Distinct neurodevelopmental patterns of bcl-2 and bcl-x expression are altered in glioneuronal hamartias of the human temporal lobe.

Bcl-2 and bcl-xL are homologous proteins that inhibit cell death and are expressed in the nervous system. We tested the hypothesis that aberrant expression of such "death suppressor" molecules may promote the survival of abnormal cells in glioneuronal lesions associated with temporal lobe epilepsy. The normal pattern of bcl-2 and bcl-x expression was studied in postmortem human fetal and adult temporal lobes. Formalin-fixed, paraffin-embedded tissue sections were probed for bcl-2 and bcl-x in immunohistochemical studies using well-characterized primary antibodies that had been raised against epitopes that are not shared by these proteins. Strong staining for both proteins was observed in the ventricular zone and in migrating, postmitotic and postmigratory young neurons of the neocortex, hippocampus, and entorhinal cortex from 6 to 20 weeks gestational age (GA). However, bcl-2 immunoreactivity gradually decreased to weak or nondetectable levels between 20 and 39 weeks GA, while strong bcl-x staining of neurons persisted throughout fetal development and into adulthood. Twenty-eight temporal lobe resections from children and adults ranging in age from 1 to 45 years (mean=19 years) with intractable epilepsy were then screened for differences in the pattern of bcl-2 and bcl-x expression compared to normal controls. Bcl-2 (but not bcl-x) was strongly immunoreactive in small, immature-appearing cells that were components of microscopic glioneuronal aggregates (hamartias) and that have been shown previously to express an embryonic form of the neural cell adhesion molecule. These immature cells were immunonegative for standard markers of neuronal and glial lineage and were negative for Ki67, suggesting that they are post-mitotic. The persistent expression of bcl-2 and apparent downregulation of bcl-x in these cells represent deviations from the normal ontogeny of these molecules in the human nervous system. These data suggest that dysregulation of bcl-2 and related proteins may be involved in the pathogenesis of some temporal lobe malformative lesions.

The amygdala in Alzheimer's disease: neuropathology and Alz 50 immunoreactivity.

Patients with Alzheimer's disease (AD) often show emotional, motivational, and memory disturbances which may have morphological substrates that include the amygdaloid complex. Neuropathological studies in other limbic areas have recently been enhanced by immunocytochemical studies with Alz 50 antibody. Therefore, we examined the distribution of Alz 50 immunoreactive (Alz 50-IR) neuritic plaques (NP) and neurofibrillary tangles (NFT) in the amygdala in AD cases, in one aged patient with Down's syndrome, and in controls of similar ages. In all AD cases numerous NP and variable numbers of NFT were observed and a distinctive subregional anatomical distribution of NP and Alz 50-IR neuropil in the amygdala existed, whereas no similar selective topography for NFT or Alz 50-IR neurons was found. A high density of NP was demonstrated in the ventromedial aspects of the basolateral and corticomedial nuclear regions. There was no correlation with the pattern of cholinergic innervation. There was, however, a correspondence between intraamygdaloid- and amygdaloid-hippocampal connections and regions of high NP density. Our findings support the concept that the disease process may occur along anatomically defined pathways, and the amygdala may be a central participant in this process.

Altered mRNA expression for brain-derived neurotrophic factor and type II calcium/calmodulin-dependent protein kinase in the hippocampus of patients with intractable temporal lobe epilepsy.

The expression of brain-derived neurotrophic factor and the alpha subunit of calcium/calmodulin-dependent protein kinase II mRNA in hippocampi obtained during surgical resections for intractable temporal lobe epilepsy were examined. Both calcium/calmodulin-dependent protein kinase II and brain-derived neurotrophic factor are localized heavily within the hippocampus and have been implicated in regulating hippocampal activity (Kang and Schuman [1995] Science 267:1658-1662; Suzuki [1994] Intl J Biochem 26:735-744). Also, the autocrine and paracrine actions of brain-derived neurotrophic factor within the central nervous system make it a likely candidate for mediating morphologic changes typically seen in the epileptic hippocampus. Quantitative assessments of mRNA levels in epileptic hippocampi relative to autopsy controls were made by using normalized densitometric analysis of in situ hybridization. In addition, correlations between clinical data and mRNA levels were studied. Relative to autopsy control tissue, decreased hybridization to mRNA of the alpha subunit of calcium/calmodulin-dependent protein kinase II and increased hybridization to brain-derived neurotrophic factor mRNA were found throughout the granule cells of the epileptic hippocampus. There also was a significant negative correlation between the duration of epilepsy and the expression of mRNA for brain-derived neurotrophic factor. These results are similar qualitatively to those found in animal models of epilepsy and suggest that chronic seizure activity in humans leads to persistent alterations in gene expression. Furthermore, these alterations in gene expression may play a role in the etiology of the epileptic condition.

