bluuebunny/crossref_metadata_2025 huggingface dataset:
Hereditary Lewy‐Body Parkinsonism and Evidence for a Genetic Etiology of Parkinson's Disease
Authors: Duvoisin Roger C. , Johnson William G.
Published: January 2008

The first systematic genetic study of Parkinson's disease (PD) was carried out by Mjönes in 1949. His results indicated autosomal dominant transmission with 60% penetrance. These conclusions, however, were long discounted because oligosymptomatic and atypical relatives were counted as secondary cases without clear justification. Subsequent surveys of patient and twin studies failed to confirm evidence of familial concentration and the hypothesis of a genetic etiology was over‐shadowed by interest in possible environmental neurotoxins. A growing accumulation of pedigrees of histologically confirmed Lewy‐body PD over the past several years has refocused attention on genetic factors. Fluorodopa positron emission tomagraphy (PET) studies in oligosymptomatic co‐twins of probands and recent clinicopathologic studies of atypical cases have provided retrospective support for Mjönes' methodology.

A survey of a personal series of PD patients showed that the majority of those for whom pedigree information was available were familial. This along with another recently reported series confirm Mjönes' data showing similar segregation ratios for siblings and parents, a low ratio of maternal: paternal transmission and a marked asymmetry in the distribution of ancestral secondary cases. These findings favor monogenic autosomal dominant inheritance and show reason to argue against a multifactorial etiology or heteroplasmy.

The clinical evidence justifies searching for gene loci linked to PD. Available methods are briefly outlined.

Preliminary investigations have examined possible allelic associations, e.g., with alleles of MAO‐A and debrisoquine hydroxylase and linkage to the tyrosine hydroxylase gene on chromosome 11p15.5 has been excluded in one study of juvenile familial parkinsonism. Linkage mapping studies are presently underway.
Microglial Reaction in the Rat Cerebral Cortex Induced by Cortical Spreading Depression
Authors: Gehrmann Jochen , Mies Guenter , Bonnekoh Petra , Banati Richard , Iijima Takehiko , Kreutzberg Georg W. , Hossmann Konstantin‐Alexander
Published: January 2008

The response of microglial cells to cortical spreading depression (CSD) was studied in rat brain by immunocytochemistry. CSD was elicited for one hour by the topical application of 4M potassium chloride solution and the microglial reaction examined immunocytochemically after 4, 16, 24 and 72 hours. CSD was sufficient to induce a microglial reaction throughout the cortex at 24 hours. Activated microglial cells furthermore showed a striking de‐novo expression of major histocompatibility complex class II antigens. In contrast, no microglial reaction was observed in the cortex of sham‐operated animals. This microglial reaction in response to CSD was not associated with histologically detectable neuronal damage. These results support the view that microglial cells are extremely sensitive to changes of the brain microenvironment. Their activation may be related to changes of ion homeostasis in the brain which are not sufficient to trigger neuronal injury.
The Molecular and Cellular Biology of Tau
Authors: Kosik Kenneth S.
Published: January 2008

Tau protein was a well‐studied molecule before it was discovered in the Alzheimer neurofibrillary tangles. As a microtubule‐associated protein (MAP), it continues to be of interest to microtubule biologists who have provided a rather rich knowledge about this protein. Recent work suggests that tau, a neuronal MAR is capable of generating some features of an axonal shape and an axon‐like organization of the cytoskeleton. The importance of tau in pathology stems from its relationship to Alzheimer paired helical filaments and dystrophic neurites. Tau was first believed to be a component of paired helical filaments based upon immunocytochemical grounds (1–6) and then conclusively demonstrated by protein chemical techniques (7–9). Most recently it was shown that bacterially expressed tau fragments from the microtubule‐binding domain can self‐assemble into paired helical filaments that resemble those from the Alzheimer brain (10).
Inherited Neuropathies: The Interface between Molecular Genetics and Pathology
Authors: Thomas P.K. , Harding A.E.
Published: January 2008

The purpose of this symposium is to review advances in inherited neuropathies, with particular emphasis on disorders where molecular genetic techniques have made a recent impact. As can be seen in the Table, this is particularly the case in familial amyloidoses and hereditary motor and sensory neuropathies (HMSN). Two of the articles in this series deal with the pathology of the latter disorders (see Hahn and Gabreël‐Festen and Gabreëls); the authors will take the opportunity to review recent genetic data on HMSN here, as well as that pertaining to other inherited neuropathies associated with rearrangements of DNA, hereditary liability to pressure palsies and X‐linked bulbospinal neuron‐opathy, which are not covered elsewhere in the symposium. Other reviews discuss mitochondrial diseases (Schröder), familial amyloides (Reilly and King) and herditary sensory neuropathies (Thomas).
Hereditary Demyelinating Motor and Sensory Neuropathy
Authors: Gabreëls‐Festen Anneke , Gabreëls Fons
Published: January 2008

