Showing papers in "Brain Pathology in 1997"

Free‐living, Amphizoic and Opportunistic Amebas

Abstract: Amebas belonging to the genera Naegleria, Acanthamoeba and Balamuthia are free-living, amphizoic and opportunistic protozoa that are ubiquitous in nature. These amebas are found in soil, water and air samples from all over the world. Human infection due to these amebas involving brain, skin, lung and eyes has increased significantly during the last 10 years. The epidemiology, immunology, protozoology, pathology, and clinical features of the infections produced by these protozoa differ strikingly. Infection by the pathogenic Naegleria fowleri is acquired by exposure to polluted water in ponds, swimming pools and man-made lakes. Raised temperatures during the hot summer months or warm water from power plants facilitate the growth of N. fowleri. N. fowleri is a thermophilic ameba that grows well in tropical and subtropical climates. The CNS infection, called Primary Amebic Meningoencephalitis (PAM), produced by N. fowleri is characterized by an acute fulminant meningoencephalitis leading to death 3-7 days after exposure. Victims are healthy, young individuals with a history of recent water-related sport activities. The portal of entry is the olfactory neuroepithelium. The pathologic changes are an acute hemorrhagic necrotizing meningoencephalitis with modest purulent exudate, mainly at the base of the brain, brain-stem and cerebellum. Trophozoites can be seen within the CNS lesions located mainly around blood vessels. Thus far 179 cases have been reported; 81 in the USA alone. Balamuthia mandrillaris and several species of Acanthamoeba are pathogenic "opportunistic" free-living amebas which cause Granulomatous Amebic Encephalitis (GAE) in humans and animals. GAE is an infection, usually seen in debilitated, malnourished individuals, in patients undergoing immunosuppressive therapy for organ transplants and in Acquired Immunodeficiency Syndrome (AIDS). The granulomatous component is negligible, particularly in immunocompromised individuals. Pathologically these amebas produce a patchy, chronic or subacute granulomatous encephalitis with the presence of trophozoites and cysts. The portal of entry is probably through the respiratory tract or an ulceration of the skin reaching the CNS by hematogenous spread. As of October 1, 1996, 166 cases (103 due to Acanthamoeba and 63 due to Balamuthia) of GAE have been reported from around the world. Of these 103 cases due to Acanthamoeba (72 have been reported in the USA alone, > 50 in AIDS). It is well known that several species of Acanthamoeba can also produce, chronic sight threatening ulceration of the cornea called Acanthamoeba keratitis (AK), mostly in contact lens wearers or in individuals with minor corneal abrasions. Hundreds of cases of AK have been documented world wide.

The Role of Macrophages in Wallerian Degeneration

Abstract: The present review focuses on macrophage properties in Wallerian degeneration. The identification of hematogenous phagocytes, the involvement of cell surface receptors and soluble factors, the state of activation during myelin removal and the signals and factors leading to macrophage recruitment into degenerating peripheral nerves after nerve transection are reviewed. The main effector cells in Wallerian degeneration are hematogenous phagocytes. Resident macrophages and Schwann cells play a minor role in myelin removal. The macrophage complement receptor type 3 is the main surface receptor involved in myelin recognition and uptake. The signals leading to macrophage recruitment are heterogenous and not yet defined in detail. Degenerating myelin and axons are suggested to participate. The relevance of these findings for immune-mediated demyelination are discussed since the definition of the role of macrophages might lead to a better understanding of the pathogenesis of demyelination.

Formation of neuronal intranuclear inclusions (NII) underlies the neurological dysfunction in mice transgenic for the HD mutation

Abstract: Huntington's disease (HD) is one of an increasing number of human neurodegenerative disorders caused by a CAG/polyglutamine-repeat expansion. The mutation occurs in a gene of unknown function that is expressed in a wide range of tissues. The molecular mechanism responsible for the delayed onset, selective pattern of neuropathology, and cell death observed in HD has not been described. We have observed that mice transgenic for exon 1 of the human HD gene carrying (CAG)115 to (CAG)156 repeat expansions develop pronounced neuronal intranuclear inclusions, containing the proteins huntingtin and ubiquitin, prior to developing a neurological phenotype. The appearance in transgenic mice of these inclusions, followed by characteristic morphological change within neuronal nuclei, is strikingly similar to nuclear abnormalities observed in biopsy material from HD patients.

