bluuebunny/crossref_metadata_2025 huggingface dataset:
Frequent In activation of CDKN2A and Rare Mutation of TP53 in PCNSL
Authors: Cobbers J.M.J. Ludwig , Wolter Marietta , Reifenberger Julia , Ring Gudrun U. , Jessen Frank , An Han‐Xiang , Niederacher Dieter , Schmidt Esther E. , Ichimura Koichi , Floeth Frank , Kirsch Lutz , Borchard Franz , Louis David N. , Collins V. Peter , Reifenberger Guido
Published: July 2010

Twenty primary central nervous system lymphomas (PCNSL) from immunocompetent patients (nineteen B‐cell lymphomas and one T‐cell lymphoma) were investigated for genetic alterations and/or expression of the genes BCL2, CCND1, CDK4, CDKN1A, CDKN2A, MDM2, MYC, RB1, REL, and TP53. The gene found to be altered most frequently was CDKN2A. Eight tumors (40%) showed homozygous and two tumors (10%) hemizygous CDKN2A deletions. Furthermore, methylation analysis of six PCNSL without homozygous CDKN2A loss revealed methylation of the CpG island within exon 1 of CDKN2A in three instances. Reverse transcription PCR analysis of CDKN2A mRNA expression was performed for 11 tumors and showed either no or weak signals. Similarly, immunocytochemistry for the CDKN2A gene product (p16) remained either completely negative or showed expression restricted to single tumor cells. None of the PCNSL showed amplification of CDK4. Similarly, investigation of CCND1 revealed no amplification, rearrangement or overexpression. The retinoblastoma protein was strongly expressed in all tumors. Only one PCNSL showed a mutation of the TP53 gene, i.e., a missense mutation at codon 248 (CGG to TGG: Arg to Trp). No evidence of BCL2 gene rearrangement was found in 11 tumors investigated. The bcl‐2 protein, however, was strongly expressed in most tumors. None of the 20 PCNSL demonstrated gene amplification of MDM2, MYC or REL. In summary, inactivation of CDKN2A by either homozygous deletion or DNA methylation represents an important molecular mechanism in PCNSL. Mutation of the TP53 gene and alterations of the other genes investigated appear to be of minor significance in these tumors.
Senile Dementia with Tangles (Tangle Predominant Form of Senile Dementia)
Authors: Jellinger Kurt A. , Bancher Christian
Published: July 2010

Senile dementia with tangles is a sporadic subset of very late onset dementia with preponderance in females over age 80 years. Neuropathology shows diffuse cerebral atrophy with neurofibrillary tangles, often ghost tangles, and neuropil threads almost limited to limbic areas (transentorhinal, entorhinal area, hippocampus ‐ not exclusively sector CA 1 ‐ and amygdala) with only rare and mild involvement of the neocortex, basal ganglia and brainstem (except nucleus basalis and locus ceruleus), absence of neuritic plaques and absence or scarcety of amyloid deposits. This pattern of fibrillary pathology corresponds to Braak stages III and IV or the “limbic” type of Alzheimer disease that is considered the main form in the oldest‐old but escapes the current criteria for the morphologic diagnosis of Alzheimer disease. It is distinct from other tau‐ or tangle‐pathology related conditions, e.g. progressive supranuclear palsy, autosomal dominant dementia with tangles, and diffuse tangles with calcification. Very low prevalence of ApoE e4 allele (0.03–0.11%) and higher frequency of ApoE e3 and/or e2 suggest a lack of promoting effect of e4 and a possible protecting effect of e2/3 on amyloidogenesis. Senile dementia with tangles is suggested to be a variant of Alzheimer disease occurring in the oldest‐old, but its nosological position within aging disorders of the brain is still controversy.
Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17: A New Group of Tauopathies
Authors: Spillantini Maria Grazia , Bird Thomas D. , Ghetti Bernardino
Published: July 2010

Frontotemporal dementia is a neurological disorder characterised by personality changes, deterioration of memory and executive functions as well as stereotypical behaviour. Sometimes a Parkinsonian syndrome is prominent. Several cases of frontotemporal dementia are hereditary and recently families have been identified where the disease is linked to chromosome 17q21–22. Although, there is clinical and neuropathological variability among and within families, they all consistently present a symptomathology that has led investigatores to name the disease “Frontotemporal Dementia and Parkinson‐ismlinked to chromosome 17.” Neuropathologically, these patients present with atrophy of frontal and temporal cortex as well as of basal ganglia and substantia nigra. In the majority of cases these features are accompanied by neuronal loss, gliosis and microtubule‐associated protein tau deposits which can be present in both neurones and glial cells. The distribution, structural and biochemical characteristics of the tau deposits differentiate them from those present in Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy and Pick's disease. No (β‐amyloid deposits are present. The clinical and neuropathological features of the disease in these families suggest that Frontotemporal Dementia and Parkinsonism linked to chromosome 17 is a distinct disorder. The presence of abundant tau deposits in the majority of these families define this disorder as a new tauopathy.
The Priori Diseases
Authors: Prusiner Stanley B.
Published: July 2010

