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Biomedical subjects

Robert E Mrak

Publications and source records attributed to Robert E Mrak.

18 recordsLinked to original sources

Phylogenetic preservation of alpha3 Na+,K+-ATPase distribution in vertebrate peripheral nervous systems.

The alpha(3) isoform of Na(+),K(+)-ATPase is uniquely expressed in afferent and efferent neurons innervating muscle spindles in the peripheral nervous system (PNS) of adult rats, but the distribution pattern of this isoform in other species has not been investigated. We compared expression of alpha(3) Na(+),K(+)-ATPase in lumbar dorsal root ganglia (DRG), spinal roots, and skeletal muscle samples of amphibian (frog), reptilian (turtle), avian (pigeon and chicken), and mammalian (mouse and human) species. In all species studied, the alpha(3) Na(+),K(+)-ATPase isoform was nonuniformly expressed in peripheral ganglia and nerves. In spinal ganglia, only 5-20% of neurons expressed this isoform, and, in avian and mammalian species, these alpha(3) Na(+),K(+)-ATPase-expressing neurons belonged to a subpopulation of large DRG neurons. In ventral root fibers of pigeons, mice, and humans, the alpha(3) Na(+),K(+)-ATPase was abundantly expressed predominantly in small myelinated axons. In skeletal muscle samples from turtles, pigeons, mice, and humans, alpha(3) Na(+),K(+)-ATPase was detected in intramuscular myelinated axons and in profiles of nerve terminals associated with the equatorial and polar regions of muscle spindle intrafusal fibers. These results show that the expression profiles for alpha(3) Na(+),K(+)-ATPase in the peripheral nervous system of a wide variety of vertebrate species are similar to the profile of rats and suggest that stretch receptor-associated expression of alpha(3) Na(+),K(+)-ATPase is preserved through vertebrate evolution.

Animals↗

Heparanase expression and TrkC/p75NTR ratios in human medulloblastoma.

Medulloblastoma (MB), the most devastating and common brain tumor in children, is highly invasive and extremely difficult to treat. Identifying the properties of MB tumors that cause them to invade and metastasize is therefore imperative for the development of novel treatments. We performed investigations to elucidate prognostic implications of heparanase (HPSE-1) and TrkC/p75(NTR) expression in MB using formalin-fixed, paraffin-embedded (FFPE) MB clinical specimens from children aged 1-19 years. Expressions of p75(NTR) and HPSE-1 correlated with each other (Pearson's correlation R = 0.899; P < 0.0001; R (2) = 81%; n = 14). In addition, TrkC:p75(NTR) ratios correlated with MB meningeal spread (R = 0.608; P = 0.0212; R (2) = 37%; n = 14). Secondly, using antibodies specific to TrkC and HPSE-1, we carried out immunohistochemistry (IHC) on 22 human MB tissue samples. IHC reaction scores revealed a significant expression of HPSE-1 in 76% of MB tissues from children aged 3 years and older (P = 0.0490; n = 17) while TrkC immunoreactivity was detected in 71% of these patient samples. Of note, TrkC was significantly present in 100% of MB female patients (P = 0.0313; n = 6). These studies support the role of p75(NTR) and HPSE-1 as two novel molecular determinants involved in the biology and clinical progression of MB.

Cerebellar Neoplasms↗

Interleukin-1 mediates Alzheimer and Lewy body pathologies.

BACKGROUND: Clinical and neuropathological overlap between Alzheimer's (AD) and Parkinson's disease (PD) is now well recognized. Such cases of concurrent AD and Lewy body disease (AD/LBD) show neuropathological changes that include Lewy bodies (alpha-synuclein aggregates), neuritic amyloid plaques, and neurofibrillary tangles (hyperphosphorylated tau aggregates). The co-occurrence of these clinical and neuropathological changes suggests shared pathogenic mechanisms in these diseases, previously assumed to be distinct. Glial activation, with overexpression of interleukin-1 (IL-1) and other proinflammatory cytokines, has been increasingly implicated in the pathogenesis of both AD and PD. METHODS: Rat primary cultures of microglia and cortical neurons were cultured either separately or as mixed cultures. Microglia or cocultures were treated with a secreted fragment (sAPPalpha) of the beta-amyloid precursor protein (betaAPP). Neurons were treated with IL-1beta or conditioned medium from sAPPalpha-activated microglia, with or without IL-1 receptor antagonist. Slow-release pellets containing either IL-1beta or bovine serum albumin (control) were implanted in cortex of rats, and mRNA for various neuropathological markers was analyzed by RT-PCR. Many of the same markers were assessed in tissue sections from human cases of AD/LBD. RESULTS: Activation of microglia with sAPPalpha resulted in a dose-dependent increase in secreted IL-1beta. Cortical neurons treated with IL-1beta showed a dose-dependent increase in sAPPalpha release, an effect that was enhanced in the presence of microglia. IL-1beta also elevated the levels of alpha-synuclein, activated MAPK-p38, and phosphorylated tau; a concomitant decrease in levels of synaptophysin occurred. Delivery of IL-1beta by slow-release pellets elevated mRNAs encoding alpha-synuclein, betaAPP, tau, and MAPK-p38 compared to controls. Finally, human cases of AD/LBD showed colocalization of IL-1-expressing microglia with neurons that simultaneously overexpressed betaAPP and contained both Lewy bodies and neurofibrillary tangles. CONCLUSION: Our findings suggest that IL-1 drives production of substrates necessary for formation of the major neuropathological changes characteristic of AD/LBD.

