bluuebunny/crossref_metadata_2025 huggingface dataset:
Low Frequency of Chromosomal Imbalances in Anaplastic Ependymomas as Detected by Comparative Genomic Hybridization
Authors: Scheil Stefanie , Brüderlein Silke , Eicker Monika , Herms Jochen , Herold‐Mende Christel , Steiner Hans‐Herbert , Barth Thomas F. E. , Möller Peter
Published: July 2010

We screened 26 ependymomas in 22 patients (7 WHO grade I, myxopapillary, myE; 6 WHO grade II, E; 13 WHO grade III, anaplastic, aE) using comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). 25 out of 26 tumors showed chromosomal imbalances on CGH analysis. The chromosomal region most frequently affected by losses of genomic material clustered on 13q (9/26). 6/7 myE showed a loss on 13q14‐q31. Other chromosomes affected by genomic losses were 6q (5/26), 4q (5/26), 10 (5/26), and 2q (4/26). The most consistent chromosomal abnormality in ependymomas so far reported, is monosomy 22 or structural abnormality 22q, identified in approximately one third of Giemsabanded cases with abnormal karyotypes. Using FISH, loss or monosomy 22q was detected in small subpopulations of tumor cells in 36% of cases. The most frequent gains involved chromosome arms 17 (8/26), 9q (7/26), 20q (7/26), and 22q (6/26). Gains on 1q were found exclusively in pediatric ependymomas (5/10). Using FISH, MYCN proto‐oncogene DNA amplifications mapped to 2p23‐p24 were found in 2 spinal ependymomas of adults. On average, myE demonstrated 9.14, E 5.33, and aE 1.77 gains and/or losses on different chromosomes per tumor using CGH. Thus, and quite paradoxically, in ependymomas, a high frequency of imbalanced chromosomal regions as revealed by CGH does not indicate a high WHO grade of the tumor but is more frequent in grade I tumors.
Increased Expression of the Normal Cellular Isoform of Prion Protein in Inclusion‐Body Myositis, Inflammatory Myopathies and Denervation Atrophy
Authors: Zanusso Gianluigi , Vattemi Gaetano , Ferrari Sergio , Tabaton Massimo , Pecini Elisa , Cavallaro Tiziana , Tomelleri Giuliano , Filosto Massimiliano , Tonin Paola , Nardelli Ettore , Rizzuto Nicola , Monaco Salvatore
Published: July 2010

The cellular isoform of the prion protein (PrPc) is a glycosylphosphatidylinositol‐anchored glycoprotein, normally expressed in neural and non‐neural tissues, including skeletal muscle. In transmissible spongiform encephalopathies, or prion diseases, PrPc, which is soluble in nondenaturing detergent and sensitive to proteinase K (PK)‐treatment, represents the molecular substrate for the production of a detergent‐insoluble and PK‐resistant isoform, termed PrPSc.

In human prion diseases, PrPSc accumulation occurs only in brain tissues, with the exception of new variant Creutzfeldt‐Jakob disease, where PrPSc is also detected in lymphoid tissues.

Increased amounts of prion protein expression and deposition have been described in pathological muscle fibers of two human muscle disorders, called sporadic inclusion‐body myositis (s‐IBM) and hereditary inclusion‐body myopathy, but it is unknown whether accumulated prion protein reflects normal PrPc or PrPSc.

We investigated the biochemical characteristics of prion protein in normal human muscle, s‐IBM, other inflammatory myopathies and denervation atrophy.

We report that 1) both the glycoform profile and size of the normal muscle PrPc are different from those of human brain PrPc; 2) in addition to s‐IBM, increased PrPc expression is seen in polymyositis, dermatomyositis and neurogenic muscle atrophy, but PrPc glycoforms are unchanged; 3) only the normal PrPc isoform, and not PrPSc, is detected in s‐IBM. The present results exclude that s‐IBM is a prion disease.
Congenital Myopathies
Authors: Bornemann Antje , Goebel Hans H.
Published: July 2010

Most congenital myopathies have been defined on account of the morphological findings in enzyme histochemical preparations. In effect, the diagnosis of this group of diseases continues to be made on the histological pattern of muscle biopsies. However, progress has been made in elucidating the molecular genetic background of several of the congenital myopathies. In this updated review we address those congenital myopathies for which gene defects and mutant proteins have been found (central core disease, nemaline myopathies, desminopathy, actinopathy, certain vacuolar myopathies, and myotubular myopathy) and the other disease with central nuclei (centronuclear myopathy).
Crosstalk Between Components of the Blood Brain Barrier and Cells of the CNS in Microglial Activation in AIDS
Authors: Langford Dianne , Masliah Eliezer
Published: July 2010

During the progression of AIDS, a majority of patients develop cognitive disorders such as HIV encephalitis (HIVE) and AIDS dementia complex (ADC), which correlate closely with macrophage infiltration into the brain and microglial activation. Microglial activation occurs in response to infection, inflammation and neurological disorders including HIVE, Alzheimer's disease, Parkinson's disease and multiple sclerosis. Microglia can be activated by immunoreactive cells independent of, but enhanced by HIV infection, from at least two routes. Activation may occur from signals originating from activated monocytes and lymphocytes in the blood stream, which initiate a cascade of stimuli that ultimately reach microglia in the brain or from activated macrophages/microglia/astrocytes within the brain. Effects of microglial activation stemming from both systemic and CNS HIV infection act together to commence signaling feedback, leading to HIVE and increased neurodegeneration. Most recent data indicate that in AIDS patients, microglial activation in the brain with subsequent release of excitotoxins, cytokines and chemokines leads to neurodegeneration and cognitive impairment. Since the presence of HIV in the brain results from migration of infected monocytes and lymphocytes across the vascular boundary, the development of novel therapies aimed at protecting the integrity of the blood brain barrier (BBB) upon systemic HIV infection is critical for controlling CNS infection.
Tumor Suppressor Loss in Pituitary Tumors
Authors: Alexander Joseph M.
Published: July 2010