A Molecular Genetic Model of Astrocytoma Histopathology

Abstract: As the molecular events responsible for astrocytoma formation and progression are being clarified, it is becoming possible to correlate these alterations with the specific histopathological and biological features of astrocytoma, anaplastic astrocytoma and glioblastoma multiforme. In WHO grade II astrocytomas, autocrine stimulation by the plateletderived growth factor system coupled with inactivation of the p53 gene may lead to a growth stimulus in the face of decreased cell death with slow net growth ensuing. Such cells would also have defective responses to DNA damage and impaired DNA repair, setting the stage for future malignant change. Such biological scenarios recapitulate many of the clinicopathological features of WHO grade II astrocytomas. Anaplastic astrocytomas further display release of a critical cell cycle brake that involves the CDKN2/p16, RB and CDK4 genes. This results in mitoses seen histologically; clinically, there is more conspicuous, rapid growth. Finally, glioblastomas may emerge from the microenvironmental outgrowth of more malignant clones in a complex vicious cycle that involves necrosis, hypoxia, growth factor release, angiogenesis and clonal selection; growth signals mediated by activation of epidermal growth factor receptors may precipitate glioblastomas. It is clear as well that glioblastoma multiforme can arise via a number of independent genetic pathways, although the clinical significance of these distinctions remains unclear.

Fas ligand expression in glioblastoma cell lines and primary astrocytic brain tumors.

Abstract: Fas/APO-1 (CD95) is a cell surface receptor that mediates apoptosis when it reacts with Fas ligand (FasL) or Fas antibody. We previously reported that Fas expression is predominantly induced in perinecrotic glioma cells, suggesting that Fas induction is associated with apoptosis and necrosis formation, a histological hallmark of glioblastomas. In this study, we assessed the expression of FasL in 10 glioblastoma cell lines and in 14 astrocytic brain tumors (three low-grade astrocytomas and 11 glioblastomas). Reverse transcriptase (RT)-PCR revealed that all glioblastoma cell lines and primary astrocytic brain tumors express FasL. Immunohistochemically, FasL was predominantly expressed on the plasma membrane of glioma cells. These results suggest that FasL expression is common in human astrocytic brain tumors and may cause apoptosis of glioma cells if Fas expression is induced.

Association of EGFR Gene Amplification and CDKN2 (p16/MTS1) Gene Deletion in Glioblastoma Multiforme

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

The Neuropathology of CAG Repeat Diseases: Review and Update of Genetic and Molecular Features

Abstract: Classification of inherited neurodegenerative diseases is increasingly based on their genetic features, which supplement, clarify, and sometimes replace the older clinical and pathologic schemata. This change has been particularly rapid and impressive for the CAG repeat disorders. In Huntington's disease, X-linked spinobulbar muscular atrophy, dentatorubropallidoluysian atrophy, and a series of autosomal dominant cerebellar atrophies, genetic advances have resolved many nosologic issues, and opened new avenues for exploration of pathogenesis. In this review, we summarize classic and current concepts in neuropathology of these CAG repeat diseases.

Primitive Neuroectodermal Tumors of the Central Nervous System

Abstract: Controversial issues relating to the pathobiology and classification of central nervous system primitive neuroectodermal tumors (PNETs) have plagued neuropathologists for more than 70 years. Hypotheses advanced in the mid-1920's have remained as fixed concepts in contemporary literature, largely consequent to repetitious support by a small number of neuropathologists despite a growing body of information discrediting these ideas from neuroembryologists, oncologists, neuroscien-tists and pathologists. Attention has largely focused upon PNETs arising in the cerebellum (commonly known as medul-loblastomas [MBs]), because about 80% of central nervous system (CNS) PNETs originate in this site. It has been asserted that the 20% which do not are biologically different, although most individuals agree that the histological features of PNETs that occur in different sites throughout the CNS are indistinguishable from those growing in the cerebellum. The historical aspects of this controversy are examined in the face of evidence that there is, in fact, a unique class of CNS tumors which should appropriately be regarded as primitive neuroectodermal in nature. Specifically, a number of different approaches to the problem have yielded data supporting this hypothesis. These approaches include the identification of patterns of expression among a variety of cellular antigens (demonstrated by the use of immunopathological techniques), molecular analyses of cell lines derived from these tumors, experimental production of PNETs and molecular genetic analyses. Differences of opinion among surgeons, oncologists and radiotherapists are typically resolved by conducting cooperative studies of patients with these tumors who are diagnosed and treated at multiple centers.

