Oxidative stress in Alzheimer's disease hippocampus: a topographical study.

Advanced glycation end-products (AGEs) and their receptor (RAGE) are molecules related to oxidative stress demonstrated in aging and in several pathological disorders including Alzheimer's disease (AD). Aging has been considered the main risk factor for AD. Amyloid deposits (Aß-D) and neurofibrillary tangles (NFT) are pathological changes related to AD involving hippocampal regions. Different degrees of AD pathology have been described according to distribution of NFTs in different topographical regions of hippocampus and cerebral cortex. The hippocampus shows a selective vulnerability under several noxes especially those including hypoxia. Hypoxia in the nervous tissue induces oxidative stress. In an attempt to find out more about anatomical distribution of the oxidative stress through hippocampal regions in AD, a collection of brains were studied. Samples from deceased patients who had suffered from AD and from age-matched controls were immunohistochemically studied with AGE and RAGE antibodies according to a topographical division of the hippocampus and brain cortical regions. Results suggest that an oxidative stress pathway starts in the CA3 sector progresses to CA1 and then continues to other hippocampal and cortical areas building a pathoclitic pathway for Alzheimer's disease progression.

Progressive multifocal leukoencephalopathy--incidental finding in the forensic neuropathological examination.

Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) caused by the human virus JC (JCV), a small DNA virus which belongs to the subfamily of polyomaviruses. JVC infection is widely extended in the human population in asymptomatic patients; however, in severely immunocompromised patients the virus is able to replicate itself and reach the brain causing PML. It is an extremely rare disease in patients with a competent immune system and few cases have been described in medical literature. We report the case of an elderly immunocompetent man, with no pathological antecedents, who died of sepsis 50 days after suffering extensive and severe flame burns. In the forensic autopsy, a PML was discovered as an incidental finding in the neuropathological examination that was not detected during his time in hospital. Diagnosis was confirmed by the detection of JCV in the brain by in situ hybridization. Possible pathophysiological mechanisms for the reactivation of the JCV and the rapid evolution to the fatal brain demyelinating lesions are discussed. One of the main clinical implications of this case is that immunocompetence should not be considered as an exclusion criterion for the diagnosis of PML.

Primitive neuroectodermal tumor of the central nervous system with glial differentiation: a FISH study of an adult case.

Primitive neuroectodermal tumors (PNETs) of the central nervous system (CNS), a rare occurrence in adults, may show glial differentiation and can be misinterpreted as pure astrocytic neoplasms. Few fluorescence in situ hybridization (FISH) studies have been carried out on these tumors; isochromosome 17q was found to be the major chromosomal abnormality. We present the case of an adult in which we performed a FISH study of both the glial and neuronal components. A complex array of FISH changes, not including an isochromosome 17q were identified.

Embolia grasa como complicación de politraumatismo por precipitación autolítica / Fat embolism as complication of polytraumatism by suicide jumping

El síndrome de embolia grasa (SEG) es un cuadro clínico debido a la oclusión de los vasos sanguíneos por glóbulos de grasa. Se asocia fundamentalmente a fracturas de los huesos largos y es una importante fuente de morbilidad y mortalidad en pacientes politraumatizados. Aunque las primeras descripciones se realizaron a finales del siglo XIX en la actualidad sigue siendo un desafío para el clínico por lo que, en ocasiones, el diagnóstico inicial se realiza en la autopsia. Presentamos un caso de SEG en una mujer de 19 años que fallece en el hospital doce días después de precipitarse desde un puente con finalidad suicida sufriendo politraumatismo con fractura de huesos largos. El SEG fue sospechado clínicamente y se diagnosticó en la autopsia macroscópica siendo posteriormente confirmado por los estudios histopatológicos. Así mismo se revisan las características clinico-patológicas del SEG

Fat embolism syndrome (FES) is a clinical entity which consists in the occlusion of blood vessels by fat droplets. It is commonly associated to long bone fractures and it's an important source of morbidity and mortality in polytraumatized patients. Although the first descriptions were made in the nineteenth century, nowadays it continues to be an important clinical challenge determining that, sometimes, the first diagnostic is made at autopsy. In this paper, we present a case of FES in a woman 19 years old who died in hospital twelve days after jumping from a bridge suffering polytraumatism with long bone fracture. FES was suspected clinically and diagnosed in the gross autopsy being confirmed microscopically. The clinic-pathological characteristics of this syndrome are also reviewed

Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease.

