bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene Therapy for Brain Tumors
Authors: Kramm Christof M. , Sena‐Esteves Miguel , Barnett Faith H. , Rainov Nikolai G. , Schuback Deborah E. , Yu John S. , Pechan Peter A. , Paulus Werner , Chiocca E. Antonio , Breakefield Xandra O.
Published: January 2008

Gene therapy has opened new doors for treatment of neoplastic diseases. This new approach seems very attractive, especially for glioblastomas, since treatment of these brain tumors has failed using conventional therapy regimens. Many different modes of gene therapy for brain tumors have been tested in culture and in vivo. Many of these approaches are based on previously established anti‐neoplastic principles, like prodrug activating enzymes, inhibition of tumor neovascularization, and enhancement of the normally weak anti‐tumor immune response. Delivery of genes to tumor cells has been mediated by a number of viral and synthetic vectors. The most widely used paradigm is based on the activation of ganciclovir to a cytotoxic compound by a viral enzyme, thymidine kinase, which is expressed by tumor cells, after the gene has been introduced by a retroviral vector. This paradigm has proven to be a potent therapy with minimal side effects in several rodent brain tumor models, and has proceeded to phase 1 clinical trials. In this review, current gene therapy strategies and vector systems for treatment of brain tumors will be described and discussed in light of further developments needed to make this new treatment modality clinically efficacious.
The Nature, Distribution and Causes of Traumatic Brain Injury
Authors: Graham D.I. , Adams J. Hume , Nicoll J.A.R. , Maxwell W.L. , Gennarelli T.A.
Published: January 2008

The identification and interpretation of brain damage resulting from a non‐missile head injury is often not easy with the result that the most obvious structural damage identified postmortem may not be the most important in trying to establish clinico‐pathological correlations. For example patients with a fracture of the skull, quite severe cerebral contusions or a large intracranial haematoma that is successfully treated can make an uneventful and complete recovery if no other types of brain damage are present. However, not infrequently more subtle forms of pathology are present and ones that can only be identified microscopically. A systematic and pragmatic approach through the autopsy is therefore required and one that recognises the need for tissue to be retained in ways that are appropriate for cellular and molecular studies.
Role of Excitatory Amino Acid‐Mediated Ionic Fluxes in Traumatic Brain Injury
Authors: Katayama Yoichi , Maeda Takeshi , Koshinaga Morimichi , Kawamata Tatsuro , Tsubokawa Takashi
Published: January 2008

One major event taking place at the moment of traumatic brain injury in neuronal cells is the occurrence of massive ionic fluxes across the plasma membrane, which can be referred to as traumatic depolarization (TD). Unlike spreading depression, TD can occur over wide brain areas simultaneously. Furthermore, recovery from TD often takes far longer than recovery from ionic perturbation elicited by the passage of a single wave of spreading depression. Neuronal cell damage caused by ischemic brain injury is also initiated by massive ionic fluxes, termed anoxic depolarization. The occurrence of similar ionic events in these two forms of brain injury may account for the genesis of diffuse ischemia‐like damage without actual episodes of hypoxia or ischemia in traumatic brain injury. We review the data indicating that excitatory amino acids (EAA) may play a vital role in producing TD, and that such EAA‐mediated ionic perturbation is responsible for a number of posttraumatic events including subcellular metabolic dysfunction and cellular responses such as microglial activation and astrocytic transformation. TD may represent one of the most important mechanisms of diffuse neuronal cell dysfunction and damage associated with traumatic brain injury.
Cellular Responses to Experimental Brain Injury
Authors: Raghupathi Ramesh , Mclntosh Tracy K. , Smith Douglas H.
Published: January 2008

Little is known regarding the molecular (genomic) events associated with the pathophysiology of traumatic brain injury (TBI). This review focusses on the experimental efforts to date elucidating the acute alterations in expression of immediate early genes (IEGs), heat shock proteins (HSPs) and cytokines following experimental brain injury. The immediate early genes, c‐fos, c‐jun and junB were observed to be bilaterally induced in the cortex and hippocampus as early as 5 min following lateral fluid‐percussion (FP) brain injury in the rat. While levels of c‐fos and junB mRNA returned to control levels by 2h, c‐jun mRNA remained elevated up to 6h post‐injury. Increased levels of mRNA for the inducible heat‐shock protein (hsp72) were observed up to 12h following injury and were restricted to the cortex ipsilateral to the impact site. Mild induction of the glucose‐regulated proteins (grp78 and grp94), which share sequence homology with hsp72, was apparent in the ipsilateral cortex. The cytokines IL‐1β and TNFα were induced at 1h following FP brain injury and remained elevated up to 6h post‐injury. These data, while indicative of the complex genomic response to TBI, are also suggestive of the trauma‐induced activation of multiple signal transduction pathways.
The Use of Transplanted Glial Cells to Reconstruct Glial Environments in the CNS
Authors: Blakemore W.F. , Olby N.J. , Franklin R.J.M.
Published: January 2008

