Human transcriptome array analysis and diffusion tensor imaging in attention-deficit/hyperactivity disorder.

The mRNA markers identified using microarray assay and diffusion tensor magnetic resonance imaging (DTI) were applied to elucidate the pathophysiology of attention-deficit hyperactivity disorder (ADHD). First, we obtained total RNA from leukocytes from three children with ADHD and three healthy controls for analysis with microarray assays. Subsequently, we applied real-time quantitative polymerase chain reaction (qRT‒PCR) assays to validate the differential expression of 7 genes (COX7B, CYCS, TFAM, UTP14A, ZNF280C, IFT57 and NDUFB5) between 130 ADHD patients and 70 controls, and we built an ADHD prediction model based on the ΔCt values of aforementioned seven genes (AUROC = 0.98). Finally, in a validation group (28 patients with ADHD and 27 healthy controls), mRNA expression of the above seven genes also significantly differentiated ADHD patients from controls (AUROC value = 0.91). The DTI analysis showed increased fractional anisotropy (FA) of the forceps minor, superior corona radiata, posterior corona radiata and anterior corona radiata in ADHD patients. Moreover, the FA of the right superior corona radiata tract was positively correlated with ΔCt levels of the COX7B gene and the IFT57 gene. The results shed a new light on a genetic profile of ADHD that may help in deciphering the white matter microstructural features in disease pathogenesis.

Correlation of potential diagnostic biomarkers (circulating miRNA and protein) of bipolar II disorder.

OBJECTIVES: We previously identified certain peripheral biomarkers of bipolar II disorder (BD-II) including circulating miRNAs (miR-7-5p, miR-142-3p, miR-221-5p, and miR-370-3p) and proteins (Matrix metallopeptidase 9 (MMP9), phenylalanyl-tRNA synthetase subunit beta (FARSB), peroxiredoxin 2 (PRDX2), carbonic anhydrase 1 (CA-1), and proprotein convertase subtilisin/kexin type 9 (PCSK9)). We try to explore the connection between these biomarkers. METHODS: We explored correlations between the peripheral levels of above circulating miRNAs and proteins in our previously collected BD-II (N = 96) patients and control (N = 115) groups. We further searched TargetScan and BioGrid websites to identify direct and indirect interactions between these protein-coding genes and circulating miRNAs. RESULTS: In the BD-II group, we identified significant correlations between the miR-221-5p and CA-1 (rho = -0.323, P = 0.001), FARSB (rho = 0.251, P = 0.014), MMP-9 (rho = 0.313, P = 0.002) and PCSK9 (rho = 0.252, P = 0.014). The miR-370-3p also significantly correlated with FARSB expression (rho = 0.330, P = 0.001) and PCSK9 expression (rho = 0.221, P = 0.031) in the BD-II group. Our findings were in line with the modulating axis identified from TargetScan and BioGrid, miR-221-5p/CA-1/MMP9 and miR-370-3p/FARSB/PCSK9, suggesting their association with BD-II. CONCLUSION: Our result supported that peripheral candidate miRNA and protein biomarkers may interact in BD-II. We concluded that miR-221-5p/CA-1/MMP9 and miR-370-3p/FARSB/PCSK9 axes might act a critical role in the pathomechanism of BD-II.

Neural Network Dynamics and Brain Oscillations Underlying Aberrant Inhibitory Control in Internet Addiction.

Previous studies have reported a role of alterations in the brain's inhibitory control mechanism in addiction. Mounting evidence from neuroimaging studies indicates that its key components can be evaluated with brain oscillations and connectivity during inhibitory control. In this study, we developed an internet-related stop-signal task with electroencephalography (EEG) signal recorded to investigate inhibitory control. Healthy controls and participants with Internet addiction were recruited to participate in the internet-related stop-signal task with 19-channel EEG signal recording, and the corresponding event-related potentials and spectral perturbations were analyzed. Brain effective connections were also evaluated using direct directed transfer function. The results showed that, relative to the healthy controls, participants with Internet addiction had increased Stop-P3 during inhibitory control, suggesting that they have an altered neural mechanism in impulsive control. Furthermore, participants with Internet addiction showed increased low-frequency synchronization and decreased alpha and beta desynchronization in the middle and right frontal regions compared to healthy controls. Aberrant brain effective connectivity was also observed, with increased occipital-parietal and intra-occipital connections, as well as decreased frontal-paracentral connection in participants with Internet addiction. These results suggest that physiological signals are essential in future implementations of cognitive assessment of Internet addiction to further investigate the underlying mechanisms and effective biomarkers.