The CAG/Polyglutamine Tract Diseases: Gene Products and Molecular Pathogenesis

Abstract: In the past few years, a new type of genetic mutation, expansion of trinucleotide repeats, has been shown to cause neurologic disease. This new class of mutations was first identified in 1991 as the underlying genetic defect in spinal and bulbar muscular atrophy and the fragile X syndrome, and in recent years, trinucleotide repeat expansions have been found to be the causative mechanism in 10 other neurologic diseases. These mutations are produced by heritable unstable DNA and are termed "dynamic mutations" because of changes in the number of repeat units inherited from generation to generation. In the normal population, these repeat units, although polymorphic, are stably inherited. To date four types of trinucleotide repeat expansions have been identified: (1) long cytosine-guanine-guanine (CGG) repeats in the two fragile X syndromes (FRAXA and FRAXE), (2) long cytosine-thymine-guanine (CTG) repeat expansions in myotonic dystrophy, (3) long guanine-adenine-adenine repeat expansions in Friedreich's ataxia and (4) short cytosine-adenine-guanine repeat expansions (CAG) which are implicated in eight neurodegenerative disorders and are the focus of this review. Diseases that are caused by trinucleotide repeat expansions exhibit a phenomenon called anticipation that can not be explained by conventional Mendelian genetics. Anticipation is defined as increase in the severity of disease with an earlier age of onset of symptoms in successive generations. Anticipation is often influenced by the sex of the transmitting parent, and for most CAG repeat disorders, the disease is more severe when paternally transmitted. The severity and the age of onset of the disease have been correlated with the size of the repeats on mutant alleles, with the age of onset being inversely correlated with the size of the expansion. In all eight disorders caused by CAG repeat expansion, the repeat is located within the coding region of the gene involved and in all cases it is translated into a stretch of polyglutamines in the respective proteins. All the proteins are unrelated outside of the polyglutamine stretch and most are novel with exception of the androgen receptor and the voltage gated alpha 1A calcium channel, which are mutated in spinal and bulbar muscular atrophy and spinocerebellar ataxia type 6. It is intriguing that the proteins are ubiquitously expressed in both peripheral and nervous tissue but in each disorder only a select population of nerve cells are targeted for degeneration as a consequence of the expanded CAG repeat. Current thinking among scientists working on the molecular mechanisms of neurodegeneration in these diseases is that the presence of an expanded polyglutamine confers a gain of function onto the involved protein. To understand the mechanisms underlying the pathogenesis of these diseases, investigators have turned to generating transgenic mice which recapitulate some of the features of the human disease and hence are excellent model systems to study the progression of the disease in vivo.

The Molecular Biology of Ependymomas

Abstract: Intracranial ependymomas are the third most common primary brain tumor in the pediatric population. Although an anaplastic variant is recognized, numerous studies examining the prognostic implications of histological features, such as necrosis, endothelial proliferation and mitoses, have yielded contradictory results. In order to improve outcome prediction in affected patients and to refine therapeutic decision-making, there is a strong need for identifying relevant biological correlates of tumor behavior. The molecular biology of tumors is a rapidly expanding field and includes investigations into cytogenetics, oncogenes, growth factors, growth factor receptors, hormonal receptors, proliferation markers, apoptosis, cell cycle genes and cell adhesion molecules, as well as factors potentially related to therapeutic resistance, such as the multidrug resistance gene. The molecular biology of astrocytic tumors in adults has been the subject of many studies; however, relatively few studies have been focused on ependymomas. Herein we review potential oncological markers in ependymomas that have been identified to date and highlight the limitations of our current knowledge as a basis for defining areas for future investigation.

