P. G. Popovich, Z. Guan, Violeta M. McGaughy, L. Fisher, William F. Hickey, D. Basso
Activated microglia and macrophages (CNS macrophages) have been implicated in the secondary or “bystander” pathology (e.g. axon injury, demyelination) that accompanies traumatic or autoimmune injury to the brain and spinal cord. These cells also can provide neurotrophic support and promote axonal regeneration. Studying the divergent functional potential of CNS macrophages in trauma models is especially difficult due to the various degradative mechanisms that are initiated prior to or concomitant with microglial/macrophage activation (e.g. hemorrhage, edema, excitotoxicity, lipid peroxidation). To study the potential impact of activated CNS macrophages on the spinal cord parenchyma, we have characterized an in vivo model of non-traumatic spinal cord neuroinflammation. Specifically, focal activation of CNS macrophages was achieved using stereotaxic microinjections of zymosan. Although microinjection does not cause direct mechanical trauma, localized activation of macrophages with zymosan acts as an “inflammatory scalpel” causing tissue injury at and nearby the injection site. The present data reveal that activation of CNS macrophages in vivo can result in permanent axonal injury and demyelination. Moreover, the pathology can be graded and localized to specific white matter tracts to produce quantifiable behavioral deficits. Further development of this model will help to clarify the biological potential of microglia and macrophages and the molecular signals that control their function within the spinal cord.
{"title":"The Neuropathological and Behavioral Consequences of Intraspinal Microglial/Macrophage Activation","authors":"P. G. Popovich, Z. Guan, Violeta M. McGaughy, L. Fisher, William F. Hickey, D. Basso","doi":"10.1093/JNEN/61.7.623","DOIUrl":"https://doi.org/10.1093/JNEN/61.7.623","url":null,"abstract":"Activated microglia and macrophages (CNS macrophages) have been implicated in the secondary or “bystander” pathology (e.g. axon injury, demyelination) that accompanies traumatic or autoimmune injury to the brain and spinal cord. These cells also can provide neurotrophic support and promote axonal regeneration. Studying the divergent functional potential of CNS macrophages in trauma models is especially difficult due to the various degradative mechanisms that are initiated prior to or concomitant with microglial/macrophage activation (e.g. hemorrhage, edema, excitotoxicity, lipid peroxidation). To study the potential impact of activated CNS macrophages on the spinal cord parenchyma, we have characterized an in vivo model of non-traumatic spinal cord neuroinflammation. Specifically, focal activation of CNS macrophages was achieved using stereotaxic microinjections of zymosan. Although microinjection does not cause direct mechanical trauma, localized activation of macrophages with zymosan acts as an “inflammatory scalpel” causing tissue injury at and nearby the injection site. The present data reveal that activation of CNS macrophages in vivo can result in permanent axonal injury and demyelination. Moreover, the pathology can be graded and localized to specific white matter tracts to produce quantifiable behavioral deficits. Further development of this model will help to clarify the biological potential of microglia and macrophages and the molecular signals that control their function within the spinal cord.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"16 1","pages":"623–633"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81884028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A subtractive expression cloning methodology was used to identify proteins having enriched expression at the blood-brain barrier (BBB) in comparison to liver and kidney tissues. A bovine brain capillary COS-1 cell cDNA expression library was screened with a BBB-specific antiserum. This strategy revealed that the membrane cofactor protein CD46, which is a regulator of complement activation in vivo and is also a potential measles virus receptor, is highly expressed at the BBB. The selective CD46 expression in brain at the BBB was confirmed by Northern blot analysis and confocal microscopy. The finding of selective expression of CD46 at the BBB is consistent with an important role played by the microvasculature in the immune surveillance of the brain.
