RESUMEN
Alzheimer's disease is characterized by relative sparing of primary sensory and motor cortex and a lack of sensory or motor symptomatology. We report a case of presenile onset dementia accompanied by a slowly progressive hemiparesis. Autopsy examination showed severe pathologic involvement of somatosensory cortex with neuritic plaques and neurofibrillary tangles, in addition to degeneration of the nucleus basalis and locus ceruleus. Neurochemical and immunocytochemical studies showed a moderate cortical cholinergic deficiency with normal somatostatin-like immunoreactivity and a profuse immunostaining of somatosensory cortex with the Alz-50 antibody. These unusual features emphasize that Alzheimer's disease is extremely variable in its clinical symptomatology, pathologic distribution, and neurochemical dimensions.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Demencia/fisiopatología , Hemiplejía/fisiopatología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Encéfalo/patología , Química Encefálica , Demencia/metabolismo , Demencia/patología , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana EdadRESUMEN
Cortical Lewy bodies may be difficult to differentiate from Pick bodies by the usual staining methods. This problem is illustrated in a case of progressive dementia with parkinsonian features. Lewy bodies were found, not only in the pigmented nuclei in the brainstem and in the cerebral cortex, but also in the dentate fascia, a predilection site for Pick bodies. The inclusion bodies were compared with the inclusion bodies in a case of Pick's disease. Intense argyrophilia of the cortical inclusion bodies argued in favor of Pick bodies; antibodies to phosphorylated neurofilaments reacted with the cortical inclusions and with classical Pick bodies, but antibodies to paired helical filaments reacted only with the Pick bodies. The most convincing evidence, that the inclusions were Lewy bodies, was obtained by electron microscopy. The filaments in the inclusions showed fuzzy deposits of electron dense material, characteristic for filaments of Lewy bodies. This contrasted with the smooth filaments of the Pick bodies. It is concluded that cortical inclusions in brains from patients with Lewy bodies in the pigmented nuclei of the brainstem most likely represent Lewy bodies. This can be confirmed by examining the ultrastructure of the inclusions.
Asunto(s)
Corteza Cerebral/patología , Demencia/patología , Cuerpos de Inclusión/ultraestructura , Neuronas/citología , Enfermedad de Parkinson/patología , Anciano , Anticuerpos Monoclonales , Corteza Cerebral/ultraestructura , Demencia/complicaciones , Hipocampo/patología , Hipocampo/ultraestructura , Humanos , Técnicas para Inmunoenzimas , Proteínas de Filamentos Intermediarios/análisis , Filamentos Intermedios/ultraestructura , Masculino , Microscopía Electrónica , Proteínas de Neurofilamentos , Neuronas/ultraestructura , Enfermedad de Parkinson/complicaciones , Sustancia Negra/patología , Sustancia Negra/ultraestructuraRESUMEN
A quantitative survey of calcitonin gene-related peptide (CGRP) in brain, peripheral nerve and cerebrospinal fluid (CSF) was performed using radioimmunoassay (RIA) with antiserum against synthetic hCGRP. High levels (approximately 2000-15,000 fmol/mg protein) were found in the dorsal spinal cord, dorsal nerve and trigeminal nerve. Relatively large amounts (500-2000) were found in parts of the hypothalamic-pituitary axis, peripheral nerve and, for the first time, in the locus caeruleus. Low levels of CGRP (less than 500) were detected in the cerebrum, subcortical nuclei and cerebellum. CGRP, not previously reported in CSF, was detectable in all of 27 CSF specimens with mean values of 30 +/- 4.5 pmol/L (SE). Simultaneous plasma CGRP levels were higher and, when elevated by antihypertensive treatment were not increased in CSF, just as astronomical plasma levels of calcitonin in medullary carcinoma of the thyroid are not reflected in CSF. Our data confirm and extend the results of previous human and animal studies with evidence of species variation: humans have low CGRP levels in subcortical nuclei whereas high levels have been found in rat caudate-putamen and amygdala. The high level of CGRP in the locus caeruleus, the major source of noradrenergic neurotransmission in the CNS, is in harmony with the presumed functions of the LC and the very potent hemodynamic activity of CGRP.