Medical outcomes of children with neurodevelopmental disorders after SARS-CoV-2 vaccination: A six-month follow-up study.

INTRODUCTION: The BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) vaccines have been approved for children and adolescents for protecting against SARS-CoV-2 infection. This longitudinal study aimed to compare adverse outcomes after SARS-CoV-2 vaccination in children with neurodevelopmental disorders (ND) (e.g., attention-deficit/hyperactivity disorder [ADHD], autism spectrum disorder [ASD], communication disorders, intellectual disability, and tic disorders) and healthy control children. METHODS: A total of 1335 children who received the SARS-CoV-2 vaccination (762 children with ND and 573 healthy controls) were recruited. All subjects were followed-up for 180 days, and outcome events were defined as outpatient department (OPD) or emergency department (ER) visits during follow-up. Multivariate Cox proportional hazards regression models were used to identify the potential differences in outcomes between the propensity score-matched ND group (n = 311) and the control group (n = 311), and to explore the factors associated with outcomes among all children with ND (n = 762). RESULTS: Compared with the control group, children with ND exhibited a higher likelihood of subsequent OPD or ER visits and paediatric neurology OPD visits after the first dose of vaccination. However, we found that only a small proportion of the children visited the OPD or ER because of adverse vaccination-related effects. Among all children with ND, those with communication disorders showed a higher likelihood of any OPD or ER visit. Paediatric neurology OPD visits were associated with communication disorders, intellectual disability, and methylphenidate and aripiprazole prescriptions. ADHD and ASD were not associated with adverse outcomes. CONCLUSIONS: No specific ND diagnosis or medication use clearly increased the risk of adverse effects of SARS-CoV-2 vaccination. Children with ND can be reassured that the SARS-CoV-2 vaccination is a safe regimen to protect themselves.

Gut mycobiome dysbiosis and its impact on intestinal permeability in attention-deficit/hyperactivity disorder.

BACKGROUND: Dysbiosis in the gut microbial community might be involved in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). The fungal component of the gut microbiome, namely the mycobiota, is a hyperdiverse group of multicellular eukaryotes that can influence host intestinal permeability. This study therefore aimed to investigate the impact of fungal mycobiome dysbiosis and intestinal permeability on ADHD. METHODS: Faecal samples were collected from 35 children with ADHD and from 35 healthy controls. Total DNA was extracted from the faecal samples and the internal transcribed spacer regions were sequenced using high-throughput next-generation sequencing (NGS). The fungal taxonomic classification was analysed using bioinformatics tools and the differentially expressed fungal species between the ADHD and healthy control groups were identified. An in vitro permeability assay (Caco-2 cell layer) was used to evaluate the biological effects of fungal dysbiosis on intestinal epithelial barrier function. RESULTS: The ß-diversity (the species diversity between two communities), but not α-diversity (the species diversity within a community), reflected the differences in fungal community composition between ADHD and control groups. At the phylum level, the ADHD group displayed a significantly higher abundance of Ascomycota and a significantly lower abundance of Basidiomycota than the healthy control group. At the genus level, the abundance of Candida (especially Candida albicans) was significantly increased in ADHD patients compared to the healthy controls. In addition, the in vitro cell assay revealed that C. albicans secretions significantly enhanced the permeability of Caco-2 cells. CONCLUSIONS: The current study is the first to explore altered gut mycobiome dysbiosis using the NGS platform in ADHD. The findings from this study indicated that dysbiosis of the fungal mycobiome and intestinal permeability might be associated with susceptibility to ADHD.

