Showing papers in "Journal of Neuropathology and Experimental Neurology in 1997"
TL;DR: The consensus recommendations for improving the neuropathological criteria for the postmortem diagnosis of Alzheimer's disease are reported here, and the "position papers" by members of the Working Group that accompany this report elaborate on the research findings and concepts upon which these recommendations were based.
Abstract: THE NATIONAL INSTITUTE ON AGING AND REAGAN INSTITUTE WORKING GROUP ON DIAGNOSTIC CRITERIA FOR THE NEUROPATHOLOGICAL ASSESSMENT OF ALZHEIMER'S DISEASE.Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. NEUROBIOL AGING18(S4) S1-S2, 1997.—This report summarizes the consensus recommenda- tions of a panel of neuropathologists from the United States and Europe to improve the postmortem diagnostic criteria for Alzheimer's disease. The recommendations followed from a two-day workshop sponsored by the National Institute on Aging (NIA) and the Ronald and Nancy Reagan Institute of the Alzheimer's Association to reassess the original NIA criteria for the postmortem diagnosis of Alzheimer's disease published in 1985 (2). The consensus recommendations for improving the neuropathological criteria for the postmortem diagnosis of Alzheimer's disease are reported here, and the "position papers" by members of the Working Group that accompany this report elaborate on the research findings and concepts upon which these recommendations were based. Further, commentaries by other experts in the field also are included here to provide additional perspectives on these recommendations. Finally, it is anticipated that future meetings of the Working Group will reassess these recommendations and the implementation of postmortem diagnostic criteria for Alzheimer's disease. © 1997 Elsevier Science Inc.
1,572 citations
TL;DR: Control the local inflammatory microenvironment of SP may hold promise for slowing lesion pathogenesis, but it still remains a fundamental challenge to determine the mechanism of neurodegeneration that results in widespread neurofibrillary degeneration and eventual synaptic and neuronal loss.
Abstract: Senile plaques (SP) are complicated lesions composed of diverse amyloid peptides and associated molecules, degenerating neuronal processes,a nd reactive glia. Evidence suggests that diffuse, neurocentric amyloid deposits evolve over time with formation of discrete niduses that eventually become neuritic SP. The evidence for differential amyloid precursor protein metabolism that may favor deposition of A beta 17-42 in this early, possibly aging-related lesion is discussed. This latter molecule, also known as P3, may represent a benign form of amyloid, since it lacks domains associated with activation and recruitment of glia to SP. Subsequent to deposition of A beta 1-42 and then growth of the amyloid with precipitation of soluble A beta 1-40, in an Alzheimer disease-specific process, SP increasingly become associated with activated microglia and reactive astrocytes. In response to interaction with amyloid peptides and possibly glycated proteins, microglia and astrocytes produce a number of molecules that may be locally toxic to neuronal processes in the vicinity of SP, including cytokines, reactive oxygen and nitrogen intermediates, and proteases. They also produce factors that lead to their reciprocal activation and growth, which potentiate a local inflammatory cascade. Paired helical filament- (PHF) type neurites appear to be associated with SP only in so far as neurofibrillary degeneration has progressed to affect neurons in those regions where the plaque forms. Thus, PHF-type neurites are readily apparent in SP in the amygdala at an early stage, while they are late in primary cortices and never detected in cerebellar plaques; where only dystrophic neurites are detected. If the various stages of SP pathogenesis can be further clarified, it may be possible to develop rational approaches to therapy directed at site-, cell type-, and stage-specific interventions. Although controlling the local inflammatory microenvironment of SP may hold promise for slowing lesion pathogenesis, it still remains a fundamental challenge to determine the mechanism of neurodegeneration that results in widespread neurofibrillary degeneration and eventual synaptic and neuronal loss, which is considered to be the proximate cause of the clinical dementia syndrome.
706 citations
TL;DR: It is concluded that Aβ is not acutely neurotoxic, but can disrupt neuronal processes and provoke an inflammatory response, similar to human senile plaques.
Abstract: The recent availability of transgenic mouse models of Alzheimer disease has allowed direct in vivo assessment of the molecular and neuropathological effects of cerebral amyloid deposition. We examined 16-month-old Tg(HuAPP695. K670N-M671L)2576 mice expressing human APP K670N-M671L (APPSw), which have amyloid deposition and behavioral deficits by 11 months of age. Transgene expression is predominantly neuronal, and results in amyloid deposits, comparable to human senile plaques, at terminal zones of transgene positive neurons in cortical and limbic regions. Amyloid deposits were associated with prominent gliosis and neuritic dystrophy, without neuronal loss in CA1, loss of synaptophysin immunoreactivity in the hippocampal dentate gyrus, or loss of messenger RNA for neuronal synaptic, cytoskeletal, or metabolic proteins. We conclude that A beta is not acutely neurotoxic, but can disrupt neuronal processes and provoke an inflammatory response.
674 citations
TL;DR: It is concluded that synaptic abnormalities in the hippocampus correlate with the severity of neuropathology and memory deficit in individuals with AD, and that this defect may predate neuropsychological evidence for cognitive impairment early in AD.
