H. Sasaki, M. Zlatescu, R. Betensky, Loki Johnk, Andrea N. Cutone, J. Cairncross, David N. Louis
Allelic loss of chromosome 1p predicts increased chemosensitivity and better survival in oligodendroglial tumors. Clinical testing for 1p loss in oligodendroglial tumors at our hospital has allowed us to postulate that certain histological appearances are associated with 1p allelic status. Forty-four cases received for genetic testing were diagnosed by referring pathologists as pure low-grade oligodendroglioma. Central neuropathological review divided the series equally into 22 cases with classical oligodendroglioma histology and 22 with more astrocytic features. Molecular genetic analyses demonstrated 1p loss in 19 of 22 classic oligodendrogliomas (86%) and maintenance of both 1p alleles in 16 of 22 gliomas with astrocytic features (73%). No glial fibrillary acidic protein-positive cell type (gliofibrillary oligodendrocyte, minigemistocyte, cellular processes) was associated with 1p allelic status. Fourteen of the 44 cases were treated with chemotherapy at tumor progression: 3 “astrocytic” gliomas with 1p loss responded to PCV chemotherapy and 2 classic oligodendrogliomas that maintained both 1p alleles included a responder and a non-responder. These results suggest that histological appearance correctly predicts genotype in approximately 80% of low-grade gliomas, but that tumor genotype more closely predicts chemosensitivity. As a result, such objective molecular genetic analyses should be incorporated into patient management and into clinical trials of low-grade diffuse gliomas.
{"title":"Histopathological‐Molecular Genetic Correlations in Referral Pathologist‐Diagnosed Low‐Grade “Oligodendroglioma”","authors":"H. Sasaki, M. Zlatescu, R. Betensky, Loki Johnk, Andrea N. Cutone, J. Cairncross, David N. Louis","doi":"10.1093/JNEN/61.1.58","DOIUrl":"https://doi.org/10.1093/JNEN/61.1.58","url":null,"abstract":"Allelic loss of chromosome 1p predicts increased chemosensitivity and better survival in oligodendroglial tumors. Clinical testing for 1p loss in oligodendroglial tumors at our hospital has allowed us to postulate that certain histological appearances are associated with 1p allelic status. Forty-four cases received for genetic testing were diagnosed by referring pathologists as pure low-grade oligodendroglioma. Central neuropathological review divided the series equally into 22 cases with classical oligodendroglioma histology and 22 with more astrocytic features. Molecular genetic analyses demonstrated 1p loss in 19 of 22 classic oligodendrogliomas (86%) and maintenance of both 1p alleles in 16 of 22 gliomas with astrocytic features (73%). No glial fibrillary acidic protein-positive cell type (gliofibrillary oligodendrocyte, minigemistocyte, cellular processes) was associated with 1p allelic status. Fourteen of the 44 cases were treated with chemotherapy at tumor progression: 3 “astrocytic” gliomas with 1p loss responded to PCV chemotherapy and 2 classic oligodendrogliomas that maintained both 1p alleles included a responder and a non-responder. These results suggest that histological appearance correctly predicts genotype in approximately 80% of low-grade gliomas, but that tumor genotype more closely predicts chemosensitivity. As a result, such objective molecular genetic analyses should be incorporated into patient management and into clinical trials of low-grade diffuse gliomas.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"24 1","pages":"58–63"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83233959","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}
T. Rabinowicz, J. M. Petétot, P. Gartside, D. Sheyn, Tony Sheyn, G. D. de Courten-Myers
Expanding previous studies of human cerebral cortical sexual dimorphism showing higher neuronal densities in males, we investigated whether gender differences also exist in the extent of neuropil, size of neuronal somata, and volumes of astrocytes. This histo-morphometric study includes select autopsy brains of 6 males and 5 females, 12 to 24 yr old. In each brain, 86 defined loci were analyzed for cortical thickness, neuronal and astrocytic (8 loci) density (stereological counts), and neuronal and astrocytic (8 loci) soma size, enabling calculations of neuropil and astrocytic volumes. The female group showed significantly larger neuropil volumes than males, whereas neuronal soma size and astrocytic volumes did not differ. The expanded data confirmed higher neuronal densities in males than in females without a gender difference in cortical thickness. These findings indicate that fundamental gender differences exist in the structure of the human cerebral cortex, with more numerous, smaller neuronal units in men and fewer, larger ones in women; they may underlie gender-specific abilities and susceptibilities to disease affecting the neocortex. Laterality differences between the sexes were restricted to neuronal soma size showing significantly larger values in the female group in the left hemisphere. This gender difference may support female's right-handedness, language advantage, and tendency for bilateral activation patterns.