Gut Leakage Markers and Cognitive Functions in Patients with Attention-Deficit/Hyperactivity Disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a commonly seen mental disorder in children. Intestinal permeability may be associated with the pathogenesis of ADHD. The study herein investigated the role of gut leakage biomarkers in the susceptibility of ADHD. A total of 130 children with ADHD and 73 healthy controls (HC) individuals were recruited. Serum concentrations of zonulin, occludin, and defensin (DEFA1) were determined. Visual attention was assessed with Conners' continuous performance test (CPT). In order to rate participants' ADHD core symptoms at home and school, their parents and teachers completed the Swanson, Nolan, and Pelham-Version IV Scale (SNAP-IV), respectively. We found significantly lower DEFA1 levels in the ADHD group compared to that in the HC group (p = 0.008), but not serum levels of zonulin and occludin. The serum levels of DEFA1 showed an inverse correlation with the inattention scores in the SNAP-IV parent form (p = 0.042) and teacher form (p = 0.010), and the hyperactivity/impulsivity scores in the SNAP-IV teacher form (p = 0.014). The serum levels of occludin showed a positive correlation with the subtest of detectability in the CPT (p = 0.020). Our study provides new reference into the relation between gut leakage markers and cognition, which may advance research of the pathophysiology of ADHD.

Effects of comorbid alcohol use disorder on bipolar disorder: Focusing on neurocognitive function and inflammatory markers.

BACKGROUND: Alcohol use disorder (AUD) is a highly prevalent comorbid disorder in patients with bipolar disorder (BD). Both BD and AUD were found to be associated with inflammation and cognitive deficits, but few study has been done on BD comorbid with AUD (BD+AUD). We aimed to investigate the impacts of comorbid AUD and BD on cognitive function, inflammatory and neurotrophic markers. METHOD: We recruited 641 BD patients, 150 patients with BD+AUD, and 185 healthy controls (HC). Neuropsychological tests [Wisconsin card sorting test (WCST), continuous performance test (CPT), and Wechsler memory scale - third edition (WMS-III)] and cytokine plasma levels [tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin-8 (IL-8), transforming growth factor-ß1 (TGF-ß1), and brain-derived neurotrophic factor (BDNF)] were assessed. RESULTS: BD+AUD patients had worse cognitive performance than those without AUD. There was a significant difference in the plasma levels of TNF-α, IL-8, and BDNF (P < 0.001, <0.001, and 0.01, respectively) between the patients and the HC groups. Post hoc analysis showed that BD+AUD patients had higher levels of TNF-α and IL-8 than BD-only patients (P < 0.001). Additionally, plasma IL-8 levels were negatively associated with number of completed categories in WCST (P = 0.02), and TNF-α levels were negatively associated with visual immediate index in WMS-III (P = 0.05). CONCLUSION: Our results suggest that comorbid AUD and BD might worsen cognitive impairments and inflammatory processes. Further longitudinal studies on BD+AUD may be needed.

Association Between Inflammatory Cytokines, Executive Function, and Substance Use in Patients With Opioid Use Disorder and Amphetamine-Type Stimulants Use Disorder.

BACKGROUND: Long-term opioid and amphetamine-type stimulants (ATS) abuse may affect immunological function and impair executive function. We aimed to determine whether biomarkers of inflammation and executive function were associated with substance use in individuals with opioid use disorder (OUD) and ATS use disorder (ATSUD). The interactions between these biomarkers were also explored. METHODS: We assessed plasma cytokines [tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-8, IL-6, transforming growth factor (TGF)-ß1, brain-derived neurotrophic factor (BDNF), and executive function in terms of the Wisconsin Card Sorting Test (WCST) and Continuous Performance Test (CPT) in OUD and ATSUD patients and healthy controls (HC). OUD and ATSUD patients were followed for 12 weeks, and their urine morphine and amphetamine tests, cytokine levels, and executive function were repeatedly measured. RESULTS: We enrolled 483 patients and 145 HC. Plasma TNF-α, CRP, IL-8, IL-6, and BDNF levels and most subscale scores on the WCST and CPT significantly differed between OUD and ATSUD patients and HC. Increased TNF-α levels and more perseveration error on the WCST were significantly associated with more urine drug-positive results and less abstinence. Plasma IL-6 and CRP levels were significantly negatively correlated with WCST and CPT performance. CONCLUSION: OUD and ATSUD patients had more inflammation and worse executive function than HC. Inflammatory markers and WCST performance were associated with their urinary drug results, and higher inflammation was associated with poor executive function. Studies on regulating the inflammatory process and enhancing executive function in OUD and ATSUD are warranted.

Interrelationships among growth hormone, thyroid function, and endocrine-disrupting chemicals on the susceptibility to attention-deficit/hyperactivity disorder.

