bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Genetics and Neuropathology of Charcot‐Marie‐Tooth Disease Type 1A
Authors: Lupski James R. , Garcia Carlos A.
Published: January 2008

Charcot‐Marie‐Tooth (CMT) syndrome describes a genetically and clinically heterogeneous group of polyneuropathies. Electrophysiologically, at least two types of CMT can be distinguished; CMT1 which has decreased nerve conduction velocities (NCV) and CMT2 which has normal or near normal NCV with decreased amplitudes. For CMT1, three gene loci (on chromosomes 1, 17 and the X chromosome) have been mapped. The locus on chromosome 17, CMT type 1A (CMT1A), is responsible for the most common form of CMT which has recently been shown to be associated with a large DNA duplication. Recent data demonstrates that the CMT1A phenotype results from an inherited DNA rearrangement and a gene dosage effect. The trembler (Tr) and allelic tremblerJ (TrJ) mice have been proposed as animal models for CMT. Tr has similar electrophysiological and neuropathological features to CMT1 patients and maps to mouse chromosome 11 in a region of conserved synteny with human chromosome 17p. Tr and TrJ have recently been shown to have different point mutations in regions encoding putative transmembrane domains of the myelin specific protein PMP‐22. The human peripheral nerve‐specific PMP‐22 gene maps within the CMT1A duplication. PMP‐22 is thus a candidate gene for CMT1A. This paper describes the molecular genetics of CMT1A and sural nerve pathology in CMT 1A patients with the CMT1A duplication.
Menkes Disease: An X‐Linked Neurological Disorder of the Copper Metabolism
Authors: Horn Nina , Tønnesen Tønne , Türner Zeynep
Published: January 2008

Menkes disease is an X‐linked, recessive disturbance of copper metabolism associated with a progressive clinical course and abnormal hair. The disease is dominated by neurological symptoms combined with connective tissue manifestations, most of which can be explained by the lack of important copper enzymes. Despite excessive accumulation of the metal in various tissues, a functional copper deficiency is evident, probably caused by a defective intracellular copper transport protein of unknown nature. The molecular basis of the copper disturbance has proven difficult to define and will most likely have to await cloning of the gene. The chromosomal region of interest has now been narrowed down to a sub‐band on the long arm of the chromosome (Xq13.3), and positional cloning is in progress in a number of laboratories including our own. Identification of the Menkes gene will be of importance for our understanding of the cellular handling of copper and other trace elements.
Oskar and Cécile Vogt, Lenin's Brain and the Bumble‐Bees of the Black Forest
Authors: Kreutzberg Georg W. , Klatzo Igor , Kleihues Paul
Published: January 2008

Oskar Vogt (1870–1955) was a prominent German neurologist and neuroanatomist with a strong interest in the pathogenesis of brain diseases. Together with his wife Cecile (1875–1962), he published landmark papers on the cyto‐ and myelo‐architecture of the brain and the functional anatomy of the basal ganglia. He developed the concept of pathoclisis, i.e., the selective vulnerability of specific neuronal populations in the CNS. In the 1920's, Vogt created a multi‐disciplinary brain research institute, the Kaiser‐Wilhelm‐Institut für Hirnforschung in Berlin‐Buch. After Lenin's death in 1924, Oskar Vogt was called to Moscow where he formed a new brain research institute, with the main purpose to investigate the revolutionary's brain. After being dismissed from office by the Nazi government in 1937, the Vogts continued their work in a privately funded institute in Neustadt, the Black Forest.
Human T cell Leukemia Virus Type I Infection and Chronic Myelopathy
Authors: Iwasaki Yuzo
Published: January 2008

The central nervous system (CNS) pathology of HTLV‐I associated myelopathy or tropical spastic paraparesis (HAM/TSP) is reviewed, based mainly on 12 autopsy cases of Japanese HAM/TSP with a serological confirmation of HTLV‐I infection. The essential histopathological feature of HAM/TSP is a chronic progressive inflammatory process heralded by parenchymal infiltration of memory CD4 cells. The inflammation involves both the grey and white matter of the spinal cord, and progresses for more than three years after the onset of neurological symptoms, resulting in preferential degeneration of the white matter. In cases with a history of more than nine years, however, the spinal cord lesions appears degenerative rather than inflammatory. Both the inflammation and the white matter degeneration are most conspicuous in the lower thoracic cord. The lateral funiculus is always and most severely affected. Although the parenchymal tissue degeneration is not confined to any particular long tracts, symmetrical degeneration of the lateral pyramidal tract is evident in all cases. The involvement of the posterior and anterior funiculi is variable and neurons are relatively well preserved. Since evidence for HTLV‐I infection in the CNS is limited to detection of proviral DNA by the polymerase chain reaction (PCR) and isolation of the virus from CSF cells, autoimmune nature of the disease is suspected, but is supported by ample evidence for derangements of the host immune system compatible with those of autoimmune diseases. Recent studies on induction of white matter degeneration in the rat with a topographical similarity to human HAM/TSP is also briefly reviewed. However, in the rat disease, inflammatory cell infiltrations are inconspicuous.
Altered Tau and Neurofilament Proteins in Neuro‐Degenerative Diseases: Diagnostic Implications for Alzheimer's Disease and Lewy Body Dementias
Authors: Trojanowski John Q. , Schmidt Marie L. , Shin Ryong‐Woon , Bramblett Gregory T. , Rao Dinesh , Lee Virginia M.‐Y.
Published: January 2008