{"title":"Structure of the Cerebral Cortex in Men and Women","authors":"T. Rabinowicz, J. M. Petétot, P. Gartside, D. Sheyn, Tony Sheyn, G. D. de Courten-Myers","doi":"10.1093/JNEN/61.1.46","DOIUrl":"https://doi.org/10.1093/JNEN/61.1.46","url":null,"abstract":"Expanding previous studies of human cerebral cortical sexual dimorphism showing higher neuronal densities in males, we investigated whether gender differences also exist in the extent of neuropil, size of neuronal somata, and volumes of astrocytes. This histo-morphometric study includes select autopsy brains of 6 males and 5 females, 12 to 24 yr old. In each brain, 86 defined loci were analyzed for cortical thickness, neuronal and astrocytic (8 loci) density (stereological counts), and neuronal and astrocytic (8 loci) soma size, enabling calculations of neuropil and astrocytic volumes. The female group showed significantly larger neuropil volumes than males, whereas neuronal soma size and astrocytic volumes did not differ. The expanded data confirmed higher neuronal densities in males than in females without a gender difference in cortical thickness. These findings indicate that fundamental gender differences exist in the structure of the human cerebral cortex, with more numerous, smaller neuronal units in men and fewer, larger ones in women; they may underlie gender-specific abilities and susceptibilities to disease affecting the neocortex. Laterality differences between the sexes were restricted to neuronal soma size showing significantly larger values in the female group in the left hemisphere. This gender difference may support female's right-handedness, language advantage, and tendency for bilateral activation patterns.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"82 1","pages":"46–57"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84220304","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}
Paola Valdo, C. Stegagno, S. Mazzucco, Elisa Zuliani, G. Zanusso, G. Moretto, C. Raine, B. Bonetti
The receptor for nerve growth factor (NGF) comprises a 75-kDa (NGFRp75) and a tyrosine kinase A (TrkA) subunit. In view of conflicting opinions on the identity of glial targets of NGF in human central nervous system (CNS), we examined the cellular distribution of both NGF receptor subunits in normal CNS and in chronic multiple sclerosis (MS) lesions. For this, we compared the pattern of recognition of 2 monoclonal antibodies (mAbs) and a polyclonal antiserum to NGFRp75. Only the 2 mAbs specifically recognized NGFRp75, while the polyclonal antiserum showed widespread reactivity. In normal CNS and silent MS lesions, immunohistochemistry with anti-NGFRp75 mAbs and for TrkA revealed perivascular cell reactivity. At the edge of chronic active MS lesions, selective NGFRp75 staining was prominent on reactive astrocytes, while throughout the lesion, NGFRp75 was expressed on microglia/macrophages. The vast majority of mature or precursor oligodendrocytes did not express NGFRp75. Both NGF receptors were co-expressed on a subset of inflammatory cells. Immunoreactivity for NGFRp75 on glial and immune cells did not correlate with the distribution of apoptotic figures, as detected by TUNEL. Thus, expression of NGF receptors in active MS lesions suggests a role for NGF in regulating the autoimmune response at both immune and glial cell levels.
