Darius Saberi, B. Ott, Carolin Dahlke, Veronika Matschke, T. Schmitt-John, C. Theiss
Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease that affects motor neurons in the spinal cord and motor cortex. Various mouse models have been used to investigate the progression of the pathology of sporadic and familial ALS. Degeneration in the spinal cord and motor cortex in the Wobbler mouse model of sporadic ALS have been documented, but alterations of the cerebellum during disease progression have not been well characterized. We analyzed neurodegeneration and inflammatory responses in the cerebellar cortex of preclinical (p20), clinical (p40), and late (p60) stages in these mice. We did not identify evidence of neuron cell death, but we observed an inflammatory response detected by IL1B and TNFA expression by quantitative PCR, increased activated microglia and astrocytosis by immunohistochemistry, and ultrastructural abnormalities in the cerebella of Wobbler mice at late stages. These alterations may be caused by protein aggregations and variations in the distribution of cytoskeletal proteins; they might be reflected in the early manifestation of head tremor, which precedes motor deficits in these mice. Thus, we conclude that, in addition to the motor cortex and spinal cord, the cerebellum is affected by neurodegenerative and inflammatory processes in the Wobbler mouse model of ALS.
{"title":"The Spatiotemporal Pattern of Degeneration in the Cerebellum of the Wobbler Mouse","authors":"Darius Saberi, B. Ott, Carolin Dahlke, Veronika Matschke, T. Schmitt-John, C. Theiss","doi":"10.1093/jnen/nlw005","DOIUrl":"https://doi.org/10.1093/jnen/nlw005","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease that affects motor neurons in the spinal cord and motor cortex. Various mouse models have been used to investigate the progression of the pathology of sporadic and familial ALS. Degeneration in the spinal cord and motor cortex in the Wobbler mouse model of sporadic ALS have been documented, but alterations of the cerebellum during disease progression have not been well characterized. We analyzed neurodegeneration and inflammatory responses in the cerebellar cortex of preclinical (p20), clinical (p40), and late (p60) stages in these mice. We did not identify evidence of neuron cell death, but we observed an inflammatory response detected by IL1B and TNFA expression by quantitative PCR, increased activated microglia and astrocytosis by immunohistochemistry, and ultrastructural abnormalities in the cerebella of Wobbler mice at late stages. These alterations may be caused by protein aggregations and variations in the distribution of cytoskeletal proteins; they might be reflected in the early manifestation of head tremor, which precedes motor deficits in these mice. Thus, we conclude that, in addition to the motor cortex and spinal cord, the cerebellum is affected by neurodegenerative and inflammatory processes in the Wobbler mouse model of ALS.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88735220","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 tropomyosin-receptor kinase fused gene (TFG), which is located on chromosome 3q12.2, was originally identified as a fusion partner that results in the formation of oncogenic products associated with multiple cancers. TFG protein interacts directly with Sec16, the scaffolding protein for coat protein II-coated vesicles that regulate endoplasmic reticulum (ER)-to-Golgi transport at ER exit sites. In 2012, a heterozygous mutation of TFG was identified as the causative gene for autosomal-dominant hereditary motor and sensory neuropathy with proximal dominant involvement. In 2013, a homozygous mutation of TFG was reported in a family with early onset spastic paraplegia, optic atrophy, and neuropathy. Another novel mutation in TFG was discovered in 2014 as a cause of dominant axonal Charcot-Marie-Tooth disease type 2. These findings suggest that mutations of TFG cause ER dysfunction and neurodegeneration in this disease spectrum, which is tightly associated with ER function. Here, we review the clinical phenotypes of these diseases and present recent insights that suggest causal roles of ER dysfunction in TFG-related neurologic disorders. Although the precise pathogenetic mechanisms underlying these TFG mutations remain to be elucidated, experimental manipulations suggest that the dysregulations of ER homeostasis that occur due to mutations in TFG lead to neurodegeneration.
