Tanycytomas: a newly characterized hypothalamic-suprasellar and ventricular tumor.

We report five cases of tumors occurring in three children and in two adults. The tumors had unusual histomorphology and a mixture of ependymal and piloid-like astrocytic features and a myxoid stroma similar to myxopapillary ependymomas. MR imaging in three of the cases showed aggressive, intensely enhancing partially cystic hypothalamic-suprasellar masses near midline and near the floor of the third ventricle. In the three pediatric cases, the tumor encased the circle of Willis. This newly characterized tumor, the tanycytoma, has neoplastic cells with histomorphologic and ultrastructural characteristics similar to those of the tanycyte.

Pigmented papillary epithelial neoplasm of the pituitary fossa: a distinct lesion of uncertain histogenesis.

Primary pigmented intracranial neoplasms are strikingly uncommon. The differential diagnosis is limited and includes both epithelial and nonepithelial tumors, most of which arise within or near the ventricular system. The authors describe a 42-year-old man who presented with a pigmented papillary epithelial lesion that arose within the sella and exhibited suprasellar extension and bony erosion. Following external beam radiotherapy and multiple surgical resections, tumor growth became rapid, necessitating additional debulking procedures. Pathologic evaluation of subsequent lesional tissue samples revealed an anaplastic lesion with malignant epithelial and spindle cell components. Occasional epithelial cells showed features reminiscent of the original papillary lesion, whereas others exhibited oncocytic morphologic features. This case represents the only report, to our knowledge, of a pigmented papillary epithelial neoplasm arising within the pituitary fossa. Although the histogenesis of this tumor is enigmatic, this appears to be a distinct lesion characterized by aggressive growth and the capacity for anaplastic progression.

Postradiation gliosarcoma with osteosarcomatous components.

A 49-year-old man developed a gliosarcoma with prominent osteoid components 15 months after surgical resection and postoperative radiation and chemotherapy for a right frontal glioblastoma multiforme. The recurrent tumor was distinguished from the original lesion by the presence of dense ossification, visible on CT, at the original tumor site. The relevant literature is reviewed.

Suprasellar monomorphous pilomyxoid neoplasm: an ultastructural analysis.

The authors report 3 patients, 2 children and 1 adult, each of whom presented with an unusual myxoid lesion reminiscent of pilocytic astrocytoma but with other features of myxopapillary ependymoma. The magnetic resonance imaging findings in all cases showed a diffusely contrast-enhancing suprasellar mass focally extending into the third ventricle. Involvement of adjacent structures was more extensive in both infants. By light microscopy, all were composed of a monotonous population of cells with delicate piloid-like processes, loosely arranged within a prominent myxoid background. Focally, the neoplastic cells converged upon small blood vessels in pseudorosette-like formations. These histomorphologic features are identical to those of the recently described astrocytoma with monomorphous pilomyxoid features. In addition, the individual tumor cells showed strong cytoplasmic immunoreactivity with antibodies to glial fibrillary acidic protein (GFAP) and vimentin, as well as nuclear and cytoplasmic staining with S-100. All stained positive for synaptophysin and negative for chromogranin. By electron microscopy, the tumor cells were bipolar with elongated processes and apical surfaces displaying microvilli, cytoplasmic blebs and rare cilia. Vesicles and coated pits were seen, as were occasional synaptoid complexes. The current study serves to expand our clincopathologic experience with this rare and enigmatic lesion, with particular attention given to the ultrastructural characteristics.

Molecular genetics of holoprosencephaly.

Holoprosencephaly (HPE) is a common developmental defect of the human forebrain and midface. Pathological studies have identified different categories of severity of the brain and craniofacial malformations observed in HPE, although the variable clinical spectrum of HPE extends in unbroken sequence from alobar HPE and cyclopia to clinically unaffected carriers in familial HPE. The etiology of HPE is extremely heterogeneous including both environmental and genetic causes. Here we focus on molecular aspects of HPE in light of the recent identification of some of the genes causing human HPE and other candidate genes involved in forebrain development, through different approaches, such as positional cloning and functional cloning, based on animal models. These approaches will aid in the identification of additional genes involved in HPE and in a better understanding of the molecular genetics of brain development.

A unique autosomal dominant disorder with indifference to pain: clinicopathologic correlation of indifference to pain and thalamic gliosis.