The human prion diseases are fatal neurodegenerative maladies that may present as sporadic, genetic, or infectious illnesses. The sporadic form is called Creutzfeldt‐Jakob disease (CJD) while the inherited disorders are called familial (f) CJD, Gerstmann‐Sträussler‐Scheinker (GSS) disease and fatal familial insomnia (FFI). Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrPSc).The normal, cellular PrP (PrPC) is converted into PrPSc through a posttranslational process during which it acquires a high β‐sheet content. In fCJD, GSS, and FFI, mutations in the PrP gene located on the short arm of chromosome 20 are the cause of disease. Considerable evidence argues that the prion diseases are disorders of protein conformation.
The Pathophysiology of Fatal Familial Insomnia
Authors: Lugaresi Elio , Tobler Irene , Gambetti Pierluigi , Montagna Pasquale
Published: July 2010

The key clinical aspects of FFI, i.e. hypovigilance and attention deficit, inability to generate EEG sleep patterns, sympathetic hyperactivity and attenuation of vegetative and hormonal circadian oscillations, are related to selective atrophy of the anteroventral and mediodorsal thalamic nuclei. These nuclei constitute the limbic part of the thalamus interconnecting limbic and paralimbic regions of the cortex and other subcortical structures in the limbic system including the hypothalamus. The hypothalamus released from cortico‐limbic control is shifted to a prevalence of activating, as opposed to deactivating, functions including loss of sleep, sympathetic hyperactivity and the attendant attenuation of autonomie circadian and endocrine oscillations. These findings document that the limbic thalamus has a strategic position in the central autonomie network running from the limbic cortical regions to the lower brain stem which regulates the body's homeostasis in an integrated fashion.
Dysautonomia in Fatal Familial Insomnia as an Indicator of the Potential Role of the Thalamus in Autonomie Control
Authors: Benarroch Eduardo E. , Stotz‐Potter Elizabeth H.
Published: July 2010

Fatal familial insomnia (FFI) is characterized by insomnia, dysautonomia, disruption of circadian rhythms, and motor dysfunction. The typical neuropathological findings in FFI are severe neuronal depletion in the mediodorsal (MD) and anteroventral nuclei of the thalamus. The interaction between the thalamus and central autonomie control mechanisms is poorly understood. The central autonomie areas include the anterior cingulate and insular cortices; amygdala, paraventricular nucleus, dorsomedial nucleus, and lateral hypothalamic area; periaqueductal gray; parabrachial nucleus; ventrolateral medulla; and nucleus of the solitary tract. Several nuclei of the thalamus have connections with areas of the central autonomie network. The paraventricular nucleus (PVT) projects to the medial prefrontal cortex, and receives multimodal visceral and somatosensory inputs. The MD nucleus is connected with several “limbic” areas involved in autonomie control. The autonomie manifestations of FFI are exaggerated sympathetic activation with preserved parasympathetic drive to the cardiovascular system. This reflects an exaggerated sympathetic drive from supramedullary structures. Bicuculline, administered into the MD, elicits an increase in arterial pressure and heart rate. The medial portion of the MD may share with the PVT a relay function for circuits controlling autonomie responses. MD involvement in FFI suggests a role of the thalamus in central autonomie and other integrative functions.
An Isoform of Ataxin‐3 Accumulates in the Nucleus of Neuronal Cells in Affected Brain Regions of SCA3 Patients
Authors: Schmidt Thorsten , Landwehrmeyer G. Bernhard , Schmitt Ina , Trottier Yvon , Auburger Georg , Laccone Franco , Klockgether Thomas , Völpel Michael , Epplen Jörg T. , Schöls Ludger , Riess Olaf
Published: July 2010

Autosomal dominant spinocerebellar ataxias (SCA) form a group of clinically and genetically heterogeneous neurodegenerative disorders. The defect responsible for SCA3/Machado‐Joseph disease (MJD) has been identified as an unstable and expanded (CAG)n trinucleotide repeat in the coding region of a novel gene of unknown function. The MJD1 gene product, ataxin‐3, exists in several isoforms. We generated polyclonal antisera against an alternate carboxy terminus of ataxin‐3. This isoform, ataxin‐3c, is expressed as a protein of approximately 42 kDa in normal individuals but is significantly enlarged in affected patients confirming that the CAG repeat is part of the ataxin‐3c isoform and is translated into a polyglutamine stretch, a feature common to all known CAG repeat disorders. Ataxin‐3 like immunoreactivity was observed in all human brain regions and peripheral organs studied. In neuronal cells of control individuals, ataxin‐3c was expressed cytoplasmatically and had a somatodendritic and axonal distribution. In SCA3 patients, however, C‐terminal ataxin‐3c antibodies as well as antiataxin‐3 monoclonal antibodies (1H9) and anti‐ubiquitin antibodies detected intranuclear inclusions (NIs) in neuronal cells of affected brain regions. A monoclonal antibody, 2B6, directed against an internal part of the protein, barely detected these NIs implying proteolytic cleavage of ataxin‐3 prior to its transport into the nucleus. These findings provide evidence that the alternate isoform of ataxin‐3 is involved in the pathogenesis of SCA3/MJD. Intranuclear protein aggregates appear as a common feature of neurodegenerative polyglutamine disorders.
Autoimmunity to Myelin Oligodendrocyte Glycoprotein in Rats Mimics the Spectrum of Multiple Sclerosis Pathology
Authors: Storch Maria K. , Stefferl Andreas , Brehm Uschi , Weissert Robert , Wallström Erik , Kerschensteiner Martin , Olsson Tomas , Linington Chris , Lassmann Hans
Published: July 2010

Multiple sclerosis is a chronic inflammatory disease characterized by perivenous inflammation and focal destruction of myelin. Many attempts have been undertaken previously to create animal models of chronic inflammatory demyelinating diseases through autoimmunity or virus infection. Recently, however, a new model of myelin oligodendrocyte glycoprotein (MOG) induced autoimmune encephalomyelitis became available, which, in a very standardized and predictable way, leads to chronic (relapsing or progressive) disease and widespread CNS demyelination.

