Pub Date : 2015-12-01DOI: 10.1097/NEN.0000000000000265
T. Richardson, D. Mathis, B. Mickey, J. Raisanen, D. Burns, C. White, K. Hatanpaa
Abstract Silent subtype III pituitary adenomas (SS-3) are nonfunctioning radiosensitive adenomas that may be associated with an increased risk of recurrence and invasion. The features that have been proposed to be diagnostically important are identifiable by electron microscopy (EM) and include an enlarged Golgi apparatus, along with several other ultrastructural features. The often limited availability of EM and the uncertainty about the relative importance of individual features pose practical challenges to the diagnosis. We hypothesized that it may be possible to diagnose SS-3 based solely on a markedly enlarged Golgi apparatus identified at the light microscopic level. In this prospective study, we used immunohistochemistry (IHC) for the Golgi apparatus with the MG-160/GLG-1 antibody to identify 10 cases with features suggestive of SS-3. Electron microscopy was performed for confirmation on 1 case. Compared with a control group of 20 conventional null cell adenomas, the SS-3 adenomas showed an increased MIB-1 proliferation index (p < 0.01), a higher risk of invasion (p < 0.01), and a higher incidence of recurrence (p < 0.01). Thus, in this first controlled study, we demonstrate that SS-3 is clinically aggressive and identifiable by IHC, without the need for EM. The routine diagnostic workup of nonsecreting adenomas should rule out SS-3, which can be done quickly and efficiently by IHC.
{"title":"Clinical Outcome of Silent Subtype III Pituitary Adenomas Diagnosed by Immunohistochemistry","authors":"T. Richardson, D. Mathis, B. Mickey, J. Raisanen, D. Burns, C. White, K. Hatanpaa","doi":"10.1097/NEN.0000000000000265","DOIUrl":"https://doi.org/10.1097/NEN.0000000000000265","url":null,"abstract":"Abstract Silent subtype III pituitary adenomas (SS-3) are nonfunctioning radiosensitive adenomas that may be associated with an increased risk of recurrence and invasion. The features that have been proposed to be diagnostically important are identifiable by electron microscopy (EM) and include an enlarged Golgi apparatus, along with several other ultrastructural features. The often limited availability of EM and the uncertainty about the relative importance of individual features pose practical challenges to the diagnosis. We hypothesized that it may be possible to diagnose SS-3 based solely on a markedly enlarged Golgi apparatus identified at the light microscopic level. In this prospective study, we used immunohistochemistry (IHC) for the Golgi apparatus with the MG-160/GLG-1 antibody to identify 10 cases with features suggestive of SS-3. Electron microscopy was performed for confirmation on 1 case. Compared with a control group of 20 conventional null cell adenomas, the SS-3 adenomas showed an increased MIB-1 proliferation index (p < 0.01), a higher risk of invasion (p < 0.01), and a higher incidence of recurrence (p < 0.01). Thus, in this first controlled study, we demonstrate that SS-3 is clinically aggressive and identifiable by IHC, without the need for EM. The routine diagnostic workup of nonsecreting adenomas should rule out SS-3, which can be done quickly and efficiently by IHC.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82026325","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}
Pub Date : 2015-12-01DOI: 10.1097/NEN.0000000000000261
J. Hay, V. Johnson, A. Young, Douglas H. Smith, W. Stewart
Abstract Traumatic brain injury (TBI) is a risk factor for dementia. Mixed neurodegenerative pathologies have been described in late survivors of TBI, but the mechanisms driving post-TBI neurodegeneration remain elusive. Increasingly, blood-brain barrier (BBB) disruption has been recognized in a range of neurologic disorders including dementias, but little is known of the consequences of TBI on the BBB. Autopsy cases of single moderate or severe TBI from the Glasgow TBI Archive (n = 70) were selected to include a range from acute (10 hours–13 days) to long-term (1–47 years) survival, together with age-matched uninjured controls (n = 21). Multiple brain regions were examined using immunohistochemistry for the BBB integrity markers fibrinogen and immunoglobulin G. After TBI, 40% of patients dying in the acute phase and 47% of those surviving a year or more from injury showed multifocal, abnormal, perivascular, and parenchymal fibrinogen and immunoglobulin G immunostaining localized to the gray matter, with preferential distribution toward the crests of gyri and deep neocortical layers. In contrast, when present, controls showed only limited localized immunostaining. These preliminary data demonstrate evidence of widespread BBB disruption in a proportion of TBI patients emerging in the acute phase and, intriguingly, persisting in a high proportion of late survivors.
