Immune function changes of the IDPN-induced Tourette syndrome rat model.

There may be immunologic alternations during Tourette syndrome (TS) development. This study aimed to determine the immune function changes in different aspects (spleen or thymus index, plasma cytokines, and T cell) in an 3,3'-iminodipropionitrile (IDPN)-induced rat model of TS. Male Sprague-Dawley rats were assigned to control and TS groups. The control group received intraperitoneal infections of normal saline (5 ml kg-1  day-1 ), and the TS rats were injected with IDPN (150 mg kg-1  day-1 ). The spleen and thymus indices were calculated. The expression of anti-inflammatory cytokines and inflammatory cytokines TNF-α, in peripheral blood were measured by ELISA and Western blotting. The proportion of CD3+, CD4+, CD8+, Treg, Th1, and Th2 cells were determined by fluorescence-activated cell sorting analysis. After 1 week of IDPN treatment, TS rats had decreased spleen and thymus weights versus control. The plasma levels of IL-4, IL-10, IL-12, IFN-γ, and TNF-α were significantly increased, while no significant difference in TGF-ß was found. Flow cytometry analysis demonstrated that TS rats had significantly reduced CD3+ and CD4+ cells in spleen, without any change in the proportion of CD8+ cells. Furthermore, the ratio of Treg cells (CD4+/CD25+/FoxP3+) was decreased in TS rats; simultaneously, Th1 cells (CD4+/IFN-γ+) and Th2 cells (CD4+/IL4+) were dramatically increased. Together, IDPN can trigger immune dysfunction through impairment of matured Th cells, in particular for the Treg subset.

Seroprevalance Anti-Toxoplasma gondii antibodies in children and adolescents with tourette syndrome/chronic motor or vocal tic disorder: A case-control study.

Toxoplasma gondii infection may be associated with psychiatric disorders due to its neurological effects. The purpose of this study was to investigate the relation between tic disorders in children and adolescents and Anti-Toxoplasma IgG. 43 children diagnosed with Tourette's syndrome(TS) and 87 with chronic motor or vocal tic disorder(CMVTD), and 130 healthy volunteers, all aged 7-18, were enrolled. Anti-Toxoplasma IgG antibody levels obtained from blood specimens were investigated. Toxoplasma IgG positivity was determined in 16(37.2%) of the patients with TS, in 27(31%) of those with CMVTD and in 12(9.2%) members of the control group. Anti-Toxoplasma gondii antibody positivity was 5.827-fold higher in subjects with TS and 4.425-fold higher in subjects with CMVTD compared to the control group. Correlation was determined between a diagnosis of TS or CMVTD and Anti-Toxoplasma gondii antibodies. We think that it will be useful for the neuropsychiatric process associated with Anti-Toxoplasma gondii antibodies to be clarified.

Relationship of serum ferritin level and tic severity in children with Tourette syndrome.

PURPOSE: Tics can be considered hyperkinetic movements akin to restless leg syndrome (RLS). Drawing the analogy of iron deficiency as an etiology of RLS, it is conceivable that iron deficiency may underlie or worsen tics in Tourette syndrome (TS). The purpose of this study was to evaluate the relationship between serum ferritin levels and tic severity, as well as consequent impact on life, in children with TS. METHODS: Children <18 years, diagnosed with TS during 2009-2015, were reviewed. Only those with serum ferritin testing were included. The following data were collected: tic severity, impact on life, medication, comorbidities, blood count, and serum ferritin at diagnosis and follow-up. RESULTS: In fifty-seven patients, M:F = 2:1, serum ferritin was 48.0 ± 33.28 ng/mL, tic severity score 2.3 ± 0.80, impact on life score 2.2 ± 0.93, and composite score 4.57 ± 1.6. Serum ferritin was not influenced by comorbid obsessive compulsive disorder (OCD), attention deficit hyperactive disorder (ADHD), or anxiety (P > 0.16). Thirty-eight percent with low serum ferritin (≤50 ng/mL) (n = 37) had severe tics (>5 composite score), compared with 25% in normal ferritin group (n = 20). Over 6-12 months, tic severity score improved in both iron treated groups, deficient (2.70 to 1.90) and sufficient (2.40 to 1.95), whereas tics worsened or remained the same when not treated with iron. CONCLUSIONS: Our data suggest iron deficiency may be associated with more severe tics with higher impact on TS children, independent of the presence of OCD, ADHD, or anxiety. Iron supplementation showed a trend towards improvement of tic severity upon follow-up. We suggest a double-blind, placebo-controlled prospective study to reach a definite conclusion.