{"title":"Subtractive Expression Cloning Reveals High Expression of CD46 at the Blood‐Brain Barrier","authors":"E. Shusta, Chunni Zhu, R. Boado, W. Pardridge","doi":"10.1093/JNEN/61.7.597","DOIUrl":"https://doi.org/10.1093/JNEN/61.7.597","url":null,"abstract":"A subtractive expression cloning methodology was used to identify proteins having enriched expression at the blood-brain barrier (BBB) in comparison to liver and kidney tissues. A bovine brain capillary COS-1 cell cDNA expression library was screened with a BBB-specific antiserum. This strategy revealed that the membrane cofactor protein CD46, which is a regulator of complement activation in vivo and is also a potential measles virus receptor, is highly expressed at the BBB. The selective CD46 expression in brain at the BBB was confirmed by Northern blot analysis and confocal microscopy. The finding of selective expression of CD46 at the BBB is consistent with an important role played by the microvasculature in the immune surveillance of the brain.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"88 1","pages":"597–604"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75742959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
G. Gu, P. Reyes, G. Golden, R. Woltjer, C. Hulette, T. Montine, Jing Zhang
Inhibition of mitochondrial respiratory chain function may contribute to dopaminergic neurodegeneration in the substantia nigra (SN) of patients with Parkinson disease (PD). Since large-scale structural changes (e.g. deletions and rearrangements in mitochondrial DNA [mtDNA]) have been associated with mitochondrial dysfunction, we tested the hypothesis that increased total mtDNA deletions/rearrangements are associated with neurodegeneration in PD. This study employed a well-established technique, long-extension polymerase chain reaction (LX-PCR), to detect the multiple mtDNA deletions/rearrangements in the SN of patients with PD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), Alzheimer disease (AD), and age-matched controls. We also compared the total mtDNA deletions/rearrangements in different brain regions of PD patients. The results demonstrated that both the number and variety of mtDNA deletions/rearrangements were selectively increased in the SN of PD patients compared to patients with other movement disorders as well as patients with AD and age-matched controls. In addition, increased mtDNA deletions/rearrangements were observed in other brain regions in PD patients, indicating that mitochondrial dysfunction is not just limited to the SN of PD patients. These data suggest that accumulation of total mtDNA deletions/rearrangements is a relatively specific characteristic of PD and may be one of the contributing factors leading to mitochondrial dysfunction and neurodegeneration in PD.
{"title":"Mitochondrial DNA Deletions/Rearrangements in Parkinson Disease and Related Neurodegenerative Disorders","authors":"G. Gu, P. Reyes, G. Golden, R. Woltjer, C. Hulette, T. Montine, Jing Zhang","doi":"10.1093/JNEN/61.7.634","DOIUrl":"https://doi.org/10.1093/JNEN/61.7.634","url":null,"abstract":"Inhibition of mitochondrial respiratory chain function may contribute to dopaminergic neurodegeneration in the substantia nigra (SN) of patients with Parkinson disease (PD). Since large-scale structural changes (e.g. deletions and rearrangements in mitochondrial DNA [mtDNA]) have been associated with mitochondrial dysfunction, we tested the hypothesis that increased total mtDNA deletions/rearrangements are associated with neurodegeneration in PD. This study employed a well-established technique, long-extension polymerase chain reaction (LX-PCR), to detect the multiple mtDNA deletions/rearrangements in the SN of patients with PD, multiple system atrophy (MSA), dementia with Lewy bodies (DLB), Alzheimer disease (AD), and age-matched controls. We also compared the total mtDNA deletions/rearrangements in different brain regions of PD patients. The results demonstrated that both the number and variety of mtDNA deletions/rearrangements were selectively increased in the SN of PD patients compared to patients with other movement disorders as well as patients with AD and age-matched controls. In addition, increased mtDNA deletions/rearrangements were observed in other brain regions in PD patients, indicating that mitochondrial dysfunction is not just limited to the SN of PD patients. These data suggest that accumulation of total mtDNA deletions/rearrangements is a relatively specific characteristic of PD and may be one of the contributing factors leading to mitochondrial dysfunction and neurodegeneration in PD.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"6 1","pages":"634–639"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79859730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Schaper, Suzanne Gergely, J. Lykkesfeldt, J. Zbären, S. Leib, M. Täuber, Stephan Christen