Abstract: We tested the hypothesis that synaptic defects in the hippocampus of individuals with Alzheimer disease (AD) correlate with the severity of cognitive impairment. Three postmortem groups were studied: controls with normal and stable cognition; cognitively intact subjects with senile plaque densities diagnostic for possible AD (p-AD) and neurofibrillary changes characteristic of early AD (Braak stage III); and individuals with definite AD and neurofibrillary changes typical of incipient to severe AD (Braak stage III, V, or VI). Synaptophysin (a presynaptic vesicle protein) levels were quantified by immunoblotting of synaptic membrane fractions isolated from hippocampus, entorhinal cortex, caudate nucleus, and occipital cortex. Average synaptophysin levels were reduced in hippocampus when comparing definite AD to controls (55%, p < 0.0001), p-AD to control (25%, p < 0.005), and definite AD to p-AD (30%, p < 0.05), but levels in entorhinal cortex, occipital cortex, and caudate nucleus were either unchanged or less significantly altered than in hippocampus. By univariate analysis, hippocampal synaptophysin levels correlated with neuropsychological measurements, including Mini-mental state examination scores (r = 0.83, p < 0.0001) and Blessed scores (r = 0.74, P < 0.001), and with senile plaque densities (r = 0.89, p < 0.0001). We conclude that synaptic abnormalities in the hippocampus correlate with the severity of neuropathology and memory deficit in individuals with AD, and that this defect may predate neuropsychological evidence for cognitive impairment early in AD.
520 citations
TL;DR: It is found that GSK-3 is prominently present in neuronal cell bodies and their processes and co-localizes with neurofibrillary changes in AD brain and is significantly increased in the postsynaptosomal supernatant from AD brains as compared to the controls.
Abstract: A number of studies have implicated a proline-directed protein kinase, glycogen synthase kinase-3 (GSK-3) in the hyperphosphorylation of tau in Alzheimer's disease (AD). Toward understanding the role of GSK-3 in the abnormal hyperphosphorylation of tau in AD we have found that GSK-3 is prominently present in neuronal cell bodies and their processes and co-localizes with neurofibrillary changes in AD brain. Furthermore, the levels of GSK-3 as determined by indirect ELISA are ∼50% increased in the postsynaptosomal supernatant from AD brains as compared to the controls. However, no increase in GSK-3 enzyme activity was detected. In AD brain, with its reduced phosphatase activity, even normal levels of GSK-3 activity might be sufficient for the hyperphosphorylation of tau.
363 citations
TL;DR: Aggregation of SOD-1 may contribute significantly to the death of motor neuron expressing mutations associated with FALS-1 and the mechanisms leading to aggregation may pertain to the specific vulnerability of motor neurons in this disease.
Abstract: Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene underlie some familial cases of amyotrophic lateral sclerosis (FALS), a neurodegenerative disorder characterized by loss of cortical, brainstem, and spinal motor neurons. To investigate the mechanisms responsible for the toxicity of mutant enzyme, SOD-1 cDNAs bearing mutations found in FALS patients (mSOD) were expressed in cultured spinal motor neurons, dorsal root ganglion (DRG) and hippocampal neurons. Many features of motor neuron disease seen in humans with FALS and in transgenic mouse models were reproduced, including preferential susceptibility of motor neurons to toxicity of mSOD. Abnormal cytoplasmic aggregation of mSOD protein was observed in mSOD-expressing motor neurons, but never in neurons expressing SODwt enzyme, and was followed by evidence of apoptotic cell death. Such aggregates were not observed in nonvulnerable neuronal populations expressing mSOD (DRG or hippocampal neurons). Aggregation of SOD-1 may contribute significantly to the death of motor neurons expressing mutations associated with FALS-1 and the mechanisms leading to aggregation may pertain to the specific vulnerability of motor neurons in this disease.
359 citations
TL;DR: The notion that astroglial EAAT2 is affected in AD and abnormal functioning and/or processing of APP might play an important role in this process is supported.
Abstract: Recent studies have shown that deficient functioning of glutamate transporters (GTs) in Alzheimer disease (AD) might lead to neurodegeneration. The main objectives of the present study were to determine which GT subtype is most affected in AD and to asses to what extent altered GT function is associated with abnormal amyloid precursor protein (APP) expression. While EAAT2-immunoreactivity (IR) was decreased in AD frontal cortex, EAAT1- and EAAT3-IR were unaffected; mRNA levels for all 3 GTs were not affected. Decreased EAAT2-IR was associated with decreased GT activity. EAAT2-IR inversely correlated with EAAT2 mRNA levels, suggesting that in AD, GT expression alterations occur due to disturbance at the post-transcriptional level. EAAT2-IR was inversely correlated with APP770 mRNA. In addition, GT activity directly correlated with APP695 mRNA and total APP protein levels, and inversely correlated with APP751/770 mRNA levels. This study supports the notion that astroglial EAAT2 is affected in AD and abnormal functioning and/or processing of APP might play an important role in this process.
311 citations
TL;DR: It is proposed that, in acquired encephalopathies, the progressive postinjury reorganization of the undamaged cortex and its consequences (acquired cortical dysplasia), rather than the original lesion, represent the main underlying mechanism in the pathogenesis of ensuing neurological sequelae, such as, epilepsy, cerebral palsy, dyslexia, cognitive impairment, and/or poor school performance.