A cytokine study of pediatric Tourette's disorder without obsessive compulsive disorder.

It has been suggested that post-infectious inflammation in central nervous system is a cause of tic disorder including Tourette's disorder (TD). Since pro-inflammatory cytokines are important mediators inducing inflammation, the cytokine levels are regarded as one of the important indicators of inflammation. Several studies have investigated the relationship of autoimmunity and the pathogenesis of TD by measuring the inflammatory cytokine levels of blood. However, when using human samples, the experimental results can be affected by the factors like size of sample, comorbidity, medication that patients take and the severity of the diseases. Thus, it is important to exclude the possibility that comorbidity and medication affects the level of inflammatory cytokines in the serum of TD patients. In our experiment, we recruited 29 patients without obsessive compulsive disorder (OCD) comorbidity and the majority of these patients did not take medication. The six pro-inflammatory cytokine levels of blood between patient and healthy groups were compared, considering the factors above, to determine more accurate results. Of the cytokines we investigated, the interleukin 12 p70 (IL-12p70) and tumor necrosis factor α (TNFα) levels increased in patient group compared to healthy controls and the patient group which have anti-streptolysin O (ASO) score under the 200 or YTGSS score from 10 to 19 also showed higher IL-12p70 or TNFα levels. In addition, the patients who did not take medication showed higher TNFα levels compared to healthy controls. In conclusion, we suggest that inflammatory pathways that involve IL-12p70 or TNFα are important to the pathogenesis of TD.

Gilles de la Tourette syndrome is not linked to contactin-associated protein receptor 2 antibodies.

BACKGROUND: In Gilles de la Tourette syndrome (GTS) an immunopathogenic influence of autoantibodies is suspected. In familial GTS a disruption of the contactin-associated protein 2 gene (CNTNAP2), coding for the contactin-associated protein 2 (CASPR2), has been reported. Autoantibodies against CASPR2 are associated with other movement disorders like Morvan's syndrome. In addition, positive oligoclonal bands (OCB) in cerebrospinal fluid (CSF) have been found in more than a third of GTS patients, indicating a pathological intrathecal immunoglobulin synthesis. These findings drove the hypothesis that CASPR2 antibodies are involved in GTS. METHODS: In this cross sectional study, 51 patients with GTS were examined for CASPR2 and other autoantibodies. We used indirect immunofluorescence or enzyme-linked visualization in cell-based assays on tissue sections from cerebellum (rat and monkey), hippocampus (rat), and immunoblots for the detection of specific or any other autoantibodies. RESULTS: Serum samples from 51 GTS patients, mean age 35.0 ± 13.1 y, were analyzed. In none of the 51 GTS sera CASPR2 antibodies were detectable. Neither had we found any other specific autoantibodies (LGI1, NMDAR, AMPA1, AMPA/2 or GABAB1/B2). An anti-nuclear pattern of immunoreactivity was observed in 7/51 (14 %) samples. In these patients an immunoblot analysis was used to rule out antibodies directed against well-defined intracellular target antigens. A specific anti-neuronal binding pattern could not be seen in any of the tissue sections. CONCLUSIONS: The results negate that CASPR2 antibodies play a role in the pathogenesis of Tourette syndrome and do not support the assumption that anti-neuronal antibodies are involved.

