bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxidative Stress and Motor Neurone Disease
Authors: Cookson Mark R. , Shaw Pamela J.
Published: July 2010

The effects of oxidative stress within post mitotic cells such as neurones may be cumulative, and injury by free radical species is a major potential cause of the age‐related deterioration in neuronal function seen in several neurodegenerative diseases. There is strong evidence that oxidative stress plays an important role in the pathogenesis of motor neurone disease (MND). Point mutations in the antioxidant enzyme Cu, Zn superoxide dismutase (SOD1) are found in some pedigrees with the familial form of MND. How mutations in this ubiquitous enzyme cause the relatively selective cell death of specific groups of motor neurones is not clear, although a number of hypotheses have been forwarded. These include (1) the formation of hydroxyl radicals, (2) the catalysis of reactions of the nitrogen centred oxidant species peroxynitrite, (3) toxicity of copper or zinc and (4) protein aggregation. Some experimental support for these different hypotheses has been produced by manipulating cells in culture to express the mutant SOD1 proteins and by generating transgenic mice which over‐express mutant SOD1. Observations in these model systems are, in some cases at least, supported by observations made on pathological material from patients with similar SOD1 mutations. Furthermore, there are reports of evidence of free radical mediated damage to neurones in the sporadic form of MND. Several lines of evidence suggest that alterations in the glutamatergic neurotransmitter system may also play a key role in the injury to motor neurones in sporadic MND. There are several important subcellular targets, which may be preferentially impaired within motor neurones, including neurofilament proteins and mitochondria. Future research will need to identify the aspects of the molecular and physiological phenotype of human motor neurones that makes them susceptible to degeneration in MND, and to identify those genetic and environmental factors which combine to cause this disease in individuals and in familial pedigrees.
Inherited Neuropathies: From Gene to Disease
Authors: Keller Marcel P. , Chance Phillip F.
Published: July 2010

Inherited disorders of peripheral nerves represent a common group of neurologic diseases. Charcot‐Marie‐Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B) and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5‐megabase (Mb) duplication in chromosome 17p11.2‐12, or in rare patients may result from a point mutation in the peripheral myelin protein‐22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P0 or MPZ) gene. The molecular defect in CMT1C is unknown. X‐linked Charcot‐Marie‐Tooth neuropathy (CMTX), which has clinical features similar to CMT1, is associated with mutations in the connexin32 gene. Charcot‐Marie‐Tooth neuropathy type 2 (CMT2) is an axonal neuropathy, also of undetermined cause. One form of CMT2 maps to chromosome 1p36 (CMT2A), another to chromosome 3p (CMT2B) and another to 7p (CMT2D). Dejerine‐Sottas disease (DSD), also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile‐onset demyelinating poly neuropathy syndrome that may be associated with point mutations in either the PMP22 gene or the P0 gene and shares considerable clinical and pathological features with CMT1. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5‐Mb deletion in chromosome 17p11.2‐12 and results from reduced expression of the PMP22 gene. CMT1A and HNPP are reciprocal duplication/deletion syndromes originating from unequal crossover during germ cell meiosis. Other rare forms of demyelinating peripheral neuropathies map to chromosome 8q, 10q and 11q. Hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) is an autosomal dominant disorder causing painful, recurrent brachial plexopathies and maps to chromosome 17q25.
Paraproteinaemic Neuropathies
Authors: Steck Andreas J. , Erne Beat , Gabriel Jean‐Marc , Schaeren‐Wiemers Nicole
Published: July 2010

In this article, we review the main clinical and pathological features of paraproteinaemic neuropathies and discuss recent experimental findings. Further knowledge of the disease process at the molecular level has allowed a better characterization of clinical syndromes and has given new insights into their pathogenesis. The most convincing evidence for a causal relationship can be drawn from IgM monoclonal gammopathies with specificities directed against carbohydrate determinants of the myelin associated glycoprotein (MAG). There remain however, many unresolved questions, such as how monoclonal anti‐MAG IgM antibodies cross the blood‐nerve barrier and trigger a chronic demyelinating polyneuropathy while the central nervous system is essentially spared. IgM paraproteins with specificity for other molecules, such as neurofilaments, sulphatide, gangliosides, chondroitin sulphate and tubulin, have also been identified, but their pathogenetic importance remains to be elucidated.

Other paraproteinaemic neuropathies such as IgG and IgA neuropathies have to be considered separately. The paraneoplastic endocrine and cytokine manifestations of rare osteosclerotic myelomas provide valuable insights into the interaction between the immune and the nervous system. The antigen‐specificity of IgG and IgA monoclonal antibodies are only poorly characterized but some have been found to be directed against endoneurial determinants and a few against axonal proteins such as neurofilaments.
Diabetic Neuropathies: Features and Mechanisms
Authors: Zochodne Douglas W.
Published: July 2010

Diabetic neuropathies include both focal neuropathies and diffuse poly neuropathy. Polyneuropathy, the most common of the diabetic neuropathies excluding focal entrapment, has not yet been explained by a single disease mechanism despite intensive investigation. A number of abnormalities appear to cascade into a ‘vicious cycle’ of progressive microvascular disease associated with motor, sensory and autonomie fiber loss. These abnormalities include excessive polyol (sugar alcohol) flux through the aldose reductase pathway, functional and structural alterations of nerve microvessels, nerve and ganglia hypoxia, oxidative stress, nonspecific glycosylation of axon and microvessel proteins, and impairment in the elaboration of trophic factors critical for peripheral nerves and their ganglia. While an initiating role for nerve ischemia in the development of poly neuropathy has been proposed, the evidence for it can be questioned. The role of sensory and autonomie ganglia in the development of poly neuropathy has had relatively less attention despite the possibility that they may be vulnerable to a variety of insults, particularly neurotrophin deficiency. Superimposed on the deficits of polyneuropathy is the failure of diabetic nerves to regenerate as effectively as nondiabetics. Polyneuropathy has not yet yielded to specific forms of treatment but a variety of new trials addressing plausible hypotheses have been initiated.

