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Increased concentrations of kynurenine pathway metabolites have been reported by several groups for disorders involving psychosis, including schizophrenia and bipolar disorder. To identify components of the pathway that may be relevant as biomarkers or may underlie the etiology of psychosis, it is essential to characterize the extent of kynurenine pathway activation and to investigate known regulators of one of the key kynurenine-producing enzymes, tryptophan 2,3-dioxygenase (TDO2), previously shown in this laboratory to be increased commensurate with kynurenine in postmortem anterior cingulate brain tissue from individuals with schizophrenia. Using this same anterior cingulate sample set from individuals with schizophrenia, bipolar disorder, depression and controls (N=12-14 per group), we measured the precursor of kynurenine and two downstream products. The precursor, tryptophan, was significantly increased only in the schizophrenia group (1.54-fold the mean control value, p=0.02), and through substrate-induced activation, may be one cause of the increased kynurenine and kynurenine metabolites. This finding for tryptophan differs from some, but not all, previous reports and methodological reasons for the discrepancies are discussed. A product of kynurenine metabolism, 3-OH-anthranilic acid was also significantly increased only in the schizophrenia group (1.68-fold the mean control value, p=0.03). 3-OH-anthranilic acid is a reactive species with cytotoxic properties, although the threshold for such effects is not known for neurons. Analysis of major pre- and post-mortem variables showed that none were confounding for these between-group experimental comparisons. Nicotinamide, a pathway end product, did not differ between groups but was associated with cause of death (suicide) within the bipolar group (p=0.03).

Cellular prion protein (PrP(c)) is a copper-binding, membrane-attached GPI-anchored glycoprotein characterized by a high degree of amino acid sequence conservation among mammals. PrP(c) expression has been demonstrated in neurons, microglia, lymphocytes, and keratinocytes. Recently, the concept that PrP(c) may be involved in the defense against oxidative stress was advanced. In the present study, we used immunohistochemistry for PrP(c) to investigate 60 brains from the Stanley Neuropathology Consortium (15 controls, 15 patients with schizophrenia, 15 with bipolar disorder, and 15 with major depression). Rating scores as well as the numerical density of PrP(c)-positive and -negative neurons and glial cells were determined in the cingulate gyrus. All four groups showed a very high interindividual variation. PrP(c)-positive glial cells were significantly reduced in the white matter of patients with schizophrenia, bipolar disorder, and major depression. A similar result was obtained for the white matter in bipolar patients using rating scales. From the confounding variables, use of medication (i.e. antipsychotics, antidepressants, and mood stabilizers) had a significant effect on the expression of PrP(c) by neurons and glial cells. PrP(c)-immunoreactivities were significantly reduced for white matter glial cells in all examined groups. However, the results are not indicative for the occurrence of oxidative stress in the brains of schizophrenic and bipolar patients. Since the effect of antipsychotic and antidepressant medication as well as of mood stabilizers on the expression of PrP(c) was significant, it needs further clarification in experimental models.

We investigated the possible involvement of OTX2, a homeobox gene crucial for forebrain development, in the pathogenesis of schizophrenia and bipolar disorder. The disruption of this gene results in cortical malformations and causes serotonergic and dopaminergic cells in the midbrain to be expressed in aberrant locations. Resequencing of DNA from OTX2 exons and surrounding introns from 60 individuals (15 schizophrenia, 15 bipolar disorder, 15 depression, and 15 control) revealed two intronic polymorphisms, rs2277499 (C/T) and rs28757218 (G/T), but no other variations. The minor allele of rs2277499 (T) did not associate with clinical diagnosis. However, using a Taqman genotyping assay, we found the rs28757218 minor allele (T) in 30 out of 720 (4.2%) individuals with bipolar disorder but only in 6 out of 526 (1.1%) control individuals (odds ratio 3.5, 95% confidence interval 1.4–10.4, P = 0.003). On the other hand, the rs28757218 minor allele was only found in 6 out of 458 (1.3%) individuals with schizophrenia. All individuals with the rs28757218 polymorphism were heterozygous for the allele. Based on this positive case-control association finding, we conclude that variations in OTX2 might confer risk for the development of bipolar disorder. © 2007 Wiley-Liss, Inc.

The quality of results from microarray studies depends on RNA quality, which can be significantly influenced by postmortem factors. The aim of this study was to determine which postmortem factors and/or RNA electropherogram characteristics best correspond to microarray output and can be used to prospectively screen RNA prior to microarray analysis. Total RNA was extracted (N=125) from gray and white matter of postmortem frontal and occipital lobe tissue, acquired from normal controls, and patients with schizophrenia, bipolar disorder or major depression. Electropherograms were generated by the Agilent BioAnalyzer 2100, allowing calculation of the 28S/18S ratio, the 18S/baseline peak ratio and the RNA Integrity Number (RIN). These values were compared to post-hybridization image analysis of Affymetrix microarrays. The postmortem variables correlated with some quality measures but could not be used as effective screening tools. Logistic regression demonstrated that all three electropherogram measures were predictive for microarray quality, and that the RIN threshold predictive of "good quality" (>35% present calls) was most consistent with that of prior studies. The optimal RIN must be determined by the investigator's specifications for false inclusion and false exclusion. In contrast to RIN, the quality threshold for the 28S/18S ratio has proven unacceptably variable, due to sensitivity to slight differences in protocol and/or tissue source. In conclusion, the measures we found useful as screening criteria do not replace the need to exclude samples after a microarray analysis is performed, as an acceptable percent call rate and other measures of microarray quality represent the desired endpoint.

