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Biomedical subjects

R E Mrak

Publications and source records attributed to R E Mrak.

At least 37 records · Page 2Linked to original sources
PubMed1999

Overexpression of s100beta in Down's syndrome: correlation with patient age and with beta-amyloid deposition.

S100beta is an astrocyte-derived uritotrophic' cytokine which has been implicated in the pathogenesis of Alzheimer's disease. S100beta overexpression by plaque-associated astrocytes correlates with growth of abnormal (strophic') neurites in beta-amyloid plaques, one of the major neuropathological hallmarks of Alzheimer's disease. As the characteristic neuropathological changes of Alzheimer's disease are virtually universal in middle-aged Down's syndrome patients, studies of Down's syndrome patients provide a unique opportunity to investigate the pathophysiological processes underlying the development of Alzheimer-type neuropathological changes. Computerized morphometric analysis was used to quantify astrocyte activation and astrocytic expression of S100beta, and to correlate these with beta-amyloid deposition, in a clinically well-characterized cohort of Down's syndrome subjects, aged 13-65 years. There were significant positive correlations between S100beta expression and patient age, and between S100beta expression and cerebral cortical beta-amyloid deposition. Moreover, the numbers of activated (enlarged) astrocytes overexpressing S100beta showed a significant correlation with the numeric density of beta-amyloid plaques, from the youngest to the oldest ages and within age ranges where pathology is most florid, while no such relationship was found between the numbers of small, non-activated S100beta-immunoreactive cells and numerical density of beta-amyloid plaques. These correlations, together with established functions of S100beta, are consistent with the idea that S100beta overexpression promotes beta-amyloid plaque formation and progression in Down's syndrome.

Adolescent↗
PubMed1999

Increased interleukin-1beta converting enzyme expression and activity in Alzheimer disease.

Increased expression of interleukin-1 in Alzheimer disease (AD) has been implicated as a driving force in neurodegenerative cascades that underlie the formation of neuritic plaques and neurofibrillary tangles, the spread of these neuropathological lesions across cerebral cortical regions, and the accompanying neuronal cell injury and loss. The beta isoform of interleukin-1 is generated from an inactive, 33-kDa precursor through the action of a specific interleukin-1beta converting enzyme (ICE), also known as caspase-1. We used mesial temporal tissue (hippocampus and parahippocampal cortex) obtained postmortem from Alzheimer and control patients for determinations of endogenous tissue ICE activity and for Western immunoblot analysis of tissue ICE concentrations. ICE activity in Alzheimer tissue was elevated 50-100% (p < 0.002, or better, at incubation times of 30 min to 10 h), and ICE protein level was elevated 180% (p = 0.01). Parahippocampal cortex of Alzheimer patients showed increased numbers of neurons with in situ evidence of DNA damage. Increased DNA degradation was also evident upon electrophoresis of isolated DNA. Overexpression and increased activity of ICE may contribute to neurodegeneration in AD through generation of biologically active interleukin-1, with consequent activation of interleukin-1-driven neurodegenerative cascades.

Alzheimer Disease↗
PubMed1998

Enlarged and phagocytic, but not primed, interleukin-1 alpha-immunoreactive microglia increase with age in normal human brain.

Microglia-mediated inflammatory responses have been implicated in the pathogenesis of neuritic plaques in Alzheimer's disease. The strong age association of Alzheimer's disease incidence suggests that events in normal aging may promote such responses. We used immunohistochemistry and computerized image analysis to determine the numbers, size, activation state, and immunoreactive intensity of interleukin-1 alpha-immunoreactive (IL-1 alpha +) microglia in mesial temporal lobe of 20 neurologically normal individuals, 2-80 years of age. We also used Northern analysis to determine tissue levels of IL-1 alpha mRNA in an additional 11 neurologically normal individuals aged 1 day to 78 years. IL-1 alpha + microglia were characterized as primed, enlarged, or phagocytic (enlarged with heterogeneous cytoplasmic contents) based on morphology. These three microglial subtypes showed significant differences in size [27 +/- 1 58 +/- 2 114 +/- 6 (mean +/- SEM) micron 2/cell, respectively, P < 0.001 for each comparison] and in immunoreactive intensity [60 +/- 1 68 +/- 2 79 +/- 2 (arbitrary units), respectively, P < 0.001 or better for each comparison]. There were significant age-associated increases in the total numbers of activated IL-1 alpha + microglia. Among microglial subtypes, there were significant increases in the numbers of enlarged (threefold) and especially phagocytic (elevenfold), but not primed, microglia. Tissue IL-1 alpha mRNA levels were higher in individuals over 60 than in those less than 60 (P < 0.05). The age-associated increases in microglial activation were independent of postmortem interval, patient sex, and the presence of Alzheimer-type 'senile' changes. Age-associated increases in microglial activation and IL-1 expression may contribute to the age-associated increased risk of Alzheimer's disease.