This review will summarize some of the clinical, pathological and experimental work applied toward understanding human diabetic neuropathy and will emphasize ideas on pathogenesis.
Tau‐positive dial Inclusions in Progressive Supranuclear Palsy, Corticobasal Degeneration and Pick's Disease
Authors: Komori Takashi
Published: July 2010

The presence of tau‐positive glial inclusions has been recently found a consistent feature in the brains of patients with progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick's disease (PiD). These inclusions are classified based on cellular origin as tau‐positive astrocytes, presumably either fibrillary or protoplasmic, coiled bodies and glial threads. Immunohistochemically, their major structural component is abnormal tau proteins, similar to those found in Alzheimer's disease. Nevertheless, their morphology, including ultrastructural profile, has been suggested to be distinctive for each disease. The profile and extent of particular glial inclusions correlate well with disease phenotype. Highly characteristic correlations include tufts of abnormal fibers in PSP, astrocytic plaques and dense glial threads in CBD and ramified astrocytes and small Pick body‐like inclusions in PiD. The significance of the inclusions in disease pathogenesis and their biochemical characteristics remain to be clarified. Nevertheless, these distinctive glial lesions most likely reflect fundamental alterations in isoform composition of tau as well as its specific cellular and regional expression in sporadic tauopathies.
Temperature Modulation (Hypothermic and Hyperthermic Conditions) and Its Influence on Histological and Behavioral Outcomes Following Cerebral Ischemia
Authors: Corbett Dale , Thornhill Jim
Published: July 2010

Core temperature (TC) is a critical determinant of the severity of neural damage that results from focal or global ischemia. Former studies indicated that especially intra‐ischemic but also post ischemic mild hypothermia significantly decreased necrotic neural damage of a focal or global insult, as assessed between 3–7 days post‐insult. More recent work shows that prolonged post‐ischemic hypothermia reduces neural damage and inhibits associated behavioral deficits for up to one year after the insult (i.e. true neuroprotection with behavioral preservation). Alternatively, increases in core temperature via external heating or with pyrogens resulting from bacterial infections, at the time of the global ischemia insult worsen the neural damage of ischemic animals from those of respective normothermic controls given the same insult. This is paralleled in the clinical setting whereby ∼50% of ischemic patients develop fevers within 2 days of the insult and have worsened neurological outcomes than non‐febrile patients. The review discusses the possible mechanisms of neuroprotection of hypothermic therapy from cerebral ischemia as well as mechanisms involved in the exacerbation of neural damage of hypoxic ischemia under hyperthermic conditions. Questions are raised as to whether the medical community has sufficient evidence to begin appropriate hypothermic therapy of acute stroke patients. The importance of accurate monitoring core temperatures of all suspected stroke patients is emphasized, noting the differences in temperature that can occur with age, sex, medication or lifestyle so that appropriate temperature treatment could be implemented, if required. A. Hypothermia and cerebral ischemia
Microglial Activation and Neuronal Apoptosis in Bornavirus Infected Neonatal Lewis Rats
Authors: Weissenböck Herbert , Hornig Mady , Hickey William F. , Lipkin W. Ian
Published: July 2010

Lewis rats neonatally infected with Borna disease virus have a behavioral syndrome characterized by hyperactivity, movement disorders, and abnormal social interactions. Virus is widely distributed in brain; however, neuropathology is focused in dentate gyrus, cerebellum, and neocortex where granule cells, Purkinje cells and pyramidal cells are lost through apoptosis. Although a transient immune response is present, its distribution does not correlate with sites of damage. Neuropathology is instead colocalized with microglial proliferation and expression of MHC class I and class II, ICAM, CD4 and CD8 molecules. Targeted pathogenesis in this system appears to be linked to microglial activation and susceptibility of specific neuronal populations to apoptosis rather than viral tropism or virus‐specific immune responses.
Apoptotic and Anti‐Apoptotic Synaptic Signaling Mechanisms
Authors: Mattson Mark P.
Published: July 2010

Although several prominent morphological features of apoptosis are evident in the cell body (e.g., cell shrinkage, membrane blebbing, and nuclear DNA condensation and fragmentation) the biochemical and molecular cascades that constitute the cell death machinery can be engaged in synaptic terminals and neurites. Initiating events such as oxyradical production and calcium influx, and effector processes such as Par‐4 production, mitochondrial alterations and caspase activation, can be induced in synapses and neurites. Several prominent signal transduction pathways in synaptic terminals play important roles in either promoting or preventing neuronal death in physiological and pathological conditions. For example, activation of glutamate receptors in postsynaptic spines can induce neuronal apoptosis, whereas local activation of neurotrophic factor receptors in presynaptic terminals can prevent neuronal death. Factors capable of inducing nuclear chromatin condensation and fragmentation can be produced locally in synaptic terminals and neurites, and may propogate to the cell body. Recent findings suggest that, beyond their roles in inducing or preventing cell death, apoptotic and anti‐apoptotic cascades play roles in synaptic plasticity (structural remodelling and long‐term functional changes). For example, caspase activation results in proteolysis of glutamate receptor (AMPA) subunits, which results in altered neuronal responsivity to glutamate. Activation of neurotrophic factor receptors in synaptic terminals can result in local changes in energy metabolism and calcium homeostasis, and can induce long‐term changes in synaptic transmission. The emerging data therefore suggest that synapses can be considered as autonomous compartments in which both pro‐ and anti‐apoptotic signaling pathways are activated resulting in structural and functional changes in neuronal circuits. A better understanding of such synaptic signaling mechanisms may reveal novel approaches for preventing and treating an array of neurodegenerative conditions that are initiated by perturbed synaptic homeostasis.
Neuronal FasL Induces Cell Death of Encephalitogenic T Lymphocytes
Authors: Flügel A. , Schwaiger F. W. , Neumann H. , Medana I. , Willem M. , Wekerle H. , Kreutzberg G.W. , Graeber M.B.
Published: July 2010