We have previously shown that antioxidants such as α-phenyl-tert-butyl nitrone or N-acetylcysteine attenuate cortical neuronal injury in infant rats with bacterial meningitis, suggesting that oxidative alterations play an important role in this disease. However, the precise mechanism(s) by which antioxidants inhibit this injury remain(s) unclear. We therefore studied the extent and location of protein oxidation in the brain using various biochemical and immunochemical methods. In cortical parenchyma, a trend for increased protein carbonyls was not evident until 21 hours after infection and the activity of glutamine synthetase (another index of protein oxidation) remained unchanged. Consistent with these results, there was no evidence for oxidative alterations in the cortex by various immunohistochemical methods even in cortical lesions. In contrast, there was a marked increase in carbonyls, 4-hydroxynonenal protein adducts and manganese superoxide dismutase in the cerebral vasculature. Elevated lipid peroxidation was also observed in cerebrospinal fluid and occasionally in the hippocampus. All of these oxidative alterations were inhibited by treatment of infected animals with N-acetylcysteine or α-phenyl-tert-butyl nitrone. Because N-acetylcysteine does not readily cross the blood-brain barrier and has no effect on the loss of endogenous brain antioxidants, its neuroprotective effect is likely based on extraparenchymal action such as inhibition of vascular oxidative alterations.
{"title":"Cerebral Vasculature Is the Major Target of Oxidative Protein Alterations in Bacterial Meningitis","authors":"M. Schaper, Suzanne Gergely, J. Lykkesfeldt, J. Zbären, S. Leib, M. Täuber, Stephan Christen","doi":"10.1093/JNEN/61.7.605","DOIUrl":"https://doi.org/10.1093/JNEN/61.7.605","url":null,"abstract":"We have previously shown that antioxidants such as α-phenyl-tert-butyl nitrone or N-acetylcysteine attenuate cortical neuronal injury in infant rats with bacterial meningitis, suggesting that oxidative alterations play an important role in this disease. However, the precise mechanism(s) by which antioxidants inhibit this injury remain(s) unclear. We therefore studied the extent and location of protein oxidation in the brain using various biochemical and immunochemical methods. In cortical parenchyma, a trend for increased protein carbonyls was not evident until 21 hours after infection and the activity of glutamine synthetase (another index of protein oxidation) remained unchanged. Consistent with these results, there was no evidence for oxidative alterations in the cortex by various immunohistochemical methods even in cortical lesions. In contrast, there was a marked increase in carbonyls, 4-hydroxynonenal protein adducts and manganese superoxide dismutase in the cerebral vasculature. Elevated lipid peroxidation was also observed in cerebrospinal fluid and occasionally in the hippocampus. All of these oxidative alterations were inhibited by treatment of infected animals with N-acetylcysteine or α-phenyl-tert-butyl nitrone. Because N-acetylcysteine does not readily cross the blood-brain barrier and has no effect on the loss of endogenous brain antioxidants, its neuroprotective effect is likely based on extraparenchymal action such as inhibition of vascular oxidative alterations.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"10 1","pages":"605–613"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72895174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gangliogliomas represent the most frequent tumor entity in young patients suffering from chronic focal epilepsies. In a series of 326 gangliogliomas collected from the University of Bonn Epilepsy Surgery Program and other departments of neuropathology in Germany, Austria, and Switzerland, epidemiological findings and histopathological hallmarks of gangliogliomas are systematically reviewed. The majority of these tumors occur within the temporal lobe and reveal a biphasic histological architecture characterized by a combination of dysplastic neurons and neoplastic glial cell elements. However, gangliogliomas exhibit a considerable variability in their histopathological appearance. Immunohistochemical studies are an important tool to discriminate these neoplasms from other tumor entities. Almost 80% of gangliogliomas reveal immunoreactivity for CD34, a stem cell epitope not expressed in normal brain. Immunohistochemical reactions for MAP2 or NeuN can be employed to characterize the dysplastic nature of neurons in those areas difficult to discriminate from pre-existing brain parenchyma. Less than 50% of the cases display binucleated neurons. With the frequent finding of “satellite” tumor clusters in adjacent brain regions, gangliogliomas are microscopically less circumscribed than previously assumed. The distinction from diffusely infiltrating gliomas is of considerable importance since tumor recurrence or malignant progression are rare events in gangliogliomas. Only little is known about the molecular pathogenesis of these glioneuronal tumors. Our findings support a dysontogenic origin from a glioneuronal precursor lesion with neoplastic, clonal proliferation of the glial cell population. Candidate genes appear to associate with neurodevelopmental signaling cascades rather than cell cycle control or DNA repair mechanisms. The reelin signaling and tuberin/insulin growth receptor pathways have recently been implicated in ganglioglioma development. Powerful new molecular genetic and biological tools can now be employed to unravel the pathogenesis of these intriguing lesions.