Journal Article↗

Glia and their cytokines in progression of neurodegeneration.

A glia-mediated, inflammatory immune response is an important component of the neuropathophysiology of Alzheimer's disease, of the midlife neurodegeneration of Down's syndrome, and of other age-related neurodegenerative conditions. All of these conditions are associated with early and often dramatic activation of, and cytokine overexpression in, microglia and astrocytes, sometimes decades before pathological changes consistent with a diagnosis of Alzheimer's disease are apparent, as in patients with Down's syndrome or head injury. Brains of normal elderly individuals also often show Alzheimer-type neuropathological changes, although to a lesser degree than those seen in Alzheimer's disease itself. These normal age-related glial changes, likely a response to the normal wear and tear of the aging process, raise the threshold of glial activation and thus may explain the fact that even genetically determined Alzheimer's disease, resulting from genetic mutations such as those in beta-amyloid precursor protein and presenilins or from genetic duplication such as of chromosome 21, only shows the full manifestation of the disease decades after birth. In the more common sporadic form of Alzheimer's disease, age-related increases in glial activation and expression of cytokines may act in synergy with other genetic and acquired environmental risks to culminate in the development of disease.

Aging↗

Postmortem locus coeruleus neuron count in three American veterans with probable or possible war-related PTSD.

The authors investigated whether war-related posttraumatic stress disorder (WR-PTSD) is associated with a postmortem change in neuronal counts in the locus coeruleus (LC) since enhanced central nervous system (CNS) noradrenergic postsynaptic responsiveness has been previously shown to contribute to PTSD pathophysiology. Using postmortem neuromorphometry, the number of neurons in the right LC in seven deceased elderly male veterans was counted. Three veterans were classified as cases of probable or possible WR-PTSD. All three veterans with probable or possible WR-PTSD were found to have substantially lower LC neuronal counts compared to four comparison subjects (three nonpsychiatric veterans and one veteran with alcohol dependence and delirium tremens). To the authors' knowledge, this case series is the first report of LC neuronal counts in patients with PTSD or any other DSM-IV-TR anxiety disorder. Previous postmortem brain tissue studies of Alzheimer's Disease (AD) demonstrated an upregulation of NE biosynthetic capacity in surviving LC neurons. The finding reported is consistent with the similar upregulation of NE biosynthetic capacity of surviving LC neurons in veterans who developed WR-PTSD. Especially if replicated, this finding in WR-PTSD may provide further explanation of the dramatic effectiveness of propranolol and prazosin for the secondary prevention and treatment of PTSD, respectively. The LC neurons examined in this study are probably the origin of the first or second "leg" of what might be termed the PTSD candidate circuit. Larger neuromorphometric studies of the LC in veterans with WR-PTSD and in other development-stress-induced and fear-circuitry disorders are warranted, especially using VA registries.

Aged↗

Potential inflammatory biomarkers in Alzheimer's disease.

The role of the brain's innate immune system in Alzheimer pathogenesis is now well established. Proinflammatory cytokines elaborated by this system, in particular activated microglia-derived interleukin-1 (IL-1), drive a cascade of neurotoxic changes that are important for the development and progression of both the neuritic plaques and neurofibrillary tangles characteristic of Alzheimer's disease. Cytokine expression may also be modulated by variants of genes. For instance, inheritance of certain IL-1 gene variants is associated with Alzheimer's disease. The potential for using blood levels of proinflammatory cytokines as biomarkers of disease progression, however, remains unrealized. The interpretation of cytokine levels in the blood is complicated by the fact, for example, that the overexpression of IL-1 in Alzheimer brain may act to increase adrenal cortisol production through the hypothalamic-pituitary-adrenal axis, which acts to limit macrophage activation and peripheral cytokine production.