Transplantation studies have demonstrated that glia‐depleted areas of the CNS can be reconstituted by the introduction of cultured cells. Thus, the influx of Schwann cells into glia‐free areas of demyelination in the spinal cord can be prevented by the combined introduction of astrocytes and cells of the O‐2A lineage. Although Schwann cell invasion of areas of demyelination is associated with destruction of astrocytes, the transplantation of rat tissue culture astrocytes (“type‐1”) alone cannot suppress this invasion, indicating a role for cells of the O‐2A lineage in reconstruction of glial environments. By transplanting different glial cell preparations and manipulating lesions so as to prevent meningeal cell and Schwann cell proliferation it is possible to demonstrate that the behaviour of tissue culture astrocytes (“type‐1”) and astrocytes derived from O‐2A progenitor cells (“type‐2”) is different. In the presence of meningeal cells, tissue culture astrocytes clump together to form cords of cells. In contrast, type‐2 astrocytes spread throughout glia‐free areas in a manner unaffected by the presence of meningeal cells or Schwann cells. Thus, progenitor‐derived astrocytes show a greater ability to fill glia‐free areas than tissue culture astrocytes. Similarly, when introduced into infarcted white matter in the spinal cord, progenitor‐derived astrocytes fill the malacic area more effectively than tissue culture astrocytes, although axons do not regenerate into the reconstituted area.
Fetal Neural Grafts and Repair of the Injured Spinal Cord
Authors: Anderson Douglas K. , Howland Dena R. , Reier Paul J.
Published: January 2008

Solid or suspension grafts of fetal spinal cord (FSC), caudal brainstem (FBSt), neocortex (FNCx) or a combination of either FSC/FNCx or FSC/FBSt were placed into cavities produced by static loading (i.e., compression) of the spinal cord of adult cats two to 30 weeks after injury. Extensively vascularized, viable graft tissue was found in all animals with the exception of two cats which showed active rejection of their transplants. Surviving grafts showed many immature characteristics 6–9 weeks after transplantation. However, by 20–30 weeks FSC and FBSt grafts were more mature. Grafts integrated with the host gray and white matter and neuritic processes from both host and graft were seen crossing the host‐graft interface. Host calcitonin gene related peptide (CGRP)‐like immunoreactive axons could be traced into FSC and FBSt grafts. A more restricted ingrowth of host serotonin (5‐HT)‐like immunoreactive fibers was seen in FSC grafts. Our results suggest that the capacity of homotypic transplants to promote recovery of function is greater than heterotypic transplants. Additionally, it appears that the functional capacity of the graft depends upon graft survival, the time interval between injury and transplantation, and whether or not the lesion cavity was debrided prior to grafting.
Neuropathological Diagnostic Criteria for Creutzfeldt‐Jakob Disease (CJD) and Other Human Spongiform Encephalopathies (Prion Diseases)
Authors: Budka Herbert , Aguzzi Adriano , Brown Paul , Brucher Jean‐Marie , Bugiani Orso , Gullotta Filippo , Haltia Matti , Hauw Jean‐Jacques , Ironside James W. , Jellinger Kurt , Kretzschmar Hans A. , Lantos Peter L. , Masullo Carlo , Schlote Wolfgang , Tateishi Jun , Weller Roy O.
Published: January 2008

Neuropathological diagnostic criteria for Creutzfeldt‐Jakob disease (CJD) and other human transmissible spongiform encephalopathies (prion diseases) are proposed for the following disease entities: CJD ‐ sporadic, iatrogenic (recognised risk) or familial (same disease in 1st degree relative): spongiform encephalopathy in cerebral and/or cerebellar cortex and/or subcortical grey matter; or encephalopathy with prion protein (PrP) immuno‐reactivity (plaque and/or diffuse synaptic and/or patchy/perivacuolar types). Gerstmann‐Sträussler‐Scheinker disease (GSS) (in family with dominantly inherited progressive ataxia and/or dementia): encephalo(myelo)pathy with multicentric PrP plaques. Familial fatal insomnia (FFI) (in member of a family with PRNP178 mutation): thalamic degeneration, variable spongiform change in cerebrum. Kuru (in the Fore population).

Without PrP data, the crucial feature is the spongiform change accompanied by neuronal loss and gliosis. This spongiform change is characterised by diffuse or focally clustered small round or oval vacuoles in the neuropil of the deep cortical layers, cerebellar cortex or subcortical grey matter, which might become confluent. Spongiform change should not be confused with non‐specific spon‐giosis. This includes status spongiosus (“spongiform state”), comprising irregular cavities in gliotic neuropil following extensive neuronal loss (including also lesions of “burnt‐out” CJD), “spongy” changes in brain oedema and metabolic encephalopathies, and artefacts such as superficial cortical, perineuronal, or perivascular vacuolation; focal changes indistinguishable from spongiform change may occur in some cases of Alzheimer's and diffuse Lewy body diseases. Very rare cases might not be diagnosed by these criteria. Then confirmation must be sought by additional techniques such as PrP immunoblotting, preparations for electron microscopic examination of scrapie associated fibrils (SAF), molecular biologic studies, or experimental transmission.
Neuropathology of Early HIV‐1 Infection
Authors: Gray Françoise , Scaravilli Francesco , Everall Ian , Chretien Fabrice , An Shu , Boche Delphine , Adle‐Biassette Homa , Wingertsmann Laure , Durigon Michel , Hurtrel Bruno , Chiodi Franceses , Belli Jeanne , Lantos Peter
Published: January 2008