Adolescent↗
PubMed1998

Distribution of interleukin-1-immunoreactive microglia in cerebral cortical layers: implications for neuritic plaque formation in Alzheimer's disease.

Activated microglia overexpressing interleukin-1 (IL-1) are prominent neuropathological features of Alzheimer's disease. We used computerized image analysis to determine the number of IL-1 alpha-immunoreactive (IL-1 alpha +) microglia in cytoarchitectonic layers of parahippocampal gyrus (Brodmann's area 28) of Alzheimer and control patients. For cortical layers I and II, the numbers of IL-1 alpha + microglia were similar in Alzheimer and control patients. For layers III-VI, the numbers of IL-1 alpha + microglia were higher than that seen in layers I-II for both Alzheimer and control patients. Moreover, for layers III-VI, the number of IL-1 alpha + microglia in Alzheimer patients was significantly greater than that in control patients (relative Alzheimer values of threefold for layer III-V and twofold for layer VI; P < 0.05 in each case). The cortical laminar distribution of IL-1 alpha + microglia in Alzheimer patients correlated with the cortical laminar distribution of beta-amyloid precursor protein-immunoreactive (beta-APP+) neuritic plaques found in Alzheimer patients (r = 0.99, P < 0.005). Moreover, the cortical laminar distribution of IL-1 alpha + microglia in control patients also correlated with the cortical laminar distribution of beta-APP+ neuritic plaques found in Alzheimer patients (r = 0.91, P < 0.05). These correlations suggest that pre-existing laminar distribution patterns of IL-1 alpha + microglia (i.e. that seen in control patients) are important in determining the observed laminar distribution of beta-APP+ neuritic plaques in Alzheimer patients. These findings provide further support for our hypothesis that IL-1 is a key driving force in neuritic plaque formation in Alzheimer's disease.

Aged↗
PubMed1998

S100 beta increases levels of beta-amyloid precursor protein and its encoding mRNA in rat neuronal cultures.

S100beta has been implicated in the formation of dystrophic neurites, overexpressing beta-amyloid precursor protein (betaAPP), in the beta-amyloid plaques of Alzheimer's disease. We assessed the effects of S100beta on cell viability of, neurite outgrowth from, and betaAPP expression by neurons in primary cultures from fetal rat cortex. S100beta (1-10 ng/ml) enhanced neuronal viability (as assessed by increased mitrochondrial activity and decreased lactic acid dehydrogenase release) and promoted neurite outgrowth. Higher levels of S100beta (100 ng/ml, but not 1 microg/ml) produced qualitatively similar, but less marked, effects. S100beta also induced increased neuronal expression of the microtubule-associated protein MAP2, an effect that is consistent with trophic effects of S100beta on neurite outgrowth. S100beta (10 and 100 ng/ml) induced graded increases in neuronal expression of betaAPP and of betaAPP mRNA. These results support our previous suggestion that excessive expression of S100beta by activated, plaque-associated astrocytes in Alzheimer's disease contributes to the appearance of dystrophic neurites overexpressing betaAPP in diffuse amyloid deposits, and thus to the conversion of these deposits into the diagnostic neuritic beta-amyloid plaques.

Amyloid beta-Protein Precursor↗
PubMed1998

Progressive neuronal DNA damage associated with neurofibrillary tangle formation in Alzheimer disease.