The demyelinating hereditary motor and sensory neuropathies (HMSN) are a group of inherited progressive neuropathies with markedly decreased nerve conduction velocity and chronic segmental demyelination in the peripheral nerve. Inheritance is autosomal dominant (AD) or autosomal recessive (AR). Autosomal dominant demyelinating HMSN (AD HMSN type I) is genetically heterogeneous and at least three different gene loci have been identified: a locus on chromosome 17 (HMSN Ia), a locus on chromosome 1 (HMSN Ib) and a locus not linked to chromosome 17 or 1 (HMSN nonla‐nonlb). HMSN type la is the most common form of AD HMSN. Recently, it has been demonstrated that the HMSN la phenotype results either from a duplication of chromosome 17p11.2 or from a point mutation in the peripheral nerve‐specific PMP‐22 gene which is located in the duplication. Pathology of type la is dominated by chronic segmental demyelination with classical onion bulbs. Autosomal recessive demyelinating HMSN shows a broad spectrum of pathological features. The genetic defect or defects are not yet known. On the basis of morphological characteristics we were able to discern four subtypes. Two AR subtypes are clinically and electro‐physiologically comparable to AD HMSN type I, namely AR HMSN type I with basal lamina onion bulbs and AR HMSN type I with focally folded myelin. Two AR subtypes with amyelination, respectively or hypomyelination of the peripheral nerves are also more severely affected both clinically and electrophysiologically and could be designated as HMSN type III. A third condition with a HMSN type III phenotype shows mainly classical onion bulbs in peripheral nerves, but the inherited nature of this disorder is uncertain and identical features have been described in steroid‐responsive inflammatory demyelinating neuropathy. The morphologically based subtypes of AR demyelinating HMSN may represent different genetic disorders, allelic differences or phenotypic variations.
In Memory of Takao Hoshino (1932–1993)
Authors: Wilson Charles B.
Published: January 2008

Internationally respected medical researcher and educator Takao Hoshino, M.D., Professor of Neurological Surgery at the University of California, San Francisco (UCSF) died of gastrointestinal cancer on Wednesday, January 21, 1993, at his home in Tokyo, Japan. He was 55 years old.
A Correlative Study of p53 Protein Alteration and p53 Gene Mutation in Glioblastoma Multiforme
Authors: Newcomb Elizabeth W. , Madonia William J. , Pisharody Sobha , Lang Frederick F. , Koslow Maxim , Miller Douglas C.
Published: January 2008

The p53 tumor suppressor gene is frequently mutated in glioblastomas. Mutations within the p53 gene often result in aberrant expression of the p53 protein leading to protein accumulation within the nucleus of the cells which can be detected by immunochemistry. Many studies have correlated alterations of p53 protein expression with p53 gene mutations. Positive staining of tumor cells for p53 protein has been widely assumed, perhaps incorrectly, to signify the presence of p53 gene mutations. This study compared the immunostaining patterns for p53 protein in 37 glioblastomas with the molecular genetic data obtained by the single strand conformation polymorphism assay. p53 gene mutations were detected in 46% (17 of 37) of glioblastomas, while 65% (24 of 37) of glioblastomas were positive for protein accumulation by immunohistochemistry. Although 30 of 37 glioblastomas analyzed showed concordance for p53 protein expression and p53 gene mutations, a subset of seven glioblastomas showed discordant accumulation of the p53 protein in the absence of any detectable p53 gene mutations. The mdm‐2 gene was assessed in 17 glioblastomas for gene rearrangements or amplification, but none were found. This result suggests that a mechanism other than p53 gene mutation can result in altered p53 protein expression.
Detection of Viral DNA in Neonatal Herpes Encephalitis Autopsy Tissues by Solution‐Phase PCR: Comparison with Pathology and Immunohistochemistry
Authors: Gressens Pierre , Langston Claire , Mitchell William J. , Martin John R.
Published: January 2008

To detect DNA sequences of herpes simplex virus (HSV) in neural and non‐neural tissue sections in disseminated human neonatal HSV infection, a solution polymerase chain reaction (PCR) protocol was developed which amplified HSV thymidine kinase and host genomic DNA sequences that were hybridized with sequence‐specific probes in Southern blots. Serial sections of formalin‐fixed, paraffin embedded autopsy tissues were tested by PCR and compared to histology and HSV antigen detection. The sensitivity, specificity and reproducibility of this PCR protocol were determined on uninfected and HSV‐infected mouse tissues and on HSV DNA from infected tissue culture cells. Samples estimated to contain as few as 60 copies of preserved HSV DNA target sequence gave a positive PCR result. In nine neonates that died during acute HSV infection, all non‐neural tissues and a minority of neural tissues with histological lesions had HSV antigen; when DNA could be amplified, HSV DNA sequences were detected by PCR. Together, these findings indicate a direct role for virus in the pathogenesis of these lesions. In the same cases, some or all brain samples were negative for HSV antigen, but nevertheless had HSV DNA sequences detected by PCR. The possible explanations for this finding are discussed. In one neonate dying seven weeks after birth, HSV sequences were found in brain lesions in the absence of HSV antigen; neither HSV DNA nor antigen were found in non‐neural tissues, suggesting a latent HSV infection in brain. It is practical to apply PCR methods to detect minute quantities of viral DNA in formalin‐fixed, paraffin embedded autopsy tissues. With careful selection of conditions, suitable controls and meticulous attention to technique, specific results can be obtained, and can be correlated with histology and immunohistochemical observations.
Brain Tumours: Morphological Aspects and Classification
Authors: Fields W.S.
Published: January 2008

In early 1987, I was approached by Professor Klaus Joachim Zülch, with a proposal that I convene at an early date a meeting in Houston, Texas, for the purpose of considering recent research developments that might have an influence on the classification of brain tumors. It was further considered that a review of this nature might ultimately necessitate revision of the WHO “Blue Book” of Histological Typing of Tumours of the Central Nervous System. Among the group which met in Houston in March 1988 were members of the original Collaborating Centre who were still active and other neuropathologists from around the world who had expertise in these matters.
The Immunopathology of Alzheimer's Disease and Some Related Disorders
Authors: Kalaria Rajesh N.
Published: January 2008