The human endogenous cannabinoid system is an appealing target in the investigation of psychiatric disorders. In schizophrenia, endocannabinoids and their receptors are involved in the pathology of the disease. Previous studies reported an increased radioligand binding to cannabinoid receptors 1 (CB(1)) in schizophrenia, both in the dorsolateral prefrontal cortex and in the anterior cingulate cortex (ACC). We analyzed the expression of the CB(1) receptors in the ACC at the protein level using immunohistochemistry. In a quantitative postmortem study, 60 patients suffering from schizophrenia, bipolar disorder, major depression and controls were included. Numerical densities of neurons and glial cells immunopositive for CB(1) receptors were evaluated. No evidence of an increased or decreased density of CB(1) receptor immunopositive cells in schizophrenia or bipolar disorder was found. In major depression, CB(1) receptor immunopositive glial cells in the grey matter were decreased. Furthermore, our data show that different medications have an impact on the expression of CB(1) receptors in the ACC.

Background In drug abusers, white matter changes have been described by neuroimaging analyses in different brain regions. A specific pattern of involvement or a predominance of a specific brain region could not be drawn. Aims To examine alterations of the white matter as a possible morphological substrate of the neuroimaging findings. Methods Brain specimens of 30 polydrug abusers and 20 controls were obtained at autopsy. The white matter from 11 different brain regions was analysed by means of immunohistochemistry for β-amyloid precursor protein (β-APP), a marker of axonal damage. Findings In the white matter of polydrug abusers, β-APP-immunopositive accumulations were increased significantly compared to controls. They were more prominent in the brains of younger drug abusers than in those of the elderly. With the exception of five cases (four polydrug abusers and one control case), there were no significant white matter changes seen on myelin-stained sections, but there was a concomitant microglial activation. Conclusions Our results show a significant axonal damage in the brains of polydrug abusers, which might represent the morphological substrate of a chronic-progressive drug-induced toxic-metabolic process. It is yet to be established if the observed changes are responsible for the alterations seen in different neuroimaging analyses and which drugs of abuse might be of major pathogenetic significance.

Although, the pathogenetic mechanisms of schizophrenia, bipolar disorder, and major depression are not clearly understood, various neurotransmitter systems are reported to have altered expression patterns of their receptor and transporter proteins. Changes in the expression of the neutral amino acid transporter 1 (ASCT-1) protein in the anterior cingulate gyrus and the hippocampus were investigated using immunohistochemistry and western blotting. A significant decrease in ASCT-1 immunoreactivity in neurons in the cingulate cortex as well as astrocytes of the white matter was seen in schizophrenia. In bipolar disorder and major depression, similar results were seen for neurons. In the hippocampus, there was a striking loss of immunoreactivity on astrocytes, neurons and interneurons in multiple regions in schizophrenia and bipolar disorder, while only minor changes were seen in major depression. The altered expression of ASCT-1 in neurons and astrocytes reflects profound changes in glutamatergic neurotransmission and highlights a significant role of astrocytes in the pathophysiology of neurotransmission in these major psychiatric disorders.

Upregulation of the kynurenine pathway has been associated with several etiologies of psychosis, an indication that increased levels of pathway intermediates might be involved in eliciting some psychotic features. In schizophrenia, tryptophan 2,3-dioxygenase (TDO2) was previously identified in postmortem frontal cortex as the enzyme likely responsible for the reported increase in pathway activity in the brain. For this follow-up study of postmortem anterior cingulate gyrus, we have found evidence of increased TDO2 activity in schizophrenia at three different levels of regulation: mRNA, protein, and metabolic product. The results were unaffected by neuroleptic status or smoking history. To make the distinction between mental disorders with psychosis and those without, this study included patients with bipolar disorder and major depression. Compared to the control group, the HPLC, RT-PCR, and immunohistochemistry results show significant elevation of (1) kynurenine in schizophrenia (1.9-fold, P = 0.02), and in bipolar disorder (1.8-fold, P = 0.04), primarily in the bipolar subgroup with psychosis (2.1-fold, P = 0.03); (2) TDO2 mRNA in schizophrenia (1.7-fold; P = 0.049); and (3) the immunohistochemistry values for the density of TDO2-positive white matter glial cells in schizophrenia (P = 0.01) and in major depression (P = 0.03) as well as the density and intensity of glial cells (in both gray and white matter) stained for TDO2 in bipolar disorder (P = 0.02). Unlike the results for schizophrenia and bipolar disorder, the increase in TDO2 protein in the major depression group was not associated with an increase in kynurenine concentration.

Left ventricular assist devices (LVAD) are used to "bridge" patients with end-stage heart failure until transplantation of a donor heart can be performed ("bridge to transplantation"). However, in a subset of patients, support by LVAD sporadically results in improved cardiac function, with heart transplantation no longer necessary even after removal of the LVAD ("bridge to recovery"). Also, LVAD appears to be an optional treatment alternative to heart transplantation in patients with contraindications for organ replacement ("destination therapy"). The processes resulting in these effects have descriptively been termed "reverse remodeling". Although the molecular mechanisms are incompletely understood at present, there are several aspects of the reverse remodeling process that have been identified in the past. Alterations of many molecular pathways are involved in the development of chronic heart failure. Some of these appear to be reversible and have been shown to be regulated by LVAD treatment. LVAD lead to lowered cardiac pressure and volume overload in the myocardium followed by decreased ventricular wall tension, reduced cardiomyocyte hypertrophy, improved coronary perfusion and decreased chronic ischemia. Improved coronary flow and myocardial perfusion as well as decreased ventricular wall tension may possibly alter the molecular systems involved in the development of chronic cardiac insufficiency. Aside from describing the morphological changes, this review focuses on the roles of signal transduction, transcriptional regulation, apoptosis, stress proteins, matrix remodeling, and neurohormonal signaling in the failing human heart before and after mechanical circulatory support. © 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