BACKGROUND: Recently described neuronal intermediate filament inclusion disease (NIFID) shows considerable clinical heterogeneity. OBJECTIVE: To assess the spectrum of the clinical and neuropathological features in 10 NIFID cases. METHODS: Retrospective chart and comprehensive neuropathological review of these NIFID cases was conducted. RESULTS: The mean age at onset was 40.8 (range 23 to 56) years, mean disease duration was 4.5 (range 2.7 to 13) years, and mean age at death was 45.3 (range 28 to 61) years. The most common presenting symptoms were behavioral and personality changes in 7 of 10 cases and, less often, memory loss, cognitive impairment, language deficits, and motor weakness. Extrapyramidal features were present in 8 of 10 patients. Language impairment, perseveration, executive dysfunction, hyperreflexia, and primitive reflexes were frequent signs, whereas a minority had buccofacial apraxia, supranuclear ophthalmoplegia, upper motor neuron disease (MND), and limb dystonia. Frontotemporal and caudate atrophy were common. Histologic changes were extensive in many cortical areas, deep gray matter, cerebellum, and spinal cord. The hallmark lesions of NIFID were unique neuronal IF inclusions detected most robustly by antibodies to neurofilament triplet proteins and alpha-internexin. CONCLUSION: NIFID is a neuropathologically distinct, clinically heterogeneous variant of frontotemporal dementia (FTD) that may include parkinsonism or MND. Neuronal IF inclusions are the neuropathological signatures of NIFID that distinguish it from all other FTD variants including FTD with MND and FTD tauopathies.

Lipoma del cuerpo calloso con crisis convulsiva que ocasiona broncoaspiración alimentaria mortal / Lipoma of the corpus callosum with seizure which causes fatal alimentary aspiration

Los lipomas del cuerpo calloso representan hasta el 5% de las malformaciones, tumorales o no, del cuerpo calloso. Actualmente son considerados malformaciones congénitas en lugar de verdaderas neoplasias. La mayoría son sintomáticos, pero algunos se asocian a síntomas neurológicos inespecíficos como retraso psicomotor, cefalea, epilepsia y parálisis cerebral. Se expone el caso de un varón de 42 años que fallece por broncoaspiración alimentaria secundaria a crisis convulsiva. El estudio neuropatológico puso de manifiesto dos lipomas situados en la rodilla del cuerpo calloso. Se destaca la necesidad de realizar tratamiento antiepiléptico en los lipomas del cuerpo calloso que se manifiestan clínicamente en forma de crisis comiciales (AU)

Lipomas of the corpus callosum make up approximately 5% of the tumours of the corpus callosum. Nowadays, they are considered congenital malformations rather than true neoplasms. They are usually asymptomatic; however they are sometimes associated with unspecific neurological symptoms such as psychomotor retardation, headache, epilepsy and cerebral palsy. A case is presented of a 42-year-old man who died due to alimentary aspiration following a seizure. Neuropathological study showed two lipomas located in the splenium of the corpus callosum. Also, we emphasise the importance of the anti-epileptic treatment in the corpus callosum lipomas which are associated with epilepsy (AU)

April 2003: 55-year-old male with necrotic pontine lesion.