The current model of human neoplasia invokes a number of potential genomic alterations that impact cellular phenotype and proliferative rates. In the majority of human tumor models, the transformation from normal cells to neoplastic lesion is a multistep process. This review offers a specific overview of the involvement of tumor suppressor genes (TSGs) in the pathogenesis of human pituitary adenomas. TSG genetic lesions, such as BRCA1 in breast cancer and p53 in Li‐Fraumeni Syndrome, have been identified in both sporadic and heritable human endocrine tumors. Familial neoplastic syndromes like multiple endocrine neoplasia type 1 (MEN1) that include pituitary tumor formation as part of a broad clinical spectrum of disease represent a unique opportunity to investigate the general mechanisms of tumorigenesis, and well as genes responsible for sporadic endocrine tumors. Similarly, homologous recombination knockout mice with selectively ablated candidate TSGs have also shed light on the molecular mechanisms of pituitary cell proliferation and tumor suppression. However, despite insights into pituitary tumorigenesis generated by heritable neoplasia syndromes and mouse knockout of critical TSGs that display a pituitary tumor phenotype, the molecular pathogenesis of human pituitary adenomas remains largely an enigma. Thus, the role of TSGs, if any, in sporadic pituitary adenoma formation has yet to be determined, despite our greater understanding of the molecular mechanisms underlying pituitary cell function and phenotype.
The Role of Hormones, Growth Factors and Their Receptors in Pituitary Tumorigenesis
Authors: Ezzat Shereen
Published: July 2010

Numerous factors have been shown to govern adenohypophysial cell proliferation. Human and animal models have documented that the hypothalamic trophic hormone growth hormone‐releasing hormone stimulates cell proliferation, and prolonged stimulation leads to tumor formation. Similarly, lack of dopaminergic inhibition of lactotrophs and lack of feedback suppression by adrenal, gonadal or thyroid hormones are implicated, perhaps through hypothalamic stimulatory mechanisms, in pituitary adenoma formation superimposed on hyperplasia. However, most pituitary tumors are not associated with underlying hyperplasia. Overexpression of growth factors and their receptors, such as EGF, TGFα, EGF‐R and VEGF has been identified in pituitary adenomas, and reduction of follistatin expression has been implicated in gonadotroph adenomas. Aberrant expression of members of the FGF family, an FGF antisense gene and FGF receptors have all been described in pituitary adenomas. The clonal composition of pituitary adenomas attests to the molecular basis of pituitary tumorigenesis, however, the evidence suggests that these various hypophysiotropic hormones and growth factors likely play a role as promoters of tumor cell growth in genetically transformed cells.
Prevalence of HSV‐1 LAT in Human Trigeminal, Geniculate, and Vestibular Ganglia and Its Implication for Cranial Nerve Syndromes
Authors: Theil Diethilde , Arbusow Viktor , Derfuss Tobias , Strupp Michael , Pfeiffer Matthias , Mascolo Andrea , Brandt Thomas
Published: July 2010

Herpes simplex virus type 1 (HSV‐1) enters sensory neurons and can remain latent there until reactivation. During latency restricted HSV‐1 gene expression takes place in the form of latency‐associated transcripts (LAT). LAT has been demonstrated to be important not only for latency but also for reactivation, which may cause cranial nerve disorders.

Tissue sections of the trigeminal ganglia (TG), geniculate ganglia (GG), and the vestibular ganglia (VG) from seven subjects were examined for the presence of LAT using the in situ hybridization technique. LAT was found on both sides in all TG (100%), on both sides of five subjects (70%) in the GG, and in none of the VG. Using a second more sensitive detection method (RT‐PCR), we found LAT in the VG of seven of ten other persons (70%).

This is the first study to demonstrate viral latency in the VG, a finding that supports the hypothesis that vestibular neuritis is caused by HSV‐1 reactivation. The distribution of LAT in the cranial nerve ganglia indicates that primary infection occurs in the TG and GG and subsequently spreads along the faciovestibular anastomosis to the VG.
Evidence for Intraaxonal Spread of Listeria Monocytogenes from the Periphery to the Central Nervous System
Authors: Antal Ellen‐Ann , Løberg Else Marit , Bracht Paula , Melby Kjetil K. , Mæhlen Jan
Published: July 2010

Rhombencephalitis due to Listeria monocytogenes is characterized by progressive cranial nerve palsies and subacute inflammation in the brain stem. In this paper, we report observations made on mice infected with L. monocytogenes. Unilateral inoculation of bacteria into facial muscle, or peripheral parts of a cranial nerve, induced clinical and histological signs of mainly ipsilateral rhombencephalitis. Similarly, unilateral inoculation of bacteria into lower leg muscle or peripheral parts of sciatic nerve was followed by lumbar myelitis. In these animals, intraaxonal bacteria were seen in the sciatic nerve and its corresponding nerve roots ipsilateral to the bacterial application site. Development of myelitis was prevented by transsection of the sciatic nerve proximally to the hindleg inoculation site. Altogether, our results support the hypothesis that Listeria rhombencephalitis is caused by intraaxonal bacterial spread from peripheral sites to the central nervous system.
The Role of Oxidative Stress in the Pathophysiology of Cerebrovascular Lesions in Alzheimer's Disease
Authors: Aliev Gjumrakch , Smith Mark A. , Seyidova Dilara , Neal Maxwell Lewis , Lamb Bruce T. , Nunomura Akihiko , Gasimov Eldar K. , Vinters Harry V. , Perry George , LaManna Joseph C. , Friedland Robert P.
Published: July 2010