Apoptosis of inflammatory cells plays a crucial role in the recovery from autoimmune CNS disease. However, the underlying mechanisms of apoptosis induction are as yet ill‐defined. Here we report on the neuronal expression of FasL and its potential function in inducing T‐cell apoptosis. Using a combination of facial nerve axotomy and passive transfer encephalomyelitis, the fate of CD4+ encephalitogenic T cells engineered to express the gene for green fluorescent protein was followed. FasL gene transcripts and FasL protein were detected in neurons by in situ‐hybridization and immunohistochemistry. T cells infiltrating preferentially the injured brain parenchyma were found in the immediate vicinity of FasL expressing neurons and even inside their perikarya. In contrast to neurons, T cells rapidly underwent apoptosis. In co‐cultures of hippocampal nerve cells and CD4+ T lymphocytes, we confirmed expression of FasL in neurons and concomitant induction of T‐cell death. Antibodies blocking neuronal FasL were shown to have a protective effect on T‐cell survival. Thus, FasL expression by neurons in neuroinflammatory diseases may constitute a pivotal mechanism underlying apoptosis of encephalitogenic T cells.
Axonal Damage Induced by Invading T Cells in Organotypic Central Nervous System Tissue in vitro: Involvement of Microglial Cells
Authors: Gimsa Ulrike , Peter Susanne VA. , Lehmann Kathrin , Bechmann Ingo , Nitsch Robert
Published: July 2010

Neuroinflammation in the course of multiple sclerosis and experimental autoimmune encephalomyelitis results in demyelination and, recently demonstrated, axonal loss. Invading neuroantigen specific T cells are the crucial cellular elements in these processes. Here we demonstrate that invasion of activated T cells induces a massive microglial attack on myelinated axons in entorhinal‐hippocampal slice cultures. Flow cytometry analysis of activation markers revealed that the activation state of invading MBP‐specific T cells was significantly lower in comparison to PMA‐activated T cells. Moreover, MBP‐specific T cells showed a significantly lower secretion of IFN‐γ. Conversely, MBP‐specific T cells displayed a significantly higher potential to trigger activation of microglial cells, i.e. upregulation of MHC class II and ICAM‐1 expression, and, most importantly, microglial phagocytosis of pre‐traced axons. Our data suggest that this was mediated via specific cellular interactions of T cells and microglial cells since IFN‐γ alone was not sufficient to induce axonal damage while such damage was apparent in response to TNF‐α which is released by activated microglial cells. TNF‐α secretion by both T cell populations was negligible. Thus, MBP‐specific T cells which invade nervous tissue in the course of neuroinflammation are more effective in axon‐damaging recruiting microglial cells than activated T cells of other specificities.
Differential Recruitment of CD8+ Macrophages During Wallerian Degeneration in the Peripheral and Central Nervous System
Authors: Jander Sebastian , Lausberg Friederike , Stoll Guido
Published: July 2010

The strong macrophage response occurring during Wallerian degeneration in the peripheral but not central nervous system has been implicated in tissue remodeling and growth factor production as key requirements for successful axonal regeneration. We have previously identified a population of CD8+ phagocytes in ischemic brain lesions that differed in its recruitment pattern from CD4+ macrophages/ microglia found in other lesion paradigms. In the present study we show that crush injury to the sciatic nerve induced strong infiltration by CD8+ macrophages both at the crush site and into the degenerating distal nerve stump. At the crush site, CD8+ macrophages appeared within 24 hours whereas infiltration of the distal nerve parenchyma was delayed to the second week. CD8+ macrophages were ED1+ and CD11b+ but always MHC class II‐. Most CD8+ macrophages coexpressed CD4 while a significant number of CD4+/CD8‐macrophages was also present. Expression of the resident tissue macrophage marker ED2 was largely restricted to the CD4+/CD8‐ population. Following intraorbital crush injury to the optic nerve, infiltration of CD8+ macrophages was strictly confined to the crush site. Taken together, our study demonstrates considerable spatiotemporal diversity of CD8+ macrophage responses to axotomy in the peripheral and central nervous system that may have implications for the different extent of axonal regeneration observed in both systems.
Regulation of Microglia by CD4+ and CD8+ T Cells: Selective Analysis in CD45‐congenic Normal and Toxoplasma gondii‐infected Bone Marrow Chimeras
Authors: Schlüter Dirk , Meyer Timothy , Strack Andreas , Reiter Sabine , Kretschmar Marianne , Wiestler Otmar D. , Hof Herbert , Deckert Martina
Published: July 2010