{"title":"Enhanced Expression of NGF Receptors in Multiple Sclerosis Lesions","authors":"Paola Valdo, C. Stegagno, S. Mazzucco, Elisa Zuliani, G. Zanusso, G. Moretto, C. Raine, B. Bonetti","doi":"10.1093/JNEN/61.1.91","DOIUrl":"https://doi.org/10.1093/JNEN/61.1.91","url":null,"abstract":"The receptor for nerve growth factor (NGF) comprises a 75-kDa (NGFRp75) and a tyrosine kinase A (TrkA) subunit. In view of conflicting opinions on the identity of glial targets of NGF in human central nervous system (CNS), we examined the cellular distribution of both NGF receptor subunits in normal CNS and in chronic multiple sclerosis (MS) lesions. For this, we compared the pattern of recognition of 2 monoclonal antibodies (mAbs) and a polyclonal antiserum to NGFRp75. Only the 2 mAbs specifically recognized NGFRp75, while the polyclonal antiserum showed widespread reactivity. In normal CNS and silent MS lesions, immunohistochemistry with anti-NGFRp75 mAbs and for TrkA revealed perivascular cell reactivity. At the edge of chronic active MS lesions, selective NGFRp75 staining was prominent on reactive astrocytes, while throughout the lesion, NGFRp75 was expressed on microglia/macrophages. The vast majority of mature or precursor oligodendrocytes did not express NGFRp75. Both NGF receptors were co-expressed on a subset of inflammatory cells. Immunoreactivity for NGFRp75 on glial and immune cells did not correlate with the distribution of apoptotic figures, as detected by TUNEL. Thus, expression of NGF receptors in active MS lesions suggests a role for NGF in regulating the autoimmune response at both immune and glial cell levels.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"52 1","pages":"91–98"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87993614","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. Euler, A. Janson, Jytte Overgaard Larsen, Åke Seiger, L. Forno, M. Bunge, Erik Sundström
Here we present evidence for spontaneous and long-lasting regeneration of CNS axons after spinal cord lesions in adult rats. The length of 200 kD neurofilament (NF)-immunolabeled axons was estimated after photochemically induced ischemic spinal cord lesions using a stereological tool. The total length of all NF-immunolabeled axons within the lesion cavities was increased 6- to 10-fold at 5, 10, and 15 wk post-lesion compared with 1 wk post-surgery. In ultrastructural studies we found the putatively regenerating axons within the lesion to be associated either with oligodendrocytes or Schwann cells, while other fibers were unmyelinated. Immunohistochemistry demonstrated that some of the regenerated fibers were tyrosine hydroxylase- or serotonin-immunoreactive, indicating a central origin. These findings suggest that there is a considerable amount of spontaneous regeneration after spinal cord lesions in rodents and that the fibers remain several months after injury. The findings of tyrosine hydroxylase- and serotonin-immunoreactivity in the axons suggest that descending central fibers contribute to this endogenous repair of ischemic spinal cord injury.
{"title":"Spontaneous Axonal Regeneration in Rodent Spinal Cord After Ischemic Injury","authors":"M. Euler, A. Janson, Jytte Overgaard Larsen, Åke Seiger, L. Forno, M. Bunge, Erik Sundström","doi":"10.1093/JNEN/61.1.64","DOIUrl":"https://doi.org/10.1093/JNEN/61.1.64","url":null,"abstract":"Here we present evidence for spontaneous and long-lasting regeneration of CNS axons after spinal cord lesions in adult rats. The length of 200 kD neurofilament (NF)-immunolabeled axons was estimated after photochemically induced ischemic spinal cord lesions using a stereological tool. The total length of all NF-immunolabeled axons within the lesion cavities was increased 6- to 10-fold at 5, 10, and 15 wk post-lesion compared with 1 wk post-surgery. In ultrastructural studies we found the putatively regenerating axons within the lesion to be associated either with oligodendrocytes or Schwann cells, while other fibers were unmyelinated. Immunohistochemistry demonstrated that some of the regenerated fibers were tyrosine hydroxylase- or serotonin-immunoreactive, indicating a central origin. These findings suggest that there is a considerable amount of spontaneous regeneration after spinal cord lesions in rodents and that the fibers remain several months after injury. The findings of tyrosine hydroxylase- and serotonin-immunoreactivity in the axons suggest that descending central fibers contribute to this endogenous repair of ischemic spinal cord injury.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"10 1","pages":"64–75"},"PeriodicalIF":0.0,"publicationDate":"2002-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82790738","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}