{"title":"Blood-Brain Barrier Disruption Is an Early Event That May Persist for Many Years After Traumatic Brain Injury in Humans","authors":"J. Hay, V. Johnson, A. Young, Douglas H. Smith, W. Stewart","doi":"10.1097/NEN.0000000000000261","DOIUrl":"https://doi.org/10.1097/NEN.0000000000000261","url":null,"abstract":"Abstract Traumatic brain injury (TBI) is a risk factor for dementia. Mixed neurodegenerative pathologies have been described in late survivors of TBI, but the mechanisms driving post-TBI neurodegeneration remain elusive. Increasingly, blood-brain barrier (BBB) disruption has been recognized in a range of neurologic disorders including dementias, but little is known of the consequences of TBI on the BBB. Autopsy cases of single moderate or severe TBI from the Glasgow TBI Archive (n = 70) were selected to include a range from acute (10 hours–13 days) to long-term (1–47 years) survival, together with age-matched uninjured controls (n = 21). Multiple brain regions were examined using immunohistochemistry for the BBB integrity markers fibrinogen and immunoglobulin G. After TBI, 40% of patients dying in the acute phase and 47% of those surviving a year or more from injury showed multifocal, abnormal, perivascular, and parenchymal fibrinogen and immunoglobulin G immunostaining localized to the gray matter, with preferential distribution toward the crests of gyri and deep neocortical layers. In contrast, when present, controls showed only limited localized immunostaining. These preliminary data demonstrate evidence of widespread BBB disruption in a proportion of TBI patients emerging in the acute phase and, intriguingly, persisting in a high proportion of late survivors.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87367573","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}
Pub Date : 2015-12-01DOI: 10.1097/NEN.0000000000000257
R. Hashimoto, H. Koike, Mie Takahashi, K. Ohyama, Y. Kawagashira, M. Iijima, G. Sobue
Abstract To elucidate the significance of uncompacted myelin lamellae (UML) and ion channel disruption at the nodes of Ranvier in the polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, we evaluated sural nerve biopsy specimens from 33 patients with POEMS syndrome and from 7 control patients. Uncompacted myelin lamellae distribution was assessed by electron microscopy and immunofluorescence microscopy. In the POEMS patient biopsies, UML were seen more frequently in small versus large myelinated fibers. Paranodes and Schmidt-Lanterman incisures, where normal physiologic UM is located, were frequently associated with UM. Widening of the nodes of Ranvier (i.e. segmental demyelination) was not associated with UML. There was axonal hollowing with neurofilament condensation at Schmidt-Lanterman incisures with abnormal UML, suggesting axonal damage at those sites in the POEMS patient biopsies. Myelin sheath irregularity was conspicuous in large myelinated fibers and was associated with abnormally widened bizarrely shaped Schmidt-Lanterman incisures. Indirect immunofluorescent studies revealed abnormalities of sodium (pan sodium) and potassium (KCNQ2) channels, even at nonwidened nodes of Ranvier. Thus, UML was not apparently associated with segmental demyelination but seemed to be associated with axonal damage. These observations suggest that nodal ion channel disruption may be associated with functional deficits in POEMS syndrome patient nerves.
{"title":"Uncompacted Myelin Lamellae and Nodal Ion Channel Disruption in POEMS Syndrome","authors":"R. Hashimoto, H. Koike, Mie Takahashi, K. Ohyama, Y. Kawagashira, M. Iijima, G. Sobue","doi":"10.1097/NEN.0000000000000257","DOIUrl":"https://doi.org/10.1097/NEN.0000000000000257","url":null,"abstract":"Abstract To elucidate the significance of uncompacted myelin lamellae (UML) and ion channel disruption at the nodes of Ranvier in the polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, we evaluated sural nerve biopsy specimens from 33 patients with POEMS syndrome and from 7 control patients. Uncompacted myelin lamellae distribution was assessed by electron microscopy and immunofluorescence microscopy. In the POEMS patient biopsies, UML were seen more frequently in small versus large myelinated fibers. Paranodes and Schmidt-Lanterman incisures, where normal physiologic UM is located, were frequently associated with UM. Widening of the nodes of Ranvier (i.e. segmental demyelination) was not associated with UML. There was axonal hollowing with neurofilament condensation at Schmidt-Lanterman incisures with abnormal UML, suggesting axonal damage at those sites in the POEMS patient biopsies. Myelin sheath irregularity was conspicuous in large myelinated fibers and was associated with abnormally widened bizarrely shaped Schmidt-Lanterman incisures. Indirect immunofluorescent studies revealed abnormalities of sodium (pan sodium) and potassium (KCNQ2) channels, even at nonwidened nodes of Ranvier. Thus, UML was not apparently associated with segmental demyelination but seemed to be associated with axonal damage. These observations suggest that nodal ion channel disruption may be associated with functional deficits in POEMS syndrome patient nerves.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89726164","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}