{"title":"Gangliogliomas: An Intriguing Tumor Entity Associated With Focal Epilepsies","authors":"I. Blümcke, O. Wiestler","doi":"10.1093/JNEN/61.7.575","DOIUrl":"https://doi.org/10.1093/JNEN/61.7.575","url":null,"abstract":"Gangliogliomas represent the most frequent tumor entity in young patients suffering from chronic focal epilepsies. In a series of 326 gangliogliomas collected from the University of Bonn Epilepsy Surgery Program and other departments of neuropathology in Germany, Austria, and Switzerland, epidemiological findings and histopathological hallmarks of gangliogliomas are systematically reviewed. The majority of these tumors occur within the temporal lobe and reveal a biphasic histological architecture characterized by a combination of dysplastic neurons and neoplastic glial cell elements. However, gangliogliomas exhibit a considerable variability in their histopathological appearance. Immunohistochemical studies are an important tool to discriminate these neoplasms from other tumor entities. Almost 80% of gangliogliomas reveal immunoreactivity for CD34, a stem cell epitope not expressed in normal brain. Immunohistochemical reactions for MAP2 or NeuN can be employed to characterize the dysplastic nature of neurons in those areas difficult to discriminate from pre-existing brain parenchyma. Less than 50% of the cases display binucleated neurons. With the frequent finding of “satellite” tumor clusters in adjacent brain regions, gangliogliomas are microscopically less circumscribed than previously assumed. The distinction from diffusely infiltrating gliomas is of considerable importance since tumor recurrence or malignant progression are rare events in gangliogliomas. Only little is known about the molecular pathogenesis of these glioneuronal tumors. Our findings support a dysontogenic origin from a glioneuronal precursor lesion with neoplastic, clonal proliferation of the glial cell population. Candidate genes appear to associate with neurodevelopmental signaling cascades rather than cell cycle control or DNA repair mechanisms. The reelin signaling and tuberin/insulin growth receptor pathways have recently been implicated in ganglioglioma development. Powerful new molecular genetic and biological tools can now be employed to unravel the pathogenesis of these intriguing lesions.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"26 1","pages":"575–584"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84526164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hereditary gelsolin amyloidosis (AGel amyloidosis) is a systemic disorder reported worldwide in kindreds with a G654A or G654T gelsolin gene mutation. The clinically characteristic peripheral nerve involvement has been poorly characterized morphologically, and its pathogenesis remains unknown. We studied peripheral nerve and skeletal muscle biopsy or autopsy specimens of 35 patients with a G654A gelsolin gene mutation. Histological, immunohistochemical, and electron microscopic studies showed consistent deposition of gelsolin amyloid (AGel), particularly in the vascular walls and perineurial sheaths. Nerve roots were more severely affected than distal nerves. The amyloid deposits also displayed variable immunoreactivity for apolipoprotein E, amyloid P component, cystatin C, and α-smooth muscle actin. Sural nerve morphometry showed preferential age-related large myelinated nerve fiber loss and reduction of myelin sheath cross-sectional area. There was evidence of denervation atrophy and fiber type grouping in skeletal muscle. Our study shows that marked proximal nerve involvement with AGel angiopathy is an essential feature of AGel amyloidosis. The preferential large fiber loss, not generally seen in amyloid neuropathy, may be caused by ischemia due to AGel angiopathy. Deficient actin modulation by variant gelsolin in neurons and Schwann cells, however, may alter axonal transport and myelination and contribute to AGel polyneuropathy.