An association of the obligatory intracellular gram-negative pathogen Chlamydia pneumoniae with coronary artery disease, myocardial infarction, and atherosclerosis was suggested. The presence of C pneumoniae was determined in different arteries (n = 165) from 23 control cases and 10 patients with stroke including coronary arteries, carotid arteries, basilar artery, and middle cerebral arteries of normal controls and patients with stroke using nested polymerase chain reaction (PCR) and immunohistochemistry (IHC). Atherosclerosis was detected in 51.5% of all investigated arteries. No significant differences were detected between controls (59.1% by IHC, 45.5% by nested PCR) and patients with stroke (40% by IHC, 40% by nested PCR). This is the first investigation demonstrating C pneumoniae by IHC and nested PCR in different intracerebral arteries in control persons and patients with stroke. No significant correlation between the presence of chlamydial DNA or antigens in arteries and stroke could be demonstrated. The presence of the C pneumoniae is indicative of a correlation between infection and atherosclerosis, but not of a specific vascular neuropathology such as stroke.

Drug abuse represents a significant forensic issue worldwide. The major substances abused include cannabis, opiates, cocaine, amphetamine, methamphetamine, and “ecstasy.” Besides cardiovascular complications, psychiatric and neurologic symptoms are the most common manifestations of drug toxicity. A broad spectrum of changes affecting the central nervous system is seen in drug abusers. The major findings result from the consequences of cerebral ischemia and cerebrovascular diseases. Especially persons with underlying arteriovenous malformation or aneurysm are at higher risk for such events. So far, except for a few instances of vasculitis, the etiology of these cerebrovascular events is not completely understood. Besides pharmacologically induced vasospasm, impaired hemostasis, platelet dysfunction, and decreased cerebral blood flow have been proposed. Based on animal experiments, the abuse of amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) has been related to neurotoxicity in human long-term abusers and to the risk of developing Parkinson’s disease. However, whether such neurotoxicity occurs remains to be established. A major focus of research in the neurobiology of addiction has been put on the drug-induced adaptations within the brain reward system. Alterations of the intracellular messenger pathways, transcription factors, and immediate early genes in these reward circuits seem to be fundamentally important for the development of addiction and chronic drug abuse.

BACKGROUND Tenascin-C (TN-C), a large extracellular matrix (ECM) glycoprotein with a molecular weight of 180–250 kilodaltons, is present in several normal adult tissues. TN-C is up-regulated during embryogenesis, in wound healing, and in tumor tissues. Glioblastoma multiforme (GBM) is the most frequent and malignant astrocytic tumor comprised of poorly differentiated, neoplastic astrocytes. Recently, TN-C-based radioimmunotherapy was administered to patients with GBM. METHODS In the current study, the authors used immunohistochemistry to conduct a systematic investigation of TN-C distribution patterns in normal human brain tissue and in a large variety of brain tumors (n = 485 tumors). Immunoreactivity for TN-C was assessed with regard to its localization within tumor cells, blood vessels, and ECM using three different monoclonal antibodies (clones BC2, BC4, and TN2). RESULTS In control human brains, a significant difference was noted in the expression of TN-C when comparing gray with white matter using either Western blot analysis or immunohistochemistry. TN-C was found in the white matter of the frontal, temporal, parietal, and occipital lobes and in the hippocampus, where the immunoreaction was especially strong in the hippocampal formation. In 181 astrocytomas of different grades (World Health Organization [WHO] Grade 2–4), TN-C immunopositivity was seen to varying degrees in the cellular and stromal components of the tumor and in tumor-associated vessels. Glioblastomas (n = 113 tumors) showed strong immunopositivity in the vessels and moderate immunopositivity of the ECM. A statistically significant reduction of TN-C immunopositivity in tumor-associated vessels or ECM was observed in anaplastic astrocytomas (WHO Grade 3) compared with GBM (WHO Grade 4). A Kaplan–Meier analysis showed that patients who had GBM lesions that lacked TN-C immunopositivity in the ECM had a significantly longer survival (median, 28 months; standard error, 7.8 months) (n = 12 patients) compared with patients who had GBM lesions with TN-C immunopositivity (median, 12 months; standard error, 1.6 months) (n = 87 patients). In meningiomas (n = 24 tumors), the neoplastic cells, the ECM of the tumor, and the vessels were TN-C negative. In schwannomas (n = 31 tumors), the tumor cells were TN-C negative; whereas, in > 50% of tumors, the vessels and the ECM of regressively altered tumor areas were positive. In metastatic carcinomas (n = 53 tumors), the tumor cells were negative; seldom were vessels stained positive for TN-C. Focal areas of the ECM, often accompanied with fibrotic changes, were immunopositive for TN-C. CONCLUSIONS The most constant TN-C immunopositivity was noted in the ECM of the fibrotic stroma in highly malignant brain tumors and along the tumor border, especially in high-grade astrocytomas. The current results suggest that TN-C expression may be correlated with the grade of malignancy in astrocytic tumors and that the presence or absence of TN-C expression in the stroma of astrocytic tumors may play a not yet clearly understood role in shortening or prolonging, respectively, the survival of patients. Cancer 2003. © 2003 American Cancer Society.