We present updated information on a previously reported kindred with an autosomal dominant disorder variably expressed as indifference to pain, dementia, and ataxia. Additional clinical and radiological information is presented, as are autopsy results form the index case. In addition to evidence of Alzheimer's disease, the autopsy revealed bilateral thalamic gliosis, which may be a neuroanatomic substrate for the indifference to pain seen in this patient. To our knowledge, this is the first reported association of thalamic gliosis and indifference to pain.

The neuropathology of a chromosome 17-linked autosomal dominant parkinsonism and dementia ("pallido-ponto-nigral degeneration").

A group of similar autosomal dominant hereditary neurodegenerative disorders have been linked to chromosome 17 in thirteen kindreds. One of these disorders, known as pallido-ponto-nigral degeneration (PPND), is characterized by extensive degeneration of the globus pallidus and substantia nigra as well as accumulation of abnormally phosphorylated tau proteins. The authors now present comprehensive data on the cellular and molecular pathology of PPND, allowing its classification among chromosome 17-linked neurodegenerative disorders as well as its classification among sporadic and other familial tauopathies. First, we showed that PPND is characterized by abundant ballooned neurons in neocortical and subcortical regions as well as by tau-rich inclusions in the cytoplasm of neurons and oligodendroglia morphologically similar to those seen in corticobasal degeneration (CBD), but in a distribution pattern resembling progressive supranuclear palsy (PSP). Second, we demonstrated that antibodies to phosphorylation-independent (Alz50, 133, 304, Tau-2, T-46) as well as phosphorylation-dependent (AT8, PHF-6, 12E8, PHF-1, T3P, pS422) epitopes in human tau proteins stain these glial and neuronal inclusions as intensely as they stain CBD or PSP inclusions. Third, we probed PPND brain by Western blots using some of the same anti-tau antibodies to reveal 2 tau immunobands with molecular weights of 69 kD and 64 kD in gray and white matter extracts, as reported for both PSP and CBD. Finally, electron microscopy showed that these abnormal tau proteins formed flat twisted ribbons with a maximum diameter of 20 nanometers (nm) and a periodicity of about 200 nm, resembling those reported in CBD. Based on this, we conclude that PPND is a hereditary neurodegenerative disorder characterized by neuronal and glial tau-rich inclusions formed from aggregated filaments and hyperphosphorylated tau proteins and, hence, can be subcategorized into the tauopathy group of chromosome 17-linked neurodegenerative disorders. Further, since the morphologic and biochemical lesions of PPND overlap with those seen in sporadic CBD and PSP, we speculate that these disorders share common pathogenetic mechanisms.

Expression of monocyte chemoattractant protein (MCP-1) and nitric oxide synthase-2 following cerebral trauma.

Traumatic injury to the brain initiates multiple interrelated processes that involve parenchymal, vascular, and infiltrating inflammatory cells. Nitric oxide (NO) and chemokines have been implicated as regulators of the central nervous system injury response. Following a cryogenic lesion of the cerebral cortex in mice, mRNA for NO synthase (NOS)-2 was detected by reverse transcriptase polymerase chain reaction ipsilaterally 12 h after injury and persisted for 2 weeks. While mRNA was also detected contralaterally, the time course of expression was shorter (1 week). By immunohistochemistry, NOS-2 protein was initially detected ipsilaterally 12 h after injury in infiltrating inflammatory cells. Astroglial cells expressed NOS-2 from 24 to 72 h after injury. The expression of monocyte chemoattractant protein (MCP-1) mRNA peaked at 6 h on the lesion side, remained for 24 h and then declined by 48 h. On the unlesioned side, MCP-1 mRNA was expressed to a much lesser extent and had declined by 24 h. The up-regulation of MCP-1 was relatively specific as a closely related mRNA encoding IP-10 was not significantly increased. These findings implicate a role for NOS-2 and MCP-1 as potential regulators of cellular events following cryogenic cerebral trauma.

Autosomal dominant dementia with widespread neurofibrillary tangles.

