Neurofibrillary Tangles of Aßx-40 in Alzheimer's Disease Brains.

The two pathognomonic lesions in the brain of AD patients are senile plaques and intraneuronal neurofibrillary tangles (NFT). Previous studies have demonstrated that amyloid-ß (Aß) is a component of both senile plaques and NFTs, and have showed that intracellular accumulation of Aß is toxic for cells and precedes the appearance of extracellular amyloid deposits. Here we report that there are numerous intraneuronal NFT and extraneuronal NFT immunoreactive for Aßx-40 in which there is no co-localization with tau staining suggesting the existence of two different neurodegenerating populations associated with the intracellular accumulation of either tau protein or Aßx-40 in AD.

The immunohistochemical localization of neuronal nitric oxide synthase in the basal forebrain of the dog.

The present work describes for the first time the anatomical distribution of neuronal nitric oxide synthase (nNOS) immunoreactivity and NADPH-d activity in the basal forebrain of the dog. As in other species, small, intensely nNOS-immunoreactive cells were seen within the olfactory tubercle, caudate nucleus, putamen, nucleus accumbens and amygdala. In addition, a population of mixed large and small nNOS positive cells was found in the medial septum, diagonal band and nucleus basalis overlapping the distribution of the magnocellular cholinergic system of the basal forebrain. Our results show that the distribution of NOS containing neurons in these nuclei in the dog is more extensive and uniform than that reported in rodents and primates. When double labeling of nNOS and NADPH-d was performed in the same tissue section most neurons were double labeled. However, a considerable number of large perikarya in the diagonal band and nucleus basalis appeared to be single labeled for nNOS. Thought a certain degree of interference between the two procedures could not be completely excluded, these findings suggest that NADPH-d histochemistry, which is frequently used to show the presence of NOS, underestimates the potential of basal forebrains neurons to produce nitric oxide. In addition, a few neurons mainly localized among the fibers of the internal capsule, appeared to be labeled only for NADPH-d. These neurons could be expressing a different isoform of NOS, not recognized by our anti-nNOS antibody, as has been reported in healthy humans and AD patients.

Validation of Immunoassay-Based Tools for the Comprehensive Quantification of Aß40 and Aß42 Peptides in Plasma.

Recent advances in neuroimaging and cerebrospinal fluid (CSF) biomarker assays have provided evidence of a long preclinical stage of Alzheimer's disease (AD). This period is being increasingly targeted for secondary prevention trials of new therapies. In this context, the interest of a noninvasive, cost-effective amyloid-ß (Aß) blood-based test does not need to be overstated. Nevertheless, a thorough validation of these bioanalytical methods should be performed as a prerequisite for confident interpretation of clinical results. The aim of this study was to validate ELISA sandwich colorimetric ABtest40 and ABtest42 for the quantification of Aß40 and Aß42 in human plasma. The validation parameters assessed included precision, accuracy, sensitivity, specificity, recovery, and dilution linearity. ABtest40 and ABtest42 proved to be specific for their target peptide using Aß peptides with sequence similar to the target. Mean relative error in the quantification was found to be below 7.5% for both assays, with high intra-assay, inter-assay, and inter-batch precision (CV <9.0% on average). Sensitivity was assessed by determination of the limit of quantification fulfilling precision and accuracy criteria; it was established at 7.60 pg/ml and 3.60 pg/ml for ABtest40 and ABtest42, respectively. Plasma dilution linearity was demonstrated in PBS; however, dilution in a proprietary formulated buffer significantly increased the recovery of both Aß40 and Aß42 masked by matrix interactions, allowing a more comprehensive assessment of the free and total peptide levels in the plasma. In conclusion, both assays were successfully validated as tools for the quantification Aß40 and Aß42 in plasma.

Neprilysin is poorly expressed in the prefrontal cortex of aged dogs with cognitive dysfunction syndrome.