Microglia, the resident macrophage population of the central nervous system, is rapidly activated in murine Toxoplasma encephalitis (TE). However, the precise contribution of microglia to intracerebral immune reactions and the in vivo regulation of microglial activity are still poorly understood. To selectively analyse microglial reactions in TE, we have established a model of radiation‐induced CD45‐congenic bone marrow chimeras between CD45.2+ C57BL/6 (recipient) and CD45.1+ B6.SJL (donor) mice. These chimeras allow a differentiation of radioresistant CD45.2+ microglia from all other leukocytes, which exhibit the CD45.1+ haplotype. In the normal brain, microglia produced tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐10, and IL‐15 mRNA. In TE, marked microglial activation was observed with a de novo expression of IL‐12p40 and inducible nitric oxide synthase mRNA, upregulation of IL‐1β and TNF‐α mRNA, a continuous production of IL‐10, and IL‐15 mRNA, an induction of major histocompatibility class I and II antigens, intercellular adhesion molecule‐1, and leukocyte function‐associated antigen‐1. Furthermore, selective depletion of CD4+ and/or CD8+ T cells in the chimeras revealed that microglial cytokine production was critically regulated by CD8+T cells, whereas expression of cell surface molecules was less dependent on T cells. These findings demonstrate a specific regulation of microglia by T lymphocytes during the course of TE.
Central Role of Microglia in Neonatal Excitotoxic Lesions of the Murine Periventricular White Matter
Authors: Tahraoui S.L. , Marret S. , Bodénant C. , Leroux P. , Dommergues M.A. , Evrard P. , Gressens P.
Published: July 2010

Periventricular leukomalacia (PVL) is the main cause of neurologic handicap in pre‐term infants. The understanding of cellular and molecular mechanisms leading to white matter damage is critical for development of innovative therapeutic strategies for PVL. The pathogenesis of PVL remains unclear but possibly involves glutamate excitotoxicity as an important molecular pathway. We previously described a neonatal mouse model of excitotoxic white matter lesion mimicking human PVL. In the present study, we used this experimental tool to investigate the cellular populations and the glutamate receptor subtypes involved in excitotoxic white matter lesions. Combined immunohistochemical, electron microscopic, and cell death detection data revealed that microglial activation and astrocytic death were the primary responses of white matter to excitotoxic insult. In vitro experiments suggested that microglia activated by ibotenate released soluble factors that kill astrocytes. The use of selective agonists and antagonists of glutamate receptors revealed that N‐methyl‐D‐aspartate (NMDA) receptor activation was essential and sufficient to produce cystic white matter lesions. NMDA receptor immunohistochemistry labeled microglial cells in the neonatal periventricular white matter. The developing white matter displayed a window of sensitivity to excitotoxic damage that was paralleled by the transient presence of NMDA receptor‐expressing white matter cells. Assuming that similar pathophysiologic mechanisms are present in human pre‐ term infants, microglia and NMDA receptors could represent key targets for treatment of PVL.
Expression of Cell Death‐Associated Proteins in Neuronal Apoptosis Associated with Pontosubicular Neuron Necrosis
Authors: Stadelmann Christine , Mews Imke , Srinivasan Anu , Deckwerth Thomas L. , Lassmann Hans , Brück Wolfgang
Published: July 2010

Expression of apoptosis‐associated proteins p53, bcl‐2, bax, and caspase‐3/CPP32, activation of caspase‐3, and modification of proteins via poly(ADP‐ribosyl)ation was studied in pontosubicular neuron necrosis (PSN), a form of perinatal brain damage revealing the morphological hallmarks of neuronal apoptosis. Immunoreactivity for p53 was completely absent. The majority of cells stained with the bax and procaspase‐3 antibodies did not show morphological signs of apoptosis. In contrast, an antibody against activated caspase‐3 almost exclusively stained cells with apoptotic morphology. Poly(ADP‐ribosyl)ated proteins were only rarely detected in cells with apoptotic morphology. The expression patterns of bax, procaspase‐3, bcl‐2, and p53 in PSN were similar to that found in age‐matched control brains. However, activated caspase‐3 and poly‐ADP‐ribosylated proteins were exclusively found in apoptotic cells. These data indicate that detection of active caspase‐3 is a reliable marker for apoptosis in formalin‐fixed human tissue, and that neuronal apoptosis in pontosubicular neuron necrosis is accompanied by a pronounced activation of caspase‐3.
4‐Hydroxynonenal Immunoreactivity is Increased in Human Hippocampus After Global Ischemia
Authors: McCracken Eileen , Graham David I. , Nilsen Margaret , Stewart Janice , Nicoll James AR , Horsburgh Karen
Published: July 2010

Oxidative stress and lipid peroxidation may contribute to the pathology of neurodegenerative disorders such as Alzheimer's disease (AD) and cerebral ischemia. 4‐Hydroxynonenal (4‐HNE) is a toxic byproduct of lipid peroxidation, and immunoreactivity to 4‐HNE has been used to examine lipid peroxidation in the pathogenesis of AD and ischemia. This study sought to determine 1) if there are cellular alterations in 4‐HNE immunoreactivity in the human hippocampus after global ischemia, and 2) whether possession of an apolipoprotein E (APOE) ε4 allele influenced the extent of 4‐HNE immunoreactivity. 4‐HNE immunoreactivity was assessed semi‐quantitatively in the temporal lobe of a group of controls (n = 44) and in a group of patients who had an episode of global ischemia as a result of a cardiorespiratory arrest and subsequently died (n = 56, survival ranged from 1hr to 42days). There was minimal cellular 4‐HNE immunoreactivity in the control group. However, compared to controls, 4‐HNE immunoreactivity was significantly increased in neurons (p<0.0002) and glia (p<0.0001) in the hippocampal formation after global ischemia. Possession of an APOEε4 allele did not influence the extent of neuronal or glial 4‐HNE immunostaining in the control or global ischemia group. There was a significant negative correlation between the extent of neuronal 4‐HNE immunoreactivity with survival period after global ischemia (r2= 0.0801; p<0.036) and a significant positive correlation between the extent of glial 4‐HNE immunoreactivity and survival after global ischemia (r2= 0.2958; p<0.0001). The data indicate a marked increase in neuronal and glial 4‐HNE. This substantiates a role for lipid peroxidation in the pathogenesis of cerebral ischemia. There was no indication that APOE genotype influenced the extent of 4‐HNE immunoreactivity.
Polymerase Chain Reaction as a Diagnostic Adjunct in Herpesvirus Infections of the Nervous System
Authors: Kleinschmidt‐DeMasters B. K. , DeBiasi Roberta L. , Tyler Kenneth L.
Published: July 2010