Alzheimer's disease (AD) and stroke are two leading causes of age‐associated dementia. A rapidly growing body of evidence indicates that increased oxidative stress from reactive oxygen radicals is associated with the aging process and age‐related degenerative disorders such as atherosclerosis, ischemia/reperfusion, arthritis, stroke, and neurodegenerative diseases. New evidence has also indicated that vascular lesions are a key factor in the development of AD. This idea is based on a positive correlation between AD and cardiovascular and cerebrovascular diseases such as arterio‐ and atherosclerosis and ischemia/reperfusion injury. In this review we consider recent evidence supporting the existence of an intimate relationship between oxidative stress and vascular lesions in the pathobiology of AD. We also consider the opportunities for therapeutic interventions based on the molecular pathways involved with these causal relationships.
Comparative Genomic Hybridization Detects An Increased Number of Chromosomal Alterations in Large Cell/Anaplastic Medulloblastomas
Authors: Eberhart Charles G. , Kratz John E. , Schuster Amy , Goldthwaite Pat , Cohen Kenneth J. , Perlman Elizabeth J. , Burger Peter C.
Published: July 2010

We correlate chromosomal changes in medulloblastomas with histologic subtype, reporting the analysis of 33 medulloblastoma specimens by comparative genomic hybridization, and a subset by fluorescence in situ hybridization. Of the 33 tumors, 5 were desmoplastic/nodular, 10 were histologically classic, and 18 were large cell/anaplastic. Chromosomal gains and losses were more common in anaplastic medulloblastomas than in non‐anaplastic ones. We identified 4 medulloblastomas with c‐myc amplification and 5 medulloblastomas with N‐myc amplification; all 9 were of the large cell/anaplastic subtype. Additional regions with high level gains included 2q14‐22, 3p23, 5p14‐pter, 8q24, 9p22‐23, 10p12‐pter, 12q24, 12p11‐12, 17p11‐12, and Xp11. The majority of these high level gains occurred in anaplastic cases. We also found loss of chromosome 17p in 7 large cell/anaplastic cases but no non‐anaplastic medulloblastomas. Finally, we detected a significantly increased overall number of chromosomal alterations in large cell/anaplastic medulloblastomas (6.8/case) compared to non‐anaplastic ones (3.3/case). These findings support an association between myc oncogene amplification, 17p loss, and large cell/anaplastic histology.
Argyrophilic Grain Disease: Neuropathology, Frequency in a Dementia Brain Bank and Lack of Relationship with Apolipoprotein E
Authors: Togo Takashi , Cookson Natalie , Dickson Dennis W.
Published: July 2010

Argyrophilic grain disease (AGD) is a recently recognized disorder whose relationship to dementia as well as genetic or biochemical features remain incompletely characterized in part due to diagnostic difficulties engendered by concomitant pathologies. In the present study, we reviewed a consecutive series of over 300 brains referred for evaluation of dementia for presence of argyrophilic grains (AGs). AGs were found in the hippocampal region and amygdala, and were accompanied by coiled bodies in the underlying white matter and ballooned neurons in the limbic lobe. Ballooned neurons were also found in the limbic lobe in a number of cases of advanced Alzheimer's disease (AD) that did not have AGs, supporting the lack of diagnostic significance of ballooned neurons confined to limbic lobe. The frequency of AGD in this series of dementia brains was 4.9% and was similar to the frequency in other autopsy series of nondemented cases, supporting the notion that there is no obligatory relationship between AGD and dementia. In the present series, ApoE E4 allele frequency of AGD was dependent on concurrent AD, with AGD cases lacking AD similar to controls and cases with concurrent AD similar to AD. This suggests that AGD is an independent disease process from AD.
Tissue Microarrays: Applications in Neuropathology Research, Diagnosis, and Education
Authors: Wang Huamin , Wang Hua , Zhang Wei , Fuller Gregory N.
Published: July 2010

Tissue microarrays (TMAs) are composite paraf‐fin blocks constructed by extracting cylindrical tissue core “biopsies” from different paraffin donor blocks and re‐embedding these into a single recipient (microarray) block at defined array coordinates. Using this technique, up to 1000 or more tissue samples can be composited into a single paraffin block. Tissue microarrays permit high‐volume simultaneous analysis of molecular targets at the DNA, mRNA, and protein levels under identical, standardized conditions on a single glass slide, and also provide maximal preservation and utilization of limited and irreplaceable archival tissue samples. This versatile technique facilitates retrospective and prospective human tissue studies, animal tissue studies, and cell line cytospin cell block studies. In this review, we present the technical aspects of TMA construction and sectioning, validation aspects of the technique, TMA advantages and limitations, and a sampling of the broad range of TMA uses in modern neuropathologic clinical diagnosis, research, and education. A specific illustration of the most widely employed and increasingly important TMA application is also presented: confirmation via TMA‐based immunohisto‐chemistry of the differential expression of a marker (IGFBP2) initially identified by gene expression pro‐filing to be overexpressed in glioblastoma.
Molecular Classification of Human Diffuse Gliomas by Multidimensional Scaling Analysis of Gene Expression Profiles Parallels Morphology‐Based Classification, Correlates with Survival, and Reveals Clinically‐Relevant Novel Glioma Subsets
Authors: Fuller Gregory N. , Hess Kenneth R. , Rhee Chang Hun , Yung W. K. Alfred , Sawaya Raymond A. , Bruner Janet M. , Zhang Wei
Published: July 2010