Neprilysin (NEP) is the principal amyloid ß (A ß ) degrading peptidase; this activity may protect against Alzheimer's disease (AD), the most important age-related neurodegenerative process. The aim of this work was to analyze NEP mRNA expression in the frontal cortex of dogs with and without canine cognitive dysfunction syndrome (CDS), which is considered a natural model for AD. Expression of canine cerebral NEP mRNA was assessed by RT-PCR followed by qPCR in young, aged-cognitively unimpaired (CU), and aged-cognitively impaired (CI) dogs. On average, aged-CI dogs showed 80% (P < 0.01) lower expression levels of NEP mRNA than their aged-CU counterparts. Furthermore, the standard deviation of the qPCR measurements was more than 6 times higher in the cognitively healthy animals (young and aged-CU) than in the aged-CI group. Another interesting find is the determination of a positive correlation between NEP expression and the number of cholinergic neurons in basal telencephalon, indicating a probable connection between both events in these types of neurodegeneration processes. These results suggest that high expression levels of NEP might be a protective factor for canine CDS and, most likely, for other A ß -associated neurodegenerative diseases, such as AD.

Expression of p75(NTR), a marker for basal forebrain cholinergic neurons, in young and aged dogs with or without cognitive dysfunction syndrome.

The canine cognitive dysfunction syndrome (CDS) has been identified as a natural model for Alzheimer's disease (AD). We have used unbiased stereology to estimate the total number of basal forebrain cholinergic neurons expressing the nerve growth factor p75(NTR) receptor in young, aged cognitively-unimpaired (CU) and aged cognitively-impaired (CI) dogs. Aged-CI dogs showed a ∼20% decrement (p = 0.009) in p75(NTR) neurons compared to both the young and the aged-CU animals. These results suggest that the basal forebrain cholinergic system is affected in dogs with CDS and provide additional support for the use this canine syndrome as a model for AD research.

Dogs with canine counterpart of Alzheimer's disease lose noradrenergic neurons.

Degeneration of noradrenergic neurons in the locus ceruleus is a well-described feature of Alzheimer's disease (AD). In spite of extensive utilization of the dog as a model for human degenerative diseases, there is no data on the response to aging of the noradrenergic system in dogs. We have used modern unbiased stereology to estimate the total number of A6-A7 noradrenergic neurons in normal, aged dogs and dogs with the canine counterpart of AD. In small-breed dogs with no cognitive impairments, the total mean number of tyrosine hydroxylase immunolabeled A6-A7 neurons was 17,228+/-1655, with no differences between young and aged dogs. In contrast, aged dogs with cognitive impairments exhibited a significant reduction in the total number of A6-A7 neurons (13,487+/-1374; P=0.001). Additionally, we found a negative correlation between the number of A6-A7 neurons and the extent of beta-amyloid deposits in the prefrontal cortex. These results suggest that the canine model could be useful in exploring the potential benefits of noradrenergic drugs for the treatment of AD.

Beta-amyloid cortical deposits are accompanied by the loss of serotonergic neurons in the dog.

Dogs may naturally suffer an age-related cognitive impairment that has aroused a great deal of interest, even beyond the field of the veterinary clinic. This canine senile dementia reproduces several key aspects of Alzheimer's disease (AD), including the presence of beta-amyloid (A beta) deposits in the cerebral cortex, neurodegeneration, and learning and memory impairments. In the present study, we have used unbiased stereological procedures to estimate the number of the dorsal and median raphe nuclei (DRN and MRN, respectively) serotonergic neurons immunolabeled with an anti-tryptophan hydroxylase (TrH) monoclonal antibody in young and aged dogs without A beta cortical deposits and in aged dogs with A beta cortical deposits. The estimated total number of TrH-labeled neurons (mean +/- SD) was 94,790 +/- 26,341 for the DRN and 40,404 +/- 8,692 for the MRN. The statistical analyses revealed that aged dogs with A beta cortical pathology had 33% fewer serotonergic neurons in the DRN and MRN than aged dogs without A beta cortical deposits (108,043 +/- 18,800 vs. 162,242 +/- 39,942, respectively; P = 0.01). In contrast, no significant variations were found between young and aged dogs without A beta cortical deposits. These results suggest that degeneration of the serotonergic neurons could be involved in the cognitive damage that accompanies A beta cortical pathology in the dog and reinforce the use of the canine model for exploring the potential mechanisms linking the cortical A beta pathology and serotonergic neurodegeneration that occurs during the course of AD.

