Oligodendroglioma with Neuronal Differentiation in Two Boxer Dogs.

Two cases of high-grade glioma comprising sheets of oligodendroglial cells multifocally disrupted by regions of remarkable neuronal differentiation are described. These tumours morphologically resemble 'oligodendroglioma with ganglioglioma-like maturation', a rare tumour of man, but appear to be phenotypically more aggressive. Neuronal markers (synaptophysin, neuron-specific enolase and ßIII-tubulin) effectively highlight neuronal elements within these tumours and could potentially help to further investigate the prevalence and biological significance of neuronal differentiation in canine oligodendroglioma.

Disrupted cerebellar cortical development and progressive degeneration of Purkinje cells in SV40 T antigen transgenic mice.

SV40 T antigen (Tag) expression directed to cerebellar Purkinje cells resulted in the generation of three transgenic mouse lines that displayed ataxia, a neurological phenotype characteristic of cerebellar dysfunction. Onset of symptoms and cerebellar pathology, characterized by specific Purkinje cell degeneration, appeared to be directly dependent upon transgene copy number. The SV5 line (containing > 30 transgene copies), exhibited embryonic transgene expression that caused selective death of immature Purkinje cells and a subsequent block in cerebellar development and ataxia at 2 weeks. The developmental effect of the disruption of Purkinje cells in SV5 mice suggests that a normal complement of these cells is required for early development of the cerebellar cortex, especially granule cell proliferation and migration from external to internal layers. Transgene expression in a second line, SV4 (10 copies), was detectable during the second postnatal week. Death of mature Purkinje cells in the SV4 line resulted in onset of ataxia at 9 weeks. Ataxia in a third line, SV6 (2 copies), was detected after 15 weeks. The distinct cerebellar phenotypes of the SV4-6 lines correlate with specific Tag-induced Purkinje cell ablation as opposed to tumorigenesis.

A pediatric case of low-grade lymphomatoid granulomatosis presenting with a cerebellar mass.

Lymphomatoid granulomatosis (LA) is a rare angiocentric lymphoreticular proliferative disease that primarily involves the lungs but may also involve extrapulmonary sites including the central nervous system, skin, and kidneys. It is rare for this condition to affect children, and presentation as a cerebellar mass is unusual. In this report, we describe a 10-year-old girl with biopsy-proved cerebellar LA.

Stereotactic radiosurgery for recurrent malignant gliomas.

PURPOSE: To evaluate the role of stereotactic radiosurgery in the management of recurrent malignant gliomas. PATIENTS AND METHODS: We treated 35 patients with large (median treatment volume, 28 cm3) recurrent tumors that had failed to respond to conventional treatment. Twenty-six patients (74%) had glioblastomas multiforme (GBM) and nine (26%) had anaplastic astrocytomas (AA). RESULTS: The mean time from diagnosis to radiosurgery was 10 months (range, 1 to 36), from radiosurgery to death, 8.0 months (range, 1 to 23). Twenty-one GBM (81%) and six AA (67%) patients have died. The actuarial survival time for all patients was 21 months from diagnosis and 8 months from radiosurgery. Twenty-two of 26 patients (85%) died of local or marginal failure, three (12%) of noncontiguous failure, and one (4%) of CSF dissemination. Age (P = .0405) was associated with improved survival on multivariate analysis, and age (P = .0110) and Karnofsky performance status (KPS) (P = .0285) on univariate analysis. Histology, treatment volume, and treatment dose were not significant variables by univariate analysis. Seven patients required surgical resection for increasing mass effect a mean of 4.0 months after radiosurgery, for an actuarial reoperation rate of 31%. Surgery did not significantly influence survival. At surgery, four patients had recurrent tumor, two had radiation necrosis, and one had both tumor and necrosis. The actuarial necrosis rate was 14% and the pathologic findings could have been predicted by the integrated logistic formula for developing symptomatic brain injury. CONCLUSION: Stereotactic radiosurgery appears to prolong survival for recurrent malignant gliomas and has a lower reoperative rate for symptomatic necrosis than does brachytherapy. Patterns of failure are similar for both of these techniques.

Spinocerebellar ataxia type 1--modeling the pathogenesis of a polyglutamine neurodegenerative disorder in transgenic mice.

