Infectious prions do not induce A β deposition in an in vivo seeding model
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 16, 2018 Category: Neurology Source Type: research

Genomic analysis reveals secondary glioblastoma after radiotherapy in a subset of recurrent medulloblastomas
AbstractDespite great advances in understanding of molecular pathogenesis and achievement of a high cure rate in medulloblastoma, recurrent medulloblastomas are still dismal. Additionally, misidentification of secondary malignancies due to histological ambiguity leads to misdiagnosis and eventually to inappropriate treatment. Nevertheless, the genomic characteristics of recurrent medulloblastomas are poorly understood, largely due to a lack of matched primary and recurrent tumor tissues. We performed a genomic analysis of recurrent tumors from 17 pediatric medulloblastoma patients. Whole transcriptome sequencing revealed t...
Source: Acta Neuropathologica - April 11, 2018 Category: Neurology Source Type: research

Loss of histone H3K27me3 identifies a subset of meningiomas with increased risk of recurrence
AbstractEpigenetic patterns on the level of DNA methylation have already been  shown to separate clinically relevant subgroups of meningiomas. We here set out to identify potential prognostic implications of epigenetic modification on the level of histones with focus on H3K27 trimethylation (H3K27me3). H3K27me3 was assessed by immunohistochemistry on 232 meningiomas from 232 patients. In 194 cases, trimethylation was detected in tumor cells. In 25 cases, staining was limited to vessels while all tumor cells were negative. Finally, 13 cases yielded equivocal staining patterns. Reduced abundance of H3K27me3 in cases wit...
Source: Acta Neuropathologica - April 7, 2018 Category: Neurology Source Type: research

Reconstructing the molecular life history of gliomas
AbstractAt the time of their clinical manifestation, the heterogeneous group of adult and pediatric gliomas carries a wide range of diverse somatic genomic alterations, ranging from somatic single-nucleotide variants to structural chromosomal rearrangements. Somatic abnormalities may have functional consequences, such as a decrease, increase or change in mRNA transcripts, and cells pay a penalty for maintaining them. These abnormalities, therefore, must provide cells with a competitive advantage to become engrained into the glioma genome. Here, we propose a model of gliomagenesis consisting of the following five consecutiv...
Source: Acta Neuropathologica - April 3, 2018 Category: Neurology Source Type: research

Acknowledgement to referees
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 3, 2018 Category: Neurology Source Type: research

Mutations in LRRK2 amplify cell-to-cell protein aggregate propagation: a hypothesis
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 29, 2018 Category: Neurology Source Type: research

An intronic VNTR affects splicing of ABCA7 and increases risk of Alzheimer ’s disease
AbstractMutations leading to premature termination codons in ATP-Binding Cassette Subfamily A Member 7 (ABCA7) are high penetrant risk factors of Alzheimer ’s disease (AD). The influence of other genetic variants inABCA7 and downstream functional mechanisms, however, is poorly understood. To address this knowledge gap, we investigated tandem repetitive regions inABCA7 in a Belgian cohort of 1529 AD patients and control individuals and identified an intronic variable number tandem repeat (VNTR). We observed strong association between VNTR length and a genome-wide associated signal for AD in theABCA7 locus. Expanded VN...
Source: Acta Neuropathologica - March 27, 2018 Category: Neurology Source Type: research

Capillary cerebral amyloid angiopathy in Alzheimer ’s disease: association with allocortical/hippocampal microinfarcts and cognitive decline
In conclusion, allocortical microinfarcts, CAA severity, and the capillary type of CAA were associated with one an other and with the development of cognitive decline. Thus, AD cases with CAA type 1 (capillary CAA) appear to develop dementia symptoms not only due to AD-related Aβ plaque and NFT pathology but also due to hippocampal microinfarcts that are associated with CAA type 1 and CAA severity, and that dam age a brain region important for memory function. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 24, 2018 Category: Neurology Source Type: research