DNA damage, as demonstrated by in situ Tdt-mediated dUTP-X-nick end labeling (TUNEL), is widespread in the cerebral cortex in end-stage Alzheimer disease, but has not been previously correlated with stages of neurofibrillary tangle formation. To assess possible relationships between neurofibrillary tangle formation and DNA damage, we used tau immunohistochemistry and TUNEL in tangle-rich fields of tissue sections of subiculum and parahippocampal cortex tissue from 12 Alzheimer and 6 control patients. Structures were classified and quantified as tau-/TUNEL-, tau-/TUNEL+, tau+/TUNEL-, or tau+/TUNEL+. Tau+ structures were subclassified into 4 stages (0-3) based on neurofibrillary tangle morphology. The total number of TUNEL+ neurons was significantly less in control than in Alzheimer patients (35 +/- 7.2 vs 90 +/- 9.3/mm2; mean +/- SEM; p < 0.05). The number of tau+/TUNEL+ neurons (40 +/- 1/mm2) was less than that of tau-/TUNEL- neurons (68 +/- 7/mm2) or tau-/TUNEL+ neurons in the same fields (50 +/- 4/mm2, p < 0.0001). Tau+/TUNEL- structures were fewer in number (21 +/- 1/mm2), with a third of these representing acellular "ghost tangles" (stage 3). Tau+ neurons were more likely than tau- neurons to be TUNEL+ (64 +/- 6% vs 44 +/- 2%; mean +/- SEM; p < 0.01), although most TUNEL+ neurons were tau-, even in these selected, tangle-rich fields. TUNEL positivity was not uniformly distributed among tangle stages. TUNEL positivity was less common among early (stage 0) tangles than in tau neurons (21 +/- 6% vs 44 +/- 2%; p < 0.001), but this rose to 53% among intermediate (stage 1) tangles, and to 87% among late (stage 2) tangles. We suggest that early stages of neurofibrillary tangle formation occur in a subpopulation of relatively healthy (TUNEL-) neurons, and that tangle progression is accompanied by increasing neuronal morbidity.

Aged↗
PubMed1998

Progressive neuronal injury associated with amyloid plaque formation in Alzheimer disease.

Neuronal injury associated with amyloid plaque progression in Alzheimer disease was examined using TUNEL combined with beta-amyloid immunolabeling. There was a progressive increase in the frequency of TUNEL-positive neurons associated with plaque types representing a hypothesized sequence of plaque evolution, from 20% of neurons not associated with plaques to 40%, 70-80%, and 100% of neurons in diffuse, neuritic, and dense-core non-neuritic plaques, respectively. The total number of neurons associated with end-stage, dense-core, non-neuritic plaques declined by 70% (per unit plaque area) compared with neuritic plaque forms. This decline, together with the fact that virtually all of those remaining were TUNEL-positive, suggests that neuronal cell damage increases as plaques evolve from diffuse to more complex forms and that eventually all plaque-associated neurons are lost. This novel demonstration of neurotoxicity associated with amyloid plaque formation and progression suggests that plaque-associated neuronal injury is a major cause of neuronal loss in Alzheimer disease.

Aged↗
PubMed1998

Grover's disease (transient acantholytic dermatosis): relationship of acantholysis to acrosyringia.

Transient acantholytic dermatosis is often associated with excessive sweating, fever, and bed confinement. The pathogenesis of this disease has been postulated to be poral occlusion of damaged eccrine intraepidermal ducts. Histological and immunohistochemical and ultrastructural studies were performed on 10 biopsies from 10 patients with transient acantholytic dermatosis. Immunoreactions for carcinoembryonic antigen and cytokeratin-7 to identify eccrine duct epithelium were performed on all 11 biopsies. In addition, 5 of the biopsies were immunoreacted for cytokeratin 8. All immunoreactions were reviewed independently by two observers to determine extent of reactivity and whether it correlated with areas of epidermal acantholysis. Among the 11 biopsies, 8 showed acantholysis not associated with eccrine duct outflow tracts. In 2 biopsies the acantholysis was consistently associated with acrosyringea; in one case acantholysis was inconsistently associated with eccrine outflow tracts. Epidermal acantholysis in patients with Grover's disease is associated with the outflow tracts of eccrine ducts in a subgroup of patients. Although leakage of sweat from occluded sweat ducts in acrosyringia may be the mechanism operating in a subgroup of patients with Grover's disease, this does not appear to be the subgroup of patients in whom Grover's disease develops in the setting of being bedridden and/or sweating.