A confocal microscopic analysis of galaninergic hyperinnervation of cholinergic basal forebrain neurons in Alzheimer's disease.

Abstract: The galanin (GAL) containing peptide fiber system innervates the basal forebrain and has been shown to hyperinnervate remaining cholinergic neurons in Alzheimer's disease (AD). GAL modulates the release of acetylcholine and, therefore, may depress this neurotransmitter in surviving cholinergic basal forebrain (CBF) neurons in AD. The aim of this study was to identify putative synaptic contacts between GAL immunoreactive processes and CBF neurons and evaluate whether these processes hypertrophy in AD patients. We observed by confocal laser microscopy a hyperinnervation of GAL-containing fibers in both AD and Parkinson's disease patients with concurrent AD (PD/AD). Galaninergic fibers were often seen in direct apposition to remaining CBF neurons and enwrapped cholinergic cell soma and dendrites. Our results demonstrate that GAL-containing fibers are in direct apposition to CBF neurons in normal-aged humans and that this phenotype is enhanced in AD and PD/AD, suggesting that direct synaptic contacts occur between GAL-containing fibers and CBF neurons. Because GAL can modulate acetylcholine release from cholinergic neurons, hyperinnervation of GAL fibers in AD and PD/AD patients may further decrease release of acetylcholine from remaining CBF neurons. We propose that therapies based solely on acetylcholinesterase inhibitors may be insufficient to effectively increase cortical levels of acetylcholine.

Clinical aspects of CAG repeat diseases.

Abstract: Seven neurodegenerative disorders are known to be caused by unstable expansions of the trinucleotide CAG within human genes, and more will be discovered in the coming years. These disorders share some clinical similarities, as well as some differences, which are summarized here. These diseases have unusual clinical genetic properties related to the dynamic nature of CAG repeat expansions, including instability of the repeat expansion in meiosis, particularly male meiosis; a strong correlation between onset age and size of the repeat expansion; anticipation (earlier disease onset in succeeding generations); new mutations arising from unstable, mutable alleles with a high-normal CAG repeat number; and reduced penetrance for alleles in the lowaffected range. Much more remains to be learned about the molecular biology and clinical pathophysiology of this new class of genetic diseases. Summary In the last six years, seven neurodegenerative diseases have been found to be caused by expansions of intragenic CAG repeat sequences. The diseases share a variable (usually adult) age of onset, which is highly dependent on the length of the CAG repeat, and effects on multiple systems within the central and peripheral nervous systems. The cerebral cortex is not a primary site of pathology for any of the diseases, and organs other than the nervous system are not primarily affected (except for SBMA). The diseases differ in their primary site of neuropathology, and for that reason have widely varying neurologic profiles. The distributions of normal and abnormal CAG repeat sizes vary among the diseases, and suggest that different mechanisms of mutagenesis or disease pathogenesis could exist for the different disorders. The dynamic nature of trinucleotide repeat mutations has clarified a number of clinical and genetic observations in these diseases. New mutations arising from mutable normal alleles have been reported for some of the diseases. The tendency to further expansion of an expanded allele provides a molecular correlate to the clinical observation of anticipation (171). Sex- and disease-dependent meiotic instability correlates with the observation of a paternal bias among juvenile onset cases for HD, SCA1 and DRPLA. Finally, reduced penetrance for alleles at the low end of the abnormal range has been observed for some (but not all) diseases in the group. Detection of CAG repeat expansions is relatively easy and inexpensive in the clinical laboratory, and molecular diagnosis has greatly improved diagnostic accuracy for this group of disorders. However, a full understanding of the biology and pathophysiology of this new class of mutations is still to come, and is awaited eagerly by clinicians and patients alike.

