Acta neuropathologica
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Acta neuropathologica · Oct 2013
Case ReportsProgressive amnestic dementia, hippocampal sclerosis, and mutation in C9ORF72.
The most common cause of familial frontotemporal lobar degeneration with TAR DNA-binding protein-43 pathology (FTLD-TDP) has been found to be an expansion of a hexanucleotide repeat (GGGGCC) in a noncoding region of the gene C9ORF72. Hippocampal sclerosis (HpScl) is a common finding in FTLD-TDP. Our objective was to screen for the presence of C9ORF72 hexanucleotide repeat expansions in a pathologically confirmed cohort of "pure" hippocampal sclerosis cases (n = 33), outside the setting of FTLD-TDP and Alzheimer's disease (AD). ⋯ There was no significant FTLD or motor neuron disease. C9RANT was found to be sensitive and specific in this autopsy-confirmed series of HpScl cases. The findings in this patient suggest that the clinical and pathologic spectrum of C9ORF72 repeat expansion is wider than frontotemporal dementia and motor neuron disease, including cases of progressive amnestic dementia with restricted TDP-43 pathology associated with HpScl.
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Acta neuropathologica · Jul 2013
Mild traumatic brain injury in the mouse induces axotomy primarily within the axon initial segment.
Traumatic axonal injury (TAI) is a consistent component of traumatic brain injury (TBI), and is associated with much of its morbidity. Increasingly, it has also been recognized as a major pathology of mild TBI (mTBI). In terms of its pathogenesis, numerous studies have investigated the susceptibility of the nodes of Ranvier, the paranode and internodal regions to TAI. ⋯ Utilizing a mouse model of mTBI, a temporal and spatial heterogeneity of axonal injury was found within the neocortical gray matter. Although axonal swellings were found in all domains along myelinated neocortical axons, the majority of TAI occurred within the AIS, which progressed without overt structural disruption of the AIS itself. The finding of primary AIS involvement has important implications regarding neuronal polarity and the fate of axotomized processes, while also raising therapeutic implications, as the mechanisms underlying such axonal injury in the AIS may be distinct from those described for nodal/paranodal injury.
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Acta neuropathologica · Apr 2013
GDNF mediates glioblastoma-induced microglia attraction but not astrogliosis.
High-grade gliomas are the most common primary brain tumors. Their malignancy is promoted by the complex crosstalk between different cell types in the central nervous system. Microglia/brain macrophages infiltrate high-grade gliomas and contribute to their progression. ⋯ In vitro migration assays also showed that GDNF is a strong chemoattractant for microglia. While GDNF release from human or mouse glioma had a profound effect on microglial attraction, the glioma-induced astrogliosis was not affected. Finally, we could show that injection of GL261 mouse glioma cells with GDNF knockdown by shRNA into mouse brains resulted in reduced tumor expansion and improved survival as compared to injection of control cells.
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Acta neuropathologica · Mar 2013
DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies.
Molecular subclassification is rapidly informing the clinical management of medulloblastoma. However, the disease remains associated with poor outcomes and therapy-associated late effects, and the majority of patients are not characterized by a validated prognostic biomarker. Here, we investigated the potential of epigenetic DNA methylation for disease subclassification, particularly in formalin-fixed biopsies, and to identify biomarkers for improved therapeutic individualization. ⋯ Incorporation of MXI1 and IL8 into current survival models significantly improved the assignment of disease risk; 46 % of patients could be classified as 'favorable risk' (>90 % survival) compared to 13 % using current models, while the high-risk group was reduced from 30 to 16 %. DNA methylation profiling enables the robust subclassification of four disease subgroups in frozen and routinely collected/archival formalin-fixed biopsy material, and the incorporation of DNA methylation biomarkers can significantly improve disease-risk stratification. These findings have important implications for future risk-adapted clinical disease management.