In the present study we actively induced MOG‐experimental autoimmune encephalomyelitis (EAE) in different inbred rat strains using different immunization protocols. The pathology found in our models closely reflects the spectrum of multiple sclerosis (MS) pathology: Classical MS as well as variants such as optic neuritis, Devic's disease and Marburg's type of acute MS are mimicked in rats immunized with MOG antigen. Furthermore we demonstrate, that by using the proper strain/sensitization regime, subforms of MS such as for instance neuromyelitis optica can be reproducibly induced. Our study further supports the notion, that incidence and expression of the disease in this model, alike the situation in multiple sclerosis, is determined by genetic and environmental factors.
Transgenic Mice in the Study of Polyglutamine Repeat Expansion Diseases
Authors: Bates Gillian P. , Mangiarini Laura , Davies Stephen W.
Published: July 2010

An increasing number of neurodegenerative diseases, including Huntington's disease (HD), have been found to be caused by a CAG/polyglutamine expansion. We have generated a mouse model of HD by the introduction of exon 1 of the human HD gene carrying highly expanded CAG repeats into the mouse germ line. These mice develop a progressive neurological phenotype. Neuronal intranuclear inclusions (NII) that are immunoreactive for huntingtin and ubiquitin have been found in the brains of symptomatic mice. In vitro analysis indicates that the inclusions are formed through self aggregation via the polyglutamine repeat into amyloid‐like fibrils composed of a cross β‐sheet structure that has been termed a polar zipper. Analysis of patient material and other transgenic lines has now shown NII to be a common feature of all of these diseases. In the transgenic models, inclusions are present prior to the onset of symptoms suggesting a causal relationship. In contrast, neurodegeneration occurs after the onset of the phenotype indicating that the symptoms are caused by a neuronal dysfunction rather than a primary cell death.
Oxidative Stress in Brain Ischemia
Authors: Love Seth
Published: July 2010

Brain ischemia initiates a complex cascade of metabolic events, several of which involve the generation of nitrogen and oxygen free radicals. These free radicals and related reactive chemical species mediate much of damage that occurs after transient brain ischemia, and in the penumbral region of infarcts caused by permanent ischemia. Nitric oxide, a water‐ and lipid‐soluble free radical, is generated by the action of nitric oxide synthases. Ischemia causes a surge in nitric oxide synthase 1 (NOS 1) activity in neurons and, possibly, glia, increased NOS 3 activity in vascular endothelium, and later an increase in NOS 2 activity in a range of cells including infiltrating neutrophils and macrophages, activated microglia and astrocytes. The effects of ischemia on the activity of NOS 1, a Ca2+‐dependent enzyme, are thought to be secondary to reversal of glutamate reuptake at synapses, activation of NMDA receptors, and resulting elevation of intracellular Ca2+. The up‐regulation of NOS 2 activity is mediated by transcriptional inducers. In the context of brain ischemia, the activity of NOS 1 and NOS 2 is broadly deleterious, and their inhibition or inactivation is neuroprotective. However, the production of nitric oxide in blood vessels by NOS 3, which, like NOS 1, is Ca2+‐dependent, causes vasodilatation and improves blood flow in the penumbral region of brain infarcts. In addition to causing the synthesis of nitric oxide, brain ischemia leads to the generation of superoxide, through the action of nitric oxide synthases, xanthine oxidase, leakage from the mito‐chondrial electron transport chain, and other mechanisms. Nitric oxide and superoxide are themselves highly reactive but can also combine to form a highly toxic an ion, peroxynitrite. The toxicity of the free radicals and peroxynitrite results from their modification of macromolecules, especially DNA, and from the resulting induction of apoptotic and necrotic pathways. The mode of cell death that prevails probably depends on the severity and precise nature of the ischemie injury. Recent studies have emphasized the role of peroxynitrite in causing singlestand breaks in DNA, which activate the DNA repair protein poly(ADP‐ribose) polymerase (PARP). This catalyzes the cleavage and thereby the consumption of NAD+, the source of energy for many vital cellular processes. Over‐activation of PARP, with resulting depletion of NAD+, has been shown to make a major contribution to brain damage after transient focal ischemia in experimental animals. Neuronal accumulation of poly(ADP‐ribose), the end‐product of PARP activity has been demonstrated after brain ischemia in man. Several therapeutic strategies have been used to try to prevent oxidative damage and its consequences after brain ischemia in man. Although some of the drugs used in early studies were ineffective or had unacceptable side effects, other trials with antioxidant drugs have proven highly encouraging. The findings in recent animal studies are likely to lead to a range of further pharmacological strategies to limit brain injury in stroke patients.
Cortical Synaptic Density is Reduced in Mild to Moderate Human Immunodeficiency Virus Neurocognitive Disorder
Authors: Everall IP , Heaton RK , Marcotte TD , Ellis RJ , McCutchan JA , Atkinson JH , Grant I , Mallory M , Masliah E ,   HNRC Group
Published: July 2010

Dendritic and synaptic damage (without frank neuronal loss) may be seen in milder human immunodeficiency virus (HIV)‐related cognitive disorders. Synapse volume estimates, performed by stereological methods, could enhance the ability to detect subtle neuronal changes that may accompany cognitive impairment in HIV infection. For the present study, synaptic density and neuronal number were assessed by combined stereology/confocal microscopy and these measures were then correlated with ante‐mortem levels of cognitive performance in AIDS patients. Three‐dimensional stereological measures showed a significant correlation between reduced synaptic density and poor neuropsychological performance. To evaluate the specificity of any observed associations, additional variables including viral burden, astrogliosis and number of calbindin‐immunoreactive neurons were measured. Factor analysis of a set of neuropathological variables revealed two factors; one defined by synaptic density and volume fraction, calbindin pyramidal neuronal densities and viral burden; the second by astrocytosis and calbindin interneuron density. Only the first factor correlated significantly with neuropsychological functioning during life.