Alzheimer Disease↗

Heparanase, TrkC and p75NTR: their functional involvement in human medulloblastoma cell invasion.

Medulloblastoma is the most common malignant childhood brain tumor. Although some previous reports have shown up to a 70% 5-year survival for some of these patients, it is at the cost of significant long-term treatment-related morbidity. The cellular mechanisms leading to metastatic disease in medulloblastoma are mainly unknown. For the first time, we demonstrate the differential expression of heparanase in medulloblastomas and how these differences at the mRNA and protein levels affect the activity and invasive properties of three newly developed cell lines. Furthermore, heparanase expression was confirmed in 7 (88%) of 8 medulloblastoma clinical samples by immunohistochemical staining. Heparanase was found to be localized in the cytoplasm and nucleus. Quantitative polymerase chain reaction revealed a negative correlation between heparanase and TrkC (which is associated with a favorable clinical outcome). The activation of TrkC or TrkC/p75NTR by NT-3 affected heparanase activity and cell-invasive properties of medulloblastoma cells in vitro. Taken together, our data extend the body of evidence that invasion and expression/functionality of heparanase, in a context linked to TrkC and p75NTR, may play critical roles in the disease progression of medulloblastoma.

Analysis of Variance↗

Funding free and universal access to Journal of Neuroinflammation.

Journal of Neuroinflammation is an Open Access, online journal published by BioMed Central. Open Access publishing provides instant and universal availability of published work to any potential reader, worldwide, completely free of subscriptions, passwords, and charges. Further, authors retain copyright for their work, facilitating its dissemination. Open Access publishing is made possible by article-processing charges assessed "on the front end" to authors, their institutions, or their funding agencies. Beginning November 1, 2004, the Journal of Neuroinflammation will introduce article-processing charges of around US$525 for accepted articles. This charge will be waived for authors from institutions that are BioMed Central members, and in additional cases for reasons of genuine financial hardship. These article-processing charges pay for an electronic submission process that facilitates efficient and thorough peer review, for publication costs involved in providing the article freely and universally accessible in various formats online, and for the processes required for the article's inclusion in PubMed and its archiving in PubMed Central, e-Depot, Potsdam and INIST. There is no remuneration of any kind provided to the Editors-in-Chief, to any members of the Editorial Board, or to peer reviewers; all of whose work is entirely voluntary. Our article-processing charge is less than charges frequently levied by traditional journals: the Journal of Neuroinflammation does not levy any additional page or color charges on top of this fee, and there are no reprint costs as publication-quality pdf files are provided, free, for distribution in lieu of reprints. Our article-processing charge will enable full, immediate, and continued Open Access for all work published in Journal of Neuroinflammation. The benefits from such Open Access will accrue to readers, through unrestricted access; to authors, through the widest possible dissemination of their work; and to science and society in general, through facilitation of information availability and scientific advancement.

Journal Article↗

Microglia and neuroinflammation: a pathological perspective.

Microglia make up the innate immune system of the central nervous system and are key cellular mediators of neuroinflammatory processes. Their role in central nervous system diseases, including infections, is discussed in terms of a participation in both acute and chronic neuroinflammatory responses. Specific reference is made also to their involvement in Alzheimer's disease where microglial cell activation is thought to be critically important in the neurodegenerative process.

Journal Article↗

PPARgamma, neuroinflammation, and disease.

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear transcription factors that are activated by fatty acids and their derivatives. One of these, PPARgamma, regulates responsiveness to insulin in adipose cells, and PPARgamma-activating drugs such as pioglitazone are used in the treatment of type 2 diabetes. PPARgamma acts in myeloid-lineage cells, including T-cells and macrophages, to suppress their activation and their elaboration of inflammatory molecules. PPARgamma activation also suppresses the activated phenotype in microglia, suggesting that PPARgamma-activating drugs may be of benefit in chronic neuroinflammatory diseases. Some, but not all, nonsteroidal anti-inflammatory agents (indomethacin and ibuprofen in particular) also have activating effects on PPARgamma. DISCUSSION AND CONCLUSIONS: These observations suggest on the one hand a role for PPARgamma-activating drugs in the treatment of chronic neuroinflammatory diseases-as shown for a patient with secondary progressive multiple sclerosis by Pershadsingh et al. in this issue of the Journal of Neuroinflammation-and suggest on the other hand a possible explanation for confusing and contradictory results in trials of nonsteroidal anti-inflammatory agents in Alzheimer's disease.

Editorial↗

Welcome to the Journal of Neuroinflammation!