Abnormal growth hormones and thyroid function may be linked to pathophysiology of attention-deficit/hyperactivity disorder (ADHD). Phthalates and bisphenol-A (BPA), two endocrine-disrupting chemicals (EDCs), may affect the human endocrine system. In this study, we aimed to perform a comprehensive investigation of whether growth hormone, thyroid function, and EDCs exhibited differential levels between ADHD patients and healthy controls. In total, 144 children with ADHD and 70 healthy control subjects were enrolled. Their endocrine systems were evaluated using the serum levels of insulin-like growth factor-1 (IGF-1), IGF-binding protein-3 (IGFBP-3), thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and Free T4. The urinary levels of EDCs, including monoethyl phthalate (MEP), mono-methyl phthalate (MMP), monoethylhexyl phthalate (MEHP), mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), and BPA, were also examined. Patients with ADHD had lower IGF-1 levels than healthy controls (p = 0.003), but we observed no significant difference in IGFBP-3, TSH, T3, T4, or Free T4. Compared to the control group, patients with ADHD demonstrated higher MEHP levels (p = 0.043), MnBP (p = 0.033), and MBzP (p = 0.040). Furthermore, MEHP levels (p < 0.001) and BPA levels (p = 0.041) were negatively correlated with IGF-1 levels, while IGF-1 levels were negatively correlated with principal components consisting of ADHD clinical symptoms and neuropsychological performance variables. We suggest that MEHP exposure may be associated with decreased serum levels of IGF-1 and increased risk of ADHD. The mechanism underlying this association may be important for protecting children from environmental chemicals that adversely affect neurodevelopment.

Cytokine Levels and Neuropsychological Function among Patients with Attention-Deficit/Hyperactivity Disorder and Atopic Diseases.

Since atopic disease and inflammatory cytokines are both involved in attention deficit hyperactivity disorder (ADHD), in this study, we examined the relationship among cytokine levels, neuropsychological function, and behavioral manifestations in patients with ADHD and atopic diseases. Participants were categorized into individuals with ADHD and atopic disease (n = 41), those with ADHD without allergy (n = 74), individuals without ADHD but with allergy (n = 23), and those without ADHD or allergy (n = 49). We used the Swanson, Nolan, and Pelham IV Scale (SNAP-IV), Conners' Continuous Performance Test (Conners CPT), and Conners' Continuous Auditory Test of Attention (CATA) to assess patients' behavioral symptoms, visual attention, and auditory attention, respectively. Participants' IFN-γ, IL-1B, IL-6, IL-10, IL-13, IL-17, MCP-1, and TNF-α plasma levels were assessed using multiplex assays. We found that the prevalence rates of atopic diseases (asthma, allergic rhinitis, or atopic dermatitis) were similar between individuals with ADHD and those without ADHD. ADHD behavioral symptoms (SNAP-IV), CPT omission scores, and CATA detectability scores demonstrated significant differences between individuals with ADHD and those without ADHD, regardless of atopic diseases. However, plasma levels of cytokines (TNF-α, IFN-γ, and IL-17) were negatively correlated with inattention symptoms. This study demonstrates a potential relationship between cytokine levels and neuropsychological function among patients with ADHD and atopic diseases.

Validation of the Chinese Version of the Schizophrenia Cognition Rating Scale.

OBJECTIVE: The Schizophrenia Cognition Rating Scale (SCoRS) is an interview-based assessment tool for evaluating the cognitive deficit and daily functioning of patients with schizophrenia. METHODS: Sixty-eight patients with schizophrenia and 68 age- and sex-matched healthy individuals were recruited to validate the Chinese version of SCoRS in this study. All participants underwent cognitive assessment using the SCoRS, which was verified by the Brief Assessment of Cognition in Schizophrenia (BACS), and the UCSD Performance-based Skills Assessment, Brief Version (UPSA-B). Patients with schizophrenia were additionally assessed using the Positive and Negative Syndrome Scale (PANSS). RESULTS: SCoRS ratings reported by patients (SCoRS-S), those reported by the interviewer (SCoRS-I), and SCoRS global scores (SCoRS-G) showed significant correlation with all subscales of the BACS and the UPSA-B. On receiver operating characteristic curve analysis, SCoRS-S, SCoRS-I, and SCoRS-G significantly differentiated patients with schizophrenia from healthy controls. Moreover, SCoRS-S and SCoRS-I ratings showed positive correlation with the negative symptoms and general symptoms of PANSS. CONCLUSION: The Chinese version of SCoRS showed good discriminant, concurrent, and external validity, suggesting that it is a useful and convenient tool for assessment of cognitive function among Mandarin-speaking patients with schizophrenia in clinical practice.