Current evidence clearly indicates that elements of the immune system are involved in the pathogenesis of the principal lesions characterizing Alzheimer's disease (AD). Findings are in accord with features associated with both the innate and adaptive immune mechanisms involved in a predominantly local inflammatory response within the parenchyma. Many of the features are unique to AD, presumably related to the unusual properties of β amyloid protein. Remarkably, the brain holds the capacity to produce almost all the immune system mediators which largely seem to be generated by glia comprising both astrocytes and microglia. While a variety of humoral mediators including classical acute phase proteins (and serpins) are increased and released, the complement seems most intrinsically involved. The cellular response is elaborated by microglia which seem the main immunocompetent cells partaking in the response. These appear to function as pluripotent macrophages expressing both classes of MHC antigens. Further characterization of this interesting response to cerebral amyloidosis will be challenging.
Cytochrome C Oxidase Deficiency and Neuronal Involvement in Menkes' Kinky Hair Disease: Immunohistochemical Study
Authors: Sparaco Marco , Hirano Asao , Hirano Micho , DiMauro Salvatore , Bonilla Eduardo
Published: January 2008

Antibodies against subunits II and IV of cytochrome c oxidase (COX) and against complex III of the respiratory chain were used to study the expression of these proteins in the cerebellum, spinal cord, and other regions of the central nervous system in an autoptic case of Menkes' kinky hair disease (MKHD). We found a reduced expression of COX subunits in all examined areas whereas staining for complex III appeared normal. Immunostaining was altered in morphologically well‐preserved neurons, suggesting that COX deficiency may have a pathogenetic role in the neuronal degeneration of MKHD.
Immediate Early Gene Expression in Experimental Epilepsy
Authors: Kiessling Marika , Gass Peter
Published: January 2008

Neuronal excitation by experimentally induced seizures elicits the rapid induction of a set of genes called immediate early genes (IEGs). The gene products of fos, jun and Krox, multimember gene families that belong to the class of IEGs, participate in a fundamental biological control mechanism, the regulation of gene transcription. IEG encoded proteins act as third messengers in an intracellular signal transduction cascade between neural cell surface receptors, cytoplasmic second messenger systems and specific target genes in the nucleus, a process for which the term ‘stimulus transcription coupling’ has been given. Almost all types of seizures cause dynamic alterations of IEG expression in neurons of the limbic system, but also in non‐limbic areas, such as the cortex, striatum and thalamus. IEG encoded transcription factors are thought to up‐ or down‐regulate effector genes with preferential expression in the central nervous system, including genes for neurotransmitters, growth factors, receptors, synaptic and axonal proteins. If the concept holds true that IEGs act as molecular switches converting epileptic short‐term excitation of neurons into alterations of the molecular phenotype, future research may help to explain hitherto unexplained phenomena in epileptogenesis including changes of synaptic efficacy, kindling and sprouting.
The Molecular Basis of Kindling
Authors: Mody Istvan
Published: January 2008

Kindling is an experimental model of epilepsy that involves activity‐dependent changes in neuronal structure and function. During kindling, pathological changes may occur at several organizational levels of the nervous system, from alterations in gene‐expression in individual neurons to the loss of specific neuronal populations and rearrangement of synaptic connectivity resulting from sustained stimulation of major excitatory pathways. This review summarizes recent developments in alterations at single neuronal and molecular levels that may be responsible for kindling epileptogenesis.
Non‐Radioactive Direct Sequencing of PCR Products Amplified from Neuropathological Specimens
Authors: Kosel Siegfried , Graeber Manuel B.
Published: January 2008

We have developed a simple, rapid and relatively inexpensive protocol for direct non‐isotopic cycle sequencing of DNA amplified using the polymerase chain reaction (PCR). PCR is performed on routine and archival neuropathological tissue. For sequencing, a 5′‐digoxigenin end‐labelled oligonucleotide primer is annealed and extended during thermal cycling, sequencing reactions are separated on a standard sequencing gel and the gel is contact‐blotted to a nylon membrane. Sequenced DNA is visualized using immunological detection of digoxigenin.
Tumour Cell Migration in the Central Nervous System
Authors: Pilkington Geoffrey J.
Published: January 2008

Intrinsic tumours of the central nervous system (CNS) are set apart from solid, non‐neural primary neoplasms in that, although they seldom metastasize to distant organs, they are generally characterised by a diffuse local invasive pattern. Indeed, it is this important biological characteristic which precludes successful therapeutic intervention in the majority of brain and spinal cord neoplasms. While tumours metastasising to the brain are generally well‐circumscribed lesions, sub‐populations of neoplastic cells from intrinsic, neuroectodermal tumours may migrate several millimetres away from the brain/tumour interface, resulting in a poor demarcation of the neoplasm. These migratory cells give rise to recurrent tumours following surgical and adjuvant chemo‐ and radio‐therapeutic intervention. The mechanisms which facilitate such migration of neoplastic neural cells into the contiguous normal nervous tissue are poorly documented. However, migration in this context is likely to be a complex multifaceted phenomenon involving cell/cell and cell/extracellular matrix (ECM) adhesion, locomotion, angiogenesis‐ and enzymic degradation of the ECM. In particular, cell adhesion molecules, ganglio‐sides, paracrine and autocrine growth and motility factors and matrix metalloproteinases (MMPs) and their inhibitors probably ail play important and inter‐dependent roles in the migration of neoplastic neural cells.
The Development of Neuropathology at the Massachusetts General Hospital and Harvard Medical School
Authors: Richardson Edward P. , Åtrom Karl Erik , Kleihues Paul
Published: January 2008