It is concluded that a combination of factors including synaptic damage, specific neuronal loss and increasing viral load underlies HIV‐associated cognitive impairment. As synaptic damage is potentially reversible, early diagnosis and treatment of mild cogntive disorders may improve functioning and prevent the progression of brain disease.
Response of Glia, Mast Cells and the Blood Brain Barrier, in Transgenic Mice Expressing Interleukin‐3 in Astrocytes, an Experimental Model for CNS Demyelination
Authors: Powell Henry C. , Garrett Robert S. , Brett Francesca M. , Chiang Chi‐Shuin , Chen Emily , Masliah Eliezer , Campbell Iain L.
Published: July 2010

Transgenic mice overexpressing cytokines facilitate analysis of the effects of these immunomodulators on indigenous cells of the central nervous system. This study examines morphological aspects of demyelination and permeability changes, in a recently described transgenic model (termed GFAP‐IL3). GFAP‐IL3 mice develop progressive motor disease at approximately 5 months. Lesions identified after disease onset, showed activation of microglia, astroglial proliferation with phagocytosis of lipids, and immigration of macrophages and mast cells into neural parenchyma. Lymphocytes failed to appear until the later stages of the disease. Later, cerebellar and brain stem white matter contained focal demyelinating lesions with intense macrophage infiltration and a proliferative astrocytosis. Dystrophic axonal changes were noted, in addition to demyelination in heavily infiltrated lesions. Mast cells, variably present in the thalamus and meninges of wild type mice, were greatly increased at these sites in GFAP‐IL3 mice. Blood‐brain barrier (BBB) defects were documented with leakage of intravenously injected horseradish peroxidase. Mast cell infiltration into the CNS and their degranulation at the site of injury, may represent initial events in a spontaneous process of macrophage mediated demyelination in which glial cells and macrophages are both involved in the phagocytic process.
No Man Alone: The Rediscovery of Alois Alzheimer's Original Cases
Authors: Graeber Manuel B.
Published: July 2010

In 1992 and 1997, respectively, the histological slides of Alois Alzheimers original cases were rediscovered in Munich. This material, which has survived two world wars, was not originally kept at the Institute of Neuropathology of the University of Munich where it was found. Parviz Mehraein, head of the institute, saved anonymous neuropathological material given away by the Psychiatric Clinic of the University of Munich and the Max‐Planck‐Institute of Psychiatry. Yet it was not until Kohshiro Fujisawa of the Tokyo Metropolitan Institute of Neuroscience wrote a letter that the search leading to the rediscovery of Alzheimer's cases was initiated. Henry deF. Webster of the National Institutes of Health in Bethesda, Maryland, had mediated his contact to Munich. Histological and molecular genetic findings obtained on the tissue sections have been reported previously (Neurogenetics 1997, 1:73‐80; 1998, 1:223‐228). The present article summarizes the unusual history of this rediscovery and at the same time illustrates the great value of international exchange in science.
The Neuropathology of Paraneoplastic Syndromes
Authors: Scaravilli Francesco , An Shu F , Groves Michael , Thom Maria
Published: July 2010

The term “paraneoplastic neurological syndromes” encompasses a number of uncommon disorders associated with systemic malignancies. In order to be classified a paraneoplastic neurological syndrome, the malignancies must not invade, compress, or metastasize to the nervous system. They can either focally or diffusely involve the central and peripheral nervous system or the neuromuscular junction.

This paper reviews the neuropathology of the syndrome. It will first describe the clinical presentation and give an account of the systemic tumors most commonly associated with the various types of disorders. Then it will review the general pathological features that consist of an inflammatory process predominantly affecting the gray matter. Finally, it will describe in detail the main clinico‐pathological types, including 1) encephalomyelitis, 2) cortical cerebellar degeneration, 3) peripheral neuropathy, 4) opsoclonus‐myoclonus and 5) retinopathy. The Lambert‐Eaton myasthenie syndrome will be dealt with separately in another paper in this symposium.
Autoimmunity in Paraneoplastic Neurological Syndromes
Authors: Giometto B. , Taraloto B. , Graus F.
Published: July 2010

In patients with Paraneoplastic Neurological Disorders, the researcher detected several autoanti‐bodies reacting with neuronal antigens and tumors; their characteristics supported the hypothesis that autoimmunity plays a part in these diseases and gave impetus to the study of these neurological disorders.

The relationship between detection of anti‐neuronal antibodies, clinical syndromes, and certain types of tumors suggested the utility of these antibodies as a new tool for clinical diagnosis, although their function in the pathogenesis of the various syndromes is still unclear.

