Jessica X. Yuan, F. Bafakih, J. Mandell, B. Horton, J. Munson
Glioblastomas, the most common primary malignant brain tumors, have a distinct tissue microenvironment. Although non-neoplastic cells contribute to glioblastoma progression, very few quantitative studies have shown the effect of tumor microenvironmental influences on patient survival. We examined relationships of the cellular microenvironment, including astrocytes, microglia, oligodendrocytes, and blood vessels, to survival in glioblastoma patients. Using histological staining and quantitative image analyses, we examined the tumor-associated parenchyma of 33 patients and developed statistical models to predict patient outcomes based on the cellular picture of the tumor parenchyma. We found that blood vessel density correlated with poorer prognosis. To examine the role of adjacent parenchymal versus higher tumor cell density bulk parenchymal tissue, we examined the glial components in these highly variable regions. Comparison of bulk and adjacent astrocytes and microglia in tissue yielded the strongest prediction of survival, with high levels of adjacent astrocytes predicted poor prognosis and high levels of microglia correlated with a better prognosis. These results indicate that parenchymal components predict survival in glioblastoma patients and in particular that the balance between reactive glial populations is important for patient prognosis.
{"title":"Quantitative Analysis of the Cellular Microenvironment of Glioblastoma to Develop Predictive Statistical Models of Overall Survival","authors":"Jessica X. Yuan, F. Bafakih, J. Mandell, B. Horton, J. Munson","doi":"10.1093/jnen/nlw090","DOIUrl":"https://doi.org/10.1093/jnen/nlw090","url":null,"abstract":"Glioblastomas, the most common primary malignant brain tumors, have a distinct tissue microenvironment. Although non-neoplastic cells contribute to glioblastoma progression, very few quantitative studies have shown the effect of tumor microenvironmental influences on patient survival. We examined relationships of the cellular microenvironment, including astrocytes, microglia, oligodendrocytes, and blood vessels, to survival in glioblastoma patients. Using histological staining and quantitative image analyses, we examined the tumor-associated parenchyma of 33 patients and developed statistical models to predict patient outcomes based on the cellular picture of the tumor parenchyma. We found that blood vessel density correlated with poorer prognosis. To examine the role of adjacent parenchymal versus higher tumor cell density bulk parenchymal tissue, we examined the glial components in these highly variable regions. Comparison of bulk and adjacent astrocytes and microglia in tissue yielded the strongest prediction of survival, with high levels of adjacent astrocytes predicted poor prognosis and high levels of microglia correlated with a better prognosis. These results indicate that parenchymal components predict survival in glioblastoma patients and in particular that the balance between reactive glial populations is important for patient prognosis.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90638092","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. Ling, Celso Pouget, F. Rech, Robin Pflaum, M. Treffel, F. Bielle, K. Mokhtari, Jean-Matthieu Casse, J. Vignaud, M. Kalamarides, M. Peyre, G. Gauchotte
Microvascular proliferation (MVP) is a hallmark of glioblastoma. Endothelial cell hypertrophy (ECH), also known as endothelial hyperplasia, is correlated with a shorter survival of patients with gliomas. However, the prognostic value of these 2 morphological features has not been studied in meningiomas. The aim of this study was to evaluate the prognostic value of angiogenesis in meningiomas, most notably ECH, MVP, and microvascular density, which were evaluated using immunohistochemistry with antibodies against CD34 and CD105 (a marker of neovascularization) in a series of 139 meningiomas. ECH, MVP, and CD105 immunoreactivity were significantly correlated with higher histological grades (p < 0.0001, p = 0.0004, and p = 0.0003, respectively). ECH and MVP but not CD105 immunoreactivities were significantly correlated with a shorter progression-free survival time (PFS) (p = 0.017, p = 0.021, and p = 0.137, respectively). In Cox multivariate analysis, ECH was an independent predictor of shorter PFS (p = 0.028). Therefore, ECH and MVP are markers of shorter PFS in meningiomas and are significantly correlated with grade. These findings give insight into the use of anti-angiogenic therapies. Further studies are needed to determine whether these markers could allow us to identify patients who could benefit from anti-angiogenic therapies.