{"title":"Neuromuscular Pathology in Hereditary Gelsolin Amyloidosis","authors":"H. Somer, A. Seppäläinen, I. Notkola, M. Haltia","doi":"10.1093/JNEN/61.6.565","DOIUrl":"https://doi.org/10.1093/JNEN/61.6.565","url":null,"abstract":"Hereditary gelsolin amyloidosis (AGel amyloidosis) is a systemic disorder reported worldwide in kindreds with a G654A or G654T gelsolin gene mutation. The clinically characteristic peripheral nerve involvement has been poorly characterized morphologically, and its pathogenesis remains unknown. We studied peripheral nerve and skeletal muscle biopsy or autopsy specimens of 35 patients with a G654A gelsolin gene mutation. Histological, immunohistochemical, and electron microscopic studies showed consistent deposition of gelsolin amyloid (AGel), particularly in the vascular walls and perineurial sheaths. Nerve roots were more severely affected than distal nerves. The amyloid deposits also displayed variable immunoreactivity for apolipoprotein E, amyloid P component, cystatin C, and α-smooth muscle actin. Sural nerve morphometry showed preferential age-related large myelinated nerve fiber loss and reduction of myelin sheath cross-sectional area. There was evidence of denervation atrophy and fiber type grouping in skeletal muscle. Our study shows that marked proximal nerve involvement with AGel angiopathy is an essential feature of AGel amyloidosis. The preferential large fiber loss, not generally seen in amyloid neuropathy, may be caused by ischemia due to AGel angiopathy. Deficient actin modulation by variant gelsolin in neurons and Schwann cells, however, may alter axonal transport and myelination and contribute to AGel polyneuropathy.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"13 1","pages":"565–571"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79441423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Evaluation of cell proliferation has been long recognized in pathology as a mainstay of diagnosis and important in the prognostication of a variety of neoplasms. Routine light microscopic evaluation of mitotic activity has long served as a reasonable assessment of cell proliferation. Counting mitotic figures has the advantage of being inexpensive and relatively quick. The main objections leveled against utilization of mitosis counts in diagnostic decision making are related to the instability of mitotic figures due to prefixation and fixation issues and problems with interobserver reproducibility of counts. This paper reviews factors that affect the identification of mitotic figures and the determination of mitosis counts. The role mitosis evaluation plays in the evaluation of certain neoplasms of the central nervous system is discussed.
{"title":"Cell Proliferation and Tumors of the Central Nervous System Part 1: Evaluation of Mitotic Activity","authors":"R. Prayson","doi":"10.1093/JNEN/61.6.501","DOIUrl":"https://doi.org/10.1093/JNEN/61.6.501","url":null,"abstract":"Evaluation of cell proliferation has been long recognized in pathology as a mainstay of diagnosis and important in the prognostication of a variety of neoplasms. Routine light microscopic evaluation of mitotic activity has long served as a reasonable assessment of cell proliferation. Counting mitotic figures has the advantage of being inexpensive and relatively quick. The main objections leveled against utilization of mitosis counts in diagnostic decision making are related to the instability of mitotic figures due to prefixation and fixation issues and problems with interobserver reproducibility of counts. This paper reviews factors that affect the identification of mitotic figures and the determination of mitosis counts. The role mitosis evaluation plays in the evaluation of certain neoplasms of the central nervous system is discussed.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"28 1","pages":"501–509"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75700818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Thom, S. Sisodiya, A. Beckett, L. Martinian, Woan-Ru Lin, W. Harkness, T. Mitchell, J. Craig, J. Duncan, F. Scaravilli