Abstract: The evolving neuropathology of primarily undamaged cortical regions adjacent to the injured site has been studied in 36 infants who survived a variety of perinatally acquired encephalopathies (microgyrias, ulegyrias, multicystic encephalopathies, porencephalies, and hydranencephalies) and later died of unrelated causes. Their survival times range from hours, days, weeks, or months, to several years. Ten of these children developed epilepsy, 2 developed cerebral palsy, and several were neurologically and mentally impaired. In all cases studied, the undamaged cortex adjacent to the injured site survives, retains its intrinsic vasculature, and is capable of continuing differentiation. However, its postinjury development is characterized by progressive alterations compatible with acquired cortical dysplasia that affects the structural and functional differentiation of its neurons, synaptic profiles, fiber distribution, glial elements, and vasculature. The synaptic profiles of many neurons are transformed by an increased number of intrinsic loci that replace extrinsic ones vacated by the destruction of afferent fibers. The intrinsic fibers of layer I and some Cajal-Retzius cells survive even in severe lesions and may be capable of interconnecting cortical regions that have lost other type of connections. Some intrinsic neurons undergo postinjury structural and functional hypertrophy, acquire new morphologic and functional features, and achieve a large size (meganeurons). Probably, these meganeurons acquire their structural and functional hypertrophy by partial endomitotic DNA and/or RNA reduplication (polyploidy). These postinjury alterations are not static but ongoing processes that continue to affect the structural and functional differentiation of the still developing cortex and may eventually influence the neurologic and cognitive maturation of affected children. This study proposes that, in acquired encephalopathies, the progressive postinjury reorganization of the undamaged cortex and its consequences (acquired cortical dysplasia), rather than the original lesion, represent the main underlying mechanism in the pathogenesis of ensuing neurological sequelae, such as, epilepsy, cerebral palsy, dyslexia, cognitive impairment, and/or poor school performance.
303 citations
TL;DR: The literature from 1977 to the present is reviewed for pathologically and genetically verified cases accompanied by relatively complete clinical descriptions so as to give the pathological features associated with this condition a clearer definition.
Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently identified cause of stroke and vascular dementia. It is a condition of mid-adulthood due to mutations of Notch 3 gene on chromosome 19. Whereas the disease was first reported in European families, since 1993 CADASIL has been observed in American, African and Asiatic pedigrees, suggesting that today, the disease probably still remains largely underdiagnosed. The pathological data first dealt with the white matter and the basal ganglia showing the features observed in Binswanger's subcortical arteriopathic encephalopathy; over the past few years, CADASIL has become appreciated as a systemic vascular disease with specific features. Here we have reviewed the literature from 1977 to the present for pathologically and genetically verified cases accompanied by relatively complete clinical descriptions so as to give the pathological features associated with this condition a clearer definition. The review will focus mainly on pathological studies and the pathophysiological mechanisms most likely to be involved in CADASIL.
268 citations
TL;DR: It is demonstrated that oligodendrocytes that survive within a region of demyelination are not induced to divide in the presence of demYelinated axons, and fully-differentiated oligodends are therefore postmitotic and do not contribute to remyelinating in the adult CNS.
Abstract: In order to investigate the remyelinating potential of mature oligodendrocytes in vivo, we have developed a model of demyelination in the adult rat spinal cord in which some oligodendrocytes survive demyelination. A single intraspinal injection of complement proteins plus antibodies to galactocerebroside (the major myelin sphingolipid) resulted in demyelination followed by oligodendrocyte remyelination. Remyelination was absent when the spinal cord was exposed to 40 Grays of x-irradiation prior to demyelination, a procedure that kills dividing cells. Quantitative Rip immunohistochemical analysis revealed a similar density of surviving oligodendrocytes in x-irradiated and nonirradiated lesions 3 days after demyelination. Rip and bromodeoxyuridine double immunohistochemical analysis of demyelinated lesions indicated that Rip+ oligodendrocytes did not divide as an acute response to demyelination. Oligodendrocytes were also identified by Rip immunostaining and electron microscopy at late time points (3 weeks) within x-irradiated areas of demyelination. These oligodendrocytes extended processes that engaged axons, and on occasion formed myelin membranes, but did not lay down new myelin sheaths. These studies demonstrate that (a) oligodendrocytes that survive within a region of demyelination are not induced to divide in the presence of demyelinated axons, and (b) fully-differentiated oligodendrocytes are therefore postmitotic and do not contribute to remyelination in the adult CNS.
268 citations
TL;DR: Findings suggest that Bax may contribute to neuronal cell death in AD, and DNA damage and the upregulation of Bax appear to precede tangle formation or may represent an alternative pathway of cellDeath in AD.
Abstract: We have shown that many neurons in Alzheimer's disease (AD) exhibit terminal deoxynucleotidyl transferase (TdT) labeling for DNA strand breaks, and upregulation of Bcl-2 is associated with neurons exhibiting nuclear DNA fragmentation, while downregulation of Bcl-2 is associated with tangle-bearing neurons in AD brains. Consequently, we examined the expression of bcl-associated X (Bax) protein in AD brain. Immunoreactivity for Bax was seen in neurons and microglia of the hippocampal formation, and was elevated in the majority of AD cases as compared to control cases. Interestingly, 3 transitional cases, which had mild degeneration changes, exhibited relatively high levels of Bax immunoreactivity. Most Bax-positive neurons showed either TdT-labeled nuclei or Bcl-2 immunoreactivity. Although Bax immunoreactivity was detected within most early tangle-bearing neurons, many Bax-positive neurons did not colocalize with later-stage tangle-bearing neurons. In regions containing relatively few tangles in mild AD brains, many TdT-labeled neurons were immunolabeled with Bax antibody and most of them lacked evidence of neurofibrillary changes. These findings suggest that Bax may contribute to neuronal cell death in AD. Furthermore, DNA damage and the upregulation of Bax appear to precede tangle formation or may represent an alternative pathway of cell death in AD.
TL;DR: The data suggest the existence of two genetic subsets of oligoastrocytomas, one genetically related to astrocytic gliomas and the other geneticallyrelated to oligodendrogliomas.