Polymerase chain reaction (PCR) is a powerful technique that allows detection of minute quantities of DNA or RNA in cerebrospinal fluid (CSF), vesicle and endoneurial fluids, blood, fresh‐frozen, and even formalin‐fixed tissues. Various infectious agents can be detected with high specificity and sensitivity, including bacteria, parasites, rickettsia and viruses. PCR analysis of CSF has revolutionized the diagnosis of nervous system viral infections, particularly those caused by human herpesviruses (HHV), and has now replaced brain biopsy as the gold standard for diagnosis of herpes simplex virus (HSV) encephalitis. PCR analysis of both CSF and nervous system tissues has also broadened our understanding of the spectrum of disease caused by HSV‐1 and ‐2, cytomegalovirus (CMV), Epstein‐Barr virus (EBV), varicella zoster virus (VZV), and HHV‐6. Nonetheless, positive tissue PCR results must be interpreted cautiously, especially in cases that lack corroborating clinical and neuropathologic evidence of infection. Moreover, positive PCR results from tissues do not distinguish latent from productive (lytic) viral infections. In several neurological diseases, negative PCR results have provided strong evidence against a role for herpesviruses as the causative agents. This review focuses on the use of PCR tests to diagnose HSV and VZV infections of the nervous system.
Neuronal Apoptosis in the Dentate Gyrus in Humans with Subarachnoid Hemorrhage and Cerebral Hypoxia
Authors: MD Roland Nau , Haase Sabine , Bunkowski Stephanie , MD Wolfgang Brück
Published: July 2010

Apoptosis of dentate granule cells is a typical feature of several animal models of disease. In 20 autopsy cases of subarachnoid hemorrhage (SAH) and global cerebral hypoxia caused by protracted shock or respiratory failure, we evaluated by light microscopy and in situ tailing whether this pattern of neuronal damage also occurs in humans. In subarachnoid hemorrhage, 4.0/mm2 (0–13.0/mm2) a poptotic neurons were observed in the dentate gyrus, in cerebral hypoxia 3.6/mm2 (0–19.9/mm2) (p>0.05), and in 10 aged‐matched control cases dying rapidly from non‐neurological diseases 0/mm2 (0–0/mm2) (median [range]) (p<0.001 versus SAH and hypoxia). Neuronal apoptosis in the dentate gyrus was most frequent, when death occurred later than 24 hours and less than 11 days after disease onset. Neuronal damage in the hippocampus was always necrotic. It was more severe in hypoxia than in SAH (median neuronal damage score 3 [range: 0–3] versus 0 [0–3], p<0.001).

Apoptosis appears to be the predominant mechanism of death in dentate granule cells irrespective of the underlying disease, whereas neuronal death in the hippocampus generally is of necrotic morphology.
Excitatory Amino Acid Transporter EAAT‐2 in Tangle‐bearing Neurons in Alzheimer's Disease
Authors: Thal Dietmar Rudolf
Published: July 2010

The excitatory amino acid transporter EAAT‐2 is physiologically expressed in astrocytes. This study demonstrates that distinct subclasses of neurons exhibited EAAT‐2 immunoreactivity in cases with Alzheimer's disease (AD). EAAT‐2 was identified in the following types of neurons: Cortical pyramidal cells, fascia dentata granule cells, neurons of the basal nucleus of Meynert, the substantia nigra, the paraventricular nucleus of the hypothalamus, oral and central raphe nuclei, locus coeruleus, parabrachial nucleus, and neurons of the reticular formation of the brain stem. All EAAT‐2‐positive neurons displayed cytoskeletal abnormalities with abnormal Γ‐protein and often showed condensed and shrunken nuclei. None of the control cases without AD‐related pathology showed EAAT‐2‐immunoreactive neurons. These results indicate that AD‐related neurodegeneration is associated with the expression of the glutamate transporter EAAT‐2 in altered neurons. Since an aberrant expression of EAAT‐1 in neurons has recently been described, the finding of a neuronal expression of EAAT‐2 strongly supports the hypothesis that abnormalities in the glutamate transport play an important role in the pathogenesis of AD.
Inflammation in the Central Nervous System: the Role for Dendritic Cells
Authors: Pashenkov Mikhail , Teleshova Natalia , Link Hans
Published: July 2010