{"title":"TFG-Related Neurologic Disorders: New Insights Into Relationships Between Endoplasmic Reticulum and Neurodegeneration","authors":"T. Yagi, D. Ito, N. Suzuki","doi":"10.1093/jnen/nlw009","DOIUrl":"https://doi.org/10.1093/jnen/nlw009","url":null,"abstract":"The tropomyosin-receptor kinase fused gene (TFG), which is located on chromosome 3q12.2, was originally identified as a fusion partner that results in the formation of oncogenic products associated with multiple cancers. TFG protein interacts directly with Sec16, the scaffolding protein for coat protein II-coated vesicles that regulate endoplasmic reticulum (ER)-to-Golgi transport at ER exit sites. In 2012, a heterozygous mutation of TFG was identified as the causative gene for autosomal-dominant hereditary motor and sensory neuropathy with proximal dominant involvement. In 2013, a homozygous mutation of TFG was reported in a family with early onset spastic paraplegia, optic atrophy, and neuropathy. Another novel mutation in TFG was discovered in 2014 as a cause of dominant axonal Charcot-Marie-Tooth disease type 2. These findings suggest that mutations of TFG cause ER dysfunction and neurodegeneration in this disease spectrum, which is tightly associated with ER function. Here, we review the clinical phenotypes of these diseases and present recent insights that suggest causal roles of ER dysfunction in TFG-related neurologic disorders. Although the precise pathogenetic mechanisms underlying these TFG mutations remain to be elucidated, experimental manipulations suggest that the dysregulations of ER homeostasis that occur due to mutations in TFG lead to neurodegeneration.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87445053","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}
Jacquelyn J. Roth, T. Fierst, A. Waanders, Liu Yimei, J. Biegel, M. Santi
The most frequent genetic alteration identified in pediatric pilocytic astrocytomas and pilomyxoid variant is the KIAA1549-BRAF fusion, which typically results from a 2.0 Mb tandem duplication in chromosome band 7q34. Less frequent abnormalities include fusion genes, BRAF, FGFR, KRAS, and NF1 point mutations, and whole chromosome gains. To correlate genetic alterations with clinical course data, we retrospectively analyzed the tumors with pilocytic and pilomyxoid histology of a cohort of 116 pediatric patients, aged 5 months to 23 years. Gross total resection was associated with a decreased risk of recurrence (p = 0.001), supporting previous findings that complete tumor excision correlates with long-term and disease-free survival. We found no significant association between recurrence rate and the presence of the KIAA1549-BRAF fusion or BRAF mutation (p = 0.167). Interestingly, gain of whole chromosome 7 (WC7) was associated with a 4.7-fold increased risk of tumor recurrence, even after adjusting for surgical status (p = 0.025), and other genetic alterations. Using fluorescence in situ hybridization, we demonstrated that when WC7 gain accompanies the KIAA1549-BRAF fusion, the fusion likely arises first. This study highlights the utility of genetic studies for risk assessment of pilocytic and pilomyxoid astrocytomas, which may impact treatment selections.
{"title":"Whole Chromosome 7 Gain Predicts Higher Risk of Recurrence in Pediatric Pilocytic Astrocytomas Independently From KIAA1549-BRAF Fusion Status","authors":"Jacquelyn J. Roth, T. Fierst, A. Waanders, Liu Yimei, J. Biegel, M. Santi","doi":"10.1093/jnen/nlw001","DOIUrl":"https://doi.org/10.1093/jnen/nlw001","url":null,"abstract":"The most frequent genetic alteration identified in pediatric pilocytic astrocytomas and pilomyxoid variant is the KIAA1549-BRAF fusion, which typically results from a 2.0 Mb tandem duplication in chromosome band 7q34. Less frequent abnormalities include fusion genes, BRAF, FGFR, KRAS, and NF1 point mutations, and whole chromosome gains. To correlate genetic alterations with clinical course data, we retrospectively analyzed the tumors with pilocytic and pilomyxoid histology of a cohort of 116 pediatric patients, aged 5 months to 23 years. Gross total resection was associated with a decreased risk of recurrence (p = 0.001), supporting previous findings that complete tumor excision correlates with long-term and disease-free survival. We found no significant association between recurrence rate and the presence of the KIAA1549-BRAF fusion or BRAF mutation (p = 0.167). Interestingly, gain of whole chromosome 7 (WC7) was associated with a 4.7-fold increased risk of tumor recurrence, even after adjusting for surgical status (p = 0.025), and other genetic alterations. Using fluorescence in situ hybridization, we demonstrated that when WC7 gain accompanies the KIAA1549-BRAF fusion, the fusion likely arises first. This study highlights the utility of genetic studies for risk assessment of pilocytic and pilomyxoid astrocytomas, which may impact treatment selections.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77390647","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}