Abstract: The histogenesis of oligoastrocytomas remains controversial, with some data arguing similarity of oligoastrocytomas to astrocytic tumors, and other data suggesting closer relationships with oligodendroglial neoplasms. Since the molecular genetic changes in astrocytomas differ from those of oligodendrogliomas, we characterized 120 astrocytic and oligodendroglial tumors, including 38 oligoastrocytomas, for genetic alterations that occur disproportionately between astrocytomas and oligodendrogliomas, i.e. TP53 gene mutations and allelic loss of chromosomes 1p, 17p and 19q. As previously reported, TP53 mutations were common in astrocytic gliomas, occurring in approximately half of WHO grade II and III astrocytomas, but in only 5% of WHO grades II and III oligodendrogliomas. Allelic losses of chromosomes 1p and 19q, however, were common in oligodendrogliomas (41% and 63%), but less frequent in astrocytomas (9% and 35%). Oligoastrocytomas showed TP53 mutations in 12/38 (32%) cases and allelic losses of chromosomes 1p and 19q in 52% and 70%, respectively. Most importantly, TP53 mutations and allelic losses on chromosomes 1p and 19q were inversely correlated in oligoastrocytomas (p < 0.011 and p < 0.019). These data suggest the existence of two genetic subsets of oligoastrocytomas, one genetically related to astrocytomas and the other genetically related to oligodendrogliomas. Histologically, those oligoastrocytomas with TP53 mutations were more often astrocytoma-predominant, while those with chromosome 19q loss were more often oligodendro-glioma-predominant.
TL;DR: The findings indicate that pathological diagnostic criteria for AD should take into account such additional pathology in demented subjects, and improve understanding of the circumstances in which the amyloid component of AD can play a decisive role in precipitating clinical dementia.
Abstract: The diagnosis of Alzheimer disease (AD) according to current criteria is a combined clinical and pathological exercise. The clinical discrimination of AD from other types of dementia may be complicated when the patient suffers from more than one disease. In particular the concomitant presence of other neurological conditions may significantly influence the severity of cognitive deficit. In this study we analyze the extent of the influence of vascular and other neurodegenerative pathology on the cognitive deficit in a consecutive series of 88 prospectively assessed elderly subjects. We find that, for any given level of cognitive deficit, the densities of either all plaques or neuritic plaques alone in the neocortex are significantly lower in cases of AD mixed with other CNS pathology than in cases of AD with no other CNS pathology. In AD combined with cerebrovascular disease, the total plaque density makes a significant contribution to cognitive deficit, while neurofibrillary tangle (NFT) densities do not. In contrast, in pure AD tangle density is the major determinant of cognitive deficit. Our findings draw attention to the influence of coexisting brain pathologies on the clinical manifestation of dementia in subjects with AD. These findings indicate that pathological diagnostic criteria for AD should take into account such additional pathology in demented subjects. They also improve understanding of the circumstances in which the amyloid component of AD can play a decisive role in precipitating clinical dementia.
TL;DR: Data indicate that parasagittal F-P brain injury results in widespread axonalDamage, that axonal damage includes both reversible and delayed patterns, and that injury severity is an important factor in determining the severity of the axonal response to TBI.
Abstract: Diffuse axonal injury (DAI) is an important consequence of human head trauma. This experimental investigation utilized the immunocytochemical visualization of beta-amyloid precursor protein (beta-APP) to document regional patterns of axonal injury after traumatic brain injury (TBI) and to determine the importance of injury severity on the magnitude of axonal damage. Rats underwent moderate (1.84-2.11 atm) or severe (2.38-2.52 atm) parasagittal fluid-percussion (F-P) brain injury or sham procedures. At 1, 3, 7 or 30 days after TBI, rats were perfusion-fixed and sections immunostained for the visualization of beta-APP. A regionally specific axonal response to TBI was documented after moderate F-P injury. Within the dorsolateral striatum, an early increase in beta-APP-positive axonal profiles at 24 hours (h) was followed by a significant decline at subsequent survival periods. In contrast, the frequency of reactive profiles was initially low within the thalamus, but increased significantly by day 7. Within the external capsule at the injury epicenter, numbers of immunoreactive axons increased significantly at 24 h and remained elevated throughout the subsequent survival periods. At multiple periods after TBI, selective cortical and thalamic neurons displayed increased staining of the perikarya. A significant increase in the overall frequency of beta-APP profiles was documented in the severe vs moderately injured rats at 72 h after TBI. These data indicate that parasagittal F-P brain injury (a) results in widespread axonal damage, (b) that axonal damage includes both reversible and delayed patterns, and (c) that injury severity is an important factor in determining the severity of the axonal response to TBI.
TL;DR: Findings indicate a loss of neurons with NMDA receptors in the neostriatum of Huntington's disease patients and controls, and a concomitant proliferation of astrocytes with GLT1 transcripts may represent a compensatory mechanism protecting neostRIatal neurons from glutamate excitotoxicity.