微血管增生(MVP)是胶质母细胞瘤的标志。内皮细胞肥大(ECH)，也称为内皮增生，与胶质瘤患者较短的生存期相关。然而，这两种形态学特征在脑膜瘤中的预后价值尚未得到研究。本研究的目的是评估脑膜瘤中血管生成的预后价值，尤其是ECH、MVP和微血管密度，在139例脑膜瘤中使用针对CD34和CD105(新生血管标志物)的抗体进行免疫组织化学评估。ECH、MVP和CD105免疫反应性与较高的组织学分级显著相关(p < 0.0001, p = 0.0004, p = 0.0003)。ECH和MVP免疫反应与较短的无进展生存时间(PFS)显著相关(p = 0.017, p = 0.021, p = 0.137)，而CD105免疫反应与PFS无关(p = 0.021, p = 0.137)。在Cox多变量分析中，ECH是较短PFS的独立预测因子(p = 0.028)。因此，ECH和MVP是脑膜瘤PFS较短的标志，并与分级显著相关。这些发现为抗血管生成疗法的使用提供了见解。需要进一步的研究来确定这些标记物是否可以让我们识别可以从抗血管生成治疗中获益的患者。
{"title":"Endothelial Cell Hypertrophy and Microvascular Proliferation in Meningiomas Are Correlated with Higher Histological Grade and Shorter Progression-Free Survival","authors":"C. Ling, Celso Pouget, F. Rech, Robin Pflaum, M. Treffel, F. Bielle, K. Mokhtari, Jean-Matthieu Casse, J. Vignaud, M. Kalamarides, M. Peyre, G. Gauchotte","doi":"10.1093/jnen/nlw095","DOIUrl":"https://doi.org/10.1093/jnen/nlw095","url":null,"abstract":"Microvascular proliferation (MVP) is a hallmark of glioblastoma. Endothelial cell hypertrophy (ECH), also known as endothelial hyperplasia, is correlated with a shorter survival of patients with gliomas. However, the prognostic value of these 2 morphological features has not been studied in meningiomas. The aim of this study was to evaluate the prognostic value of angiogenesis in meningiomas, most notably ECH, MVP, and microvascular density, which were evaluated using immunohistochemistry with antibodies against CD34 and CD105 (a marker of neovascularization) in a series of 139 meningiomas. ECH, MVP, and CD105 immunoreactivity were significantly correlated with higher histological grades (p < 0.0001, p = 0.0004, and p = 0.0003, respectively). ECH and MVP but not CD105 immunoreactivities were significantly correlated with a shorter progression-free survival time (PFS) (p = 0.017, p = 0.021, and p = 0.137, respectively). In Cox multivariate analysis, ECH was an independent predictor of shorter PFS (p = 0.028). Therefore, ECH and MVP are markers of shorter PFS in meningiomas and are significantly correlated with grade. These findings give insight into the use of anti-angiogenic therapies. Further studies are needed to determine whether these markers could allow us to identify patients who could benefit from anti-angiogenic therapies.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78033076","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}
Z. Rohan, I. Milenkovic, Mirjam I. Lutz, R. Matěj, G. Kovacs
Pathological protein deposits in oligodendroglia are common but variable features of various neurodegenerative conditions. To evaluate oligodendrocyte response in neurodegenerative diseases (NDDs) with different extents of oligodendroglial protein deposition we performed immunostaining for tubulin polymerization-promoting protein p25&agr; (TPPP/p25&agr;), &agr;-synuclein (&agr;-syn), phospho-tau, ubiquitin, myelin basic protein, and the microglial marker HLA-DR. We investigated cases of multiple system atrophy ([MSA] n = 10), Lewy body disease ([LBD] n = 10), globular glial tauopathy ([GGT] n = 7) and progressive supranuclear palsy ([PSP] n = 10). Loss of nuclear TPPP/p25&agr; immunoreactivity correlated significantly with the degree of microglial reaction and loss of myelin basic prtein density as a marker of tract degeneration. This was more prominent in MSA and GGT, which, together with enlarged cytoplasmic TPPP/p25&agr; immunoreactivity and inclusion burden allowed these disorders to be grouped as predominant oligodendroglial proteinopathies. However, distinct features, ie more colocalization of &agr;-syn than tau with TPPP/p25&agr;, more obvious loss of oligodendrocyte density in MSA, but more prominent association of tau protein inclusions in GGT to loss of nuclear TPPP/p25&agr; immunoreactivity, were also recognized. In addition, we observed previously underappreciated oligodendroglial &agr;-synuclein pathology in the pallidothalamic tract in LBD. Our study demonstrates common and distinct aspects of oligodendroglial involvement in the pathogenesis of diverse NDDs.