Pub Date : 2015-08-01DOI: 10.1097/NEN.0000000000000217
D. Perl, L. Adelman
Stanley Maynard Aronson died on January 28, 2015, in Providence, Rhode Island. He was 92 years old. During his long career, he had been Professor of Pathology at Downstate Medical Center, Director of Laboratories at Kings County Hospital, Chief of Pathology at the Miriam Hospital, and Chairman of Pathology and Founding Dean of the Alpert School of Medicine at Brown University. He was born and raised in Brooklyn, New York, and graduated from the City College of New York and New York University Medical School. He trained in neuropathology under Abner Wolf at Columbia and then did bench research on polio with Gregory Schwartzman at Mount Sinai. For a greater description of these early years, see his autobiography (1). In 1954, he accepted a position at the State University of New York, Downstate Medical Center, where he established the Division of Neuropathology and had a National Institutes of Health–funded training program in neuropathology. He was also the Dean for Financial Aid at the Medical School. He trained a generation of neuropathologists, …
斯坦利·梅纳德·阿伦森于2015年1月28日在罗德岛州普罗维登斯去世。他享年92岁。在他漫长的职业生涯中，他曾担任过Downstate Medical Center的病理学教授，Kings County Hospital的实验室主任，Miriam Hospital的病理学主任，以及Brown University的Alpert医学院的病理学主席和创始院长。他在纽约布鲁克林出生长大，毕业于纽约城市学院和纽约大学医学院。他在哥伦比亚大学跟随艾布纳·沃尔夫学习神经病理学然后在西奈山和格雷戈里·施瓦茨曼一起做小儿麻痹症的实验研究。1954年，他接受了纽约州立大学下州医学中心的一个职位，在那里他建立了神经病理学部门，并参加了由美国国立卫生研究院资助的神经病理学培训项目。他也是医学院的财政援助主任。他培养了一代神经病理学家……
{"title":"Stanley Maynard Aronson, MD 1922–2015","authors":"D. Perl, L. Adelman","doi":"10.1097/NEN.0000000000000217","DOIUrl":"https://doi.org/10.1097/NEN.0000000000000217","url":null,"abstract":"Stanley Maynard Aronson died on January 28, 2015, in Providence, Rhode Island. He was 92 years old. During his long career, he had been Professor of Pathology at Downstate Medical Center, Director of Laboratories at Kings County Hospital, Chief of Pathology at the Miriam Hospital, and Chairman of Pathology and Founding Dean of the Alpert School of Medicine at Brown University.\u0000\u0000He was born and raised in Brooklyn, New York, and graduated from the City College of New York and New York University Medical School. He trained in neuropathology under Abner Wolf at Columbia and then did bench research on polio with Gregory Schwartzman at Mount Sinai. For a greater description of these early years, see his autobiography (1).\u0000\u0000In 1954, he accepted a position at the State University of New York, Downstate Medical Center, where he established the Division of Neuropathology and had a National Institutes of Health–funded training program in neuropathology. He was also the Dean for Financial Aid at the Medical School. He trained a generation of neuropathologists, …","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72733735","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}
Pub Date : 2015-06-01DOI: 10.1097/nen.0000000000000205
Erika G. Lin-Hendel, Meagan J. McManus, D. Wallace, S. Anderson, J. Cotter, V. Tang, Mercedes Paredes, E. Huang
Mitochondrial dysfunction has been increasingly linked to neurodevelopmental disorders such as intellectual disability, childhood epilepsy and autism spectrum disorder; conditions also associated with cortical GABAergic interneuron dysfunction. Although interneurons have some of the highest metabolic demands in the postnatal brain, the importance of mitochondria during interneuron development is unknown. Remarkably, we find that the migration of interneurons is exquisitely sensitive to perturbations in oxidative phosphorylation. Both pharmacologic and genetic inhibition of Adenine Nucleotide Transferase 1 (Ant1) preferentially disrupts the non-radial, long-distance migration of interneurons from the basal forebrain to the cortex, thus reducing the numbers of cortical interneurons. These results provide a novel mechanism for the pathogenesis of neurocognitive disorders associated with mitochondrial dysfunction or other causes of oxidative stress, and suggest a common mechanistic pathway upon which multiple developmental and metabolic perturbations may converge.