Abstract: The distribution of NMDA receptor subunit (NR1, NR2B) and glia-bound glutamate transporter (GLT1) mRNAs was investigated in postmortem brains of Huntington's disease (HD) patients and controls by means of in situ hybridization using radiolabeled deoxyoligonucleotides. In the neostriatum of HD, NR1, NR2B and GLT1mRNA decreased in correlation to disease severity. GLT1mRNA was not as low as NR1/NR2BmRNA. Losses were more prominent in putamen than in the distinctly atrophied caudate. NR1/NR2BmRNA decreased corresponding to neuronal loss, GLT1mRNA due to reduced cellular expression. The number of GLT1mRNA expressing cells identified as astrocytes increased in the neostriatum (astrogliosis). In contrast to controls, most of these astrocytes contained glial fibrillary acidic protein. NR1/NR2B and GLT1mRNA expression was not homogeneously lower in the neostriatum; zones with stronger hybridization signals corresponded to the matrix compartment and consisted of a larger number of cells with high mRNA levels. Early in the disease, cellular NR1/ NR2BmRNA levels were higher in these zones than in controls. These findings indicate a loss of neurons with NMDA receptors in the neostriatum of HD. A concomitant proliferation of astrocytes with GLT1 transcripts may represent a compensatory mechanism protecting neostriatal neurons from glutamate excitotoxicity.
TL;DR: Examination of immunocytochemical localizations of both Ps and ubiquitin in sections of various abnormal structures that are known to be ubiquitinated in various neurodegenerative diseases and in the elderly indicated that Ps is involved in the metabolism of some, but not all, ubiquitinations.
Abstract: To determine at the tissue level whether the proteasome (Ps), a unique nonlysosomal protease, is involved in the metabolism of ubiquitinated proteins, we examined for the first time the immunocytochemical localizations of both Ps and ubiquitin (Ub) in sections of various abnormal structures that are known to be ubiquitinated in various neurodegenerative diseases and in the elderly. Concomitant increases of Ps and Ub were observed at the sites of most dystrophic neurites in Alzheimer disease (AD) and parkinsonism-dementia complex on Guam (PDC) and in Lewy bodies in Parkinson's disease and diffuse Lewy body disease, but not in neurofibrillary tangles in AD or PDC, in filamentous inclusions within anterior horn cells in sporadic motor neuron disease, or in eosinophilic granules in the olivary nucleus of the elderly. These results at the tissue level indicated that Ps is involved in the metabolism of some, but not all, ubiquitinated proteins and structures in various neurodegenerative disorders. This suggests that the involvement of Ps in the metabolism of ubiquitinated structures differs in different cases and at different stages of disease. These results and our previous immunocytochemical studies of lysosomal cathepsin proteases suggest that both nonlysosomal and lysosomal systems are involved in the metabolism of various ubiquitinated proteins and that their involvements differ in different structures and at different stages of degeneration of the structures.
TL;DR: Age-associated vascular changes not clearly linked to systemic conditions including hyaline arteriosclerotic changes with formation of arterial tortuosities in small intracranial vessels and the radiographic changes in deep cerebral white matter known as “leukoaralosis".
Abstract: 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.
TL;DR: A progressive association of activated IL-1α+ microglia and activated S100β+ astrocytes with tau2+ tangle stages suggests a role for glial-neuronal interactions in the degeneration of tangle-bearing neurons in Alzheimer disease.
Abstract: 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.
TL;DR: The results suggest that the nonimpact inertial loading model used to induce brain trauma in miniature swine is clinically relevant and useful for evaluating mechanisms of inertial brain trauma.
Abstract: Dynamic deformation applied to white matter tracts is a common feature of human brain trauma, and may result in diffuse axonal injury (DAI). To produce DAI in an experimental model, we have utilized nonimpact inertial loading to induce brain trauma in miniature swine. This species was chosen due to its large gyrencephalic brain with substantial white matter domains. Twenty anesthetized (2% isoflurane) miniature swine were subjected to pure impulsive centroidal rotation 110 degrees in the coronal plane in 4 to 6 ms; peak accelerations ranged from 0.6 to 1.7 x 10(5) rad/s2. Seven days following injury, the brains were fixed (4% paraformaldehyde). Histopathologic examination was performed on 40 microns sections stained with cresyl violet (Nissl), antibodies targeting neurofilament (axonal damage), GFAP (astrocytes), and pig IgG (protein extravasation). Widespread multifocal axonal injury was observed in combination with gliosis throughout the brain, most commonly in the root of gyri and at the interface of the gray and white matter. Very little vascular disruption was noted in regions of axonal injury. Neuronal damage was primarily found in the CA1 and CA3 subfields of the hippocampus. These results suggest that this model is clinically relevant and useful for evaluating mechanisms of inertial brain trauma.
TL;DR: An important role for human macrophages capable of producing the free radical nitric oxide (NO), which may contribute to the cytotoxicity of oligodendrocytes and destruction of myelin in MS brain and spinal cord is suggested.
Abstract: The cellular localization and distribution of inducible and constitutive nitric oxide synthase (iNOS/cNOS) was determined in tissue sections from multiple sclerosis (MS) and control brain and spinal cord. Immunocytochemical techniques were applied using specific iNOS- and cNOS-directed antibodies. In addition, NADPH-diaphorase histochemistry was performed. To establish the identity of iNOS-, cNOS- and NADPH-diaphorase-positive cells single and double staining was performed on tissue sections with the macrophage marker KP1 (CD68) and with the astrocyte marker glial fibrillary acidic protein (GFAP). Areas of myelin breakdown and demyelination were determined using a staining for neutral lipids, Oil Red O (ORO). Furthermore, macrophages isolated from active demyelinating MS lesions were stained for iNOS, cNOS, KP1 and ORO. In active MS lesions strong iNOS immunoreactivity was found exclusively in perivascular and parenchymal macrophages distributed within regions of active demyelination. In these active MS lesions immunoreactivity for cNOS was also found in macrophages. Macrophages isolated from active MS lesions also showed immunoreactivity for iNOS and cNOS. Moreover, these isolated macrophages produced nitric oxide (NO; >30 microM) in vitro. NADPH-diaphorase activity was detected in KP1-positive perivascular and parenchymal macrophages and in GFAP-positive reactive astrocytes in active MS lesions and in reactive astrocytes located in the hypercellular rims of chronic active MS lesions. cNOS-positive reactive astrocytes were detected in both active and chronic active MS lesions. Inside chronic active lesions some residual macrophages were weakly iNOS-positive. In control brain and spinal cord no iNOS immunoreactivity could be detected. These results suggests an important role for human macrophages capable of producing the free radical nitric oxide (NO), which may contribute to the cytotoxicity of oligodendrocytes and destruction of myelin in MS brain and spinal cord.