This paper intends to review the characteristics of the anti‐neuronal antibodies so far identified, their correlation with clinical syndromes, and the function of antigens. In addition, the paper will offer some insights on the immunological mechanisms of neuronal damage and on treatment options.
Mechanisms of Immune Regulation in the Peripheral Nervous System
Authors: Gold Ralf , Archelos Juan J. , Hartung Hans‐Peter
Published: July 2010

The peripheral nervous system (PNS) is a target for heterogenous immune attacks mediated by different components of the systemic immune compartment. T cells, B cells, and macrophages can interact with endogenous, partially immune‐competent glial cells and contribute to local inflammation. Cellular and humoral immune functions of Schwann cells have been well characterized in vitro. In addition, the interaction of the humoral and cellular immune system with the cellular and extracellular components in the PNS may determine the extent of tissue inflammation and repair processes such as remyelination and neuronal outgrowth. The animal model experimental autoimmune neuritis (EAN) allows direct monitoring of these immune responses in vivo. In EAN contributions to regulate autoimmunity in the PNS are made by adhesion molecules and by cytokines that orchestrate cellular interactions. The PNS has a significant potential to eliminate T cell inflammation via apoptosis, which is almost lacking in other tissues such as muscle and skin. In vitro experiments suggest different scenarios how specific cellular and humoral elements in the PNS may sensitize autoreactive T cells for apoptosis in vivo. Interestingly several conventional and novel immunotherapeutic approaches like glucocorticosteroids and high‐dose antigen therapy induce T cell apoptosis in situ in EAN. A better understanding of immune regulation and its failure in the PNS may help to develop improved, more specific immunothérapies.
Taylor's Cortical Dysplasia: A Confocal and Ultrastructural Immunohistochemical Study
Authors: Garbelli Rita , Munari Claudio , De Biasi Silvia , Vitellaro‐Zuccarello Laura , Galli Carlo , Bramerio Manuela , Mai Roberto , Battaglia Giorgio , Spreafico Roberto
Published: July 2010

In the present report we describe the neuropathological characteristics of tissue surgically resected from three patients affected by intractable epilepsy secondary to cortical dysplasia. Common features, suggestive of a focal cortical dysplasia of Taylor, were observed in all specimens. Immunocytochemical procedures were performed using neuronal and glial markers and the sections were observed at light traditional and confocal microscopes. This part of the investigation pointed out: 1. cortical laminar disruption; 2. very large neurons displaying a pyramidal or round shape; 3. ballooned cells; 4. decrease of calcium binding proteins immunoreactivity; 5. abnormal nets of parvalbumin‐ and glutamic acid decarboxylase‐positive puncta around giant neurons but not around ballooned cells. Ultrastructural investigation on the same material provided evidence of a high concentration of neurofilaments in giant neurons and of glial intermediate filaments in ballooned cells. In addition, immunolabeled GABAergic terminals clustered around giant neurons were not found to establish synapses on their cell bodies.

The present data, derived from a limited sample of patients but showing very consistent features, suggest that in Taylor's type of cortical dysplasia a disturbance of migratory events could be paralleled by a disruption of cell differentiation and maturation and by an impairment of synaptogenesis.This latter mechanism seemed to affect especially the inhibitory elements, and could account for the hyperexcitability of this tissue and thus for the high epileptogenicity of Taylor's dysplasia.
Frequent Co‐Alterations of TP53, p16/CDKN2A, p14ARF, PTEN Tumor Suppressor Genes in Human Glioma Cell Lines.
Authors: Ishii Nobuaki , Maier Daniel , Merlo Adrian , Tada Mitsuhiro , Sawamura Yutaka , Diserens Annie‐Claire , Van Meir Erwin G.
Published: July 2010

In this study we established the simultaneous status of TP53, p16, p14ARF and PTEN tumor suppressor genes in 34 randomly chosen human glioma cell lines. Nine cell lines (26.4%) harbored mutations or deletions in all four tumor suppressor genes and 22 cell lines (64%) had alterations in at least three. Mutations/deletions were found at the following frequencies: TP53 (76.5%), p14ARF (64.7%), p16 (64,7%), PTEN (73.5%). Thus, there was a high incidence of alterations in the cellular pathways involving the p53 transcription factor (94.1%), the retinoblastoma protein (64.7%) and the PTEN phosphatase (73.5%) and 91% of cell lines carried mutations in two or more pathways. This provides the first clear genetic evidence that these tumor suppressors participate in biological pathways which are functioning separately/independently in glioma cells. The status of the gene alterations did not correlate with tumorigenicity in immunocompromized mice or any clinical parameters. Although the mutation rate was higher in glioma cell lines than that reported for glioma tissues, the alterations were molecularly representative of those found in adult de novo glioblastoma. This study highlights the importance of developing therapeutic approaches applicable to tumors with a broad range of genetic alterations and also provides an invaluable panel of glioma cell lines to make this possible.
Postnatal Cerebral Cortical Multipotent Progenitors: Regulatory Mechanisms and Potential Role in the Development of Novel Neural Regenerative Strategies
Authors: Mehler Mark F. , Gokhan Solen
Published: July 2010