The April Case of the Month (COM). A 55-year-old male with history of diabetes mellitus presented with progressive loss of sensitivity on the left side of the body and horizontal diplopia. Symptoms appeared after a right basal pneumonia one month before admission. A CT scan showed an large inoperable lesion in the pons. The patient was treated with corticoids. One week later, the patient showed general deterioration. The fifth and sixth right cranial nerves were affected. Ataxia and disorders in swallowing were also present. A second CT scan showed that the pontine mass had become larger. The patient died 7 days after his admission and the autopsy was limited to CNS. The right middle cerebellar peduncle showed a 2-cm well-defined white brownish necrotic lesion that extended to the pons and periventricular gray matter. Microscopic examination revealed toxoplasmosis, which was confirmed by immunohistochemical studies. The brain tissue was negative for HIV by PCR. Toxoplasmosis is a well-known complication of AIDS, and has been reported in post-transplant patients as well, but only a few reports of toxoplasmosis in diabetics have been reported.

Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology.

BACKGROUND: Epidemiologic and experimental data suggest that cholesterol may play a role in the pathogenesis of AD. Modulation of cholesterolemia in transgenic animal models of AD strongly alters amyloid pathology. OBJECTIVE: To determine whether a relationship exists between amyloid deposition and total cholesterolemia (TC) in the human brain. METHODS: The authors reviewed autopsy cases of patients older than 40 years and correlated cholesterolemia and presence or absence of amyloid deposition (amyloid positive vs amyloid negative subjects) and cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. To remove the effect of apoE isoforms on cholesterol levels, cases were genotyped and duplicate analyses were performed on apoE3/3 subjects. RESULTS: Cholesterolemia correlates with presence of amyloid deposition in the youngest subjects (40 to 55 years) with early amyloid deposition (diffuse type of senile plaques) (p = 0.000 for all apoE isoforms; p = 0.009 for apoE3/3 subjects). In this group, increases in cholesterolemia from 181 to 200 almost tripled the odds for developing amyloid, independent of apoE isoform. A logistic regression model showed consistent results (McFadden rho2 = 0.445). The difference in mean TC between subjects with and without amyloid disappeared as the age of the sample increased (>55 years: p = 0.491), possibly reflecting the effect of cardiovascular deaths among other possibilities. TC and amyloid load were not linearly correlated, indicating that there are additional factors involved in amyloid accumulation. CONCLUSIONS: Serum hypercholesterolemia may be an early risk factor for the development of AD amyloid pathology.

Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psychoses.

Disturbed neural development has been postulated as a crucial factor in the pathophysiology of schizophrenic psychoses. The neurobiochemical basis for such changes of cytoarchitecture and changed neural plasticity could involve an alteration in the regulation of neurotrophic factors. In order to test this hypothesis, BDNF and NT-3 levels in post-mortem brain tissue from schizophrenic patients were determined by ELISA. There was a significant increase in BDNF concentrations in cortical areas and a significant decrease of this neurotrophin in hippocampus of patients when compared with controls. NT-3 concentrations of frontal and parietal cortical areas were significantly lower in patients than in controls. These findings lend further evidence to the neurotrophin hypothesis of schizophrenic psychoses which proposes that alterations in expression of neurotrophic factors could be responsible for neural maldevelopment and disturbed neural plasticity, thus being an important event in the etiopathogenesis of schizophrenic psychoses.

Apolipoprotein E genotype in Spanish schizophrenic patients.

Apolipoprotein E (ApoE) is a lipoprotein that, in the central nervous system, is thought to play a role in neuronal growth and repair. ApoE has three isoforms (ApoE2, ApoE3 and ApoE4) coded by three different alleles (epsilon2, epsilon3 and epsilon4). Evidence from family, twin and adoption studies suggest that there is an important genetic contribution to the etiology of schizophrenia. Schizophrenia is in some cases associated with cognitive impairment similar to that of Alzheimer patients; therefore, one may postulate that the ApoE gene, whose role in the dementia of Alzheimer's type has been clearly demonstrated, may also be involved in schizophrenia. In the present study, we have genotyped 114 schizophrenic Spanish patients and 94 healthy matched controls, and found no association between the ApoE genotype and schizophrenia. Subdivision of patients in clinical subgroups showed a slight increase of ApoE4 in early-age onset of the disease and a slight decrease in positive family history for psychiatric diseases; the group with a poor response to neuroleptic drugs had a lower ApoE2 allele frequency. However, as the differences did not reach statistical significance, we cannot draw evidence of an association. Our negative data do not support an involvement of ApoE in schizophrenia, and suggest that the underlying mechanism for the cognitive impairment found in schizophrenic patients is not related to that of Alzheimer's patients nor to a higher prevalence of the ApoE allele 4.