Cocaine abuse represents a worldwide significant forensic issue as it is becoming widely recognized as one of the most dangerous illicit drugs in common use today. Besides cardiovascular complications, psychiatric and neurologic symptoms are the most common manifestations of cocaine toxicity. The latter include seizures, movement disorders and cerebrovascular complications. In chronic cocaine abusers morphological, physiological, and neurochemical abnormalities have been demonstrated by using neuroradiological techniques such as computed tomography, magnetic resonance imaging, positron emission tomography or single photon emission computed tomography. The spectrum of neuropathologic changes encountered in the brains of cocaine abusers is broad, but the major findings consist of ischemic and hemorrhagic stroke, subarachnoid and intracerebral hemorrhages and cerebral ischemia. Especially persons with underlying arteriovenous malformation or aneurysm are at risk for such events. Except for a few instances of vasculitis, the etiology of cocaine-related cerebrovascular accidents is still unclear. Besides pharmacologically-induced vasospasm, impaired hemostasis and platelet function and decreased cerebral blood flow have been proposed. At the cellular level, abnormalities in the expression of transcription factors and changes of brain neurotransmitter systems have been reported.

A patient with a history of an uterine leiomyosarcoma presented with diplopia, gait disturbances, and hypesthesia of the right face. MRI of the head showed a lesion located in the pons and causing obstructive hydrocephalus. Open biopsy revealed a metastatic tumor with histological features of leiomyosarcoma. Despite whole-brain irradiation, the patient died due to respiratory arrest. This case illustrates that brain stem metastasis may occur as a rare complication in uterine leiomyosarcoma.

Background/Aims: To identify somatic mutations in the mitochondrial DNA of glioblastomas, in a previous study the displacement loops of 17 glioblastomas and corresponding blood samples were sequenced and instabilities in repeats or transitions were detected in seven tumours. This study was extended by sequencing 10 DNA samples of diffuse astrocytomas (World Health Organisation grade II) and corresponding blood samples. Methods: The 10 DNA samples of diffuse astrocytomas and corresponding blood samples were amplified and sequenced using fluorescent nucleotides. Results: No sequence differences were detected, with the exception of a quantitative shift between two genotypes heteroplasmic within the hypervariable region 2, which can be interpreted as mitotic drift. In the glioblastoma series, any particular somatic mutation was usually found in only one tumour. The only frequent alteration was coupled to a mitochondrial germline polymorphism under-represented in the low grade astrocytoma group. Moreover, a single mutation in two patients with secondary glioblastomas had already been detected in diffuse astrocytomas of these individuals. Conclusions: A lower percentage of mitochondrial DNA mutations in low grade tumours cannot be deduced from these data.

We present the case of a young woman who suffered from acute lymphatic leukaemia when she was 8 years old. She was treated with bone marrow transplantation and intrathecal chemotherapy. The girl recovered and was considered disease-free. The Ommaya-reservoir and catheter to the ventricle in the right frontal lobe were left in situ. Twenty years later, a tumour was diagnosed that was located around the catheter. Histology disclosed an anaplastic oligo-astrocytoma WHO III.

The stabilization of telomeres by upregulation of telomerase is compulsive for indefinite proliferation and cell immortalization therefore representing a main feature of malignant solid tumors, including gliomas. However, the mechanisms responsible for cancer-associated telomerase activation are not completely understood. Recently, defined mutations in the TERT promoter were identified in a variety of tumors, most frequent in primary glioblastomas (GBM). Presence of the mutations was associated with increased TERT expression. In the present study GBM derived tumor tissue from 126 patients operated at the Wagner Jauregg Hospital were screened for TERT promoter mutations. Subsequently the collected data were correlated with telomere associated parameters (telomerase activity, TERT mRNA expression, telomere lengths), the glioma biomarkers MGMT promoter methylation and IDH1 mutation as well as clinical parameters including patient survival. Using direct sequencing, the TERT promoter mutations (C228T, C250T) were found in 73% of tumors with predominance of C228T (72% of the mutated cases). Thirty-four (27%) samples contained none of the investigated TERT promoter mutations while mutations at both sites occurred in none of the investigated GBM cases. TERT promoter mutations were accompanied by a significant upregulation of telomerase activity (p = 0.0005) and TERT mRNA expression (p = 0.0004). Accordingly, telomere lengths of TERT promoter mutated tumors were significantly shorter compared to the TERT promoter wild-type subgroup (p = 0.001). Moreover, Kaplan-Meier survival analyses revealed a significantly shorter overall survival for GBM patients harbouring mutant tumors (p < 0.0001). In the multivariate Cox regression analysis TERT promoter mutation was found to have independent prognostic power (p = 0.049) but reached elevated significance in the interaction with age (p = 0.007). Accordingly, the prognostic quality of TERT promoter mutations was confined to the subgroup of patients aged younger than 65 years and completely absent in the older patient cohort. Significantly enhanced TERT mRNA expression and reduced telomere lengths in the aged patients were only observed in the subgroup lacking TERT promoter mutations. Summarizing, these results suggest that the negative prognostic value of TERT promoter mutation is restricted to patients of younger age further corroborating age-associated differences in the way of glioblastoma-associated telomere stabilization.

Abnormalities of the sarcotubular system presenting as tubular aggregates (TAs) have been described in a variety of neuromuscular disorders. Here, we report on immunohistochemical and biochemical findings in 7 patients (2 familial and 5 sporadic cases) suffering from myopathies with TAs. In muscle biopsy specimens from 5 of the 7 patients, TAs were immunopositive for the ryanodine receptor (RYR 1) of the sarcoplasmic reticulum (SR), the SR Ca 2+ pump (SERCA2-ATPase), and the intraluminal SR Ca 2+ binding protein calsequestrin, indicating an SR origin of these aggregates. Furthermore, these 5 cases showed decreased respiratory chain enzyme activities (NADH:CoQ oxidoreductase, complex I and cytochrome c oxidase [COX], complex IV), while the remaining 2 patients exhibited normal values. Our findings indicate a functional link between mitochondrial dysfunction and the presence of TAs originating from the sarcoplasmic reticulum.

