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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

Neuronal complex I deficiency occurs throughout the Parkinson ’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage
AbstractMitochondrial complex I deficiency occurs in the substantia nigra of individuals with Parkinson ’s disease. It is generally believed that this phenomenon is caused by accumulating mitochondrial DNA damage in neurons and that it contributes to the process of neurodegeneration. We hypothesized that if these theories are correct, complex I deficiency should extend beyond the substantia nigra to other affected brain regions in Parkinson’s disease and correlate tightly with neuronal mitochondrial DNA damage. To test our hypothesis, we employed a combination of semiquantitative immunohistochemical analyses, W...
Source: Acta Neuropathologica - December 21, 2017 Category: Neurology Source Type: research

Distinguishing features of microglia- and monocyte-derived macrophages after stroke
AbstractAfter stroke, macrophages in the ischemic brain may be derived from either resident microglia or infiltrating monocytes. Using bone marrow (BM)-chimerism and dual-reporter transgenic fate mapping, we here set out to delimit the responses of either cell type to mild brain ischemia in a mouse model of 30  min transient middle cerebral artery occlusion (MCAo). A discriminatory analysis of gene expression at 7 days post-event yielded 472 transcripts predominantly or exclusively expressed in blood-derived macrophages as well as 970 transcripts for microglia. The differentially regulated genes were fu rther col...
Source: Acta Neuropathologica - December 16, 2017 Category: Neurology Source Type: research

Spread of aggregates after olfactory bulb injection of α-synuclein fibrils is associated with early neuronal loss and is reduced long term
AbstractParkinson ’s disease is characterized by degeneration of substantia nigra dopamine neurons and by intraneuronal aggregates, primarily composed of misfolded α-synuclein. The α-synuclein aggregates in Parkinson’s patients are suggested to first appear in the olfactory bulb and enteric nerves and then prop agate, following a stereotypic pattern, via neural pathways to numerous regions across the brain. We recently demonstrated that after injection of either mouse or human α-synuclein fibrils into the olfactory bulb of wild-type mice, α-synuclein fibrils recruited endogenous α-...
Source: Acta Neuropathologica - December 5, 2017 Category: Neurology Source Type: research

Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis
AbstractHexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (C9 ALS). The main hypothesized pathogenic mechanisms are C9orf72 haploinsufficiency and/or toxicity from one or more of bi-directionally transcribed repeat RNAs and their dipeptide repeat proteins (DPRs) poly-GP, poly-GA, poly-GR, poly-PR and poly-PA. Recently, nuclear import and/or export defects especially caused by arginine-containing poly-GR or poly-PR have been proposed as significant contributors to pathogenesis based on disease models. We quantitatively studied and compared DPRs, nuclear pore prote...
Source: Acta Neuropathologica - December 1, 2017 Category: Neurology Source Type: research

Polygenic hazard score: an enrichment marker for Alzheimer ’s associated amyloid and tau deposition
AbstractThere is an urgent need for identifying nondemented individuals at the highest risk of progressing to Alzheimer ’s disease (AD) dementia. Here, we evaluated whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo cerebrospinal fluid (CSF) or positron emission tomography (PET) biomarkers of amyloid, and CSF tau pathology to prospectively predict cognitive and clinical d ecline in 347 cognitive normal (CN; baseline age range = 59.7–90.1, 98.85% white) and 599 mild cognitively impaired (MCI; baseline age range = 54.4–91.4, 98.83% white) indiv...
Source: Acta Neuropathologica - November 24, 2017 Category: Neurology Source Type: research

Neuropathology of iatrogenic Creutzfeldt –Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology
AbstractAbeta deposits and tau pathology were investigated in 24 French patients that died from iatrogenic Creutzfeldt –Jakob disease after exposure to cadaver-derived human growth hormone (c-hGH) in the 1980s. Abeta deposits were found only in one case that had experienced one of the longest incubation periods. Three cases had also intracellular tau accumulation. The analysis of 24 batches of c-hGH, produced betw een 1974 and 1988, demonstrated for the first time the presence of Abeta and tau contaminants in c-hGH (in 17 and 6 batches, respectively). The incubation of prion disease was shorter in the French patients...
Source: Acta Neuropathologica - November 22, 2017 Category: Neurology Source Type: research