Brain-derived neurotrophic factor and neurotrophin-3 levels in Alzheimer's disease brains.

In the present study, we investigated the levels of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in post-mortem brain tissue of Alzheimer's disease (AD) patients, and we observed a significant increase of BDNF concentration in hippocampus and parietal cortex of AD patients, as well as a negative correlation between NT-3 levels and age in hippocampus and putamen of control subjects, and for BDNF in frontal cortex. A defining feature of AD is the post-mortem identification of neuritic plaques and neurofibrillary tangles in the brain, however, a more significant neuropathological finding is the degeneration of cholinergic neurones of the basal forebrain, critically involved in memory and cognition. Neurotrophic factors are partly responsible for the maintenance of neuronal function and structural integrity in the adult brain. Our results provide, therefore, evidence that, under conditions of progressive neurodegeneration the brain stimulates the over expression of certain neurotrophic factors as a possible mechanisms of compensation, and that during senescence the expression of these molecules is regulated.

Biologic parameters that correlate with the prognosis of human gliomas.

Much clinical and biologic data have been processed in the search for useful objective parameters to predict brain tumor behavior. Seventy cases of astrocytic glioma collected by a single clinical team were studied using a full complement of clinical procedures: follow up (7 years), histologic analysis, DNA content estimation, and cell kinetics by flow cytometry. Proliferating cell nuclear antigen (PCNA) was determined by immunocytochemical-coupling flow cytometry (PFC) and also by counting under light microscopy (PIHC). A statistical evaluation was carried out to establish the usefulness of several parameters for glioma prognosis. The cases were histologically classified as 14 low-grade astrocytomas, 20 anaplastic astrocytomas, and 36 glioblastomas multiforme. The survival curve showed significant differences between histologic groups. Diploid populations were more frequent in low-grade astrocytomas, and aneuploid tumors often had increased S-phase and proliferative fractions. The PCNA-labeled index (PCNA-LI) increased with malignancy and correlated with histologic grading (P = 0.01). The PCNA-LI and age segregated low- from high-grade astrocytomas (including anaplastic astrocytoma and glioblastoma multiforme), but none of the variables considered differentiated anaplastic astrocytoma from glioblastoma multiforme. The Cox regression test displayed significant values for age, histologic diagnosis, and PCNA determinations when considered in tandem. Discriminant analysis obtained a function integrating age and specifically PIHC-LI to help in the prognosis of doubtful cases. The results emphasize the importance of parameters integrating different variables in an attempt to provide an accurate prognosis, the most significant being age, histopathologic diagnosis, and the proliferative fraction determined by PCNA.

Increased frequency of the alpha-1-antichymotrypsin T allele in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a process of unknown etiology characterized by amyloid deposition in the wall of small cerebral and meningeal blood vessels. CAA is also a feature of Alzheimer's disease (AD) and of a subgroup of elderly people. Alpha-1-Antichymotrypsin (ACT) is a serum glycoprotein frequently associated with vascular and senile plaque amyloid. The ACT gene is known to have a bi-allele polymorphism that causes a simple amino acid substitution. In an attempt to clarify the possible role of ACT polymorphism in AD and in cases of CAA, the ACT genotype was investigated in AD, CAA, and intellectually intact controls. Representative brain areas (cerebral cortex, hippocampus, putamen, white matter, and gyrus cinguli) from all cases were studied using classical histologic staining techniques (hematoxylin-eosin (HE), Mallory's thrichromic or alkaline congo red stain), and immunohistochemistry for tau and beta-amyloid proteins. There was a significantly increased T allele and TT genotype frequency in the CAA group, but not in the AD group, suggesting a role for the ACT genotype in the development of vascular lesions. The presence of the apolipoprotein E4 allele (ApoE4) did not correlate with the ACT-A allele, as previously reported, and appeared to be independent of the risk for developing AD.