The comparative effectiveness of antidepressants for youths with major depressive disorder: a nationwide population-based study in Taiwan.

Background: Guidelines recommend fluoxetine as a first-line medication for youths diagnosed with major depressive disorder (MDD). However, little is known about the long-term effectiveness of different antidepressants in juveniles in the real world. This study aimed to compare the effectiveness of antidepressants in youths with MDD. Methods: Youths (<20 years old) with a diagnosis of MDD who were new users of antidepressants were selected from a nationwide population-based cohort in Taiwan between 1997 and 2013. We divided a total of 16,981 users (39.9% male; mean age: 16.6 years) into 10 different antidepressant groups (fluoxetine, sertraline, paroxetine, venlafaxine, citalopram, escitalopram, bupropion, fluvoxamine, mirtazapine and moclobemide). Regarding treatment outcomes (hospitalisation and medication discontinuation), Cox proportional hazards regression models were applied to estimate the hazards of such outcomes. Results: Compared with the youths treated with fluoxetine, the bupropion-treated group demonstrated lower rates of hospitalisation and discontinuation. Mirtazapine-treated group demonstrated a higher hospitalisation risk mainly when administered for single depressive episodes. Furthermore, patients treated with sertraline and fluvoxamine had higher discontinuation rates. Among the younger teenage subgroups (< 16 years), significantly higher rates of discontinuation were observed in those treated with sertraline, escitalopram and fluvoxamine. Among the older teenage subgroups (⩾ 16 years), bupropion was superior to fluoxetine in preventing hospitalisation and discontinuation. Conclusion: We concluded that bupropion might surpass fluoxetine with regard to hospitalisation prevention and drug therapy maintenance among youths with MDD, while mirtazapine users demonstrated a higher hospitalisation risk. Our findings might serve as a reference for clinicians in future studies.

Growth Hormone and Thyroid Function in Children With Attention Deficit Hyperactivity Disorder Undergoing Drug Therapy.

CONTEXT: The trends in hormone indices of children with attention deficit hyperactivity disorder (ADHD) who received long-term medication treatment remains controversial. OBJECTIVE: This prospective study aimed to examine the changes in the growth hormone and thyroid hormone systems among children with ADHD undergoing various medication treatments. METHODS: In total, 118 children who were diagnosed with ADHD and were drug-naive were observed naturalistically over 12 months. Of them, 22 did not receive any medication, while 39, 40, and 17 were treated with low doses of short-acting methylphenidate (MPH) (14 ±â€…6.7 mg/day), osmotic-release oral system (OROS) long-acting MPH (32 ±â€…9.6 mg/day), and atomoxetine (29.2 ±â€…9.7 mg/day), respectively. Blood samples were obtained at both the baseline and the endpoint (month 12) to measure serum levels of insulin-like growth factor 1 (IGF-1), IGF binding protein 3 (IGFBP-3), prolactin, thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and free T4. RESULTS: Trends for IGF-1, IGFBP-3, prolactin, TSH, T3, T4, and free T4 levels were similar among the 4 groups. Changes in serum levels of IGF-1 were positively correlated with changes in height and weight of all the children with ADHD. However, patients who received MPH treatment had less body weight gain than the nonmedicated group. The ratio of MPH doses to body weight was inversely correlated with the increment in height. CONCLUSION: There were no changes in thyroid or growth hormones associated with the low doses of ADHD medications used in this study within 1 year's duration. Nonetheless, patients' growth and the appropriateness of drug dosage should be closely monitored.

Effect of Bifidobacterium bifidum on Clinical Characteristics and Gut Microbiota in Attention-Deficit/Hyperactivity Disorder.