In an earlier study, we showed that heteroplasmy in the mitochondrial genome of gliomas sometimes occurs in a D-loop polycytosine tract. We extended this study by pairwise comparisons between glioma samples and adjacent brain tissue of 55 patients (50 glioblastomas, 1 astrocytoma WHO grade III, 4 astrocytomas WHO grade II). We used a combination of laser microdissection and PCR to detect and quantify variations in the polycytosine tract. New length variants undetectable in the adjacent brain tissue were observed in 5 glioblastomas (9%). In 2 of these cases, samples from a lower tumor stage (WHO grade II) could be analyzed and revealed the early occurrence of these mutations in both cases. Since the mitochondrial D-loop contains additional repeats and highly polymorphic non-coding sequences, we compared 17 glioblastomas with the corresponding blood samples of the same patients by direct sequencing of the complete D-loop. In 6 of these tumors (35%), instability was detected in 1 or 2 of 3 repeat regions; in 1 of these repeats, the instability was linked to a germline T-to-C transition. Furthermore, of 2 tumors (12%) 1 carried 1 and the other 9 additional transitions. In the latter patient, 6.7 kb of the protein coding mtDNA sequence were analyzed. Six silent transitions and 2 missense mutations (transitions) were found. All base substitutions appeared to be homoplasmic upon sequencing, and 89% occurred at known polymorphic sites in humans. Our data suggest that the same mechanisms that generate inherited mtDNA polymorphisms are strongly enhanced in gliomas and produce somatic mutations.

A broad spectrum of neuropathologic changes are encountered in the brains of heroin abusers. The main findings are due to infections, either due to bacterial spread from bacterial endocarditis, mycoses, or from HIV-1 infection. Other complications include hypoxic-ischemic changes with cerebral edema, ischemic neuronal damage and neuronal loss, which are assumed to occur under conditions of prolonged heroin-induced respiratory depression, stroke due to, for example, thromboembolism, vasculitis, septic emboli, hypotension, and positional vascular compression. Myelopathy is believed to be the result of an isolated vascular accident within the spinal cord due to an as yet unknown mechanism. A distinct entity, spongiform leukoencephalopathy, has been described mainly after inhalation of pre-heated heroin. A lipophilic toxin-induced process was considered to be due to contaminants and to be induced or enhanced by cerebral hypoxia, but a definite toxin could not be identified. At the cellular level, abnormalities in signal transduction systems and changes of various receptor densities have been reported. The exact etiology of the different neuropathological alterations associated with heroin abuse is still unclear, but may also be related to additional substances used as adulterants.

Extrapyramidal motor disorders are frequently noted in HIV-1-infected patients. In the present study, the substantia nigra was analyzed morphometrically to detect neuronal changes which might contribute to the pathogenetic mechanisms causing extrapyramidal motor dysfunction in HIV-1-infected patients. The numerical density and the size of pigmented, non-pigmented small, and non-pigmented large neurons in four nuclei of the substantia nigra pars compacta (antero-medial, antero-intermediolateral, postero-lateral, and postero-medial nuclei) in HIV-1-infected patients and in age-matched normal controls were determined. In HIV-1-infected brains, the numerical density of total neurons (i.e., pigmented and non-pigmented) as well as of pigmented neurons was significantly decreased, whereas that of non-pigmented neurons was not significantly changed in all investigated nuclei of the substantia nigra as compared to normal controls. A specific pattern of increase and decrease of non-pigmented large and non-pigmented small neurons was observed. The size of total neurons (pigmented and non-pigmented neurons) and of pigmented neurons was significantly reduced in all investigated nuclei of HIV-1-infected brains. The results suggest that neuronal degeneration in the substantia nigra commonly occurs and may be related to extrapyramidal symptoms in HIV-1-infected patients.

A rare case of gliosarcoma in a 61-year-old woman is presented with a stable situation over 22 years with an excellent quality of life.The patient was initially symptomatic and was operated on in 1975 for a deep-seated left parietal gliosarcoma. During the following 20 years, she was clinically asymptomatic until she complained of increasing headache in 1995. Neuroradiological imaging showed a sharply demarcated lesion on MRI at the former operative site, which was operated on again. Four months later, the residual tumour did grow again.As radiation therapy could not stop tumour progression and the neurological status worsened, the patient was operated on again for a massive tumour mass in the left parieto-occipital region, filling out nearly all of the previous resection cavity. Despite radio-immunotherapy, the patient finally died 22 years after the first discovery of the tumour.The present case shows that, in rare instances, gliosarcomas may show prolonged survival, although the underlying pathogenetic mechanisms for this clinical behaviour are not understood.

Two cases of unexpected death in persons with epileptic seizures due to a brain tumor are presented which encompassed an astrocytoma WHO grade II and an anaplastic astrocytoma WHO grade III. A 35-year-old man was found somnolent and disoriented at home. A computed tomography (CT) scan revealed a tumor of the right frontal lobe suggestive for an oligodendroglioma. During an angiographic examination the patient experienced an epileptic seizure. Some weeks later, the man was found dead in front of his house with a fresh bite mark of the tongue. Neuropathological examination revealed an astrocytoma WHO grade II of the right frontal lobe. A 47-year-old man plunged into a swimming-pool and was found submerged some minutes later. After resuscitation he survived comatous for 8 days but finally died due to severe hypoxic brain damage. He had been operated on a brain tumor of the temporal lobe 1 year before the accident. Neuropathological examination revealed residual tumor tissue at the operation site corresponding to an anaplastic astrocytoma WHO grade III. Although rare, death in persons with epileptic seizures due to brain tumors is an important mechanism of death encountered by the forensic pathologist.

