Astrocytic gliosis in the amygdala in Down's syndrome and Alzheimer's disease.
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Adolescent↗
Biomedical subjects
W G Ellis
Publications and source records attributed to W G Ellis.
Alzheimer's disease. Beta-amyloid precursor protein expression in the nucleus basalis of Meynert.
The nucleus basalis of Meynert (nbM) was examined using immunocytochemistry for beta-amyloid precursor protein (beta APP) expression in Alzheimer's disease (AD). In mild AD cases, light labeling of the cell body and proximal processes was observed, and small intracellular structures were labeled rarely. In the more severe cases, intense cytoplasmic beta APP labeling was seen, often along with small beta APP-positive structures. Double-labeling experiments demonstrated that in the more severe cases these small structures were also decorated by a neurofibrillary tangle (NFT) antiserum. Other neurons in the severe cases showed incorporation of beta APP into large inclusions, which were also labeled with the NFT antiserum. However, some large inclusions in the severe cases were labeled by the NFT antiserum but contained no beta APP. Extraneuronal NFTs did not show beta APP labeling and did not react with an antibody to the beta-amyloid peptide. These results suggest that increased expression of beta APP coincides with intracellular NFT formation in the nbM, but that the formation of extraneuronal NFTs results in a loss of beta APP immunoreactivity.
Adult↗
Alzheimer's disease: beta-amyloid precursor protein expression in plaques varies among cytoarchitectonic areas of the medial temporal lobe.
The anatomic distributions of beta-amyloid peptide (beta AP) and beta-amyloid precursor protein (beta APP) in the medial temporal lobe were examined with immunocytochemistry in Alzheimer's disease. beta AP-containing plaques were found most frequently in the cortical and basal regions of the amygdala, and in the hippocampal CA1, subiculum, and dentate molecular layer. beta APP expression in plaques was found in a similar distribution, with some, but not all beta AP plaques also showing beta APP. In the cortical and basal amygdala, some cases showed beta APP in the centers of plaques, whereas in the hippocampus, all cases displayed beta APP mainly in plaque neurites. The lateral regions of the amygdala contained mainly diffuse beta AP plaques which had little beta APP. These findings suggest that although beta APP expression and beta AP deposition generally colocalize, processing of beta APP may vary among closely interconnected anatomic regions.
Adult↗
The amygdala in Down's syndrome and familial Alzheimer's disease: four clinicopathological case reports.
Senile plaques and neurofibrillary tangles were quantified in 14 subnuclei of the amygdala in the brains of 3 patients with Down's syndrome (DS), aged 19, 56, and 64 years, and in 1 patient with familial Alzheimer's disease (AD), aged 54 years. The amygdala of the 19-year-old Down's case contained numerous senile plaques (SPs) but no neurofibrillary tangles (NFTs). The distribution of neuropathological change in the amygdala was similar among the Down's and the Alzheimer's cases. Medical and ventral regions contained more SPs and NFTs than did lateral regions, and the SPs in ventromedial subnuclei generally were the "mature" type with a prominent amyloid core. In general, the numbers of SPs and NFTs were parallel in a given subnucleus with the striking exceptions of the deep medial basal, deep cortical, and lateral central nuclei that contained far more SPs than NFTs, and the medial and lateral superficial cortical nuclei that contained numerous NFTs but few SPs. Several subnuclei strongly interconnected with hippocampus and entorhinal cortex were more heavily involved than subnuclei related to the nucleus basalis of Meynert. The patterns of SP and NFT deposition are consistent with amygdaloid abnormalities found by others in sporadic AD. These findings demonstrate the similarity in amygdaloid pathology among Down's syndrome, familial Alzheimer's disease, and sporadic AD. The presence of senile plaques in the amygdala of the 19-year-old patient with DS suggests that the amygdala is a focus of early pathological change in DS and possibly AD.