Several familial dementing conditions with atypical features have been characterized, but only rarely is the neuropathology dominated solely by neurofibrillary lesions. We present a Midwestern American pedigree spanning four generations in which 15 individuals were affected by early-onset dementia with long disease duration, with an autosomal dominant inheritance pattern, and with tau-rich neurofibrillary pathology found in the brain post mortem. The average age at presentation was 55 years with gradual onset and progression of memory loss and personality change. After 30 years' disease duration, the proband's neuropathologic examination demonstrated abundant intraneuronal neurofibrillary tangles (NFTs) involving the hippocampus, pallidum, subthalamic nucleus, substantia nigra, pons, and medulla. Only sparse neocortical tangles were present and amyloid plaques were absent. The tangles were recognized by antibodies specific for phosphorylation-independent (Tau-2, T46, 133, and Alz-50) and phosphorylation-dependent epitopes (AT8, T3P, PHF-1, 12E8, AT6, AT18, AT30) in tau proteins. Electron microscopy of NFTs in the dentate gyrus and midbrain demonstrated paired helical filaments. Although the clinical phenotype resembles Alzheimer's disease, and the neuropathologic phenotype resembles progressive supranuclear palsy, an alternative consideration is that this familial disorder may be a new or distinct disease entity.

Periodontoid calcium pyrophosphate dihydrate deposition disease: "pseudogout" mass lesions of the craniocervical junction.

Between 1984 and 1996, seven patients with symptomatic masses located posterior to the odontoid process and containing calcium pyrophosphate dihydrate crystals were evaluated by the senior author (A.H.M). All patients presented with distal paresthesias and myelopathy and underwent transoral-transpharyngeal resection of the anterior arch of C-I, the odontoid process, and the compressing mass. Histological examination revealed the characteristic changes of calcium pyrophosphate dihydrate (CPPD) deposition disease, with nodular deposits of birefringent rhomboid crystals. On magnetic resonance imaging, the masses appeared predominantly isointense with neural tissue on T1-weighted images and iso-to hyperintense on T2-weighted images. On computerized tomography scans, small area of calcifications within the masses were apparent in all cases. All patients improved postoperatively, with six of seven patients requiring posterior fixation for instability as a second procedure. Calcium pyrophosphate dihydrate deposition causing periodontoid mass lesions is a distinct clinical disease entity that probably is underdiagnosed. In the authors' l opinion, the diagnosis can often be established preoperatively by the distinctive neuroradiological appearance of the masses. Therefore, CPPD deposition disease should be considered in the differential diagnosis of masses of the craniocervical junction, because it is amenable to early surgical intervention. The consulting neuropathologist should be made aware of this diagnostic possibility at the time of surgery.

Pontine neurocytoma.

A case of neurocytoma arising in the rostral pontine region of an 18 year old man is reported. The patient developed a right trochlear nerve palsy and was shown to have a well circumscribed, contrast enhancing mass on magnetic resonance imaging. The tumour was characterised histologically by a uniform population of medium sized round nuclei and slightly eosinophilic cytoplasm or occasional perinuclear halos, with delicate branching capillaries, patches of fibrillary matrix, and occasional perivascular pseudorosettes. Immunohistochemical studies demonstrated strong reactivity for synaptophysin in the fibrillary processes and cytoplasm of tumour cells. The present tumour is an exceptional case of neurocytoma arising in the pons.

Alterations in nitrogen monoxide-synthesizing cortical neurons in amyotrophic lateral sclerosis with dementia.

Cognitive impairment in the absence of lesions indicative of Alzheimer's disease and other dementing conditions has long been recognized in a subgroup of patients with motor neuron disease MND), including amyotrophic lateral sclerosis. However, the mechanisms underlying this cognitive deterioration and its relationship with the relatively selective involvement of motor neurons remains elusive. We used histo- and immunocytochemical labeling methods to study the nitrogen monoxide (NO; a.k.a. nitric oxide) synthase (NOS)-/NADPH diaphorase-containing neurons (NOSN) in three patients with MND and dementia (MND+D), two patients with MND without dementia, and 19 controls that included patients with Alzheimer and non-Alzheimer dementias. Patients with MND+D, but not those with MND without dementia, exhibit numerous dystrophic perikarya and neurites throughout all sensory, motor, association, and limbic neocortices examined. Interestingly, affected NOSN appear to correspond to some subtypes (smooth stellate and spiny neurons), while other neurons containing the same molecular phenotype (such as layer I local circuit neurons and layer II granule cells) are either spared or significantly less affected. These observations indicate that cognitive impairment and dementia in MND may be due, at least in part, to a pancortical involvement of certain types of NOSN. Consequently, the elucidation of the factors that make NOSN vulnerable in MND, and the prevention or pharmacological palliation of their loss, may eventually help to prevent or ameliorate cognitive impairment in MND and may also shed some light on the nature of the insult that targets motor neurons.