Few institutions have shaped neuropathology as a discipline as profoundly as Massachusetts General Hospital (MGH) and Harvard Medical School. Their fascination over many decades is due to a unique accumulation of excellent, intellectually stimulating neurologists with a sincere interest in the morphologic and pathogenetic basis of nervous system diseases. Their approach was strictly case oriented and clinico‐pathological conferences were developed to the highest standard. In this review, the foundations of neuropathology in Boston are recounted.
Molecular Mechanisms of Developmental and Tumor Angiogenesis
Authors: Plate Karl H. , Breier Georg , Risau Werner
Published: January 2008

Angiogenesis, the sprouting of capillaries from preexisting vessels, is of fundamental importance during embryonic development and is the principal process by which the brain and certain other organs become vascularized. Angiogenesis occurs during embryonic development but is almost absent in adult tissues. Transient and tightly controlled (physiological) angiogenesis in adult tissues occurs during the female reproductive cycle and during wound healing. In contrast, pathological angiogenesis is characterized by the persistent proliferation of endothelial cells, and is a prominent feature of diseases such as proliferative retinopathy, rheumathoid arthritis, and psoriasis. In addition, many tumors are able to attract blood vessels from neighbouring tissues. Tumor‐induced angiogenesis requires a constitutive activation of endothelial cells. These endothelial cells dissolve their surrounding extracellular matrix, migrate toward the tumor, proliferate, and form a new vascular network, thus supplying the tumor with nutrients and oxygen and removing waste products. The onset of angiogenesis in human gliomas is characterized by the expression of genes encoding angiogenic growth factors such as vascular endothelial growth factor (VEGF), platelet‐derived growth factor (PDGF) in tumor cells, and coordinate induction of genes in endothelial cells which encode the respective growth factor receptors. Developmental and tumor angiogenesis appear to be regulated by a paracrine mechanism involving VEGF and VEGF receptor‐1 and ‐2.
Glial Fibrillary Acidic Protein: Dynamic Property and Regulation by Phosphorylation
Authors: Inagaki Masaki , IMakamura Yu , Takeda Masatoshi , Nishimura Tsuyoshi , Inagaki Naoyuki
Published: January 2008

Glial fibrillary acidic protein (GFAP) is an intermediate filament (IF) protein of astroglia, and belongs to the type III subclass of IF proteins. IF proteins are composed of an amino‐terminal HEAD domain, a central ROD domain and a carboxyterminal TAIL domain. GFAP, with a molecular mass of ˜50 KDa, has the smallest HEAD domain among type III IF proteins. Despite its insolubility, GFAP is in dynamic equilibrium between assembled filaments and unassembled subunits, as demonstrated using fluo‐rescently labeled GFAP molecules. Like other IF proteins, assembly of GFAP is regulated by phosphory‐lation‐dephosphorylation of the HEAD domain by altering its charge. This regulation of GFAP assembly contributes to extensive remodeling of glial frameworks in mitosis. Another type III IF protein, vimentin, colocalizes with GFAP in immature, reactive or radial glia, thereby indicating that vimentin has an important role in the build up of the glial architecture.
Glial Fibrillary Acidic Protein: Regulation by Hormones, Cytokines, and Growth Factors
Authors: Laping Nicholas J. , Teter Bruce , Nichols Nancy R. , Rozovsky Irina , Finch Caleb E.
Published: January 2008

Levels of glial fibrillary acidic protein (GFAP), an astrocyte‐specific intermediate filament protein, are altered during development and aging, GFAP also responds dynamically to neurodegenerative lesions. Changes in GFAP expression can occur at both transcriptional and translational levels. Modulators of GFAP expression include steroids, cytokines, and growth factors. GFAP expression also shows brain region‐specific responses to sex steroids and of astrocyte‐neuronal interactions. The 5′‐upstream sequences of rat, mouse, and human are compared for the presence of response elements that are candidates for transcriptional regulation of GFAP. We propose that the regulation of the GFAP gene has evolved a system of controls that allow integrated responses to neuroendocrine and inflammatory modulators.
Astrocytes Upregulate Glial Fibrillary Acidic Protein (GFAP), but not Insulin‐like Growth Factor‐I (IGF‐I) during Experimental Autoimmune Neuritis (EAN)
Authors: Gehrmann Jochen , Yao Da‐Lin , Bonetti Bruno , Brenner Michael , Bondy Carolyn , Wekerle Hartmut , Kreutzberg Georg W. , Webster Henry deF.
Published: January 2008