Spinocerebellar ataxia type 1 (SCA1) is one of a group of dominantly inherited neurodegenerative diseases caused by a mutant expansion of a polyglutamine-repeated sequence within the affected gene. One of the major cell types affected by the gene (ataxin-1) mutation in SCA1 is the cerebellar Purkinje cell. Targeted expression of mutant ataxin-1 in Purkinje cells of transgenic mice produces an ataxic phenotype with pathological similarities to the human disease. Other transgenic experiments using altered forms of mutant ataxin-1 have shown that nuclear localization of the mutant protein is necessary for pathogenesis and that nuclear aggregates of ubiquitinated mutant protein, while a feature of SCA1 and other polyglutamine diseases, are not a requirement for pathogenesis in transgenic models of SCA1. Present and future generations of transgenic mouse models of SCA1 will be valuable tools to further address mechanisms of pathogenesis in polyglutamine-related disorders.

Mouse models of human CAG repeat disorders.

Expansions of CAG trinucleotide repeats encoding glutamine have been found to be the causative mutations of seven human neurodegenerative diseases. Similarities in the clinical, genetic, and molecular features of these disorders suggest they share a common mechanism of pathogenesis. Recent progress in the generation and characterization of transgenic mice expressing the genes containing expanded repeats associated with spinal and bulbar muscular atrophy (SBMA), spinocerebellar ataxia type 1 (SCA1), Machado-Joseph disease (MJD/SCA3), and Huntington's disease (HD) is beginning to provide insight into the underlying mechanisms of these neurodegenerative disorders.

An intravenous technique for the measurement of cerebral vascular extraction fraction in the rat.

An intravenous injection method to measure cerebral vascular extraction fractions of highly diffusible substances in the rat is described. The brain extraction fractions of 3H-labeled water (Ew) and ethanol (Ee) were defined as the ratio of either of those tracers to the freely diffusible reference tracer, 14C-butanol, in the brain, divided by the ratio of the tracers available for the extraction during the time between simultaneous intravenous injection of the tracers and decapitation of the rat. Ew and Ee were measured in five regions of brain, including brainstem and cerebellum, under PaCO2 conditions ranging from 15 to 85 mm Hg. The extraction fractions for both test tracers were shown to vary with PaCO2-induced flow changes according to the equation, ln(1 - E) = -PS/F. When PS/F values calculated from regional measurements of Ew and Ee were plotted versus PaCO2, least squares regression equations of the plots could be used to compare permeabilities of both tracers at any given PaCO2 value. Ratios of the permeabilities of water and ethanol varied regionally but were relatively constant in a given region under different flow states. This intravenous injection method allows for accurate measurement of the extraction fractions of even highly diffusible tracers under varied flow conditions in all brain regions regardless of arterial blood supply.

Olfactory bulb lesions in Alzheimer's disease.

The olfactory bulb (OB), with its comparatively simple and well-delineated connectivity, presents an interesting system for examining cell-specific pathology in neurologic degenerative disorders such as Alzheimer's disease (AD). We have found that in AD the large, efferently projecting neurons (mitral cells) of the OB degenerate, typically without classical Alzheimer neurofibrillary changes. In some cases, with less severe neocortical pathology, the terminal arborizations of olfactory nerve appear hyperplastic and are associated with focal accumulations of A-4 (beta-amyloid) immunoreactivity that are not detectable by standard amyloid stains. These abnormalities may represent a pathologic manifestation of normally occurring plasticity in the olfactory system.

A beta-associated cerebral angiopathy and senile plaques with neurofibrillary tangles and cerebral hemorrhage in an aged wolverine (Gulo gulo).

In this study of an aged wolverine (Gulo gulo), we document neuropathologic lesions (cerebral amyloid angiopathy (CAA), neuritic plaques (NPs), neurofibrillary tangles (NFTs), and granulovacuolar degeneration strikingly similar to those present in aging and Alzheimer's disease (AD), with the additional finding of concurrent cerebral hemorrhage. A beta immunoreactive cerebral amyloid angiopathy and senile plaques (neuritic and diffuse) were present throughout the cerebral cortex and hippocampus. Ubiquitin immunoreactivity was noted in peripheral portions of some of the plaques. Argyrophilic intracellular neurofibrillary tangles containing abnormally phosphorylated (Ser 202) tau protein were present within cortical and hippocampal neurons. The wolverine should be added to the list of nonhuman species (dogs, nonhuman primates, polar bears) with amyloid deposits similar to those in aged humans and in humans with AD. The aged wolverine appears to be distinct from other nonhuman species in possessing plaques and NFTs, as well as other histologic cerebral lesions frequently associated with AD.

Middle cerebral artery dissection: a clinicopathologic study.

We present a case report of a 17-year-old young man who developed fatal dissection of the middle cerebral artery after what appeared to be trivial trauma. The dissection was not evident on cerebral arteriogram but was identified at autopsy. Arterial dissection should be considered in the differential diagnosis of supraclinoid occlusion of the internal carotid artery seen by cerebral angiography.