✓ Epidural cavernous hemangiomas are increasingly identified as a cause of acute or chronic progressive spinal cord syndrome and local back pain or radiculopathy. The authors present three cases of spinal epidural cavernous hemangiomas manifesting as spinal cord syndrome, thoracic radiculopathy, and lumbar radiculopathy. Based on the imaging characteristics of these three cases and a review of the literature, the clinical signs and symptoms and their implications, the role of preoperative neuroradiological diagnosis, and the need for complete surgical resection are discussed. Epidural cavernous hemangiomas display consistent magnetic resonance imaging properties: T1-weighted images most commonly show a homogeneous signal intensity similar to those of spinal cord and muscle, and contrast enhancement is homogeneous or slightly heterogeneous. On T2-weighted images the signal of the lesion is consistently high and slightly less intense than that of cerebrospinal fluid. Frequently, the lesion is characterized by its extension through the intervertebral foramen. Awareness of these characteristics facilitates diagnosis and treatment of the lesions. Despite the risk of bleeding, in all three cases complete surgical excision was achieved.

The ability to visualize median-sagittal brain structures by magnetic resonance imaging improves planning for surgery to treat lesions of the third ventricle. The most appropriate path to the third ventricle is the transcallosal approach. The present study was undertaken to describe the surgical anatomy and landmarks encountered during this approach.The transcallosal-interforniceal approach was undertaken in 30 formalin-fixed brains using an operating microscope. The surface landmarks for the approach pathway were the two points, P5 and P7, located 5 and 7 cm anterior to the central sulcus, respectively. Using these two points on the cortical surface as references, a variety of measurements were made to provide quantitative information about distances between brain structures that are encountered during the surgical approach. Measurements that were made include the following: 1) the distance between P5 and the cingulate sulcus, 2) the distance between the cingulate sulcus and the corpus callosum, 3) the height of the corpus callosum, 4) the distance between the anterior commissure and the foramen of Monro, and 5) the distance between the lower margin of the corpus callosum and the fornix.Mean values for these key measurements were as follows: 1) 23.96 mm (range, 15.0-32.0 mm); 2) 13.50 mm (range, 8.0-20.0 mm) with reference to P5 and 12.73 mm (range, 16.0-18.0 mm) with reference to P7; 3) 6.12 mm (range, 4.0-8.0 mm) with reference to P5 and 6.60 mm (range, 4.0-9.0 mm) with reference to P7; 4) 4.96 mm (range, 2.5-10.0 mm), independent of P5 and P7; and 5) 8.46 mm (range, 3.0-16.0 mm) with reference to P5 and 11.04 mm (range, 6.0-22.0 mm) with reference to P7.The detailed quantitative information obtained in this study about the interforniceal approach permitted definition of surgical approach pathways that preserve important anatomic structures, such as the motor strip, genu of the corpus callosum, fornical commissure (hippocampal commissure), anterior commissure, and fornical columns. The approach through this surgical corridor can easily be planned and performed in individual cases using median-sagittal magnetic resonance imaging scans.

OBJECTIVE AND IMPORTANCE: Endodermal cysts are rare lesions that primarily affect the spinal cord. Only a few reports have been published that describe intracranial endodermal cysts, and, in most of the cases, the cysts were located in the posterior fossa. To our knowledge, there have been no reports of endodermal cysts of the third ventricle. CLINICAL PRESENTATION: A symptomatic endodermal cyst of the third ventricle in a 28-year-old man is presented. The patient demonstrated signs of increased intracranial pressure and reported a progressive loss of vision in his right eye. Neuroradiological imaging revealed obstructive hydrocephalus and a lesion inside the third ventricle measuring 1.2 cm in diameter and occluding the interventricular foramen. INTERVENTION: The cyst was successfully removed via a transcallosal-transforaminal approach. Postoperatively, the patient developed bifrontal effusions for some days. Hydrocephalus was diminished, but his vision had only slightly improved. CONCLUSION: To our knowledge, this is the first published report of an endodermal cyst occurring in the third ventricle, and represents a further example of the broad spectrum of lesions affecting that location.

Defects of respiratory chain complexes were considered as possible pathogenetic mechanisms in Parkinson's disease (PD). Changes of cytochrome c oxidase (COX) in four different nuclei of the substantia nigra of 8 PD cases and 10 age-matched controls were investigated by means of morphometry and immunohistochemistry. Pigmented neurons with COX defects were randomly distributed within the the four nuclei of PD cases, but only in the posterolateral nucleus was the numerical density of pigmented neurons with COX defects significantly increased compared with controls. The numerical density of pigmented neurons without COX defects was significantly reduced in the anteromedial, anterointermediolateral, and posterolateral nuclei in PD. The cell size of pigmented neurons with and without COX defects was significantly diminished in the anteromedial and posterolateral nuclei of PD cases. It is suggested that complex IV defects in nigral neurons are most probably a result of accelerated aging, but are least likely to be a primary aspect of the pathogenetic processes occurring in PD.