H. Yokoo, Minako Yokoo, Y. Yonekawa, P. Kleihues, H. Ohgaki
Oligodendrogliomas are characterized by frequent loss of heterozygosity (LOH) on chromosomes 1p and 19q, but additional genetic alterations are likely to be involved. In this study, we screened 28 oligodendrogliomas (WHO grade II) and 20 anaplastic oligodendrogliomas (WHO grade III) for alterations in the RB1/CDK4/p16INK4a/p15INK4b and TP53/p14ARF/MDM2 pathways. In oligodendrogliomas, hypermethylation of RB1 (1 case) and p14ARF (6 cases) were the only detectable genetic changes (7/28, 25%). In anaplastic oligodendrogliomas, the RB1/CDK4/p16INK4a/p15INK4b signaling pathway regulating the G1 → S transition of the cell cycle was altered in 13/20 (65%) cases, by either RB1 alteration, CDK4 amplification, or p16INK4a/p15INK4b homozygous deletion or promoter hypermethylation. Further, 50% (10/20) of anaplastic oligodendrogliomas showed alterations in the TP53 pathway through promoter hypermethylation or homozygous deletion of the p14ARF gene and, less frequently, through TP53 mutation or MDM2 amplification. Of 13 anaplastic astrocytomas with an altered RB1 pathway, 9 (69%) also showed a dysregulated TP53 pathway. Thus, simultaneous disruption of the RB1/CDK4/p16INK4a/p15INK4b and the TP53/p14ARF/MDM2 pathways occurs in 45% (9/20) of anaplastic oligodendrogliomas, suggesting that these phenomena contribute to their malignant phenotype.
{"title":"Concurrent Inactivation of RB1 and TP53 Pathways in Anaplastic Oligodendrogliomas","authors":"H. Yokoo, Minako Yokoo, Y. Yonekawa, P. Kleihues, H. Ohgaki","doi":"10.1093/JNEN/60.12.1181","DOIUrl":"https://doi.org/10.1093/JNEN/60.12.1181","url":null,"abstract":"Oligodendrogliomas are characterized by frequent loss of heterozygosity (LOH) on chromosomes 1p and 19q, but additional genetic alterations are likely to be involved. In this study, we screened 28 oligodendrogliomas (WHO grade II) and 20 anaplastic oligodendrogliomas (WHO grade III) for alterations in the RB1/CDK4/p16INK4a/p15INK4b and TP53/p14ARF/MDM2 pathways. In oligodendrogliomas, hypermethylation of RB1 (1 case) and p14ARF (6 cases) were the only detectable genetic changes (7/28, 25%). In anaplastic oligodendrogliomas, the RB1/CDK4/p16INK4a/p15INK4b signaling pathway regulating the G1 → S transition of the cell cycle was altered in 13/20 (65%) cases, by either RB1 alteration, CDK4 amplification, or p16INK4a/p15INK4b homozygous deletion or promoter hypermethylation. Further, 50% (10/20) of anaplastic oligodendrogliomas showed alterations in the TP53 pathway through promoter hypermethylation or homozygous deletion of the p14ARF gene and, less frequently, through TP53 mutation or MDM2 amplification. Of 13 anaplastic astrocytomas with an altered RB1 pathway, 9 (69%) also showed a dysregulated TP53 pathway. Thus, simultaneous disruption of the RB1/CDK4/p16INK4a/p15INK4b and the TP53/p14ARF/MDM2 pathways occurs in 45% (9/20) of anaplastic oligodendrogliomas, suggesting that these phenomena contribute to their malignant phenotype.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"51 1","pages":"1181–1189"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84454812","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}
Previous criteria for Frontotemporal Dementia have primarily been designed for research purposes (1–5). An international group of experts on clinical and neuropathological aspects of frontotemporal dementia (FTD) recently re-assessed criteria for the diagnosis of FTD at a meeting entitled “The Frontotemporal Dementia and Pick's Disease Criteria Conference” held at the National Institutes of Health in Bethesda, MD on July 7, 2000 (see ref #1 and the roster of meeting participants in the Acknowledgments). Building upon a substantial literature on these disorders, the goal of the conference was to update previous FTD diagnostic criteria, taking into account recent research advances to refine guidelines for the clinical and neuropathological diagnosis of FTD (1). Here we provide a brief overview of the most salient points of the neuropathology recommendations for disorders included among FTDs. Although Pick's disease can be considered the prototype of FTDs, in the last 3 decades it became increasingly clear to several research groups that there were a number of other distinct FTD variants that lacked the lobar atrophy and related neuropathology of Pick's disease (1). This prompted the use of a number of different names to designate these disorders, including FTD, frontal lobe degeneration of the non-Alzheimer-type, frontotemporal lobar degeneration (FTLD), dementia lacking distinct histopathology (DLDH), progressive aphasia and semantic dementia (1). Moreover, since several kindreds with FTD and parkinsonism linked to chromosome 17 were shown to have pathogenic tau gene mutations, the term FTDP-17 was used to refer to this hereditary group of FTDs, while a less well-characterized disorder in other patients with evidence of FTD as well as clinical and pathological findings of motor neuron disease (MND) has been designated FTD with MND, and hereditary forms of this disease have been linked to chromosome 9 (1). Since these and other terms have been used to refer to …