T cell‐mediated autoimmune neuritis produces rapid activation of spinal cord microglia. To determine whether this microglial response upregulates astrocytic expression of IGF‐related proteins, we induced EAN and used in situ hybridization and immunocytochemistry to examine the mRNAs and peptides for glial fibrillary acidic protein (GFAP), insulin‐like growth factor‐I (IGF‐I), IGF‐I receptor (IGFR‐I) and IGF binding protein‐2 (IGFBP‐2). Relative levels of GFAP mRNA and peptide were highest in the lumbar spinal cord 4–10 d following T cell transfer and significant GFAP elevations were still present after three weeks. The astrocytes expressing GFAP mRNA and peptide were localized around motoneurons which were related topographically to axons in peripheral nerve inflammatory lesions. In the nucleus gracilis, where terminals of dorsal root ganglion neurons are located, astrocytic levels of GFAP mRNA and peptide rose later and did not reach their highest levels until 21 d after T cell transfer. Even though microglia were activated in both locations 2–4 d after transfer, astrocytic levels of IGF‐I, IGFR‐I and IGFBP‐2 mRNA and peptide did not differ significantly from those observed in controls. The dissociation of GFAP and IGF‐I expression in EAN suggests that these astrocytic responses may be independently regulated. We also suggest that the type and severity of remote neuronal injury are probably more important inducers and regulators of these astrocytic responses than microglial cell activation.
Evidence for Subarachnoid Spread in the Development of Multiple Meningiomas
Authors: von Deimling Andreas , Kraus Jürgen A. , Stangl Armin P. , Wellenreuther Ruth , Lenartz Doris , Schramm Johannes , Louis David N. , Ramesh Vijaya , Gusella James F. , Wiestler Otmar D.
Published: January 2008

Meningiomas are among the most common human brain tumors. Occasionally patients develop multiple meningiomas. While it has been surmised that these are multiple primary meningiomas, it is possible that they represent spread of a single primary tumor. Recently, the neurofibromatosis type 2 (NF2) tumor suppressor gene has been shown to carry mutations in meningiomas. In the present study we have analyzed multiple meningiomas from two patients for point mutations in the NF2 gene by SSCP analysis and direct sequencing. We detected point mutations in the meningiomas from both patients. The first patient from which six tumors were available had a three base pair deletion in the splice donor region of exon 7. All tumors showed the identical mutation. The second patient with two independent meningiomas had a nonsense mutation in exon 8 which was the same in both tumors. Analysis of constitutional DNA revealed a wildtype DNA sequence in both cases. There was no family history of neurofibromatosis type 2 in either patient. These data provide strong evidence for a monoclonal origin of multiple meningiomas. Early subarachnoid spread is the most likely mechanism for the formation of these tumors.
Fatal Familial Insomnia and Familial Creutzfeldt‐Jakob Disease: Clinical, Pathological and Molecular Features
Authors: Gambetti Pierluigi , Parchi Piero , Petersen Robert B. , Chen Shu G. , Lugaresi Elio
Published: January 2008

Fatal familial insomnia (FFI) and a subtype of familial Creutzfeldt‐Jakob disease (CJD178) are two prion diseases that have different clinical and pathological features, the same aspartic acid to asparagine mutation (D178N) at codon 178 of the prion protein (PrP) gene, but distinct genotypes generated by the methionine‐valine polymorphism at codon 129 (129M or 129V) in the mutant allele of the PrP gene. The D178N, 129M allele segregates with FFI while the D178N, 129V allele segregates with CJD178. The proteinase K resistant PrP (PrPres) isoforms present in FFI and CJD178 differ in degree of glycosylation and size. Thus, the amino acid, methionine or valine, at position 129 of the mutant allele, in conjunction with D178N mutation results in significant alterations of PrPres in FFI and CJD178. The 129 polymorphic site also exerts influence through the normal allele: the course of the disease is shorter in the patients homozygous at codon 129 and other minor but consistent phenotypic differences occur between homozygous and heterozygous FFI patients. The comparative study of PrPres distribution in FFI homozygotes and heterozygotes at codon 129 has lead to the conclusion that the phenotypic differences observed between these two FFI patient populations may be the result of different rates of conversion of normal PrP into PrPres, at least in some brain regions.
Prion Protein Transgenes and the Neuropathology in Prion Diseases
Authors: DeArmond Stephen J. , Prusiner Stanley B.
Published: January 2008

The concept that prions are novel pathogens which are different from both viroids and viruses has received increasing support from many avenues of investigation over the past decade. Enriching fractions from Syrian hamster (SHa) brain for scrapie prion infectivity led to the discovery of the prion protein (PrP). Prion diseases of animals include scrapie and “mad cow” disease; those of humans present as inherited, sporadic and infectious neurodegenerative disorders, two of which are called Creutzfeldt‐Jakob disease (CJD) and Gerstmann‐Sträussler‐Scheinker disease (GSS). The inherited human prion diseases are genetically linked to mutations in the PrP gene that result in non‐conservative amino acid substitutions. Transgenic (Tg) mice expressing PrP carrying a GSS mutation developed neurodegeneration spontaneously and produced prions de novo. In other studies, Tg mice expressing both SHa and mouse (Mo) PrP genes were used to demonstrate that the “species barrier” for scrapie prions resides in the primary structure of PrP. This concept was strengthened by the results of studies in which mice expressing chimeric Mo/human (Hu) PrP transgenes were constructed which differ from MoPrP by nine amino acids between residues 96 and 167. All of the Tg(MHu2M) mice developed neurologic disease ∼200 days after inoculation with brain homogenate from three patients who died of CJD. About 10% of Tg(HuPrP) mice expressing HuPrP and non‐Tg mice developed neurologic disease >500 days after inoculation with CJD prions. The different susceptibilities of Tg(HuPrP) and Tg(MHu2M) mice to human prions indicate that additional species specific factors such as chaperone proteins are involved in prion replication. Diagnosis, prevention and treatment of human prion diseases should be facilitated by study of Tg(MHu2M) mice. Our findings and those from other studies suggest that mutant and wtPrP interact, perhaps through a chaperone‐like protein, during the pathogenesis of the prion diseases.
Transgenic and Natural Mouse Models of Proteolipid Protein (PLP)‐Related Dysmyelination and Demyelination
Authors: Griffiths I.R. , Schneider A. , Anderson J. , Nave K‐A.
Published: January 2008

