Clinical Neuroscience

[Investigation of the dopamine dysregulation hypothesis of schizophrenia with neuroimaging techniques]

SZEKERES György, PÁVICS László, JANKA Zoltán

AUGUST 20, 2002

Clinical Neuroscience - 2002;55(07-08)

[The most elaborated biochemical concept of schizophrenia is the dopamine hypothesis. However, this classical theory is based on indirect observations. It has recently become possible to study this theory directly by means of advanced functional neuroimaging techniques, the development of specific radioligands and study protocols that are eligible to monitor dynamic changes in the neurotransmitter systems. According to the early concept, the essence of schizophrenia is the hyperactivity of the dopamine system. Nevertheless, this idea has gone through many modifications. In accordance with the modified dopamine hypothesis, the cognitive deficit and negative symptoms are related to the hypoactivity of the dorsolateral prefrontal cortex while the acute phasis of the disease associates with hyperactivity of the ventral striatal elements of the dopaminergic system. Between these dysfunctions there is causality via their exuberant connections. Beyond that, the interactions between the prefrontal and striatal anomalies implicate the involvement of other neurotransmitters than dopamine. Observations from model psychosis induced by N-methyl-D-aspartate antagonists and in vivo neuroimaging investigations in humans support primarily the role of glutamatergic system. Our developing knowledge about the neurochemical mechanism of schizophrenia can significantly affect therapeutic strategies as well.]



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[Cerebellar venous anomalies with symptomatic vascular malformations]


[Cerebral and cerebellar venous anomalies (previously known as venous angiomas) form the alternative venous drainage of the surrounding nervous tissue because of the un-development of the normal venous system. They are made up of veins with abnormal structure: thick walls, lumens dilated and of irregular calibre that converge radially towards a wide draining vein (caput medusae). They are thought to be a benign condition although they are sometimes associated with cerebellar hemorrhages. Authors report three patients with cerebellar venous anomalies associated either with pontine cavernoma, cerebellar arteriovenous malformation or cerebellar infarct. They illustrate that cerebellar venous anomalies are benign conditions, but their presence might be a marker for additional, pathogenic malformation. It might be difficult to detect the associated malformations even by sophisticated imaging methods, but their presence can modify the treatment options.]

Clinical Neuroscience

[The molecular genetic control of bony developmental malformations affecting the craniocervical junction and the cervical spine]


[In this review a new interpretation of the origin of bony developmental malformations affecting the craniocervical junction and the cervical spine is presented based on recent advances in the understanding of embryonic development of the spine and its molecular genetic control. Radiographs, CT and MRI scans or CT myelograms of patients with Klippel-Feil syndrome were used for demonstration. Detailed clinical and radiologial analysis of these patients was published earlier [David KM, Stevens JM, Thorogood P, Crockard HA. The dysmorphic cervical spine in Klippel-Feil syndrome: interpretations from developmental biology. Neurosurg Focus 1999;6(6):1.]. Homeotic transformation due to mutations or disturbed expression of Hox genes is a possible mechanism responsible for C1 assimilation. Notochordal defects and/or signalling problems, that result in reduced or impaired Pax-1 gene expression, may underlie vertebral fusions. This, together with asymmetrical distribution of paraxial mesoderm cells and a possible lack of communication across the embryonic mid-line, could cause the asymmetrical fusion patterns. The wide and flattened shape of the fused vertebral bodies, their resemblance to the embryonic cartilaginous vertebrae and the process of progressive bony fusion with age suggest that the fusions occur before or, at the latest, during chondrification of vertebrae. The authors suggest that the aforementioned mechanisms are likely to be, at least in part, responsible for the origin of the bony developmental malformations affecting the craniocervical junction and the cervical spine.]

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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

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Clinical Neuroscience

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

PULAY Attila József, KOLLER Júlia, NAGY László, MOLNÁR Mária Judit, RÉTHELYI János

[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. ]

Clinical Neuroscience

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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.]