Correlation between Apolipoprotein-E polymorphism and Alzheimer's disease pathology.

Alzheimer's disease (AD) and small vessel disease dementia (SVDD) are common causes of dementia. The ApoE genotype has been proposed as a risk factor for AD. The frequency of the three ApoE alleles was correlated with the neuropathological changes of AD (senile plaques, neurofibrillary tangles and amyloid angiopathy) and SVDD (status lacunaris, status cribosus, leucoencephalopathy, micronecrosis and vascular fibrohyalinosis) in order to validate previous ApoE genotyping results in AD and to identify pre-clinical AD. Representative cerebral regions (cortex, gyrus cinguli, putamen, hippocampus, white matter) from 28 AD cases, 7 SVDD and 38 non-neurological controls were studied using classical histological techniques and immunohistochemistry for tau protein and amyloid-beta. The frequency of the ApoE allele 4 was significantly increased not only in AD patients but also in aged controls. However, following a detailed histopathological examination was found 62% of this group to exhibit histological changes associated with AD in limited brain areas (entorhinal region, hippocampus and adjacent temporal cortex or entorhinal region and hippocampus, or only in the entorhinal region), but 87% of these cases were found to be ApoE4 positive. The significant differences found in the distribution of ApoE allele frequencies were more marked when these cases were excluded from the control group and included as AD cases. In contrast, the frequency of the ApoE allele 2 is significantly increased in SVDD patients. Using histological techniques we confirmed the clinical diagnoses of all cases and classified the AD patients according to the severity of cortical pathology related to AD, while re-grouping from the control group those cases which had no clinical history of the disease but exhibited typical AD and SVDD histological lessions which could be considered as "pre-clinical" forms of these diseases.

Expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor-beta (PDGFR-beta) in human gliomas.

The growth of solid tumors is highly dependent on vascular proliferation. Vascular endothelial growth factor (VEGF), the main mediator of angiogenesis, and platelet-derived growth factor receptor-beta (PDGFR-beta), receptor for the potent mitogen PDGF, are two indicators of the angiogenic potential of human gliomas. We studied a series of 57 surgical biopsies of astrocytic neoplasms by immunohistochemistry to elucidate the relationship between tumor proliferation, quantified as Ki67-LI, and the expression of these two proteins. Ki67-LI increases throughout histological malignancy, although staining in endothelial cells has rarely been recorded. Elevated amounts of VEGF-positive tumor cells (VEGF-LI) were found in anaplastic astrocytomas and glioblastomas, mainly around areas of necrosis, cysts, or edema. Endothelium of blood vessels was consistently stained. PDGFR-beta positivity was found in glomeruloid formations and in tumor cells, excluding pilocytic astrocytomas. Multinucleated giant cells and perivascular tumor cells were positive in glioblastomas. In addition, peritumoral microglia-like cells were also stained in some cases. Statistical correlation was only found between PDGFR-beta and Ki67 LIs. In conclusion, VEGF as permeability factor is involved in the development of secondary neoplastic changes, whereas PDGFR-beta is directly correlated to proliferation indexes. Strong expression of VEGF and PDGFR-beta found in endothelium and tumor cells would seem to support a combined role in tumoral neoangiogenesis.

Evaluation of neuronal loss, astrocytosis and abnormalities of cytoskeletal components of large motor neurons in the human anterior horn in aging.