Circulating miRNAs profiles in Tourette syndrome: molecular data and clinical implications.

BACKGROUND: Tourette Syndrome (TS) is a highly prevalent childhood neuropsychiatric disorder (about 1 %), characterized by multiple motor and one or more vocal tics. The syndrome is commonly associated to comorbid conditions (e.g., Attention Deficit Hyperactivity Disorder and Obsessive Compulsive Disorder), which considerably aggravate clinical symptoms and complicate diagnosis and treatment. To date, TS molecular bases are unknown and its molecular diagnosis is unfeasible. RESULTS: Due to their master role within cell networks and pathways both in physiology as in pathology, we sought to determine the transcriptome of circulating miRNAs in TS patients: by TaqMan Low Density Arrays, we profiled the expression in serum of 754 miRNAs in six TS patients and three unaffected controls (NCs) (discovery set). These data were validated by single TaqMan assays on serum from 52 TS patients and 15 NCs (validation set). Network and Gene-ontology analysis were performed by using Cytoscape and Babelomics server. We found that miR-429 is significantly underexpressed in TS patients with respect to NCs. Decreased serum levels of miR-429 allowed us to discriminate TS patients from NCs with 95 % of sensitivity and 42 % of specificity. Intriguingly, computational analysis of the network comprising miR-429 targets demonstrates their involvement in differentiation of midbrain and hindbrain and synaptic transmission. CONCLUSIONS: Our data open the way to further molecular characterization of TS and eventual identification of the corresponding genotypes. Circulating miR-429 may be immediately useful as sensitive molecular biomarker to support TS diagnosis, actually based only on DSM-V criteria.

[Effect of Ningdong Granule on the levels of IL-12 and TNF-alpha in children patients with Tourette's syndrome].

OBJECTIVE: To observe the effect of Ningdong Granule (NG) on serum levels of interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF-alpha) of children patients with Tourette's syndrome (TS). METHODS: Totally 90 TS children patients were randomly assigned to the NG group, the NG + Tiapride group (abbreviated as the combined treatment group), and the Tiapride group, 30 in each group. Besides,another 30 healthy children were recruited as the healthy control group. Patients in the NG group were treated with NG (consisting of all gastrodia rhizome, Codonopsis pilosula, Ophiopogon japonicus, white peony root, Rhinocerotidae, oyster, earthworm, licorice root, etc.), one dose daily, administered by dissolving it in boiled water, taken in two portions in the morning and in the evening respectively. Patients in the Tiapride group took Tiapride Tablet, 50 -100 mg each time, twice daily. The dosage was adjusted according to individual difference and changes of pathogenic conditions. The maximal dosage was 300 mg per day. Those in the combined treatment group were treated with equal dose of NG and Tiapride Tablet in combination. The treatment course was 3 months for all. Changes of pathogenic condition before and after treatment were assessed by Yale global tic severity scale (YGTSS). Serum levels of IL-12 and TNF-alpha were detected by enzyme-labeled immunosorbent assay (ELISA) before and after treatment. RESULTS: (1) The total effective rate of the NG group, the combined treatment group, and the Tiapride group was 79.3%, 83.3%, and 67.9%, respectively. It was the lowest in the Tiapride group (P < 0.05). It was significantly higher in the combined treatment group than in the NG group (P < 0.05). (2) The post-treatment YGTSS score was obviously lower in each group after treatment than before treatment (P < 0.05). The posttreatment YGTSS score was obviously lower in the NG group and the combined treatment group than in the Tiapride group (P < 0.05), but with no statistical difference between the fromer two groups (P > 0.05).(3) Compared with the healthy control group before treatment, serum levels of IL-12 and TNF-alpha (pg/mL) were 124.95 +/- 22.78 and 209.52 +/- 21.69 in the NG group, 126.14 +/- 25.65 and 208.97 +/- 22.46 in the combined treatment group, 123.00 +/- 24.26 and 205.10 +/- 26.16 in the Tiapride group, being higher than those in the healthy control group (64.56 +/- 27.59 and 78.13 +/- 33.42; P < 0.05). After treatment, serum levels of of IL-12 and TNF-alpha were 104.67 +/- 16.84 and 183.01 +/- 24.95 in the NG group, 109.04 +/- 16.81 and 179.87 +/- 23.45 in the combined treatment group, significantly lower than before treatment (P < 0.05). But there was no statistical difference in serum levels of IL-12 or TNF-alpha in the Tiapride group between before treatment (123.00 +/- 24.26 and 205.10 +/- 26.16) and after treatment (117.75 +/- 16.79 and 199.76 +/- 33.21; P > 0.05). CONCLUSION: NG could modulate abnormal serum levels of IL-12 and TNF-alpha in TS children patients, which might be one of its pharmacodynamic mechanisms for treating TS.