Phenotypic and pathologic evaluation of the myd mouse. A candidate model for facioscapulohumeral dystrophy.

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant disease of unknown pathogenesis which is characterized by weakness of the face and shoulder girdle. It is associated with a sensorineural hearing loss which may be subclinical. FSHD has been mapped to the distal most portion of 4q35, although the gene has not yet been identified. Distal 4q has homology with a region of mouse chromosome 8 to which a mouse mutant, myodystrophy (myd), has been mapped. Muscle from homozygotes for the myd mutation appears dystrophic, showing degenerating and regenerating fibers, inflammatory infiltrates, central nuclei, and variation in fiber size. Brainstem auditory evoked potentials reveal a sensorineural hearing loss in myd homozygotes. Based on the homologous genetic map locations, and the phenotypic syndrome of dystrophic muscle with sensorineural hearing loss, we suggest that myd represents an animal model for the human disease FSHD.

Genetic mapping near the myd locus on mouse chromosome 8.

Myodystrophy (myd), an autosomal recessive mutation of the mouse characterized by progressive weakness and dystrophic muscle histology, maps to the central portion of Chromosome (Chr) 8 (Lane et al. J. Hered 67, 135, 1976). This portion of Chr 8 contains the genes for a mitochondrial uncoupling protein (Ucp) and kallikrein (Kal3), which map to distal 4q in the human, providing evidence for a segment of homology. Characteristics of the myd phenotype coupled with this homology suggest that myd may be a mouse homolog of facioscapulohumeral muscular dystrophy (FSHD), which maps to human 4q35. We have confirmed and expanded the region of mouse 8-human 4 homology by generating a map of Chr 8 in an interspecific backcross of C57BL/6J and a partially inbred strain derived from M. spretus. The map is comprised of the genes for Ucp, coagulation factor XI (Cfl1), and chloride channel 5 (Clc5), all of which have homologs on distal human 4q, 15 microsatellite loci, and the membrane cofactor protein pseudogene (Mcp-ps). To place myd in the genetic map, 75 affected progeny from an intersubspecific backcross of animals heterozygous for myd with Mus musculus castaneus were genotyped with Chr 8 microsatellite loci. The mutation maps between D8Mit30 and D8Mit75, an interval that is flanked by genes with human homologs at distal 4q. These results are consistent with the possibility that myd is the mouse homolog of FSHD.

Mouse myodystrophy (myd) mutation: refined mapping in an interval flanked by homology with distal human 4q.

Myodystrophy (myd) is an autosomal-recessive mouse mutation with dystrophic skeletal muscle. We propose that myd may be a model of the human disorder facioscapulohumeral dystrophy (FSHD) on the basis of clinical features and homologous genetic map locations. FSHD maps to human 4q35, while myd maps to mouse chromosome 8. To explore the relationship between FSHD and myd, it is necessary to define the homologous regions of human chromosome 4 and mouse chromosome 8, and ultimately, identify the genes underlying both disorders. A kallikrein gene (Kal3) was previously mapped by in situ hybridization to mouse chromosome 8 and human 4q35. We report the genetic map location of Kal3, bringing to 4 the number of genes with homologues on human 4q31-35 placed on the genetic map of mouse chromosome 8. As a first step in gene isolation, we have narrowed the interval containing myd by typing 125 affected mice with microsatellite markers. Analysis of recombinants placed myd in an interval that is flanked by genes with homologues in human 4q.

Mouse myodystrophy (myd) mutation: refined mapping in an interval flanked by homology with distal human 4q.

Myodystrophy (myd) is an autosomal-recessive mouse mutation with dystrophic skeletal muscle. We propose that myd may be a model of the human disorder facioscapulohumeral dystrophy (FSHD) on the basis of clinical features and homologous genetic map locations. FSHD maps to human 4q35, while myd maps to mouse chromosome 8. To explore the relationship between FSHD and myd, it is necessary to define the homologous regions of human chromosome 4 and mouse chromosome 8, and ultimately, identify the genes underlying both disorders. A kallikrein gene (KaL3) was previously mapped by in situ hybridization to mouse chromosome 8 and human 4q35. We report the genetic map location of Kal3, bringing to 4 the number of genes with homologues on human 4q31-35 placed on the genetic map of mouse chromosome 8. As a first step in gene isolation, we have narrowed the interval containing myd by typing 125 affected mice with microsatellite markers. Analysis of recombinants placed myd in an interval that is flanked by genes with homologues in human 4q.