Indium-111 platelet scintigraphy in cerebrovascular disease.

We obtained scintigraphic images of the neck from 100 patients with suspected cerebrovascular disease after injecting indium-111-labeled autologous platelets. One or more focuses of increased activity, implying local platelet accumulation, were seen along the course of the cervical carotid arteries in 52 patients. In 64 patients, there was a highly significant correlation between the results of scintigraphy and carotid arteriography (p = 10(6)). There was no significant correlation between the scintigraphic findings and the previous or subsequent occurrence of transient ischemic attack or cerebral infarction in the carotid circulation. These data suggest that factors other than the simple formation of platlet thrombi in the cervical carotid arteries are of primary importance in the pathogenesis of stroke.

Single dose versus fractionated stereotactic radiotherapy for recurrent high-grade gliomas.

PURPOSE: To evaluate the efficacy of stereotactic radiotherapy (SRT) in patients with recurrent high-grade gliomas by comparing two different treatment regimens, single dose or fractionated radiotherapy. METHODS AND MATERIALS: Between April 1991 and January 1998, 71 patients with recurrent high-grade gliomas were treated with SRT. Forty-six patients (65%) were treated with single dose radiosurgery (SRS) and 25 patients (35 %) with fractionated stereotactic radiotherapy (FSRT). For the SRS group, the median radiosurgical dose of 17 Gy was delivered to the median of 50% isodose surface (IDS) encompassing the target. For the FSRT group, the median dose of 37.5 Gy in 15 fractions was delivered to the median of 85% IDS. RESULTS: Actuarial median survival time was 11 months for the SRS group and 12 months for the FSRT group (p = 0.3, log-rank test). Variables predicting longer survival were younger age (p = 0.006), lower grade (p = 0.0006), higher Karnofsky Performance Scale (KPS) (p = 0.0005), and smaller tumor volume (p = 0.02). Patients in the SRS group had more favorable prognostic factors, with median age of 48 years, KPS of 70, and tumor volume of 10 ml versus median age of 53 years, KPS of 60, and tumor volume of 25 ml in the FSRT group. Late complications developed in 14 patients in the SRS group and 2 patients in the FSRT group (p<0.05). CONCLUSION: Given that FSRT patients had comparable survival to SRS patients, despite having poorer pretreatment prognostic factors and a lower risk of late complications, FSRT may be a better option for patients with larger tumors or tumors in eloquent structures. Since this is a nonrandomized study, further investigation is needed to confirm this and to determine an optimal dose/fractionation scheme.

Gastric stromal tumors. Reappraisal of histogenesis.

Twenty-eight gastric wall tumors classified by light microscopy as leiomyomas or leiomyosarcomas were reevaluated for histogenesis. Each case was analyzed for the presence of S-100 protein, a marker for cells derived from neuroectoderm, by the immunoperoxidase technique. Eight tumors contained cells with positive immunostaining for S-100 protein. Usually this staining was focal, but in one case staining was diffuse. In three additional cases the immunostaining outlined a nerve within the tumor. In contrast, two esophageal and 10 uterine leiomyomas, as well as normal gastric smooth muscle, gave negative reactions for S-100 protein. Twelve cases had tissue processed for electron microscopy. Only two of the tumors, one leiomyoma and one leiomyosarcoma, contained cytoplasmic myofilaments with densities expected in cells derived from smooth muscle; neither of these tumors stained for S-100 protein. In one case, the tumor with diffuse staining for S-100 protein, the cells resembled Schwann cells ultrastructurally. The remaining nine cases had neither smooth muscle nor Schwann cell features. They did contain interposed cell processes, primitive junctions, and large cytoplasmic vacuoles. The results of this study indicate that many gastric wall tumors are not derived from smooth muscle. The presence of S-100 protein suggests a nerve sheath origin in some cases. While the ultrastructure of many gastric tumors does not resemble nerve sheath cells in most peripheral nerves, the myenteric nervous system is a possible source for perineurial or mesenchymal nerve sheath cells with distinctive fine structure. Further study is needed to refine our knowledge of the histogenesis of gastric stromal tumors.

The adoptive transfer of chronic relapsing experimental allergic encephalomyelitis with lymph node cells sensitized to myelin proteolipid protein.