Early HIV‐1 invasion of the central nervous system has been demonstrated by many cerebrospinal fluid studies; however, most HIV‐1 carriers remain neurologically unimpaired during the so called “asymptomatic” period lasting from seroconversion to symptomatic AIDS. Therefore, neuropathological studies in the early pre‐AIDS stages are very few, and the natural history of central nervous system changes in HIV‐1 infection remains poorly understood. Examination of brains of asymptomatic HIV‐1 positive individuals who died accidentally and of rare cases with acute fatal encephalopathy revealing HIV infection, and comparison with experimental simian immunodeficiency virus and feline immunodeficiency virus infections suggest that, invasion of the CNS by HIV‐1 occurs at the time of primary infection and induces an immunological process in the central nervous system. This includes an inflammatory T‐cell reaction with vasculitis and leptomeningitis, and immune activation of brain parenchyma with increased number of microglial cells, upregulation of major histocompatibility complex class II antigens and local production of cytokines. Myelin pallor and gliosis of the white matter are usually found and are likely to be the consequence of opening of the blood brain barrier due to vasculitis; direct damage to oligodendrocytes by cytokines may also interfere. These white matter changes may explain, at least partly, the early cerebral atrophy observed, by magnetic resonance imaging, in asymptomatic HIV‐1 carriers. In contrast, cortical damage seems to be a late event in the course of HIV‐1 infection. There is no significant neuronal loss at the early stages of the disease, no accompanying increase in glial fibrillary acid protein staining in the cortex, and only exceptional neuronal apoptosis. Although HIV‐1 proviral DNA may be demonstrated in a number of brains, viral replication remains very low during the asymptomatic stage of HIV‐1 infection. This makes it likely that, although opening of the blood brain barrier may facilitate viral entry into the brain, specific immune responses including both neutralising antibodies and cytotoxic T‐lymphocytes, continuously inhibits viral replication at that stage.
Utrophin: A Structural and Functional Comparison to Dystrophin
Authors: Blake Derek J. , Tinsley Jonathon M. , Davies Kay E.
Published: January 2008

Utrophin is an autosomally‐encoded homologue of dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene. Although, Utrophin is very similar in sequence to dystrophin and possesses many of the protein‐binding properties ascribed to dystrophin, both proteins are expressed in an apparently reciprocal manner and may be coordinately regulated. In normal skeletal muscle, Utrophin is found at the neuromuscular junction (NMJ) whereas dystrophin predominates at the sarcolemma. However, during development, and in some myopathies including DMD, utrophin is also found at the sarcolemma. This re‐distribution is often associated with a significant increase in the levels of utrophin. At the NMJ utrophin co‐localizes with the acetylcholine receptors (AChR) and may play a role in the stabilization of the synaptic cytoskeleton. Because utrophin and dystrophin are so similar, utrophin may be able to replace dystrophin in dystrophin deficient muscle. This review compares the structure and function of utrophin to dystrophin and discusses the rationale behind the use of utrophin as a potential therapeutic agent.
Clinical and Histopathological Features of Abnormalities of the Dystrophin‐Based Membrane Cytoskeleton
Authors: Hoffman Eric P.
Published: January 2008

The majority (∼70%) of cases of childhood and adult onset muscular dystrophies in males, and ∼10% of dystrophy in girls and women, show underlying primary abnormalities of dystrophin. Approximately 2% of childhood/adult onset muscular dystrophy patients have a primary defect of one of the three sarcoglycan proteins identified to date (α, β, γ). The finding of a sarcoglycan deficiency in muscle generally does not reflect the primary underlying defect, and thus testing of biopsies for sarcoglycans should be used only after normal dystrophin findings, and in conjunction with gene mutation testing. Approximately 30% of neonatal onset congenital muscular dystrophy has been shown to be due α2‐laminin (merosin) deficiency. α2‐laminin is a component of the myofiber basal lamina, and this protein interacts with the dystrophin‐based membrane cytoskeleton. Due to the similar clinical and histopathological features of the different etiologies of muscular dystrophies, molecular testing of peripheral blood DNA and muscle biopsy protein are a critical part of the clinical work‐up of dystrophy patients. Many patients carrying a Becker dystrophy or limb‐girdle dystrophy diagnosis should be re‐evaluated with molecular tests to provide accurate genetic counseling to their families.
Cerebral Amyloid β Protein Deposits and Other Alzheimer Lesions in Non‐Demented Elderly East Africans
Authors: Ogeng'o J.A. , Cohen D.L. , Sayi J. G. , Matuja W.B. , Chande H. M. , Kitinya J. N. , Kimani U.K. , Friedland R. P. , Moris H. , Kalaria R.N.
Published: January 2008