病理蛋白沉积在少突胶质细胞是常见的，但变化的特点，各种神经退行性疾病。为了评估神经退行性疾病(ndd)中不同程度少突胶质蛋白沉积的少突胶质细胞反应，我们对微管蛋白聚合促进蛋白p25&agr进行了免疫染色;(TPPP/p25&agr;)， &agr;-synuclein (&agr;-syn)，磷酸化-tau，泛素，髓鞘碱性蛋白，以及小胶质标记物HLA-DR。我们调查了多系统萎缩([MSA] n = 10)、路易体病([LBD] n = 10)、球状胶质病变([GGT] n = 7)和进行性核上性麻痹([PSP] n = 10)的病例。核电TPPP/p25&agr损失;免疫反应性与小胶质细胞反应的程度和髓鞘碱性蛋白密度的损失显著相关，髓鞘碱性蛋白密度是神经束变性的标志。这在MSA和GGT中更为突出，同时胞质TPPP/p25&agr增大;免疫反应性和包涵负担使这些疾病被归类为主要的少突胶质蛋白病。然而，明显的特征，即&agr;-syn比tau与TPPP/p25&agr更共定位，MSA中少突胶质细胞密度的损失更明显，但GGT中tau蛋白包裹体与核TPPP/p25&agr的损失的关联更突出;免疫反应性也得到了确认。此外，我们还观察到LBD患者丘脑半球束的少突胶质突触核蛋白病理学。我们的研究展示了不同ndd发病机制中少突胶质细胞参与的共同和独特方面。
{"title":"Shared and Distinct Patterns of Oligodendroglial Response in &agr;-Synucleinopathies and Tauopathies","authors":"Z. Rohan, I. Milenkovic, Mirjam I. Lutz, R. Matěj, G. Kovacs","doi":"10.1093/jnen/nlw087","DOIUrl":"https://doi.org/10.1093/jnen/nlw087","url":null,"abstract":"Pathological protein deposits in oligodendroglia are common but variable features of various neurodegenerative conditions. To evaluate oligodendrocyte response in neurodegenerative diseases (NDDs) with different extents of oligodendroglial protein deposition we performed immunostaining for tubulin polymerization-promoting protein p25&agr; (TPPP/p25&agr;), &agr;-synuclein (&agr;-syn), phospho-tau, ubiquitin, myelin basic protein, and the microglial marker HLA-DR. We investigated cases of multiple system atrophy ([MSA] n = 10), Lewy body disease ([LBD] n = 10), globular glial tauopathy ([GGT] n = 7) and progressive supranuclear palsy ([PSP] n = 10). Loss of nuclear TPPP/p25&agr; immunoreactivity correlated significantly with the degree of microglial reaction and loss of myelin basic prtein density as a marker of tract degeneration. This was more prominent in MSA and GGT, which, together with enlarged cytoplasmic TPPP/p25&agr; immunoreactivity and inclusion burden allowed these disorders to be grouped as predominant oligodendroglial proteinopathies. However, distinct features, ie more colocalization of &agr;-syn than tau with TPPP/p25&agr;, more obvious loss of oligodendrocyte density in MSA, but more prominent association of tau protein inclusions in GGT to loss of nuclear TPPP/p25&agr; immunoreactivity, were also recognized. In addition, we observed previously underappreciated oligodendroglial &agr;-synuclein pathology in the pallidothalamic tract in LBD. Our study demonstrates common and distinct aspects of oligodendroglial involvement in the pathogenesis of diverse NDDs.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84238448","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}
S. Ito, M. Takao, T. Fukutake, H. Hatsuta, Sayaka Funabe, N. Ito, Y. Shimoe, T. Niki, I. Nakano, M. Fukayama, S. Murayama
Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a nonhypertensive hereditary cerebral small vessel disease that is caused by mutations in a single gene, HTRA1. The HTRA1 protein normally represses transforming growth factor-&bgr; (TGF-&bgr;) signaling and its mutations result in vascular changes. Ten homozygous, 1 compound heterozygous, and 1 homozygous frameshift mutation have been identified in the HTRA1 gene of patients with genetically confirmed CARASIL. However, few studies have compared neuropathologic findings in patients with the same or different mutations in HTRA1. We analyzed histopathologic alterations in 3 autopsied patients with genetically confirmed CARASIL: 2 of them had the HTRA1 p.R302X mutation and 1 had the HTRA1 p.A252T mutation. All 3 had similar cerebral arteriopathy showing myointimal proliferation, multi-layering and splitting of elastic laminae, and marked loss of medial smooth muscle cells. One CARASIL patient with the p.R302X mutation had atherosclerosis-like intimal thickening and arteriolosclerosis in the arteries of visceral organs, indicating that atherosclerotic changes are not confined to the intracranial vasculature but can occur throughout the body. CARASIL is a unique hereditary disease that shows similar neuropathology, systemic vascular pathology, and other TGF-&bgr;1-related pathology associated with HTRA1 mutation.