This study aimed to examine whether probiotics supplements using Bifidobacterium bifidum (Bf-688) can improve clinical characteristics and gut microbiomes among patients with attention-deficit/hyperactivity disorder (ADHD). This open-label, single-arm trial consisted of 30 children aged 4-16 years who met the criteria for ADHD diagnosis. Each subject took Bf-688, with one sachet in the morning and one in the evening (daily bacteria count 5 × 109 CFUs), for 8 weeks. Patients' clinical symptoms were assessed using the Swanson, Nolan, and Pelham Rating Scale (SNAP-IV). We collected stool samples at the baseline, the 8th week, and the 12th week for gut microbiota examination. During the 8-week Bf-688 supplement period, patients' inattention symptoms and hyperactivity/impulsive symptoms improved, and their weights and BMIs increased. For gut microbiota, the Firmicutes to Bacteroidetes ratio (F/B ratio) decreased significantly. LEfSe analysis revealed that Firmicutes significantly decreased while Proteobacteria significantly increased during the 8-week treatment period. After Bf-688 was discontinued for 4 weeks (12 weeks from baseline), Bacteroidota significantly decreased and Shigella significantly increased. The probiotic Bf-688 supplement was associated with an improvement of clinical symptoms and with weight gain among ADHD children. Furthermore, gut microbiota composition was significantly altered by the Bf-688 supplement. A future randomized control trial is warranted to verify these findings.

Gut microbiota and plasma cytokine levels in patients with attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood mental disorder with undetermined pathophysiological mechanisms. The gut microbiota and immunological dysfunction may influence brain functions and social behaviours. In the current study, we aimed to explore the correlation of gut microbiome imbalance and inflammation in the pathophysiology of ADHD. Forty-one children with ADHD and thirty-nine healthy-control (HC) individuals were recruited. Faecal samples from all participants were collected and submitted for 16 S rRNA V3-V4 amplicon microbiome sequencing analysis. The plasma levels of 10 cytokines, including TNF-α, IL-6, IL-1ß, IL-2, IL-10, IL-13, IL-17A, IFN-α2, IFN-γ, and MCP-1, were determined using a custom-made sandwich enzyme-linked immunosorbent assay (ELISA) developed by Luminex Flowmetrix. There was no significant difference between the ADHD and HC groups in species diversity in the faeces, as determined with α-diversity and ß-diversity analysis. In the ADHD group, three differentially abundant taxonomic clades at the genus level were observed, namely Agathobacter, Anaerostipes, and Lachnospiraceae. Top differentially abundant bacteria and representative biological pathways were identified in children with ADHD using linear discriminant analysis (LDA) effect size (LEfSe), and the phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) analysis, respectively. The plasma levels of TNF-α were significantly lower in children with ADHD than in HCs. Within the ADHD group, the levels of TNF-α were negatively correlated with ADHD symptoms and diversity of the gut microbiome. Our study provides new insights into the association between gut microbiome dysbiosis and immune dysregulation, which may contribute to the pathophysiology of ADHD.

MicroRNAs serve as prediction and treatment-response biomarkers of attention-deficit/hyperactivity disorder and promote the differentiation of neuronal cells by repressing the apoptosis pathway.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder. This study aimed to examine whether miRNA expression abundance in total white blood cells (WBCs) facilitated the identification of ADHD and reflected its response to treatment. Furthermore, whether miRNA markers facilitated the growth of the human cortical neuronal (HCN-2) cells was also investigated. Total WBC samples were collected from 145 patients and 83 controls, followed by RNA extraction and qPCR assays. Subsequently, WBC samples were also collected at the endpoint from ADHD patients who had undergone 12 months of methylphenidate treatment. The determined ΔCt values of 12 miRNAs were applied to develop an ADHD prediction model and to estimate the correlation with treatment response. The prediction model applying the ΔCt values of 12 examined miRNAs (using machine learning algorithm) demonstrated good validity in discriminating ADHD patients from controls (sensitivity: 96%; specificity: 94.2%). Among the 92 ADHD patients completing the 12-month follow-up, miR-140-3p, miR-27a-3p, miR-486-5p, and miR-151-5p showed differential trends of ΔCt values between treatment responders and non-responders. In addition, the in vitro cell model revealed that miR-140-3p and miR-126-5p promoted the differentiation of HCN-2 cells by enhancing the length of neurons and the number of junctions. Microarray and flow cytometry assays confirmed that this promotion was achieved by repressing apoptosis and/or necrosis. The findings of this study suggest that the expression levels of miRNAs have the potential to serve as both diagnostic and therapeutic biomarkers for ADHD. The possible biological mechanisms of these biomarker miRNAs in ADHD pathophysiology were also clarified.

Plasma BDNF and Cytokines Correlated with Protein Biomarkers for Bipolar II Disorder.

