[Brain development before onset of the first psychotic episode and during outcome of schizophrenia]. / Die Gehirnentwicklung vor der psychotischen Erstmanifestation und im weiteren Verlauf der Schizophrenie.

A circumscribed association between copy number variations and the diagnosis of schizophrenia or autism but not bipolar disorder supports the notion of schizophrenia and autism principally representing a disturbed brain development. Data of multiply affected families show certain brain structural (e. g. hippocampal) changes to also be present in their first-grade relatives without leading to psychopathological abnormalities. It thus can be concluded that there exist regional fronto-temporal changes in schizophrenia due to genetically early determined primary vulnerability. The transition of this vulnerability into a prodrome to the point of the fully developed disease is triggered by relevant environmental factors. Hippocampal brain structural changes do not base on neuronal loss, for which reason the underlying mechanism might be a reduction of neuropil and thus a disturbance of synaptic processes or even regenerative mechanisms. Thus, disturbed regenerative mechanisms might be linked to the course of schizophrenic psychosis: the more pronounced the negative symptoms, the more evident the impaired synaptic or neuronal plasticity. Based on initial data we speculate the disturbed synaptic/plastic processes to result from an impaired epigenetic regulation. This could explain how relevant environmental factors (pregnancy and birth complications, early childhood abuse or cannabis abuse) via risk genes might lead to a destabilized neuronal network which in the end could trigger schizophrenia symptoms on the behavioral level.

Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: a study of the BrainNet Europe Consortium.

AIMS: Frontotemporal lobar degeneration with Pick bodies (Pick's disease) is characterized by the presence of tau immunoreactive spherical structures in the cytoplasm of neurones. In view of confusion about the molecular pathology of Pick's disease, we aimed to evaluate the spectrum of tau pathology and concomitant neurodegeneration-associated protein depositions in the characteristically affected hippocampus. METHODS: We evaluated immunoreactivity (IR) for tau (AT8, 3R, 4R), α-synuclein, TDP43, p62, and ubiquitin in the hippocampus, entorhinal and temporal cortex in 66 archival cases diagnosed neuropathologically as Pick's disease. RESULTS: Mean age at death was 68.2 years (range 49-96). Fifty-two (79%) brains showed 3R immunoreactive spherical inclusions in the granule cells of the dentate gyrus. These typical cases presented mainly with the behavioural variant of frontotemporal dementia, followed by progressive aphasia, mixed syndromes or early memory disturbance. α-Synuclein IR was seen only in occasional spherical tau-positive inclusions, TDP-43 IR was absent, and 4R IR was present only as neurofibrillary tangles in pyramidal neurones. Aß IR was observed in 16 cases; however, the overall level of Alzheimer's disease-related alterations was mainly low or intermediate (n = 3). Furthermore, we identified six cases with unclassifiable tauopathy. CONCLUSIONS: (i) Pick's disease may occur also in elderly patients and is characterized by a relatively uniform pathology with 3R tau inclusions particularly in the granule cells of dentate gyrus; (ii) even minor deviation from these morphological criteria suggests a different disorder; and (iii) immunohistological revision of archival cases expands the spectrum of tauopathies that require further classification.

Clinical, radiological and pathological correlates of leukoaraiosis.

INTRODUCTION: Leukoaraiosis is characterized by an abnormal appearance of the brain white matter on imaging. Its pathogenesis is still a matter of investigation. The purpose of this study was to investigate the radiological, clinical and pathological correlates of leukoaraiosis. METHODS: The study population consisted of 93 deceased patients. The pre-mortem T2W magnetic resonance images were evaluated for the presence and grading of leukoaraiosis. The clinical and pathological characteristics based on the clinical charts and autopsy reports were evaluated. Tissue specimens of the blocks of 19 brains that demonstrated severe leukoaraiosis and those of five control brains were excised and stained. RESULTS: The variables found to be significantly associated with leukoaraiosis were age and a clinical history of Parkinson's disease. Other risk factors and pathological markers of atherosclerosis were not significantly correlated with leukoaraiosis. No significant difference was found between the scoring of the myelin integrity, glial fibrillary acidic protein, cluster of differentiation 68 and smooth muscle actin. There was a significant difference with respect to thickening of vessels walls. CONCLUSIONS: Our pathological results indicate that structural vascular abnormalities characterized by vessel wall thickening are associated with leukoaraiosis, supporting the assertion that vascular changes and ischemia generate leukoaraiosis. The relations between parkinsonism and leukoaraiosis may be explicable through vascular effects on the circuitry of the basal ganglia.

Increased incidence of genetic human prion disease in Hungary.

The authors performed analysis of the prion protein gene (PRNP) in 27 out of 109 confirmed prion disease patients between 1994 and 2004. E200K mutation was found in 17 cases. Another 10 patients, lacking PRNP analysis, showed positive family history. The mean annual incidence (0.27/million) and proportion (25.6%) of genetic prion disease is unusually high in Hungary and might be related to the migration of ancestors from the Slovakian focus.

