OBJECTIVE: Until recently, riluzole was the only drug licensed for amyotrophic lateral sclerosis (ALS). In spite of its efficacy, the mechanism of action remains elusive, and both blocking of glutamate release and antioxidant properties have been postulated. Here we characterized human SH-SY5Y neuroblastoma cell lines, taking advantage of their insensitivity to excitotoxic insults, in order to selectively assess the presence of a direct antioxidant effect of riluzole. METHODS: SH-SY5Y cells, either parental or overexpressing the G93A SOD1 mutation, were exposed for 24 hours to the selected stimuli. RESULTS: Riluzole (1–10 μM) was able to counteract the effects of H₂O₂ exposure (200 μM/24 hr), limiting both cell death and whole-cell reactive oxygen species (ROS) increase. The same experiments were repeated using SH-SY5Y cells carrying the familial ALS-related G93A-SOD1 mutation and constitutively expressing two-fold increased whole-cell ROS levels with respect to wild-type cells: riluzole was ineffective in this paradigm. Analogously, riluzole was ineffective in preventing cell death induced by exposing SH-SY5Y cells to 3-morpholino-sydnonimine (SIN-1, 1.5 mM/24 hr), a reactive nitrogen species (RNS) donor. CONCLUSION: Our data support a direct antioxidant action of riluzole. Furthermore, the lack of efficacy of riluzole observed in the SOD1 cell model mirrors the lack of efficacy already demonstrated in cognate mouse models of ALS, plausibly reflecting differences in the underlying pathogenic mechanisms. Finally, riluzole inefficacy against nitrosative stress might support the idea that a combined therapeutic intervention may result more effective in ALS patients, as in the case of co-administration of edaravone, a drug known to reduce RNS.
Amyotrophic Lateral Sclerosis ; Animals ; Antioxidants ; Cell Death ; Cell Line ; Endophenotypes ; Glutamic Acid ; Humans ; Mice ; Neuroblastoma ; Parents ; Reactive Nitrogen Species ; Reactive Oxygen Species ; Riluzole ; Tissue Donors

Neurocognitive deficits are frequently observed in patients with schizophrenia and major depressive disorder (MDD). The relations between cognitive features may be represented by neurocognitive graphs based on cognitive features, modeled as Gaussian Markov random fields. However, it is unclear whether it is possible to differentiate between phenotypic patterns associated with the differential diagnosis of schizophrenia and depression using this neurocognitive graph approach. In this study, we enrolled 215 first-episode patients with schizophrenia (FES), 125 with MDD, and 237 demographically-matched healthy controls (HCs). The cognitive performance of all participants was evaluated using a battery of neurocognitive tests. The graphical LASSO model was trained with a one-vs-one scenario to learn the conditional independent structure of neurocognitive features of each group. Participants in the holdout dataset were classified into different groups with the highest likelihood. A partial correlation matrix was transformed from the graphical model to further explore the neurocognitive graph for each group. The classification approach identified the diagnostic class for individuals with an average accuracy of 73.41% for FES vs HC, 67.07% for MDD vs HC, and 59.48% for FES vs MDD. Both of the neurocognitive graphs for FES and MDD had more connections and higher node centrality than those for HC. The neurocognitive graph for FES was less sparse and had more connections than that for MDD. Thus, neurocognitive graphs based on cognitive features are promising for describing endophenotypes that may discriminate schizophrenia from depression.
Adult ; Algorithms ; Depressive Disorder, Major ; classification ; diagnosis ; Endophenotypes ; analysis ; Female ; Humans ; Machine Learning ; Male ; Markov Chains ; Neuropsychological Tests ; Schizophrenia ; classification ; diagnosis ; Young Adult

Brain disease is one of the greatest threats to public health. Brain theranostics is recently taking shape, indicating the treatments of stroke, inflammatory brain disorders, psychiatric diseases, neurodevelopmental disease, and neurodegenerative disease. However, several factors, such as lack of endophenotype classification, blood-brain barrier (BBB), target determination, ignorance of biodistribution after administration, and complex intercellular communication between brain cells, make brain theranostics application difficult, especially when it comes to clinical application. So, a more thorough understanding of each aspect is needed. In this review, we focus on recent studies regarding the role of exosomes in intercellular communication of brain cells, therapeutic effect of graphene quantum dots, transcriptomics/epitranscriptomics approach for target selection, and in vitro/in vivo considerations.
Blood-Brain Barrier ; Brain Diseases ; Brain ; Classification ; Endophenotypes ; Exosomes ; Graphite ; Neurodegenerative Diseases ; Public Health ; Quantum Dots ; Stroke ; Theranostic Nanomedicine