Welcome to the Journal of Neuroinflammation, an open-access, peer-reviewed, online journal that focuses on innate immunological responses of the central nervous system, involving microglia, astrocytes, cytokines, chemokines, and related molecular processes. 'Neuroinflammation' is an encapsulization of the idea that microglial and astrocytic responses and actions in the central nervous system have a fundamentally inflammation-like character, and that these responses are central to the pathogenesis and progression of a wide variety of neurological disorders. This concept has its roots in the discoveries of inflammatory cytokines and proteins in the plaques of Alzheimer disease, and these ideas have been extended to other neurodegenerative diseases, to ischemic/toxic diseases, to tumor biology and even to normal brain development. The Journal of Neuroinflammation, published by BioMed Central, will bring together work focusing on microglia, astrocytes, cytokines, chemokines, and related molecular processes in the central nervous system. All articles published in the Journal of Neuroinflammation will be immediately listed in PubMed, and access to published articles will be universal and free through the internet.

Journal Article↗

Atypical extraventricular neurocytoma with oligodendroglioma-like spread and an unusual pattern of chromosome 1p and 19q loss.

An insular cortex tumor in a 54-year-old woman showed unequivocal neurocytic features, including open nuclei, distinct nucleoli, and strong synaptophysin immunoreactivity. Ultrastructurally, there were neuritic-type processes with microtubules and hillock-like attachments, and there were dense-core granules. Atypical features were mitotic activity, prominent vasculature, and small foci of necrosis. Peripherally, there was oligodendroglia-like histology with single-cell infiltration of white matter and perineuronal spread in cortex. Fluorescence in situ hybridization analysis with chromosome 1 and 19 probes showed 3 copies of 1q and 2 copies of 1p and showed 2 copies of 19q and 4 copies of 19p. This yielded a 1p-19q loss of heterozygosity pattern similar to that seen in oligodendrogliomas, although the actual chromosomal abnormality is distinct. This tumor, best classified as an atypical neurocytoma with oligodendroglia-like spread, supports suggestions of a close histogenic relationship between oligodendroglial and neurocytic tumors. This case also illustrates the limitations of relying exclusively on loss of heterozygosity analysis for tumor classification.

Brain Neoplasms↗

Microglial activation by uptake of fDNA via a scavenger receptor.

The fate of the fragmented DNA (fDNA) observed in neuronal nuclei in Alzheimer brain is unknown. However, its fate is suggested as fDNA is found in the cytoplasm of adjacent activated microglia. After a brief incubation with fDNA, approximately 70% of microglia had fDNA in their cytoplasm, were activated, and overexpressed interleukin-1beta. Microglial activation enhanced uptake whereas blocking scavenger receptors suppressed this uptake. These results suggest that the brain rids itself of fDNA from dying neurons through microglial uptake, activation, and overexpression of IL-1. Such overexpression of IL-1 in Alzheimer brain has been linked to Alzheimer pathogenesis.

Alzheimer Disease↗

Trisomy 21 and the brain.

In fetuses with Down syndrome, neurons fail to show normal dendritic development, yielding a "tree in winter" appearance. This developmental failure is thought to result in mental retardation. In adults with Down syndrome, neuronal loss is dramatic and neurofibrillary and neuritic Abeta plaque pathologies are consistent with Alzheimer disease. These pathological changes are thought to underlie the neuropsychological and physiological changes in older individuals with Down syndrome. Two chromosome 21-based gene products, beta-amyloid precursor protein (betaAPP) and S100B, have been implicated in these neuronal and interstitial changes. Although not necessary for mental retardation and other features, betaAPP gene triplication is necessary, although perhaps not sufficient, for development of Alzheimer pathology. S100B is overexpressed throughout life in Down patients, and mice with extra copies of the S100B gene have dendritic abnormalities. S100B overexpression correlates with Alzheimer pathology in post-adolescent Down syndrome patients and has been implicated in Abeta plaque pathogenesis. Interleukin-1 (IL-1) is a non-chromosome-21-based cytokine that is also overexpressed throughout life in Down syndrome. IL-1 upregulates betaAPP and S100B expression and drives numerous neurodegenerative and self-amplifying cascades that support a neuroinflammatory component in the pathogenesis of sporadic and Down syndrome-related Alzheimer disease.

Amyloid beta-Protein Precursor↗

Profound infantile neuroretinal dysfunction in a heterozygote for the CLN3 genetic defect.