Adult↗
Elevation in relative levels of brain membrane unsaturated fatty acids in Alzheimer's disease: high resolution proton spectroscopic studies of membrane lipid extracts.
Unsaturation indices of cerebral cortex membrane phospholipids in Alzheimer's disease were determined utilizing high resolution proton nuclear magnetic resonance (NMR) spectroscopy of lipid extracts. The unsaturation index of Alzheimer's brain was found to be significantly higher (P less than 0.01) than that of age-matched controls. The study provides further support for the hypothesis that alteration in phospholipid metabolism, especially an elevation in unsaturated fatty acids, may play a role in the pathogenesis of Alzheimer's disease.
Aged↗
Astrocyte hypertrophy in the Alzheimer's disease hippocampal formation.
In Alzheimer's disease (AD), neuritic plaques are often found in the hippocampal dentate gyrus along the boundary between inner and outer molecular layers. The dentate outer molecular layer in AD also exhibits axon sprouting in response to an early loss of entorhinal neurons. The relationship between the laminar arrangement of plaques and the sprouting remains unclear. In experimental entorhinal lesions in the rat, the denervated dentate outer molecular layer demonstrates hypertrophic astrocytes which may provide trophic support for the sprouting response. It is not known whether an equivalent astrocyte response occurs in AD or whether this response is related to the distribution of plaques. We used immunohistochemical staining for glial fibrillary acidic protein (GFAP) to demonstrate reactive astrocytes in the hippocampus in AD patients and age-matched controls. These results were compared to the astrocyte response to an experimental entorhinal lesion in the rat. Quantitative and qualitative analyses demonstrated a significant increase in GFAP-positive hypertrophic astrocytes in the dentate outer molecular layer in AD compared to controls. These astrocytes were randomly distributed within the outer layer and did not parallel the distribution of neuritic plaques. In the entorhinal-lesioned rat, reactive hypertrophied astrocytes also showed a selective distribution within the denervated outer molecular layer. Our results further support the similarity of the hippocampal response in AD and experimental entorhinal lesion but do not explain the laminar distribution of neuritic plaques along the denervated zone.
Alzheimer Disease↗
Effects on the fetal rat eye of maternal benomyl exposure and protein malnutrition.
Benomyl, a benzimidazole fungicide, produced ocular and craniocerebral malformations in fetal rats when administered to the dams by gavage in a dose of 62.4 mg/kg of maternal body weight/day on days 7-21 of gestation. Ocular anomalies included retinal dysplasia, cataracts, microphthalmia, and anophthalmia. These anomalies occurred in 43.3% of fetuses exposed to benomyl and a normal protein diet but increased to 62.5% when benomyl administration was combined with a protein deficient (8% casein) diet. Microscopic examination of the malformed eyes revealed that the most common abnormality, retinal dysplasia, consisted of rosettes of retinal cells and retinal infolding. The majority of rosettes had a single layer and a limiting membrane. Rosettes with two or three layers were also observed, particularly in fetuses exposed both to protein deficiency and benomyl. Although anophthalmia was identified macroscopically in five fetuses, only a single instance of true anophthalmia was found microscopically. These data support the results of previous investigators that benomyl induces ocular malformation and that protein deficiency enhances the teratogenic effects of benomyl. The disorderly proliferation of retinal cells and rosette formation resembled the periventricular cell masses that accumulate in brains exposed to benomyl and certain other teratogenic agents. The anti-tubulin action of benomyl is known to impair microtubule formation and it may produce brain and ocular malformations by disruption of neuronal proliferation and migration.
Abnormalities, Drug-Induced↗
Antigenic profile of plaques and neurofibrillary tangles in the amygdala in Down's syndrome: a comparison with Alzheimer's disease.