Hippocampal sclerosis (HS) is the most common pathological substrate for temporal lobe epilepsy with a characteristic pattern of loss of principle neurons primarily in CA1 and hilar subfields. Other cytoarchitectural abnormalities have been identified in human HS specimens, including dispersion of dentate granule cells and cytoskeletal abnormalities in residual hilar cells. The incidence of these features, their relationship to the severity of HS and potential indication of underlying hippocampal maldevelopment is unverified. In a series of 183 hippocampectomies we identified classical HS (grades 3 and 4) in 90% of specimens, granule cell disorganization or severe dispersion in 40% of cases with a bilaminar pattern in 10%, and cytoskeletal abnormalities in hilar cells in 55% of cases. The severity of granule cell disorganization correlated closely with the degree of hippocampal neuronal loss but not with the age at first seizure or a history of a precipitating event for epilepsy such as prolonged febrile seizures. These findings suggest that granule cell disorganization is closely linked with the progression of HS rather than a hallmark of impaired hippocampal maturation. Furthermore, stereological quantitation of granule cells showed evidence of cell loss but greater numbers in regions of maximal dispersion, which may indicate enhanced neurogenesis of these cells. Quantitation of reelin-and calretinin-positive Cajal-Retzius cells in the dentate gyrus molecular layer in 26 cases showed no correlation between the number of these cells and the severity of granule cell dispersion, but increased numbers of these cells were present in HS with respect to control groups. Although a role for Cajal-Retzius cells is therefore not implicated in the mechanism of granule cell disorganization, their excess number may be indicative of underlying hippocampal maldevelopment in HS.
{"title":"Cytoarchitectural Abnormalities in Hippocampal Sclerosis","authors":"M. Thom, S. Sisodiya, A. Beckett, L. Martinian, Woan-Ru Lin, W. Harkness, T. Mitchell, J. Craig, J. Duncan, F. Scaravilli","doi":"10.1093/JNEN/61.6.510","DOIUrl":"https://doi.org/10.1093/JNEN/61.6.510","url":null,"abstract":"Hippocampal sclerosis (HS) is the most common pathological substrate for temporal lobe epilepsy with a characteristic pattern of loss of principle neurons primarily in CA1 and hilar subfields. Other cytoarchitectural abnormalities have been identified in human HS specimens, including dispersion of dentate granule cells and cytoskeletal abnormalities in residual hilar cells. The incidence of these features, their relationship to the severity of HS and potential indication of underlying hippocampal maldevelopment is unverified. In a series of 183 hippocampectomies we identified classical HS (grades 3 and 4) in 90% of specimens, granule cell disorganization or severe dispersion in 40% of cases with a bilaminar pattern in 10%, and cytoskeletal abnormalities in hilar cells in 55% of cases. The severity of granule cell disorganization correlated closely with the degree of hippocampal neuronal loss but not with the age at first seizure or a history of a precipitating event for epilepsy such as prolonged febrile seizures. These findings suggest that granule cell disorganization is closely linked with the progression of HS rather than a hallmark of impaired hippocampal maturation. Furthermore, stereological quantitation of granule cells showed evidence of cell loss but greater numbers in regions of maximal dispersion, which may indicate enhanced neurogenesis of these cells. Quantitation of reelin-and calretinin-positive Cajal-Retzius cells in the dentate gyrus molecular layer in 26 cases showed no correlation between the number of these cells and the severity of granule cell dispersion, but increased numbers of these cells were present in HS with respect to control groups. Although a role for Cajal-Retzius cells is therefore not implicated in the mechanism of granule cell disorganization, their excess number may be indicative of underlying hippocampal maldevelopment in HS.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"80 1","pages":"510–519"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91491985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Peterson, L. Bö, S. Mörk, Ansi Chang, R. Ransohoff, B. Trapp
The distribution and lineage of vascular cell adhesion molecule-1 (VCAM-1)-positive cells was investigated in 43 lesions from the brain tissue of patients with multiple sclerosis (MS). Numerous VCAM-1-positive macrophages/microglia were detected at the edges of MS lesions. Quantitative analysis of 6 active, 7 chronic active, and 4 chronic inactive MS lesions identified most VCAM-1-positive cells at the actively demyelinating borders of active (102/mm3) and chronic active (29/mm3) lesions, but rarely in chronic inactive lesions (4/mm3). Further, approximately 17% of the VCAM-1-positive cells closely apposed or surrounded oligodendrocyte perikarya at the edges of active and chronic active lesions that were sites of ongoing demyelination. Endothelial cells were VCAM-1-negative in both lesion and non-lesion MS brain tissue. This report is the first to document direct microglial interaction with oligodendrocytes in MS.