K. Fritchie, Long Jin, B. Rubin, P. Burger, S. Jenkins, S. Barthelmeß, E. Moskalev, F. Haller, Andre M Oliveira, C. Giannini
Meningeal solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) are considered to be distinct entities in the WHO Classification of CNS Tumours (2007). They harbor NAB2-STAT6 fusions similar to their soft tissue counterparts, supporting the view that they are part of a tumor continuum. We examined 30 meningeal-based tumors originally diagnosed as either SFT or HPC. These showed a spectrum of morphologic features and were diagnosed as SFTs, malignant SFTs, HPCs, or tumors with “intermediate” features. All of the tumors showed nuclear expression of STAT6. SFTs consistently expressed diffuse CD34, while HPCs and intermediate tumors had heterogeneous staining. NAB2-STAT6 fusions were identified in 20 cases, including 7 with exon 4-exon 3, 9 with exon 6-exon 17, and 4 with exon 6-exon 18 fusions. NAB2 exon 4-STAT6 exon 3 fusion correlated with classic SFT morphology and older age and showed a trend toward less mitotic activity; there was also a trend toward more aggressive behavior in tumors lacking NAB2 exon 4-STAT6 exon 3. Thus, despite their clinical and morphologic differences, meningeal-based SFTs, HPCs, and tumors with intermediate features, similar to their soft tissue counterparts, form a histopathologic spectrum unified by STAT6 immunoexpression and NAB2-STAT6 fusion.
{"title":"NAB2-STAT6 Gene Fusion in Meningeal Hemangiopericytoma and Solitary Fibrous Tumor","authors":"K. Fritchie, Long Jin, B. Rubin, P. Burger, S. Jenkins, S. Barthelmeß, E. Moskalev, F. Haller, Andre M Oliveira, C. Giannini","doi":"10.1093/jnen/nlv026","DOIUrl":"https://doi.org/10.1093/jnen/nlv026","url":null,"abstract":"Meningeal solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) are considered to be distinct entities in the WHO Classification of CNS Tumours (2007). They harbor NAB2-STAT6 fusions similar to their soft tissue counterparts, supporting the view that they are part of a tumor continuum. We examined 30 meningeal-based tumors originally diagnosed as either SFT or HPC. These showed a spectrum of morphologic features and were diagnosed as SFTs, malignant SFTs, HPCs, or tumors with “intermediate” features. All of the tumors showed nuclear expression of STAT6. SFTs consistently expressed diffuse CD34, while HPCs and intermediate tumors had heterogeneous staining. NAB2-STAT6 fusions were identified in 20 cases, including 7 with exon 4-exon 3, 9 with exon 6-exon 17, and 4 with exon 6-exon 18 fusions. NAB2 exon 4-STAT6 exon 3 fusion correlated with classic SFT morphology and older age and showed a trend toward less mitotic activity; there was also a trend toward more aggressive behavior in tumors lacking NAB2 exon 4-STAT6 exon 3. Thus, despite their clinical and morphologic differences, meningeal-based SFTs, HPCs, and tumors with intermediate features, similar to their soft tissue counterparts, form a histopathologic spectrum unified by STAT6 immunoexpression and NAB2-STAT6 fusion.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88939711","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 cell-mediated inflammatory myopathies (polymyositis [PM] and inclusion body myositis [IBM]) sometimes arise in conjunction with HIV infection; however, it is not understood whether PM and IBM arising in the context of HIV (HIV-PM and HV-IBM) differ from PM and IBM arising sporadically in HIV-negative individuals (sPM and sIBM). Here, we report the largest series of T cell-mediated inflammatory myopathies from HIV-infected patients (19 biopsies from 15 subjects); 5 cases were pathologically classified as PM (HIV-PM) and 14 as IBM (HIV-IBM). As with sporadic cases, quantitative immunohistochemistry for LC3, p62, and TDP-43 showed significantly greater percentage of stained fibers (% FS) in HIV-IBM compared to HIV-PM samples; however, there was no significant difference in % FS for any of the three markers between HIV-associated and sporadic cases. Despite histologic similarities between HIV-IBM and sIBM but in concordance with prior case reports, patients with HIV-IBM were significantly younger at diagnosis than patients with sIBM; in contrast, the mean age of HIV-PM and sPM patients was not significantly different. In summary, HIV-PM and HIV-IBM are morphologically similar to sPM and sIBM; thus, it remains unclear why patients with HIV-IBM, in contrast to patients with sIBM, sometimes show clinical improvement in response to immunosuppressive therapy.