The X chromosome‐linked PLP/DM‐20 gene is the CNS myelin gene most frequently associated with mutations, resulting in dysmyelination in several species including man (Pelizaeus‐Merzbacher disease, X‐linked Spastic Paraplegia). The pathology of most PLP gene mutations is characterized by hypomyelination, glial cell proliferation, increased numbers of microglia, and premature oligodendrocyte death. In most mutants, residual myelin structures have an abnormal ultrastructure and periodicity. Surprisingly, transgenic mice which carry extra copies of the wild type PLP gene show dysmyelination, demonstrating that the PLP gene is dosage sensitive. Pathological changes of transgenic mice vary from the phenotype of natural mutants. Specifically, many Golgi saccules of oligodendrocytes are vacuolated and the cytoplasm contains autophagic vacuoles hinting at a perturbation in protein trafficking. In fact, upon transgenic overexpression PLP becomes a prominent peripheral myelin protein, whereas in normal Schwann cells PLP is restricted from entering the myelin compartment. Surprisingly, transgenic animals which overexpress PLP/DM‐20 at a low level appear normal during early development, but later spontaneously demyelinate. The mechanisms underlying this demyelination phenotype is unknown but an immune‐mediated process has been suggested. All attempts to correct the phenotype of natural PLP mutants, such as jimpy mice, with a wild type transgene have had little effects, indicating a dominant‐negative effect of the mutant gene product. On the other hand, mice with a targeted disruption of the PLP/DM‐20 gene have suprisingly minor clinical signs. This suggests that the lethal phenotype associated with the majority of PLP gene mutations is a complex combination of loss and gain‐of‐function effects of a mutant myelin protein.
Ludwig Merzbacher (1875–1942): The man behind the disease
Authors: Peiffer Jüirgen , Gehrmann Jochen
Published: January 2008

Ludwig Merzbacher (1875–1942) is widely known for his seminal work on the pathology of the dysmyelinating CNS disease named for the clinician Friedrich Pelizaeus and himself. Yet his training, his scientific achievements and his list of publications suggest a scientist with broad interests in neuropathology, neuroscience, neurology and psychiatry. Among several studies in experimental and clinical neuropathology, Merzbacher's work on scavenger cells is the most outstanding. While working in Alois Alzheimer's laboratory in Munich in 1906/1907, Ludwig Merzbacher analyzed in great detail the reaction patterns of these cells, which are nowadays known as reactive microglia, and already attempted to elucidate their function in brain pathology.
Tissue Handling in Suspected Creutzfeldt‐Jakob Disease (CJD) and Other Human Spongiform Encephalopathies (Prion Diseases)
Authors: Budka Herbert , Aguzzi Adriano , Brown Paul , Brucher Jean‐Marie , Bugiani Orso , Collinge John , Diringer Heino , Gullotta Filippo , Haltia Matti , Hauw Jean‐Jacques , Ironside James W. , Kretzschmar Hans A. , Lantos Peter L. , Masullo Carlo , Pocchiari Maurizio , Schlote Wolfgang , Tateishi Jun , Will Robert G.
Published: January 2008

Despite many sensational and intimidating reports in the mass media, transmissible spongiform encephalopathies (prion disease) are not contagious in the usual sense. Successful transmission requires both specific material (an affected individual's tissue, from or adjacent to CNS) and specific modes (mainly penetrating contact with the recipient). Nevertheless, specific safety precautions are mandatory to avoid accidental transmission and to decontaminate any infectivity. Autopsy is essential for definite diagnosis of these disorders. Recommendations are given here for performance of the autopsy, for neuropathology service and appropriate decontamination; they are based on the current literature and on precautions taken in most laboratories with experience in handling tissue from transmissible spongiform encephalopathies. In particular, special care must be taken to avoid penetrating wounds, possible contamination should be kept to a minimum, and potential infectious material must be adequately decontaminated by specific means.
Pathogenesis and Classification of Primary Central Nervous System Lymphoma: An Update
Authors: Morgello Susan
Published: January 2008

Primary central nervous system lymphoma has undergone a remarkable increase in incidence over the last decade, both in immunosuppressed and immunocompetent individuals. Its clinicopathologic evaluation requires knowledge of current hema‐topathologic systems for lymphoma classification, as well as specific understanding of unique central nervous system determinants. In immuno‐compromised individuals, the tumor has a constant association with Epstein‐Barr virus. The form of Epstein‐Barr virus in these tumors appears to be predominantly latent, however, the precise mechanism relating virus to tumor pathogenesis is still unclear. In immunocompetent patients, risk factors and oncogenic associations are completely unknown. Critical to the formation of these tumors is the trafficking of B‐cells, whether pre‐ or post‐transformation, across the blood‐brain barrier. These B‐cell migrations may require perturbations to the barrier that originate in or around neural parenchyma, such as localized injury or infection.
Update on the Pathophysiology and Pathology of Acute Spinal Cord Injury
Authors: Tator Charles H.
Published: January 2008