There is little knowledge of the existence of Alzheimer disease (AD) or Alzheimer type of dementia in indigenous populations of developing countries. In an effort to evaluate this, we assessed the deposition of amyloid β (Aβ) protein and other lesions associated with AD in brains of elderly East Africans. Brain tissues were examined from 32 subjects, aged 45 to 83 years with no apparent neurological disease, who came to autopsy at two medical Institutions in Nairobi and Dar es Salaam. An age‐matched sample from subjects who had died from similar causes in Cleveland was assessed in parallel. Of the 20 samples from Nairobi, 3 (15%) brains exhibited neocortical Aβ deposits that varied from numerous diffuse to highly localized compact or neuritic plaques, many of which were also thioflavin S positive. Two of the cases had profound AS deposition in the prefrontal and temporal cortices and one of these also exhibited moderate to severe cerebral amyloid angiopathy. Similarly, 2 of the 12 samples from Dar es Salaam exhibited diffuse and compact Aβ deposits that were also predominantly reactive for the longer Aβ42 species compared to Aβ40. We also noted that Aβ plaques were variably immunoreactive for amyloid associated proteins, apolipoprotein E, serum amyloid P and complement C3. Tau protein reactive neurofibrillary tangles (NFT) were also evident in the hippocampus of 4 subjects. By comparison, 4 (20%) of the 20 samples from randomly selected autopsies performed in Cleveland showed Aβ deposits within diffuse and compact parenchymal plaques and the vasculature. These observations suggest Aβ deposition and some NFT in brains of non‐demented East Africans are qualitatively and quantitatively similar to that in age‐matched elderly controls from Cleveland. While our small scale study does not document similar prevalence rates of preclinical AD, it suggests that elderly East Africans are unlikely to escape AD as it is known in developed countries.
Hereditary Cerebral Hemorrhage with Amyloidosis‐Dutch type (HCHWA‐D): II ‐ A Review of Histopathological Aspects
Authors: Maat‐Schieman Marion LC , van Duinen Sjoerd G , Bornebroek Marjolijn , Haan Joost , Roos Raymund AC
Published: January 2008

Cerebral amyloid‐β (Aβ) angiopathy is the histopathological hallmark of hereditary cerebral hemorrhage with amyloidosis (Dutch) (HCHWA‐D). Aβ deposits are found mainly in the cerebral and cerebellar meningocortical blood vessels and as plaques throughout the cerebrocortical gray matter. Aβ deposition in arteries and arterioles starts at the junction of media and adventitia and proceeds to involve the media causing degeneration of the vascular smooth muscle cells. Cerebrocortical arterioles often show one or two layers of radial Aβ around a layer of homogenous Aβ that replaces the media. Degenerating neurites, reactive astrocytes and microglial cells may surround cerebrocortical angiopathic arterioles and capillaries, probably in reaction to invasion of the perivascular neuropil by Aβ fibrils. Furthermore, clusters of coarse extracellular matrix deposits may be found near Aβ‐laden cerebrocortical arterioles. The amyloid‐associated proteins, cystatin C, and βPP colocalize diffusely with Dutch vascular Aβ, whereas HLA‐DR immunoreactivity is found only in the periphery of the diseased vessel wall. The latter phenomenon may be related to the presence of perivascular cells. Angiopathic blood vessels frequently show structural changes. The relation of the described pathology to the development of hemorrhage, infarction and leukoencephalopathy needs further elucidation.
Brain Amyloid — A Physicochemical Perspective
Authors: Maggie John E. , Mantyh Patrick W.
Published: January 2008

The ability to form stable cross‐β fibrils is an intrinsic physicochemical characteristic of the human β‐amyloid peptide (Aβ), which forms the brain amyloid of Alzheimer's disease (AD). The high amyloidogenicity and low solubility of this hydrophobic =40‐mer have been barriers to its study in the past, but the availability of synthetic peptide and new physical methods has enabled many novel approaches in recent years. Model systems for Aβ aggregation (relevant to initial nidus formation) and Aβ deposition (relevant to plaque growth and maturation! in vitro have allowed structure/activity relationships and kinetics to be explored quantitatively, and established that these processes' are biochemically distinct. Different forms of the peptide, with different physicochemical characteristics, are found in vascular and parenchymal amyloid. Various spectroscopic methods have been used to explore the three‐dimensional conformation of Aβ both in solution and in solid phase, and demonstrated that the peptide adopts a different configuration in each state. A significant conformational transition is essential to the transformation of Aβ from solution to fibril. These observations suggest new therapeutic targets for the treatment of AD.
Peripheral Nerve Amyloidosis
Authors: Reilly Mary M , Staunton Hugh
Published: January 2008

Peripheral nerve amyloidosis is the cardinal feature of familial amyloid polyneuropathy (FAP) but can also be seen in primary light chain (AL) amyloidosis and dialysis (β2‐microglobulin) related amyloidosis. The generalized neuropathy seen in all forms of peripheral nerve amyloidosis is similar, characterized by a severe progressive mixed neuropathy with autonomic dysfunction. Pathologically, amyloid is found in the peripheral nervous system as amorphous, eosinophilic, extracellular deposits. FAP is most commonly associated with variant plasma transthyretin (TTR), although it has also been described in association with mutant apolipoprotein A‐1 and gelsolin. There are now at least 36 point mutations in the TTR gene associated with FAP and these continue to be described. Recent studies on the possible role individual point mutations in the TTR gene may play in amyloidosis have helped give us an insight into the mechanisms behind peripheral nerve amyloidosis. This article reviews the clinical and pathological features of the peripheral nerve amyloidosis and discusses theories of amyloidogenesis based on studies of FAP.
Brain Parenchymal and Microvascular Amyloid in Alzheimer's Disease
Authors: Vinters Harry V. , Wang Zhen Zhen , Secor Diana Lenard
Published: January 2008