{"title":"Histopathologic Analysis of Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CARASIL): A Report of a New Genetically Confirmed Case and Comparison to 2 Previous Cases","authors":"S. Ito, M. Takao, T. Fukutake, H. Hatsuta, Sayaka Funabe, N. Ito, Y. Shimoe, T. Niki, I. Nakano, M. Fukayama, S. Murayama","doi":"10.1093/jnen/nlw078","DOIUrl":"https://doi.org/10.1093/jnen/nlw078","url":null,"abstract":"Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a nonhypertensive hereditary cerebral small vessel disease that is caused by mutations in a single gene, HTRA1. The HTRA1 protein normally represses transforming growth factor-&bgr; (TGF-&bgr;) signaling and its mutations result in vascular changes. Ten homozygous, 1 compound heterozygous, and 1 homozygous frameshift mutation have been identified in the HTRA1 gene of patients with genetically confirmed CARASIL. However, few studies have compared neuropathologic findings in patients with the same or different mutations in HTRA1. We analyzed histopathologic alterations in 3 autopsied patients with genetically confirmed CARASIL: 2 of them had the HTRA1 p.R302X mutation and 1 had the HTRA1 p.A252T mutation. All 3 had similar cerebral arteriopathy showing myointimal proliferation, multi-layering and splitting of elastic laminae, and marked loss of medial smooth muscle cells. One CARASIL patient with the p.R302X mutation had atherosclerosis-like intimal thickening and arteriolosclerosis in the arteries of visceral organs, indicating that atherosclerotic changes are not confined to the intracranial vasculature but can occur throughout the body. CARASIL is a unique hereditary disease that shows similar neuropathology, systemic vascular pathology, and other TGF-&bgr;1-related pathology associated with HTRA1 mutation.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86420882","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}
Lymphocytic choriomeningitis virus (LCMV) infection during pregnancy injures the human fetal brain. Neonatal rats inoculated with LCMV are an excellent model of congenital LCMV infection because they develop cerebellar injuries similar to those in humans. To evaluate the role of T-lymphocytes in LCMV-induced cerebellar pathology, congenitally athymic rats, deficient in T-lymphocytes were compared with euthymic rats. Peak viral titers and cellular targets of infection were similar, but viral clearance from astrocytes was impaired in the athymic rats. Cytokines and chemokines rose to higher levels and for a greater duration in the euthymic rats than in their athymic counterparts. The euthymic rats developed an intense lymphocytic infiltration, accompanied by destructive lesions of the cerebellum and a neuronal migration defect because of T-cell-mediated alteration of Bergmann glia. These pathologic changes were absent in the athymic rats but were restored by adoptive transfer of lymphocytes. Athymic rats were not free of pathologic effects, however, as the virus induced cerebellar hypoplasia. Thus, T-lymphocytes play key roles in LCMV clearance, cytokine/chemokine responses, and pathogenesis of destructive lesions and neuronal migration disturbances but not all pathology is T-lymphocyte-dependent. Cerebellar hypoplasia from LCMV occurs even in the absence of T-lymphocytes and is likely due to the viral infection itself.