Asunto(s)
Encéfalo/metabolismo , Neuropéptidos/metabolismo , Péptido Relacionado con Gen de Calcitonina , Humanos , Locus Coeruleus/metabolismo , Neuropéptidos/líquido cefalorraquídeo , Nervios Periféricos/metabolismo , Médula Espinal/metabolismo , Distribución TisularRESUMEN
Delayed radiation damage of normal brain can be a devastating complication of radiation therapy and generally occurs months to years after the initiation of therapy. Primarily restricted to the white matter, radiation damage is characterized by a number of histopathologic changes including coagulation necrosis, vascular alterations with fibrinoid necrosis, edema, and demyelination. Normal dogs were exposed to either 10, 15, or 30 Gy of X rays to a single hemisphere and the gross and histopathologic changes were evaluated qualitatively. A spectrum of changes was observed ranging from white matter edema to extensive white matter necrosis, and the extent, location, and type of damage were dependent upon radiation dose. Histopathologic changes were separated into three major categories based on the character and size of the lesions, with the most severe changes being similar to the types of changes described in human patients who have developed delayed radiation necrosis. Less severe forms of damage such as multifocal, sometimes confluent areas of microscopic necrosis with spongiotic borders and edema with severe axonal swelling were also observed. These latter changes are not well recognized as being due to radiation. The findings of this study also indicate that many of the changes ascribed to combined treatment with methotrexate and radiation in humans are induced in the normal dog brain by radiation alone. The results of his study show that the dog is a suitable model of the human brain for studying radiation brain injury and may be useful for investigation of drug-radiation interactions.
Asunto(s)
Encefalopatías/patología , Traumatismos Experimentales por Radiación/patología , Animales , Encéfalo/patología , Encéfalo/efectos de la radiación , Edema Encefálico/etiología , Edema Encefálico/patología , Perros , Relación Dosis-Respuesta en la Radiación , Necrosis , Factores de TiempoRESUMEN
The histopathological changes associated with ultrasonic heating of normal cat brain have been correlated with thermal distributions. Ultrasound energy was applied for 50 min at different intensities to generate tissue temperatures from 42 to 48 degrees C. Animals were sacrificed at various intervals from 1 to 56 days. The organization and resolution of thermal damage was characterized by three stages of histopathological changes within the nervous tissue. The acute stage (Days 1-3) was defined by (1) extensive coagulation necrosis, (2) pyknosis of neuronal elements in the gray matter, (3) edema and vacuolation in the white matter, and (4) polymorphonuclear leukocytes. The subacute stage (Days 3-21) was characterized by (1) the appearance of lipid-laden macrophages, (2) liquefaction of the necrotic regions, (3) fibroblastic proliferation, and (4) vascular proliferation with some perivascular inflammatory infiltration (lymphocytes). Lastly, the chronic stage (Days 21-56) was defined by (1) fibrosis (reticulin and collagen formation) and (2) gliosis (reactive astrocytic proliferation) occurring around the fluid-filled necrotic center. Analysis of these data has also included a study of the lesion size versus the dose (temperature for 50 min) of heating. The results demonstrate a significant linear dose-response correlation. The results of this study indicate that the histological appearance and time course of repair of thermal injury in the normal brain tissue are analogous to acute brain necrosis resulting from cerebral infarction, except the thermal damage does not result in significant hemorrhage.
Asunto(s)
Encéfalo/patología , Hipertermia Inducida/efectos adversos , Terapia por Ultrasonido , Animales , Edema Encefálico/etiología , Edema Encefálico/patología , Gatos , Infarto Cerebral/etiología , Infarto Cerebral/patología , Femenino , Macrófagos/patología , Masculino , Necrosis , Neutrófilos/patología , Factores de TiempoRESUMEN
A case is presented of the ataxic variety of Creutzfeldt-Jakob disease with particular reference to the cerebellar cortex. The main features were loss of granule cells, subtotal in the vermis, severe in the lateral lobes, mild to moderate loss of Purkinje cells and preservation of tangential and basket fibres. The Purkinje cell dendrites showed malorientation and hypertrophy of the primary and secondary branches, the so-called "antler" or "staghorn" deformity. These findings indicate that remodelling of the dendritic tree may start early in the course of the disease even in adults, the total length of history in this case being eight months. They do not throw any additional light on the pathogenesis of the dendritic abnormalities, in particular on the controversy whether they are a non-specific response of the Purkinje cell to a variety of noxious agents or a reaction to partial deafferentation. The authors favour the latter hypothesis.
Asunto(s)
Síndrome de Creutzfeldt-Jakob/patología , Células de Purkinje/patología , Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/fisiopatología , Dendritas/patología , Humanos , Masculino , Persona de Mediana Edad , Plasticidad NeuronalRESUMEN
The neurotoxic effects and cerebrospinal fluid (CSF) pharmacokinetics of bleomycin were evaluated in beagles after chronic intraventricular administration twice a week for 8 consecutive weeks. Bleomycin was reasonably well tolerated at doses of 0.067 to 0.3 mg/week. Doses higher than 0.3 mg/week produced marked elevation of CSF protein levels and a necrotizing vasculitis within the central nervous system. Pharmacokinetic studies were performed approximately 1 month after the completion of the toxicity studies. [3H]inulin was used as a reference compound. Both [3H]inulin and bleomycin were cleared from the CSF more slowly than in previous studies and more slowly than in normal dogs, which suggests that bulk CSF absorption was reduced by the drug, probably secondary to protein-induced blockage of the arachnoid granulations through which CSF is normally absorbed. Because a "minimally toxic" dose of bleomycin (approximately 0.1 mg/week) produces a CSF C X t of only 1.9 mg/min/ml, we believe that a Phase I clinical trial would be too dangerous given the limited therapeutic potential that a dose of 0.1 mg/week could achieve.