Acantholysis↗
PubMed1998

Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression.

The role of glial inflammatory processes in Alzheimer's disease has been highlighted by recent epidemiological work establishing head trauma as an important risk factor, and the use of anti-inflammatory agents as an important ameliorating factor, in this disease. This review advances the hypothesis that chronic activation of glial inflammatory processes, arising from genetic or environmental insults to neurons and accompanied by chronic elaboration of neuroactive glia-derived cytokines and other proteins, sets in motion a cytokine cycle of cellular and molecular events with neurodegenerative consequences. In this cycle, interleukin-1 is a key initiating and coordinating agent. Interleukin-1 promotes neuronal synthesis and processing of the beta-amyloid precursor protein, thus favoring continuing deposition of beta-amyloid, and activates astrocytes and promotes astrocytic synthesis and release of a number of inflammatory and neuroactive molecules. One of these, S100beta, is a neurite growth-promoting cytokine that stresses neurons through its trophic actions and fosters neuronal cell dysfunction and death by raising intraneuronal free calcium concentrations. Neuronal injury arising from these cytokine-induced neuronal insults can activate microglia with further overexpression of interleukin-1, thus producing feedback amplification and self-propagation of this cytokine cycle. Additional feedback amplification is provided through other elements of the cycle. Chronic propagation of this cytokine cycle represents a possible mechanism for progression of neurodegenerative changes culminating in Alzheimer's disease.

Alzheimer Disease↗
PubMed1997

In vitro 1H-magnetic resonance spectroscopy of postmortem brains with schizophrenia.

Some evidence suggests that thalamic dysfunction could explain some of the signs and symptoms of schizophrenia. We measured the absolute concentrations of amino acid metabolites in thalamus, frontal pole, and cerebellar vermis in extracts of postmortem brains from 8 schizophrenics and 10 controls using high-resolution 1H-magnetic resonance spectroscopy. The concentrations of N-acetyl aspartate, glutamate, and valine tended to be reduced in the thalamus of the schizophrenic group. Although it is difficult to ascribe significance to the "tendencies," these data may tend to support other data suggesting decreased thalamic volume or neuronal number in schizophrenia.

Adult↗
PubMed1997

Sudden death in septo-optic dysplasia. Report of 5 cases.

OBJECTIVES: To report our experience with sudden death in children with septo-optic dysplasia and to identify specific risk factors and suggest preventive measures to minimize mortality. METHODS: Clinical data from 5 children with septo-optic dysplasia who died suddenly and unexpectedly were evaluated retrospectively. RESULTS: All children had corticotropin deficiency, all had thermoregulatory disturbances, and 4 children had diabetes insipidus. In at least 4 children, clinical deterioration was caused by fever and dehydration from a presumed viral illness, which appeared to precipitate adrenal crisis. CONCLUSIONS: Children with septo-optic dysplasia and hypocortisolism are at risk for sudden death during febrile illness. Thermoregulatory disturbances and dehydration from diabetes insipidus may potentiate clinical deterioration. Prevention of sudden death in septo-optic dysplasia requires early recognition and treatment of these major risk factors.

Adrenocorticotropic Hormone↗
PubMed1997

Lesioning of the inferior olive using a ventral surgical approach. Characterization of temporal and spatial astrocytic responses at the lesion site and in cerebellum.

Activated astrocytes, intrinsic components of both local and remote (axonal target regions) central nervous system injury responses, are now recognized as active metabolic and regulatory mediators in many neurological disorders. To further define these responses, we devised a new ventral surgical approach to unilaterally lesion the inferior olivary nuclear complex, which has a single predominant remote target, the cerebellum. Activated astrocyte number, volume, and density, as well as the total volume of brainstem involved in the astrocytic response, all peaked at postlesion day (pld) 4, returning toward, but not to, unoperated control values at pld 24 (p < 0.05). In contrast, the peak astrocyte response in the cerebellum was delayed, being greatest at pld 6 (p < 0.05 compared to control or pld 2). These responses were associated with increases in overexpression of S100 beta, an astrocyte-derived neurite growth factor, and with an increase in cerebellar steady-state levels of a neuronal injury response protein, the beta-amyloid precursor protein (beta-APP). This is similar to correlated increases in these two proteins that are found in epilepsy and Alzheimer disease. Our studies defining remote astrocytic and neuronal responses may be important for understanding glial-neuronal mechanisms underlying the spread of neuropathological changes in conditions such as Alzheimer disease.