Dendritic cells (DCs) are a subclass of antigen‐presenting cells critical in the initiation and regulation of adaptive immunity against pathogens and tumors, as well as in the triggering of autoimmunity. Recent studies have provided important knowledge regarding distribution of DCs in the central nervous system (CNS) and their role in intrathecal immune responses. DCs are present in normal meninges, choroid plexus, and cerebrospinal fluid, but absent from the normal brain parenchyma. Inflammation is accompanied by recruitment and/or development of DCs in the affected brain tissue. DCs present in different compartments of the CNS are likely to play a role in the defence against CNS infections, and also may contribute to relapses/chronicity of CNS inflammation and to break‐down of tolerance to CNS autoantigens. CNS DCs can therefore be viewed as a future therapeutic target in chronic inflammatory diseases such as multiple sclerosis.
Detection of HIV‐1 DNA in Microglia/ Macrophages, Astrocytes and Neurons Isolated from Brain Tissue with HIV‐1 Encephalitis by Laser Capture Microdissection
Authors: Trillo‐Pazos G. , Diamanturos A , Rislove L. , Menza T. , Chao W. , Belem P. , Sadiq S. , Morgello S. , Sharer L. , Volsky D.J.
Published: July 2010

In HIV‐1 encephalitis, HIV‐1 replicates predominantly in macrophages and microglia. Astrocytes also carry HIV‐1, but the infection of oligodendrocytes and neurons is debated. In this study we examined the presence of HIV‐1 DNA in different brain cell types in 6 paraffin embedded, archival post‐mortem pediatric and adult brain tissues with HIV‐1 encephalitis by Laser Capture Microdissection (LCM). Sections from frontal cortex and basal ganglia were stained by immunohistochemistry for CD68 (microglia), GFAP (astrocytes), MAP2 (neurons), and p24 (HIV‐1 positive cells) and different cell types were microdissected by LCM. Individual cells or pools of same type of cells were lysed, the cell lysates were subjected to PCR using HIV‐1 gag SK38/SK39 primers, and presence of HIV‐1 DNAwas confirmed by Southern blotting. HIV‐1 gag DNAwas consistently detected by this procedure in the frontal cortex and basal ganglia in 1 to 20 p24 HIV‐1 capsid positive cells, and in pools of 50 to 100 microglia/macrophage cells, 100 to 200 astrocytes, and 100 to 200 neurons in HIV‐1 positive cases but not in HIV‐1 negative controls. These findings suggest that in addition to microglia, the infection of astro‐cytes and neurons by HIV‐1 may contribute to the development of HIV‐1 disease in the brain.
Meningeal Tumors of Childhood and Infancy. An Update and Literature Review.
Authors: Perry Arie , Dehner Louis P.
Published: July 2010

Meningeal derived tumors of the first 2 decades of life are often diagnostically challenging due to the wide morphologic spectrum encountered and the rarity of most individual entities. The 2 most common patterns include the dural/leptomeningeal‐based mass and neoplastic meningitis. Both primary and secondary meningeal presentations may occur, either early or late in the course of various meningothelial, mesenchymal, embryonal, glial, hematopoietic, histiocytic, melanocytic, and inflammatory tumors. As in other areas of pediatric pathology, there are significant differences between this patient cohort and adults, differences which will be emphasized in this review.
Frequent LOH at Chromosome 12q22‐23 and Apaf‐1 Inactivation in Glioblastoma
Authors: Watanabe Takuya , Hirota Yuichi , Arakawa Yasuaki , Fujisawa Hironori , Tachibana Osamu , Hasegawa Mitsuhiro , Yamashita Junkoh , Hayashi Yutaka
Published: July 2010

Glioblastoma (GB) often has loss of heterozygosity on the chromosomes, 1p, 10p, 10q, 11p, 17p, 19q, 22q, and several others. In the case of chromosome 12q; however, it remains to be seen whether LOH occurs. Apaf‐1, the apoptotic protease activating factor‐1, located at chromosome 12q22‐23, is a major effecter of the p53 mediated apoptosis pathway, and Apaf‐1 inactivation due to chromosome 12q22‐23 LOH and hypermethylation may be involved in some of the neoplasms in malignancy. However, little is known about the frequency of the 12q22‐23 LOH or the state of Apaf‐1 in GB. To elucidate their involvement in GB, we analyzed a series of 33 GBs for chromosome 12q22‐23 LOH, Apaf‐1 mRNA expression, and Apaf‐1 protein expression, using microsatellite analysis, reverse transcription (RT) ‐PCR analysis, and immunohistochemical (IHC) analysis, respectively. We also evaluated if and how the 12q22‐23 LOH correlated with the p53 gene mutation and EGFR gene amplification. Chromosome 12q22‐23 LOH was detected in 14 (42%) of 33 cases. Among the examined cases with LOH at 12q22‐23, a low expression of Apaf‐1 mRNA was detected in 9 (69%) of 13 cases, and a low expression of Apaf‐1 protein was detected in 12 (86%) of 14 cases. The 12q22‐23 LOH was significantly correlated with low expression of mRNA and protein (p<0.05, p<0.001 respectively). The p53 gene mutation and EGFR gene amplification were found in 13 cases (39%) and 8 cases (24%), respectively, and these gene alterations were inversely correlated. However, 12q22‐23 LOH had no correlations with the p53 gene mutation or EGFR gene amplification. Six of 9 GBs (67%) with neither p53 gene mutation nor EGFR gene amplification tested positive for 12q22‐23 LOH. These GBs are likely to belong to another subset independent from the 2 common genetic subsets in GB (one with p53 gene mutation and without EGFR gene amplification, and the other with EGFR gene amplification and without p53 gene mutation). Twenty‐three (70%) out of the 33 GBs with the 12q22‐23 LOH also tested positive for Apaf‐1 inactivation or p53 gene mutation. This high frequency of alterations in the apoptosis‐associated factors prompts a speculation that abrogation of the Apaf‐1 and p53 mediated apoptosis pathway may play an important role in the tumorigenesis of GB.
Will Preventing Protein Aggregates Live Up to Its Promise as Prophylaxis Against Neurodegenerative Diseases?
Authors: Lee Hyoung‐gon , Petersen Robert B. , Zhu Xiongwei , Honda Kazuhiro , Aliev Gjumrakch , Smith Mark A. , Perry George
Published: July 2010