The function of the cellular prion protein in health and disease
AbstractThe essential role of the cellular prion protein (PrPC) in prion disorders such as Creutzfeldt –Jakob disease is well documented. Moreover, evidence is accumulating that PrPC may act as a receptor for protein aggregates and transduce neurotoxic signals in more common neurodegenerative disorders, such as Alzheimer ’s disease. Although the pathological roles of PrPC have been thoroughly characterized, a general consensus on its physiological function within the brain has not yet been established. Knockout studies in various organisms, ranging from zebrafish to mice, have implicated PrPC in a diverse range...
Source: Acta Neuropathologica - November 18, 2017 Category: Neurology Source Type: research

Parkinson ’s disease: experimental models and reality
AbstractParkinson ’s disease (PD) is a chronic, progressive movement disorder of adults and the second most common neurodegenerative disease after Alzheimer’s disease. Neuropathologic diagnosis of PD requires moderate-to-marked neuronal loss in the ventrolateral substantia nigra pars compacta and α-synuclein (α S) Lewy body pathology. Nigrostriatal dopaminergic neurodegeneration correlates with the Parkinsonian motor features, but involvement of other peripheral and central nervous system regions leads to a wide range of non-motor features. Nigrostriatal dopaminergic neurodegeneration is shared with...
Source: Acta Neuropathologica - November 18, 2017 Category: Neurology Source Type: research

Changes in chromatin state reveal ARNT2 at a node of a tumorigenic transcription factor signature driving glioblastoma cell aggressiveness
AbstractAlthough a growing body of evidence indicates that phenotypic plasticity exhibited by glioblastoma cells plays a central role in tumor development and post-therapy recurrence, the master drivers of their aggressiveness remain elusive. Here we mapped the changes in active (H3K4me3) and repressive (H3K27me3) histone modifications accompanying the repression of glioblastoma stem-like cells tumorigenicity. Genes with changing histone marks delineated a network of transcription factors related to cancerous behavior, stem state, and neural development, highlighting a previously unsuspected association between repression ...
Source: Acta Neuropathologica - November 17, 2017 Category: Neurology Source Type: research

Co-occurrence of mixed proteinopathies in late-stage Huntington ’s disease
AbstractAccumulating evidence highlights the potential role of mixed proteinopathies (i.e., abnormal protein aggregation) in the development of clinical manifestations of neurodegenerative diseases (NDD). Huntington ’s disease (HD) is an inherited NDD caused by autosomal-dominant expanded CAG trinucleotide repeat mutation in the gene coding for Huntingtin (Htt). Previous studies have suggested the coexistence of phosphorylated-Tau, α-synuclein (α-Syn) and TAR DNA-binding protein 43 (TDP-43) inclusions in HD . However, definite evidence that HD pathology in humans can be accompanied by other proteinopathie...
Source: Acta Neuropathologica - November 13, 2017 Category: Neurology Source Type: research

Artificial intelligence in neurodegenerative disease research: use of IBM Watson to identify additional RNA-binding proteins altered in amyotrophic lateral sclerosis
AbstractAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no effective treatments. Numerous RNA-binding proteins (RBPs) have been shown to be altered in ALS, with mutations in 11 RBPs causing familial forms of the disease, and 6 more RBPs showing abnormal expression/distribution in ALS albeit without any known mutations. RBP dysregulation is widely accepted as a contributing factor in ALS pathobiology. There are at least 1542 RBPs in the human genome; therefore, other unidentified RBPs may also be linked to the pathogenesis of ALS. We used IBM Watson® to sieve through all RBPs in the g...
Source: Acta Neuropathologica - November 13, 2017 Category: Neurology Source Type: research