There are several currently employed classification systems for diffuse gliomas that sort tumors based on histological features. Contemporary molecular techniques, however, offer the promise of improved tumor classification and resultant patient stratification for treatment and prognosis. In particular, gene expression profiling has shown exceptional promise for providing an alternative and more objective molecular approach to glioma classification. In this study, we used cDNA array technology to profile the gene expression of 30 primary human glioma tissue samples comprising 4 different glioma subtypes as defined by current World Health Organization (WHO 2000) criteria: glioblastoma (GM, WHO grade IV), anaplastic astrocytoma (AA, WHO grade III), anaplastic oligodendroglioma (AO, WHO grade III), and oligodendroglioma (OL, WHO grade II). Gene expression data alone were used to group the tumors using multidimensional scaling, which is an unsupervised statistical method. Results show that impressive separation of the 4 glioma subtypes can be achieved solely on the basis of molecular data. In addition, a subcluster of 3 glioblastomas was identified as distinct from other GMs and from the oligodendroglial tumors. These 3 patients have shown extended survival compared to other GMs in the study. Survival analysis of the full data set revealed a good correlation with the molecular classification. Results of this proof‐of‐principle study demonstrate that molecular profiling alone can recapitulate conventional histologic classification and grading with high fidelity. In addition, results show that the molecular approach to tumor classification can generate clinically meaningful patient stratification, and, more importantly, is an efficient class‐discovery tool for human gliomas, permitting the identification of previously unrecognized, clinically relevant tumor subsets.
Genetic Modeling of Glioma Formation in Mice
Authors: Begemann Martin , Fuller Gregory N. , Holland Eric C.
Published: July 2010

In addition to the histological features that define gliomas, mutations and other alterations in gene expression and signal transduction are classically found in these tumors. Some of these alterations are likely to be the effects of the neoplastic phenotype, while others may be causative agents essential to the etiologic origin of the disease. The determination of whether specific genetic alterations, either individually or in combination, can serve as the etiology of gliomas requires modeling in animals with the fulfillment of Koch's postulates. Animal modeling studies not only provide information on the potential causes of glioma formation, they also identify novel candidate targets for therapy and provide tumorbearing animals for preclinical trials. Recently, remarkable strides have been made in the generation of mouse models of the diffuse gliomas that provide unparalleled opportunities for advancing our knowledge of the etiology, maintenance, and treatment of this lethal class of tumors.
Neurodevelopmental Disorders as a Cause of Seizures: Neuropathologic, Genetic, and Mechanistic Considerations
Authors: Crino Peter B. , Miyata Hajime , Vinters Harry V.
Published: July 2010

This review will consider patterns of developmental neuropathologic abnormalities—malformations of cortical development (MCD)—encountered in infants (often with infantile spasms), children, and adults with intractable epilepsy. Treatment of epilepsy associated with some MCD, such as focal cortical dysplasia and tubers of tuberous sclerosis, may include cortical resection performed to remove the “dysplastic” region of cortex. In extreme situations (eg, hemimegalencephaly), hemispherectomy may be carried out on selected patients. Neuropathologic (including immunohistochemical) findings within these lesions will be considered. Other conditions that cause intractable epilepsy and often mental retardation, yet are not necessarily amenable to surgical treatment (eg, lissencephaly, periventricular nodular heterotopia, double cortex syndrome) will be discussed. Over the past 10 years there has been an explosion of information on the genetics of MCD. The genes responsible for many MCD (eg, TSC1, TSC2, LIS‐1, DCX, FLN1) have been cloned and permit important mechanistic studies to be carried out with the purpose of understanding how mutations within these genes result in abnormal cortical cytoarchitecture and anomalous neuroglial differentiation. Finally, novel techniques allowing for analysis of patterns of gene expression within single cells, including neurons, is likely to provide answers to the most vexing and important question about these lesions: Why are they epileptogenic?
Drug‐induced Apoptotic Neurodegeneration in the Developing Brain
Authors: Olney John W. , Wozniak David F. , Jevtovic‐Todorovic Vesna , Farber Nuri B. , Bittigau Petra , Ikonomidou Chysanthy
Published: July 2010

Physiological cell death (PCD), a process by which redundant or unsuccessful neurons are deleted by apoptosis (cell suicide) from the developing central nervous system, has been recognized as a natural phenomenon for many years. Whether environmental factors can interact with PCD mechanisms to increase the number of neurons undergoing PCD, thereby converting this natural phenomenon into a pathological process, is an interesting question for which new answers are just now becoming available. In a series of recent studies we have shown that 2 major classes of drugs (those that block NMDA glutamate receptors and those that promote GABAA receptor activation), when administered to immature rodents during the period of synaptogenesis, trigger widespread apoptotic neurodegeneration throughout the developing brain. In addition, we have found that ethanol, which has both NMDA antagonist and GABAmimetic properties, triggers a robust pattern of apoptotic neurodegeneration, thereby deleting large numbers of neurons from many different regions of the developing brain. These findings provide a more likely explanation than has heretofore been available for the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome (FAS). The period of synaptogenesis, also known as the brain growth spurt period, occurs in different species at different times relative to birth. In rats and mice it is a postnatal event, but in humans it extends from the sixth month of gestation to several years after birth. Thus, there is a period in pre‐ and postnatal human development, lasting for several years, during which immature CNS neurons are prone to commit suicide if exposed to intoxicating concentrations of drugs with NMDA antagonist or GABAmimetic properties. These findings are important, not only because of their relevance to the FAS, but because there are many agents in the human environment, other than ethanol, that have NMDA antagonist or GABAmimetic properties. Such agents include drugs that may be abused by pregnant mothers (ethanol, phencyclidine [angel dust], ketamine [Special K], nitrous oxide [laughing gas], barbiturates, benzodiazepines), and many medicinals used in obstetric and pediatric neurology (anticonvulsants), and anesthesiology (all general anesthetics are either NMDA antagonists or GABAmimetics).
Mechanistic Approaches to Parkinson's Disease Pathogenesis
Authors: Betarbet Ranjita , Sherer Todd B. , Di Donato A. , Greenamyre J. Timothy
Published: July 2010