Protein aggregation and misfolding characterize most age‐related neurodegenerative diseases including Alzheimer, Parkinson and Huntington diseases. Protein aggregation has generally been assumed to be responsible for neurodegeneration in these disorders due to association and genetics. However, protein aggregation may, in fact, be an attempt to protect neurons from the stress resulting from the disease etiology. In this review, we weigh the evidence of whether removal of amyloids, aggregates and neuronal inclusions represent a reasonable strategy for protecting neurons.
The Pathogenesis of Neonatal Post‐hemorrhagic Hydrocephalus
Authors: Cherian Shobha , Whitelaw Andrew , Thoresen Marianne , Love Seth
Published: July 2010

Hydrocephalus after intraventricular hemorrhage (IVH) has emerged as a major complication of preterm birth and is especially problematic to treat. The hydrocephalus is usually ascribed to fibrosing arachnoiditis, meningeal fibrosis and subependymal gliosis, which impair flow and resorption of cerebrospinal fluid (CSF). Recent experimental studies have suggested that acute parenchymal compression and ischemic damage, and increased parenchymal and perivascular deposition of extracellular matrix proteins—probably due at least partly to upregulation of transforming growth factor‐β (TGF‐β)—are further important contributors to the development of the hydrocephalus. IVH is associated with damage to periventricular white matter and the damage is exacerbated by the development of hydrocephalus; combinations of pressure, distortion, ischaemia, inflammation, and free radical‐mediated injury are probably responsible. The damage to white matter accounts for the high frequency of cerebral palsy in this group of infants. The identification of mechanisms and mediators of hydrocephalus and white matter damage is leading to the development of new treatments to prevent permanent hydrocephalus and its neurological complications, and to avoid shunt dependence.
Insights into the Pathogenesis of Hydrocephalus from Transgenic and Experimental Animal Models
Authors: Crews Leslie , Wyss‐Coray Tony , Masliah Eliezer
Published: July 2010

Hydrocephalus is a progressive brain disorder characterized by abnormalities in the flow of cerebrospinal fluid (CSF) and ventricular dilatation that leads to cerebral atrophy, and if left untreated, can be fatal. Genetic mutations, congenital malformations, infectious diseases, intracerebral hemorrhages and tumors are common conditions resulting in hydrocephalus. Although the causes of obstructive hydrocephalus are better understood, the mechanisms resulting in chronic, progressive communicating congenital and acquired hydrocephalus are less well understood. In this regard, recent studies in transgenic (tg) mice suggest that increased expression of cytokines such as TGF‐β1 might play an important role by disrupting the vascular extracellular matrix (ECM) remodeling, promoting hemorrhages, and altering the reabsorption of CSF. In this context, the main objective of this manuscript is to provide an overview on the cellular and molecular mechanisms of hydrocephalus based on studies derived from tg and experimental animal models.
FEBRUARY 2004: A 44‐YEAR‐OLD MAN WITH A 2‐YEAR HISTORY OF EPISTAXIS
Authors: Di Patre Pier Luigi , Szalay Ildiko , Delavelle Jacqueline
Published: July 2010

CASE OF THE MONTH: ABSTRACT

FEBRUARY 2004 COM. A 44‐year old man presented with a 2‐year history of epistaxis and a nodular lesion in the nasopharyngeal mucosa. Neuroimaging revealed a midline nasopharyngeal tumor extending through the skull base to the clivus. Following surgical resection, histological studies showed a paraganglioma, a tumor with a typical nesting pattern, abundant capillary network, and strong immunoreactivity for neuroendocrine markers. Paragangliomas of the head and neck are rare tumors, which may come to the neuropathologist's attention because of their propensity for intracranial spread. In particular, paragangliomas located in the nasopharynx may generate diagnostic difficulties, as they appear to have no connection with major paraganglia in the region. Morphologic criteria do not allow distinguishing between benign and malignant forms.
Chronic Ethanol Treatment Enhances Inflammatory Mediators and Cell Death in the Brain and in Astrocytes
Authors: Vallés Soraya L. , Blanco Ana M. , Pascual María , Guerri Consuelo
Published: July 2010

Inflammatory processes and cytokine expression have been implicated in the pathogenesis of several neurodegenerative disorders. Chronic ethanol intake induces brain damage, although the mechanisms involved in this effect are not well understood.

We tested the hypothesis that activation of glial cells by ethanol would induce stimulation of signaling pathways and inflammatory mediators in brain, and would cause neurotoxicity. We used cerebral cortex from control and chronic ethanol‐fed rats, which received ethanol‐liquid diet for 5 months and cultured of astrocytes exposed to 75 mM ethanol for 7 days. Our results demonstrate that chronic ethanol treatment up‐regulates iNOS, COX‐2 and IL‐1β in rat cerebral cortex and in cultured astrocytes.