BackgroundHuman prion diseases are a group of rare fatal neurodegenerative conditions with well-developed clinical and neuropathological diagnostic criteria. Recent observations have expanded the spectrum of prion diseases beyond the classically recognized forms.ResultsIn the present study we report six patients with a novel, apparently sporadic disease characterised by thalamic degeneration and rapidly progressive dementia (duration of illness 2–12 months; age at death: 55–81 years). Light and electron microscopic immunostaining for the prion protein (PrP) revealed a peculiar intraneuritic distribution in neocortical regions. Proteinase K resistant PrP (PrPres) was undetectable by Western blotting in frontal cortex from the three cases with frozen tissue, even after enrichment for PrPres by centrifugation or by phosphotungstic acid precipitation. Conformation-dependent immunoassay analysis using a range of PK digestion conditions (and no PK digestion) produced only very limited evidence of meaningful D-N (denatured/native) values, indicative of the presence of disease-associated PrP (PrPSc) in these cases, when the results were compared with appropriate negative control groups.ConclusionsOur observation expands the spectrum of conditions associated with rapidly progressive dementia and may have implications for the understanding of the pathogenesis of prion diseases.

Based on morphological, biochemical, and molecular biologic analyses, degeneration of the dopaminergic nigrostriatal system has been reported to occur with normal aging. In the present study, the substantia nigra of 36 human brains with normal aging was investigated by means of morphometry and immunohistochemistry. The anteromedial (Am), anterointermediolateral (Ail), posteromedial (Pm), and posterolateral (Pl) nuclei of the substantia nigra were analyzed using antibodies directed against the subunits II/III of cytochrome c oxidase (COX), the complex IV of the respiratory chain. The numerical density of melanin-positive neurons with COX defects was significantly increased in the four investigated nuclei, namely Am, Ail, Pm, and Pl. These cells did not show any histologic signs of degeneration. The numerical density of melanin-positive neurons without COX defects was decreased with aging. The data of the present study indicate that complex IV defects of neurons in the substantia nigra might be one cause of neuronal dysfunction occurring during aging.

Motor dysfunction is frequently noted in human immunodeficiency virus type 1 (HIV-1)-infected patients. Until recently, neuropathological changes found in the basal ganglia were advanced as pathogenetic mechanisms. In the present study, further brain structures involved in motor control were analyzed morphometrically. The volume density, numerical density, and the size of neurons in the cerebellar dentate nucleus and in both inferior olivary nuclei were determined. In both regions of HIV-1-infected brains, a significant reduction in the volume density, the numerical density of neurons and neuronal size was apparent. The morphometric data from the present study disclose involvement of both types of nuclei investigated during the course of HIV-1 infection, and might constitute a possible morphological substrate for the motor dysfunction seen in HIV-1-infected patients.

A case of an AIDS patient with a CMV-infected subependymoma of the fourth ventricle is presented. The tumor was incidentally found at autopsy and was not suspected during the clinical course. This is the first report of a subependymoma in HIV-1 infection. Moreover, infection of a tumor with CMV is an extremely rare condition, which has until now been described only once in an anaplastic astrocytoma.

Die Veranderungen der unterschiedlichen Zellsysteme im Gehirn von HIV-1 infizierten, verstorbenen Patienten wurden mit morphometrischen Methoden untersucht.

Gliomas frequently occur in boxer dogs and are often located in the rhinencephalic allocortex. This brain region contains unusual glial cell nests (GCN). The presence of structural abnormalities in the GCN in the boxer dog might indicate that they are involved in the development of gliomas, which would explain the predisposition of this canine breed for glioma formation. Therefore, the brains of six brachycephalic (boxer dogs) and five dolichocephalic dogs were investigated morphometrically. The volumes of the whole brain, the allocortex, and the GCN were estimated following Cavalieri's principle. Unbiased estimates of the numerical density and total number of the two prevailing cell populations within the GCN were obtained using the optical disector method. There was no significant difference for the estimated parameters between brachycephalic and dolichocephalic dogs. The results of the present study did not show any evidence of boxer dog-specific features of the GCN, thus, failing to explain the striking glioma predisposition of boxer dogs.

Sind wissenschaftliche Untersuchungen des menschlichen Gehirns auf makroskopischer Ebene heutzutage noch angebracht? Die kombinierte Anwendung von Morphometrie und 3D Rekonstruktion einerseits sowie CT und MR andererseits, ergeben neue und interessante Aspekte fur Untersuchungen des menschlichen Gehirns auf makroskopischer Ebene. Um diese Pramisse aufzuzeigen, wurden folgende Untersuchungen durchgefuhrt: (1) Die Veranderungen des Gehirns bei Personen mit Down Syndrom wurden morphometrisch an MR-Bildern erfast. (2) Mittels CT und MR wurde das menschliche Gehirn dreidimensional rekonstruiert.

The activation pattern of microglia in the cerebral cortex of AIDS patients with the neuropathological diagnosis of HIV-1 encephalitis was investigated by immunohistochemistry and morphometry. The number of activated microglial cells in the grey and white matter of five cortical regions was determined. In the grey and white matter of all cortical regions a significant increase in the number of microglial cells was demonstrated in HIV-1 infected brains. Moreover, the activation of microglia was not correlated with the presence of HIV-1 antigen in the brain region. The data show a significantly increased number of microglia in HIV-1 infected brains. These activated microglial cells could, among others, be those cells producing cytotoxic factors which, in turn, cause brain damage.

