXTR rs53576 was genotyped. RESULTS: There were significant correlations between the oxytocin level and fasting glucose level (r = -0.29, P <0.01), insulin level (r = -0.26, P = 0.01), and homeostasis model assessment-estimated insulin resistance (HOMA-IR) (r = -0.25, P = 0.01), when adjusted for age, gender, and body mass index (BMI). When further considering the stratification effects of OXTR variation, we found that the oxytocin level was significantly correlated with the fasting glucose level (r = -0.25, P = 0.04), insulin level (r = -0.35, P = 0.03), and HOMA-IR (r = -0.35, P < 0.01) in subjects with the OXTR A allele (n = 75) after adjustment for age, gender, and BMI. In addition, the oxytocin level in those with the GG genotype of OXTR was significantly negatively correlated with the leptin level (n = 14, r = -0.66, P = 0.02). CONCLUSION: The results demonstrated that the polymorphism of OXTR plays an important role in individual differences in the correlation of oxytocin and glucose homeostasis in non-diabetic subjects.

Availability of Striatal Dopamine Transporter in Healthy Individuals With and Without a Family History of ADHD.

OBJECTIVE: ADHD is the most prevalent neurodevelopmental disorder. It is highly heritable and multifactorial, but the definitive causes remain unknown. Abnormal dopamine transporter (DAT) availability has been reported, but the data are inconsistent. The aim of this study was to examine whether DAT availability differs between healthy parents with and without ADHD offspring. METHOD: Eleven healthy parents with ADHD offspring and 11 age- and sex-matched healthy controls without ADHD offspring were recruited. The availability of DAT was approximated using single-photon emission computed tomography, with [99mTc] TRODAT-1 as the ligand. RESULTS: DAT availability in the basal ganglia, caudate nucleus, and putamen was significantly lower in the parents with ADHD offspring than in the healthy controls without ADHD offspring. CONCLUSION: The results suggest that ADHD could be heritable via abnormal DAT activities.

Heart Rate Variability is Associated with Memory in Females.

Research into the association between heart rate variability (HRV) and cognitive function is scarce, particularly with regard to gender differences. HRV in 182 healthy volunteers was assessed by the root mean square of the successive difference (RMSSD) and spectrum analysis, while the Wechsler Memory Scale-Revised (WMS-R) was used to determine memory function. Robust and significant associations were found to exist between HRV (RMSSD and high-frequency HRV) and domains of the WMS-R in females. Caution should therefore be taken to control for gender when conducting studies on the relationships between HRV and cognitive variables.

Higher mortality and years of potential life lost of suicide in patients with schizophrenia.

Patients with schizophrenia could have a higher risk of mortality. We compared the risk of mortality and the years of potential life lost (YPLL) associated with various causes of death between patients with schizophrenia and the general population. A total of 4,298 patients with schizophrenia were included. The cohort was linked to the Taiwan Death Register between 1998 and 2010 using personal identification numbers, which showed 367 patients with schizophrenia had died by the end of 2010. The standard mortality ratios (SMRs) and YPLL were analyzed by age, sex and cause of death. The overall SMR was significantly higher in patients with schizophrenia. Suicide had the most significantly greater SMR, and the SMRs for physical illnesses, accidents and injuries were all significantly greater in patients with schizophrenia. Suicide had the largest YPLL/deaths among all causes of mortality in patients with schizophrenia. Suicide had the most significantly greater risk of mortality among patients with schizophrenia as compared with the general population. Patients with schizophrenia are highly vulnerable in terms of increased mortality and require special attention.

Prefrontal cortex modulates the correlations between brain-derived neurotrophic factor level, serotonin, and the autonomic nervous system.

Top-down regulation in the human brain and anatomical connections between the prefrontal cortex (PFC) and specific catecholamine-related regions have been well-studied. However, the way in which the PFC modulates downstream neuro-networks in terms of serotonin and the autonomic nervous system (ANS) by variation in the level of brain-derived neurotrophic factor (BDNF) is still unclear. We recruited sixty-seven healthy subjects. Serotonin transporter (SERT) availability was examined by SPECT with [123I]ADAM analysis; heart rate variability (HRV) testing was performed, and the BDNF level was measured. The Wisconsin card-sorting test (WCST), which assesses PFC activation, was also conducted. The interactions of BDNF level and SERT availability were significant in relation to the HRV indexes of low frequency, high frequency, total power, and mean heart rate range. Moderate to significant positive correlations between SERT availability and the above-mentioned HRV indexes existed only in subjects with a low BDNF level. Furthermore, in the low BDNF level group, only those with high WCST perseveration errors or low category completions exhibited significant positive correlations between SERT availability and HRV indexes. A lower BDNF level and poorer PFC function might modulate the synergistic effects of serotonergic and ANS systems in order to maintain brain physiological and psychological homeostasis.