Asunto(s)
Bleomicina/toxicidad , Encéfalo/efectos de los fármacos , Animales , Bleomicina/líquido cefalorraquídeo , Encéfalo/patología , Perros , Relación Dosis-Respuesta a Droga , Inyecciones Intraventriculares , Inulina/líquido cefalorraquídeo , Cinética , MasculinoRESUMEN
The central nervous system toxicity and cerebrospinal fluid (CSF) pharmacokinetics of 3-[(4-amino-2-methyl-5-pyrimidinyl)ethyl]-1-(2-chloroethyl)-1- nitrosoureas, a (ACNU) were determined in beagles and compared to those for three other nitrosoureas, 1-(2-chloroethyl)-3-(2,6-dioxo-3-piperidyl)-1-nitrosourea, 1,3-bis(2-chloroethyl)-1-nitrosourea, and chlorozotocin. Of the four drugs, ACNU was tolerated best and at doses of 0.2 to 0.8 mg/week for 8 consecutive weeks. We found that the average half-time for CSF elimination of ACNU was 18 min (range, 12 to 38 min). This value exceeded the known rate of ACNU decomposition in aqueous solution (28 to 29 min), implying that the disappearance of ACNU from CSF was due to hydrolytic decomposition and cellular entry and/or transcapillary loss across central nervous system capillaries. The drug exposure integral (C X t) of ACNU in the CSF after a "toxic dose low" of 0.8 mg in the dogs would achieve the equivalent of in vitro cell kills in excess of 3 logs for rat 9L and human glioma 126 cells. As a potential therapeutic agent for meningeal neoplasia, the major limiting factor may be that the CSF elimination of ACNU is rapid compared to its equilibration time from ventricle to spinal- and cerebral convexity-subarachnoid space. Based on these results, we have instituted clinical Phase I trials of intra-CSF ACNU.
Asunto(s)
Antineoplásicos/toxicidad , Encéfalo/efectos de los fármacos , Compuestos de Nitrosourea/toxicidad , Animales , Antineoplásicos/líquido cefalorraquídeo , Encéfalo/metabolismo , Encéfalo/patología , Permeabilidad Capilar/efectos de los fármacos , Ventrículos Cerebrales/efectos de los fármacos , Perros , Inulina/líquido cefalorraquídeo , Cinética , Masculino , Nimustina , Compuestos de Nitrosourea/líquido cefalorraquídeoRESUMEN
A digital video fluorescence microscopy technique was used to evaluate the distribution of hematoporphyrin derivative (HPD) in the rat intracerebral 9L gliosarcoma brain-tumor model at 4, 24, 48, and 72 hours after intravenous administration of 10 mg/kg of the drug. Compared to surrounding normal brain, there was significant preferential uptake of HPD into the tumor. In sections surveyed, fluorescence reached a maximum value by 24 hours; however, only 33% to 44% of the tumor was fluorescent. In contrast, fluorescence within the surrounding normal brain was maximum at 4 hours, but was present in less than 1% of the brain tissue evaluated. The effect of HPD sensitization to a laser light dose (633 nm) of 30 joules/sq cm delivered through the intact skull was evaluated histologically in 10 rats. A patchy coagulation necrosis, possibly corresponding to the distribution of HPD fluorescence seen within the tumor, was observed. There was evidence that photoradiation therapy (PRT) affects defective tumor vasculature and that a direct tumor cell toxicity spared normal brain tissue. Despite these findings, limited uptake of HPD in tumor and the brain adjacent to tumor may decrease the effectiveness of PRT in the 9L gliosarcoma brain-tumor model. Because of the similarity between the capillary system of the 9L tumor and human brain tumors, PRT may have a limited therapeutic effect in patients with malignant brain tumors.