TL;DR: In this paper, the authors reported that traumatic brain injury evokes local changes in axolemma's permeability, in concert with local cytoskeletal changes involving neurofilament (NF) compaction and sidearm loss, all of which contribute to the genesis of reactive axonal change.
Abstract: Recently we reported that traumatic brain injury evokes local changes in the axolemma's permeability, in concert with local cytoskeletal changes involving neurofilament (NF) compaction and sidearm loss, all of which contribute to the genesis of reactive axonal change. Since it was of concern that these events may be either injury model- or species-specific, we sought to address these phenomena in a different but well-characterized animal model and species. Further, to provide more compelling insight into the potential for NF compaction and sidearm alteration, we also employed antibodies specific for the NF rod domains, which are readily visualized only when the NF sidearms are disturbed. Rats were subjected to impact acceleration injury. To assess the potential for altered axolemmal permeability, 5 animals received intrathecal horseradish peroxidase (HRP), normally excluded by the intact axolemma. To assess the potential for NF sidearm alteration, another 14 animals were processed for the visualization of antibodies targeting the NF rod domain at 5 minutes (min) to 24 hours (h) postinjury. All animals were evaluated at the LM and EM levels. Those animals receiving intrathecal HRP showed immediate focal alterations in the axolemma's permeability to the normally excluded tracer. Over a 2 h period, these axons demonstrated NF compaction. Antibodies targeted to the rod domains revealed focal intra-axonal immunoreactivity in sites closely correlated with those showing altered axolemmal permeability. These same sites also demonstrated evidence of NF compaction and sidearm loss/perturbation. Collectively, these findings suggest that occurrence of altered axolemmal permeability and concomitant cytoskeletal change are features common to traumatic brain injury in various animal models and species. Further, these studies underscore the utility of antibodies targeting the rod domain for the early detection of traumatically induced reactive change.
TL;DR: The data suggest that over the course of AD, continuous neurofibrillary tangle formation and continuous neuronal loss occur in the hippocampal subdivisions and the rate of neuronal loss appears to be similar for CA1, CA4, and the subiculum.
Abstract: The total numbers of neurons with and without neurofibrillary changes in the hippocampal subdivisions were estimated in 16 subjects with Alzheimer disease (AD) and in 5 normal elderly controls. On the basis of clinical symptoms, AD patients were subdivided into relatively less (AD-1, Functional Assessment Staging [FAST] stages 7a to 7c) and more severely affected (AD-2, FAST stages 7e to 7f) patient groups. In the AD-1 group relative to controls, the total number of neurons was reduced only in CA1 and in the subiculum. In the AD-2 group, neuronal losses were found in all sectors of the cornu Ammonis and in the subiculum and ranged from 53% in CA3 to 86% in CA1. The dentate gyrus was the only hippocampal subdivision without significant neuronal loss. Within the combined AD patient groups, significant correlations were noted between both clinical stage and duration of AD and both the total number of neurons and the percentage of neurons with neurofibrillary changes in CA1, CA4, and the subiculum. Regression analyses predicted neuronal losses over the maximal observed duration of 22 years of 87% in CA1, 63% in CA4, and 77% in the subiculum. Our data suggest that over the course of AD, continuous neurofibrillary tangle formation and continuous neuronal loss occur in the hippocampal subdivisions. The rate of neuronal loss appears to be similar for CA1, CA4, and the subiculum.
TL;DR: The term “atypical central neurocytoma” is proposed for the latter subset, corresponding to WHO grade II, and a highly significant difference in disease-free survival between the 2 groups is shown.
Abstract: The proliferative potential of central neurocytomas was determined in a biopsy series of 36 cases and compared with clinical outcome. The mean size of the growth fraction, as determined by MIB-1 labeling index (MIB-1 LI) at first biopsy, was 2.8 +/- 2.5 with a range of 0.1 to 8.6%. Neurocytomas with an MIB-1 LI > 2% comprised 39% of cases and showed a close correlation with the presence of vascular proliferation (p = 0.0006). The Kaplan-Meier analysis showed a highly significant difference in disease-free survival between the 2 groups (p = 0.0068). Over an observation time of 150 months, there was a 22% relapse among patients with an MIB-1 LI less than 2% and a 63% chance of relapse among those with an MIB-1 LI greater than 2%. We propose the term "atypical central neurocytoma" for the latter subset, corresponding to WHO grade II.
TL;DR: Results suggest that MDM2 overexpression with or without gene amplification constitutes a molecular mechanism of escape from p53-regulated growth control, operative in the evolution of primary glioblastomas that typically lack p53 mutations.