In the present study, the morphological features as well as the age-dependent changes of the glial cell nests (GCN) within the rhinencephalic allocortex of the dog are described. A combination of two stereological methods, i.e., Cavalieri's principle and the optical disector, was used to obtain unbiased estimates of the volumes of the whole brain, the allocortex, and the GCN. Furthermore, the numerical densities and total number of the two prevailing populations of undifferentiated cells within these nests were determined. Cells with medium-sized dark nuclei (CMD) and cells with large pale nuclei (CLP) were distinguished. The volume of the GCN in relation to the volume of the allocortex decreased with increasing age. The numerical density and the total number of all cells of the GCN and of the CMD were reduced with age, whereas the numerical density and number of the CLP increased with advancing age. Similar morphological features as well as age-dependent changes have already been described of the cell populations in the subependymal layer. Therefore, in analogy, we presume that the glial cells of the GCN have emigrated from the subependymal layer. The significance of these age-dependent changes remains as obscure as does the function of the GCN. © 1994 Wiley-Liss, Inc.

Using stereological methods, two cerebral cortical areas from AIDS brains were investigated. Neuronal density, profile area of neurons, and perikaryon volume fraction were measured and compared to age-matched control brains. In the fronto-orbital cortex (area 11) of AIDS brains, a significant loss of neurons was seen. The perikaryon volume fraction was likewise decreased. The size of neurons did not differ between control and AIDS brains. In patients with clinical signs of progressive dementia and in brains with human immunodeficiency virus (HIV)-specific neuropathology (HIV-leukoencephalopathy and/or HIV-encephalitis) as compared to patients lacking these features, a small decrease in neuronal density was noted but this difference did not reach the level of statistical significance (P = 0.16). In the superior parietal lobule (area 7) of AIDS brains, no loss of nerve cells was noted. AIDS patients with progressive dementia and brains with HIV-specific neuropathology showed no difference in neuronal densities as compared to those without such features. We conclude that the fronto-orbital cortex, in contrast to the parietal cortex, is mainly damaged in AIDS brains. Neuronal loss was not significantly correlated with development of dementing symptoms and of HIV-specific neuropathology.

hTERT represents the catalytic subunit of telomerase leading to cell immortalization by stabilizing telomere lengths. Aim of this study was to characterise hTERT expression in gliomas and the derived cell cultures with a focus on glioblastomas (GBM) and to investigate its relation with tumor cell immortalization in vitro and disease progression in vivo. During the last nine years primary cell cultures were established from 265 tumor tissues obtained during surgery and histologically verified according to WHO criteria as low grade glioma WHO I/II (n=22) and anaplastic astrocytoma WHO III (n=15), GBM WHO IV (n=219), gliosarcoma (n=7) and giant cell glioblastoma (n=2). hTERT gene expression was investigated in all primary cell cultures and additionally in GBM tumor tissues (n=80) by RT-PCR. hTERT mRNA expression levels were calculated relatively to GAPDH mRNA amplified concomitantly and in subgroups verified by real-time RT-PCR. Telomerase enzyme activity was confirmed using the Telomeric Repeat Amplification Protocol (TRAP) of the TRAPeze Telomerase Detection Kit (Chemicon). hTERT expression data were compared to overall survival of GBM patients. Thirty-one percent (81/265) of the analysed cell cultures displayed hTERT gene expression. All of the hTERT-expressing primocultures, which were exclusively high grade gliomas (WHO III/ IV), developed into stable, immortal cell lines whereas hTERT negative cells failed to grow in vitro or ceased growth between passages 1 to 10. In contrast, all low grade gliomas (WHO I/II; n=22) were negative with respect to hTERT expression and characterised by limited in vitro cultivation demonstrating the less aggressive potential of these tumors. In parallel in vivo hTERT expression was analysed in 80 GBM tumor samples. 37/80 (46%) showed detectable hTERT expression and 54% (43/80) were negative with respect to hTERT. Kaplan-Meier survival estimates revealed a significant survival benefit for patients whose tumors lacked hTERT expression (p< 0.04) with a median survival of 20.1 months versus 14.3 months for patients whose tumors expressed hTERT. Summing up our data show that a) telomerase activity, reflected by hTERT expression is essential for successful in vitro growth of brain glioma-derived primocultures/cell lines. Thus in vitro studies on GBM generally focus exclusively on the hTERT-positive patient subgroup. b) hTERT gene expression can predict the potential to establish a stable, immortal cell model from a brain tumor specimen. Focussing on hTERT expression in vivo our data revealed that hTERT expression is associated with significantly shorter overall survival in GBM patients. Thus hTERT might have quality as prognostic biomarker predicting tumor aggressiveness. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3215.

A new powerful stereological tool for exact quantification of brain structures on magnetic resonance imaging (MRI) scans was used. Applying Cavalieri's principle, unbiased estimation of volume can be obtained. The method was applied to estimate the volume of different brain structures from normal controls. Data were used for comparison with data obtained by analyzing the brains of persons with Down's syndrome. A normalization procedure based on volume of cranial cavity is introduced and its advantages discussed, as is the coefficient of error as an indicator for the precision of the measurement.

In Reply. —In their letter, Weis and Haug1analyze the problem of the measurement of the morphological substrate of cerebral asymmetry. In a recent work,2we describe a method to measure the total surface of any portion of the cerebral cortex. This procedure permits the determination of the absolute values of the surface extent of the superficial, as well as the deep, cortex. In order to determine the reproducibility of this method, the surface extent of the cerebral cortex of the same anatomic piece was measured nine times and the [unk]±SD were 8.33 ± 0.16 cm2, which gives a coefficient of variation of only 1.92%. Consequently, we consider that this method fulfils the necessary requirements to be used to determine absolute values of the extent of cortical surface. On the other hand, as the gyri and their respective portions are isolated in a standard manner, the

The human corpus callosum was investigated with regard to sexual dimorphism by means of morphometry. At the macroscopical level, no part of the corpus callosum showed significant differences between the sexes. The concept that sex-related functional hemispherical discrepancies are correlated with the gross anatomy of the human corpus callosum was not confirmed.