Asunto(s)
Neoplasias Encefálicas/patología , Glioma/patología , Hematoporfirinas/análisis , Microscopía Fluorescente , Animales , Neoplasias Encefálicas/análisis , Glioma/análisis , Derivado de la Hematoporfirina , Masculino , Ratas , Ratas Endogámicas F344 , Grabación de Cinta de VideoRESUMEN
The magnitude and time course of contrast enhancement in spontaneous canine brain tumors was determined for two contrast agents: meglumine iothalamate and sodium meglumine ioxaglate. Tumor enhancement during contrast infusion and at 5, 10, 15, 30 and 45 minutes was measured using quantitative computed tomography. Blood iodine was measured using x-ray fluorescence. Peak contrast enhancement occurred during the infusion, and the magnitude was the same for both agents. Per gram of iodine infused, blood iodine was 12.4% higher with ioxaglate than iothalamate. The monoionic dimer ioxaglate is as effective as iothalamate for enhancement of canine brain tumors.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Medios de Contraste , Tomografía Computarizada por Rayos X , Animales , Astrocitoma/diagnóstico por imagen , Astrocitoma/veterinaria , Neoplasias Encefálicas/veterinaria , Enfermedades de los Perros/diagnóstico por imagen , Perros , Yotalamato de Meglumina , Ácido Yoxáglico , Neoplasias Meníngeas/diagnóstico por imagen , Meningioma/diagnóstico por imagen , Meningioma/veterinaria , Neoplasias de Células Germinales y Embrionarias/diagnóstico por imagen , Neoplasias de Células Germinales y Embrionarias/veterinaria , Concentración Osmolar , Ácidos TriyodobenzoicosRESUMEN
Radiation damage induced by megavoltage X irradiation in normal brain tissue can manifest as one of several pathologic processes depending upon the time of brain examination after irradiation. Serial quantitative computed tomography (QCT) analyses were used to study the development of radiation damage in the normal canine brain. Tissue density, volume of low density areas, magnitude and volume of contrast uptake, and ventricular volume were measured following hemibrain irradiation and were correlated with histopathology. Low density areas correlated with edema, demyelination, axonal swelling, and necrosis and appeared 3-4 months after irradiation. Large regions of contrast enhancement (coagulation necrosis and associated vascular changes) appeared 5-6 months after irradiation. Results from this study demonstrated that the pathologic changes induced in the dog brain after single doses of X rays were similar to the changes observed in nonhuman primates and man after exposure to radiation.
Asunto(s)
Encéfalo/efectos de la radiación , Traumatismos Experimentales por Radiación/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Perros , Masculino , Traumatismos Experimentales por Radiación/patologíaRESUMEN
The magnitude and time course of contrast enhancement in spontaneous canine brain tumors was determined for two contrast agents: meglumine iothalamate and sodium meglumine ioxaglate. Tumor enhancement during contrast infusion and at 5, 10, 15, 30, and 45 min was measured using quantitative computed tomography. Blood iodine was measured using x-ray fluorescence. Peak contrast enhancement occurred during the infusion, and the magnitude was the same for both agents. Per gram of iodine infused, blood iodine was 12.4% higher with ioxaglate than iothalamate. The monoionic dimer ioxaglate is as effective as iothalamate for enhancement of canine brain tumors.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Medios de Contraste , Tomografía Computarizada por Rayos X , Animales , Medios de Contraste/metabolismo , Perros , Yodo/sangre , Yotalamato de Meglumina/metabolismo , Ácido Yoxáglico , Cinética , Concentración Osmolar , Factores de Tiempo , Ácidos Triyodobenzoicos/metabolismoRESUMEN
Brain tumors in 4 dogs were treated with external beam, megavoltage radiation. X-ray computed tomography was used to localize and characterize brain tumors and to assess treatment response. Total radiation doses were 3,000 or 3,600 rad, given in 5 or 6 fractions over 14 to 19 days. Complete tumor regression, as determined from computed tomography scans, improvement in clinical signs, and reduction in medication, were documented in all irradiated dogs. The median survival time for irradiated dogs was 322 days, which was significantly (P less than 0.05) longer than the median survival time of 56 days in 8 dogs with brain tumors treated symptomatically. The one-year survival rate for the irradiated dogs, after correcting for deaths from intercurrent disease, was 100%. It was concluded that canine brain tumors may be treated effectively by use of megavoltage radiation.
Asunto(s)
Neoplasias Encefálicas/veterinaria , Enfermedades de los Perros/radioterapia , Animales , Neoplasias Encefálicas/radioterapia , Neoplasias del Ventrículo Cerebral/radioterapia , Neoplasias del Ventrículo Cerebral/veterinaria , Perros , Femenino , Masculino , Dosificación Radioterapéutica/veterinaria , Radioterapia de Alta Energía/veterinariaRESUMEN
We have developed a beagle dog model to study the pharmacology and toxicology of anticancer drugs administered through the 3rd or lateral ventricles. A Foltz-type reservoir was implanted SC and connected by tube into a cerebral ventricle. Drugs were administered directly into the reservoir; CSF sampling of drugs administered into the ventricle was achieved directly by tapping the reservoir or by percutaneous puncture of the cisterna magna. In the current study, we evaluated the CSF pharmacokinetics and CNS toxicity of two inhibitors of polyamine metabolism, alpha-difluoromethylornitine (DFMO) and methylglyoxal bisguanylhydrazone (MGBG). Both drugs were judged too toxic to justify intrathecal or intraventricular studies with these agents in patients.