Regio entorhinalis in schizophrenia: more evidence for migrational disturbances and suggestions for a new biological hypothesis.

Recently we were able to replicate the original finding of migrational disturbances in the entorhinal cortex (ERC) of schizophrenic patients by measuring the distance of pre-alpha cell clusters to the pial surface. In order to replicate this finding, we performed a detailed analysis of the pre-alpha cell clusters in the ERC in post mortem brains of 22 schizophrenic patients and 15 control subjects. Cluster position relative to gray/white matter boundary were measured and normalized by the widths of the gray matter. In the ERC the pre-alpha cell clusters were situated significantly closer to the gray/white matter junction compared to normal controls (around 30 %, F = 9.52, p = 0.004). No specific effects of sex, age or region of investigation were found. In summary, this is another quantitative replication of pre-alpha cell cluster migrational disturbances in schizophrenia, which are possibly linked to neurobiological abnormalities, e.g. myeloarchitectonic changes. This supports the notion that developmental abnormalities are a core feature of schizophrenia and that the search for candidate genes has to include this aspect, too. However, it is very probable that vulnerability-associated changes - as outlined here - have to be distinguished from disease-related changes.

Autopsy verifies demyelination and lack of vascular damage in partially reversible radiation myelopathy.

STUDY DESIGN: Case report of recovering radiation myelopathy. OBJECTIVE: To present autopsy and functional imaging findings on a unique case of slowly recovering radiation myelopathy with the aim of the clarification of the underlying mechanism. PATIENT: The cervical spinal cord and the distal part of the medulla oblongata of a 36-year-old thyroid cancer patient had been incorrectly irradiated with a total dose of 61 Gy and a fraction size of 3.4 Gy (J Neurol Sci 1999; 163:39-43), resulting in incomplete cervical transection with a 5-month latency period following the termination of radiotherapy. This was followed by a 9.5-year spontaneous improvement until her demise, during which the check-ups were supplemented by positron emission tomography (PET) investigations; these indicated increased [18F]deoxyglucose and [15O]butanol uptakes, but a diminished [11C]methionine accumulation by the irradiated spinal cord segment. RESULTS: Autopsy revealed demyelination (with axonal loss) and neuronal damage in the cervical spinal cord and the distal part of the medulla oblongata. In the same region, only minimal vascular injury (thickening of some of the capillary walls) was detected, but not cell proliferation or chronic inflammation. Bilateral, secondary pyramidal tract degeneration caudal to the irradiated segment was observed. The PET and autopsy findings, although separated by 2 years, are consistent. CONCLUSIONS: The pathological state of the spinal cord revealed by the autopsy is concordant with the incomplete cervical transection, implying that the functional recovery is supported by a process that probably differs from the restoration of the mechanism destroyed by the radiotherapy. For the restoration of the function, we suggest an altered conduction mechanism of the action potential, involving an increased number of sodium channels along the demyelinated segments of the injured axons, which is fully congruent with the PET findings.

Key factors in Alzheimer's disease: beta-amyloid precursor protein processing, metabolism and intraneuronal transport.

During the last years it has become evident that the beta-amyloid (Abeta) component of senile plaques may be the key molecule in the pathology of Alzheimer's disease (AD). The source and place of the neurotoxic action of Abeta, however, is still a matter of controversy. The precursor of the beta-amyloid peptide is the predominantly neuronal beta-amyloid precursor protein. We, and others, hypothesize that intraneuronal misregulation of APP leads to an accumulation of Abeta peptides in intracellular compartments. This accumulation impairs APP trafficking, which starts a cascade of pathological changes and causes the pyramidal neurons to degenerate. Enhanced Abeta secretion as a function of stressed neurons and remnants of degenerated neurons provide seeds for extracellular Abeta aggregates, which induce secondary degenerative events involving neighboring cells such as neurons, astroglia and macrophages/microglia. Beta-amyloid precursor protein has a pivotal role in Alzheimer's disease.

Lewy body variant of Alzheimer's disease: alpha-synuclein in dystrophic neurites of A beta plaques.

The contribution of alpha-synuclein accumulation in Alzheimer's disease (AD) plaques is currently a matter of scientific debate. In the present study antisera against the N- and C-terminus, the full-length protein and the central so-called non-amyloid component (NAC) domain of the alpha-synuclein protein were used to address this question in brains of cases with typical AD and of cases with the Lewy body (LB) variant of AD. In typical AD cases, none of the antisera revealed evidence for co-accumulation of alpha-synuclein with extracellular A beta peptides in plaques or in dystrophic neurites decorating the plaque core. Interestingly, cases with mixed pathology of the LB variant of AD revealed accumulation of alpha-synuclein in LBs and in dystrophic neurites of A beta plaques.

Can intravascular lymphomatosis mimic sinus thrombosis? A case report with 8 months' follow-up and fatal outcome.