The neuronal cytoskeleton is one of the most profoundly altered organelles in late life neurodegenerative disorders that are characterized by progressive impairments in cognitive abilities. The elucidation of the protein building blocks of these organelles as well as advances in understanding how these proteins become altered in Alzheimer's disease (AD) and other less common dementing illnesses, i.e., diffuse Lewy body disease (DLBD) or the Lewy body variant of AD (LBVAD), will provide insights into the molecular basis of these disorders. Within, we review evidence that normal adult human tau is abnormally phosphorylated and converted into the subunits of AD paired helical filaments (PHFs), and that Lewy bodies (LBs) represent accumulation of altered neurofilament (NF) triplet subunits. Although the precise biological consequences of PHF and LB formation in neurons is unknown, growing evidence suggests that the formation of PHFs and LBs from normal neuronal cytoskeletal proteins could have deleterious effects on neuronal function and survival. Finally, insights into the composition of PHFs and LBs could lead to the development of novel strategies for the timely and accurate diagnosis of AD, DLBD and the LBVAD.
Synapsin I, Synapsin II, and Synaptophysin: Marker Proteins of Synaptic Vesicles
Authors: Thiel Gerald
Published: January 2008

The nerve terminal of neurons is filled with small synaptic vesicles, specialized secretory organelles involved in the storage and release of neurotransmitters. The synapsins are a family of four proteins that are the major peripheral proteins on the cytoplasmic face of synaptic vesicles. Synaptophysin is the major integral membrane protein of synaptic vesicles. The characterization of the synapsins and of synaptophysin during the last years has revealed exciting information about their structure, regulation and possible function. To understand the role of the synapsins and synaptophysin in the biology of a nerve cell means to elucidate the fundamental mechanism of brain function, the release of neurotransmitter.
Hereditary Motor and Sensory Neuropathy: HMSN Type II (Neuronal Type) and X‐linked HMSN
Authors: Hahn Angelika F.
Published: January 2008

The neuronal forms of hereditary motor and sensory neuropathy (HMSN) are genetically heterogeneous with observed autosomal dominant, autosomal recessive and X‐linked dominant inheritance. All three forms are characterized by degeneration of select populations of motor and sensory neurons with accompanying atrophy and degeneration of their axons. Large calibre myelinated fibres are predominantly affected and fibre degeneration and fibre loss progresses from distally to proximally. Attempts of regeneration are noted in all except the severe childhood form. The clinical picture is that of peroneal and distal leg muscle wasting and weakness, distal sensory loss and areflexia. Hand muscles may be severely affected in the autosomal recessive and X‐linked dominant forms. Motor and sensory nerve conduction velocities are only moderately slowed and evoked maximum compound motor and sensory amplitudes are reduced according to the degree of fibre loss. The gene locus remains unknown in both the autosomal dominant and autosomal recessive types. For the X‐linked dominant HMSN, the gene locus has been mapped closely by linkage analysis to DNA loci in the pericentromeric region of the X‐chromosome.
Hereditary Sensory Neuropathies
Authors: Thomas P.K.
Published: January 2008

Hereditary sensory neuropathies have not shared in the major advances that have taken place in the molecular genetics of the hereditary demyelinating motor and sensory neuropathies. Thus far, classification depends upon their mode of inheritance and clinical features. The delineation of the various clinical syndromes is still not complete. This is a necessary preliminary to establishing the genetic basis of these neuropathies. The hereditary sensory neuropathies can be accordingly grouped into those with predominantly sensory and some associated autonomic features and those in which a sensory neuropathy is part of a spinocerebellar degeneration or other multisystem degeneration.
Familial Amyloid Polyneuropathy
Authors: Reilly Mary M. , King Rosalind H.M.
Published: January 2008

Familial amyloid polyneuropathy (FAP) is most commonly associated with variant plasma transthyretin, although it has also been described in association with mutant apolipoprotein A‐1 and gelsolin. There are now approximately 26 point mutations in the transthyretin gene associated with FAP. Because of the overlapping clinical phenotypes described with these mutations, it is now more appropriate to classify the various forms of FAP according to the underlying genetic defect rather than on clinical grounds. Many questions concerning the amyloidogenic nature of transthyretin and the variability of organ involvement depending on the underlying mutation remain unanswered. The recent use of liver transplantation for treatment appears to be promising.
Neuropathy Associated with Mitochondrial Disorders
Authors: Schröder J. Michael
Published: January 2008