Amyloid beta-Peptides↗
PubMed1997

Neuritic plaque evolution in Alzheimer's disease is accompanied by transition of activated microglia from primed to enlarged to phagocytic forms.

Activated microglia, overexpressing the potent neuroactive cytokine interleukin-1, have been implicated as a driving force in the evolution of diffuse amyloid deposits into diagnostic neuritic plaques in Alzheimer's disease. To evaluate this role further, we used double-label immunohistochemistry to classify and quantify plaque-associated and non-plaque-associated activated interleukin-1-immunoreactive microglia in parahippocampal tissue from 11 patients with Alzheimer's disease. These activated microglia were subclassified as primed (only slightly enlarged), enlarged, or phagocytic (enlarged with heterogeneous cytoplasmic contents). We further determined the distribution of these microglial subtypes among four defined plaque types. Most (84%) primed microglia were not plaque associated, although 13% were present in diffuse non-neuritic plaques and 3% were present in diffuse neuritic plaques. In contrast, most enlarged (55%) and phagocytic (91%) microglia were plaque associated. Of plaque-associated enlarged microglia, most (71%) were found in diffuse neuritic plaques with the remainder evenly distributed between diffuse non-neuritic and dense-core neuritic plaques (15% each). Of plaque-associated phagocytic microglia, a few were present in diffuse non-neuritic plaques (5%), but most were found in diffuse neuritic plaques (62%) and dense-core neuritic plaques (33%). These findings show preferential association of primed microglia with diffuse amyloid deposits and imply that microglial transformation from primed, to enlarged, to phagocytic types occurs in concert with the evolution of amyloid plaques from diffuse amyloid deposits to the neuritic beta-amyloid plaque forms in Alzheimer's disease. Microglial phagocytic activity in neuritic plaques may reflect involvement in the processing of diffuse amyloid into condensed beta-amyloid, or in clearance of neuritic debris.

Aged↗
PubMed1997

Aging-associated changes in human brain.

A wide variety of anatomic and histological alterations are common in brains of aged individuals. However, identification of intrinsic aging changes--as distinct from changes resulting from cumulative environmental insult--is problematic. Some degree of neuronal and volume loss would appear to be inevitable, but recent studies have suggested that the magnitudes of such changes are much less than previously thought, and studies of dendritic complexity in cognitively intact individuals suggest continuing neuronal plasticity into the eighth decade. A number of vascular changes become more frequent with age, many attributable to systemic conditions such as hypertension and atherosclerosis. Age-associated vascular changes not clearly linked to such conditions include hyaline arteriosclerotic changes with formation of arterial tortuosities in small intracranial vessels and the radiographic changes in deep cerebral white matter known as "leukoaraiosis." Aging is accompanied by increases in glial cell activation, in oxidative damage to proteins and lipids, in irreversible protein glycation, and in damage to DNA, and such changes may underlie in part the age-associated increasing incidence of "degenerative" conditions such as Alzheimer disease and Parkinson disease. A small number of histological changes appear to be universal in aged human brains. These include increasing numbers of corpora amylacea within astrocytic processes near blood-brain or cerebrospinal fluid-brain interfaces, accumulation of the "aging" pigment lipofuscin in all brain regions, and appearance of Alzheimer-type neurofibrillary tangles (but not necessarily amyloid plaques) in mesial temporal structures.

Aging↗
PubMed1997

The role of chronic self-propagating glial responses in neurodegeneration: implications for long-lived survivors of human immunodeficiency virus.