The neuronal ceroid-lipofuscinoses are a group of diseases that are characterized by progressive neuroretinal symptomatology, progressive accumulation of autofluorescing waxy lipopigments (ceroid-lipofuscin) within the brain and other tissues, and cerebral atrophy. Juvenile neuronal ceroid-lipofuscinosis, or Batten disease, is a form of neuronal ceroid-lipofuscinosis that is characterized by onset of neuroretinal symptoms between 4 and 10 years. Juvenile neuronal ceroid-lipofuscinosis is the most common type of neuronal ceroid-lipofuscinosis in the United States and Europe and is inherited as an autosomal recessive genetic disorder. Research in the last decade has led to the identification of the responsible gene for juvenile neuronal ceroid-lipofuscinosis, which is designated as CLN3. CLN3 is located on chromosome 16p11.2-12.1. The major mutation is a 1.02 kb deletion, which removes exons 7 and 8. Both homozygotic and heterozygotic deletions at the CLN3 gene site have been associated with the clinical syndromes of juvenile neuronal ceroid-lipofuscinosis. We report a possible atypical case of neuronal ceroid-lipofuscinosis, an infant, who presented at 5 months of age with a lack of developmental milestones, poor vision, severe retinopathy, intractable seizures, and progressive cerebral atrophy. Extensive laboratory investigations, including thorough metabolic evaluations, were unremarkable except for neuroimaging studies, electroencephalography, and electroretinography, all of which showed abnormalities confirming both cerebral and retinal degeneration. Although skin and conjunctival biopsies did not show classic fingerprint cytosomes by electron microscopic study, which characterize juvenile neuronal ceroid-lipofuscinosis, a diagnosis of an atypical form of juvenile neuronal ceroid-lipofuscinosis was suspected on the basis of the clinical picture. The retinal abnormalities, surprisingly, were those believed to be diagnostic of juvenile-onset neuronal ceroid-lipofuscinosis, or Batten disease. Subsequently, a heterozygous mutation for the common 1.02 kb deletion characteristic of juvenile neuronal ceroid-lipofuscinosis was established.

Alleles↗

The Big Eye in the 21st century: the role of electron microscopy in modern diagnostic neuropathology.

Electron microscopy (EM) remains a powerful and even essential tool in modern diagnostic neuropathology. tumors are still encountered that defy histological or immunohistochemical classification, and EM can often provide answers in these cases. Tumors of the CNS for which EM is useful include unusual or atypical variants of meningioma, ependymoma, and schwannoma; oligodendroglioma-like tumors composed of small "clear" cells; and small "blue cell" tumors of childhood. EM is of great value in identifying site of origin for metastatic adenocarcinomas of unknown origin-an under-recognized and under-utilized potential for this technique. EM is useful in the diagnosis of peripheral nerve sheath tumors and gastrointestinal autonomic nerve tumors. EM is also important in the evaluation of certain congenital, inherited and metabolic diseases-including ceroid lipofuscinoses, CADASIL syndrome, certain myopathies, and mitochondrial encephalomyopathies--and of certain toxic and drug-induced peripheral neuropathies. An important application of EM is its utility in initiating a workup of an atypical tumor or metabolic condition, for which clinical and histological clues point in no obvious direction. In these situations, EM may provide either an answer outright (including answers to questions not asked) or important clues that guide further workup and narrow the range of diagnostic possibilities.

Central Nervous System Diseases↗

Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease.

Interleukin-1 (IL-1), a key molecule in systemic immune responses in health and disease, has analogous roles in the brain where it may contribute to neuronal degeneration. Numerous findings suggest that this is the case. For example, IL-1 overexpression in the brain of Alzheimer patients relates directly to the development and progression of the cardinal neuropathological changes of Alzheimer's disease, i.e., the genesis and accumulation of beta-amyloid (Abeta) plaques and the formation and accumulation of neurofibrillary tangles in neurons, both of which contribute to neuronal dysfunction and demise. Several genetic studies show that inheritance of a specific IL-1A gene polymorphism increases risk for development of Alzheimer's disease by as much as sixfold. Moreover, this increased risk is associated with earlier age of onset of the disease. Homozygosity for this polymorphism in combination with another in the IL-1B gene further increases risk.

Adult↗

Autopsy 101 (CE).

Although autopsy remains the only definitive way to confirm and sometimes diagnose disease, the autopsy rate has continued to decline during the past 3 decades. Despite numerous publications citing its value, the nursing literature lacks information addressing the benefits and implications of the autopsy to nurses who provide direct care to older adults. This article provides geriatric nurses with information about the benefits, purpose, process, and barriers of autopsy to better inform nurses as they ease family concerns and assist physicians in obtaining consent for autopsy.

Aged↗