Altered mitochondria within peripheral nerves were found in most cases of mitochondrial myopathy, in all cases of hereditary motor and sensory neuropathy with optic atrophy (HMSIM VI) and in 25 cases out of a larger series of 280 unselected neuropathies studied by electron microscopy for diagnostic purposes. The mitochondrial changes differed from those seen in the corresponding skeletal muscle fibres. They comprised enlargements with an amorphous matrix and distorted cristae, hexagonal para‐crystalline inclusions, sometimes longitudinally arranged in a zig‐zag pattern, prominent cristae containing oblique striations and a variety of rare changes. Most mitochondrial abnormalities were found in Schwann cells. An occasional perineurial cell was also involved showing a unique paracrys‐talline inclusion. An increase of the number of mitochondria was noted in smooth muscle and endothelial cells of epineurial arterioles in three cases of mitochondrial encephalomyopathy (two cases with Kearns Sayre syndrome, and one with mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes, i.e., “MELAS”). Neuropathy was present in all cases of mitochondrial myopathy as judged by morphometric analysis. Whether neuropathy is caused directly by mitochondrial dysfunction or by other pathogenetic mechanisms remains to be determined. Yet peripheral motor and sensory neurons with their peripheral axons are postmitotic, terminally differentiated cells which should be similarly prone to deleterious deletions of mitochondrial DNA as has been suggested as an etiologic factor for the predilection of mitochondrial diseases in muscle and brain.
Paraneoplasia and Autoimmunologic Injury of the Nervous System: The Anti‐Hu Syndrome
Authors: Rosenblum Marc K.
Published: January 2008

In recent years, antineuronal autoantibodies of varying antigenic specificity have come to be associated with a number of paraneoplastic neurologic disorders. Anti‐Hu is a polyclonal complement‐fixing IgG directed against a 35 to 40 kilodalton protein concentrated in the nuclei of neurons throughout the central and peripheral neuraxes. Its elaboration at high titer in serum and cerebrospinal fluid is invariably associated with a neurologic syndrome characterized chiefly by subacutely evolving sensory neuropathy and an array of central disturbances that include bulbar and cerebellar dysfunction, limbic encephalitis and motor neuron disease. The manufacture of anti‐Hu IgG is triggered in a great majority of cases by underlying small cell carcinomas of pulmonary origin, typically limited in stage and otherwise silent, that aberrantly express the native neuronal antigen or an antigenically indistinguishable epitope. Both neoplastic and diseased neural tissues contain lymphocytes of B and T lineage specifically cognizant of the Hu antigen as well as concentrated anti‐Hu IgG bound to tumor cells and neurons, respectively. These observations suggest that an immune response serving initially to limit the growth and spread of its inciting neoplasm comes subsequently to be misdirected against the nervous system of the host, resulting in autoimmunologically‐mediated neurologic injury. Clinical, neuropathologic and immunologic data derived from a series of 71 sero‐confirmed cases of the anti‐Hu‐associated paraneoplastic sensory neuronopathy/encephalomyelitis complex are reviewed.
Dysembryoplastic Neuroepithelial Tumours
Authors: Daumas‐Duport Catherine
Published: January 2008

Dysembryoplastic neuroepithelial tumours (DNTs) are a group of supratentorial cortical benignant lesions that superficially resemble mixed oligoastrocytomas, oligodendrogliomas or astrocytomas. Clinically these tumours are associated with partial seizures beginning before the age of 20 years, with no neurologic deficit and no stigmata of phacomatosis. In the revised WHO classification, DNTs have been incorporated among the category of neuronal and mixed neuronoglial tumours. This classification describes a histologic variant characterized by the following criteria: cortical location, multinodular architecture ‐ the nodule being made of multiple variants looking like astrocytomas, oligodendrogliomas or oligo‐astrocytomas, foci of dysplastic cortical disorganization and the presence of a glioneuronal element showing a columnar structure perpendicular to the cortical surface. A study of 14 cases for which only a specific glioneuronal element could be identified demonstrated that this specific element is sufficient for diagnosing DNTs and that the spectrum of DNTs includes a simple form with a unique glioneuronal element. Preoperative imaging follow‐up data, in the series of 23 simple and complex forms, indicated that DNTs are perfectly stable. However, these tumours may show a high MIB1 labeling index.
Surgical Pathology of Chronic Epileptic Seizure Disorders
Authors: Wolf Helmut K. , Wiestler Otmar D.
Published: January 2008

The surgical treatment of chronic epilepsies is increasing rapidly and involves neuropathologists in the care of patients with chronic and medically intractable seizure disorders. Herein we review the histopathologic findings in 279 consecutive surgical specimens of patients with chronic pharmaco‐resistant epileptic disorders. Aspects that are relevant to the diagnostic surgical pathologist such as the terminology of developmental lesions and Amnion's horn sclerosis are discussed. In 87 cases (31.2%), there were tumors in which all but two were of low histopathological grade (WHO grade I or grade II). The most common tumors were gan‐gliogliomas, pilocytic astrocytomas, oligodendrogliomas, fibrillary astrocytomas and dysembryo‐plastic neuroepithelial tumors. Among the most frequent non‐neoplastic focal lesions, microscopic glioneuronal hamartias, circumscribed vascular malformations, glioneuronal hamartomas and porencephalic defects were most frequent. The hippocampal formation was structurally well preserved in 71 specimens of patients with temporal lobe epilepsy. In 51 of these (71.8%) cases. Amnion's horn sclerosis was present. The findings suggest that the structural lesions observed in the great majority of the specimens are closely related to the pathogenesis of intractable seizures.
Excitotoxicity and Selective Neuronal Loss in Epilepsy
Authors: Meldrum Brian S.
Published: January 2008