{"title":"VCAM‐1‐Positive Microglia Target Oligodendrocytes at the Border of Multiple Sclerosis Lesions","authors":"J. Peterson, L. Bö, S. Mörk, Ansi Chang, R. Ransohoff, B. Trapp","doi":"10.1093/JNEN/61.6.539","DOIUrl":"https://doi.org/10.1093/JNEN/61.6.539","url":null,"abstract":"The distribution and lineage of vascular cell adhesion molecule-1 (VCAM-1)-positive cells was investigated in 43 lesions from the brain tissue of patients with multiple sclerosis (MS). Numerous VCAM-1-positive macrophages/microglia were detected at the edges of MS lesions. Quantitative analysis of 6 active, 7 chronic active, and 4 chronic inactive MS lesions identified most VCAM-1-positive cells at the actively demyelinating borders of active (102/mm3) and chronic active (29/mm3) lesions, but rarely in chronic inactive lesions (4/mm3). Further, approximately 17% of the VCAM-1-positive cells closely apposed or surrounded oligodendrocyte perikarya at the edges of active and chronic active lesions that were sites of ongoing demyelination. Endothelial cells were VCAM-1-negative in both lesion and non-lesion MS brain tissue. This report is the first to document direct microglial interaction with oligodendrocytes in MS.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"45 1","pages":"539–546"},"PeriodicalIF":0.0,"publicationDate":"2002-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84572536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R. Schröder, W. Kunz, F. Rouan, E. Pfendner, K. Tolksdorf, K. Kappes-Horn, Manuela Altenschmidt-Mehring, R. Knoblich, P. V. D. van der Ven, J. Reimann, D. Fürst, I. Blümcke, S. Vielhaber, D. Zillikens, S. Eming, T. Klockgether, J. Uitto, G. Wiche, A. Rolfs
Mutations of the human plectin gene (Plec1) cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). Here, we report on molecular mechanisms leading to severe dystrophic muscle alterations in EBS-MD. Analysis of a 25-yr-old EBS-MD patient carrying a novel homozygous 16-bp insertion mutation (13803ins16/13803ins16) close to the intermediate filament (IF) binding site of plectin showed severe disorganization of the myogenic IF cytoskeleton. Intermyofibrillar and subsarcolemmal accumulations of assembled but highly unordered desmin filaments may be attributed to impaired desmin binding capability of the mutant plectin. This IF pathology was also associated with severe mitochondrial dysfunction, suggesting that the muscle pathology of EBS-MD caused by IF disorganization leads not only to defects in mechanical force transduction but also to metabolic dysfunction. Beyond EBS-MD, our data may contribute to the understanding of other myopathies characterized by sarcoplasmic IF accumulations such as desminopathies or α-B-crystallinopathies.
人凝集素基因(Plec1)突变可引起常染色体隐性大疱性单纯表皮松解伴肌营养不良(eb - md)。在这里，我们报告了导致EBS-MD严重营养不良肌肉改变的分子机制。对一名25岁的eb - md患者的分析显示，在粘连素的中间丝(IF)结合位点附近携带一种新的16 bp纯合插入突变(13803ins16/13803ins16)，表明肌源性IF细胞骨架严重紊乱。肌纤维间和肌上皮下聚集了高度无序的聚丝，这可能是由于突变的粘连蛋白结合能力受损。这种IF病理还与严重的线粒体功能障碍相关，提示IF紊乱引起的EBS-MD肌肉病理不仅导致机械力传导缺陷，还会导致代谢功能障碍。除了EBS-MD，我们的数据可能有助于理解其他以肌浆性IF积累为特征的肌病，如desminopathy或α- b - crystallinopathy。
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