Parkinson's disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration and development of cytoplasmic proteinaceous aggregates known as Lewy bodies. Although the pathogenic mechanisms responsible for PD are not completely understood, many clues have come from biochemical, epidemiological, and genetic studies. Mutations in certain genes found in rare, familial cases of PD, such as α‐synuclein and parkin, suggest a role for the ubiquitin‐proteosome system and aberrant protein aggregation. Biochemical analyses have implicated mitochondrial dysfunction in PD. Epidemiological and animal model studies point to a role for environmental toxins, some of which are mitochondrial inhibitors. Mitochondrial dysfunction, resulting from either genetic defects, environmental exposures or an interaction between the two, may cause α‐synuclein aggregation or neurodegeneration through oxidative stress or excitotoxicity. A better understanding of the mechanisms underlying PD should reveal novel therapeutic targets.
Green Fluorescent Protein Immunohistochemistry as a Novel Experimental Tool for the Detection of Glioma Cell Invasion In Vivo
Authors: Zagzag David , Miller Douglas C. , Chiriboga Luis , Yee Herman , Newcomb Elizabeth W.
Published: July 2010

In vivo animal models of primary brain tumors are necessary to advance knowledge related to the complex interactions between glioma cells and the adjacent brain. A cardinal feature of glioma growth, and a major reason why neurosurgical and adjunctive therapies ultimately fail in most patients is their invasive properties. We have adapted a previously described animal model developed by one of us to give better histological detail while preserving the identification of single infiltrating glioma cells. GL261 glioma cells were first transfected with the plasmid encoding green fluorescent protein (GFP) and then implanted into the brains of syngeneic C57BL/6 mice. Identification of GFP‐positive tumor cells in paraffin sections of the brains of tumorbearing animals utilized an antibody for conventional immunoperoxidase immunohistochemistry. This method is a more powerful technique compared with the prior use of frozen sections and fluorescence microscopy to identify GFP‐tagged tumor cells. We find that this new method provides improved morphology and proves to be a sensitive and reliable system for detection of invading glioma cells. Using this methodology with other advanced technologies (eg, laser capture microdissection) holds out the promise of helping to elucidate the molecular mechanisms of glioma cell infiltration and invasion into the surrounding brain.
Astrocyte Activation and Apoptosis: Their Roles in the Neuropathology of HIV Infection
Authors: Sabri Farideh , Titanji Kehmia , De Milito Angelo , Chiodi Francesca
Published: July 2010

Astrogliosis is a common neuropathological finding in the brains of HIV infected individuals; both activation and apoptosis of astrocytes are seen. This review aims to discuss the Fas pathway in the context of proliferation and apoptosis of astrocytes during HIV infection, and as a result of astrogliosis, the dysregulation of astrocyte‐neuron networks. The presence of molecules reflecting astrocyte activation, which are derived from the sol‐ubilization of receptor/ligand from the surface of proliferating astrocytes, in the cerebrospinal fluid may be used to evaluate the degree of brain cell activation during HAART therapy. A better understanding of the molecular pathway(s) leading to increase activation and apoptosis of astrocytes, in parallel with studies conducted to unravel the molecules involved in T‐cell apoptosis during HIV infection, may lead to the development of new therapeutic strategies for controlling HIV replication and tissue damage.
Promoter Hypermethylation of the DNA Repair Gene O6‐Methylguanine‐DNA Methyltransferase is an Independent Predictor of Shortened Progression Free Survival in Patients with Low‐grade Diffuse Astrocytomas
Authors: Komine Chiaki , Watanabe Takao , Katayama Yoichi , Yoshino Atsuo , Yokoyama Takakazu , Fukushima Takao
Published: July 2010

The O6‐methylguanine‐DNA methyltransferase (MGMT) plays a major role in repairing DNA damage from alkylating agents. In several human neoplasms including low‐grade diffuse astrocytomas, promoter hypermethylation of MGMT has been shown to correlate with an increased frequency of p53 mutation. In the present study, we analyzed MGMT promoter methylation by the methylation‐specific PCR in 49 newly diagnosed WHO grade II astrocytomas and evaluated its clinical usefulness. MGMT promoter methylation was found in 21 (43%) of the 49 tumors. A tight correlation existed between MGMT methylation and p53 protein accumulation (P=0.0424). The presence of MGMT methylation was significantly associated with a shorter progression free survival (PFS) on both univariate analysis (P=0.0014) and multivariate analysis (P=0.0081). It was a more powerful determinant of the PFS than age, sex, performance status, proliferative activity, or p53 expression, and was independent of the extent of surgery. In terms of the overall survival, MGMT methylation demonstrated a prognostic utility in the univariate analysis but not in the multivariate analysis. The present findings indicate that aberrant methylation of the MGMT promoter independently augurs for an unfavorable clinical course in patients with low‐grade diffuse astrocytomas. Since the presence of MGMT methylation is expected to predict an increased sensitivity to alkylating chemotherapeutic agents, earlier chemotherapy could serve to improve an unfavorable natural history in tumors with MGMT methylation.
Changing Patterns in the Neuropathogenesis of HIV During the HAART Era
Authors: Langford T. D. , Letendre S. L. , Larrea G. J. , Masliah E.
Published: July 2010