The early stages of selective neuronal loss occurring in the hippocampus and other brain regions after prolonged epileptic activity have fine structural characteristics matching those induced by excitotoxic agents. NMDA receptor antagonists provide protection against such damage. The extracellular concentration of glutamate or aspartate may be transiently raised prior to or early in seizure activity but tends not to match the levels associated with hypothalamic damage in the original paradigm of excitotoxicity. Various aspects of the excitotoxic process are examined to see if they can account for particular details of the pattern of selective neuronal loss. A full explanation of selective vulnerability will take into account not only a range of characteristics of the vulnerable neuron but also its functional network during sustained activity.
Evidence of Nuclear DNA Fragmentation Following Hypoxia‐Ischemia in the Infant Rat Brain, and Transient Forebrain Ischemia in the Adult Gerbil
Authors: Ferrer Isidro , Tortosa Avelina , Macaya Alfons , Sierra Angels , Moreno Dolores , Munell Francina , Blanco Rosa , Squier Waney
Published: January 2008

Wistar rats, eight days old, were subjected to permanent bilateral forebrain ischemia, followed by hypoxia for 15 minutes. A cerebral infarct, mainly involving the cerebral neocortex, hippocampus, amygdala, striatum and subcortical white matter was produced. Neurons and glia showing punctate chromatin condensation and karyorrhectic cells were observed 12 hours after hypoxia‐ischemia. Their number increased during the first two days and recruitment of cells with degenerating nuclei occurred until day five. In situ labeling of nuclear DNA fragmentation stained many normal‐appearing nuclei, as well as punctate chromatin condensations and nuclear fragments in karyorrhectic cells. Delayed neuronal death in the CA1 area of the hippocampus was observed after 20 minutes of transient forebrain ischemia in the adult gerbil. In situ labeling of nuclear DNA fragmentation demonstrated stained punctate chromatin condensation in a few degenerating cells at 48 hours post‐ischemia. Substantial labeling of CA1 neurons occurred in the fourth day.

Agarose gel electrophoresis of extracted brain DNA from ischemic infant rats and adult gerbils showed a ladder‐type pattern which is typical of nuclear DNA fragmentation into oligonucleosomal fragments (internucleosomal cleavage). These findings suggest that endonuclease(s) activation may play a role in cell death induced by different forms of hypoxia‐ischemia.
Do Chemokines Mediate Inflammatory Cell Invasion of the Central Nervous System Parenchyma?
Authors: Tani Marie , Ransohoff Richard M.
Published: January 2008

Inflammatory cell recruitment into the central nervous system (CNS) is a critical step in the response to diverse insults, including infection, trauma and infarction, as well as immune‐mediated disorders such as multiple sclerosis (MS). Despite considerable advances in understanding immune surveillance and antigen recognition in the CNS, the signals resulting in parenchymal inflammation are incompletely understood. Members of a novel family of chemo‐attractant cytokines, the chemokines, are made in the CNS and are emerging as likely mediators of inflammatory cell migration into the CNS.
Immunohistochemistry of the Glial Fibrillary Acidic Protein: Basic and Applied Considerations
Authors: McLendon Roger E. , Bigner Darell D.
Published: January 2008

The immunohistochemical localization of glial fibrillary acidic protein has proven its utility in the histologic identification of benign astrocytes and neoplastic cells of glial lineage in the central nervous system. Its application in the developing nervous system has contributed significantly to following the histogenesis of neural tissue. Its identification in various forms of injury and neoplasia has helped in discovering the function of astrocytes in these processes. In diagnostic neuropathology, its greatest contribution has been in the elucidation of the cellular constituencies of neoplasms previously considered of enigmatic origin.
GFAP and Astrogliosis
Authors: Eng Lawrence F. , Ghirnikar Roopa S.
Published: January 2008

One of the most remarkable characteristics of astrocytes is their vigorous response to diverse neurologic insults, a feature that is well conserved across a variety of different species. The astroglial response occurs rapidly and can be detected within one hour of a focal mechanical trauma (Mucke et al., 1991). Prominent reactive astrogliosis is seen; in AIDS dementia; a variety of other viral infections; prion associated spongiform encephalopathies; inflammatory demyelinating diseases; acute traumatic brain injury; neurodegenerative diseases such as Alzheimer's disease. The prominence of astroglial reactions in various diseases, the rapidity of the astroglial response and the evolutionary conservation of reactive astrogliosis indicate that reactive astrocytes fulfill important functions of the central nervous system (CNS). Yet, the exact role reactive astrocytes play in the injured CNS has so far remained elusive. This chapter summaries the various experimental models and diseases that exhibit astrogliosis and increase in glial fibrillary acidic protein (GFAP). Recent in vitro studies to inhibit GFAP synthesis are also presented.
Structure and Transcriptional Regulation of the GFAP Gene
Authors: Brenner Michael
Published: January 2008

Transcriptional regulation of the GFAP gene is intimately connected with astrocyte function: its initial activation marks the differentiation of astrocytes, and its up‐regulation accompanies the reactive response to CNS injury. Studies of GFAP transcription should thus provide insights into multiple regulatory pathways operating in these cells. In addition, they should identify DNA elements that could be used to direct synthesis of other proteins to astrocytes in transgenic animals, permitting creation of disease models, and the testing of cause and effect relationships. This review describes several GFAP cDNA and genomic clones that have been isolated, including homology comparisons of the encoded RNAs and proteins. Cell transfection studies by several laboratories are summarized that have identified a DNA segment immediately upstream of the RNA start site that is essential for transcriptional activity, but which have yielded conflicting results concerning the importance of other segments located both further upstream and downstream of the RNA start site. Two procedures are recounted that have led to the successful expression of GFAP‐transgenes in astrocytes in mice. One of these incorporates the transgene into the first exon of a fragment spanning the entire GFAP gene, while the other links it to a 2 kb 5′‐flanking segment. Results already produced by GFAP‐transgenic studies include demonstration of a neurotoxic effect of the HIV‐1 gp120 coat protein, and creation of a hydrocephalic mouse model.
Familial Brain Tumour Syndrome Associated with a p53 Germline Deletion of Codon 236
Authors: Lübbe Jann , von Ammon Klaus , Watanabe Kunihiko , Hegi Monika E. , Kleihues Paul
Published: January 2008