In this report we describe the transfer of chronic relapsing experimental allergic encephalomyelitis (EAE) with in vitro-stimulated lymph node cells (LNC) from SJL/J mice immunized with human myelin proteolipid protein (PLP). No additional immune enhancing procedures were applied in the transfer recipients. Clinical and histological EAE was transferred with 10-30 X 10(6) LNC to 27/28 mice. The LNC proliferated in vitro to PLP, but not to myelin basic protein (MBP), and induced delayed-type hypersensitivity. Enrichment for lymphoblasts by Ficoll centrifugation was essential for the disease development. The clinical course usually showed an early episode of acute paralytic illness, followed by chronic relapsing disease, and resembled the transfer of EAE using MBP-specific cells, both clinically and histologically.

Hemorrhagic periventricular leukomalacia: diagnosis by real time ultrasound and correlation with autopsy findings.

Hemorrhage into areas of periventricular leukomalacia may occur and range in size from microscopic to massive. Hitherto, the definitive diagnosis has been made only at autopsy. A case is described in which the diagnosis of hemorrhagic periventricular leukomalacia was made antemortem by real-time ultrasound scanning and confirmed at autopsy. Periventricular/intraventricular hemorrhage, a more common hemorrhagic lesion, may extend into periventricular with matter in a location ventral and medial to hemorrhagic periventricular leukomalacia. Real-time ultrasound scanning is a safe and reliable means of defining the topography of these two hemorrhagic lesions and, thereby, of suggesting the correct diagnosis.

Gerstmann-Sträussler-Scheinker disease with the PRNP P102L mutation and valine at codon 129.

The most common mutation causing Gerstmann-Sträussler-Scheinker (GSS) disease is P102L in the prion protein. Previously, this mutation has only been found in coupling with methionine at residue 129. We describe a patient with GSS disease in whom the P102L mutation is in coupling with valine at residue 129. The clinical presentation in P102L-V129 differs greatly from that seen in P102-M129 patients.

Long-term antidepressant treatment: alterations in cerebral capillary permeability.

Chronic treatment of rats with amitriptyline (AMI) induced a persistent increase in the diffusibility of water into the brain (EW). This effect was observable 12 h after the last dose. AMI induces this alteration at plasma drug concentrations of 71 +/- 13 ng/ml (the therapeutic range for man is 100--250 ng/ml). Furthermore, chronic treatment potentiated the increase observed after acute drug administration and resulted in a 350% enhancement in the permeability of water across the cerebral capillary. Thus, long-term antidepressant administration can chronically influence cerebral function by affecting capillary permeability.

Identification of dystrophic sympathetic axons in experimental diabetic autonomic neuropathy.

Markedly dilated dystrophic post-ganglionic sympathetic axons have been identified by dopamine-beta-hydroxylase immunohistochemistry in the paravascular ileal mesenteric nerves of rats with chronic streptozotocin diabetes. Many axons contained multiple dilatations with interposed axonal segments of near normal dimensions. These axonal abnormalities were absent in control animals. The time course of the development of the axonopathy and its distribution in the alimentary tract correlate with quantitative ultrastructural findings previously reported in this system.

Hypertension induced changes in cerebral capillary permeability to water are mediated by afferent neuronal connections from the carotid sinus to the brain.

Mild acute hypertension was induced in rats pharmacologically and non-pharmacologically with metaraminol, angiotensin II or bilateral vagotomy. The extraction fraction of water (Ew) was measured in both hypertensive and normotensive animals. It was demonstrated that cerebral blood flow did not change during hypertensive states. Under constant flow conditions Ew becomes a direct index of the cerebral capillary permeability to water. Ew was significantly decreased (P less than 0.001) in all brain regions examined in the hypertensive animals as compared to normotensive controls. However, the decrease Ew induced by hypertension was not observed if the animal had previously received bilateral carotid sinus denervation. This observation indicated that the capillary permeability response induced by hypertension is mediated by a neurogenic mechanism involving information transfer from the peripheral baroreceptors in the carotid sinus along afferent connections into the central nervous system.

Measurement of cerebral vascular extraction fractions in the rat using intracarotid injection techniques.

A small volume (5 microliters) common carotid arterial injection method is described for the quantitation of cerebral vascular extraction fractions (Et) of diffusion limited tracer molecules in the rat. The method is a modification of a technique introduced by Oldendorf and widely used for the study of blood-brain barrier phenomena. While the Oldendorf technique has proven valuable for estimating the relative permeabilities of substances, it is limited in measuring Et under conditions of physiologically or pharmacologically altered permeability or blood flow. The method described in this paper--using a small volume (5 microliters) common carotid injection, a freely diffusible reference tracer, [14C]butanol, and a 5 sec circulation time--allows for measurements of Et that reflect changes in blood flow and small differences in permeability. The modified method is important for the study of the regulation of cerebral vascular permeability and flow in an inexpensive animal model.