We report a case of intravascular lymphomatosis of the brain with 8 months' follow-up and fatal outcome. Several MRI investigations revealed variegated, rapidly changing infarct-like lesions and invasion of the walls of the superior sagittal sinus and deep veins. When disturbances of the venous outflow are detected with multifocal infarct-like lesions, intravascular lymphomatosis should be considered in the differential diagnosis. Brain biopsy may ensure the proper diagnosis ante mortem, but failure of biopsy is frequent, as in our case.

Apolipoprotein E polymorphism in Pick's disease and in Huntington's disease.

The polymorphism of apolipoprotein E (apoE) has been recognized as a genetic risk factor in different neurodegenerative disorders, with or without tau protein- related neuropathology, but few published epidemiological data are available as concerns the association of different apoE alleles with two relatively rare forms of dementia, Pick's disease (PiD) and Huntington's disease (HD). In this study the frequency of the apoE4 allele was examined in 36 persons with histopathologically proven PiD and compared with that of the apoE genotype in 28 HD probands and 79 aged healthy controls. The E4 allele was overrepresented selectively in PiD (42%) as compared with the control population (7%). No such association was found for HD probands (9%). This finding lends further support to the hypothesis that the E4 genotype is not an Alzheimer's disease specific susceptibility factor, and that it could be present in diverse dementing disorders with tau protein related neuropathology, such as PiD.

Axonal changes in chronic demyelinated cervical spinal cord plaques.

Imaging and pathomorphological studies in multiple sclerosis suggest that axonal injury and axonal loss are playing a crucial role in those with persistent disability and long-standing disease. Although the existence of axonal injury in multiple sclerosis is proven, especially in the zone of active inflammation, the effect of chronic inflammation on the axons remains elusive. The aim of this study was to perform a quantitative morphometrical analysis, estimating axonal loss and evaluating axonal degenerative changes in cervical spinal cord samples of patients suffering from secondary progressive multiple sclerosis. Completely demyelinated plaques, normal appearing white matter (NAWM) and control material from anatomically identical regions of the cord have been compared. Neurofilament immunostaining was used for identification of the axons. We observed a significant reduction of axonal density (number of axons/mm(2)) in multiple sclerosis, both in the plaque and in the NAWM compared with the control cases. Axons under approximately 3.3 microm diameter seemed to be more affected. The intensity of the immunostaining was significantly reduced in the plaque compared with either NAWM or control. Our results on the cervical cord combined with other observations support the concept of slow axonal degeneration rather than acute damage as a cause of chronic disability in multiple sclerosis.

Prion protein immunohistochemistry in Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease is a transmissible spongiform encephalopathy characterized clinically by dementia, myoclonus and, in some cases, periodic triphasic EEG-patterns. Neuropathologically the main features are spongiform change, astrocytosis, neuronal cell loss and, in a small percent of cases, amyloid plaques. Prion protein immunohistochemistry is used for definitive diagnosis of these diseases. In our study we present different immunostaining patterns in light microscopy using anti prion protein, and with immunogold labelling for ultrastructural localization of prion protein. Our results demonstrate the clinicopathological heterogeneity of Creutzfeldt-Jakob disease and reveal the role of the endosomal-lysosomal system in the pathogenesis.

[Creutzfeldt-Jakob disease]. / A Creutzfeldt-Jakob-betegségröl.

A most common form of human prion disease, also known as non-conventional slow virus diseases; Creutzfeldt-Jakob's disease is described in detail. The available data on the pathogenesis of the illness have recently changed and constitute a most exciting article of contemporary medicine. 109 cases are introduced that have been verified neuropathologically in Hungary until now; their summed up clinical data, the pathological findings and their epidemiological characteristics are discussed. It must be emphasized that the diagnosis of the illness cannot be inevitably confirmed clinically. Transplantation of organs or tissues of all deceased, who suffered of an illness with dementia, should be strictly avoided accordingly.

[Non-ketotic hyperglycinemia]. / Non-ketoticus hyperglycinaemia.

Three children with non-ketotic hyperglycinaemia (NKH) is reported. Two patients had typical neonatal form of NKH, one patients had atypical form of NKH. The clinical symptoms laboratory findings and therapeutical approach are discussed. One of the patients with typical neonatal form of NKH is died, neuropatological examination revealed corpus callosal agenesis and diffuse hypomyelinisation. The two children treated with N-methyl-D-aspartate-antagonist drugs reached a significantly better clinical condition. The authors reviewed the data of the literature, especially focused on the therapeutical possibilities.

[Wernicke encephalopathy in childhood osteosarcoma]. / Gyermekkori osteosarcomában elöforduló Wernicke-encephalopathia.

Two children with osteosarcoma are presented in whom Wernicke encephalopathy with vomiting occurred during the chemotherapy. One of the children died with symptoms of toxic cardiomyopathy. Autopsy revealed Wernicke encephalopathy. The other child had similar symptoms (ocular signs, ataxia, somnolence). Parenteral thiamine had been given and after this therapy the child recovered from the encephalopathy. The authors emphasize the importance of the recognition of this neurological disorder occurring rarely in childhood: it can be cured with parenteral thiamine. Without thiamine treatment this condition is lethal.