Clinical Neuroscience

[Multilocus genetic analysis implicates neurodevelopment and immune system in the etiology of schizophrenia]

PULAY Attila József1, KOLLER Júlia2, NAGY László3, MOLNÁR Mária Judit1, RÉTHELYI János1,4

MARCH 30, 2017

Clinical Neuroscience - 2017;70(03-04)


[Background - Schizophrenia is a severe psychiatric disorder of poorly understood etiology, characterized by high heritability, multifactorial inheritance and high heterogeneity. Multilocus associaton methods may reduce the genetic heterogeneity and improve the probability of replication between analyses. Objectives - The aims of our study were twofold: 1. To analyse genetic risk factors of schizophrenia by using multilocus genetic tests. 2. To assess the replication probability attributable to the various multilocus tests. Subjects - Discovery set: case-parent trios of unaffected parents and affected probands with a DSM-IV schizophrenia diagnosis (n=16); replication set: schizophrenia cases and unaffected controls (n=5337). Methods - Associations of single nucleotide and indel markers were transferred to gene- and geneset-based associations, furthermore to geneset-enrichment tests and functional annotation cluster analyses in a two-staged designs. Associations with p<0.1 from the discovery set were tested in the replication sample. Familywise p-value correction for multiple comparisons were performed during the replication step. Results - After correction for multiplicity, no significant association or enrichment were detected for gene-based nor canonical pathway analyses, but significant association of the 14q31 cytoband and enrichments of the 5q31 and Xq13 cytobands were found (p_corr: 0.002, 0.006 and 0.048, respectively). Functional annotation clustering yielded statistically significant enrichment scores for clusters of splicing/alternative splicing, neurodevelopment and embryonic development. Improvements in replication probabilty were found with increased test complexity (P_rep: 0, 0.015, 0.21). Conclusions - Our results corroborate the involvement of neurodevelopment, synaptic plasticity and immune mechanisms in the etiology of schizophrenia. Also, our findings indicated improvement of replication probability by using multilocus genetic analyses. ]


  1. Semmelweis Egyetem, Pszichiátriai és Pszichoterápiás Klinika, Budapest
  2. Semmelweis Egyetem, Genomikai Medicina és Ritka Betegségek Intézete, Budapest
  3. Debreceni Egyetem, Biokémiai és Molekuláris Biológiai Intézet, Debrecen
  4. MTA-SE NAP-B Molekuláris Pszichiátriai és in vitro Betegségmodellezési Kutatócsoport, Budapest



Further articles in this publication

Clinical Neuroscience

Procedural learning and its consolidation in autism spectrum disorder


Children with autism spectrum disorder (ASD) show altered learning and memory. A number of recent studies have debated whether procedural learning in ASD is intact or not. Our aim was to further assess the question of whether the implicit, non-conscious form of procedural learning in ASD children is intact or not, furthermore, how shifts towards a more explicit, attention-demanding task setting can alter this performance. We administered a modified version of the Alternating Serial Reaction Time (ASRT) Task to children with ASD and IQ- and age-matched typically developing (TD) children. The task consisted of alternating blocks of cued (explicit) and uncued (implicit probe) blocks, and was repeated after a 16-hour delay. We found that ASD and TD children showed similar sequence-specific learning in cued explicit blocks, however, on the uncued probe blocks ASD children performed better compared to TD children. After the 16-hour delay both groups showed retention of the previously acquired knowledge. Finally, when we investigated the performance in different parts of the blocks, we found that ASD children did not show an effect of fatigue by the second part of the blocks. Our results suggest that children with ASD have increased implicit procedural learning skills compared to TD children. Differences in cued (explicit) and uncued (implicit) settings indicate that children with ASD are not affected by the lack of explicit instructions in probe blocks, suggesting a resistance for changes in task settings. These findings can help in a more thorough planning of cognitive therapeutic setups for ASD children.

Clinical Neuroscience

Surveillance and management of patients with tuberous sclerosis complex

FOGARASI András, GYORSOK Zsuzsanna, BODÓ Tímea

Tuberous sclerosis complex (TSC) is an autosomal dominant disease due to the uncontrolled differentiation, proliferation, and migration of cells in several organs. Clinical expression is highly variable, from mild skin findings and asymptomatic brain lesions to seizures, mental retardation, autism, and potentially fatal kidney, cardiac, or pulmonary disease. Aim of this paper is to summarize the diagnostic criteria, surveillance and therapeutic issues of this multisystemic disorder emphasizing the most important neurological consequences. Presenting the state-of-the-art management recommendations and comparing them with the local protocols, we hope that our review might help in the proper assessment of one of the most important single gene disorder.