Rapidly progressive autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration.

We describe a family with nearly 300 members over 8 generations with 32 affected individuals who have an autosomal dominant neurodegenerative disease characterized by progressive parkinsonism with dystonia unrelated to medications, dementia, ocular motility abnormalities, pyramidal tract dysfunction, frontal lobe release signs, perseverative vocalizations, and urinary incontinence. The course is exceptionally aggressive; symptom onset and death consistently occur in the fifth decade. Positron emission tomographic studies with [18F]6-fluoro-L-dopa (6FD) were performed in 4 patients and 7 individuals at risk for development of the disease. All affected subjects had markedly reduced striatal uptake of 6FD (p less than 0.001). All individuals at risk had normal striatal uptake, but high 6FD uptake rate constants were noted in 3 of the 7 studied. Autopsy findings revealed severe neuronal loss with gliosis in substantia nigra, pontine tegmentum, and globus pallidus, with less involvement of the caudate and the putamen. There were no plaques, tangles, Lewy bodies, or amyloid bodies. This kindred appears to represent a neurodegenerative disease not heretofore described. We propose the following name for this new genetic disease: autosomal dominant parkinsonism and dementia with pallido-ponto-nigral degeneration.

Vascular smooth muscle hyperplasia underlies the formation of glomeruloid vascular structures of glioblastoma multiforme.

The origin of the vascular hyperplasia seen in glioblastoma multiforme is a matter of debate. To test the predominant hypothesis that these glomeruloid structures are of endothelial origin the following study was undertaken. Seven glioblastomas containing prominent glomeruloid vascular structures were stained with Ulex europaeus agglutinin I (UEA-1) and with antibodies against factor VIII/related antigen (fVIII/RAg), glial fibrillary acidic protein (GFAP), S-100 protein, muscle specific alpha-actin (MSA) and smooth muscle specific alpha-actin (SMSA). The GFAP and S-100 antibodies stained the neoplastic glial component of each tumor but did not bind to vascular cells. Endothelial cells lining the lumina of normal vessels and the lumina of glomeruloid vascular structures stained positively with both UEA-1 and fVIII/RAg antibody. No other cells were found to be stained by UEA-1 or by fVIII/RAg antibody. Smooth muscle cells of the normal vasculature stained positively exclusively with anti-MSA and anti-SMSA antibodies. The same pattern of positive actin antibody staining was seen in the majority of cells forming the glomeruloid structures; however, the cells lining the vascular lumina did not bind the MSA and SMSA antibodies. These data strongly suggest that the vascular proliferation resulting in glomeruloid structures is due in large measure to smooth muscle hyperplasia.

Smooth muscle can comprise the sarcomatous component of gliosarcomas.

The sarcomatous component of gliosarcomas is thought by many to originate from the vascular proliferation seen in glioblastoma multiforme and has, therefore, been assumed to be endothelial. Immunohistochemical staining of four gliosarcomas has led us to an alternate theory. Pathologically all four tumors were composed of at least two cell types; the first had a stellate, glial appearance and the second was either spindled or polygonal in shape. Polygonal cells were associated with glomeruloid vascular structures in some areas. Both components of each neoplasm were cytologically malignant. Glial fibrillary acidic protein and S-100 antibodies stained most of the glial-appearing cells and some of the spindled cells, but not the polygonal cells. Muscle specific alpha-actin and smooth muscle specific alpha-actin antibodies stained only the malignant spindled and polygonal cells and normal vascular smooth muscle. Ulex europaeus agglutinin I and anti-factor VIII/related antigen antibody stained only cells lining vascular lumina. The staining results suggest that the malignant mesenchymal component of these tumors is of smooth muscle origin. Having demonstrated elsewhere that glomeruloid vascular structures of glioblastoma multiforme contain smooth muscle cells, we propose here that gliosarcomas can represent one end of the spectrum of glioma-induced vascular smooth muscle proliferation.