Availability of dopamine transporters and auditory P300 abnormalities in adults with attention-deficit hyperactivity disorder: preliminary results.

OBJECTIVE: Previous studies have indicated that there is dopamine transporter (DAT) dysregulation and P300 abnormality in adults with attention-deficit hyperactivity disorder (ADHD); however, the correlations among the three have not been fully explored. METHODS: A total of 11 adults (9 males and 2 females) with ADHD and 11 age-, sex-, and education-level-matched controls were recruited. We explored differences in DAT availability using single-photon emission computed tomography and P300 wave of event-related potentials between the two groups. The correlation between DAT availability and P300 performance was also examined. RESULTS: DAT availability in the basal ganglia, caudate nucleus, and putamen was significantly lower in the ADHD group. Adults with ADHD had lower auditory P300 amplitudes at the Pz and Cz sites, as well as longer Fz latency than controls. DAT availability was negatively correlated to P300 latency at Pz and Fz. CONCLUSIONS: Adults with ADHD had both abnormal DAT availability and P300 amplitude, suggesting that ADHD is linked to dysfunction of the central dopaminergic system and poor cognitive processes related to response selection and execution.

Unaltered Dopamine Transporter Availability in Drug-Naive Patients With Schizophrenia After 6 Months of Antipsychotics Treatment: A Naturalistic Study.

BACKGROUND: Dopaminergic dysfunction, namely, dopamine transporter (DAT) availability variations in patients with drug-naive schizophrenia after long-term treatment, is still not well understood. The aims of the study were to explore (i) whether the DAT availability in patients with drug-naive schizophrenia differed after antipsychotic treatment and (ii) whether treatment with different generations of antipsychotics influenced the DAT availability after follow-up for 6 months. METHODS: Twenty-four first-episode, drug-naive patients with schizophrenia were divided into first- and second-generation antipsychotic groups naturalistically. After 6 months of follow-up, 7 patients who received first-generation antipsychotic treatment and 17 patients who received second-generation antipsychotic treatment completed the study. The patients underwent premedication and 6-month follow-up measurements using single-photon emission computed tomography with technetium Tc 99m (Tc) TRODAT-1. Psychopathological evaluations and adverse effects were recorded using appropriate scales. RESULTS: Both of the treatment groups significantly improved according to Positive and Negative Symptoms Scale evaluation. However, no significant difference was noticed between the premedication and 6-month follow-up DAT scans. Nonsignificant differences existed even in the groups of different generations of antipsychotics. CONCLUSIONS: Improvements in psychotic symptoms in patients with schizophrenia may not be influenced by DAT availability, even under treatment with different antipsychotics for a sufficient treatment period.

Poor performance of fine motor activity among biological parents of children with attention deficit/hyperactivity disorder.

It has been proposed that the dopaminergic system and heritability may play roles in attention deficit/hyperactivity disorder (ADHD). We assessed the performance of healthy parents of children with ADHD in the finger tapping test (FTT) in this study, which is a reliable test and sensitive to central dopamine activity. A total of 16 parents of children with ADHD and 32 controls were enrolled. The FTT was conducted. The 16 healthy parents of children with ADHD exhibited a significantly poorer performance in the FTT, using the nondominant hand, than the 32 healthy controls. This finding indicated that poor motor function could be a potential characteristic in parents of offspring with ADHD.

The correlation between perceived social support, cortisol and brain derived neurotrophic factor levels in healthy women.

In this study, the role of brain derived neurotrophic factor (BDNF) in stress resilience was investigated. With a focus on healthy subjects, we explored whether plasma BDNF levels are correlated with the dexamethasone suppression test (DST) and subjectively perceived social support status. Moreover, we examined the possible interacting effect of DST status and perceived social support on BDNF levels. Seventy-two healthy volunteers, 44 females and 28 males, were recruited from the community and completed the perceived routine support subscale of Measurement of Support Function (PRS_MSF) questionnaire. Plasma BDNF levels and DST suppression rate with the low dose DST were measured. There was a significant positive correlation between BDNF and DST suppression rate in the female subjects. This was also true for the plasma BDNF levels and PRS_MSF in the female subjects. The positive correlation between BDNF and PRS_MSF was significant only in female subjects with low DST suppression rates. Plasma BDNF levels were associated with stress resilience in a sex-specific manner. Subjects' belief in social support might buffer the biological stress reactions. Differences in social perception and the biological stress response between men and women merits further investigation.