{"title":"American Association of Neuropathologists, Inc. Abstracts of the 91st Annual Meeting June 11–14, 2015 Denver, CO","authors":"Erika G. Lin-Hendel, Meagan J. McManus, D. Wallace, S. Anderson, J. Cotter, V. Tang, Mercedes Paredes, E. Huang","doi":"10.1097/nen.0000000000000205","DOIUrl":"https://doi.org/10.1097/nen.0000000000000205","url":null,"abstract":"Mitochondrial dysfunction has been increasingly linked to neurodevelopmental disorders such as intellectual disability, childhood epilepsy and autism spectrum disorder; conditions also associated with cortical GABAergic interneuron dysfunction. Although interneurons have some of the highest metabolic demands in the postnatal brain, the importance of mitochondria during interneuron development is unknown. Remarkably, we find that the migration of interneurons is exquisitely sensitive to perturbations in oxidative phosphorylation. Both pharmacologic and genetic inhibition of Adenine Nucleotide Transferase 1 (Ant1) preferentially disrupts the non-radial, long-distance migration of interneurons from the basal forebrain to the cortex, thus reducing the numbers of cortical interneurons. These results provide a novel mechanism for the pathogenesis of neurocognitive disorders associated with mitochondrial dysfunction or other causes of oxidative stress, and suggest a common mechanistic pathway upon which multiple developmental and metabolic perturbations may converge.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2015-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84062957","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}
Pub Date : 2012-06-01DOI: 10.1097/nen.0b013e31825c0526
Brent Orr, Michael Haffner, Charles Eberhart, Jessica Hicks, William Nelson, S. Yegnasubramanian
Background: Malignant peripheral nerve sheath tumors occurring in the setting of neurofibromatosis type 1 (NF1) are thought to be the result of malignant transformation of a preexisting (plexiform) neurofibroma. This study compared features of MPNSTs and plexiform neurofibromas in the setting of NF1 patients. Design: 12 cases of MPNSTs arising within preexisting plexiform neurofibromas were selected. For each case RNA was isolated from formalin fixed paraffin embedded (FFPE) neurofibroma and the matched MPNST. The resulting 24 samples were used to analyze the expression of 519 kinase genes using Nanostring nCounter technology. Differentially expressed kinases between neurofibromas and MPNSTs were assessed. The protein expression of some identified genes was then analyzed by immunohistochemical staining of tissue array slides. Results: Principle component analysis of kinase expression demonstrates that differential expression of kinase genes is sufficient to separate most of MPNSTs from neurofibromas. Interestingly, two of the MPNSTs clustered more closely with neurofibromas than the remaining MPNSTs. These were the only MPNSTs that were not clearly high-grade. The neurofibromas formed a tighter cluster, while MPNSTs were more heterogenous. Genes that were differentially expressed between neurofibroma and MPNST from the same individual were identified by ranking fold changes. Although there was extensive diversity in these lists, reflecting the diversity of MPNSTs, a few common genes were apparent. These included the genes of kinases important in the process of chromosome segregation. Differences in the expression of two of these latter genes were confirmed by immunohistochemical studies that showed significance differences in staining between neurofibromas and MPNSTs. Conclusion: The pattern of kinase gene expression performed on FFPE samples using this platform can separate MPNSTs and neurofibromas. Genes important for mitotic regulation may be important in the process of malignant transformation of neurofibromas.
{"title":"Abstract American Association of Neuropathologists, Inc. Abstracts of the 88th Annual Meeting June 21–24, 2012 Chicago, IL","authors":"Brent Orr, Michael Haffner, Charles Eberhart, Jessica Hicks, William Nelson, S. Yegnasubramanian","doi":"10.1097/nen.0b013e31825c0526","DOIUrl":"https://doi.org/10.1097/nen.0b013e31825c0526","url":null,"abstract":"Background: Malignant peripheral nerve sheath tumors occurring in the setting of neurofibromatosis type 1 (NF1) are thought to be the result of malignant transformation of a preexisting (plexiform) neurofibroma. This study compared features of MPNSTs and plexiform neurofibromas in the setting of NF1 patients. Design: 12 cases of MPNSTs arising within preexisting plexiform neurofibromas were selected. For each case RNA was isolated from formalin fixed paraffin embedded (FFPE) neurofibroma and the matched MPNST. The resulting 24 samples were used to analyze the expression of 519 kinase genes using Nanostring nCounter technology. Differentially expressed kinases between neurofibromas and MPNSTs were assessed. The protein expression of some identified genes was then analyzed by immunohistochemical staining of tissue array slides. Results: Principle component analysis of kinase expression demonstrates that differential expression of kinase genes is sufficient to separate most of MPNSTs from neurofibromas. Interestingly, two of the MPNSTs clustered more closely with neurofibromas than the remaining MPNSTs. These were the only MPNSTs that were not clearly high-grade. The neurofibromas formed a tighter cluster, while MPNSTs were more heterogenous. Genes that were differentially expressed between neurofibroma and MPNST from the same individual were identified by ranking fold changes. Although there was extensive diversity in these lists, reflecting the diversity of MPNSTs, a few common genes were apparent. These included the genes of kinases important in the process of chromosome segregation. Differences in the expression of two of these latter genes were confirmed by immunohistochemical studies that showed significance differences in staining between neurofibromas and MPNSTs. Conclusion: The pattern of kinase gene expression performed on FFPE samples using this platform can separate MPNSTs and neurofibromas. Genes important for mitotic regulation may be important in the process of malignant transformation of neurofibromas.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2012-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86437886","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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