Most patients with Down's syndrome (DS) undergo a premature cognitive decline with aging, and eventually develop the neuropathologic changes of Alzheimer's disease (AD), including amyloid-containing neuritic plaques, and the formation of neurofibrillary tangles. The amygdala is a focus of marked neuropathologic change in older patients with DS and in AD. We examined the amygdala with immunocytochemical and histochemical methods in 6 cases with DS, ages 19, 20, 27, 29, 56 and 64 years and compared them to 4 cases with AD, ages 54, 76, 77 and 80 years. An antiserum to the A4 amyloid peptide demonstrated amyloid deposition in plaques in all 10 cases. Plaques were also revealed in all cases by the Alcian blue stain for glycosaminoglycans and by the Bielschowsky and Bodian silver stains. An antiserum to alpha-1-antichymotrypsin (ACT) showed plaques in the AD cases and in the 19, 56 and 64 year old DS cases. Neurofibrillary tangles were observed with silver stains only in the older DS and in the AD cases, and not in the 19, 20, 27 and 29 year old DS cases. Likewise, antisera to paired helical filament, to microtubule associated proteins tau and microtubule associated protein-2 (MAP-2), and to ubiquitin, all of which are components of neurofibrillary tangles, reacted with tangles and abnormal neurites only in the older DS and the AD cases. An antiserum to neurofilament epitopes labeled NFTs in the older DS cases and the AD cases, but not in the younger DS cases, except for two intraneuronal NFTs in the 27 year old case.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Beta-amyloid precursor detected in human cerebral cortex.
1. Amyloid deposition is one of the pathologic hallmarks of Alzheimer's disease. Since the isolation of the beta-amyloid gene, which revealed that the amyloid forming 4 kD protein is part of a larger precursor, interest has focused on the process by which amyloid is generated and deposited. 2. The authors have developed an immunologic means of detecting amyloid precursor proteins in human brain. 3. The method involves the expression of human beta-amyloid precursor cDNA in a recombinant vaccinia virus, so that antibodies are produced against the precursor proteins in their native forms. 4. By using this expression system, the amyloid precursor immunogens incorporate post-translational modifications that normally occur in vivo; this cannot be achieved with small synthetic peptides. 5. Using antibodies to the 695 residue amyloid precursor, we have detected using Western blot analysis a protein of approximately 120 kD in samples of cerebral cortex from three subjects with Alzheimer's disease and one control subject. 6. Additional antibodies to other amyloid-related proteins have been developed. These are being used to assess the differential expression of the various amyloid precursors and subdomains in additional cases.
Adult↗
Membrane fatty acid composition shows delta-6-desaturase abnormalities in Alzheimer's disease.
Brain membrane phospholipid fatty acid composition is investigated in Alzheimer's disease using fresh pathologically proven autopsy material. The most striking abnormalities in Alzheimer brains compared to age-matched controls are found in the n - 6 line of polyunsaturated fatty acids (PUFA) showing an elevation of 18:2 (n - 6) associated with a reduction of 20:4 (n - 6) and 22:4 (n - 6). The findings strongly indicate abnormalities in delta 6-desaturation. The decrease in 22:6 (n - 3) also supports delta 6-desaturase abnormalities. Alteration in PUFA desaturation/elongation processes and resultant membrane abnormalities may play a key role in the pathogenesis of Alzheimer's disease.
Aged↗
Arthrogryposis multiplex congenita: prenatal ultrasonographic diagnosis.
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Adult↗
Cavernous angioma of the tentorium cerebelli. Case report.
The case of a cavernous angioma of the tentorium cerebelli is described. This is the seventh reported case of a cavernous angioma in this unusual location and the first of a dural cavernous angioma demonstrated by magnetic resonance imaging. The clinical presentation, radiographic features, and surgical treatment of these rare tumors are discussed, along with a review of the literature.
Cerebellar Neoplasms↗
Neuropathologic documentation of prenatal brain damage.