{"title":"T-Cells Underlie Some but Not All of the Cerebellar Pathology in a Neonatal Rat Model of Congenital Lymphocytic Choriomeningitis Virus Infection","authors":"H. Klein, Glenda K. Rabe, B. Karacay, D. Bonthius","doi":"10.1093/jnen/nlw079","DOIUrl":"https://doi.org/10.1093/jnen/nlw079","url":null,"abstract":"Lymphocytic choriomeningitis virus (LCMV) infection during pregnancy injures the human fetal brain. Neonatal rats inoculated with LCMV are an excellent model of congenital LCMV infection because they develop cerebellar injuries similar to those in humans. To evaluate the role of T-lymphocytes in LCMV-induced cerebellar pathology, congenitally athymic rats, deficient in T-lymphocytes were compared with euthymic rats. Peak viral titers and cellular targets of infection were similar, but viral clearance from astrocytes was impaired in the athymic rats. Cytokines and chemokines rose to higher levels and for a greater duration in the euthymic rats than in their athymic counterparts. The euthymic rats developed an intense lymphocytic infiltration, accompanied by destructive lesions of the cerebellum and a neuronal migration defect because of T-cell-mediated alteration of Bergmann glia. These pathologic changes were absent in the athymic rats but were restored by adoptive transfer of lymphocytes. Athymic rats were not free of pathologic effects, however, as the virus induced cerebellar hypoplasia. Thus, T-lymphocytes play key roles in LCMV clearance, cytokine/chemokine responses, and pathogenesis of destructive lesions and neuronal migration disturbances but not all pathology is T-lymphocyte-dependent. Cerebellar hypoplasia from LCMV occurs even in the absence of T-lymphocytes and is likely due to the viral infection itself.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87349617","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}
Radiation-induced vascular “malformations”, designated cavernous hemangiomas/cavernomas (“RICHs”), are seldom biopsied and are usually diagnosed based on neuroimaging features. They are an increasingly recognized complication of both CNS external beam radiation therapy and stereotactic radiosurgery. We identified 13 patients with radiation-induced vascular “malformations” in our surgical neuropathology databases searched from 2000 to 2016; 4 had received their therapy during childhood; 5 had received radiosurgery. Inclusion required identifiable vascular abnormalities on neuroimaging and/or, if recurrent tumor was additionally present, the vascular lesion had been a separately submitted specimen at the time of resection. Trichrome, and elastic stains and immunohistochemistry (IHC) for CD31, CD34, and smooth muscle actin (SMA) were performed. Five RICHs showed histological and IHC overlap with 12 non-radiation-induced cavernomas; 8/13 had organizing coagulum containing recanalized vasculature and fibrinous deposits. Markedly altered vasculature in these 8 lacked the back-to-back caverns typical of cavernomas; there was near absence of SMA immunopositivity in their ill-defined vessel walls. These coagulum-like lesions likely represented organized fibrinous exudates caused by subacute/remote radiation-induced fibrinoid vascular necrosis and vascular leakage. Thus, RICHs occur as 2 distinct histological types, without direct correlation between histological type and age at receipt, or type, of radiation. Two different etiological mechanisms likely underlie their pathogenesis.
{"title":"Radiation-Induced Cerebral Vascular “Malformations” at Biopsy","authors":"B. Kleinschmidt-DeMasters, K. Lillehei","doi":"10.1093/jnen/nlw085","DOIUrl":"https://doi.org/10.1093/jnen/nlw085","url":null,"abstract":"Radiation-induced vascular “malformations”, designated cavernous hemangiomas/cavernomas (“RICHs”), are seldom biopsied and are usually diagnosed based on neuroimaging features. They are an increasingly recognized complication of both CNS external beam radiation therapy and stereotactic radiosurgery. We identified 13 patients with radiation-induced vascular “malformations” in our surgical neuropathology databases searched from 2000 to 2016; 4 had received their therapy during childhood; 5 had received radiosurgery. Inclusion required identifiable vascular abnormalities on neuroimaging and/or, if recurrent tumor was additionally present, the vascular lesion had been a separately submitted specimen at the time of resection. Trichrome, and elastic stains and immunohistochemistry (IHC) for CD31, CD34, and smooth muscle actin (SMA) were performed. Five RICHs showed histological and IHC overlap with 12 non-radiation-induced cavernomas; 8/13 had organizing coagulum containing recanalized vasculature and fibrinous deposits. Markedly altered vasculature in these 8 lacked the back-to-back caverns typical of cavernomas; there was near absence of SMA immunopositivity in their ill-defined vessel walls. These coagulum-like lesions likely represented organized fibrinous exudates caused by subacute/remote radiation-induced fibrinoid vascular necrosis and vascular leakage. Thus, RICHs occur as 2 distinct histological types, without direct correlation between histological type and age at receipt, or type, of radiation. Two different etiological mechanisms likely underlie their pathogenesis.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77765433","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. Honda, K. Matsuzono, S. Fushimi, Kota Sato, Satoshi O. Suzuki, K. Abe, T. Iwaki