In order to identify possible morphological changes which occur in the anterior horn of normal individuals during aging, 40 controls with no neurological disease were studied. Brain and spinal cord tissue was processed according to a brain banking protocol. Controls were grouped according to age in 10 year intervals. Serial sections (20 microm) of formalin fixed, paraffin-embedded tissue were obtained, from each cervical, thoracic and lumbar spinal cord segment. Every 5th section (until 2 mm) was stained with haematoxylin and eosin and the numbers of motor neurons in the anterior horn counted at x400 magnification. Descriptive statistical analysis was performed using the SPSS program. Parallel sections (5 microm) of the same spinal segments were immunostained with a panel of antibodies including glial fibrillary acidic protein (GFAP), tau, ubiquitin and two phosphorylated neurofilaments subunits. Significant neuronal loss with aging was found by regression line analysis where three equations were used to calculate the number of motor neurons by age in each spinal segment. In 24/40 cases spheroids were observed and they were more numerous in the lumbar segment. GFAP staining revealed a distinctive cellular pattern in the anterior horn of oldest cases. Large and intensely stained astrocytes were seen in the anterior horn of cases aged over 75 years. The number of astrocytes increased progressively with age up to 70 years. Some of the changes observed in the present study may be the result of a selective vulnerability of large motor neurons to aging which could play an important role in the progression of MND. Most of these changes may also have similar pathophysiological mechanisms.

Variants in neurotrophic factor genes and schizophrenic psychoses: no associations in a Spanish population.

Possible associations between schizophrenic psychoses, a ciliary neurotrophic factor (CNTF) null mutation and a neurotrophin in 3 (NT3) bi-allele polymorphism were investigated in a Spanish population. The sample consisted of 107 patients suffering from schizophrenic psychoses and 100 healthy volunteers. There was no statistical difference in the frequencies of the mutant CNTF allele in the index and control groups (0.125 vs. 0.121). The frequency of the rare NT3 allele (Glu) was very low and similar in both groups (0.005). Previous findings supporting the involvement of these genetic markers in the pathogenesis of schizophrenic psychoses were thus not confirmed. In light of neurodevelopmental hypotheses of schizophrenia, however, genes coding for neurotrophic factors remain interesting susceptibility loci in schizophrenia research. Subsequent studies should not focus exclusively on genetic alterations but also take into account secondary changes of the neurotrophic factor system at the mRNA and protein levels. Further, the current unsatisfying operationalized classification of the heterogeneous syndrome 'schizophrenia' remains a crucial problem that could be partially resolved by introducing more differentiated diagnoses defined on the basis of neurobiological criteria.

Cerebellar cortex delayed maturation in sudden infant death syndrome.

The cerebellum shows afferent and efferent connections with intrinsic bulbar nuclei and plays an important role in respiration and cardiovascular control. Pathological and neurochemical abnormalities of bulbar nuclei including the arcuate nucleus have been postulated in sudden infant death syndrome (SIDS). Most of these abnormalities have been related to impairment in brain development. The cerebellar cortex has a well-documented evolution from fetal life until infancy; thus, it may be a very good model to assess brain maturation in SIDS. The present study was conducted to investigate changes in the cerebellar cortex in 19 SIDS cases compared with 12 age-related controls using morphological, quantitative, and statistical approaches. Five-microns paraffin sections from the midsagittal cerebellar vermis were stained with hematoxylin and eosin (H&E). Immunohistochemical staining was carried out using a polyclonal antiserum to glial fibrillary acidic protein (GFAP). Each case consisted of a 25-microns parallel paraffin section stained with H&E, where the cerebellar external granular layer (EGL) cell density was obtained in one field magnification (x1,000) using an optical dissector procedure on the basis of a stereological method. A statistically significant high EGL cell density, mostly related to the presence of immature bipolar, elongated neuronal cells of the premigratory zone with hyperchromatic, oval or poor differentiated nuclei, was observed in SIDS. In these cases, EGL expressed immunoreactivity for GFAP mainly in the subpial and the postmitotic zone. These findings demonstrate a delayed or slower decline in the number of EGL neurons in SIDS, suggesting either a prolongation of the growth phase related to postnatal cerebellar foliation or a delay in inward migration. These results suggest that in SIDS there is delayed maturation of the cerebellar cortex/EGL, which may support the hypothesized cardiopulmonary control dysfunction, leading to death in a vulnerable period of postnatal development.