{"title":"T-Cell-Mediated Inflammatory Myopathies in HIV-Positive Individuals: A Histologic Study of 19 Cases","authors":"A. Hiniker, B. Daniels, M. Margeta","doi":"10.1093/jnen/nlv023","DOIUrl":"https://doi.org/10.1093/jnen/nlv023","url":null,"abstract":"T cell-mediated inflammatory myopathies (polymyositis [PM] and inclusion body myositis [IBM]) sometimes arise in conjunction with HIV infection; however, it is not understood whether PM and IBM arising in the context of HIV (HIV-PM and HV-IBM) differ from PM and IBM arising sporadically in HIV-negative individuals (sPM and sIBM). Here, we report the largest series of T cell-mediated inflammatory myopathies from HIV-infected patients (19 biopsies from 15 subjects); 5 cases were pathologically classified as PM (HIV-PM) and 14 as IBM (HIV-IBM). As with sporadic cases, quantitative immunohistochemistry for LC3, p62, and TDP-43 showed significantly greater percentage of stained fibers (% FS) in HIV-IBM compared to HIV-PM samples; however, there was no significant difference in % FS for any of the three markers between HIV-associated and sporadic cases. Despite histologic similarities between HIV-IBM and sIBM but in concordance with prior case reports, patients with HIV-IBM were significantly younger at diagnosis than patients with sIBM; in contrast, the mean age of HIV-PM and sPM patients was not significantly different. In summary, HIV-PM and HIV-IBM are morphologically similar to sPM and sIBM; thus, it remains unclear why patients with HIV-IBM, in contrast to patients with sIBM, sometimes show clinical improvement in response to immunosuppressive therapy.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82500253","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}
P. Andrade, M. Jardim, A. C. D. da Silva, Paula Saraiva Manhães, S. Antunes, R. Vital, Rhana Berto da Silva Prata, R. B. Petito, R. Pinheiro, E. Sarno
Mycobacterium leprae (ML) infection causes nerve damage that often leads to permanent loss of cutaneous sensitivity and limb deformities, but understanding of the pathogenesis of leprous neuropathy that would lead to more effective treatments is incomplete. We studied reactional leprosy patients with (n = 9) and without (n = 8) acute neuritis. Nerve conduction studies over the course of the reactional episode showed the findings of demyelination in all patients with neuritis. Evaluation of patient sera revealed no correlation of the presence of antibodies against gangliosides and the clinical demyelination. In nerve biopsies of 3 patients with neuritis, we identified tumor necrosis factor (TNF), TNF receptors, and TNF-converting enzyme in Schwann cells (SCs) using immunofluorescence. To elucidate immunopathogenetic mechanisms, we performed experiments using a human SC line. ML induced transmembrane TNF and TNF receptor 1 expression in the SCs; TNF also induced interleukin (IL)-6 and IL-8 production by the SCs; and ML induced IL-23 secretion, indicating involvement of this previously unrecognized factor in leprosy nerve damage. These data suggest that ML may contribute to TNF-mediated inflammation and focal demyelination by rendering SCs more sensitive to TNF within the nerves of patients with leprous neuropathy.