Prion protein (PrP) has 2 glycosylated sites and a glycosylphosphatidylinositol (GPI) anchor on the C-terminal. Reports on genetic prion disease with GPI anchorless PrP are very limited. In this study, we characterized the molecular alterations of mutated PrP in a 37-year-old female autopsy case with a recently identified PRNP mutation involving a 2-bp deletion in codon 178 that results in a premature stop codon mutation in codon 203. Postmortem examination revealed numerous irregularly shaped coarse PrP deposits and multicentric plaques in the brain that were mainly comprised of C-terminal deleted abnormal PrP primarily derived from the mutant allele. Additionally, abnormal PrP deposits were detected in almost all other examined organs. PrP was mainly deposited in peripheral nerves, smooth muscles, and blood vessels in non-CNS tissues. Western blot analysis after proteinase K treatment showed protease-resistant PrP (PrPres) signals with a molecular weight of 9 kDa; weak PrPres smear signals of 9 to ∼80 kDa were also noted. Gel filtration revealed that PrPres oligomers were mainly composed of the PrP fragments. In conclusion, the mutated PrP lacking that GPI anchor was truncated shortly and deposited in almost every examined organ.
{"title":"C-Terminal-Deleted Prion Protein Fragment Is a Major Accumulated Component of Systemic PrP Deposits in Hereditary Prion Disease With a 2-Bp (CT) Deletion in PRNP Codon 178","authors":"H. Honda, K. Matsuzono, S. Fushimi, Kota Sato, Satoshi O. Suzuki, K. Abe, T. Iwaki","doi":"10.1093/jnen/nlw077","DOIUrl":"https://doi.org/10.1093/jnen/nlw077","url":null,"abstract":"Prion protein (PrP) has 2 glycosylated sites and a glycosylphosphatidylinositol (GPI) anchor on the C-terminal. Reports on genetic prion disease with GPI anchorless PrP are very limited. In this study, we characterized the molecular alterations of mutated PrP in a 37-year-old female autopsy case with a recently identified PRNP mutation involving a 2-bp deletion in codon 178 that results in a premature stop codon mutation in codon 203. Postmortem examination revealed numerous irregularly shaped coarse PrP deposits and multicentric plaques in the brain that were mainly comprised of C-terminal deleted abnormal PrP primarily derived from the mutant allele. Additionally, abnormal PrP deposits were detected in almost all other examined organs. PrP was mainly deposited in peripheral nerves, smooth muscles, and blood vessels in non-CNS tissues. Western blot analysis after proteinase K treatment showed protease-resistant PrP (PrPres) signals with a molecular weight of 9 kDa; weak PrPres smear signals of 9 to ∼80 kDa were also noted. Gel filtration revealed that PrPres oligomers were mainly composed of the PrP fragments. In conclusion, the mutated PrP lacking that GPI anchor was truncated shortly and deposited in almost every examined organ.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78561196","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}
The present state of pediatric neuropathology practice is in rudimentary developmental stages in most parts of sub-Saharan Africa. We sought to determine the pattern of neurosurgical lesions in children diagnosed in southwestern Nigeria and briefly address issues surrounding the practice of this aspect of pathology in Africa. We performed a retrospective review of histopathologic results of biopsies obtained from pediatric patients with neurosurgical lesions at the Department of Pathology, Obafemi Awolowo University Teaching Hospitals Complex, Ile–Ife, Nigeria, between January 2001 and December 2011. Demographic and clinical data were extracted from the Ife-Ijesha cancer registry and histopathological diagnoses were confirmed. A total of 111 biopsies were reviewed with a maximum of 17 in 2001 and minimum of 3 in 2005. Patient ages ranged between 1 day and 16 years with a male:female ratio of 1.02:1. There were 53 spinal lesions, 15 intracranial lesions, 36 scalp masses, 6 skull lesions and 1 muscle biopsy. Most of the specimens were from myelomeningoceles. This documentation of the major types of pediatric neurological conditions encountered in clinical practice in this relatively resource-limited setting indicate the need for collaboration with better developed centers to improve training in neurosurgery and neuropathology to enhance the quality of clinical care for young patients in Africa.