Brains of patients with Alzheimer disease/senile dementia of Alzheimer type (AD/SDAT) develop a progressive accumulation of amyloid, which deposits primarily in the form of characteristic parenchyma!‘plaques’ (senile or neuritic plaques/SP's) and as mural deposits in the walls of capillaries and arterioles (cerebral amyloid angiopa‐thy/CAA). A major component of this amyloid is a small and unique peptide composed of 39–43 amino acids, beta/A4, which is cleaved from a much larger precursor protein (APP) that has several isoforms. Brain amyloid can be detected in autopsy or biopsy brain tissue by classical, immunohistochemical and ultrastructural (including immuno‐electron microscopic) methods of varying sensitivity and specificity. Beta/A4 amyloid deposition is remarkably variable (e.g. predominantly parenchyma! or vascular, or a mixture of parenchymal and vascular) among patients with AD/SDAT. Despite its abundance in the brains of AD/SDAT patients, the precise role of beta/A4 in the pathogenesis of the neurological deficit, neocortical atrophy and progressive synapse loss associated with AD/SDAT has yet to be determined. However, mutations in the gene that encodes APP are clearly associated with familial AD syndromes in which there is significant brain amyloid deposition. CAA, in addition to its association with AD/SDAT, can result in hemorrhagic and (possibly) ischemic forms of stroke. Work with recently developed transgenic mice which express large amounts of beta/A4 in the central nervous system is likely to elucidate mechanisms by which the protein is selectively deposited in the brain in a parenchymal or microvascular form, and how it contributes to the pathogenesis of neurodegeneration.
Overexpression of the EGF Receptor and p53 Mutations are Mutually Exclusive in the Evolution of Primary and Secondary Glioblastomas
Authors: Watanabe Kunihiko , Tachibana Osamu , Sato Kazufumi , Yonekawa Yasuhiro , Kleihues Paul , Ohgaki Hiroko
Published: January 2008

Glioblastoma multiforme, the most malignant human brain tumor, may develop de nova (primary glioblastoma) or through progression from low‐grade or anaplastic astrocytoma (secondary glioblastoma). We present further evidence that primary and secondary glioblastomas constitute distinct disease entities which develop through the acquisition of different genetic alterations. We analyzed p53 mutations, p53 protein accumulation and epidermal growth factor receptor (EGFR) overexpression in 49 biopsies classified as primary or secondary glioblastorna according to clinical and histopathologic criteria. Patients with primary glioblastoma were selected on the basis of a clinical history of less than 3 months and histopathologic features of glioblastoma at the first biopsy 119 cases; mean age, 55 years). The diagnosis of secondary glioblastomas required at least two biopsies and clinical as well as histologic evidence of progression from low grade or anaplastic astrocytoma (30 cases; mean age, 39 years). DNA sequence analysis showed that p53 mutations were rare in primary glioblastomas (11%) while secondary glioblastomas had a high incidence of p53 mutations (67%), of which 90% were already present in the first biopsy. The incidence of p53 protein accumulation (nuclear immunoreactivity to PAb 1801) was also lower in primary (37%) than in secondary glioblastornas (97%). In contrast, immunoreactivity for the EGF receptor prevailed in primary glioblastornas (63%) but was rare in secondary glioblastornas (10%). Only one out of 49 glioblastomas showed EGFR overexpression and a p53 mutation. These data indicate that overexpression of the EGF receptor and mutations of the p53 tumor suppressor gene are mutually exclusive events defining two different genetic pathways in the evolution of glioblastoma as the common phenotypic endpoint.
Neuronal Ceroid‐Lipofuscinosis ‐ Late‐Infantile or Jansky‐Bielschowsky Type ‐ Revisited
Authors: Goebel Hans H. , Gerhard Lieselotte , Kominami Eiki , Haltia Matti
Published: January 2008

The tissues from three patients with late‐infantile NCL originally described by Max Bielschowsky became available to apply modern techniques such as fluorescence microscopy, electron microscopy and immunohistochernistry. While regular tinctorial preparations of the tissues documented a neuronal storage disorder in all three patients' tissues, the accumulated material proved to be autofluorescent, showed the ultrastructure of curvilinear lipopig‐ments, and reacted strongly with an antibody against the subunit‐C of mitochondrial ATP syn‐thase, a major component of lipopigments in NCL and also with an antibody against sphingolipid activator proteins. Thus, these modern morphological techniques demonstrated that the originally described three siblings with late‐infantile “amau‐rotic familial idiocy” really had neuronal ceroid‐lipo‐fuscinosis of the late‐infantile or Jansky‐Bielschowsky type, according to current diagnostic criteria. This type of archival study may also contribute to the mosaic of medical history.
Biochemistry of Demyelination
Authors: Cuzner M. L. , Norton W. T.
Published: January 2008

The myelin sheath, a lipid‐rich multilamellar membrane of relative stability, both insulates and enhances conduction in nerve axons. A notable feature of myelin‐specific proteins, in particular myelin basic protein, is their susceptibility to prote‐olytic activity and their encephalitogenicity, which induces inflammatory demyelination in the CNS. The final common pathway of myelin breakdown in viva is well documented and there is evidence that myelin disruption can be mediated directly by soluble (circulating) factors and for following receptor‐driven phagocytosis by macrophages. However the exact mechanism(s) of demyelination in multiple sclerosis is still unresolved, both antigen‐specific and ‐ non‐specific events having the potential to generate the myelinolytic process.
Lymphocyte Targeting of the Central Nervous System: A Review of Afferent and Efferent CNS‐Immune Pathways
Authors: Weller Roy O. , Engelhardt Britta , Phillips Marian J.
Published: January 2008

