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.

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.

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.

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.

Case of multivertebral anomalies, cloacal dysgenesis, and other anomalies presenting prenatally as cystic kidneys.

We describe a newborn boy on whom prenatal ultrasonography demonstrated intrauterine growth retardation, multiple vertebral anomalies, cystic kidneys, and oligohydramnios. Autopsy findings included multiple vertebral anomalies, cloacal dysgenesis (imperforate anus, vesicorectal fistula, and bilateral renal dysplasia), sacral absence, single umbilical artery, pulmonary hypoplasia, scoliosis, and hexadactyly of the left thumb. Although our case resembles a previously described case, a definitive diagnosis could not be made. The differential diagnosis included a variant of spondylocostal dysostosis and the VATER association.

Partial protection from salt-induced stroke and mortality by high oral calcium in hypertensive rats.

BACKGROUND AND PURPOSE: Repeated demonstration of an antihypertensive effect of high oral calcium in stroke-prone spontaneously hypertensive rats led us to determine whether it also protects such rats from premature mortality and stroke-related lesions. METHODS: Female stroke-prone rats (11-13 per diet) were fed high- and low-calcium (2.0% and 0.4%, respectively) diets with both high and low salt (7.0% and 0.3%, respectively) content from age 4 weeks until spontaneous death. In addition to life span, other variables measured included blood pressures, plasma chemistries, and histological characterization of stroke-related lesions. RESULTS: Life span was increased from 51 +/- 4 to 68 +/- 1 weeks (p less than 0.05) by high versus low oral calcium in rats fed high-salt diets; it was further increased to greater than or equal to 82 weeks (p less than 0.05) in rats fed low-salt (+/- added calcium) diets. As seen previously, high oral calcium attenuated salt-induced hypertension but did not affect blood pressure in rats fed low-salt diets. High versus low oral calcium exerted contrasting effects (p less than 0.05) on brain lesions (hemorrhages and infarctions) in rats fed high-salt diets, decreasing lesion size (242 +/- 21 versus 712 +/- 276 microns per rat [diameters seen in histological sections]) but increasing lesion number (8.9 +/- 2.4 versus 3.4 +/- 2.2 per rat); it exerted little influence on the few brain lesions that appeared in rats fed low-salt diets. CONCLUSIONS: High oral calcium may protect stroke-prone hypertensive rats from early salt-induced mortality at least partially by decreasing severity (size) of stroke-related lesions, an effect which may relate to decreased blood pressure. However, this protection may be limited by increased number (incidence) of such lesions, an effect which suggests that high oral calcium may increase the number of brain vessels susceptible to stroke-related injury independent of change in blood pressure.

Quantitative assessment of ALZ-50 immunoreactivity in Alzheimer's disease.

A quantitative assay for ALZ-50 immunoreactivity was evaluated in samples of superior temporal gyrus taken at autopsy from 13 Alzheimer patients and 11 controls. The assayable immunoreactivity appears to be stable for at least 24 hours postmortem but was lost with formalin fixation. The mean value of the Alzheimer patients was tenfold higher than that of the controls (P less than .002). The values of four Alzheimer samples overlapped with the low levels seen in controls, but no controls had elevated levels. In this sample population, therefore, the assay had a sensitivity of 69% and specificity of 100%.

The role of radiation therapy in the management of ependymomas of the spinal cord.

Twenty patients with biopsy-proven ependymomas of the spinal cord were treated between 1960 and 1984-7 with surgery only, 3 with radiation therapy only, and 10 with surgery and postoperative radiation therapy. Of these, 2 patients developed recurrent tumor at the primary site, 3 developed a recurrent tumor in the thecal sac, and 1 developed distant metastasis. The absolute 5- and 10-year survival rates were 95% (19/20) and 86% (12/14), respectively. None of 13 patients who were treated with radiation therapy only or combined surgery and postoperative radiation therapy developed recurrent tumor at the primary site, and none of 7 patients who received thecal sac irradiation developed thecal sac recurrences. In contrast, 2 of 7 patients (29%) treated with surgery alone developed recurrent tumor at the primary site, and 3 of 13 patients (23%) who received no thecal sac irradiation developed a recurrent tumor in the thecal sac. The failure rates following surgery were greatest in patients who had tumor removed in a piecemeal fashion (43%, 6/14). The results show that radiation therapy is probably not necessary if the tumor has been removed completely in an en bloc fashion. However, radiation therapy is needed if the tumor has been incompletely removed or removed in a piecemeal fashion. If the tumor has been removed in a piecemeal fashion, the radiation portals should be extended to include the thecal sac. Histologic subtypes influenced the pattern of recurrence. Myxopapillary ependymomas and high grade cellular ependymomas appear to be more likely to recur in the thecal sac. However, no big difference could be detected in local recurrence.

Pigmented neuroectodermal tumor of infancy. A light microscopic and immunohistochemical study.

We studied two cases of pigmented neuroectodermal tumor of infancy (PNTI) by routine light microscopy and immunohistochemistry on formalin fixed, paraffin embedded tissues using antibodies to HMB-45 "melanoma associated" antigen, S-100 protein, neuron specific enolase (NSE), Leu-7 antigen, chromogranin, epithelial membrane antigen, collagen Type IV, alpha-fetoprotein and muscle-specific actin and to the intermediate filaments cytokeratin (CK), vimentin, desmin and neural filaments. We found that the large epithelioid cells, many of which contained melanin pigment, were strongly positive for CK and HMB-45, and less intensively positive for vimentin and NSE. The small neuroblast-like cells revealed only focal, weak NSE positivity. Both cell types were negative for S-100 protein and for the other antigens examined. Our results suggest that: (1) the large and small cell populations in PNTI have different immunophenotypes; (2) the expression of CK and HMB-45, together with the S-100 negativity, appears unique for the pigmented cells; and (3) this profile may be helpful in the exclusion of melanoma and peripheral neuroblastoma from the differential diagnosis.

Diagnostic yield in CT-guided stereotactic biopsy of gliomas.

Twenty-seven patients underwent 29 computerized tomography (CT)-guided stereotactic biopsy procedures for untreated or recurrent malignant astrocytomas. Biopsies were obtained from the hypodense center, enhancing margin, and hypodense periphery as seen on contrast-enhanced CT scans, with diagnostic yields of (number of biopsies yielding tumor/number of biopsies obtained): 34/61 (56%), 68/101 (67%), and 8/22 (36%) from these three zones, respectively. Although tumor was identified in all three zones, diagnostic yield was significantly higher in the hypodense center and enhancing margin. Comparison of patients with untreated tumors to those with recurrent tumors demonstrated no statistical difference in tumor distribution, although there was a trend toward a higher yield from the hypodense periphery in the recurrent tumor group. Tumor was found up to 15 mm beyond the CT-enhancing margin, in addition to extending beyond the area of abnormality on T2-weighted magnetic resonance images. These findings suggest that serial stereotactic biopsies should be targeted to the hypodense center and enhancing margin for improved diagnostic yield. Biopsy material obtained from the hypodense periphery that demonstrates tumor also indicates that a tumor volume beyond the confines of the CT-enhancing margin should be considered when calculating dosimetry for interstitial radiation.