This report describes clinical, neuropathological and molecular genetic findings in a Swiss family with four brain tumours in only two generations. The neoplasms observed covered a wide range of biologic behaviour, from a slowly growing lesion already apparent at birth, to anaplastic astrocytoma in a young adult and glioblastomas at the age of less then 10 years. The only non‐neural neoplasms in this family were a case of leukemia and an adrenocortical carcinoma. A germline deletion of codon 236 of the p53 tumour suppressor gene was identified as an underlying cause and detected in all affected family members. This mutation has not previously been reported as germline transmission or in sporadic tumours. The unusual accumulation of CNS tumours may be due to a certain organ‐specific effect of this particular p53 mutation or it may reflect the specific genetic back‐ground of this family.
Neuropathology and the Scrapie‐Kuru Connection
Authors: Hadlow William J.
Published: January 2008

When their kinship was surmised 35 years ago, scrapie and kuru were linked mainly by their neuropathologic similarity. Most notable were neuronal degeneration and intense astrocytosis with little, if any, inflammation. Especially eye‐catching in kuru were the vacuolated neurons ‐ the histologic hallmark of scrapie that drew me to the human disease from the start. Because spongiform change in gray matter neuropil is variable and usually lacks prominence in both scrapie and kuru, it was not part of the resemblance I saw in them. Amyloid plaques, so characteristic of kuru, also did not figure in the similarity, for they had not yet been reported in scrapie. Despite the uncertainty at the time about the pathologic essence of scrapie, the two diseases still looked alike. Their eventual connection ‐ however tenuously held together initially by the few likenesses ‐ has survived as a tribute to morphologic observation. It provided the essential link that helped ensure the kinship a lasting place in comparative neuropathology.
The Nosology of Creutzfeldt‐Jakob Disease and Conditions Related to the Accumulation of PrPCJD in the Nervous System
Authors: Richardson Edward P. , Masters Colin L.
Published: January 2008

Although typical cases of Creutzfeldt‐Jakob disease are readily recognized pathologically and clinically, variant forms often pose a diagnostic challenge. From the 1920's, when this disease was first characterized, until quite recently diagnosis relied heavily on morphologic changes. New advances in immunoassays and PrP gene analysis now provide important adjuncts in recognizing the spectrum of disorders of PrP metabolism associated with these transmissible encephalopathies.
The Neuropathology and Epidemiology of Bovine Spongiform Encephalopathy
Authors: Wells Gerald A. H. , Wilesmith John W.
Published: January 2008

Bovine spongiform encephalopathy (BSE), defined originally from its characteristic neuropathology, retains a place of particular interest in the scrapie‐like or prion disease group, presenting uniquely an example of such diseases occurring as a nationwide food‐borne epidemic in Great Britain. Comprehensive monitoring of the epidemic, both pathologically and epidemiologically, has facilitated our present understanding of the disease. BSE presents the classical neuropathological features of the transmissible spongiform encephalopathies. Although particularly similar to natural scrapie of sheep, BSE has, unlike scrapie, a stereotypic lesion profile from which it has been concluded that host and agent factors, including probably the strain of agent, which influence the profile, are constant in this disease. Neuronal loss in BSE may make an important but hitherto inapparent contribution to functional deficits. Preliminary ultrastructural studies have confirmed light microscopic features of brain changes in BSE but have as yet not established significant new findings.

Immunohistochemical studies of PrP accumulation reveal distinctive forms and distributions of immunolabelling, confirming features reported previously in experimental models of scrapie, including perineuronal and perineuritic “synapse‐like” reactivity.

The histopathological diagnosis of BSE, validated on a single section of the medulla for the statutory diagnosis of large numbers of cases, is supplemented where necessary by fibril (SAF) examination which performs similarly to the histological diagnosis in the majority of cases.

Epidemiological studies of BSE have supported the pathological findings that there is no detectable variation in susceptibility within the cattle population. The detailed monitoring of the epidemic has revealed the expected effects on the incidence as a result of statutory measures intended to prevent food‐borne exposure after July 1988. The main effect has been a reduction in the national incidence during 1993 which has been continued into 1994. Analytical studies have not revealed any means of transmission, other than the food‐borne source, capable of maintaining the epidemic in Great Britain. An international comparison of risk factors for the occurrence of BSE indicates that an epidemic of similar magnitude outside the British Isles is unlikely.
Myoclonic Epilepsy with Ragged‐red Fibers (MERRF): An Immunohistochemical Study of the Brain
Authors: Sparaco Marco , Schon Eric A. , DiMauro Salvatore , Bonilla Eduardo
Published: January 2008