Genetics of Glioma Progression and the Definition of Primary and Secondary Glioblastoma

Abstract: Summary Glioblastoma multiforme, the most malignant human brain tumor, may develop de novo (primary glioblastoma) or through progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). We present evidence that these subtypes of glioblastoma constitute distinct disease entities which evolve through different genetic pathways, affect patients at different age and are likely to differ in prognosis and response to therapy. Primary glioblastomas develop in older patients (mean, 55 years) and typically show EGFR overexpres-sion or, less frequently, MDM2 overexpression and pi6 deletion. Secondary glioblastomas develop in younger patients (mean, 40 years) and frequently contain TP53 mutations and, less consistently, loss of DCC expression. Although primary and secondary glioblastomas are considered to be histologically indistinguishable, we found that the pattern and pathogenesis of necrosis are different, large areas of ischaemic necrosis surrounded by Fas expressing tumor cells being a hallmark of primary glioblastomas. The giant cell glioblastoma occupies an intermediate position. Like the primary glioblastoma, it rapidly develops de novo but manifests in younger patients (including children) and has genetic alterations typical for secondary glioblastomas, i.e. frequent TP53 mutations and lack of EGFR overexpression.

Toward understanding the molecular pathology of huntington's disease

Abstract: Huntington's Disease (HD) is caused by expansion of a CAG trinucleotide beyond 35 repeats within the coding region of a novel gene. Recently, new insights into the relationship between CAG expansion in the HD gene and pathological mechanisms have emerged. Survival analysis of a large cohort of affected and at-risk individuals with CAG sizes between 39 and 50 repeats have yielded probability curves of developing HD symptoms and dying of HD by a certain age. Animals transgenic for the first exon of huntingtin with large CAG repeats lengths have been reported to have a complex neurological phenotype that bears interesting similarities and differences to HD. The repertoire of huntingtin-interacting proteins continues to expand with the identification of HIP1, a protein whose yeast homologues have known functions in regulating events associated with the cytoskeleton. The ability of huntingtin to interact with two of its four known protein partners appears to be influenced by CAG length. Caspase 3 (apopain), a key cysteine protease known to play a seminal role in neural apoptosis, has also been demonstrated to specifically cleave huntingtin in a CAG length-dependent manner. Many of these features are combined in a model suggesting mechanisms by which the pathogenesis of HD may be initiated. The development of appropriate in vitro and animal models for HD will allow the validity of these models to be tested.

Pathology and Immunocytochemistry of a Kuru Brain

Abstract: We report here results of modern staining techniques including anti-prion protein (PrP) immunocytochemistry to a set of archival brain specimens of a 16 year-old male who died from kuru in 1967. Brain suspensions transmitted disease to chimpanzees and New World monkeys. The PrP gene is homozygous for valine at the polymorphic codon 129. Histology shows neuronal loss, spongiform change, and astrogliosis. Lesions are maximal in parasagittal and interhemispheric areas of frontal, central and parietal cortex, cingulate cortex, striatum, and thalamus, and are accentuated in middle and deep cerebral cortical layers. PrP accumulates as diffuse synaptic type deposits and mostly unicentric plaques. PrP deposition is maximal in parasagittal and interhemispheric areas of frontal, central and parietal cortex, cingulate cortex, basal ganglia, and cerebellar cortex. Plaques are prominent in the striatum, thalamus, and granular layer of cerebellar cortex. Meticulous examination reveals only rare “florid” plaques with surrounding vacuolation. We conclude that 1) pathology including immunomorphology of PrP deposition in this kuru brain is within the lesion spectrum of Creutzfeldt-Jakob disease although plaques are unusually prominent and widespread; 2) kuru does not share the neuropathological hallmarks of the new Creutzfeldt-Jakob disease variant recently reported in the UK and France; 3) topographic prominence of PrP deposition parallels that of spongiform change and/or astrogliosis.