[Effect of ningdong granule on stereotyped behaviors in Tourette syndrome model rats of different Chinese medical syndromes].

OBJECTIVE: To observe the effect of Ningdong Granule (NDG) on stereotyped behaviors in Tourette's syndrome (TS) model rats of different Chinese medical syndromes. METHODS: Thirty-two Wistar rats were used to establish TS models of different Chinese medical syndromes (n =8) induced by TS children patients' sera of 4 syndromes, i.e., Xin-Gan deficiency syndrome (XGDS), Gan-Shen yin deficiency syndrome (GSYDS), sputum-turbid blocking aperture syndrome (STBAS), and Gan hyperactivity Pi deficiency syndrome (GHPDS). Corresponding sera was micro-infused to them while administering NDG (120 mg/kg each time, thrice daily, for 3 successive weeks). Besides, another normal control group (n =8) was set up by injecting sera from healthy children plus intragastric perfusion of normal saline. Stereotyped behaviors were recorded on the 1st, 7th, 14th, and 21st day after administration of NDG. RESULTS: The anti-neural antibody serum concentration in TS children was significantly higher than that in healthy control [(1.28 +/- 0.36) UL vs. (0.52 +/- 0.24) U/L, P < 0.01 ]. It was (1.34 +/- 0.41) U/L in the XGDS group, (1.19 +/- 0.51) U/L in the GSYDS group, (1.29 +/- 0.61) U/L in the STBAS group, and (1. 17 +/- 0.45) U/L in the GHPDS group, showing no statistical difference (P > 0.05). There was no statistical difference in stereotypic behaviors of rats after treatment among the four different Chinese medical syndromes (P > 0.05). At day 7, 14, and 21 after treatment by NDG, the times of stereotyped behaviors were significantly less in the XGDS group than in the other three groups at the same time points except in the GHPDS group at day 14 (P < 0.05, P < 0.01). Meanwhile, the total numbers of stereotyped behaviors in the XGDS group [(42.8 +/- 12.6)] was obviously superior to that in the GSYDS group [(29.3 +/- 13.7)], the STBAS group [(21.9 +/- 10.4)], and the GHPDS group [(30.6 +/- 9.6)], showing statistical difference (P < 0.01, P < 0.05) after treatment by NDG at day 21. CONCLUSIONS: The anti-neural antibody serum concentration in TS children was significantly higher than that in healthy children. Stereotyped behaviors could be induced in rats after intrastriatal micro-infusion of TS sera rich in anti-neural antibody. TS model rats of XGDS were better improved than rats in the other 3 groups after treatment by NDG.

Anti-streptococcal, tubulin, and dopamine receptor 2 antibodies in children with PANDAS and Tourette syndrome: single-point and longitudinal assessments.