Molecular characterization of medulloblastomas with extensive nodularity (MBEN)
AbstractMedulloblastoma with extensive nodularity (MBEN) is a rare histological variant of medulloblastoma (MB). These tumors are usually occurring in the first 3  years of life and are associated with good prognosis. Molecular analyses of MBEN, mostly limited to single cases or small series, have shown that they always classify as sonic hedgehog (SHH)-driven MB. Here, we have analyzed 25 MBEN through genome-wide DNA methylation, copy-number profiling and ta rgeted next-generation sequencing. Results of these analyses were compared with molecular profiles of other SHH MB histological variants. As expected, the vast ma...
Source: Acta Neuropathologica - March 22, 2018 Category: Neurology Source Type: research

Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations
In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations ofCDKN2A/B andATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 21, 2018 Category: Neurology Source Type: research

The natural HLA ligandome of glioblastoma stem-like cells: antigen discovery for T cell-based immunotherapy
AbstractGlioblastoma is the most frequent malignant primary brain tumor. In a hierarchical tumor model, glioblastoma stem-like cells (GSC) play a major role in tumor initiation and maintenance as well as in therapy resistance and recurrence. Thus, targeting this cellular subset may be key to effective immunotherapy. Here, we present a mass spectrometry-based analysis of HLA-presented peptidomes of GSC and glioblastoma patient specimens. Based on the analysis of patient samples (n = 9) and GSC (n = 3), we performed comparative HLA peptidome profiling against a dataset of normal human tissues. Usi...
Source: Acta Neuropathologica - March 20, 2018 Category: Neurology Source Type: research

Energy metabolism in ALS: an underappreciated opportunity?
AbstractAmyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disorder that primarily affects motor neurons. Despite our increased understanding of the genetic factors contributing to ALS, no effective treatment is available. A growing body of evidence shows disturbances in energy metabolism in ALS. Moreover, the remarkable vulnerability of motor neurons to ATP depletion has become increasingly clear. Here, we review metabolic alterations present in ALS patients and models, discuss the selective vulnerability of motor neurons to energetic stress, and provide an overview of tested and...
Source: Acta Neuropathologica - March 16, 2018 Category: Neurology Source Type: research

Aberrant cerebellar Purkinje cell function repaired in vivo by fusion with infiltrating bone marrow-derived cells
AbstractBone marrow-derived cells are known to infiltrate the adult brain and fuse with cerebellar Purkinje cells. Histological observations that such heterotypic cell fusion events are substantially more frequent following cerebellar injury suggest they could have a role in the protection of mature brain neurons. To date, the possibility that cell fusion can preserve or restore the structure and function of adult brain neurons has not been directly addressed; indeed, though frequently suggested, the possibility of benefit has always been rather speculative. Here we report, for the first time, that fusion of a bone marrow-...
Source: Acta Neuropathologica - March 14, 2018 Category: Neurology Source Type: research

Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target
AbstractAdamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations inCTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. β-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular...
Source: Acta Neuropathologica - March 14, 2018 Category: Neurology Source Type: research

Interaction of amyloidogenic proteins in pancreatic β cells from subjects with synucleinopathies
We examined the pancreatic accumulation of phosphorylated α-synuclein and of the islet amyloid polypeptide precursor (IAPP), an a myloidogenic protein that plays an unknown role in diabetes mellitus, but that can promote α-synuclein amyloid deposition in vitro. Moreover, we performed proximity ligation assays to assess whether these two proteins interact in the pancreas of these subjects. Cytoplasmic phosphorylated α-synucle in deposits were found in the pancreatic β cells of 14 subjects with Parkinson’s disease (93%), in 11 subjects with Lewy body Dementia (85%) and in 8 subjects with incident...
Source: Acta Neuropathologica - March 13, 2018 Category: Neurology Source Type: research

The referee who agrees to review and never responds again (NERO): a series of 37 cases of an emerging entity
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 6, 2018 Category: Neurology Source Type: research

Fatal A β cerebral amyloid angiopathy 4 decades after a dural graft at the age of 2 years
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 5, 2018 Category: Neurology Source Type: research