{"title":"Pediatric Neuropathology in Africa: Local Experience in Nigeria and Challenges and Prospects for the Continent","authors":"B. Olasode, Chiazor Udochukwu Onyia","doi":"10.1093/jnen/nlw076","DOIUrl":"https://doi.org/10.1093/jnen/nlw076","url":null,"abstract":"The present state of pediatric neuropathology practice is in rudimentary developmental stages in most parts of sub-Saharan Africa. We sought to determine the pattern of neurosurgical lesions in children diagnosed in southwestern Nigeria and briefly address issues surrounding the practice of this aspect of pathology in Africa. We performed a retrospective review of histopathologic results of biopsies obtained from pediatric patients with neurosurgical lesions at the Department of Pathology, Obafemi Awolowo University Teaching Hospitals Complex, Ile–Ife, Nigeria, between January 2001 and December 2011. Demographic and clinical data were extracted from the Ife-Ijesha cancer registry and histopathological diagnoses were confirmed. A total of 111 biopsies were reviewed with a maximum of 17 in 2001 and minimum of 3 in 2005. Patient ages ranged between 1 day and 16 years with a male:female ratio of 1.02:1. There were 53 spinal lesions, 15 intracranial lesions, 36 scalp masses, 6 skull lesions and 1 muscle biopsy. Most of the specimens were from myelomeningoceles. This documentation of the major types of pediatric neurological conditions encountered in clinical practice in this relatively resource-limited setting indicate the need for collaboration with better developed centers to improve training in neurosurgery and neuropathology to enhance the quality of clinical care for young patients in Africa.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84958684","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}
F. Rodriguez, D. Hill, Cheng-Ying Ho, A. Melo, F. Tovar-Moll, P. Oliveira-Szejnfeld, A. Camacho, G. C. Gomes, F. O. Melo, A. G. M. Batista, H. N. Machado, E. Awad, Thales A. Ferreira, R. Andrade, R. Mello, M. Arruda, R. Brindeiro, Rodrigo Delvechio, A. Tanuri
Congenital Zika virus infection is a developing public health emergency, leading to microcephaly, intracerebral calcifications, and often fetal death. Here we present the neuropathological findings from an autopsy of a 20week fetus in which congenital Zika virus infection was diagnosed in utero. Though microcephaly or intracerebral calcification was not yet identified, fetal ultrasound and MRI findings revealed mild hydrocephalus with a markedly thinned cortical rim and partial corpus callosum agenesis. Following pregnancy termination, autopsy revealed a brain within the normal weight range for gestational age, however the thinned cortex was grossly notable. Histologic evaluation of the brain showed abundant apoptosis diffusely involving the “intermediately differentiated” neurons in neocortex. The subventricular zone and white matter demonstrated severe volume loss with axonal injuries and macrophage infiltrates. Additionally, an aggregate of intracellular particles identified on electron microscopy was consistent with viral infection. There was relative sparing of the developmentally mature deep grey matter nuclei and limbic regions, which showed only rare microglial aggregates. Similarly, the germinal matrix of the ganglionic eminence was morphologically intact and void of inflammation. Our imaging and pathologic findings suggest that the Zika virus-associated brain injury is likely a consequence of direct viral injury and post-infectious inflammatory damage to a subpopulation of central nervous sytemsystem cells. Whether the viral infection has an effect on the developmental sequence remains unclear. Future studies across multiple time points of pregnancy will offer better insight into the role of Zika virus infection in brain development.