OBJECTIVES: According to previous studies, the Chromogranin B (CHGB) gene could be an important candidate gene for schizophrenia which is located on chromosome 20p12.3. Some studies have linked the polymorphism in CHGB gene with the risk of schizophrenia. Meanwhile, smooth pursuit eye movement (SPEM) abnormality has been regarded as one of the most consistent endophenotype of schizophrenia. In this study, we investigated the association between the polymorphisms in CHGB gene and SPEM abnormality in Korean patients with schizophrenia. METHODS: We measured SPEM function in 24 Korean patients with schizophrenia (16 male, 8 female) and they were divided according to SPEM function into two groups, good and poor SPEM function groups. We also investigated genotypes of polymorphisms in CHGB gene in each group. A logistic regression analysis was performed to find the association between SPEM abnormality and the number of polymorphism. RESULTS: The natural logarithm value of signal/noise ratio (Ln S/N ratio) of good SPEM function group was 4.19 ± 0.19 and that of poor SPEM function group was 3.17 ± 0.65. In total, 15 single nucleotide polymorphisms of CHGB were identified and the genotypes were divided into C/C, C/R, and R/R. Statistical analysis revealed that two genetic variants (rs16991480, rs76791154) were associated with SPEM abnormality in schizophrenia (p = 0.004). CONCLUSIONS: Despite the limitations including a small number of samples and lack of functional study, our results suggest that genetic variants of CHGB may be associated with SPEM abnormality and provide useful preliminary information for further study.
Chromogranin B* ; Endophenotypes ; Eye Movements* ; Genetic Variation* ; Genotype ; Humans ; Logistic Models ; Male ; Polymorphism, Single Nucleotide ; Pursuit, Smooth* ; Schizophrenia*

OBJECTIVES: This study intended to identify the deficits of cognitive control among patients with bipolar I disorder and their first-degree relatives, and identify the possibility of cognitive control as an endophenotype of bipolar disorder. METHODS: The study included three groups: euthymic states patients with bipolar I disorder (n = 55), unaffected first-degree relatives of probands with bipolar I disorder (n = 30), and a healthy control group (n = 51), that was matched on age, sex, and years of education. The AX version of the continuous performance test (CPT) was used to examine cognitive control. Error rate, correct response times of each subsets (AX, BX, AY, BY), and d' as an indication of accuracy sensitivity index were calculated. Psychopathology, intelligence, and psychomotor speed were also assessed. RESULTS: Patients with bipolar I disorder showed significantly worse error rates in the AX (p = 0.01) and BX (p = 0.02) subsets and d' (p = 0.05) than the others. They also showed more delayed correct response times than the healthy control group and first-degree relatives in all subsets (p < 0.01). But first-degree relatives showed neither high error rates nor delayed correct response times than healthy control group. CONCLUSIONS: These findings suggest that cognitive control is impaired in bipolar I disorder but less likely to be an endophynotype of bipolar I disorder.
Bipolar Disorder ; Education ; Endophenotypes ; Humans ; Intelligence ; Psychopathology ; Reaction Time

OBJECTIVES: This study aimed to identify the differences in the profiles of cognitive control deficits among schizophrenic patients and endophenotypes. METHODS: The study examined three groups: remitted patients with schizophrenia (n=54), unaffected first-degree relatives of the probands with schizophrenia (n=36), and a healthy control group (n=51), which were all matched for age, sex, and years of education. The AX version of the continuous performance test was used to examine cognitive control. The error rate, correct response times of each subset (AX, BX, AY, BY), and d′ as an indication of the accuracy sensitivity index were calculated. The psychopathology, intelligence, and psychomotor speed were also assessed. RESULTS: Patients with schizophrenia showed significantly poorer error rates and d′ in the AX and BX subsets than the others. They showed more delayed correct response times than the healthy control group in all subsets. The first-degree relatives also showed more delayed correct response times in the BX and AY subsets than the healthy control group, but were similar to the patients. CONCLUSION: These findings suggest that cognitive control is impaired in schizophrenia and endophynotypes possibly share this delayed information processing from the higher loading states of cognitive control.
Automatic Data Processing ; Education ; Endophenotypes ; Humans ; Intelligence ; Psychopathology ; Reaction Time ; Schizophrenia*