Opportunistic cerebral vasculopathy and stroke in patients with the acquired immunodeficiency syndrome.

OBJECTIVE: To describe an unusual cause of stroke in patients with the acquired immunodeficiency syndrome. DESIGN: An observational case series of hospitalized patients with subsequent autopsy. MEASURES: Clinical, radiological, and pathological examinations were performed. RESULTS: In three of 14 patients with stroke, the infarctions were secondary to an opportunistic vasculopathy caused by Candida albicans, cytomegalovirus, or lymphoma. CONCLUSION: Opportunistic conditions may lead to vascular abnormalities and subsequent stroke in patients with the acquired immunodeficiency syndrome.

Divergent differentiation in pleomorphic xanthoastrocytoma. Evidence for a neuronal element and possible relationship to ganglion cell tumors.

We report the detection of cytoplasmic immunoreactivity for neuronal/neuroendocrine antigens in a subpopulation of tumor cells within seven pleomorphic xanthoastrocytomas (PXAs). The expression of glial and neuronal polypeptides was examined in routinely prepared surgical resections by immunohistochemistry using well-characterized antibodies that recognize glial fibrillary acidic protein (GFAP), synaptophysin (SYN), and neurofilament triplet polypeptides (NFPs) in microwave-enhanced single- and double-immunolabelling experiments. Each neoplasm contained cells that were immunoreactive for SYN and/or NFPs, GFAP, and occasionally for both GFAP and either NFP or SYN. We conclude that abortive neuronal/neuroendocrine differentiation may occur in PXAs, suggesting a relationship between PXA and other developmental neoplasms that reveal a more overt neuronal phenotype, such as ganglioglioma, dysembryoplastic neuroepithelial tumor, and desmoplastic ganglioglioma, and with tumors expressing ambiguous glial/neuronal lineage, such as the subependymal giant cell tumor of tuberous sclerosis. These findings suggest that aberrant expression and accumulation of neuronal intermediate filaments may account for the large, pleomorphic cell morphology observed in many of these tumors.

Carbon disulfide effects on the visual system. II. Retinogeniculate degeneration.

We examined the morphological effects of carbon disulfide exposure on neurons and vasculature of the visual system of macaque monkeys. Five monkeys were exposed to 256 ppm carbon disulfide (CS2) by inhalation for 6 hr a day, 5 days a week. One monkey, sacrificed immediately after exposure, had numerous axonal swellings in the distal optic tract. Four other monkeys survived the exposure period for at least 1 year and were found to have suffered marked degeneration of central retinal ganglion cells, with little or no effect on other neurons in the retina. No evidence was found for arteriosclerotic or aneurysmal changes, suggesting that visual system injury in primates induced by carbon disulfide exposure is not dependent on the occurrence of structural changes in retinal blood vessels.

Carbon disulfide effects on the visual system. I. Visual thresholds and ophthalmoscopy.

The visual effects of carbon disulfide exposure were studied in macaque monkeys with measurements of visual thresholds, fluorescein angiography and fundus photography. Five monkeys were exposed by inhalation for 6 hr a day, 5 days a week to 256 ppm carbon disulfide (CS2). The motor dysfunction observed in these monkeys appeared to be entirely reversible. All five suffered severe reductions in visual acuity and contrast sensitivity although flicker resolution was not affected. Visual loss was found to be irreversible, with degeneration of substantial numbers of retinal ganglion cells (companion paper) in those monkeys permitted to survive after the termination of exposure. None of the monkeys developed retinal microaneurysms or hemorrhages, major accepted signs of visual toxicity in CS2 exposed humans; thus, permanent visual loss may result from carbon disulfide exposure even in the absence of retinal vascular effects.