Integrated neurodegenerative disease autopsy diagnosis
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 3, 2018 Category: Neurology Source Type: research

Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity
AbstractThe accumulation of misfolded α-synuclein (aSyn) and neuron loss define several neurodegenerative disorders including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). However, the precise relationship between pathology and neurotoxicity and why these processes disproportionately affect certain neuron subpopulatio ns are poorly understood. We show here that Math2-expressing neurons in the hippocampalCornu ammonis (CA), a region significantly affected by aSyn pathology in advanced PD and DLB, are highly susceptible to pathological seeding with pre-formed fibrils (PFFs), in contrast to dentate...
Source: Acta Neuropathologica - March 3, 2018 Category: Neurology Source Type: research

cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma , H3 K27M - mutant and diffuse astrocytoma/anaplastic astrocytoma , IDH - mutant
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 1, 2018 Category: Neurology Source Type: research

Mechanical disruption of the blood –brain barrier following experimental concussion
AbstractAlthough concussion is now recognized as a major health issue, its non-lethal nature has limited characterization of the underlying pathophysiology. In particular, potential neuropathological changes have typically been inferred from non-invasive techniques or post-mortem examinations of severe traumatic brain injury (TBI). Here, we used a swine model of head rotational acceleration based on human concussion to examine blood –brain barrier (BBB) integrity after injury in association with diffuse axonal injury and glial responses. We then determined the potential clinical relevance of the swine concussion find...
Source: Acta Neuropathologica - February 19, 2018 Category: Neurology Source Type: research

Diffuse gliomas classified by 1p/19q co-deletion, TERT promoter and IDH mutation status are associated with specific genetic risk loci
AbstractRecent genome-wide association studies of glioma have led to the discovery of single nucleotide polymorphisms (SNPs) at 25 loci influencing risk. Gliomas are heterogeneous, hence to investigate the relationship between risk SNPs and glioma subtype we analysed 1659 tumours profiled for IDH mutation,TERT promoter mutation and 1p/19q co-deletion. These data allowed definition of five molecular subgroups of glioma: triple-positive (IDH mutated, 1p/19q co-deletion,TERT promoter mutated);TERT-IDH (IDH mutated,TERT promoter mutated, 1p/19q-wild-type); IDH-only (IDH mutated, 1p/19q wild-type,TERT promoter wild-type); tripl...
Source: Acta Neuropathologica - February 19, 2018 Category: Neurology Source Type: research

Evidence of amyloid- β cerebral amyloid angiopathy transmission through neurosurgery
AbstractAmyloid- β (Aβ) is a peptide deposited in the brain parenchyma in Alzheimer’s disease and in cerebral blood vessels, causing cerebral amyloid angiopathy (CAA). Aβ pathology is transmissible experimentally in animals and through medical procedures in humans, such as contaminated growth hormone or dura ma ter transplantation in the context of iatrogenic prion disease. Here, we present four patients who underwent neurosurgical procedures during childhood or teenage years and presented with intracerebral haemorrhage approximately three decades later, caused by severe CAA. None of these patients car...
Source: Acta Neuropathologica - February 15, 2018 Category: Neurology Source Type: research

RNA versus protein toxicity in C9orf72 ALS/FTLD
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - February 15, 2018 Category: Neurology Source Type: research

Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis
In this study, we investigated pathological correlates of disease course in MS using the autopsy cohort of the Netherlands Brain Bank (NBB), containing 182 MS brain donors. Using a standardized autopsy procedure including systematic dissection from standard locations, 3188 tissue blocks containing 7562 MS lesions were dissected. Unbiased measurements of lesion load were made using the tissue from standard locations. Lesion demyelinating and innate inflammatory activity were visualized by immunohistochemistry for proteolipid protein and human leukocyte antigen. Lesions were classified into active, mixed active/inactive (als...
Source: Acta Neuropathologica - February 13, 2018 Category: Neurology Source Type: research

Deep sequencing of WNT-activated medulloblastomas reveals secondary SHH pathway activation
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - February 12, 2018 Category: Neurology Source Type: research