OBJECTIVES: The study compared the intelligence test profiles of Tourette's Disorder (TD), attention-deficit hyperactivity disorder (ADHD), and TD with ADHD (TD+ADHD) groups. METHODS: The Korean Wechsler Intelligence Scale for Children-third edition (K-WISC-III) and Korean Wechsler Intelligence Scale for Children-fourth edition (K-WISC-IV) were administered to 13 children and adolescents with TD, 17 children and adolescents with ADHD, and 15 children and adolescents with TD+ADHD. Each parameter was compared among the groups using the Kruskal-Wallis test. RESULTS: The mean scores of the freedom from distractibility/working memory index (FD/WMI) and the digit span and arithmetic subtests of the TD+ADHD group were significantly lower than those of the TD group. CONCLUSION: According to the intelligence test results, the comorbid ADHD+TD group showed a significant decrease in working memory compared to the TD group. These findings are similar to those of previous research on cognitive functions and suggest that the TD+ADHD comorbid and TD alone groups exhibit different endophenotypes. The results also imply that WISC-III and WISC-IV, the most commonly used intelligence tests clinically, are effective in evaluating cognitive functions such as attention. Further research is required to confirm these results.
Adolescent ; Child ; Cognition ; Endophenotypes ; Freedom ; Humans ; Intelligence Tests* ; Intelligence* ; Memory ; Memory, Short-Term ; Tourette Syndrome*

OBJECTIVES: Local gyrification reflects the early neural development of cortical connectivity, and is regarded as a potential neural endophenotype in psychiatric disorders. Several studies have suggested altered local gyrification in patients with bipolar I disorder (BD-I). The purpose of the present study was to investigate the alterations in the cortical gyrification of whole brain cortices in patients with BD-I. METHODS: Twenty-two patients with BD-I and age and sex-matched 22 healthy controls (HC) were included in this study. All participants underwent T1-weighted structural magnetic resonance imaging (MRI). The local gyrification index (LGI) of 66 cortical regions were analyzed using the FreeSurfer (Athinoula A. Martinos Center for Biomedical Imaging). One-way analysis of covariance (ANCOVA) was used to analyze the difference of LGI values between two groups adjusting for age and sex as covariates. RESULTS: The patients with BD-I showed significant hypogyria in the left pars opercularis (uncorrected-p = 0.049), the left rostral anterior cingulate gyrus (uncorrected-p = 0.012), the left caudal anterior cingulate gyrus (uncorrected-p = 0.033). However, these findings were not significant after applying the multiple comparison correction. Severity or duration of illness were not significantly correlated with LGI in the patients with BD-I. CONCLUSIONS: Our results of lower LGI in the anterior cingulate cortex and the ventrolateral prefrontal cortex in the BD-I group implicate that altered cortical gyrification in neural circuits involved in emotion-processing may contribute to pathophysiology of BD-I.
Bipolar Disorder ; Brain ; Broca Area ; Endophenotypes ; Gyrus Cinguli ; Humans ; Magnetic Resonance Imaging ; Prefrontal Cortex

OBJECTIVES: Obsessive-compulsive disorder (OCD) and schizophrenia have many common clinical and neurocognitive features. However, not all of them share the same underlying mechanism. The aim of this study was to discover evidences that indicate a pathophysiological mechanism specific to OCD by comparing correlations of quantitative electroencephalography (QEEG) patterns and neurocognitive function in patients with OCD and schizophrenia. METHODS: Resting-state QEEG data of total 265 patients were acquired retrospectively and parameters such as absolute power, relative power and peak frequency were analyzed from the data. Stroop test and Trail Making Test results as well as demographic features were reviewed for this study. The correlation of neurocognitive functions and brain electrical activities in each group were assessed and compared by correlation analysis. RESULTS: Compared with the OCD group, the schizophrenia group performed poorly in neurocognitive tests. Mean values of QEEG parameters in patients with OCD and schizophrenia did not show significant differences. Both absolute and relative power of alpha rhythm in central and frontal regions showed significant positive correlation with Stroop test results in OCD patients. CONCLUSIONS: Findings in this study shows distinctive correlations between frontal executive dysfunction and frontal alpha rhythm in the OCD patients, both of which might be a candidate for endophenotype underlying obsessive rumination.
Alpha Rhythm ; Brain ; Electroencephalography* ; Endophenotypes ; Humans ; Obsessive-Compulsive Disorder* ; Retrospective Studies ; Schizophrenia* ; Stroop Test ; Trail Making Test

OBJECTIVES: This study was conducted to investigate the possibility of neurological soft signs as an endophenotype for schizophrenia by examining neurological soft signs in patients, their unaffected siblings and normal comparison subjects. METHODS: The study sample consisted of 32 patients, 25 of their unaffected siblings and 30 normal comparison subjects. Neurological soft signs were evaluated using the Cambridge Neurological Inventory Part 2. soft sign assessment. RESULTS: The patients were significantly more impaired than normal comparison subjects (p = 0.047) on primitive reflex. The patients were significantly more impaired than siblings (p = 0.004) and normal comparison subjects (p = 0.021) on motor coordination. The siblings performed better on sensory integration than the patients (p = 0.020) and normal comparison subjects (p = 0.036). CONCLUSIONS: This study suggests that neurological soft signs might be a potential biomarker for schizophrenia, but might not be an endophenotype for schizophrenia.
Endophenotypes ; Humans ; Reflex ; Schizophrenia* ; Siblings*