Trinucleotide Repeat Instability: Genetic Features and Molecular Mechanisms

Abstract: Trinucleotide repeat expansions are an important cause of inherited neurodegenerative disease. The expanded repeats are unstable, changing in size when transmitted from parents to offspring (intergenerational instability, "meiotic instability") and often showing size variation within the tissues of an affected individual (somatic mosaicism, "mitotic instability"). Repeat instability is a clinically important phenomenon, as increasing repeat lengths correlate with an earlier age of onset and a more severe disease phenotype. The tendency of expanded trinucleotide repeats to increase in length during their transmission from parent to offspring in these diseases provides a molecular explanation for anticipation (increasing disease severity in successive affected generations). In this review, I explore the genetic and molecular basis of trinucleotide repeat instability. Studies of patients and families with trinucleotide repeat disorders have revealed a number of factors that determine the rate and magnitude of trinucleotide repeat change. Analysis of trinucleotide repeat instability in bacteria, yeast, and mice has yielded additional insights. Despite these advances, the pathways and mechanisms underlying trinucleotide repeat instability in humans remain largely unknown. There are many reasons to suspect that this uniquely human phenomenon will significantly impact upon our understanding of development, differentiation and neurobiology.

Classification and grading of low-grade astrocytic tumors in children.

Abstract: This article reviews current perspectives in the classification and grading of astrocytomas in children and calls attention to several histologically distinct groups of low-grade tumors that characteristically arise during childhood. Recognition of these tumors and the range of histological features that they may exhibit is essential for making rational assessments regarding their expected behavior and, more importantly, for guiding therapeutic intervention. For example, pleomorphic xanthoastrocytoma, which may exhibit "anaplastic" features, generally carries a relatively favorable prognosis and should not be classified with other high-grade gliomas, such as anaplastic astrocytoma and glioblastoma multiforme. Similarly, the finding of anaplastic features, such as vascular proliferation or necrosis, in pilocytic astrocytomas does not automatically portend the unfavorable prognosis that such features would imply for "diffuse" astrocytomas. Increased appreciation of the morphological diversity of astrocytomas in children should help to improve the management of children with low-grade astrocytic tumors by avoiding potentially dangerous overtreatment of otherwise indolent lesions.

Huntington's disease and dentatorubral-pallidoluysian atrophy : proteins, pathogenesis and pathology

Abstract: Each of the glutamine repeat neurodegenerative diseases has a particular pattern of pathology largely restricted to the CNS. However, there is considerable overlap among the regions affected, suggesting that the diseases share pathogenic mechanisms, presumably involving the glutamine repeats. We focus on Huntington's disease (HD) and Dentatorubral-pallidoluysian atrophy (DRPLA) as models for this family of diseases, since they have striking similarities and also notable differences in their clinical features and pathology. We review the pattern of pathology in adult and juvenile onset cases. Despite selective pathology, the disease genes and their protein products (huntingtin and atrophin-1) are widely expressed. This presents a central problem for all the glutamine repeat diseases-how do widely expressed gene products give rise to restricted pathology? The pathogenic effects are believed to occur via a "gain of function" mechanism at the protein level. Mechanisms of cell death may include excitotoxicity, metabolic toxicity, apoptosis, and free radical stress. Emerging data indicate that huntingtin and atrophin-1 may have distinct protein interactions. The specific interaction partners may help explain the selective pathology of these diseases.

Optic chiasmatic-hypothalamic glioma

Abstract: Optic chiasmatic-hypothalamic gliomas (OCHGs) have been considered benign tumors and self-limiting in growth potential because of their histological appearance. Unfortunately, most clinical series have reported significant morbidity and mortality especially with the more extensive, posteriorly positioned tumors. The biological behavior of OCHGs is age-dependent, with patients younger than five years and older than 20 years typically having tumors that exhibit aggressive growth. There are no specific pathological features to help differentiate the clinical behavior of such tumors. The emergence of modern imaging techniques, including magnetic resonance imaging (MRI), has facilitated the monitoring of the natural history of the disease and the determination of the effects of therapy. Most patients with OCHGs survive for many years. While the natural history of an OCHG for any individual may be indeterminate, enough data are now available from large series to make recommendations for treatment. Our current treatment policy for patients with OCHGs in the context of NF-I without visual failure is a conservative one involving CSF shunting for hydrocephalus if present and medical therapy for endocrinologic dysfunction. Patients with or without NF-I with visual deterioration or progressive neurological deficits and a rapidly expanding suprasellar mass lesion are treated surgically. After tumor resection, patients whose vision is significantly compromised or who show progression of their disease on serial neuroimaging scans receive chemotherapy. If chemotherapy proves ineffective in disease stabilization, then considerations of radiation therapy are given to children over five years old.