Neuropathologic evidence of prenatal brain damage, chiefly in cerebral white matter, was found in 25% of infants who died at 7 days of age or less, with a total of ten preterm (16%) and 12 term (48%) infants among the 89 subjects studied. Few clinical features distinguished infants with prenatal injury from those without such injuries. Apgar scores were low, seizures were rare, and acute intracranial hemorrhage occurred equally often in both groups. Few pregnancies were entirely normal, but hydramnios was the only factor that occurred more often in prenatally injured infants, a statistically significant difference only among term infants. Oligohydramnios was not associated with prenatal brain injury. Unless fetal/maternal abnormalities in late gestation are identified and corrected, improved neonatal care will increase survival for prenatally damaged infants and the incidence of cerebral palsy may rise.
Brain↗
Relationship of periventricular overgrowth to hydrocephalus in brains of fetal rats exposed to benomyl.
Benomyl, a benzimidazole fungicide, was administered by gavage to pregnant Sprague-Dawley rats in a daily dose of 62.5 mg/kg of maternal body weight beginning at gestational day (GD) 7. Fetuses examined histologically at GD16 or GD20 revealed a high incidence of craniocerebral anomalies--82.6% of those examined at GD16 and 100% of those examined at GD20. Hydrocephalus occurred in 65.2% of fetuses examined at GD16 and in 58.8% at GD20 but was more severe in the GD20 fetuses. A second common anomaly, termed periventricular "overgrowth" (PVO), consisted of subependymal cell masses that in some fetuses obliterated normal subcortical structures. PVO occurred in 34.8% of fetuses examined at GD16 and 76.5% at GD20. The size of the subependymal masses and the regions involved were considerably greater in the GD20 than the GD16 fetuses. Less common anomalies in the GD20 fetuses were periventricular necrosis (41.2%), a single fetus with exencephaly and another with porencephaly. In the majority of malformed fetuses, the severity of hydrocephalus did not parallel the severity of PVO around the lateral and third ventricles. PVO involved tissues surrounding the cerebral aqueduct in 17.4% of GD16 fetuses and 38.2% of GD20 fetuses. This "overgrowth" distorted the cerebral aqueduct in a large number of fetuses with ventriculomegaly, and at GD20 moderate and severe ventriculomegaly was in every instance associated with a narrow or completely occluded cerebral aqueduct. These relationships suggest that PVO in the midbrain may play a role in the production of aqueductal stenosis and hydrocephalus in this experimental model.
Abnormalities, Drug-Induced↗
Neurotoxicity of amphotericin B methyl ester in dogs.
Clinical and neuropathologic effects of chronically administered intravenous (iv) amphotericin B methyl ester (AME) were observed in 3 male dogs (2 German shorthaired pointers and 1 pit bull). Each dog received 6.2-7.3 g of AME (299-327 mg/kg body weight) over a period of 11-12 weeks. One dog developed neurologic signs of severe diffuse brain dysfunction and at necropsy all 3 dogs had a marked leukoencephalopathy, most severe in centrum ovale and subcortical white matter of frontal lobes. Brain histopathology included diffuse myelin loss, oligodendrocyte depletion, accumulation of macrophages filled with sudanophilic lipid, fibrillary astrogliosis, and swelling or fragmentation of many axons. Two control dogs administered iv glucose showed no neuropathologic abnormalities. These findings closely resemble the clinical and neuropathologic abnormalities that developed in patients during the first human trial of AME for treatment of fungal infections, but differ from those of animal studies that did not closely simulate the long-term drug administration required for antifungal therapy in humans. It was concluded that before human clinical trial is authorized, experimental protocols for animal studies of drug toxicity should reflect the anticipated human use of the drug, both in dose and duration.
Amphotericin B↗
Pathology of renal and hepatic anomalies in Meckel syndrome.