The central nervous system (CNS) is considered to be an immunological privileged site. However, inflammatory reactions in response to virus infections, in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAEl suggest that there are definite connections between the CNS and the immune system. In this review, we examine evidence for afferent and efferent pathways of communication between the CNS and the immune system, the pivotal role of regional lymph nodes in T‐cell mediated autoimmune disease of the CNS, and the factors involved in lymphocyte targeting of the CNS. Afferent pathways of lymphatic drainage of the brain are well established in a variety of species, especially rodents. Fluid and antigens appear to drain along perivascular spaces populated by immunocompetent perivascular cells. Drainage pathways connect directly via the cribriform plate to nasal lymphatics and cervical lymph nodes. Soluble antigens draining from the brain induce antibody production in the cervical lymph nodes. Using a model of cryolesion‐enhanced EAE, we review the role of lymphatic drainage and cervical lymph nodes in the enhancement of cerebral EAE. If a brain wound in the form of a cryolesion is produced 8 days post inoculation (dpi) of antigen in the induction of acute EAE, there is a 6‐fold increase in severity of cerebral EAE by 15 dpi. Removal of the cervical lymph nodes significantly reduces such enhancement of EAE. These findings suggest that drainage of antigens from the brain to the cervical lymph nodes, in the presence of activated lymphocytes in the meninges or CNS, resuIts in an enhanced second wave of lymphocytes targeting the brain. In examining the efferent immune pathway by which lymphocytes home to the CNS, several studies have characterized the phenotype of infiltrating T lymphocytes by the use of immunocy‐tochemistry or FACS analysis. T‐cells infiltrating the CNS are recently activated/memory lymphocytes typified by their high expression of CD44, LFA‐1 and ICAM‐1 and low expression of CD45RB in the mouse. Following the induction of EAE in susceptible mice, ICAM‐1 and VCAM‐1 are dramatically upregulated on CNS vessels; lymphocytes bind to such vessels via the interaction of their known ligands, LFA‐1/Mac‐1 and 1times4‐integrins, at least in vitro. It appears that 1times4‐integrin plays a key role in lymphocyte recruitment across the blood‐brain barrier and may be a major factor in lymphocyte targeting of the CNS. Definition of factors involved in the afferent and efferent connections between the CNS and the immune system may clarify mechanisms involved in immune privilege of the CNS and may open significant therapeutic opportunities for multiple sclerosis.
Animal Models of Demyelination
Authors: Bradl M. , Linington C.
Published: January 2008

Demyelination is a pathological feature that is characteristic of many diseases of the central nervous system (CNS) including multiple sclerosis (MS), sub‐acute sclerosing panencephalomyelitis (SSPE), metachromatic leukodystrophy and Pelizaeus‐Merzbacher disease. While demyelination is a pathological end‐point that is common to all of these diseases, the cellular and molecular mechanisms responsible for this pathology are very different. These range from genetic defects that affect lipid metabolism in the leukodystrophies, cytopathic effects of viral infection in SSPE to the action of immunological effector mechanisms in MS and the viral encephalopathies. Irrespective of the initial cause of myelin degradation, many of these disorders are associated with some degree of CNS inflammation, as indicated by the local activation of microglia, recruitment of macrophages or the intrathecal synthesis of immunoglobulin. Many of these phenomena are now being duplicated in animal models, providing not only new insights into the pathogenesis of human demyelinating diseases, but also unexpected interrelationships between the immune response in the CNS and the pathogenesis of diseases such as Alzheimers disease and HIV encephalopathy. Autoimmune mediated models of inflammatory demyelinating CNS disease have proved particularly valuable in this respect as they allow the effects of defined immune effector mechanisms to be studied in the absence of CNS infection.
Localization of Tuberous Sclerosis 2 mRNA and its Protein Product Tuberin in Normal Human Brain and in Cerebral Lesions of Patients with Tuberous Sclerosis
Authors: Kerfoot Christopher , Wienecke Ralf , Menchine Michael , Emelin Jessica , Maize John C. , Welsh Cynthia T. , Norman Margaret G. , DeClue Jeffrey E. , Vinters Harry V.
Published: January 2008

Tuberous sclerosis (TSC), an autosomal dominant disorder, is characterized by malformations, hamartomas and tumors in various organs including the brain. TSC is genetically linked to two loci: TSC1 on chromosome 9q34 and TSC2 on 16p13.3. TSC2 has been cloned, sequenced and encodes a protein (tuberin) which functions as a tumor suppressor. We have analyzed the distribution of TSC2 mRNA and tuberin in the brains of TSC patients and non‐affected individuals using both autopsy and biopsy material. High levels of transcript and protein expression were observed in choroid plexus epithelium, ependymal cells, most brainstem and spinal cord motor neurons, Purkinje cells and the external granule cell layer of the cerebellum in both TSC and control cases. Individual balloon cells from TSC patients showed very faint expression while other glia showed no expression of either transcript or tuberin. Neocortical and hippocampal neurons expressed high levels of TSC2 transcript, but only modest levels of tuberin. The internal granule cell layer of the cerebellum expressed abundant transcript but low levels of tuberin. These observations suggest either that tuberin expression is controlled at the level of both transcription and translation or the antibody and in‐situ hybridization recognize different splice variants of the TSC2 gene. In TSC patients, dysmorphic cytomegalic neurons expressed high levels of tuberin and transcript, particularly when in an ‘ectopic’ location. Individual cells within subependymal giant cell astrocytomas (SEGAs) and hamartomas from TSC patients expressed moderate to high levels of TSC2 transcript and tuberin. While the TSC2 transcript is widely expressed primarily within neurons, tuberin is demonstrable primarily within dysplastic/cytomegalic cells of the cortex and subependymal hamartomas/SEGAs. CIMS expression of tuberin is unique in that primarily non‐dividing cells express it in this location, whereas extra‐CNS expression of tuberin is mainly found in actively proliferating cell types such as epithelium.
Review: Creutzfeldt‐Jakob Disease
Authors: Ironside J. W.
Published: January 2008