Clinical Neuroscience

Electrophysiological alterations and general toxic signs obtained by subacute administration of titanium dioxide nanoparticles to the airways of rats

HORVÁTH Tamara, PAPP András, KOVÁCS Dávid, KÁLOMISTA Ildikó, KOZMA Gábor, VEZÉR Tünde

Introduction and aims - Particles of titanium dioxide (TiO2) with typical size below 100 nm have gained a broad range of application by now, partly involving direct human exposure. Their known properties - high specific surface, mobility within the organism, induction of oxidative stress, release of inflammation mediators etc. - raise the possibility of nervous system damage but the available data regarding this are scarce and contradictory. Based on that, and the experiences with other metal oxide nanoparticles, the aim of the present study was to investigate certain general end nervous system toxic effects of TiO2 nanoparticles applied in the airways of rats. Materials and methods - Young adult Wistar rats (5 groups of 10 rats each) received, daily for 28 days, intratracheal instillations of titanium dioxide nanoparticles of ca. 10 nm diameter, suspended in 1% hydroxyethyl cellulose dissolved in phosphate-buffered saline, in the doses of 1, 3, and 10 mg/kg b. w. Vehicle controls received the suspension medium and there was also an untreated control group. During treatment, the rats’ body weight was measured, and their clinical state observed, daily. After the 28 days, spontaneous cortical activity, sensory evoked potentials and tail nerve action potential was recorded in urethane anesthesia, then the rats were dissected and tissue samples were taken for Ti level determination and biochemical measurements of some oxidative stress indicators. Results - The two higher doses reduced the rate of body weight gain significantly. Sensory evoked potentials and tail nerve action potential were significantly slowed, but the change in the spectrum of spontaneous cortical activity was not significant. Correlation of moderate strength was found between certain evoked potential parameters and brain Ti level and oxidative stress data. Conclusion - Our results underlined the possible neurotoxicity of TiO2 NPs but also the need for further investigations.

Clinical Neuroscience

Pazopanib induced unilateral posterior reversible encephalopathy syndrome

ARSLAN Beyza Muhsine, BAJRAMI Arsida, DEMIR Elif, CABALAR Murat, YAYLA Vildan

Posterior reversible encephalopathy syndrome (PRES) is a reversible clinical and neuroradiological syndrome which may appear at any age and characterized by headache, altered consciousness, seizures, and cortical blindness. The exact incidence is still unknown. The most commonly identified causes include hypertensive encephalopathy, eclampsia, and some cytotoxic drugs. Vasogenic edema related subcortical white matter lesions, hyperintense on T2A and FLAIR sequences, in a relatively symmetrical pattern especially in the occipital and parietal lobes can be detected on cranial MR imaging. These findings tend to resolve partially or completely with early diagnosis and appropriate treatment. Here in, we present a rare case of unilateral PRES developed following the treatment with pazopanib, a testicular tumor vascular endothelial growth factor (VEGF) inhibitory agent.

Clinical Neuroscience

[Relationship between sport and traumatic brain injury - risks and sequelaes]

TAMÁS Viktória, KOVÁCS Noémi, BÜKI András

[Traumatic brain injury represents major public health problem worldwide. A typical form of brain injuries is the injury suffered during sports, which according to severity ranges from mild injuries to fatal damages. The significance of the sport related minor head injuries derives form the high incidence, the excessive involvement of the younger age groups, and their potential repetitive nature. The repeated mild head injuries may accumulate, leading to complex structural, neurochemical, neuroendocrine, and psychological alterations, which in long term may result in changes of the patients quality of life and in significant deterioration of participation in the everyday activity. Actually we neither have enough knowledge about the ne-gative consequences, nor the way of prevention, or protection against the harmful long term results. With this study summary we would like to draw attention to the potential hazards emerging from sport injuries, moreover we would like to emphasize the importance of study participation and follow up of articles in this field.]

All articles in the issue

Related contents

Clinical Neuroscience

TLR4 (Toll-like receptor-4) expression and frontal-cingulate volumes in schizophrenia

LI Hua, KÉRI Szabolcs

Evidence suggests that pathogen-associated pattern recognition receptors (Toll-like receptors, TLRs) are implicated in the pathophysiology of schizophrenia. TLRs are important in both peripheral immune responses and neuronal plasticity. However, the relationship between peripheral TLR expression and regional brain volumes is unknown in schizophrenia. We therefore assessed 30 drug-naïve, first-episode patients with schizophrenia. TLR4+/TLR1+ monocytes were measured using flow-cytometry. High resolution magnetic resonance images (T1 MRI) were obtained and analyzed with FreeSurfer. Results revealed significant negative correlations between the percentage of TLR4+ monocytes, mean fluorescent intensities, and brain volumes in frontal and anterior cingulate regions. The measures of TLR1+ monocytes did not show significant relationships with regional brain volumes. These results raise the possibility that abnormal TLR-activation is associated with decreased brain volumes in schizophrenia.