We have previously identified five candidate proteins (matrix metallopeptidase 9 (MMP9), phenylalanyl-TRNA synthetase subunit beta (FARSB), peroxiredoxin 2 (PRDX2), carbonic anhydrase 1 (CA-1), and proprotein convertase subtilisin/kexin Type 9 (PCSK9)) as potential biomarkers for bipolar II disorder (BD-II). These candidate proteins have been associated with neuroprotective factors (BDNF) and inflammatory factors (cytokines, C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α)). However, the correlations between these proteins with plasma BDNF and inflammatory factors remain unknown. We recruited a total of 185 patients with BD-II and 186 healthy controls. Plasma levels of candidate proteins, BDNF, cytokines (TNF-α, CRP, and interleukin-8 (IL-8)) were assessed from each participant. The correlations between levels of candidate proteins, BDNF, and cytokines were analyzed. In the BD-II group, we found that the level of FARSB was positively correlated with the BDNF level (r = 0.397, p < 0.001) and IL-8 (r = 0.320, p < 0.001). The CA-1 level positively correlated with IL-8 (r = 0.318, p < 0.001). In the control group, we found that the FARSB level positively correlated with the BDNF level (r = 0.648, p < 0.001). The CA-1 level positively correlated with TNF-α (r = 0.231, p = 0.002), while the MMP-9 level positively correlated with the CRP level (r = 0.227, p = 0.002). Our results may help in clarifying the underlying mechanism of these candidate proteins for BD-II.

Identification of potential plasma protein biomarkers for bipolar II disorder: a preliminary/exploratory study.

The diagnostic peripheral biomarkers are still lacking for the bipolar II disorder (BD-II). We used isobaric tags for relative and absolute quantification technology to identify five upregulated candidate proteins [matrix metallopeptidase 9 (MMP9), phenylalanyl-tRNA synthetase subunit beta (FARSB), peroxiredoxin 2 (PRDX2), carbonic anhydrase 1 (CA-1), and proprotein convertase subtilisin/kexin type 9 (PCSK9)] for the diagnosis of BD-II. We analysed the differences in the plasma levels of these candidate proteins between BD-II patients and controls (BD-II, n = 185; Controls, n = 186) using ELISA. To establish a diagnostic model for the prediction of BD-II, the participants were divided randomly into a training group (BD-II, n = 149; Controls, n = 150) and a testing group (BD-II, n = 36; Controls, n = 36). Significant increases were found in all five protein levels between BD-II and controls in the training group. Logistic regression was analysed to form the composite probability score of the five proteins in the training group. Receiver-operating characteristic curve analysis revealed the diagnostic validity of the probability score [area under curve (AUC) = 0.89, P < 0.001]. The composite probability score of the testing group also showed good diagnostic validity (AUC = 0.86, P < 0.001). We propose that plasma levels of PRDX2, CA-1, FARSB, MMP9, and PCSK9 may be associated with BD-II as potential biomarkers.

Peripheral BDNF correlated with miRNA in BD-II patients.

OBJECTIVES: We have identified the association between peripheral levels of candidate miRNAs (miR-7-5p, miR-142-3p, miR-221-5p, and miR-370-3p) for BD-II in previous study. Most of these miRNAs are associated with regulation of expression of peripheral brain derived neurotrophic factor (BDNF) levels. In order to clarify the underlying mechanism of BDNF and miRNAs in the pathogenesis of BD-II, it is of interest to investigate the relation between the peripheral levels of miR-7-5p, miR-142-3p, miR-221-5p, miR-370-3p with BDNF levels. Because the BDNF Val66Met polymorphism influence the secretion of BDNF, we further stratified the above correlations by this polymorphism. METHODS: We have recruited 98 BD-II patients. Beside analyzing peripheral levels of miR-7-5p, miR-142-3p, miR-221-5p, miR-370-3p, and BDNF, the genetic distribution of the BDNF Val66Met polymorphism was also analyzed. RESULTS: We found that the miR7-5p, miR221-5p, and miR370-3p significantly correlated with the BDNF levels for all patients. If stratified by the BDNF Val66Met polymorphism, the significant correlation between miR221-5p and miR370-3p with BDNF only remained in the Val/Met genotype. However, the correlation between miR7-5p and BDNF level is significant in all 3 genotypes. CONCLUSION: Our result supported that these miRNAs may be involved in the pathomechanism of BD-II through relation with BDNF.