Abstract: Glioblastoma multiforme (WHO Grade IV), the most malignant neoplasm of the human nervous system, develops rapidly de novo (primary glioblastoma) or through progression from low-grade or anaplastic astrocytoma (secondary glioblastoma). We recently reported that mutations of the p53 gene are present in more than two-thirds of secondary glioblastomas but rarely occur in primary glioblastomas, suggesting the presence of different genetic pathways (Watanabe et al, Brain Pathol 1996:6:217-24). In the present study, primary and secondary glioblastomas were screened by immunohistochemistry for MDM2 overexpression and by differential PCR for gene amplification. Tumor cells immunoreactive to MDM2 were found in 15 of 29 primary glioblastomas (52%), but in only 3 of 27 secondary glioblastomas (11%; P=0.0015). MDM2 amplification occurred in 2 primary (7%) glioblastomas but in none of the secondary glioblastomas. Only one out of 15 primary glioblastomas overexpressing MDM2 contained a p53 mutation. These results suggest that MDM2 overexpression with or without gene amplification constitutes a molecular mechanism of escape from p53-regulated growth control, operative in the evolution of primary glioblastomas that typically lack p53 mutations.
TL;DR: There is a significant difference between the interaction of apoE3 and APoE4 with lipid peroxidation in the brains of AD patients, and this is proposed to be the cause of increased immunoreactivity in AD patients.
Abstract: Increasing age and inheritance of the epsilon 4 allele of apolipoprotein E (APOE4) are significant risk factors for sporadic and late onset familial Alzheimer disease (AD); however, the mechanisms by which either leads to AD are unknown. Numerous studies have associated advancing age with increased indices of oxidative challenge to brain, and with still further increased oxidative damage to relevant brain regions in AD patients. A major consequence of oxidative damage to brain is lipid peroxidation with production of the neurotoxic metabolite 4-hydroxy-2-nonenal (HNE). HNE reacts with protein to yield several adducts, including a pyrrole adduct that forms irreversibly in biological systems. Previously, we have shown in a small number of AD and control patients that HNE pyrrole adduct antiserum is immunoreactive with neurofibrillary tangles (NFT), and that this reactivity was significantly associated with inheritance of APOE4. Others have confirmed this pattern of immunoreactivity in AD brain but did not observe an association with APOE4. Herein, we have expanded the study group to 19 AD patients homozygous for APOE4 or APOE3, as well as 30 patients with other neurodegenerative diseases, including diffuse Lewy body disease, Pick's disease, progressive supranuclear palsy, Parkinson's disease, and human immunodeficiency virus-1 encephalitis. HNE pyrrole adduct immunoreactivity on NFT in AD patients was strongly associated with APOE4 homozygosity. With the exception of rare immunoreactive Pick bodies in one case of Pick's disease, no other structure was recognized by HNE pyrrole adduct antiserum in this series of patients. We propose that there is a significant difference between the interaction of apoE3 and apoE4 with lipid peroxidation in the brains of AD patients.
TL;DR: The view that astrocytes are directly involved in the pathologic process of ALS, and might explain the selective vulnerability of motor neurons by their relative lack of antioxidant defenses, is supported.
Abstract: There is increasing evidence that oxidative damage plays a major role in amyotrophic lateral sclerosis (ALS), but how it contributes to motor neuron degeneration and astrocytic gliosis, two pathologic hallmarks of the disease, is unknown. A few studies have suggested that ALS motor neurons die via apoptosis and show upregulation of c-jun, an immediate early gene that is necessary for neuronal apoptosis. In order to elucidate the mechanisms of cell damage induced by oxidant stress, we have studied in ALS and control spinal cord the immunohistochemical expression of c-Jun, of JNK/SAPK, a kinase that activates c-Jun following various types of stress, and of NF-kappa B, a transcription factor that is induced by oxidant stress and has prominent neuroprotective functions. An in situ end-labeling assay was performed for detecting apoptotic cells. We show that (a) the JNK/SAPK-c-Jun pathway is dramatically overexpressed in ALS spinal cord; (b) the strongest activation occurs in astrocytes, while motor neurons show unusually low expression of the pathway; (c) increased JNK/SAPK expression in glial cells is accompanied by NF-kappa B activation, indicating the presence of a protective response to oxidant sress, which is deficient in motor neurons; (d) activation of JNK/SAPK, c-Jun and NF-kappa B is unrelated to apoptotic cell death. These results support the view that astrocytes are directly involved in the pathologic process of ALS, and might explain the selective vulnerability of motor neurons by their relative lack of antioxidant defenses.
TL;DR: A series of 8 third ventricular neoplasms with a distinctive chordoid appearance that appear to represent a clinicopathologic entity are encountered, ranging in age from 31 to 70 years, and consist of cords and clusters of cohesive, oval- to-polygonal epithelioid cells with abundant eosinophilic cytoplasm, relatively uniform round-to-oval nuclei, and inconspicuous nucleoli.