{"title":"Inflammatory Cytokines Are Involved in Focal Demyelination in Leprosy Neuritis","authors":"P. Andrade, M. Jardim, A. C. D. da Silva, Paula Saraiva Manhães, S. Antunes, R. Vital, Rhana Berto da Silva Prata, R. B. Petito, R. Pinheiro, E. Sarno","doi":"10.1093/jnen/nlv027","DOIUrl":"https://doi.org/10.1093/jnen/nlv027","url":null,"abstract":"Mycobacterium leprae (ML) infection causes nerve damage that often leads to permanent loss of cutaneous sensitivity and limb deformities, but understanding of the pathogenesis of leprous neuropathy that would lead to more effective treatments is incomplete. We studied reactional leprosy patients with (n = 9) and without (n = 8) acute neuritis. Nerve conduction studies over the course of the reactional episode showed the findings of demyelination in all patients with neuritis. Evaluation of patient sera revealed no correlation of the presence of antibodies against gangliosides and the clinical demyelination. In nerve biopsies of 3 patients with neuritis, we identified tumor necrosis factor (TNF), TNF receptors, and TNF-converting enzyme in Schwann cells (SCs) using immunofluorescence. To elucidate immunopathogenetic mechanisms, we performed experiments using a human SC line. ML induced transmembrane TNF and TNF receptor 1 expression in the SCs; TNF also induced interleukin (IL)-6 and IL-8 production by the SCs; and ML induced IL-23 secretion, indicating involvement of this previously unrecognized factor in leprosy nerve damage. These data suggest that ML may contribute to TNF-mediated inflammation and focal demyelination by rendering SCs more sensitive to TNF within the nerves of patients with leprous neuropathy.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73328715","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 choroid plexus is composed of epithelial cells resting on a basal lamina. These cells produce the cerebrospinal fluid (CSF), which has many functions including rendering mechanical support, providing a route for some nutrients, removing by-products of metabolism and synaptic activity, and playing a role in hormonal signaling. The choroid plexus synthesizes many growth factors, including insulin-like, fibroblast, and platelet-derived growth factors. The tight junctions located between the apical parts of the choroid plexus epithelial cells form the blood-CSF barrier (BCSFB), which is crucial for the homeostatic regulation of the brain microenvironment along with the blood-brain barrier (BBB). Morphological changes such as atrophy of the epithelial cells and thickening of the basement membrane suggest altered CSF production occurs in aging and in Alzheimer disease. In brain injuries and infections, leukocytes accumulate in the CSF by passing through the choroid plexus. In inflammatory CNS diseases (eg, multiple sclerosis), pathogenic autoreactive T lymphocytes may migrate through the BBB and BCSFB into the CNS. The development of therapeutic strategies to mitigate disruption of the BCSFB may be helpful to curtail the entry of inflammatory cells into the CSF and hence reduce inflammation, thereby overcoming choroid plexus dysfunction in senescence and in various diseases of the CNS.
{"title":"The Choroid Plexus in Healthy and Diseased Brain","authors":"C. Kaur, Gurugirijha Rathnasamy, E. Ling","doi":"10.1093/jnen/nlv030","DOIUrl":"https://doi.org/10.1093/jnen/nlv030","url":null,"abstract":"The choroid plexus is composed of epithelial cells resting on a basal lamina. These cells produce the cerebrospinal fluid (CSF), which has many functions including rendering mechanical support, providing a route for some nutrients, removing by-products of metabolism and synaptic activity, and playing a role in hormonal signaling. The choroid plexus synthesizes many growth factors, including insulin-like, fibroblast, and platelet-derived growth factors. The tight junctions located between the apical parts of the choroid plexus epithelial cells form the blood-CSF barrier (BCSFB), which is crucial for the homeostatic regulation of the brain microenvironment along with the blood-brain barrier (BBB). Morphological changes such as atrophy of the epithelial cells and thickening of the basement membrane suggest altered CSF production occurs in aging and in Alzheimer disease. In brain injuries and infections, leukocytes accumulate in the CSF by passing through the choroid plexus. In inflammatory CNS diseases (eg, multiple sclerosis), pathogenic autoreactive T lymphocytes may migrate through the BBB and BCSFB into the CNS. The development of therapeutic strategies to mitigate disruption of the BCSFB may be helpful to curtail the entry of inflammatory cells into the CSF and hence reduce inflammation, thereby overcoming choroid plexus dysfunction in senescence and in various diseases of the CNS.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87751372","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}
N. Pirot, M. Crahès, H. Adle-Biassette, A. Soares, M. Bucourt, A. Boutron, L. Carbillon, C. Mignot, L. Trestard, S. Bekri, A. Laquérriere
To distinguish pyruvate dehydrogenase deficiency (PDH) from other antenatal neurometabolic disorders thereby improving prenatal diagnosis, we describe imaging findings, clinical phenotype, and brain lesions in fetuses from 3 families with molecular characterization of this condition. Neuropathological analysis was performed in 4 autopsy cases from 3 unrelated families with subsequent biochemical and molecular confirmation of PDH complex deficiency. In 2 families there were mutations in the PDHA1 gene; in the third family there was a mutation in the PDHB gene. All fetuses displayed characteristic craniofacial dysmorphism of varying severity, absence of visceral lesions, and associated encephaloclastic and developmental supra- and infratentorial lesions. Neurodevelopmental abnormalities included microcephaly, migration abnormalities (pachygyria, polymicrogyria, periventricular nodular heterotopias), and cerebellar and brainstem hypoplasia with hypoplastic dentate nuclei and pyramidal tracts. Associated clastic lesions included asymmetric leukomalacia, reactive gliosis, large pseudocysts of germinolysis, and basal ganglia calcifications. The diagnosis of PDH deficiency should be suspected antenatally with the presence of clastic and neurodevelopmental lesions and a relatively characteristic craniofacial dysmorphism. Postmortem examination is essential for excluding other closely related entities, thereby allowing for biochemical and molecular confirmation.