{"title":"Update on the Neuropathological Diagnosis of Frontotemporal Dementias","authors":"J. Trojanowski, Dennis W. Dickson","doi":"10.1093/JNEN/60.12.1123","DOIUrl":"https://doi.org/10.1093/JNEN/60.12.1123","url":null,"abstract":"Previous criteria for Frontotemporal Dementia have primarily been designed for research purposes (1–5). An international group of experts on clinical and neuropathological aspects of frontotemporal dementia (FTD) recently re-assessed criteria for the diagnosis of FTD at a meeting entitled “The Frontotemporal Dementia and Pick's Disease Criteria Conference” held at the National Institutes of Health in Bethesda, MD on July 7, 2000 (see ref #1 and the roster of meeting participants in the Acknowledgments). Building upon a substantial literature on these disorders, the goal of the conference was to update previous FTD diagnostic criteria, taking into account recent research advances to refine guidelines for the clinical and neuropathological diagnosis of FTD (1). Here we provide a brief overview of the most salient points of the neuropathology recommendations for disorders included among FTDs.\u0000\u0000Although Pick's disease can be considered the prototype of FTDs, in the last 3 decades it became increasingly clear to several research groups that there were a number of other distinct FTD variants that lacked the lobar atrophy and related neuropathology of Pick's disease (1). This prompted the use of a number of different names to designate these disorders, including FTD, frontal lobe degeneration of the non-Alzheimer-type, frontotemporal lobar degeneration (FTLD), dementia lacking distinct histopathology (DLDH), progressive aphasia and semantic dementia (1). Moreover, since several kindreds with FTD and parkinsonism linked to chromosome 17 were shown to have pathogenic tau gene mutations, the term FTDP-17 was used to refer to this hereditary group of FTDs, while a less well-characterized disorder in other patients with evidence of FTD as well as clinical and pathological findings of motor neuron disease (MND) has been designated FTD with MND, and hereditary forms of this disease have been linked to chromosome 9 (1). Since these and other terms have been used to refer to …","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"17 4 1","pages":"1123–1126"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84570951","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}
Extracellular matrix (ECM) alterations in the central nervous system (CNS) of multiple sclerosis (MS) patients result from blood-brain barrier breakdown, release and activation of proteases, and synthesis of ECM components. To elucidate their potential pathophysiologic roles, we analyzed expression of major CNS ECM proteoglycans (PGs) in MS and control CNS tissues. In active MS plaque edges, 3 CNS lecticans (versican, aggrecan, and neurocan) and dermatan sulfate PG were increased in association with astrocytosis; in active plaque centers they were decreased in the ECM and accumulated in foamy macrophages, suggesting that these ECM PGs are injured and phagocytosed along with myelin. In inactive lesions they were diminished and in normal-appearing white matter they showed heretofore-unappreciated abnormal heterogeneous aggregation. Phosphacan, an ECM PG abundant in both gray and white matter, was less markedly altered. Since in development the spaciotemporal expression of ECM PGs influences neurite outgrowth, cell migration, axon guidance, and myelination, these data suggest that 1) enhanced white matter lectican and dermatan sulfate PG expression in the pro-inflammatory milieu of expanding lesion edges contributes to their sharp boundaries and the failure of neuronal ingrowth; 2) decreases in plaque centers may preclude regeneration and repair; and 3) diffuse ECM PG damage relates to axon degeneration outside of overt lesions. Thus, ECM PG alterations are specific, temporally dynamic, and widespread in MS patients and may play critical roles in lesion pathogenesis and CNS dysfunction.