In the developing postnatal cerebral cortex, protracted generation of glia and neurons occurs and precise matching of local cell types is needed for the functional organization of regional microdomains characteristic of complex CNS tissues. Recent studies have suggested that multipotent progenitors play an important role in neural lineage elaboration during neurogenesis and gliogenesis after migration from paramedian generative zones. The presence of a separate reservoir of cerebral cortical multipotent cells under strict local environmental regulation would provide an appropriate mechanism for terminal developmental sculpting and for reconstitution of regional cellular pools after injury. We have isolated distinct pools of EGF‐ and bFGF‐responsive multipotent progenitors from the postnatal mammalian cerebral cortex independent of the subventricular zone. These progenitor populations are under tight environmental regulation by specific hierarchies of cytokine subclasses that program the progressive elaboration of intermediate lineage‐restricted progenitors and differentiated type I and II astrocytes, myelinating oligodendrocytes and neuronal subtypes that express specific neuromodulatory proteins. Neural lineage development from these cortical multipotent progenitors is a graded developmental process involving sequential induction of specific cytokine receptors, acquisition of factor responsiveness and complex lineage interdependence. The cortical multipotent progenitor pathways program the elaboration of neural lineage species with distinct cellular response properties when compared with analogous species derived from subventricular zone progenitors, indicating that the cortical multipotent cells contribute to the establishment of lineage diversity within the developing cortical cortex. In addition, the cortical multipotent cells generate dynamic intermediate progenitor pools that utilize temporally‐coded environmental cues to alter neural fate decisions. These cumulative observations suggest that postnatal cerebral cortical multipotent cells represent a novel set of progenitor pathways necessary for normal mammalian cortical maturation, and may have important implications for our understanding of a wide variety of neuropathological conditions and for the development of more effective regenerative strategies to combat these pervasive neurological disorders.
Building Brains: Neural Chimeras in the Study of Nervous System Development and Repair
Authors: Brüstle Oliver
Published: July 2010

The ability to isolate multipotential neuroepithelial precursor cells from the mammalian nervous system provides exciting perspectives for thein vitroanalysis of early nervous system development and the generation of donor cells for neural repair. New models are needed to study the properties of these cellsin vivo.Neural chimeras have revealed a remarkable degree of plasticity in the developmental potential of neuroepithelial precursor cells. Following transplantation into the cerebral ventricle of embryonic hosts, precursors derived from various brain regions and developmental stages participate in host brain development and undergo region‐specific differentiation into neurons and glia. These findings indicate that in the developing nervous system, migration and differentiation of neural precursors cells are regulated to a large extent by extrinsic signals. Neural chimeras composed of genetically modified cells will permit the study of the molecular mechanisms underlying these guidance cues, which may eventually be exploited for cell replacement strategies in the adult brain. A key problem in neural transplantation is the availability of suitable donor tissue. Neural chimeras composed of embryonic stem (ES) cell‐derived neurons and glia depict ES cells as a versatile and virtually unlimited donor source for neural repair. Generation of interspecies neural chimeras composed of human and rodent cells facilitates the translation of these advances into clinical strategies for human nervous system repair.
Comparative Biochemistry of Tau in Progressive Supranuclear Palsy, Corticobasal Degeneration, FTDP‐17 and Pick's Disease
Authors: Buée Luc , Delacourte André
Published: July 2010

Neurodegenerative disorders referred to as tauopathies have cellular hyperphosphorylated tau protein aggregates in the absence of amyloid deposits. Comparative biochemistry of tau aggregates shows that they differ in both phosphorylation and content of tau isoforms. The six tau isoforms found in human brain contain either three (3R) or four microtubule‐binding domains (4R). In Alzheimer's disease, all six tau isoforms are abnormally phosphorylated and aggregate into paired helical filaments. They are detected by immunoblotting as a major tau triplet (tau55, 64 and 69). In corticobasal degeneration and progressive supranuclear palsy, only 4R‐t.au isoforms aggregate into twisted and straight filaments respectively. They appear as a major tau doublet (tau64 and 69). Finally, in Pick's disease, only 3R‐tau isoforms aggregate into random coiled filaments. They are characterized by another major tau doublet (tau55 and 64). These differences in tau isoforms may be related to either the degeneration of particular cell populations in a given disorder or aberrant cell trafficking of particular tau isoforms. Finally, recent findings provide a direct link between a genetic defect in tau and its abnormal aggregation into filaments in fronto‐temporal dementia with Parkinsonism linked to chromosome 17, demonstrating that tau aggregation is sufficient for nerve cell degeneration. Thus, tau mutations and polymorphisms may also be instrumental in many neurodegenerative disorders.
Transgenic Models of Tauopathies and Synucleinopathies
Authors: Trojanowski John Q. , Lee Virginia M.‐Y.
Published: July 2010

Rapidly emerging concepts about the pathobiology and defining phenotypes of two major classes of neurodegenerative disease known as tauopathies and synucleinopathies are bringing these diseases into shaper focus. Significantly, recent research has substantially advanced understanding of these neurodegenerative disorders thereby providing fresh opportunities for the development of transgenic (TG) mouse models. Since the availability of such animal models will accelerate efforts to discover more effective therapies, we review the current status of efforts to generate informative TG mouse models for tauopathies and synucleinopathies and other neurodegenerative disorders characterized by prominent filamentous brain lesions.
Pineal Parenchymal Tumors: A Correlation of Histological Features with Prognosis in 66 Cases
Authors: Jouvet Anne , Saint‐Pierre Ghislaine , Fauchon François , Privat Karen , Bouffet Eric , Ruchoux MarieMagdeleine , Chauveinc Laurent , Fèvre‐Montange Michelle
Published: July 2010