Acrylamide effects on the macaque visual system. I. Psychophysics and electrophysiology.

Oral acrylamide produces axonal swelling and later degeneration and gliosis in the distal optic tract, especially within the lateral geniculate nucleus, of macaque monkeys. Measures of visual thresholds and cortical-evoked potentials were used to study the time course of visual changes during exposure to acrylamide in macaque monkeys. Contrast sensitivity, visual acuity, and flicker fusion frequency were reduced during exposure, and only flicker fusion recovered rapidly and completely after exposure. Pattern-reversal-evoked responses exhibited increased latency and reduced amplitude during dosing but substantially recovered after exposure. Visual acuity and contrast sensitivity for high spatial frequencies were decreased throughout the 140 days of testing after dosing. These results suggest an acute general depression of visual capacities as the initial effect of acrylamide exposure, whereas later effects were confined to high spatial frequencies.

Acrylamide effects on the macaque visual system. II. Retinogeniculate morphology.

Oral acrylamide dosing for 6-10 weeks produced axonal swellings with neurofilament accumulation in the distal optic tract and lateral geniculate nucleus of macaques. No swellings were seen in the retina or optic nerve. Monkeys that were killed 6-8 months after similar dosing showed a marked neuronal degeneration in the visual pathways that was more pronounced after two than after a single period of exposure. This degeneration was characterized by the following: loss of ganglion cells in central retina with relative sparing of other retinal neurons; disproportionate degeneration of temporal to central optic nerve and the dorsal optic tract; and neuronal atrophy in parvocellular layers of the lateral geniculate nucleus, with relative sparing of magnocellular layers. The pattern of neuronal loss suggests that one type of retinal ganglion cell or its axon may be especially vulnerable to damage by acrylamide. The selective neuronal damage produced by acrylamide may help explain the nature of the visual dysfunction associated with this intoxication.

In situ hybridization of calcium/calmodulin dependent protein kinase II and tau mRNAs; species differences and relative preservation in Alzheimer's disease.

Abnormal phosphorylation of the microtubule associated protein tau component of neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) may result from alterations in protein kinase expression. Calcium/calmodulin dependent protein kinase II (CaM kinase II) has been shown to phosphorylate tau in vitro in such a way to decrease its electrophoretic mobility. A68, apparently a modified form of tau in AD brain, also shows abnormal phosphorylation and slower mobility than tau. To further examine the role of CaM kinase II in AD, in situ hybridization studies were performed on tissues from rat, monkey and human to examine and compare the patterns of CaM kinase II mRNA expression in different brain regions. The most notable differences among the three species were observed in dendrites in layer I of isocortex, in the molecular layer of the dentate gyrus and stratum radiatum and stratum lacunosum-moleculare in hippocampus, where hybridization was detected in rat, but not in monkey or human brain. In addition, comparisons between tau and CaM kinase II mRNA expression were made in tissue from normal aged adults and AD patients, especially in areas prone to NFT formation. CaM kinase II and tau mRNAs were co-expressed in many neuronal populations, both those which are prone to NFT formation as well as those which are rarely affected by AD changes. No major differences in the relative abundance of either CaM kinase II or tau mRNA within particular neuronal populations was noted between normal aged and AD brain. Diminished hybridization was associated with serve neuronal pathology and cell loss.

Epithelial differentiation in meningiomas. An immunohistochemical, histochemical, and ultrastructural study--with review of the literature.

Meningiomas possess features indicative of epithelial differentiation. The present study further documents this finding by a multimodality approach on serial sections from 25 meningiomas of all histologic and clinical categories. Standard light microscopic examination, immunohistochemical staining with a variety of epithelial and nonepithelial markers, and histochemical staining for mucin were performed on each case. Directed electron microscopic examination was performed on selected examples of epithelial feature-positive and -negative cases. All cases were immunoreactive for vimentin and epithelial membrane antigen. Thirty-two percent were reactive for cytokeratin and 39% for S-100. Twenty percent showed mucin positivity by histochemistry. Electron microscopic examination of cytokeratin-positive cases showed either intracellular lumina (secretory areas) or cytoplasmic tonofibrils, whereas cytokeratin-negative tumors lacked lumina and tonofibrils. Previous studies showing epithelial features in meningiomas are reviewed with emphasis on the studies using immunohistochemistry. These histochemical, immunohistochemical, and ultrastructural characteristics are of utility in the examination of tumors of suspected meningeal origin, particularly when dealing with atypical presentations or histomorphologic features.