Aplicación del análisis de correspondencia múltiple para laclasificación de perfiles de vulnerabilidad em la poblácion de mujeres embarazadas de Argentina / Application of multiple correspondence analysis to classify the em vulnerability profiles among pregnant women in Argentina

Se ilustra el uso del análisis de correspondencias múltiples (ACM) en la identificación de distintos perfiles de embarazadas que caractericen la estructura y fuerza de la relación entredeterminantes distales e intermedios de la morbimortalidad materna según el marco conceptual de Mc Carthy y Maine (1992). Se utilizó información de la Encuesta Nacional de Nutrición y Salud (ENNYS, 2005) provista por 1.612 embarazadas que reportaron datos socioeconómicos y demográficos, niveles de hemoglobina, factores de riesgo para enfermedades crónicas no transmisibles como la tensión arterial anormal y sobre programas de alimentación. De un total de 314 variables de la ENNYS se seleccionaron y se recategorizaron según el modelo de Mc Carthy y Maine un total de 118 variables; de acuerdo a este arreglo 54/118 fueron determinantes distales y 64/118 fueron determinantes intermedios de la morbimortalidad. A través de rondas sucesivas de ACM se obtuvo un modelo final compuestopor 18 determinantes distales y tres determinantes intermedios. Se identificaron tres perfiles que agruparon a un conjunto de variables que permitieron caracterizar a las embarazadas como indigentes, pobres y no pobres. Estos perfiles se formaron con variables de los subdominios de determinantes de Mc Carthy y Maine: Posición de la mujer en su familia, laposición de la familia en su comunidad, y la posición de la comunidad . Las variables que determinaron la posición de la familia de la embarazada en la comunidad se encontraron sobrerepresentadas en la ENNYS. Los determinantes intermedios como la tension arterial por encima de lo normal y la anemia del embarazo si bien se ubicaron junto a los determinantes distales que conformaron el perfil deembarazadas indigentes y pobres, su contribución a la formación de dichos perfiles fue baja...

The use of the analysis of multiple correspondences (ACM) is illustrated in the identification of different profiles of pregnant women that characterize the structure and strength of the relationship between determinants distal and intermediate of the maternal morbidity and mortality according to the conceptual framework of Mc Carthyand Maine (1992). There was used information on the National Survey of Nutrition and Health (ENNYS, 2005) provided by 1,612 pregnant women who reported socioeconomic and demographic data, hemoglobin levels, risk factors for chronic noncommunicable diseases as the abnormal arterial tension, and programs of feeding. Of a total of 314 variables of the ENNYS they were selected and they were reclassifiedaccording to Mc Carthy and Maine for the study of 118 variables, 54/118 weredeterminants distal and 64/118 were intermediate determinants of the morbidity and mortality. Using successive rounds of ACM a final model made up of 18 distal determinants was obtained and three intermediate determinants were selected. Therewere identified three profiles that grouped to a set of variables that characterized the indigent, poor, and non-poor pregnant women. These profiles were formed with variables of the subdomaines of determinants of Mc Carthy and Maine: women´s status in the family, family´s status in community, and community´s status. The variables that determine the family´s status in community were found over represented in the ENNYS. The intermediate determinants as arterial tension abnormal and anemiawere located with the determinants distal that they formed the profile of indigent and poor pregnant women respectively, but her contribution to the inertia of the principal axis was below the average.

Angiomas cavernosos del tronco cerebral / Cavernous angiomas of the brain stem

Se presenta una serie de seis casos operados por angiomas cavernosos del tronco cerebral. Todos ellos habían sangrado por lo menos una vez y tenían compromiso neurológico moderado y severo. El diagnóstico en todos los casos fue por resonancia magnética y confirmado con el estudio anatomopatológico de la lesión. La presentación clínica, los hallazgos quirúrgicos y la evolución son similares a los ya establecidos. La evaluación fue favorable en cinco casos. Hubo una muerte por complicaciones propias de la gravedad, pero sin haber sufrido agravacion posoperatoria. Se hace hincapié en los beneficios de la cirugía a pesar de la gravedad que pueden presentar los episodios hemorrágicos de los angiomas

Actualizacion de la malformación de Chiari / Up to date on Chiari malformation

Luego del advenimiento de la resonancia magnética como recurso diagnóstico, la malformación de Chiari ha merecido una revisión conceptual y se han implementado nuevas directivas terapéuticas. Se analizan estos nuevos conceptos y los resultados beneficiosos obtenidos en el tratamiento quirúrgico de cinco casos de distintas edades, cuatro de ellos correspondientes a Chiari tipo I y uno a Chiari tipo II. En particular se destaca la mejoría de la clínica y la imagenología determinadas por la hidrosiringomielia asociada, luego de la decompresión de fosa posterior, sin necesidad de actuar sobre las cavidades siringomiélicas