Single-point-in-time ELISA optical densities for three putative antibodies identified in Sydenham's chorea, the streptococcal group A carbohydrate antigen, N-acetyl-beta-d-glucosamine, tubulin, and the dopamine 2 receptor, showed no differences in children with PANDAS (n=44) or Tourette syndrome (n=40) as compared to controls (n=24). Anti-tubulin and D2 receptor antibodies assessed in serial samples from 12 PANDAS subjects obtained prior to a documented exacerbation, during the exacerbation (with or without a temporally associated streptococcal infection), and following the exacerbation, showed no evidence of antibody levels correlating with a clinical exacerbation. These data do not support hypotheses suggesting an autoimmune hypothesis in either TS or PANDAS.

Metabolic effects of aripiprazole and pimozide in children with Tourette syndrome.

This study assessed the metabolic effects of aripiprazole and pimozide in pediatric Tourette syndrome, a neurodevelopmental condition characterized by multiple motor and phonic tics. Patients receiving aripiprazole (n = 25) or pimozide (n = 25) were compared with medication-free patients (n = 25). Body mass index, glycemia, triglyceridemia, and cholesterolemia were monitored at baseline and 12 and 24 months after commencing treatment. The aripiprazole group demonstrated significant increases in cholesterolemia. The pimozide group demonstrated significant increases in glycemia. Both groups demonstrated elevations in triglyceridemia not significantly different from those in unmedicated control subjects. The effect of aripiprazole on cholesterol was apparent after 12 months, but leveled off during year 2 of treatment. Longitudinal studies are required to evaluate the full extent of glycemic alterations with pimozide. Both agents appear relatively safe for use in pediatric Tourette syndrome. These findings will help guide medication selection in patients with specific medical vulnerabilities.

Effectiveness of a web-based protocol for the screening and phenotyping of individuals with Tourette syndrome for genetic studies.

Genome-wide association studies (GWAS) and other emerging technologies offer great promise for the identification of genetic risk factors for complex psychiatric disorders, yet such studies are constrained by the need for large sample sizes. Web-based collection offers a relatively untapped resource for increasing participant recruitment. Therefore, we developed and implemented a novel web-based screening and phenotyping protocol for genetic studies of Tourette syndrome (TS), a childhood-onset neuropsychiatric disorder characterized by motor and vocal tics. Participants were recruited over a 13-month period through the membership of the Tourette Syndrome Association (TSA; n = 28,878). Of the TSA members contacted, 4.3% (1,242) initiated the questionnaire, and 79.5% (987) of these were enrollment eligible. 63.9% (631) of enrolled participants completed the study by submitting phenotypic data and blood specimens. Age was the only variable that predicted study completion; children and young adults were significantly less likely to be study completers than adults 26 and older. Compared to a clinic-based study conducted over the same time period, the web-based method yielded a 60% larger sample. Web-based participants were older and more often female; otherwise, the sample characteristics did not differ significantly. TS diagnoses based on the web-screen demonstrated 100% accuracy compared to those derived from in-depth clinical interviews. Our results suggest that a web-based approach is effective for increasing the sample size for genetic studies of a relatively rare disorder and that our web-based screen is valid for diagnosing TS. Findings from this study should aid in the development of web-based protocols for other disorders.

[Effects of Jing'an Oral Liquid on the central neurotransmitter of multiple tics children].

OBJECTIVE: To study the effects of Jing'an Oral Liquid (JOL) on the central neurotransmitters of multiple tics (MT) children. METHODS: Sixty MT children patients were randomly assigned to the treatment group and the control group, 30 cases in each group. Another 30 healthy children were recruited as the health group. JOL and Tiapride Tablet (TT) was respectively given to patients in the treatment group and the control group. The treatment course was 2 months. The levels of central neurotransmitters [dopamine (DA), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT), norepinephrine (NE), glutamic acid (GLU), aspartate (ASP), gamma-aminobutyric acid (GABA)] were measured using high performance liquid chromatography (HPLC) before and after treatment, and compared with the health group. RESULTS: Compared with the health group, the levels of 5-HT, HVA, GLU, and ASP significantly increased in the treatment group and the control group before treatment (P < 0.05), GABA significantly decreased (P < 0.05). Compared with before treatment in the same group, the levels 5-HT, HVA, and GLU significantly decreased in the treatment group (P < 0.05), while the levels of NE and GABA significantly increased (P < 0.05). The levels of DA, 5-HT, GLU, and ASP significantly decreased, while the levels of NE ang GABA significantly increased in the control group, showing statistical difference (P < 0.05). There was no statistical difference in each index between the treatment group and the control group before and after treatment (P > 0.05). CONCLUSIONS: (1) The imbalance of a variety of monoamines and amino acid neurotransmitters can lead to MT, especially in the changes of 5-HT, HVA, GLU, ASP, and GABA. (2) JOL can significantly reduce the levels of 5-HT, HVA, and GLU, and significantly increase the levels of NE and GABA, which might be its pharmacodynamic mechanisms for treating MT.

Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders.

Recent reports of autoantibodies that bind to neuronal surface receptors or synaptic proteins have defined treatable forms of autoimmune encephalitis. Despite these developments, many cases of encephalitis remain unexplained. We have previously described a basal ganglia encephalitis with dominant movement and psychiatric disease, and proposed an autoimmune aetiology. Given the role of dopamine and dopamine receptors in the control of movement and behaviour, we hypothesized that patients with basal ganglia encephalitis and other putative autoimmune basal ganglia disorders harboured serum autoantibodies against important dopamine surface proteins. Basal ganglia encephalitis sera immunolabelled live surface cultured neurons that have high expression of dopamine surface proteins. To detect autoantibodies, we performed flow cytometry cell-based assays using human embryonic kidney cells to express surface antigens. Twelve of 17 children (aged 0.4-15 years, nine males) with basal ganglia encephalitis had elevated immunoglobulin G to extracellular dopamine-2 receptor, compared with 0/67 controls. Immunofluorescence on wild-type mouse brain showed that basal ganglia encephalitis sera immunolabelled microtubule-associated protein 2-positive neurons in striatum and also in cultured striatal neurons, whereas the immunolabelling was significantly decreased in dopamine-2 receptor knock-out brains. Immunocytochemistry confirmed that immunoreactivity localized to the surface of dopamine-2 receptor-transfected cells. Immunoabsorption of basal ganglia encephalitis sera on dopamine-2 receptor-transfected human embryonic kidney cells decreased immunolabelling of dopamine-2 receptor-transfected human embryonic kidney cells, neurons and wild-type mouse brain. Using a similar flow cytometry cell-based assay, we found no elevated immunoglobulin G binding to dopamine 1, 3 or 5 receptor, dopamine transporter or N-methyl-d-aspartate receptor. The 12 dopamine-2 receptor antibody-positive patients with encephalitis had movement disorders characterized by parkinsonism, dystonia and chorea. In addition, the patients had psychiatric disturbance with emotional lability, attention deficit and psychosis. Brain magnetic resonance imaging showed lesions localized to the basal ganglia in 50% of the patients. Elevated dopamine-2 receptor immunoglobulin G was also found in 10/30 patients with Sydenham's chorea, 0/22 patients with paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and 4/44 patients with Tourette's syndrome. No dopamine-1 receptor immunoglobulin G was detected in any disease or control groups. We conclude that assessment of dopamine-2 receptor antibodies can help define autoimmune movement and psychiatric disorders.

Gene expression changes in peripheral blood from Chinese Han patients with Tourette syndrome.