Myoclonic epilepsy with ragged‐red fibers (MERRF) is a maternally inherited disorder of oxidative phos‐phorylation due to specific point mutations within the mitochondrial tRNALvs gene. Mitochondrial dysfunction in the central nervous system (CNS) of patients with MERRF accounts for the neurological manifestations of the disease. Antibodies against subunits of complex I, III, IV and V of the respiratory chain were used to study the expression of these proteins in the frontal cortex, cerebellum and medulla from an autoptic case of MERRF. We found a selective decreased expression of subunit II of cytochrome c oxidase (COX‐II) in these regions. Immunohistochemical abnormalities were more widespread than the lesions described by traditional histopathological techniques and made possible an attempt of explanation for the neurological symptoms of the patient.
Neuropathology and Molecular Genetics of Neurofibromatosis 2 and Related Tumors
Authors: Louis David N. , Ramesh Vijaya , Gusella James F.
Published: January 2008

Neurofibromatosis 2 (NF2) is an uncommon, autosomal dominant disorder in which patients are predisposed to neoplastic and dysplastic lesions of Schwann cells (schwannomas and schwannosis), meningeal cells (meningiomas and meningioan‐giomatosis) and glial cells (gliomas and glial hamar‐tomas). Clinical and genetic criteria that distinguish NF2 from neurofibromatosis 1 have allowed more accurate assignment of specific pathological features to NF2. The NF2 tumor suppressor gene on chromosome 22q12 encodes a widely expressed protein, named merlin, which may link the cytoskeleton and cell membrane. Germline NF2 mutations in NF2 patients and somatic NF2 mutations in sporadic schwannomas and meningiomas have different mutational spectra, but most NF2 alterations result in a truncated, inactivated merlin protein. In NF2 patients, specific mutations do not necessarily correlate with phenotypic severity, although grossly truncating alterations may result in a more severe phenotype. In schwannomas, NF2 mutations are common and may be necessary for tumorigenesis. In meningiomas, NF2 mutations occur more commonly in fibroblastic than meningothelial subtypes, and may cluster in the first half of the gene. In addition, in meningiomas, a second, non‐NF2 meningioma locus is probably also involved. Future efforts in NF2 research will be directed toward elucidating the role of merlin in the normal cell and the sequelae of its inactivation in human tumors.
Clinical, Neuropathological and Genetic Aspects of the Tuberous Sclerosis Complex
Authors: Short M. Priscilla , Richardson Edward P. , Haines Jonathan L. , Kwiatkowski David J.
Published: January 2008

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome in which patients develop hamartomatous lesions in the nervous system and a host of other organs. While considerable experience has been gained in defining the clinical spectrum of TSC, a number of nosological questions remain. Neuropathological studies have continued to refine our knowledge of the nervous system abnormalities that characterize TSC. Molecular genetic studies have implicated two chromosomal regions in the genesis of TSC, one on chromosome 9q and the other on chromosome 16p. The chromosome 16p gene, designated TSC2, has been cloned, although its function remains speculative. The identification of the TSC1 gene on chromosome 9q, along with functional studies and mutational analyses of both TSC genes, will likely provide fascinating insights into the pathogenesis of TSC.
Von Hippel‐Lindau Syndrome
Authors: Neumann Hartmut P.H. , Lips Cornells J.M. , Hsia Y. Edward , Zbar Berton
Published: January 2008

After a decade of intensive clinical and molecular genetic efforts the von Hippel‐Lindau (VHL) gene was cloned in 1993. The open reading frame encodes the putative protein of 284 amino acids. A large number of different mutations have been identified so far, including single base mutations, deletions, rearrangements and more complex mutations. So far, in about 75% of the VHL families germline mutations were detected. Geno‐phenotypic comparision has revealed specific mutations with distinct manifestation patterns. Not all of the 6 classical lesions (hemangioblastoma of the CNS, retinal angiomatosis, pancreatic cysts, renal cysts and carcinoma, pheochromocytoma and epididymal cystadenoma) are present in VHL families. Pedigrees with pheochromocytoma but without renal cancer in general have point mutations. These recent results provide insight in the pathogenesis of a multiorgan cancer susceptibility tumor suppressor gene and allow determination of carrier status.
The Original Gerstmann‐Sträussler‐Scheinker Family of Austria: Divergent Clinicopathological Phenotypes but Constant PrP Genotype
Authors: Hainfellner Johann A. , Brantner‐Inthaler Sigrid , Cervenáková Larisa , Brown Paul , Kitamoto Tetsuyuki , Tateishi Jun , Diringer Heino , Liberski Pawel P. , Regele Heinz , Feucht Martha , Mayr Norbert , Wessely Peter , Summer Kurt , Seitelberger Franz , Budka Herbert
Published: January 2008