Under both experimental conditions, up‐regulation of these inflammatory mediators and IL‐1 RI concomitantly occurs with the stimulation of IRAK and MAP kinases, including ERK1/2, p‐38 and JNK, which trigger the downstream activation of oxidant‐sensitive transcription factors NF‐kB and AP‐1. These effects were associated with an increased in both caspase‐3 and apoptosis in ethanol‐fed rats and in astrocytes exposed to ethanol. In conclusion, chronic ethanol treatment stimulates glial cells, upregulating the production and the expression of inflammatory mediators in the brain, and activating signalling pathways and transcription factors involved in inflammatory damage and cell death.
Genetic Alterations of Phosphoinositide 3‐kinase Subunit Genes in Human Glioblastomas
Authors: Mizoguchi Masahiro , Nutt Catherine L. , Mohapatra Gayatry , Louis David N.
Published: July 2010

Genetic alterations of PI3K (phosphoinositide 3‐kinase) subunits have been documented in a number of tumor types, with increased PI3K activity linked to gene amplification and mutation of catalytic subunits, as well as mutations of regulatory subunits. Among high grade gliomas, activation of the PI3K‐AKT signaling pathway through loss of PTEN function is common. We therefore investigated whether genetic alteration of class IA PI3Ks might provide a mechanism for deregulation of this pathway in glioblastomas. We studied a series of glioblastomas with FISH to assess copy number of catalytic subunits (PIK3CA and PIK3CD) and with PCR‐SSCP to screen for somatic mutations of conserved regions of both catalytic and regulatory subunits. FISH revealed frequent balanced copy number increases of both PIK3CA and PIK3CD, and one case showed an extra copy limited to PIK3CA. One glioblastoma exhibited a 9‐bp deletion that encompassed the exon‐intron junction of exon 12 of PIK3R1, documenting for the first time a mutation within a PI3K regulatory subunit in human glioblastoma. This deletion would be predicted to yield a truncated protein that lacks the inhibitory domain, resulting in increased PI3K activity. Furthermore, the case with selected PIK3CA copy number gain and the case with a truncating PIK3R1 mutation both featured AKT activation without PTEN mutation. These results suggest that genetic alterations of class IA PI3K subunit genes can occasionally play a role in human glioblastoma by activating the PI3K‐AKT signaling pathway independently of PTEN mutation.
Amyloid β‐Peptide(1‐42) Contributes to the Oxidative Stress and Neurodegeneration Found in Alzheimer Disease Brain
Authors: Butterfield D. Allan , Boyd‐Kimball Debra
Published: July 2010

Oxidative stress is extensive in Alzheimer disease (AD) brain. Amyloid β‐peptide (1–42) has been shown to induce oxidative stress and neurotoxicity in vitro and in vivo. Genetic mutations that result in increased production of Aβ1–42 from amyloid precursor protein are associated with an early onset and accelerated pathology of AD. Consequently, Aβ1–42 has been proposed to play a central role in the pathogenesis of AD as a mediator of oxidative stress. In this review, we discuss the role of Aβ1–42 in the lipid peroxidation and protein oxidation evident in AD brain and the implications of such oxidative stress for the function of various proteins that we have identified as specifically oxidized in AD brain compared to control, using proteomics methods. Additionally, we discuss the critical role of methionine 35 in the oxidative stress and neurotoxic properties exhibited by Aβ1–42.
MAY 2004: NEWBORN WITH INTRACRANIAL MASS
Authors: Scheil Stefanie , Horn Torsten , Kunz Ulrich , Gabelmann Andreas , Sirén Anna‐Leena , Klein Rüdiger , Schindler Christoph , Möller Peter , Sommer Clemens
Published: July 2010

May 2004: We present the case of a male newborn (38th week of gestation) with a 3‐week history of a sonographically detected parietal mass of 5‐cm diameter. The entire mass was removed at surgery. Surprisingly, microscopy revealed an intracerebral hemorrhage and nests of glycophorin‐A immunoreactive blasts and nucleated erythrocytes in the surrounding parenchyma. The final diagnosis was chronic intracerebral hemorrhage of unknown etiology with reactive changes of the surrounding brain tissue and perifocal extramedullary erythropoiesis. This case is unique because, to date, intracranial extramedullary erythropoiesis has only been described in chronic subdural hemorrhage.
Lesion‐associated Expression of Transforming Growth Factor‐Beta‐2 in the Rat Nervous System: Evidence for Down‐regulating the phagocytic Activity of Microglia and Macrophages
Authors: Stoll Guido , Schroeter Michael , Jander Sebastian , Siebert Heike , Wollrath Anja , Kleinschnitz Christoph , Brück Wolfgang
Published: July 2010

The mechanisms that control the phagocytic activities of microglia and macrophages during disorders of the nervous system are largely unknown. In the present investigation, we assessed the functional role of transforming growth factor (TGF)β2 in vitro and studied TGFβ‐2mRNA and protein expression two CNS lesion paradigms in vivo characterized by fundamental differences in microglia/macrophage behaviour: optic nerve crush exhibiting slow, and focal cerebral ischemia exhibiting rapid phagocytic transformation. Furthermore, we used sciatic nerve crush injury as a PNS lesion paradigm comparable to brain ischemia in its rapid phagocyte response. In normal and degenerating optic nerves, astrocytes strongly and continuously expressed TGF‐β2 immunoreactivity. In contrast, TGF‐β2 was downregulated in Schwann cells of degenerating sciatic nerves, and was not expressed by reactive astrocytes in the vicinity of focal ischemic brain lesions during the acute phagocytic phase In line with its differential lesion‐associated expression pattern, exogenous TGF‐β2 suppressed spontaneous myelin phagocytosis by microglia/macrophages in a mouse ex vivo assay of CNS and PNS Wallerian degeneration. In conclusion, we have identified TGF‐β2 as a nervous system intrinsic cytokine that could account for the differential regulation of phagocytic activities of microglia and macrophages during injury.