There is evidence from both clinical and experimental studies that the spinal cord suffers both primary and secondary damage after acute spinal cord injury. The pathophysiology of secondary injury involves a multitude of cellular and molecular events which progress over the first few days after injury, the most important of which are systemic and local vascular insults, electrolyte shifts, oedema and excitotoxicity. These secondary processes contribute to the evolution of the pathological changes which in the severe injuries progress from central haemorrhagic necrosis involving mainly the grey matter to infarction of both the white and grey matter at the injury site and for a considerable distance proximally and distally. Less severe injuries show a variety of axonal and myelin changes. The concept of secondary injury is consistent with the results of therapeutic approaches to improve outcome.
Are the Pathobiological Changes Evoked by Traumatic Brain Injury Immediate and Irreversible?
Authors: Povlishock John T. , Jenkins Larry W.
Published: January 2008

Traumatic brain injury has long been thought to evoke immediate and irreversible damage to the brain parenchyma and its intrinsic vasculature. In this review, we call into question the correctness of this assumption by citing two traumatically related brain parenchymal abnormalities that are the result of a progressive, traumatically induced perturbation. In this context, we first consider the pathogenesis of traumatically induced axonal damage to show that it is not the immediate consequence of traumatic tissue tearing. Rather, we illustrate that it is a delayed consequence of complex axolemmal and/or cytoskeletal changes evoked by the traumatic episode which then lead to cytoskeletal collapse and impairment of axoplasmic transport, ultimately progressing to axonal swelling and disconnection. Second, we consider the traumatized brain's increased neuronal sensitivity to secondary ischemic insult by showing that even after mild traumatic brain injury, CA1 neuronal cell loss can be precipitated by the induction of sublethal ischemic insult within 24 hrs of injury. In demonstrating this increased sensitivity to secondary insult, evidence is provided that it is triggered by the neurotransmitter storm evoked by traumatic brain injury, allowing for sublethal neuroexcitation. In relation to this phenomenon, the protective effect of receptor antagonists are discussed, as well as the concept that this relatively prolonged posttraumatic brain hypersensitivity offers a potential window for therapeutic intervention. Collectively, it is felt that both examples of the brain parenchyma's response to traumatic brain injury show that the resulting pathobiology is much more complex and progressive than previously envisioned, and as such, rejects many of the previous beliefs regarding the pathobiology of traumatic brain injury.
MEETING REPORT
Authors: Kalaria Rajesh N. , Akiyama Haruhiko
Published: January 2008

Inflammatory and Immune Responses in Brain Injury and Neurodegenerative Disease, Kyoto, Japan, July 9–14, 1995
Mouse Inoculation Studies Reveal No Transmissible Agent in Amyotrophic Lateral Sclerosis
Authors: Fraser Hugh , Behan Wilhelmina , Chree Aileen , Crossland Graham , Behan Peter
Published: January 2008

Amyotrophic lateral sclerosis (ALS) resembles the spongiform encephalopathies in its dual pattern of inherited and sporadic cases, its uniform prevalence in different populations, its late onset (suggestive of a long incubation period) and its pathological picture of neuronal degeneration without inflammation. There is a well‐established protocol for primary transmission of scrapie and related diseases to mice. Using this, we inoculated four long‐lived, inbred, mouse strains with cord material fresh‐frozen within three hours of death, from a case of ALS or a control case. No motor neuron loss, gliosis or tract demyelination was found in the experimental group. Fifty per cent of each group were observed for more than 600 days. Two types of lesions were found in these animals at death: widespread foci of white matter vacuolation and bilateral thalamic mineral deposits. They were present in the control group at the same incidence and severity as in the experimental group and were thus considered to represent an age‐related change. Attention is drawn to them because they have been claimed as significant when found in a transgenic model of spongiform encephalopathy. The results of our carefully‐controlled experiment suggest that it is unlikely that ALS is caused by a scrapie‐like agent capable of transmission to mice.
Hereditary Cerebral Hemorrhage with Amyloidosis‐Dutch Type (HCHWA‐D): I ‐ A Review of Clinical, Radiologic and Genetic Aspects
Authors: Bornebroek Marjolijn , Haan Joost , Maat‐Schieman Marion LC , Duinen Sjoerd G Van , Roos Raymund AC
Published: January 2008

Hereditary cerebral hemorrhage with amyloidosis ‐ Dutch type (HCHWA‐D) is an autosomal dominant disease caused by deposition of β‐amyloid in the leptomeningeal arteries and cortical arterioles, in addition to preamyloid deposits and amyloid plaques in the brain parenchyma.

The disease is due to a point mutation at codon 693 of the amyloid precursor protein (βPP) gene at chromosome 21. Since this point mutation is diagnostic for HCHWA‐D, presymptomatic testing is feasible and offered, together with genetic counselling and psychological support, to subjects at risk. HCHWA‐D is clinically characterized by recurrent strokes, in addition to dementia, which can occur after the first stroke but also preceding it. Radiological studies revealed focal lesions (hemorrhages, hemorrhagic and non‐hemorrhagic infarctions) and diffuse white matter damage. Diffuse white matter hyperintensities on MRI are an early symptom of HCHWA‐D since they have been found on MRI scans of subjects who had not suffered a stroke.