The WHO classification of CNS tumors divides pineal parenchymal tumors (PPT) into pineocytoma (PC), pineoblastoma (PB) and mixed pineocytomapineoblastoma or PPT with intermediate differentiation. The reported incidence of mixed/intermediate PPT varies and this may reflect the difficulty in classifying tumors of this type. In an attempt to overcome the problem of the classification of PPT with intermediate differentiation, we describe the relationship between histological features and patient survival in a large cooperative series of 66 PPT from 12 neurosurgical centres. All tumors were studied with both light microscopy and immunohistochemically using antibodies against glial markers or neural/neuroendocrine markers. Our series included 11 PC, 39 mixed/intermediate PPT and 16 PB. A number of mitoses greater than 6 and the presence of necrosis were associated with a poorer outcome, while positive immunostaining for neurofilaments was associated with a better survival. We propose a new prognostic grading of 4 grades, grade I for PC, grade II for PPT with fewer than 6 mitoses and positive immunolabelling for neurofilaments, grade III for PPT with either 6 or more than 6 mitoses or fewer than 6 mitoses but without immunostaining for neurofilaments and grade IV for PB.
Inflammation and Stroke: Putative Role for Cytokines, Adhesion Molecules and iNOS in Brain Response to Ischemia
Authors: del Zoppo Gregory , Ginis Irene , Hallenbeck John M. , Iadecola Constantino , Wang Xinkang , Feuerstein Giora Z.
Published: July 2010

Ischemic stroke is a leading cause of death and disability in developed countries. Yet, in spite of substantial research and development efforts, no specific therapy for stroke is available. Several mechnism for neuroprotection have been explored including ionchannels, excitatory amino acids and oxygen raicals yet none has culminated in an effective therapeutic effect. The review article on “inflammation and stroke” summarizes key data in support for the possibility that inflammatory cells and mediators are important contributing and confounding factors in ischemic brain injury. In particular, the role of cytokines, endothelial cells and leukocyte adhesion molecules, nitric oxide and cyclooxygenase (COX‐2) products are discussed. Furthermore, the potential role for certain cytokines in modulation of brain vulnerability to ischemia is also reviewed.The data suggest that novel therapeutic strategies may evolve from detailed research on some specific inflammatory factors that act in spatial and temporal relationships with traditionally recognized neurotoxic factors. The dual nature of some mediators in reformatting of brain cells for resistance or sensitivity to injury demonstrate the delicate balance needed in interventions based on anti‐inflammatory strategies.
Inflammatory Mediators of Cerebral Endothelium: A Role in Ischemic Brain Inflammation
Authors: Stanimirovic Danica , Satoh Kei
Published: July 2010

Brain inflammation has been implicated in the development of brain edema and secondary brain damage in ischemia and trauma. Adhesion molecules, cytokines and leukocyte chemoattractants released/presented at the site of blood‐brain barrier (BBB) play an important role in mobilizing peripheral inflammatory cells into the brain. Cerebral endothelial cells (CEC) are actively engaged in processes of microvascular stasis and leukocyte infiltration by producing a plethora of pro‐inflammatory mediators. When challenged by external stimuli including cytokines and hypoxia, CEC have been shown to release/express various products of arachidonic acid cascade with both vasoactive and pro‐inflammatory properties, including prostaglandins, leukotrienes, and platelet‐activating factor (PAF). These metabolites induce platelet and neutrophil activation and adhesion, changes in local cerebral blood flow and blood rheology, and increases in BBB permeability. Ischemic CEC have also been shown to express and release bioactive inflammatory cytokines and chemokines, including IL‐Iβ, IL‐8 and MCP‐1. Many of these mediators and ischemia in vitro and in vivo have been shown to up‐regulate the expression of both selectin and Ig‐families of adhesion molecules in CEC and to facilitate leukocyte adhesion and transmigration into the brain. Collectively, these studies demonstrate a pivotal role of CEC in initiating and regulating inflammatory responses in cerebral ischemia.

Inflammatory genes/mediators are involved in molecular/biochemical cascades determining stroke outcome. Cerebral endothelial cells, targeted by inflammatory mediators produced in ischemic brain, undergo pro‐inflammatory activation by expressing/secreting various inflammatory mediators, thus becoming a source of inflammation themselves. A unique position of the cerebral endothelial cells at the interface between blood and brain establishes their role as principal regulators of peripheral inflammatory cell recruitment into the brain during stroke. Cerebral endothelial cells also exhibit ability to regulate vasomotor responses of brain microcirculation and the permeability of the BBB, both important components of inflammation. Therefore, approaches to attenuate consequences of stroke must take into consideration cerebral endothelial cells as an easily accessible target to interfere with the ischemic brain inflammation.
Leukocyte Recruitment and the Acute Inflammatory Response
Authors: Kubes Paul , Ward Peter A.
Published: July 2010

Leukocyte recruitment is a hallmark feature of the inflammatory response. This review summarizes the generally accepted paradigm of leukocyte recruitment based on studies using intravital microscopy to visualize the microcirculation. The role of selectins and α4‐integrin in rolling as well as integrin‐mediated adhesion is discussed. However, it is becoming increasingly clear that the recruitment cascade within organs differs and therefore the review also attempts to highlight what is and is not known regarding leukocyte recruitment into the brain microvasculature. In the second part of this review, we provide some discussion of mechanisms by which the inflammatory response may be terminated. Particular emphasis on nuclear factor NfκB and how IL10, IL13 and secreted leukocyte protease inhibitor (SLPI) may impact upon the NfκB‐dependent inflammatory response is presented.
Energy Requirement for Caspase Activation and Neuronal Cell Death
Authors: Nicotera Pierluigi , Leist Marcel , Fava Eugenio , Berliocchi Laura , Volbracht Christiane
Published: July 2010