Rapid progress in the development of highly active antiretroviral therapy has changed the observed patterns in HIV encephalitis and AIDS‐related CNS opportunistic infections. Early in the AIDS epidemic, autopsy studies pointed to a high prevalence of these conditions. With the advent of nucleoside reverse transcriptase inhibitors, the prevalence at autopsy of opportunistic infections, such as toxoplasmosis and progressive multifocal leukoencephalopathy, declined while that of HIV encephalitis increased. After the introduction of protease inhibitors, a decline in both HIV encephalitis and CNS opportunistic infections was observed. However, with the increasing resistance of HIV strains to anti‐retrovirals, there has been a resurgence in the frequency of HIV encephalitis and HIV leukoencephalopathy. HIV leukoencephalopathy in AIDS patients failing highly active antiretroviral therapy is characterized by massive infiltration of HIV infected monocytes/macrophages into the brain and extensive white matter destruction. This condition may be attributable to interactions of anti‐retrovirals with cerebrovascular endothelium, astroglial cells and white matter of the brain. These interactions may lead to cerebral ischemia, increased blood‐brain barrier permeability and demyelination. Potential mechanisms of such interactions include alterations in host cell signaling that may result in trophic factor dysregulation and mitochondrial injury. We conclude that despite the initial success of combined anti‐retroviral therapy, more severe forms of HIV encephalitis appear to be emerging as the epidemic matures. Factors that may contribute to this worsening include the prolonged survival of HIV‐infected patients, thereby prolonging the brain's use of increasingly toxic combinations of poorly penetrating drugs in highly antiretroviral‐experienced AIDS patients, and selection of more virulent HIV strains with higher replication rates and greater virulence in neural tissues.
Pattern of Hypocretin (Orexin) Soma and Axon Loss, and Gliosis, in Human Narcolepsy
Authors: Thannickal Thomas C , Siegel Jerome M. , Nienhuis Robert , Moore Robert Y.
Published: July 2010

Human narcolepsy is correlated with a greatly reduced number of hypocretin (orexin) containing neurons and axons, and an elevated level of hypothalamic gliosis. We now report that the percentage loss of Hcrt cells and percentage elevation of GFAP staining are variable across forebrain and brainstem nuclei, and are maximal in the posterior and tuberomammillary hypothalamic region. Regional gliosis and percent loss of hypocretin axons in narcoleptics are not correlated with regional hypocretin cell soma density in normals or with regional percent soma loss in narcoleptics. Rather they are independently and strongly correlated with the regional density of hypocretin axons and the message density for hypocretin receptor 2, as quantified in the rat. These results are consistent with the hypotheses that the loss of hypocretin function in narcolepsy results from a cytotoxic or immunologically mediated attack focused on hypocretin receptor 2 or an antigen anatomically linked to hypocretin receptor 2, and that this process is intensified in regions of high axonal density.
Neuropathology and Neurodegeneration in Rodent Brain Induced by Lentiviral Vectormediated Overexpression of α‐Synuclein
Authors: Lauwers Erwin , Debyser Zeger , Van Dorpe Jo , De Strooper Bart , Nuttin Bart , Baekelandt Veerle
Published: July 2010

Two mutations in α‐synuclein, the main constituent of Lewy bodies, have been identified in familial Parkinson's disease. We have stereotactically injected lentiviral vectors encoding wild‐type and A30P mutant human α‐synuclein in different brain regions (striatum, substantia nigra, amygdala) of mice. Overexpression of α‐synuclein induced timedependent neuropathological changes reminiscent of Lewy pathology: abnormal accumulation of α‐synuclein in cell bodies and neurites, α‐synuclein‐positive neuritic varicosities and cytoplasmic inclusions that stained with ubiquitin antibodies and became larger and more frequent with time. After one year, α‐synuclein‐ and ubiquitin‐positive neurons displayed a degenerative morphology and a significant loss of α‐synuclein‐positive cells was observed. Similar findings were observed with both the wild‐type and the A30P mutant form of α‐synuclein and this in different brain regions. This indicates that overexpression of α‐synuclein is sufficient to induce Lewy‐like pathology and neurodegeneration and that this effect is not restricted to dopaminergic cells. Our data also demonstrate the use of lentiviral vectors to create animal models for neurodegenerative diseases.
A1 Adenosine Receptors Accumulate in Neurodegenerative Structures in Alzheimer's Disease and Mediate Both Amyloid Precursor Protein Processing and Tau Phosphorylation and Translocation
Authors: Angulo Ester , Casadó Vicent , Mallol Josefa , Canela Enric I. , Viñals Francesc , Ferrer Isidre , Lluis Carmen , Franco Rafael
Published: July 2010