Clinical Neuroscience

Symptom profiles and parental bonding in homicidal versus non-violent male schizophrenia patients

HALMAI Tamás, TÉNYI Tamás, GONDA Xénia

Objective - To compare the intensity and the profile of psychotic symptoms and the characteristics of parental bonding of male schizophrenia patients with a history of homicide and those without a history of violent behaviour. Clinical question - We hypothesized more intense psychotic symptoms, especially positive symptoms as signs of a more severe psychopathology in the background of homicidal behaviour. We also hypothesized a more negatively perceived pattern (less Care more Overprotection) of parental bonding in the case of homicidal schizophrenia patients than in non-violent patients and non-violent healthy controls. Method and subjects - Symptom severity and symptom profiles were assessed with the Positive and Negative Syndrome Scale in a group of male schizophrenia patients (n=22) with the history of committed or attempted homicide, and another group (n=19) of male schizophrenia patients without a history of violent behaviour. Care- and Overprotection were assessed using the Parental Bonding Instrument (PBI) in a third group of non-violent healthy controls (n=20), too. Results - Positive, negative and general psychopathology symptoms in the homicidal schizophrenia group were significantly (p<0.005) more severe than in the non-violent schizophrenia group. Non-violent schizophrenia patients scored lower on Care and higher on Overprotection than violent patients and healthy controls. Homicidal schizophrenia patients showed a pattern similar to the one in the healthy control group. Conclusions - It seems imperative to register intense positive psychotic symptoms as predictive markers for later violent behaviour. In the subgroup of male homicidal schizophrenia patients negatively experienced parental bonding does not appear to be major contributing factor to later homicidal behaviour.

Clinical Neuroscience

[Event-related potentials and clinical symptoms in schizophrenia]


[The investigation of schizophrenia’s aetiology and pathomechanism is of high importance in neurosciences. In the recent decades, analyzing event-related potentials have proven to be useful to reveal the neuropsychological dysfunctions in schizophrenia. Even the very early stages of auditory stimulus processing are impaired in this disorder; this might contribute to the experience of auditory hallucinations. The present review summarizes the recent literature on the relationship between auditory hallucinations and event-related potentials. Due to the dysfunction of early auditory sensory processing, patients with schizophrenia are not able to locate the source of stimuli and to allocate their attention appropriately. These deficits might lead to auditory hallucinations and problems with daily functioning. Studies involving high risk groups may provide tools for screening and early interventions; thus improving the prognosis of schizophrenia. ]

Clinical Neuroscience

[Shifting function of working memory in psychotic disorders]


[Background and aims - Mental disorders with psychotic features are overlapping in many ways and there are a growing number of comparative studies in the last decades regarding this. Cognitive deficit is well underpinned in schizophrenia, but fewer studies are conducted in this area including patients with bipolar affective disorder. Therefore the aim of the present study was to investigate the cognitive performance of these two patient groups and healthy controls. The Wisconsin Card Sorting Task is a very sensitive measure of the shifting function. Schizophrenic patients perform consistently poorer on this task than healthy controls, while there are not much data about individuals with bipolar affective disorder. Methods - The Wisconsin Card Sorting Task and clinical symptom rating scales were administered to 26 patients with schizophrenia, 24 with bipolar affective disorder and 21 healthy controls. Results - Significant differences were found among the performance of the three groups using four different dimensions of the Wisconsin Card Sorting Task. The schizophrenic group made more perseverative errors and achieved less conceptual level responses and completed fewer categories compared to healthy controls. Patients with schizophrenia were able to complete fewer categories and had fewer conceptual level responses than the bipolar group. No significant differences were observed between patients with bipolar disorder and healthy controls. Conclusions - According to these results, patients with schizophrenia and bipolar affective disorder showed no similarities on the Wisconsin Card Sorting Task. Bipolar patients performed the task on the same level as healthy individuals did. The two mental disorders influence cognitive performance differently.]

Clinical Neuroscience

[Myasthenia in a patient with sarcoidosis and schizophrenia (in English language)]

RÓZSA Csilla, KIS Gábor, KOMOLY Sámuel

[A 44-year-old male patient was hospitalised with paranoid schizophrenia in 1985. Depot neuroleptic treatment was started which successfully prevented further psychotic relapses for the next ten years. His myasthenia gravis started with bulbar signs in 1997 and the symptoms soon became generalized. The diagnosis of myasthenia gravis was confirmed by electromyography, by positive anticholinesterase test and by the detection of anti-acetylcholine receptor antibodies in the serum. Mediastinal CT examination showed enlarged hilar lymph nodes on the left but no thymic pathology was observed. Mediastinoscopy was performed and biopsies were obtained from the affected nodes. Histology revealed sarcoidosis. The patient suffered respiratory crisis following the thoracic intervention (in September 1998). Combined oral corticosteroid (64 mg methylprednisolone/e.o.d.) and azathioprine (150 mg/day) treatment regimen was initiated and complete remission took place in both the myasthenic symptoms and the sarcoidosis. The follow-up CT scans showed no mediastinal pathology (January 2000). During steroid treatment a transient psychotic relapse occured which was successfully managed by supplemental haloperidol medication added to his regular depot neuroleptics. The patient currently takes 150 mg/day azathioprine and receives 40 mg/month flupentixol depot im. His physical and mental status are stable and he has been completely symptome free in the last 24 months. The association of myasthenia gravis and sarcoidosis is very rare. To our best knowledge no case has been reported of a patient suffering from myasthenia gravis, sarcoidosis, and schizophrenia at the same time.]