Disseminated microsporidiosis especially infecting the brain, heart, and kidneys. Report of a newly recognized pansporoblastic species in two symptomatic AIDS patients.

Microsporidia have emerged as important opportunistic AIDS pathogens of the alimentary, respiratory, and urinary tracts. Although nonhuman mammalian microsporidia infections typically include encephalitis, CNS microsporidiosis has not been reported in patients with AIDS. A 33-year-old white male and an 8-year-old black girl presented with seizures and declining mental status. Central nervous system (CNS) imaging studies revealed small peripherally and diffusely enhancing lesions present for at least 2 and 4 months before death, respectively. Both patients expired despite empirical anti-toxoplasma therapy. Their brains contained innumerable soft gray matter lesions that consisted of central areas of necrosis, filled with free spores and spore-laden macrophages, surrounded by microsporidia-infected astrocytes. The complete autopsy of the child also revealed necrotizing and sclerosing cardiac and renal microsporidiosis and infection of the pancreas, thyroid, parathyroids, liver, spleen, lymph nodes, and bone marrow. Infected cells included astrocytes, cardiac myocytes, epithelium, endothelium, vascular smooth muscle cells, hepatocytes, adipocytes, Schwann cells, and macrophages. Light and electron microscopic studies revealed pansporoblastic development within thick-walled sporophorous vacuoles of parasite origin. Although most similar to Pleistophora sp and Thelohania sp, this microsporidian is different from any known species. Microsporidiosis should be considered as the possible cause of a wide range of diseases in AIDS patients, including CNS, cardiac, and renal.

MAP2 expression in the developing human fetal spinal cord and following xenotransplantation.

Human fetal spinal cord (FSC) tissue was obtained from elective abortions at 6-14 wk gestational age (GA). The specimens were then either immediately processed for immunohistochemical analysis or xenotransplantation. In the latter case, donor tissue was prepared as a dissociated cell suspension and then introduced either subpially or intraspinally into contusion lesions of the adult rat midthoracic spinal cord. The xenografts were subsequently examined by conventional histological and immunohistochemical methods at 2-3 mo postgrafting. Immunostaining showed that MAP2 was expressed heavily in cells residing in the mantle layer of the human fetal spinal cord in situ as early as 6 wk GA. Subpial and intraparenchymal xenografts also were intensely immunoreactive for MAP2, but no staining of surrounding host neural tissue was detected. We conclude that the differential expression of MAP2 can be used to distinguish human graft tissue from the surrounding rat spinal cord in this xenograft paradigm. Under appropriate staining conditions, MAP2 can thus serve to facilitate analyses of host-graft integration, donor cell migration, and neuritic outgrowth.

Selective acrylamide-induced degeneration of color opponent ganglion cells in macaques.

P beta (color opponent) retinal ganglion cells in macaques were found to degenerate as a result of oral administration of acrylamide. Histological examination, wheat germ agglutinin-horseradish peroxidase transport and cytochrome oxidase histochemistry indicate that other retinal ganglion cells and other neurons in the visual pathways were spared.

Selective degeneration of the parvocellular-projecting retinal ganglion cells in a New World monkey, Saimiri sciureus.

Selective degeneration of retinal ganglion cells projecting to parvocellular layers of the dorsal lateral geniculate nucleus (LGN) was observed in squirrel monkeys (Saimiri sciureus) exposed to a range of doses of acrylamide monomer. Similar acrylamide-induced neuronal loss has previously been reported in parvocellular-projecting ganglion cells of macaques, but no such selective degeneration has been found in acrylamide-dosed rats, squirrels, rabbits or cats. The extent of ganglion cell loss observed in the present study suggests that in the squirrel monkey, as in the macaque, a majority of ganglion cells project to parvocellular layers of the LGN. The locus of optic tract degeneration suggests that the squirrel monkey parvocellular pathway passes in dorsolateral optic tract, as does that of the macaque. Patterns of decreases in cytochrome oxidase activity confirm that, in both of these primates, geniculocortical pathways driven by these vulnerable neurons project to cortical layers 4A and 4C beta. These results suggest close parallels in the neuroanatomical projections and toxic vulnerability of the parvocellular-projecting pathway in New and Old World monkeys. They indicate that acrylamide intoxication can be used to selectively damage this pathway in order to study the functional roles of parallel visual pathways in both New and Old World monkeys.