To evaluate whether gene expression in chromosome 15q13-q22.3 region is responsible for the development of Tourette syndrome (TS). Eighty-four unrelated Chinese Han patients with TS (male/female = 68/16; mean age 9.92 ± 3.98 years) and 100 sex, age, and ethnicity matched normal controls (male/female = 80/20; mean age 10.90 ± 5.86 years) were enrolled in this study. We performed quantitative real-time PCR on a subset of seven genes: the L-histidine decarboxylase gene (HDC), the HECT domain and RCC-1 like domain 1 gene (HERC1), the HECT domain and RCC-1 like domain 2 gene (HERC2), the cholinergic receptor, neuronal nicotinic alpha polypeptide 7 gene (CHRNA7), the ubiquitin protein ligase E3A gene (UBE3A), the ubiquitin specific peptidase 3 gene (USP3) and the amyloid precursor protein-binding protein A2 gene (APBA2) previously reported to be stably expressed in brain tissue. A significant difference was shown for the APBA2 gene expression of peripheral lymphocytes between Chinese Han TS group and healthy controls (relative expression: 0.21 ± 0.16-fold decrease in patients versus normal, P < 0.01). Indicating that the APBA2 gene is a promising peripheral blood biomarker that discriminates between patients with TS and healthy subjects. Further studies into this gene and its protein products may provide insights into the pathogenesis of TS.

Effects of Chinese herbal medicine Ningdong granule on regulating dopamine (DA)/serotonin (5-TH) and gamma-amino butyric acid (GABA) in patients with Tourette syndrome.

Many studies have indicated that a variety of neurotransmitters are implicated in the pathophysiology of Tourette syndrome (TS), including dopamine (DA), serotonin (5-TH), homovanillic acid (HVA), and gamma-amino butyric acid (GABA). Our previous studies found that Ningdong granule (NDG) is effective on a rat model with TS. NDG can regulate the metabolic disturbance of DA, 5-TH and HVA in the rat brain. However, the mechanisms of NDG in patients with TS are still not clear. To further evaluate the efficiency, safety, and possible mechanisms of NDG, a randomized and double-blind study was carried out. One hundred and twenty patients with TS were enrolled in this study, that were randomly divided into 4 groups (NDG group, Haloperidol (Hal) group, NDG + Hal group and Control group). First, the efficiency of NDG was assessed using the Yale Global Tic Severity Score (YGTSS). Second, the concentration of DA, HVA, 5-TH, 5-hydroxyindoleacetic acid (5-HIAA) and GABA in sera were tested by ELISA. In addition, the influence of NDG on liver and renal function was recorded. We found that NDG could ameliorate tics significantly according the YGTSS score. The concentration of HVA and GABA were increased after treatment with NDG. Furthermore, we found that there was no liver or renal damage in children treated with NDG. We also found that the NDG + Hal group was more effective and safe compared with other groups. In conclusion, the current study indicates that NDG might be effective on patients with TS by regulating dopamine (DA)/serotonin (5-TH) and gamma-amino butyric acid (GABA).

Hyperpolarisation-activated cyclic nucleotide channel 4 (HCN4) involvement in Tourette's syndrome autoimmunity.

OBJECTIVES: We previously found that antibodies in Tourette's syndrome (TS) patients' sera reacted with a 120 kDa protein from rat brain tissue. Here, we sought to identify this protein and determine if it was involved in TS pathogenesis. METHODS: The 120 kDa protein was identified using immunoprecipitation, Western blotting, and mass spectrometry. ELISAs were used to quantify anti-120 kDa protein antibodies in serum of interest using samples from 32 TS patients, 47 patients with attention deficit hyperactivity disorder (ADHD) and 14 healthy controls. Involvement of the 120 kDa protein in TS was confirmed using co-localisation assays with GH3 cells. TS sera were micro-infused into SD rats' brain striatum and their stereotypical behaviours were monitored. RESULTS: The brain protein was identified as hyperpolarisation-activated cyclic nucleotide channel 4 (HCN4). TS patients' sera contained significantly more anti-HCN4 antibodies than ADHD patient and control sera. After microinfusing TS serum, SD rats exhibited increased stereotyped tic behaviours, which were correlated with the amount of infused anti-HCN4 antibody. CONCLUSIONS: Anti-HCN4 antibodies in the brain might contribute to the pathogenesis of tic symptoms in TS patients. However, further studies are needed to investigate the validity of this animal model of TS induced by microinfusing anti-HCN4 antibody.