{"title":"Phenotypic and Neuropathological Characterization of Fetal Pyruvate Dehydrogenase Deficiency","authors":"N. Pirot, M. Crahès, H. Adle-Biassette, A. Soares, M. Bucourt, A. Boutron, L. Carbillon, C. Mignot, L. Trestard, S. Bekri, A. Laquérriere","doi":"10.1093/jnen/nlv022","DOIUrl":"https://doi.org/10.1093/jnen/nlv022","url":null,"abstract":"To distinguish pyruvate dehydrogenase deficiency (PDH) from other antenatal neurometabolic disorders thereby improving prenatal diagnosis, we describe imaging findings, clinical phenotype, and brain lesions in fetuses from 3 families with molecular characterization of this condition. Neuropathological analysis was performed in 4 autopsy cases from 3 unrelated families with subsequent biochemical and molecular confirmation of PDH complex deficiency. In 2 families there were mutations in the PDHA1 gene; in the third family there was a mutation in the PDHB gene. All fetuses displayed characteristic craniofacial dysmorphism of varying severity, absence of visceral lesions, and associated encephaloclastic and developmental supra- and infratentorial lesions. Neurodevelopmental abnormalities included microcephaly, migration abnormalities (pachygyria, polymicrogyria, periventricular nodular heterotopias), and cerebellar and brainstem hypoplasia with hypoplastic dentate nuclei and pyramidal tracts. Associated clastic lesions included asymmetric leukomalacia, reactive gliosis, large pseudocysts of germinolysis, and basal ganglia calcifications. The diagnosis of PDH deficiency should be suspected antenatally with the presence of clastic and neurodevelopmental lesions and a relatively characteristic craniofacial dysmorphism. Postmortem examination is essential for excluding other closely related entities, thereby allowing for biochemical and molecular confirmation.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74086457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
J. Ringman, Sarah E. Monsell, Denise W. Ng, Yan Zhou, Andy Nguyen, G. Coppola, V. Van Berlo, Mario F. Mendez, Spencer Tung, S. Weintraub, M. Mesulam, E. Bigio, D. Gitelman, Amanda O. Fisher-Hubbard, R. Albin, H. Vinters
Alzheimer disease (AD) represents a genetically heterogeneous entity. To elucidate neuropathologic features of autosomal dominant AD ([ADAD] due to PSEN1, APP, or PSEN2 mutations), we compared hallmark AD pathologic findings in 60 cases of ADAD and 120 cases of sporadic AD matched for sex, race, ethnicity, and disease duration. Greater degrees of neuritic plaque and neurofibrillary tangle formation and cerebral amyloid angiopathy (CAA) were found in ADAD (p values < 0.01). Moderate to severe CAA was more prevalent in ADAD (63.3% vs. 39.2%, p = 0.003), and persons with PSEN1 mutations beyond codon 200 had higher average Braak scores and severity and prevalence of CAA than those with mutations before codon 200. Lewy body pathology was less extensive in ADAD but was present in 27.1% of cases. We also describe a novel pathogenic PSEN1 mutation (P267A). The finding of more severe neurofibrillary pathology and CAA in ADAD, particularly in carriers of PSEN1 mutations beyond codon 200, warrants consideration when designing trials to treat or prevent ADAD. The finding of Lewy body pathology in a substantial minority of ADAD cases supports the assertion that development of Lewy bodies may be in part driven by abnormal &bgr;-amyloid protein precursor processing.