We describe 9 cases of Meckel syndrome (dysencephalia splanchnocystica), ranging in gestational age from 17 to 39 weeks. Five were liveborn, and the longest survival was 30 hours. Six of the 9 had all 3 elements of the classically defined triad, namely occipital encephalocele, renal cystic dysplasia, and postaxial polydactyly. The remaining 3 cases had only 2 elements of the triad. The renal abnormalities in the 9 cases resembled one another closely, varying only slightly in severity. They consisted of renal cystic dysplasia with different degrees of nephronic differentiation. The 8 available livers all contained intrahepatic bile duct anomalies. Seven of them had the classic "ductal plate malformation," as defined by Jorgensen [1977]; the remaining case had a less severe form of this malformation. The livers of the Meckel syndrome fetuses were compared to those of age-matched control fetuses, and it was concluded that the hepatic abnormality represents an arrested development of the intrahepatic biliary system at the stage of biliary cylinders with varying degrees of reactive bile duct proliferation, bile duct dilatation, portal fibrosis, and portal fibrous vascular obliteration superimposed on the arrested pattern. The case showing the least severe hepatic lesion also had the least severe renal lesion. The anomalies that were present are listed. The relationship of the different lesions to each other is briefly discussed. It was concluded that the hepatic lesion appears to be a consistent manifestation in Meckel syndrome and is of diagnostic value as the renal lesion has previously been shown to be.
Abnormalities, Multiple↗
Benomyl-induced craniocerebral anomalies in fetuses of adequately nourished and protein-deprived rats.
Benomyl, a benzimidazole fungicide, produced craniocerebral and systemic malformations in fetal rats when administered by gavage in doses of 31.2, 62.5, and 125 mg/kg of maternal body weight on days 7-21 of gestation. Malformations increased in incidence and severity with increasing benomyl dosage and nearly doubled when coupled with a protein-deficient diet. Protein deficiency alone produced only decreased fetal weight. High benomyl doses produced higher percentages of fetal resorptions and late fetal deaths, and these percentages also increased with protein deficiency. A benomyl dose of 62.5 mg/kg in protein-deficiency dams, the optimal combination for a high incidence of anomalies and low fetal wastage, produced hydrocephalus in 69.4% of fetuses, meningocele in 8.2%, encephalocele in 14.3%, exencephaly in 44.9%, anencephaly in 14.3%, corpus callosum agenesis in 26.5%, periventricular necrosis in 26.5%, and periventricular cellular "overgrowth" in 55.1%. The most common combination of anomalies was hydrocephalus, exencephaly, and periventricular "overgrowth." Common systemic malformations included cleft palate, micromelia, hydroureter, and misshapen tails. No fetus was entirely normal at the highest benomyl dose. Benomyl has been shown by others to bind tubulin and inhibit the formation of microtubules that are important in neurulation, mitosis, and cell migration during early brain development. Thus, it is suggested that benomyl, coupled with a protein-deficient diet, offers a teratogenic model with a spectrum of abnormalities similar to hypervitaminosis A but with a higher yield of specific craniocerebral anomalies.
Animals↗
Inter-male aggressive signals in weakly electric fish are modulated by monoamines.
Apteronotus leptorhynchus is a gymnotid fish producing a constant high frequency electric organ discharge (EOD). Males of this species use transient increases in EOD frequency (chirps) as aggressive signals. They will also shift the frequency of their EOD away from the similar frequency of a nearby conspecific in order to protect their ability to electrolocate (jamming avoidance response, JAR). Monoamines have been implicated as modulatory agents for various sensorimotor and affective systems, including aggressive behaviour. Since these monoamines are present in the brain of this fish (unpublished observation), we have used these simple and quantifiable behaviours to study the role of monoamines, with special emphasis on possible specific effects on aggressive signalling (chirps). When serotonin (0.1 microgram) is injected directly into the ventricle of these fish it briefly inhibits chirping (aggression) without inhibiting the JAR; this is consistent with the hypothesis that, in mammals, serotonin inhibits aggressive behaviour. Noradrenaline (0.1 microgram) enhances both chirping and the JAR. Dopamine (0.1 microgram) enhances the JAR; it has powerful but inconsistent effects on chirping (inhibition or excitation).
Aggression↗