We present new data on the original Austrian kindred with Gerstmann‐Sträussler‐Scheinker disease (GSS) which encompasses currently 221 members in 9 generations. The mode of inheritance is autosomal dominant. Predominant clinical features are slowly progressive ataxia and late impairment of higher cerebral functins. In contrast, a recent case with proven P102L mutation of the PRNP gene had rapidly developing dementia and severe cortical damage indistinguishable from the clinicopathological phenotype of Creutzfeldt‐Jakob disease (CJD). PRNP codon 129 was homozygous for methionine in both the historic and recent cases. Neuropathology confirms spongiosis of variable degree and numerous protease resistant / prion protein (PrP) amyloid plaques scattered throughout most of the brain as constant features in this family. Some amyloid deposits are surrounded by dystrophic neurites with accumulation of phosphorylated neurofilaments and abnormal organelles, reminiscent of Alzheimer‐type plaques. Severe telencephalic damage and a synaptic‐type fine granular immunoreactivity in laminar distribution in the cortex with anti‐PrP after hydrated autoclaving of sections were seen only in the recent patient. In conclusion, factors in addition to the PRNP genotype at codons 102 and 129 must play a role in determining clinicopathological characteristics of this inherited brain amyloidosis.
Neuronal Cell Death in Scrapie‐Infected Mice Is Due to Apoptosis
Authors: Giese Armin , Groschup Martin H. , Hess Barbara , Kretzschmar Hans A.
Published: January 2008

Neuronal loss is a salient yet poorly understood feature in the pathology of transmissible spongiform encephalopathies (prion diseases). Cell culture experiments with neurotoxic prion protein fragments suggest that neuronal cell death in these diseases may be due to apoptosis. To test this hypothesis in vivo we used the in situ end‐labeling (ISEL) technique and electron microscopy to study cell death in an experimental scrapie system in the mouse. ISEL, which relies on the incorporation of labeled nucleotides in fragmented DNA by terminal transferase, showed labeled nuclei in the brains and retinae of mice infected with the 79A strain of scrapie, whereas no labeling was observed in control animals. In the retina the highest numbers of labeled nuclei were found in the outer nuclear layer 120 days post infection followed by massive cell loss in this layer. In the brain, labeled nuclei were mainly found in the granular layer of the cerebellum of terminally ill mice. This corresponded to the presence of small dark nuclei with condensed and occasionally fragmented chromatin at the light and electron microscopical levels. Our results support the hypothesis that neuronal loss in spongiform encephalopathies is due to apoptosis. This may explain the almost complete absence of inflammatory response in prion diseases in the face of widespread neuronal cell death, and may also have therapeutic implications in the future.
Presence of CD4+ and CD8+ T Cells and Expression of MHC Class I and MHC Class II Antigen in Horses with Borna Disease Virus‐Induced Encephalitis
Authors: Bilzer Thomas , Planz Oliver , Lipkin W. Ian , Stitz Lothar
Published: January 2008

Tissues from 9 horses and 1 donkey suffering from natural Borna disease were investigated immunomorphologically. Lymphocytic inflammatory reactions and increased expressions of MHC class I and class II antigen were found in the brain as well as in the trigeminal and olfactory system. Perivascular inflammatory infiltrates were dominated by CD4+ T cells, whereas the majority of CD8+ T cells were disseminated intraparenchymally. No evidence of inflammation was found in the retina. Borna disease virus proteins and nucleic acids were present in the hippocampus, thalamus and medulla oblongata in all 10 animals, in the cerebral cortex, retina, trigeminal ganglion and nerve in 9, in the olfactory epithelium in 6 and in roots and proximal parts of large peripheral nerves in 3. No evidence of infection was found in the autonomic nervous system, lung, heart, liver, kidney or gut. BDV‐ proteins and nucleic acids were even more abundant in the trigeminal system than in the olfactory system, suggesting that infection may have occured via the trigeminal nerve.
Molecular Basis of Common Hereditary Motor and Sensory Neuropathies in Humans and in Mouse Models
Authors: Snipes G. Jackson , Suter Ueli
Published: January 2008

The Hereditary Motor and Sensory Neuropathies (HMSNs) are well known to be clinically, morphologically, and genetically heterogeneous. Yet, recent advances in the cellular and molecular biology of the peripheral nervous system coupled with remarkable progress in human and mouse genetics have provided a framework that has profoundly changed our understanding of the pathogenesis of these diseases. It now appears that most of the HMSNs are related to mutations affecting genes encoding Schwann cell proteins, specifically the Peripheral Myelin Protein PMP22, Myelin Protein Zero, and one of the gap junction proteins, connexin‐32. Accordingly, these findings are discussed in the context of the clinical and pathologic features of the human HMSNs, but are interpreted in the context of basic research findings on the cellular and molecular biology of the peripheral nervous system derived from in vivo and in vitro studies in spontaneously‐occurring and genetically engineered animal models for the HMSNs.
Adrenoleukodystrophy: Molecular Genetics, Pathology, and Lorenzo's oil
Authors: Moser Hugo W. , Powers James M. , Smith Kirby D.
Published: January 2008

Knowledge about adrenoleukodystrophy (ALD), a disorder which was described first in 1923, has increased greatly during recent years. The principal biochemical abnormality, the presumed enzyme defect, and the gene defect, have been defined. A dietary therapy has been proposed and attracted world‐wide attention through a motion picture. Nevertheless, many questions remain and cannot be answered without a more fundamental understanding of pathology and pathogenesis. This article will provide a review of the history, clinical features, pathology, biochemistry, and the gene defect, and then appraise current efforts to clarify pathogenesis and develop therapeutic approaches.
Neuropathology and Genetics of Pelizaeus‐Merzbacher Disease
Authors: Seitelberger Franz
Published: January 2008

