Helmut Beckmann

Prenatal developmental disturbances in the limbic allocortex in schizophrenics

Sixty-four autopsied brains of schizophrenic patients were neuropathologically examined and compared with 10 brains of non-schizophrenic controls. Clinical diagnoses were established retrospectively according to the Research Diagnostic Criteria and the International Classification of Diseases. We found: 1. brains without deviations of the sulcogyral pattern of the temporal lobe or abnormal gross configuration (n=22); 2. brains with abnormal sulcogyral pattern of the temporal lobe or abnormal gross configuration (n=42): a) with definite cytoarchitectonic abnormalities of the rostral entorhinal region in the parahippocampal gyrus and, in 16 cases only, in the ventral insular cortex (n=20); b) with equivocal changes of the cytoarchitecture in these two regions (n=22). brains without deviations of the sulcogyral pattern of the temporal lobe or abnormal gross configuration (n=22); brains with abnormal sulcogyral pattern of the temporal lobe or abnormal gross configuration (n=42): with definite cytoarchitectonic abnormalities of the rostral entorhinal region in the parahippocampal gyrus and, in 16 cases only, in the ventral insular cortex (n=20); with equivocal changes of the cytoarchitecture in these two regions (n=22). Generally, these anatomical abnormalities were asymmetric. The histological findings in the two limbic regions consisted mainly of poorly developed structure in the upper layers, with a heterotopic displacement of single groups of nerve cells in the entorhinal region. Particularly, the disturbed structure of the second layer Pre-α in medial and central fields of the entorhinal region, situated in the parahippocampal gyrus (group 2 a), suggests a disturbance of neuronal migration in a later phase of cortical development.

Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain.

Significant differences in the content of iron (III) and total iron were found in post mortem substantia nigra of Parkinsons disease. There was an increase of 176% in the levels of total iron and 255% of iron (III) in the substantia nigra of the parkinsonian patients compared to age matched controls. In the cortex (Brodmann area 21), hippocampus, putamen, and globus pallidus there was no significant difference in the levels of iron (III) and total iron. Thus the changes in total iron, iron (III) and the iron (II)/iron (III) ratio in the parkinsonian substantia nigra are likely to be involved in the pathophysiology and treatment of this disorder.

[3H]MK-801 binding sites in postmortem brain regions of schizophrenic patients

[3H]MK-801 binding was used as a marker for the NMDA receptor-ion channel complex in postmortem brain samples from the frontal cortex, hippocampus, putamen, entorhinal region, and amygdala of schizophrenic patients and controls. In schizophrenia [3H]MK-801 binding levels were increased in all brain regions investigated reaching significance in the putamen.

3H-spiperone binding sites in post-mortem brains from schizophrenic patients: Relationship to neuroleptic drug treatment, abnormal movements, and positive symptoms

In post-mortem putamen samples from 27 schizophrenics and 27 controls D2 receptors were measured by Scatchard analysis using3H-spiperone as a ligand. Maximum number of binding sites (Bmax) and apparent dissociation constant (KD) were significantly increased only in patients in whom neuroleptic medication had been given within a three-month period before death. When the neuroleptic medication had been withdrawn at least 3 month before death, there was a slight, but not significant, reduction in Bmax values and unchanged KD values. Withdrawal of neuroleptic drugs was followed by a normalization of the KD values within 2 weeks and a slower reduction of Bmax values. There were 6 schizophrenic patients with mainly positive schizophrenic symptoms and 17 patients with mainly negative symptoms; positive schizophrenic symptoms were not related to higher Bmax values. There was no difference in3H-spiperone binding between patients with and without movement disorders (tardive dyskinesia or extrapyramidal symptoms).

Splitting schizophrenia: periodic catatonia-susceptibility locus on chromosome 15q15.

The nature of subtypes in schizophrenia and the meaning of heterogeneity in schizophrenia have been considered a principal controversy in psychiatric research. We addressed these issues in periodic catatonia, a clinical entity derived from Leonhards classification of schizophrenias, in a genomewide linkage scan. Periodic catatonia is characterized by qualitative psychomotor disturbances during acute psychotic outbursts and by long-term outcome. On the basis of our previous findings of a lifetime morbidity risk of 26.9% of periodic catatonia in first-degree relatives, we conducted a genome scan in 12 multiplex pedigrees with 135 individuals, using 356 markers with an average spacing of 11 cM. In nonparametric multipoint linkage analyses (by GENEHUNTER-PLUS), significant evidence for linkage was obtained on chromosome 15q15 (P = 2.6 x 10(-5); nonparametric LOD score [LOD*] 3.57). A further locus on chromosome 22q13 with suggestive evidence for linkage (P = 1.8 x 10(-3); LOD* 1.85) was detected, which indicated genetic heterogeneity. Parametric linkage analysis under an autosomal dominant model (affecteds-only analysis) provided independent confirmation of nonparametric linkage results, with maximum LOD scores 2.75 (recombination fraction [theta].04; two-point analysis) and 2.89 (theta =.029; four-point analysis), at the chromosome 15q candidate region. Splitting the complex group of schizophrenias on the basis of clinical observation and genetic analysis, we identified periodic catatonia as a valid nosological entity. Our findings provide evidence that periodic catatonia is associated with a major disease locus, which maps to chromosome 15q15.

Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder suggest a contribution of the A2a gene to the development of disease.

Several lines of evidence suggest a contribution of adenosinergic neurotransmission to the development of panic disorder. We therefore hypothesized that variation in the A1 and A2a adenosine receptor (AR) genes modifies genetic susceptibility to panic disorder. To test this hypothesis, we screened 38 patients with panic disorder for mutations in the coding sequence of the A1AR and A2aAR genes. An association study between the identified DNA sequence variants and panic disorder was performed in an extended sample of 89 patients and matched controls. One silent mutation (716T/G) in the A1AR gene and two silent mutations (432C/T and 1083C/T) in the A2aAR gene were detected. The association sample shows a significant association between the 1083T allele (P = 0.01) and 1083T/T genotype (P = 0.024) of the A2AR gene and panic disorder. Our findings thus lend further support to the hypothesis that the A2aAR gene, or a locus in linkage disequilibrium with it, confers susceptibility to panic disorder. Replication studies in independent samples with nuclear families applying the transmission disequilibrium test (TDT) are warranted.

Cortex, white matter, and basal ganglia in schizophrenia : a volumetric postmortem study

Postmortem volumetry of cortex, white matter, and basal ganglia was performed in 23 brains of schizophrenic patients and 23 brains of controls closely matched for gender, age, and hemisphere. Stereological methods were applied to serial coronal sections of complete hemispheres. We found no significant volume changes of cortex and white matter in schizophrenics. Striatal volume of schizophrenics was increased bilaterally reaching a significant level on the left side. Volumes of the globus pallidus were increased in both hemispheres reaching a significant level on the right side. After psychopathological differentiation, basal ganglia volume increase was also found in the subgroup of paranoid-hallucinatory schizophrenics.

Systematic search for variation in the human norepinephrine transporter gene : Identification of five naturally occurring missense mutations and study of association with major psychiatric disorders

The complete coding region of the norepinephrine transporter (NET) gene was systematically screened for genetic variants in 137 unrelated individuals (including 46 probands with bipolar affective disorder and 45 schizophrenic probands, as well as 46 blood donors) using single-strand conformation analysis. We identified 13 DNA sequence variants, among them five missense substitutions. The missense substitutions Val69Ile, Thr99Ile, Val245Ile, Val449Ile, and Gly478Ser are located at putative transmembrane domains (TMD) 1, 2, 4, 9, and 10, respectively. The Thr99Ile substitution is at the 5th position of the putative leucine-zipper in TMD2. In a case-control study distribution of missense substitutions was found to be similar in 103 patients with bipolar affective disorder, in 228 schizophrenia patients and in 187 controls, indicating that presence of these variants is not causally related to major psychiatric diseases. The detection of a highly polymorphic silent 1287G/A polymorphism was utilized to demonstrate biallelic expression of the NET in adult human brain.

Parkinson’s disease and depression: evidence for an alteration of the basal limbic system detected by transcranial sonography

OBJECTIVES Depression is a frequent symptom in Parkinson’s disease. Compelling evidence suggests a role of the brainstem in the control of mood and cognition. In patients with unipolar depression transcranial sonography (TS) studies have shown structural alteration of the mesencephalic brainstem raphe which could suggest an involvement of the basal limbic system in the pathogenesis of primary mood disorders. The objective of the present study was to evaluate whether a similar alteration could be found in depressed patients with Parkinson’s disease using TS. METHODS Thirty patients with Parkinson’s disease and 30 age and sex adjusted controls were examined by TS. Raphe echogenicity was rated semiquantitatively. The severity of motor symptoms and depression was rated using standard research instruments. RESULTS Raphe echogenicity was significantly reduced in depressed patients with Parkinson’s disease compared with non-depressed patients with Parkinson’s disease and control subjects. Raphe echogenicity correlated negatively with degree of motor impairment, and differences in raphe echo between depressed and non-depressed patients with Parkinson’s disease were upheld when motor impairment was controlled for. CONCLUSION These preliminary findings suggest that, as in unipolar depression, a morphological alteration of the brainstem raphe might be involved in the pathogenesis of depression in Parkinson’s disease. This raphe alteration may reflect involvement in the basal limbic system in the pathogenesis of secondary depression. This concept is in line with current knowledge on the pathogenesis of both depression in Parkinson’s disease and primary depressive disorders.

Prenatal disturbances of nerve cell migration in the entorhinal region : a common vulnerability factor in functional psychoses ?

Both types of functional psychosis schizophrenia and manic depressive illness (MDI) share several epidemiological, clinical and genetic characteristics. Subtle morphological changes as evidenced by neuroimaging techniques have also been reported in both entities. Thus far, neuropathological changes have been described in schizophrenia only. We report four cases of MDI with neuropathological changes similar to those found in schizophrenia, i.e. definite disturbances in the cytoarchitecture within the entorhinal region indicating a migrational malformation in the superficial layers possibly originating in the second fetal trimester. A limited sector of the rostro-ventral insula showed a diminution of the nerve cell population. We suggest a vulnerability factor secondary to fetal developmental impairment in the entorhinal region common to both schizophrenia and MDI.