Detection of autoantibodies and increased concentrations of interleukins in plasma from patients with Tourette's syndrome.

The aim of this study was to assess levels of autoantibodies and cytokines in patients with Tourette's syndrome (TS, n = 40) and healthy control individuals (n = 40). Plasma interleukin (IL)-1ß, IL-6, IL-17, and soluble gp130 concentrations were significantly higher in the TS group compared with the control group (P < 0.001); whereas the soluble IL-6 receptor concentration was significantly decreased in the TS group compared with the control group (P < 0.001). Significantly more patients in the TS group were positive for antibrain and antinuclear antibodies, and antistreptolysin compared with the control group (P < 0.05). These findings suggest that immune activity is altered in patients with TS.

Altered monocyte activation markers in Tourette's syndrome: a case-control study.

BACKGROUND: Infections and immunological processes are likely to be involved in the pathogenesis of Tourette's syndrome (TS). To determine possible common underlying immunological mechanisms, we focused on innate immunity and studied markers of inflammation, monocytes, and monocyte-derived cytokines. METHODS: In a cross-sectional study, we used current methods to determine the number of monocytes and levels of C-reactive protein (CRP) in 46 children, adolescents, and adult patients suffering from TS and in 43 healthy controls matched for age and sex. Tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), soluble CD14 (sCD14), IL1-receptor antagonist (IL1-ra), and serum neopterin were detected by immunoassays. RESULTS: We found that CRP and neopterin levels and the number of monocytes were significantly higher in TS patients than in healthy controls. Serum concentrations of TNF-alpha, sIL1-ra, and sCD14 were significantly lower in TS patients. All measured values were within normal ranges and often close to detection limits. CONCLUSIONS: The present results point to a monocyte dysregulation in TS. This possible dysbalance in innate immunity could predispose to infections or autoimmune reactions.

No significant association between Catechol-O-methyl transferase (COMT) -287A/G gene polymorphism and Tourette's syndrome in family-based association study in Chinese Han population.

To identify the association of Catechol-O-methyl transferase (COMT) -287A/G polymorphism with susceptibility to TS in Chinese Han population. We evaluated the genetic contribution of the COMT -287A/G polymorphism in 108 TS patients including all their parents in Chinese Han population using transmission disequilibrium test and haplotype relative risk design. Our results revealed that no significant association was found in COMT -287A/G genotypic and allelic frequencies with TS. Our results also suggested that there may be a lack of association between the TS and -287A/G polymorphism of COMT in Chinese Han population.

Antibody binding to neuronal surface in Sydenham chorea, but not in PANDAS or Tourette syndrome.

OBJECTIVE: To test the hypothesis that Sydenham chorea (SC) immunoglobulin G (IgG) autoantibodies bind to specific neuronal surface proteins, whereas IgG from patients with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) or Tourette syndrome (TS) do not bind to neuronal surface proteins. METHODS: We used live differentiated SH-SY5Y cells, which have neuronal and dopaminergic characteristics. Using flow cytometry, we measured serum IgG cell surface binding in patients with SC (n = 11), PANDAS (n = 12), and TS (n = 11), and compared the findings to healthy controls (n = 11) and other neurologic controls (n = 11). In order to determine the specificity of binding to neuronal antigens, we also used a non-neuronal cell line, HEK 293. RESULTS: The mean IgG cell surface binding was significantly higher in the SC group compared to all other groups (p < 0.001). By contrast, there was no difference between the PANDAS or TS groups and the controls. Using the non-neuronal HEK-293 cells, there was no significant difference in IgG cell surface binding between any groups. CONCLUSIONS: Serum autoantibodies that bind to neuronal cell surface antigens are present in SC, but not in PANDAS or TS. These findings strengthen the hypothesis that SC is due to a pathogenic autoantibody, but weaken the autoantibody hypothesis in PANDAS and TS.