The clinicopathological spectrum of Creutzfeldt‐Jakob disease has recently been extended by the identification of an apparently new variant of this disorder in the UK. The hypothesis that this new disorder is causally related to the transmissible agent responsible for bovine spongiform encephalopathy has prompted re‐evaluation of the relationships between human and animal transmissible spongiform encephalopathies, and reinforced the need for adequate experimental models to investigate this field. Recent experimental transmission studies of bovine spongiform encephalopathy into primates have supported the hypothesis, and reinforced the central role of neuropathology in the investigation of this group of diseases. Whilst clearly of distinctive etiology, Creutzfeldt‐Jakob disease shares both clinical and neuropathological features with other human dementias; renewed evaluation of potentially similar disease mechanisms in these devastating conditions might provide new information of both scientific and therapeutic value.
Programmed Cell Death in the Developing Nervous System
Authors: Burek Michael J. , Oppenheim Ronald W.
Published: January 2008

Virtually all cell populations in the vertebrate nervous system undergo massive “naturally‐occurring” or “programmed” cell death (PCD) early in development. Initially neurons and glia are overproduced followed by the demise of approximately one‐half of the original cell population. In this review we highlight current hypotheses regarding how large‐scale PCD contributes to the construction of the developing nervous system. More germane to the theme of this symposium, we emphasize that the survival of cells during PCD depends critically on their ability to access “trophic” molecular signals derived primarily from interactions with other cells. Here we review the cell‐cell interactions and molecular mechanisms that control neuronal and glial cell survival during PCD, and how the inability of such signals to suppress PCD may contribute to cell death in some diseases such as spinal muscular atrophy. Finally, by using neurotrophic factors (e.g. CNTF, GDNF) and genes that control the cell death cascade (e.g. Bcl‐2) as examples, we underscore the importance of studying the mechanisms that control neuronal and glial cell survival during normal development as a means of identifying molecules that prevent pathology‐induced cell death. Ultimately this line of investigation could reveal effective strategies for arresting neuronal and glial cell death induced by injury, disease, and/or aging in humans.
Axotomy as an Experimental Model of Neuronal Injury and Cell Death
Authors: Koliatsos Vassilis E. , Price Donald L.
Published: January 2008

Axonal transaction provides very useful paradigms to study cellular responses to injury, mechanisms of regeneration and plasticity, and processes that lead to nerve cell degeneration. Moreover, models of axotomy are valuable for testing experimental therapeutic approaches. Lesions can be made with great precision, and, depending on the neural system, location of the lesion, and age of the animal, these models allow the opportunity to examine a range of neuronal responses. Many parameters influence the character, evolution, and outcomes of axotomy‐related processes. The most severe outcome of axotomy is cell death, very common in lesions of neurons of the central nervous system (CNS), although neurons of the peripheral nervous system (PNS) may also die if the transection is sufficiently close to the neuronal cell body or if lesions are performed in young animals. Studies of axotomy models have provided clues into the cellular/molecular events associated with neuronal death and the ways in which interventions can delay or prevent processes that lead to cell death. In this review, we select examples, primarily from our own work, to illustrate how axotomy models have enhanced our understanding of neuronal responses to injury, clarified mechanisms of both regeneration/plasticity and degeneration / cell death, and allowed assessments of the utility of therapeutic approaches.
Neuropathogenesis of Chimeric Simian/Human Immunodeficiency Virus infection In Pig‐tailed and Rhesus Macaques
Authors: Raghavan Ravi , Stephens Edward B , Joag Sanjay V , Adany Istvan , Pinson David M , Li Zhuang , Jia Fenglan , Sahni Manisha , Wang Chunyang , Leung Kevin , Foresman Larry , Narayan Opendra
Published: January 2008

We recently reported that a chimeric simian/human immunodeficiency virus (SHIVKU‐1) developed in our laboratory caused progressive depletion of CD4+T lymphocytes and AIDS within 6 months of inoculation into pig‐tailed macaques (M.nemestrina). None of the pig‐tailed macaques showed productive SHIV infection in the central nervous system (CNS). In this report, we show that by further passage of the pathogenic virus in rhesus macaques [M. mulatta], we have derived a new strain of SHIV (SHIVKU‐2) that has caused AIDS and productive CNS infection in 3 of 5 rhesus macaques infected with the virus. Productive replication of SHIV in the CNS was clearly shown by high infectivity titers and p27 protein levels in brain homogenates, and in 2 of the 3 rhesus macaques this was associated with disseminated, nodular, demyelinating lesions, including focal multinucleated giant cell reaction, largely confined to the white matter. These findings were reminiscent of HIV‐1 associated neurological disease, and our immunohistochemical and in situ hybridization data indicated that the neuropathological lesions were associated with the presence of SHIV‐specific viral antigens and nucleic acid respectively. However, the concomitant reactivation of opportunistic infections in these macaques suggested that such pathogens may have influenced the replication of SHIV in the CNS, or modified the neuropathological sequelae of SHIV infection in the rhesus species, but not in pig‐tailed macaques. Our findings in the two species of macaques highlight the complexities of lentiviral neuropathogenesis, the precise mechanisms of which are still elusive.
Association of EGFR Gene Amplification and CDKN2 (p16/MTS1) Gene Deletion in Glioblastoma Multiforme
Authors: Hayashi Yutaka , Ueki Keisuke , Waha Andreas , Wiestler Otmar D. , Louis David N. , von Deimlina Andreas
Published: January 2008