The presence of the diagnostic point mutation makes HCHWA‐D a useful model to study the effects of cerebral amyloid angiopathy in vivo. The characteristic pathological abnormalities and its implications for Alzheimer's disease will be discussed in Part II of this article
Long‐lasting Transneuronal Changes in Rat Dentate Granule Cell Dendrites after Entorhinal Cortex Lesion. A Combined Intracellular Injection and Electron Microscopy Study
Authors: Diekmann Silvia , Ohm Thomas G. , Nitsch Robert
Published: January 2008

Following entorhinal cortex lesion, inhibitory hippocampal neurons show a persistent rarefication of those dendrites formally receiving entorhinal input. Physiological data indicate a long lasting disequilibrium of inhibition and excitation in the deentorhinated hippocampus. We analyzed the intracellularly‐stained dendritic tree of de‐entorhinated excitatory rat granule cells. Granule cells of controls and animals surviving 2, 8, 60 and 270 days after unilateral entorhinal cortex lesion were impaled. Dendrites of control cells were of typical shape, traced to the hippocampal fissure and a complete dye filling of dendrites was ascertained by EM‐analysis. Conversely, 60 and 270 days following lesioning, dendrites were only rarely seen to extend into the outer portions of the molecular layer and the dendritic architecture became significantly rarefied. Sixty days post‐lesion, intracellularly filled dendrites extending to the middle molecular layer were surrounded by cell clusters resembling glia. Some of these contained the neuronally applied dye, suggesting a close association of the cytosolic compartments with the altered dendrites. These observed alterations exceed the process of sprouting and de novo synaptogenesis of remaining afference for long periods of time. The dendritic morphology of both inhibitory and excitatory neurons seems to require specific input from the entorhinal cortex. Moreover, sprouting of remaining afferents is apparently not sufficient to compensate for this loss of input.
Distinct Patterns of Multiple Sclerosis Pathology Indicates Heterogeneity in Pathogenesis
Authors: Lucchinetti Claudia F. , Brück Wolfgang , Rodriguez Moses , Lassmann Hans
Published: January 2008

Multiple sclerosis is an inflammatory demyeli‐nating disease of the central nervous system. The hallmark of its pathology is the demyelinated plaque with reactive glial scar formation. However, a detailed analysis of the patterns of demyelination, oligodendroglia cell pathology and the reaction of other tissue components suggests that the pathogenesis of myelin destruction in this disease may be heterogeneous. In this review we present a new classification scheme of lesional activity on the basis of the molecular composition of myelin degradation products in macrophages. When these criteria are used, different patterns of demyelination can be distinguished, including demyelination with relative preservation of oligodendrocytes, myelin destruction with concomitant and complete destruction of oligodendrocytes or primary destruction or disturbance of myelinating cells with secondary demyelination. Furthermore, in some cases a primary selective demyelination may be followed by secondary oligodendrocyte loss in the established lesions. Finally, some extraordinarily severe conditions may result in destructive lesions with loss of myelin, oligodendrocytes, axons and astro‐cytes. This heterogeneity of plaque pathology is discussed in the context of recent experimental models of inflammatory demyelination, which show that different immunological pathways may lead to the formation of demyelinated plaques that reveal the diverse structural aspects described above. Our data indicate, that the demyelinated plaques of multiple sclerosis may reflect a common pathological end point of a variety of different immunological mechanisms of myelin destruction in this disease.
Regulation of Oligodendrocyte Development and CNS Myelination by Growth Factors: Prospects for Therapy of Demyelinating Disease
Authors: McMorris F. Arthur , McKinnon Randall D.
Published: January 2008

Multiple sclerosis (MS), the most common neurological disorder diagnosed in young adults, is characterized by autoimmune demyelination in the central nervous system (CNS). Promotion of remyelination in the brain and spinal cord is a potential strategy for therapeutic intervention in MS and other demyelinating diseases. Recent studies have shown that the development of oligoden‐drocytes, the myelin‐forming cells of the CNS, is extensively controlled by growth factors. These factors regulate the proliferation, migration, differentiation, survival and regeneration of oligoden‐drogtial cells and the synthesis of myelin, and often interact in a complex manner. Moreover, insulin‐like growth factor 1 (IGF‐I) has proven effective for therapy of experimental autoimmune encephalomyelitis (EAE), an animal model of autoimmune demyelination. In this review we summarize recent findings on the regulation of oligodendrocyte development and CNS myelination by growth factors, and discuss these findings in the context of possible clinical application for the therapy of neurological disease in humans.
Central Nervous System Remyelination Clinical Application of Basic Neuroscience Principles
Authors: Miller David J. , Asakura Kuni , Rodriguez Moses
Published: January 2008

Studies in both humans and experimental animals have demonstrated that myelin repair in the CNS is a normal physiological response to myelin damage, similar to tissue injury elsewhere in the body. The unanswered question is why myelin repair is incomplete in multiple sclerosis patients. In this paper we review the morphological characteristics of remyelination, discuss the available animal models of CNS demyelination and their usefulness to identify the molecular, cellular, and morphological events involved in CNS myelin repair, examine the use of immunosuppression, immunoglobu‐lins, protein growth factors, and glial cell transplantation as the primary experimental therapies designed to promote CNS remyelination, and address the potential electrophysiological and clinical benefits of myelin repair in the CNS.