Neuropathogenesis of chimeric simian/human immunodeficiency virus infection in pig-tailed and rhesus macaques.

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

Kuru: forty years later, a historical note

Abstract: Introduction Kuru (6), the first neurodegenerative human disease caused by infectious amyloids (also known as slow unconventional viruses (14, 15) or \"prions\") was first reported to Western medicine in 1957 by Gajdusek and Zigas (23, 24, 25, 27). The elucidation of Kuru opened a new field in human medicine and initiated more than a quarter of century of research which contributed enormously to our understanding of neurodegenerative disorders of the central nervous system. Kuru in the Fore language means to shiver or to shake from fever and cold (1, 13, 18). The Fore used the noun of the Kuru-verb to describe the always fatal plague which affected their children and adult women, rarely men (2, 3, 5, 17, 21, 26, 34). It has been and s t i l l is restricted to natives of the Fore linguistic group at Papua New Guinea's Eastern Highlands (Fig. 1) and those neighboring linguistic groups which intermarry with Fore people (Auiana, Awa, Usurufa, Kanite, Keiagana, late, Kamano, Kimi). Neighboring groups into which Kuru -affected villages did not settle through marriage or adoption, such as Anga (Kukukuku), and remote Iagaria, Kamano and Auiana people were not affected. Kuru first appeared at the turn of this century in Uwami village of Keiagana people and spread from there to the Awande in the North Fore where the Uwami had social contacts through marriage and adoption. Within 20 years it had spread further into the Kasokana and Miarasa villages of North Fore and a decade later, about 30 years before Kuru investigation started, it had reached the South Fore at the Wanikanto and Kamira villages. Kuru became endemic in all villages that it entered and became hyperendemic in the South Fore region.

Neurofibromatosis 1 and 2

Abstract: Neurofibromatosis (NF) 1 and 2 are multisystem disorders associated with a variety of neoplastic and non-neoplastic manifestations that typically progress in severity during the lifetime of the affected patient. The importance of appropriately diagnosing these disorders stems from the fact that the natural history of an associated neoplasm, such as a peripheral nerve tumor or an optic glioma, may be significantly different depending on whether or not the lesion arises in a person with NF. In addition, the indications for therapeutic intervention, hierarchy of treatment options and long-term management goals may differ substantially for patients with NF-related versus sporadic tumors. Finally, recognition of the diagnosis comprises an essential step for providing appropriate multidisciplinary evaluation and counseling to affected patients and their families. This article addresses the principal manifestations of these disorders and provides a contemporary review of the diagnostic and therapeutic issues that arise in children with NF1 and NF2.

Mouse Models of Human CAG Repeat Disorders

Abstract: Expansions of CAG trinucleotide repeats encoding glutamine have been found to be the causative mutations of seven human neurodegenerative diseases Similarities in the clinical, genetic, and molecular features of these disorders suggest they share a common mechanism of pathogenesis Recent progress in the generation and characterization of transgenic mice expressing the genes containing expanded repeats associated with spinal and bulbar muscular atrophy (SBMA), spinocerebellar ataxia type 1 (SCA1), Machado-Joseph disease (MJD/SCA3), and Huntington's disease (HD) is beginning to provide insight into the underlying mechanisms of these neurodegenerative disorders

Characterization of neural cell lines derived from SV40 large T-induced primitive neuroectodermal tumors.

Abstract: We recently reported intriguing properties of neural tumors generated by retrovirus-mediated transfer of the SV40 large T antigen into fetal rat brain transplants. Histopathologically, these neoplasms displayed characteristic features of primitive neuroectodermal tumors (PNET) and exhibited a striking potential for migration into the host brain. In the present study, four cell lines were derived from these PNETs and characterized. Two lines with an immature phenotype expressed the embryonal form of the neural cell adhesion molecule and nestin. They showed spheroid formation and delicate cell processes. The remaining cell lines had a flat, epitheloid appearance and were immunoreactive for synaptophysin, neurofilament proteins and glial fibrillary acidic protein. These cells constitute valuable tools to study the cellular origin(s) and molecular basis of PNETs, differentiation of neural progenitors and tumor cell migration in the brain.