Recent work has shown that execution of the apoptotic program involves a relatively limited number of pathways. According to a general view, these would converge to activate the caspase family of proteases. However, there is increasing evidence that apoptotic‐like features can be found also when cells are treated with inhibitors of caspases as the cell permeable tripeptide, Z‐Val‐Ala‐Asp‐fluoromethyl‐ketone (Z‐VAD‐fmk), or analogous compounds. This has posed the question as to whether apoptosis may occur in a caspase independent way, and whether caspase inhibitors may then be used to treat diseases characterised by an excess apoptosis. It is also becoming clear, that ATP depletion during the early phases of apoptosis can preclude caspase activation, and consequently switch execution of cell death towards necrosis. In vivo, a block or partial inhibition of the typical apoptotic demise may have profound implications, as persistence of damaged but “undead” cells within the nervous system, followed by delayed lysis may favour neuroinflammatory reactions. In this review, we discuss some recent findings, which suggest that cells may use diverging execution pathways, with different implications in neuropathology and therapy.
Neuroprotection by the Inhibition of Apoptosis
Authors: Robertson George S. , Crocker Stephen J. , Nicholson Donald W. , Schulz Jörg B.
Published: July 2010

Accumulating evidence strongly suggests that apoptosis contributes to neuronal cell death in a variety of neurodegenerative contexts. Activation of the cysteine protease caspase‐3 appears to be a key event in the execution of apoptosis in the central nervous system (CNS). As a result, mice null for caspase‐3 display considerable neuronal expansion usually resulting in death by the second week of life. At present, 14 caspase family members have been identified and subdivided into three subgroups on the basis of preference for specific tetrapeptide motifs using a positional scanning combinatorial substrate library. Caspase‐3 is a group II member (2, 3, 7) categorized by an absolute substrate requirement for aspartic acid in the P4 position of the scissile bond. The preferred cleavage motif (DExD) for group II caspases is found in many structural, metabolic and repair proteins essential for cellular homeostasis. Consistent with the proposal that apoptosis plays a central in role human neurodegenerative disease, caspase‐3 activation has recently been observed in stroke, spinal cord trauma, head injury and Alzheimer's disease. Indeed, peptide‐based caspase inhibitors prevent neuronal loss in animal models of head injury and stroke suggesting that these compounds may be the forerunners of non‐peptide small molecules that halt apoptosis processes implicated in these neurodegenerative disorders. A clear link between an hereditary neurodegenerative disorder and failed caspase inhibition has recently been proposed for spinal muscular atrophy (SMA). In severe SMA, the neuronal specific inhibitor of apoptosis (IAP) family member known as NAIP is often dysfunctional due to missense and truncation mutations. IAPs such as NAIP potently block the enzymatic activity of group II caspases (3 and 7) suggesting that NAIP mutations may permit unopposed developmental apoptosis to occur in sensory and motor systems resulting in lethal muscular atrophy. Conversely, adenovirally‐mediated overexpression of NAIP or the X‐linked IAP called XIAP reduces the loss of CA1 hippocampal neurons following transient forebrain ischemia. Taken together, these findings suggest that anti‐apoptotic strategies may some day have utility in the treatment of neurodegenerative disease. The present review will summarize some of the recent evidence suggesting that apoptosis inhibitors may become a practical therapeutic approach for both acute and chronic neurodegenerative conditions.
Toward an Understanding of Polyglutamine Neurodegeneration
Authors: Paulson Henry L.
Published: July 2010

Polyglutamine expansion is now recognized to be a major cause of inherited human neurodegenerative disease. The polyglutamine expansion diseases identified so far are slowly progressive disorders in which distinct yet overlapping brain regions are selectively vulnerable to degeneration. Despite their clinical differences these diseases likely share a common pathogenic mechanism, occurring at the protein level and centered on an abnormal conformation of expanded polyglutamine in the respective disease proteins. Recently there has been remarkable progress in our understanding of polyglutamine disease, but still there are many unanswered questions. In this review, I first outline some of the shared features of polyglutamine diseases and then discuss several issues relevant to an understanding of pathogenesis, paying particular attention to possible mechanisms of neurotoxicity.
Key Factors in Alzheimer's Disease: β‐amyloid Precursor Protein Processing, Metabolism and Intraneuronal Transport
Authors: Bayer Thomas A. , Wirths Oliver , Majtényi Katalin , Hartmann Tobias , Multhaup Gerd , Beyreuther Konrad , Czech Christian
Published: July 2010

During the last years it has become evident that the β‐amyloid (Aβ) component of senile plaques may be the key molecule in the pathology of Alzheimer's disease (AD). The source and place of the neurotoxic action of Aβ, however, is still a matter of controversy. The precursor of the β‐amyloid peptide is the predominantly neuronal β‐amyloid precursor protein. We, and others, hypothesize that intraneuronal misregulation of APP leads to an accumulation of Aβ peptides in intracellular compartments. This accumulation impairs APP trafficking, which starts a cascade of pathological changes and causes the pyramidal neurons to degenerate. Enhanced Aβ secretion as a function of stressed neurons and remnants of degenerated neurons provide seeds for extracellular Aβ aggregates, which induce secondary degenerative events involving neighboring cells such as neurons, astroglia and macrophages/microglia.