{"title":"White Matter Extracellular Matrix Chondroitin Sulfate/Dermatan Sulfate Proteoglycans in Multiple Sclerosis","authors":"R. Sobel, A. Ahmed","doi":"10.1093/JNEN/60.12.1198","DOIUrl":"https://doi.org/10.1093/JNEN/60.12.1198","url":null,"abstract":"Extracellular matrix (ECM) alterations in the central nervous system (CNS) of multiple sclerosis (MS) patients result from blood-brain barrier breakdown, release and activation of proteases, and synthesis of ECM components. To elucidate their potential pathophysiologic roles, we analyzed expression of major CNS ECM proteoglycans (PGs) in MS and control CNS tissues. In active MS plaque edges, 3 CNS lecticans (versican, aggrecan, and neurocan) and dermatan sulfate PG were increased in association with astrocytosis; in active plaque centers they were decreased in the ECM and accumulated in foamy macrophages, suggesting that these ECM PGs are injured and phagocytosed along with myelin. In inactive lesions they were diminished and in normal-appearing white matter they showed heretofore-unappreciated abnormal heterogeneous aggregation. Phosphacan, an ECM PG abundant in both gray and white matter, was less markedly altered. Since in development the spaciotemporal expression of ECM PGs influences neurite outgrowth, cell migration, axon guidance, and myelination, these data suggest that 1) enhanced white matter lectican and dermatan sulfate PG expression in the pro-inflammatory milieu of expanding lesion edges contributes to their sharp boundaries and the failure of neuronal ingrowth; 2) decreases in plaque centers may preclude regeneration and repair; and 3) diffuse ECM PG damage relates to axon degeneration outside of overt lesions. Thus, ECM PG alterations are specific, temporally dynamic, and widespread in MS patients and may play critical roles in lesion pathogenesis and CNS dysfunction.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"81 1","pages":"1198–1207"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81623594","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. Takao, B. Ghetti, J. Murrell, F. Unverzagt, G. Giaccone, F. Tagliavini, O. Bugiani, P. Piccardo, C. Hulette, B. Crain, M. Farlow, A. Heyman
We report clinical, neuropathologic and molecular genetic data from an individual affected by a familial Alzheimer disease (AD) variant. The proband had an onset of dementia at age 29 followed by generalized seizures a year later. He died at age 40. Neuropathologically, he had severe brain atrophy and characteristic histopathologic lesions of AD. Three additional neuropathologic features need to be emphasized: 1) severe deposition of Aβ in the form of diffuse deposits in the cerebral and cerebellar cortices, 2) numerous Aβ deposits in the subcortical white matter and in the centrum semiovale, and 3) numerous ectopic neurons, often containing tau-immunopositive neurofibrillary tangles, in the white matter of the frontal and temporal lobes. A molecular genetic analysis of DNA extracted from brain tissue of the proband revealed a S169L mutation in the Presenilin 1 (PSEN1) gene. The importance of this case lies in the presence of ectopic neurons in the white matter, early-onset seizures, and a PSEN1 mutation. We hypothesize that the PSEN1 mutation may have a causal relationship with an abnormality in neuronal development.