The recent history of Pelizaeus‐Merzbacher Disease (PMD) demonstrates paradigmatically the impact of basic biological research on clinical neurology and brain pathology: this rare and peculiar hereditary disease has become one of the best known disorders of its kind, through a cooperative research effort in neuropathology, human genetics, neurochemistry and molecular biology. PMD, a genetic dysmyelination restricted to the CNS, has been identified as a disease that involves the X chromosome‐linked gene for myelin proteolipid protein (PLP), a major structural myelin component. Today more than 30 different mutations in this gene have been defined and associated with PMD or the clinically distinct form X‐linked spastic paraplegia type‐2 (SPG‐2). Improved scanning techniques, specifically the non‐invasive magnetic resonance imaging (MRI), allow its early diagnosis in the heterogeneous group of CNS myelin deficiencies. These remarkable achievements have, at the same time, caused a problem for disease classification. Myelin disorders have been grouped in the past on the basis of clinical and neuropathological criteria, creating a system that has now to be reconciled with molecular‐genetic data.
Programmed Cell Death in the Dysmyelinating Mutants
Authors: Skoff Robert P.
Published: January 2008

A large number of genetic mutants that are missing a particular myelin protein or that have an aberrant myelin protein composition have been described. These mutations usually cause dysmyelination in the PNS or CNS. Similarly, the nervous system of animals experimentally altered to block synthesis of myelin proteins have recently been generated that show aberrations in the myelin sheath. For both groups of animals, the numbers of myelinating cells remain relatively stable and glial cell death is minimal. The exception is animals with mutations in the proteolipid protein (PLP) gene which exhibit extensive death of oligodendrocytes (OLs). The degree of OL death in the PLP mutants generally correlates with the amount of dysmyelination. Dying OLs in the PLP mutants exhibit the classical features of apoptotic cells. Programmed cell death (PCD) is often, but not necessarily, manifested by cleavage of DNA into abundant oligonucleosomal fragments. Detection of these abundant DNA fragments was examined in normal and jimpy (jp) mice using the TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) method. In normal spinal cord and brain, at least twice as many cells exhibited DNA fragmentation when compared to numbers of pyknotic glia observed microscopically. In jp spinal cord and brain, roughly onehalf of cells exhibited DNA fragmentation when compared to numbers of pyknotic glia observed microscopically. PCD of cells in normal development involving DNA fragmentation has been previously described and our results support that conclusion. The data obtained from the jp mice suggests that the mechanism of apoptosis due to PLP mutations is somewhat different from that which occurs in normal development.
Glial Cell Transplants: Experimental Therapies of Myelin Diseases
Authors: Duncan Ian D. , Milward Elizabeth A.
Published: January 2008

Transplantation of cells into the CNS of human patients with neurodegenerative disorders offers a radical new approach to the treatment of previously incurable diseases. Considerable success has been achieved in Parkinson's disease following transplantation of human fetal dopaminergic neurons. Disorders of myelination of the brain, of either inherited or acquired origin, might also be treated by glial cell transplantation although there are additional challenges. Cells of the oligodendrocyte lineage have been found to be capable of myelinating axons on transplantation into numerous experimental pathological environments, including the CNS of myelin mutants and focal areas of demyelination in normal animals made by injection of myelinotoxic chemicals. In general, primary cells and progenitors are likely to have the greatest myelinating capacity. Cell lines can also be used, but those driven by oncogenes may produce little myelin, and tumor formation is likely. Schwann cells are also a potential source of cells, possibly as a homograft, and may be primed by treatment ex vivo with glial growth factors. The variable CNS milieu seen in human myelin disease will mean that transplanted cells must be able to migrate appropriately and myelinate axons in an adult, pathological environment, and this awaits experimental confirmation. Physiological analysis of transplants in such situations in adult animals will provide the functional data which may expedite clinical trials.
Intercellular Adhesion Molecule‐1 (ICAM‐1) Upregulation in Human Brain Tumors as an Expression of Increased Blood‐Brain Barrier Permeability
Authors: Lossinsky Albert S. , Mossakowski Miroslaw J. , Pluta Ryszard , Wisniewski Henryk M.
Published: January 2008

The distribution of intercellular adhesion molecule (ICAM‐1) binding sites was studied in the microvasculature of several types of human brain tumor biopsies (angioma, glioblastoma multiforme and meningioma). Immunoelectron microscopy was performed with the application of immuno‐HRP or gold probes using a pre‐embedding technique. Ultrastructural analysis demonstrated a pronounced ICAM‐1 upregulation on the luminal EC and/or perivascular surfaces. Reaction product for ICAM‐1 was observed associated with some but not all blood vessels of the tumors examined. The strongest reaction product was noted associated with the angioma cases with lesser expression observed on the glioblastoma multiforme and meningioma cases. The reaction product using immuno‐HRP probe was observed most pronounced on the luminal endothelial cell surface and also within vesiculo‐tubular structures. Concentrated immunosignals with gold label were often expressed on EC microvilli. These data suggest that several types of brain tumors are actively involved in the process of upregulating ICAM‐1, presumably for tumor cell adhesion and trafficking, the process of angiogenesis or both. We suggest that the ICAM‐1‐positive vesiculo‐tubular structures reflect specialized, targeted regions on the ECs for tumor cell adhesion and eventual trans‐BBB passage. Further, our studies also provide evidence that adhesion molecules may be a useful tool for the study of blood‐brain barrier injury.