Glioblastoma multiforme (GBM) can be divided into genetic subsets: approximately one‐third of GBM, primarily in older adults, have EGFR amplification; another one‐third, primarily in younger adults, have TP53 mutation. The majority of GBM also have homozygous deletions of the CDKN2 (p16/MTS1) gene, resulting in cell cycle deregulation and elevated proliferation indices. We evaluated the relationship between CDKN2 deletions and the GBM subsets as defined by EGFR amplification or TP53 mutation in 70 GBM. Twenty‐eight cases (40%) had EGFR amplification, 21 (30%) had TP53 mutation, and 21 (30%) had neither change. CDKN2 deletions were present in 36 (51%) GBM. Of the 28 GBM with EGFR amplification, 20 (71%) had CDKN2 deletion (p = 0.0078). The remaining 16 cases with CDKN2 loss were divided between GBM with TP53 mutations (6 cases) and GBM with neither EGFR amplification nor TP53 mutation (10 cases). Thus, CDKN2 deletions occur twice as commonly in GBM with EGFR amplification (71%) than in GBM with TP53 mutation (29%). CDKN2 deletions occurred in GBM from patients somewhat older than those patients with GBM lacking CDKN2 deletion (mean age 53 vs. 48 years). Specifically among GBM with EGFR amplification, those with CDKN2 deletions also occurred in patients slightly older than those few GBM without CDKN2 deletions (mean age 55 vs. 51 years). The presence of CDKN2 deletions in most GBM with EGFR amplification and in generally older patients may provide one explanation for the potentially more aggressive nature of such tumors.
Clinical Aspects of CAG Repeat Diseases
Authors: Nance Martha A.
Published: January 2008

Seven neurodegenerative disorders are known to be caused by unstable expansions of the trinucleotide CAG within human genes, and more will be discovered in the coming years. These disorders share some clinical similarities, as well as some differences, which are summarized here. These diseases have unusual clinical genetic properties related to the dynamic nature of CAG repeat expansions, including instability of the repeat expansion in meiosis, particularly male meiosis; a strong correlation between onset age and size of the repeat expansion; anticipation (earlier disease onset in succeeding generations); new mutations arising from unstable, mutable alleles with a high‐normal CAG repeat number; and reduced penetrance for alleles in the lowaffected range. Much more remains to be learned about the molecular biology and clinical pathophysiology of this new class of genetic diseases.

In the last six years, seven neurodegenerative diseases have been found to be caused by expansions of intragenic CAG repeat sequences. The diseases share a variable (usually adult) age of onset, which is highly dependent on the length of the CAG repeat, and effects on multiple systems within the central and peripheral nervous systems. The cerebral cortex is not a primary site of pathology for any of the diseases, and organs other than the nervous system are not primarily affected (except for SBMA). The diseases differ in their primary site of neuropathology, and for that reason have widely varying neurologic profiles. The distributions of normal and abnormal CAG repeat sizes vary among the diseases, and suggest that different mechanisms of mutagenesis or disease pathogenesis could exist for the different disorders.

The dynamic nature of trinucleotide repeat mutations has clarified a number of clinical and genetic observations in these diseases. New mutations arising from mutable normal alleles have been reported for some of the diseases. The tendency to further expansion of an expanded allele provides a molecular correlate to the clinical observation of anticipation (171). Sex‐ and disease‐dependent meiotic instability correlates with the observation of a paternal bias among juvenile onset cases for HD, SCA1 and DRPLA. Finally, reduced penetrance for alleles at the low end of the abnormal range has been observed for some (but not all) diseases in the group. Detection of CAG repeat expansions is relatively easy and inexpensive in the clinical laboratory, and molecular diagnosis has greatly improved diagnostic accuracy for this group of disorders. However, a full understanding of the biology and pathophysiology of this new class of mutations is still to come, and is awaited eagerly by clinicians and patients alike.
March 1997‐4 Year Old Girl with Ring Chromosome 22 and Brain Tumor
Authors: Rubio Ana
Published: January 2008

Case Abstract

A four year old Caucasian girl with a constitutional ring chromosome 22 abnormality and developmental delay presented with increasing ataxia and a six week history of non‐specific symptoms. Imaging studies demonstrated a large third ventricular tumor with apparent involvement of the septum. Microscopic and immunohistochemical studies demonstrated an atypical teratoid/rhabdoid tumor. This tumor is compared and contrasted to peripheral malignant rhabdoid tumors and central primitive neuroectodermal tumors. The role of a putative tumor suppressor gene on the long arm of chromosome 22 in the pathogenesis of these tumors is also discussed.