{"title":"Ectopic White Matter Neurons, a Developmental Abnormality That May Be Caused by the PSEN1 S169L Mutation in a Case of Familial AD with Myoclonus and Seizures","authors":"M. Takao, B. Ghetti, J. Murrell, F. Unverzagt, G. Giaccone, F. Tagliavini, O. Bugiani, P. Piccardo, C. Hulette, B. Crain, M. Farlow, A. Heyman","doi":"10.1093/JNEN/60.12.1137","DOIUrl":"https://doi.org/10.1093/JNEN/60.12.1137","url":null,"abstract":"We report clinical, neuropathologic and molecular genetic data from an individual affected by a familial Alzheimer disease (AD) variant. The proband had an onset of dementia at age 29 followed by generalized seizures a year later. He died at age 40. Neuropathologically, he had severe brain atrophy and characteristic histopathologic lesions of AD. Three additional neuropathologic features need to be emphasized: 1) severe deposition of Aβ in the form of diffuse deposits in the cerebral and cerebellar cortices, 2) numerous Aβ deposits in the subcortical white matter and in the centrum semiovale, and 3) numerous ectopic neurons, often containing tau-immunopositive neurofibrillary tangles, in the white matter of the frontal and temporal lobes. A molecular genetic analysis of DNA extracted from brain tissue of the proband revealed a S169L mutation in the Presenilin 1 (PSEN1) gene. The importance of this case lies in the presence of ectopic neurons in the white matter, early-onset seizures, and a PSEN1 mutation. We hypothesize that the PSEN1 mutation may have a causal relationship with an abnormality in neuronal development.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"45 1","pages":"1137–1152"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87904441","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}
C. Atzori, B. Ghetti, R. Piva, A. Srinivasan, P. Zolo, M. Delisle, S. Mirra, A. Migheli
JNK and p38, two members of the MAP kinase family, are strongly induced by various stresses including oxidative stress and have been involved in regulation of apoptosis. As both kinases phosphorylate tau protein in vitro, we have investigated their immunohistochemical localization in a group of neurodegenerative diseases characterized by intracellular deposits of hyperphosphorylated tau. Cases included Alzheimer disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, Gerstmann-Sträussler-Scheinker disease-Indiana kindred, and frontotemporal dementia with parkinsonism linked to chromosome 17. In all tissue samples, strong immunoreactivity for both MAP kinases was found in the same neuronal or glial cells that contained tau-positive deposits. By double immunohistochemistry, JNK and p38 colocalized with tau in the inclusions. Analysis of apoptosis-related changes (DNA fragmentation, activated caspase-3) showed that the expression of JNK and p38 was unrelated to activation of an apoptotic cascade. Our data indicate that phospho-JNK and phospho-p38 are associated with hyperphosphorylated tau in a variety of abnormal tau inclusions, suggesting that these kinases may play a role in the development of degenerative diseases with tau pathology.