Granulomatous angiitis of the spinal cord: a case report.

A 12-year-old caucasian boy presented with a thoracic myelopathy. Magnetic resonance T1-weighted images revealed an enhancing lesion infiltrating the lower thoracic spinal cord to the level of the conus. Evaluation of the lesion by open biopsy revealed granulomatous angiitis of the spinal cord. Granulomatous angiitis is a rare vasculitic process that typically involves the brain and, less frequently, the spinal cord. Diagnosis must be established early by histopathological examination so that treatment with corticosteroids and/or cytotoxic agents may be instituted. When left untreated, patients with granulomatous angiitis of the spinal cord have developed fatal intracranial manifestations.

Vascular malformations presenting as spinal cord neoplasms: case report.

Three cases of adult patients with subacute courses of progressive caudal spinal cord disease are presented. Computed tomography, magnetic resonance imaging, and myelographic studies were interpreted preoperatively as representing a spinal cord neoplasm in each case. No evidence of enlarged or abnormal surface vessels was observed by neuroimaging or intraoperatively. Biopsy specimens from each spinal cord lesion showed the typical histopathological features of a spinal vascular malformation. We conclude that vascular malformations of the caudal spinal cord can appear as isolated intramedullary lesions with apparently normal surface vessels and that these lesions may be difficult to distinguish from spinal cord neoplasms.

Spatio-temporal vision of macaques with severe loss of P beta retinal ganglion cells.

Anatomical and physiological studies indicate major structural and functional differences between the two parallel retinogeniculate visual pathways in the macaque. We have examined the contribution of these pathways to achromatic visual capacities by behaviorally testing spatio-temporal vision in monkeys with severe damage to the P beta (medium cell) pathway. This loss was produced by systemic administration of a neurotoxicant, acrylamide monomer, a treatment that apparently spares other visual system neurons. Monkeys dosed with acrylamide showed large reductions of contrast sensitivity at high spatial as well as low temporal frequencies. On the other hand, they had normal sensitivity for stimuli of high temporal, low spatial frequency. In addition, dosed monkeys retained normal flicker resolution thresholds for unpatterned stimuli. These findings suggest that the medium cell retinogeniculate pathway contributes primarily to the detection of higher spatial, lower temporal frequencies, while the large cell pathway is involved primarily in sensitivity to lower spatial and higher temporal frequencies.

Delayed occurrence of cerebellar pleomorphic xanthoastrocytoma after supratentorial pleomorphic xanthoastrocytoma removal. Case report.

The authors report the case of a 36-year-old woman who underwent gross total resection of a right cerebellar pleomorphic xanthoastrocytoma with atypical features. She had undergone surgery 16 years previously for what was thought to be a right frontal glioblastoma multiforme. In retrospect, based on the histopathology and the clinical course, both lesions were considered to represent atypical variants of pleomorphic xanthoastrocytoma. This report examines the histological and clinical characteristics of this posterior fossa lesion, which exhibited histologically malignant features but has run a relatively indolent course.

Tardive dyskinesia in Alzheimer's disease: clinical features and neuropathologic correlates.

Medical record review was conducted on 14 patients with neuropathologically confirmed Alzheimer's disease, all of whom had been treated with antipsychotic medications, to determine the relationship between neuropathology and the development of tardive dyskinesia. Four cases were found to have chart descriptions of hyperkinetic movement disorders consistent with tardive dyskinesia. When the group with tardive dyskinesia was compared to the group without tardive dyskinesia, there were no statistically significant differences regarding gender, age of onset of dementia, duration of dementia, age at death, or duration of antipsychotic treatment. Neuropathologic comparisons revealed greater degenerative changes in the substantia nigra in those patients with tardive dyskinesia. These preliminary observations suggest that patients with Alzheimer's disease and significant coexisting substantia nigra pathologic changes may be at higher risk for developing tardive dyskinesia when treated with antipsychotic medication.