5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma
AbstractGliomas demonstrate epigenetic dysregulation exemplified by the Glioma CpG Island Methylator Phenotype (G-CIMP) seen inIDH1 mutant tumors. 5-Hydroxymethylcytosine (5hmC) is implicated in glioma pathogenesis; however, its role inIDH1 mutant gliomas is incompletely understood. To characterize 5hmC inIDH1 mutant gliomas further, we examine 5hmC in a  cohort ofIDH1 mutant and wild-type high-grade gliomas (HGG) using a quantitative locus-specific approach. Regions demonstrating high 5hmC abundance and differentially hydroxymethylated regions (DHMR) enrich for enhancers implicated in glioma pathogenesis. Among these...
Source: Acta Neuropathologica - February 10, 2018 Category: Neurology Source Type: research

Malignant rhabdoid tumors originating within and outside the central nervous system are clinically and molecularly heterogeneous
AbstractMultifocal synchronous or metachronous atypical teratoid rhabdoid tumors (ATRTs) and non-central nervous system malignant rhabdoid tumors (extra-CNS MRTs) are rare cancers. We reviewed the clinical and radiologic characteristics of affected patients seen at our institution. Genotyping and analysis of copy number abnormalities (CNAs) inSMARCB1 were performed in germline and tumor samples. Tumor samples underwent genome-wide DNA methylation and CNA analysis. The median age at diagnosis of 21 patients was 0.6  years. Two-thirds of ATRTs and extra-CNS MRTs were diagnosed synchronously. Although kidney tumors predo...
Source: Acta Neuropathologica - February 10, 2018 Category: Neurology Source Type: research

The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?
AbstractBrain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K+, Ca2+, and protein to optimise signalling and minimise neurotoxicity. At the same time, neuronal and astroglial waste must be promptly removed. The interstitial fluid (ISF) of the brain tissue and the cerebrospinal fluid (CSF) bathing the CNS are integral to this homeostasis and the idea of a glia-lymph or ‘glymphatic’ system for waste clearance from brain has developed over the last 5 years. This links bulk (convective) flow of CSF into brain along the outside of penetrating arteries, glia-mediate...
Source: Acta Neuropathologica - February 10, 2018 Category: Neurology Source Type: research

Multinodular and vacuolating neuronal tumor of the cerebrum is a clonal neoplasm defined by genetic alterations that activate the MAP kinase signaling pathway
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - February 10, 2018 Category: Neurology Source Type: research

NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease
AbstractA novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2  months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. In the affected children, neuropathology revealed increased angiomatosis-like leptomeningeal, cortical and superficial white matte...
Source: Acta Neuropathologica - February 8, 2018 Category: Neurology Source Type: research

Functional morphology of the blood –brain barrier in health and disease
In conclusion, a deep understanding of signals that maintain the healthy BBB and promote fluctuations in BBB permeability in disease states will be key to elucidate disease mechanisms and to identify potential targets for diagnostics and therapeutic modulation of the BBB. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - February 6, 2018 Category: Neurology Source Type: research

Activin receptors regulate the oligodendrocyte lineage in health and disease
AbstractThe most prevalent neurological disorders of myelin include perinatal brain injury leading to cerebral palsy in infants and multiple sclerosis in adults. Although these disorders have distinct etiologies, they share a common neuropathological feature of failed progenitor differentiation into myelin-producing oligodendrocytes and lack of myelin, for which there is an unmet clinical need. Here, we reveal that a molecular pathology common to both disorders is dysregulation of activin receptors and that activin receptor signaling is required for the majority of myelin generation in development and following injury. Usi...
Source: Acta Neuropathologica - February 3, 2018 Category: Neurology Source Type: research

Cluster: barriers of the central nervous system
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - February 3, 2018 Category: Neurology Source Type: research

Correction to: Paragangliomas arise through an autonomous vasculo-angio-neurogenic program inhibited by imatinib
AbstractThe given and family names of two co-authors were incorrect in the published article. The correct spelling should read as: Sampath Chandra Prasad and Vinagolu K Rajasekhar. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - February 1, 2018 Category: Neurology Source Type: research