{"title":"Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database","authors":"J. Ringman, Sarah E. Monsell, Denise W. Ng, Yan Zhou, Andy Nguyen, G. Coppola, V. Van Berlo, Mario F. Mendez, Spencer Tung, S. Weintraub, M. Mesulam, E. Bigio, D. Gitelman, Amanda O. Fisher-Hubbard, R. Albin, H. Vinters","doi":"10.1093/jnen/nlv028","DOIUrl":"https://doi.org/10.1093/jnen/nlv028","url":null,"abstract":"Alzheimer disease (AD) represents a genetically heterogeneous entity. To elucidate neuropathologic features of autosomal dominant AD ([ADAD] due to PSEN1, APP, or PSEN2 mutations), we compared hallmark AD pathologic findings in 60 cases of ADAD and 120 cases of sporadic AD matched for sex, race, ethnicity, and disease duration. Greater degrees of neuritic plaque and neurofibrillary tangle formation and cerebral amyloid angiopathy (CAA) were found in ADAD (p values < 0.01). Moderate to severe CAA was more prevalent in ADAD (63.3% vs. 39.2%, p = 0.003), and persons with PSEN1 mutations beyond codon 200 had higher average Braak scores and severity and prevalence of CAA than those with mutations before codon 200. Lewy body pathology was less extensive in ADAD but was present in 27.1% of cases. We also describe a novel pathogenic PSEN1 mutation (P267A). The finding of more severe neurofibrillary pathology and CAA in ADAD, particularly in carriers of PSEN1 mutations beyond codon 200, warrants consideration when designing trials to treat or prevent ADAD. The finding of Lewy body pathology in a substantial minority of ADAD cases supports the assertion that development of Lewy bodies may be in part driven by abnormal &bgr;-amyloid protein precursor processing.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72633602","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. Körner, S. Böselt, Klaudia Wichmann, N. Thau-Habermann, A. Zapf, S. Knippenberg, R. Dengler, S. Petri
Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disorder that leads to progressive paralysis of skeletal muscles and death by respiratory failure. There is increasing evidence that ALS is at least in part an axonopathy and that mechanisms regulating axonal degeneration and regeneration might be pathogenetically relevant. Semaphorin 3A (Sema3A) is an axon guidance protein; it acts as an axon repellent and prevents axonal regeneration. Increased Sema3A expression has been described in a mouse model of ALS in which it may contribute to motor neuron degeneration. This study aimed to investigate Sema3A mRNA and protein expression in human CNS tissues. We assessed Sema3A expression using quantitative real-time PCR, in situ hybridization, and immunohistochemistry in motor cortex and spinal cord tissue of 8 ALS patients and 6 controls. We found a consistent increase of Sema3A expression in the motor cortex of ALS patients by all 3 methods. In situ hybridization further confirmed that Sema3A expression was present in motor neurons. These findings indicate that upregulation of Sema3A may contribute to axonal degeneration and failure of regeneration in ALS patients. The inhibition of Sema3A therefore might be a promising future therapeutic option for patients with this disease.
{"title":"The Axon Guidance Protein Semaphorin 3A Is Increased in the Motor Cortex of Patients With Amyotrophic Lateral Sclerosis","authors":"S. Körner, S. Böselt, Klaudia Wichmann, N. Thau-Habermann, A. Zapf, S. Knippenberg, R. Dengler, S. Petri","doi":"10.1093/jnen/nlw003","DOIUrl":"https://doi.org/10.1093/jnen/nlw003","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disorder that leads to progressive paralysis of skeletal muscles and death by respiratory failure. There is increasing evidence that ALS is at least in part an axonopathy and that mechanisms regulating axonal degeneration and regeneration might be pathogenetically relevant. Semaphorin 3A (Sema3A) is an axon guidance protein; it acts as an axon repellent and prevents axonal regeneration. Increased Sema3A expression has been described in a mouse model of ALS in which it may contribute to motor neuron degeneration. This study aimed to investigate Sema3A mRNA and protein expression in human CNS tissues. We assessed Sema3A expression using quantitative real-time PCR, in situ hybridization, and immunohistochemistry in motor cortex and spinal cord tissue of 8 ALS patients and 6 controls. We found a consistent increase of Sema3A expression in the motor cortex of ALS patients by all 3 methods. In situ hybridization further confirmed that Sema3A expression was present in motor neurons. These findings indicate that upregulation of Sema3A may contribute to axonal degeneration and failure of regeneration in ALS patients. The inhibition of Sema3A therefore might be a promising future therapeutic option for patients with this disease.","PeriodicalId":16434,"journal":{"name":"Journal of Neuropathology & Experimental Neurology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74336357","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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