Within the last decade there has arisen increasing appreciation of the role of glia-derived immune and neurotrophic cytokines, especially microglia-derived interleukin-1 and astrocyte-derived S100beta, in the pathophysiology of Alzheimer's disease and of neurodegeneration in general. Available evidence now suggests that these neurotrophic and immune cytokines, produced in response to neuronal cell dysfunction or death, may elicit cellular and molecular responses resulting in further activation of glia and glial cytokine secretion, producing a cytokine cycle. In conditions characterized by chronic glial activation this cycle becomes self propagating, promoting further neurodegeneration and subsequent further induction of glial cell activation with production of cytokines. In Alzheimer's disease, for instance, such self-propagation is essential to the progressive accumulation of neuropathological changes that underlie progressive dementia. Conditions that predispose one to Alzheimer-type 'senile' neuropathological changes, and to later development of Alzheimer's disease, also exhibit glial activation and overexpression of glial cytokines, providing further evidence of a pathogenic role for glial activation and cytokine cycle elements in the initiation and propagation of Alzheimer lesions. HIV produces a chronic viral infection of the central nervous system that has been associated with chronic glial activation and overexpression of some of the same cytokines that have been implicated in Alzheimer pathogenesis. These observations, together with established functions of cytokine cycle elements, suggest that chronic HIV infection in sufficiently long-lived HIV-infected individuals might confer additional risk for later development of Alzheimer's disease.

Alzheimer Disease↗
PubMed1997

Glial-neuronal interactions in Alzheimer disease: progressive association of IL-1alpha+ microglia and S100beta+ astrocytes with neurofibrillary tangle stages.

Activated microglia, overexpressing interleukin-1 (IL-1), and activated astrocytes, overexpressing S100beta, have been implicated in the formation and evolution of tau2-immunoreactive (tau2+) neuritic plaques in Alzheimer disease. In this study, we assessed the role of IL-1alpha+ microglia and S100beta+ astrocytes in the pathogenesis of another cardinal histopathological feature of Alzheimer disease: tau2+ neurofibrillary tangles. Four distinct stages of neurofibrillary tangle formation were identified: neurons with granular perikaryal tau2 immunoreactivity (stage 0); fibrillar neuronal inclusions (stage 1); dense, neuronal soma-filling inclusions (stage 2); and acellular, fibrillar deposits (stage 3, "ghost tangles"). The numbers of tangles in randomly selected fields of parahippocampal cortex from 11 Alzheimer patients correlated with both the numbers of IL-1alpha+ microglia and the numbers of S100beta+ astrocytes in these fields (r = 0.72, p < 0.02; r = 0.73, p = 0.01, respectively). There were progressive increases in frequency of association between tangle stages and both IL-1alpha+ microglia and S100beta+ astrocytes: 48, 56, 67, and 92% of stage 0-3 tangles, respectively, had associated IL-1alpha+ microglia; and 21, 37, 55, and 91% of stage 0-3 tangles had associated S100beta+ astrocytes. This progressive association of activated IL-1alpha+ microglia and activated S100beta+ astrocytes with tau2+ tangle stages suggests a role for glial-neuronal interactions in the degeneration of tangle-bearing neurons in Alzheimer disease.

Aged↗
PubMed1996

Broad A band disease: a new benign congenital myopathy.

We report a second child with broad A band disease. This child differs from the first in having normal vision and no electrophysiological evidence of a congenital retinal dystrophy. Neurological abnormalities at presentation included diffuse hypotonia, developmental delay, and delayed speech development. Histological and preliminary histochemical evaluation of biopsied thigh muscle showed no abnormality. However, 1-micrometer-thick plastic sections and electron microscopy showed numerous foci of broadened A bands accompanied by loss of distinct I bands. The Z lines in these areas were normal except for a fine waviness. Ultrastructurally, the thick filaments in these lesions appeared misaligned. Immunohistochemical reactions for desmin, vimentin, connectin (titin), and 2B myosin showed normal reactivity. An immunohistochemical reaction for fetal myosin showed sparse reacting fibers, which were unremarkable on adjacent sections stained with hematoxylin and eosin. These findings differ from those of other previously described congenital myopathies. Both of our patients have shown good strength and motor development by 5 years of age, suggesting that this ultrastructural abnormality is essentially benign.

Child Development↗