Sense and antisense RNA are not toxic in Drosophila models of C9orf72 -associated ALS/FTD
AbstractA GGGGCC hexanucleotide repeat expansion in theC9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Neurodegeneration may occur via transcription of the repeats into inherently toxic repetitive sense and antisense RNA species, or via repeat-associated non-ATG initiated translation (RANT) of sense and antisense RNA into toxic dipeptide repeat proteins. We have previously demonstrated that regular interspersion of repeat RNA with stop codons prevents RANT (RNA-only models), allowing us to study the role of repeat RNA in isolation. Here we have created novel RNA-o...
Source: Acta Neuropathologica - January 29, 2018 Category: Neurology Source Type: research

cIMPACT-NOW update 1: Not Otherwise Specified (NOS) and Not Elsewhere Classified (NEC)
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 25, 2018 Category: Neurology Source Type: research

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease
AbstractThe barrier between the blood and the ventricular cerebrospinal fluid (CSF) is located at the choroid plexuses. At the interface between two circulating fluids, these richly vascularized veil-like structures display a peculiar morphology explained by their developmental origin, and fulfill several functions essential for CNS homeostasis. They form a neuroprotective barrier preventing the accumulation of noxious compounds into the CSF and brain, and secrete CSF, which participates in the maintenance of a stable CNS internal environment. The CSF circulation plays an important role in volume transmission within the de...
Source: Acta Neuropathologica - January 24, 2018 Category: Neurology Source Type: research

The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS
AbstractMeninges that surround the CNS consist of an outer fibrous sheet of dura mater (pachymeninx) that is also the inner periosteum of the skull. Underlying the dura are the arachnoid and pia mater (leptomeninges) that form the boundaries of the subarachnoid space. In this review we (1) examine the development of leptomeninges and their role as barriers and facilitators in the foetal CNS. There are two separate CSF systems during early foetal life, inner CSF in the ventricles and outer CSF in the subarachnoid space. As the foramina of Magendi and Luschka develop, one continuous CSF system evolves. Due to the lack of ara...
Source: Acta Neuropathologica - January 24, 2018 Category: Neurology Source Type: research

The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033
AbstractThe optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial. Overall survival ranges from 2 to over 15  years depending on molecular and clinical factors. Hence, risk-adjusted treatments are required for optimizing outcome and quality of life. We aim at identifying mechanisms and associated molecular markers predictive for benefit from radiotherapy (RT) or temozolomide (TMZ) in LGG patients treated in the randomized phase III trial EORTC 22033. As candidate biomarkers for these genotoxic treatments, we considered the DNA methylome of 410 DNA damage response (DDR) genes. We...
Source: Acta Neuropathologica - January 24, 2018 Category: Neurology Source Type: research

T lymphocytes facilitate brain metastasis of breast cancer by inducing Guanylate-Binding Protein 1 expression
AbstractThe discovery of genes and molecular pathways involved in the formation of brain metastasis would direct the development of therapeutic strategies to prevent this deadly complication of cancer. By comparing gene expression profiles of Estrogen Receptor negative (ER-) primary breast tumors between patients who developed metastasis to brain and to organs other than brain, we found that T lymphocytes promote the formation of brain metastases. To functionally test the ability of T cells to promote brain metastasis, we used an in vitro blood –brain barrier (BBB) model. By co-culturing T lymphocytes with breast can...
Source: Acta Neuropathologica - January 19, 2018 Category: Neurology Source Type: research

BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology
AbstractBACE1 is the rate-limiting protease in the production of synaptotoxic β-amyloid (Aβ) species and hence one of the prime drug targets for potential therapy of Alzheimer’s disease (AD). However, so far pharmacological BACE1 inhibition failed to rescue the cognitive decline in mild-to-moderate AD patients, which indicates that treatment at the symptomatic stage might be too late. In the current study, chronic in vivo two-photon microscopy was performed in a transgenic AD model to monitor the impact of pharmacological BACE1 inhibition on early β-amyloid pathology. The longitudinal approach allowed ...
Source: Acta Neuropathologica - January 11, 2018 Category: Neurology Source Type: research