{"title":"Activation of the JNK/p38 Pathway Occurs in Diseases Characterized by Tau Protein Pathology and Is Related to Tau Phosphorylation But Not to Apoptosis","authors":"C. Atzori, B. Ghetti, R. Piva, A. Srinivasan, P. Zolo, M. Delisle, S. Mirra, A. Migheli","doi":"10.1093/JNEN/60.12.1190","DOIUrl":"https://doi.org/10.1093/JNEN/60.12.1190","url":null,"abstract":"JNK and p38, two members of the MAP kinase family, are strongly induced by various stresses including oxidative stress and have been involved in regulation of apoptosis. As both kinases phosphorylate tau protein in vitro, we have investigated their immunohistochemical localization in a group of neurodegenerative diseases characterized by intracellular deposits of hyperphosphorylated tau. Cases included Alzheimer disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, Gerstmann-Sträussler-Scheinker disease-Indiana kindred, and frontotemporal dementia with parkinsonism linked to chromosome 17. In all tissue samples, strong immunoreactivity for both MAP kinases was found in the same neuronal or glial cells that contained tau-positive deposits. By double immunohistochemistry, JNK and p38 colocalized with tau in the inclusions. Analysis of apoptosis-related changes (DNA fragmentation, activated caspase-3) showed that the expression of JNK and p38 was unrelated to activation of an apoptotic cascade. Our data indicate that phospho-JNK and phospho-p38 are associated with hyperphosphorylated tau in a variety of abnormal tau inclusions, suggesting that these kinases may play a role in the development of degenerative diseases with tau pathology.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"42 1","pages":"1190–1197"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87192468","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}
Endothelial cells of the blood-brain barrier (BBB) have the ability to regulate and restrict the passage of cells and molecules from the periphery to the CNS. We have used an in vitro assay of lymphocyte migration across monolayers of human adult brain endothelial cells (HBEC) as a model of lymphocyte migration across the BBB. We found that human allogeneic or MBP-reactive Th2-polarized lymphocytes migrate more avidly than Th1-polarized lymphocytes. Migration of Th2 but not Th1 cells across brain endothelium was inhibited by antibodies directed at MCP-1, a chemokine produced by HBECs. We could detect CCR2, a chemokine receptor that recognizes MCP-1 on Th2 but not Th1 lymphocytes. ICAM-1 and VCAM-1 molecules were expressed on the surface of HBECs under basal conditions and were upregulated by Th1 but not Th2 cell-derived supernatants. Migration of both lymphocyte subsets was dependent on LFA-1/ICAM-1 interactions. Blocking VLA-4/VCAM-1 binding did not influence actual trans-endothelial migration. These results suggest that HBECs composing the BBB favor the migration of Th2 cells. We postulate that this selectivity may help prevent activated Th1 lymphocytes, the putative CNS autoimmune disease initiating cells, from reaching the CNS parenchyma and favor entry of Th2 cells, a putative means to induce bystander suppression in the CNS.
{"title":"Regulation of Th1 and Th2 Lymphocyte Migration by Human Adult Brain Endothelial Cells","authors":"A. Prat, M. Blain, J. Antel","doi":"10.1093/JNEN/60.12.1127","DOIUrl":"https://doi.org/10.1093/JNEN/60.12.1127","url":null,"abstract":"Endothelial cells of the blood-brain barrier (BBB) have the ability to regulate and restrict the passage of cells and molecules from the periphery to the CNS. We have used an in vitro assay of lymphocyte migration across monolayers of human adult brain endothelial cells (HBEC) as a model of lymphocyte migration across the BBB. We found that human allogeneic or MBP-reactive Th2-polarized lymphocytes migrate more avidly than Th1-polarized lymphocytes. Migration of Th2 but not Th1 cells across brain endothelium was inhibited by antibodies directed at MCP-1, a chemokine produced by HBECs. We could detect CCR2, a chemokine receptor that recognizes MCP-1 on Th2 but not Th1 lymphocytes. ICAM-1 and VCAM-1 molecules were expressed on the surface of HBECs under basal conditions and were upregulated by Th1 but not Th2 cell-derived supernatants. Migration of both lymphocyte subsets was dependent on LFA-1/ICAM-1 interactions. Blocking VLA-4/VCAM-1 binding did not influence actual trans-endothelial migration. These results suggest that HBECs composing the BBB favor the migration of Th2 cells. We postulate that this selectivity may help prevent activated Th1 lymphocytes, the putative CNS autoimmune disease initiating cells, from reaching the CNS parenchyma and favor entry of Th2 cells, a putative means to induce bystander suppression in the CNS.","PeriodicalId":14858,"journal":{"name":"JNEN: Journal of Neuropathology & Experimental Neurology","volume":"45 1","pages":"1127–1136"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83065034","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}
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