Abstract: We have encountered a series of 8 third ventricular neoplasms with a distinctive chordoid appearance that appear to represent a clinicopathologic entity. The tumors occurred in 7 females and 1 male, ranging in age from 31 to 70 years. In all cases, imaging studies showed a large well-circumscribed third ventricular mass; a cystic component was noted in 2. The tumors consisted of cords and clusters of cohesive, oval-to-polygonal epithelioid cells with abundant eosinophilic cytoplasm, relatively uniform round-to-oval nuclei, and inconspicuous nucleoli. Mitotic activity was absent. The stroma consisted of scant, coarse fibrillar processes, as well as prominent, slightly basophilic, extracellular mucin resembling that in chordomas. Throughout the tumor, and surrounding its well-defined borders, were infiltrates of mature lymphocytes and plasma cells. Russell bodies were prominent in the latter. Adjacent brain tissue showed reactive changes with gliosis and numerous Rosenthal fibers. Immunohistochemically, tumor cells were strongly reactive for GFAP and vimentin, but negative or only weakly staining for EMA. The MIB-1 labeling index was approximately 1%. Ultrastructural examination of 4 cases revealed focal microvilli, scattered "intermediate" junctions, and focal basal lamina formation. Neither desmosomes nor cilia were seen. Total resections were achieved in 2 cases; only subtotal removals were achieved in 6. Subsequent tumor enlargement was noted in 3 of the 6 patients with incomplete resection, and of these, two died at post-operative intervals of 8 months and 3 years. The other patient survives 4 years post-operatively with stable residual disease. Of the 2 patients with total resection, 1 was lost to follow-up; the other, during a brief follow-up period, did well without evidence of recurrence.
TL;DR: Observations show that correlations between microglial cell activation and pathologic features of AD are only rarely significant, and when significant linkage was present, it involved NFTs and not SPs, and depended on which sector of hippocampus was examined.
Abstract: Microglial cells are the main component of the brain's resident immune system and are activated in Alzheimer disease (AD). We quantified the density of activated microglial cells (AMG) in 8 sectors of human hippocampus to determine if their density is correlated with senile plaque (SP) and neurofibrillary tangle (NFT) formation. Ferritin-stained microglia, Bielschowsky-stained neuritic plaques, and perikarya containing NFTs were counted in 8 young adults, 9 nondemented elderly adults, and 9 demented patients with AD. Microglial cell activation was moderately higher in elderly nondemented subjects. In AD there was a more striking activation in all sectors of the hippocampus. Most AMGs were distributed diffusely in neuropil and were not delimited to SPs or NFTs. Senile plaque counts were not linked with AMG counts within any sector. Neurofibrillary tangle counts were correlated significantly with AMG counts within one sector, the subiculum. When variations within and between sectors were factored out statistically, the burden of AMGs was correlated significantly with the burden of NFTs (r = 0.34; p < 0.005), but not SPs. Neuropathologic changes at the origin of the perforant pathway were correlated significantly with orthograde microglial cell activation in the termination field. These observations show that correlations between microglial cell activation and pathologic features of AD are only rarely significant. When significant linkage was present, it involved NFTs and not SPs, and depended on which sector of hippocampus was examined.
TL;DR: It is concluded that neocortical LB and ChAT depletion contribute to cognitive impairment in DLB and that concomitant AD pathology in LBV, represented by higher Braak stages and NP, promotes increased dementia severity compared with that encountered in DLBD.
Abstract: Dementia with Lewy bodies (DLB) is the second leading cause of cognitive impairment among the elderly. While it is usually accompanied by the neocortical neuritic plaques (NP) and entorhinal neurofibrillary tangles (NFT) characteristic of Alzheimer disease (AD), and so can be construed as a Lewy body variant of AD (LBV), it also occurs in pure form as diffuse Lewy body disease (DLBD). We assessed cognitive status in 17 DLB patients (12 with LBV and 5 with DLBD) and compared the results with 12 AD subjects and 5 controls. We then sought to determine which neuropathologic abnormalities correlated with cognitive impairment. Among DLB cases, neocortical Lewy body (LB) counts, modified Braak stages of NFT burden in the entorhinal cortex, neocortical NP counts, and loss of choline acetyltransferase (ChAT) activity all correlated with dementia severity. Unlike AD, neocortical NFT and anti-synaptophysin reactivity were uncorrelated with DLB dementia. Despite comparable LB counts and ChAT losses, the DLBD were significantly less demented than the LBV patients. We conclude that neocortical LB and ChAT depletion contribute to cognitive impairment in DLB and that concomitant AD pathology in LBV, represented by higher Braak stages and NP, promotes increased dementia severity compared with that encountered in DLBD.
TL;DR: The results indicate that the immediate breakdown of the BBB in the cold lesion is unrelated to VEGF, and the association of maximal V EGF immunoreactivity with endothelial proliferation and neovascularization suggests that VEGf promotes angiogenesis and repair following brain trauma.
Abstract: The role of vascular endothelial growth factor (VEGF) in blood-brain barrier (BBB) breakdown and angiogenesis, observed previously in the cerebral cortical cold-injury model, was investigated. Immunohistochemistry was used to assess BBB permeability to plasma fibronectin and to localize VEGF protein in the cortical cold-injury model over a period of 10 min to 14 days post-injury. BBB breakdown to fibronectin in lesion vessels was observed at 10 min post-injury, was maximal between 2 and 4 days and declined gradually thereafter, while occasional perilesional vessels remained permeable up to 6 days. Increased VEGF immunoreactivtiy occurred later-it was observed in pial vessels after 6 hours (h), and persisted up to day 14. Arterioles within the cold lesion showed VEGF immunoreactivity at 36 h, thus preceding the onset of endothelial proliferation and angiogenesis that occurred from day 3 to day 5. VEGF immunoreactivity was also observed in inflammatory cells and astrocytes. These results indicate that the immediate breakdown of the BBB in the cold lesion is unrelated to VEGF. The presence of mural VEGF in permeable pial vessels and lesional arterioles suggests that VEGF is one of several factors that mediates BBB breakdown in this model. The association of maximal VEGF immunoreactivity with endothelial proliferation and neovascularization suggests that VEGF promotes angiogenesis and repair following brain trauma.