March 1997--4 year old girl with ring chromosome 22 and brain tumor.

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

August 1996 — Frontal Lobe Tumor in 11 Year Old Girl

Abstract: Case Abstract An 11 year old girl presented with an 8 month history of left temporal headaches with new onset of nausea and vomiting with increased severity of headaches. An MRI scan showed a frontal lobe mass. The tumor was resected and histologic studies demonstrated a central neurocytoma. The clinical, radiologic and pathologic aspects (including immunohistochemistry and electron microscopy) of central neurocytomas are reviewed and the atypical features of this case described.

Viruses and rickettsiae.

Abstract: In this review I shall try to provide a brief, up-to-date, account of the neuropathology of those viral and rickettsial diseases that are particularly prevalent in tropical regions. These diseases are not, however, exclusive to the tropics. Some, such as AIDS, are common in temperate regions as well, though others are closer to being exclusively tropical, such as some of the arthropod-borne (ARBO) virus encephalides. The latter are dependent for their dissemination on an existence during part of their infectious cycle in insects which are, in turn, climatically and seasonally sensitive. This necessarily limits their geographical distribution. Factors that influence some of the other diseases are less closely dependent on climate and geography and reflect more the social or cultural conditions under which people live. Thus, diseases that depend for their spread on forms of human behavior such as promiscuity or drug abuse (AIDS), or poor hygiene and living conditions (polio, rickettsial diseases) or on contact with domestic and other animals (rabies) may occur in a more widespread distribution, for the tropics are not the only places that afford opportunities for these diseases to flourish. I shall select for discussion aspects of the pathology of these diseases that are currently undergoing investigation but will aim to present these against the backdrop of more established aspects of their pathology. Recent reviews of the pathology of viral encephalitis can be found in Hamilton and Wiley (33) and Esiri and Kennedy (20) and of HIV-1 infection in Price & Sidtis (78) and Scaravilli (85).

Cytokines and Reperfusion in Ischemic Stroke

Abstract: The clinical syndrome known as ischemic stroke, secondary to the occlusion of an intracranial artery, once considered an ineluctably catastrophic event, may be susceptible of being improved through the application of newly developed therapeutic interventions. The evidence favoring this optimistic outlook is based on three separate but probably interrelated observations: (1) There exists a lapse of hours, perhaps days, between the ictus (i.e., the appearance of a focal neurologic deficit or stroke) and the time when irreversible tissue injury (i.e., widespread pannecrosis) becomes demonstrable. This time interval, generally known as the therapeutic window, may be measured in hours or days depending on the degree or severity of the post occlusive ischemia. (2) Reopening the artery, within a reasonable period of time, has beneficial effects in terms of: (a) improving the neurologic function, and (b) decreasing the numbers of necrotic neurons as well as preventing the appearance of pannecrosis or infarction. (3) The progression from the early ischemic changes (potentially reversible) to the development of an infarct may be influenced by the effects of selected cytokines, in particular those of interleukin 1 (IL-1). In this review we illustrate selected structural features of the various brain lesions induced by either permanent or transient arterial occlusions. Moreover, we discuss the possible Involvement of interleukins in the progression of the brain lesion based on experiments utilizing the administration of a human recombinant IL-1 receptor antagonist. Combined with the efforts aimed at restoring the normal circulatory conditions, therapeutic interventions that inhibit specific cytokines may contribute to improve the outcome of ischemic strokes.

Degenerative Non‐Alzheimer Dementias

Abstract: 1. Diseases which have been traditionally regarded as being subcortical may present as a cortical pathology dominated by cognitive dysfunction. In some cases patients may not have clinical evidence of subcortical involvement. Diseases falling into this group are: Dementia with cortical Lewy bodies. Dementia with changes of motor neuron disease. Dementia with changes of corticobasal degeneration. Dementia with changes of progressive supranuclear palsy.