Paragangliomas arise through an autonomous vasculo-angio-neurogenic program inhibited by imatinib
In conclusion, we explain the biphasic vasculoneural structure of paragangliomas and identify an early and pharmacologically actionable phase of paraganglioma organization. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 5, 2018 Category: Neurology Source Type: research

Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations
In this study, we show that inflammatory microglia produce extracellular vesicles (EVs) which are enriched in a set of miRNAs that regulate the expression of key synaptic proteins. Among them, miR-146a-5p, a microglia-specific miRNA not present in hippocampal neurons, controls the expression of presynaptic synaptotagmin1 (Syt1) and postsynaptic neuroligin1 (Nlg1), an adhesion protein which play a crucial role in dendritic spine formation and synaptic stability. Using aRenilla-based sensor, we provide formal proof that inflammatory EVs transfer their miR-146a-5p cargo to neuron. By western blot and immunofluorescence analys...
Source: Acta Neuropathologica - January 4, 2018 Category: Neurology Source Type: research

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism
AbstractThe exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGGGCC repeat expansion inC9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine –arginine and proline–arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these ...
Source: Acta Neuropathologica - January 4, 2018 Category: Neurology Source Type: research

Circumscribed/non-diffuse histology confers a better prognosis in H3K27M-mutant gliomas
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 4, 2018 Category: Neurology Source Type: research

Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration
AbstractParaneoplastic cerebellar degenerations with anti-Yo antibodies (Yo-PCD) are rare syndromes caused by an auto-immune response against neuronal antigens (Ags) expressed by tumor cells. However, the mechanisms responsible for such immune tolerance breakdown are unknown. We characterized 26 ovarian carcinomas associated with Yo-PCD for their tumor immune contexture and genetic status of the 2 onconeural Yo-Ags,CDR2 andCDR2L. Yo-PCD tumors differed from the 116 control tumors by more abundant T and B cells infiltration occasionally organized in tertiary lymphoid structures harboring CDR2L protein deposits. Immune cells...
Source: Acta Neuropathologica - January 3, 2018 Category: Neurology Source Type: research

Functional requirement of a wild-type allele for mutant IDH1 to suppress anchorage-independent growth through redox homeostasis
In this study, we demonstrate that heterozygousIDH1R132H suppresses but hemizygousIDH1R132H promotes anchorage-independent growth. Whereas genetic deletion of the wild-type allele inIDH1R132H-heterozygous cells resulted in a pronounced increase in neurosphere genesis, restoration ofIDH1 expression inIDH1R132H-hemizygous cells led to the contrary. Conversely, anchorage-independent growth was antagonistic to the mutant IDH1 function by inhibiting gene expression and 2-HG production. Furthermore, we identified that in contrast toIDH1R132H-hemizygous neurosphere,IDH1R132H-heterozygous cells maintained a low level of reducing p...
Source: Acta Neuropathologica - December 29, 2017 Category: Neurology Source Type: research

First confirmed case of chronic traumatic encephalopathy in a professional bull rider
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - December 28, 2017 Category: Neurology Source Type: research

Synapse loss in the prefrontal cortex is associated with cognitive decline in amyotrophic lateral sclerosis
AbstractIn addition to motor neurone degeneration, up to 50% of amyotrophic lateral sclerosis (ALS) patients present with cognitive decline. Understanding the neurobiological changes underlying these cognitive deficits is critical, as cognitively impaired patients exhibit a shorter survival time from symptom onset. Given the pathogenic role of synapse loss in other neurodegenerative diseases in which cognitive decline is apparent, such as Alzheimer ’s disease, we aimed to assess synaptic integrity in the ALS brain. Here, we have applied a unique combination of high-resolution imaging of post-mortem tissue with neurop...
Source: Acta Neuropathologica - December 22, 2017 Category: Neurology Source Type: research