Immunostaining of adenosine receptors in the hippocampus and cerebral cortex from necropsies of Alzheimer's disease (AD) patients shows that there is a change in the pattern of expression and a redistribution of receptors in these brain areas when compared with samples from controls. Adenosine A1 receptor (A1R) immunoreactivity was found in degenerating neurons with neurofibrillary tangles and in dystrophic neurites of senile plaques. A high degree of colocalization for A1R and pA4 amyloid in senile plaques and for A1R and tau in neurons with tau deposition, but without tangles, was seen. Additionally, adenosine A2A receptors, located mainly in striatal neurons in controls, appeared in glial cells in the hippocampus and cerebral cortex of patients. On comparing similar samples from controls and patients, no significant change was evident for metabotropic glutamate receptors. In the human neuroblastoma SH‐SY5Y cell line, agonists for A1R led to a dose‐dependent increase in the production of soluble forms of amyloid precursor protein in a process mediated by PKC. A1R agonist induced p21 Ras activation and ERK1/2 phosphorylation. Furthermore, activation of A1R led to and ERK‐dependent increase of tau phosphorylation and translocation towards the cytoskeleton. These results indicate that adenosine receptors are potential targets for AD.
Selective Neuronal Vulnerability Following Mild Focal Brain Ischemia in the Mouse
Authors: Katchanov Juri , Waeber Christian , Gertz Karen , Gietz Andrea , Winter Benjamin , Brück Wolfgang , Dirnagl Ulrich , Veh Rüdiger W. , Endres Matthias
Published: July 2010

The evolution of cellular damage over time and the selective vulnerability of different neuronal subtypes was characterized in the striatum following 30‐minute middle cerebral artery occlusion and reperfusion in the mouse. Using autoradiography we found an increase in the density of [3H]PK11195 binding sites—likely reflecting microglial activation—in the lesion border at 3 days and in the whole striatum from 10 days to 6 weeks. This was accompanied by a distinct loss of [3H]flumazenil and [3H]CGP39653 binding sites from 10 days up to 6 weeks reflecting neuronal loss. Brain ischemia resulted in a substantial loss of medium spiny projection neurons as seen at three days by Nissl staining, TUNEL and immunocytochemistry using antibodies against microtubule‐associated protein (MAP2), NeuN, (μ‐opioid receptors, substance P, Lenkephalin, neurokinin B, choline acetyltransferase, parvalbumin, calretinin and somatostatin. Both patch and matrix compartments were involved in ischemic damage. In contrast, the numbers of cholinergic, GABAergic, and somatostatin‐containing interneurons in the ischemic striatum were not different from those in the contralateral hemisphere at 3 and 14 days. A low density of glutamate receptors, the ability to sequester calcium by calcium‐binding proteins and other hitherto unidentified factors may explain this relative resistance of interneurons to acute ischemia.
Fatal Fulminant Pan‐Meningo‐Polioencephalitis Due to West Nile Virus
Authors: Omalu Bennet I. , Shakir Abdulrazek A. , Wang Guoji , Lipkin W. Ian , Wiley Clayton A.
Published: July 2010

We report a case of fatal fulminant West Nile virus (WNV) meningoencephalitis in an 87‐year‐old white male gardener. The Pennsylvania patient presented with a 3‐day history of flu‐like symptoms. His hospital course was gravely precipitous with onset of coma, ventilator dependence, loss of cortical and brainstem functions within ten days of admission. Acute serum and cerebrospinal fluid samples revealed elevated levels of WNV IgM antibodies by ELISA as well as elevated CSF white blood cells, protein and glucose. A complete autopsy revealed a multifocal lymphocytic myocarditis and severe chronic tubulointerstitial nephritis. Viral culture and PCR analysis of post‐mortem samples of the spleen, kidney and brain were positive for WNV. Histological sections from all regions of the brain and spinal cord demonstrated a severe, non‐necrotizing, subacute, polio‐meningoencephalitis. While both gray and white matter were inflamed, gray matter was much more severely involved. Many gray matter nuclei showed severe neuronal loss with residual dying neurons surrounded by activated microglia. Immunohistochemical stains revealed profuse infiltration of the meninges and cerebral parenchyma by CD8 T‐lymphocytes and perivascular B‐lympho‐cytes. Electron micrographs revealed diffuse intracellular and extracellular edema but no viral particles were identified. Immunohistochemical and immunofluorescent staining for WNV filled the cytoplasm of residual neurons. West Nile virus mediates a predominantly polioencephalitis secondary to direct infection of neurons.
Localization of Phosphorylated ERK/MAP Kinases to Mitochondria and Autophagosomes in Lewy Body Diseases
Authors: Zhu Jian‐Hui , Guo Fengli , Shelburne John , Watkins Simon , Chu Charleen T.
Published: July 2010

We previously found that sustained ERK activation contributes to toxicity elicited by the parkinsonian neurotoxin 6‐hydroxydopamine. In addition, substantia nigra neurons from patients with incidental Lewy body disease, Parkinson's disease (PD), and diffuse Lewy body dementia (DLB) display abnormal phospho‐ERK accumulations in the form of discrete cytoplasmic granules. In this study, we investigated the subcellular localization of phospho‐ERK immunoreactive granules using double label confocal microscopy and immunoelectron microscopy. A small percentage of phospho‐ERK granules colocalized with the early endosome marker Rab5, but not with cathepsin D, 20S proteasome β‐subunit, or cytochrome P450 reductase. Phospho‐ERK immunoreactivity was often associated with mitochondrial proteins (MnSOD, 60 kDa and 110 kDa mitochondrial antigens), and some vesicular‐appearing phospho‐ERK granules appeared to envelop enlarged mitochondria by confocal laser scanning microscopy. Ultrastructural immuno‐gold studies revealed phospho‐ERK labeling in mitochondria and in association with bundles of ∼10 nm fibrils. Heavily labeled mitochondria were observed within autophagosomes. As mitochondrial pathology may play a pivotal role in Parkinson's and other related neurodegenerative diseases, these studies suggest a potential interaction between dysfunctional mitochondria, autophagy, and ERK signaling pathways.
Early‐onset Dementia with Lewy Bodies
Authors: Takao Masaki , Ghetti Bernardino , Yoshida Hirotaka , Piccardo Pedro , Narain Yolanda , Murrell Jill R. , Vidal Ruben , Glazier Bradley S. , Jakes Ross , Tsutsui Miho , Spillantini Maria Grazia , Crowther R. Anthony , Goedert Michel , Koto Atsuo
Published: July 2010