{"title":"American Association of Neuropathologists, Inc. Abstracts of the 92nd Annual Meeting June 16–19, 2016 Baltimore, MD","authors":"F. Rodriguez, D. Hill, Cheng-Ying Ho, A. Melo, F. Tovar-Moll, P. Oliveira-Szejnfeld, A. Camacho, G. C. Gomes, F. O. Melo, A. G. M. Batista, H. N. Machado, E. Awad, Thales A. Ferreira, R. Andrade, R. Mello, M. Arruda, R. Brindeiro, Rodrigo Delvechio, A. Tanuri","doi":"10.1093/jnen/nlw038","DOIUrl":"https://doi.org/10.1093/jnen/nlw038","url":null,"abstract":"Congenital Zika virus infection is a developing public health emergency, leading to microcephaly, intracerebral calcifications, and often fetal death. Here we present the neuropathological findings from an autopsy of a 20week fetus in which congenital Zika virus infection was diagnosed in utero. Though microcephaly or intracerebral calcification was not yet identified, fetal ultrasound and MRI findings revealed mild hydrocephalus with a markedly thinned cortical rim and partial corpus callosum agenesis. Following pregnancy termination, autopsy revealed a brain within the normal weight range for gestational age, however the thinned cortex was grossly notable. Histologic evaluation of the brain showed abundant apoptosis diffusely involving the “intermediately differentiated” neurons in neocortex. The subventricular zone and white matter demonstrated severe volume loss with axonal injuries and macrophage infiltrates. Additionally, an aggregate of intracellular particles identified on electron microscopy was consistent with viral infection. There was relative sparing of the developmentally mature deep grey matter nuclei and limbic regions, which showed only rare microglial aggregates. Similarly, the germinal matrix of the ganglionic eminence was morphologically intact and void of inflammation. Our imaging and pathologic findings suggest that the Zika virus-associated brain injury is likely a consequence of direct viral injury and post-infectious inflammatory damage to a subpopulation of central nervous sytemsystem cells. Whether the viral infection has an effect on the developmental sequence remains unclear. Future studies across multiple time points of pregnancy will offer better insight into the role of Zika virus infection in brain development.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77446776","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}
Keun-Hwa Jung, K. Chu, Soon-Tae Lee, Y. Shin, Keon-Joo Lee, Dongeon Park, Jung-Suk Yoo, Soyun Kim, Manho Kim, Sang Kun Lee, J. Roh
Optimal models are needed to understand the pathophysiology of human cerebral aneurysms (CA). We investigated the development of experimental CA by decreasing the activity of lysyl oxidases by dietary copper deficiency from the time of gestation and then augmenting vascular stress by angiotensin II infusion in adulthood. Rats were fed copper-free, low-copper, or normal diets at different time periods from gestation to adulthood. The incidences of CAs were evaluated and autopsies performed to determine the coexistence of cardiovascular diseases. A copper-free diet from gestation was associated with high mortality rates (79.1%) resulting from rupture of ascending aorta aneurysms; a low-copper diet led to acceptable mortality rates (13.6%) and produced CAs and subarachnoid hemorrhage in 46.4% and 3.6% of animals, respectively. Higher proportions of CAs (up to 33.3%) in the rats primed for copper deficiency from gestation ruptured following angiotensin II infusion from adulthood. Gene expression array analyses of the CAs indicated that genes involving extracellular matrix and vascular remodeling were altered in this model. This model enables future research to understand the entire pathogenetic basis of CA development and rupture in association with systemic vasculopathies.
{"title":"Experimental Induction of Cerebral Aneurysms by Developmental Low Copper Diet","authors":"Keun-Hwa Jung, K. Chu, Soon-Tae Lee, Y. Shin, Keon-Joo Lee, Dongeon Park, Jung-Suk Yoo, Soyun Kim, Manho Kim, Sang Kun Lee, J. Roh","doi":"10.1093/jnen/nlw020","DOIUrl":"https://doi.org/10.1093/jnen/nlw020","url":null,"abstract":"Optimal models are needed to understand the pathophysiology of human cerebral aneurysms (CA). We investigated the development of experimental CA by decreasing the activity of lysyl oxidases by dietary copper deficiency from the time of gestation and then augmenting vascular stress by angiotensin II infusion in adulthood. Rats were fed copper-free, low-copper, or normal diets at different time periods from gestation to adulthood. The incidences of CAs were evaluated and autopsies performed to determine the coexistence of cardiovascular diseases. A copper-free diet from gestation was associated with high mortality rates (79.1%) resulting from rupture of ascending aorta aneurysms; a low-copper diet led to acceptable mortality rates (13.6%) and produced CAs and subarachnoid hemorrhage in 46.4% and 3.6% of animals, respectively. Higher proportions of CAs (up to 33.3%) in the rats primed for copper deficiency from gestation ruptured following angiotensin II infusion from adulthood. Gene expression array analyses of the CAs indicated that genes involving extracellular matrix and vascular remodeling were altered in this model. This model enables future research to understand the entire pathogenetic basis of CA development and rupture in association with systemic vasculopathies.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82629995","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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