The clinical and neuropathological characteristics of an atypical form of dementia with Lewy bodies (DLB) are described. The proband experienced difficulties in her school performance at 13 years of age. Neurological examination revealed cognitive dysfunction, dysarthria, parkinsonism and myoclonus. By age 14 years, the symptoms had worsened markedly and the proband died at age 15 years. On neuropathological examination, the brain was severely atrophic. Numerous intracytoplasmic and intraneuritic Lewy bodies, as well as Lewy neurites, were present throughout the cerebral cortex and subcortical nuclei; vacuolar changes were seen in the upper layers of the neocortex and severe neuronal loss and gliosis were evident in the cerebral cortex and substantia nigra. Lewy bodies and Lewy neurites were strongly immunoreactive for α‐synuclein and ubiquitin. Lewy bodies were composed of filamentous and granular material and isolated filaments were decorated by α‐synuclein antibodies. Immunohistochemistry for tau or β‐amyloid yielded negative results. The etiology of this atypical form of DLB is unknown, since there was no family history and since sequencing of the exonic regions of α‐Synuclein, β‐Synuclein, Synphilin‐1, Parkin, Ubiquitin C‐terminal hydrolase L1 and Neurofilament‐M failed to reveal a pathogenic mutation. This study provides further evidence of the clinical and pathological heterogeneity of DLB.
Detection of Ectopic B‐cell Follicles with Germinal Centers in the Meninges of Patients with Secondary Progressive Multiple Sclerosis
Authors: Serafini Barbara , Rosicarelli Barbara , Magliozzi Roberta , Stigliano Egidio , Aloisi Francesca
Published: July 2010

Multiple sclerosis (MS) is characterized by synthesis of oligoclonal immunoglobulins and the presence of B‐cell clonal expansions in the central nervous system (CNS). Because ectopic lymphoid tissue generated at sites of chronic inflammation is thought to be important in sustaining immunopathological processes, we have investigated whether structures resembling lymphoid follicles could be identified in the CNS of MS patients. Sections from post‐mortem MS brains and spinal cords were screened using immunohistochemistry for the presence of CD20+ B‐cells, CD3+ T‐cells, CD 138+ plasma cells and CD21+, CD35+ follicular dendritic cells, and for the expression of lymphoid chemokines (CXCL13, CCL21) and peripheral node addressin (PNAd). Lymphoid follicle‐like structures containing B‐cells, T‐cells and plasma cells, and a network of follicular dendritic cells producing CXCL13 were observed in the cerebral meninges of 2 out of 3 patients with secondary progressive MS, but not in relapsing remitting and primary progressive MS. We also show that proliferating B‐cells are present in intrameningeal follicles, a finding which is suggestive of germinal center formation. No follicle‐like structures were detected in parenchymal lesions. The formation of ectopic lymphoid follicles in the meninges of patients with MS could represent a critical step in maintaining humoral autoimmunity and in disease exacerbation.
Moderate and Severe Traumatic Brain Injury: Epidemiologic, Imaging and Neuropathologic Perspectives
Authors: McArthur David L. , Chute Dennis J. , Villablanca J. Pablo
Published: July 2010

This article examines 3 contexts in which moderate or severe traumatic brain injury can be approached. The epidemiologic background of moderate and severe traumatic brain injury is presented, with particular attention paid to new findings from the study of a national hospital inpatient database. We review aspects of neuroimaging and how new imaging modalities can reveal fine detail about traumatic brain injury. Finally we examine the current state of neuropathologic evaluation of, and recent developments in, understanding of the neural disruptions that occur following traumatic brain injury, together with cellular reactions to these disruptions.
Entorhinal Cortex Lesion in the Mouse Induces Transsynaptic Death of Perforant Path Target Neurons
Authors: Kovac Adam D. , Kwidzinski Erik , Heimrich Bernd , Bittigau Petra , Deller Thomas , Nitsch Robert , Bechmann Ingo
Published: July 2010

Entorhinal cortex lesion (ECL) is a well described model of anterograde axonal degeneration, subsequent sprouting and reactive synaptogenesis in the hippocampus. Here, we show that such lesions induce transsynaptic degeneration of the target cells of the lesions pathway in the dentate gyrus. Peaking between 24 and 36 hours postlesion, dying neurons were labeled with DeOlmos silver‐staining and antisera against activated caspase 3 (CCP32), a downstream inductor of programmed cell death. Within caspase 3‐positive neurons, fragmented nuclei were co‐localized using Hoechst 33342 staining. Chromatin condensation and nuclear fragmentation were also evident in semithin sections and at the ultrastructural level, where virtually all caspase 3‐positive neurons showed these hallmarks of apoptosis. There is a well‐described upregulation of the apoptosis‐inducing CD95/L system within the CNS after trauma, yet a comparison of caspase 3‐staining patterns between CD95 (lpr)‐ and CD95L (gld)‐deficient with non‐deficient mice (C57/bl6) provided no evidence for CD95L‐mediated neuronal cell death in this setting. However, inhibition of NMD A receptors with MK‐801 completely suppressed caspase 3 activation, pointing to glutamate neurotoxicity as the upstream inducer of the observed cell death. Thus, these data show that axonal injury in the CNS does not only damage the axotomized neurons themselves, but can also lethally affect their target cells, apparently by activating glutamate‐mediated intracellular pathways of programmed cell death.