Regional levels of physiological α-synuclein are directly associated with Lewy body pathology
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 13, 2017 Category: Neurology Source Type: research

Uncoupling N -acetylaspartate from brain pathology: implications for Canavan disease gene therapy
AbstractN-Acetylaspartate (NAA) is the second most abundant organic metabolite in the brain, but its physiological significance remains enigmatic. Toxic NAA accumulation appears to be the key factor for neurological decline in Canavan disease —a fatal neurometabolic disorder caused by deficiency in the NAA-degrading enzyme aspartoacylase. To date clinical outcome of gene replacement therapy for this spongiform leukodystrophy has not met expectations. To identify the target tissue and cells for maximum anticipated treatment benefit, we employed comprehensive phenotyping of novel mouse models to assess cell type-specif...
Source: Acta Neuropathologica - November 7, 2017 Category: Neurology Source Type: research

Cofactors influence the biological properties of infectious recombinant prions
AbstractPrion diseases are caused by a misfolding of the cellular prion protein (PrP) to a pathogenic isoform named PrPSc. Prions exist as strains, which are characterized by specific pathological and biochemical properties likely encoded in the three-dimensional structure of PrPSc. However, whether cofactors determine these different PrPSc conformations and how this relates to their specific biological properties is largely unknown. To understand how different cofactors modulate prion strain generation and selection, Protein Misfolding Cyclic Amplification was used to create a diversity of infectious recombinant prion str...
Source: Acta Neuropathologica - November 1, 2017 Category: Neurology Source Type: research

Diffuse midline gliomas with subclonal H3F3A K27M mutation and mosaic H3.3 K27M mutant protein expression
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 23, 2017 Category: Neurology Source Type: research

Multiple system atrophy: experimental models and reality
AbstractMultiple system atrophy (MSA) is a rapidly progressing fatal synucleinopathy of the aging population characterized by parkinsonism, dysautonomia, and in some cases ataxia. Unlike other synucleinopathies, in this disorder the synaptic protein, α-synuclein (α-syn), predominantly accumulates in oligodendroglial cells (and to some extent in neurons), leading to maturation defects of oligodendrocytes, demyelination, and neurodegeneration. The mechanisms through which α-syn deposits occur in oligodendrocytes and neurons in MSA are not compl etely clear. While some studies suggest that α-syn might ...
Source: Acta Neuropathologica - October 20, 2017 Category: Neurology Source Type: research

Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours
AbstractGlioneuronal tumours are an important cause of treatment-resistant epilepsy. Subtypes of tumour are often poorly discriminated by histological features and may be difficult to diagnose due to a lack of robust diagnostic tools. This is illustrated by marked variability in the reported frequencies across different epilepsy surgical series. To address this, we used DNA methylation arrays and RNA sequencing to assay the methylation and expression profiles within a large cohort of glioneuronal tumours. By adopting a class discovery approach, we were able to identify two distinct groups of glioneuronal tumour, which only...
Source: Acta Neuropathologica - October 20, 2017 Category: Neurology Source Type: research

Phenotyping cognitive impairment in dialysis patients: insights from experimental mouse models
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 20, 2017 Category: Neurology Source Type: research

Accumulation of dysfunctional SOD1 protein in Parkinson ’s disease is not associated with mutations in the SOD1 gene
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 19, 2017 Category: Neurology Source Type: research

Molecular and clinical heterogeneity of adult diffuse low-grade IDH wild-type gliomas: assessment of TERT promoter mutation and chromosome 7 and 10 copy number status allows superior prognostic stratification
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 19, 2017 Category: Neurology Source Type: research

Does Parkinson ’s disease start in the gut?
AbstractParkinson ’s disease (PD) is pathologically characterized by the presence of intraneuronal inclusions, termed Lewy bodies and Lewy neurites, whose main component is alpha-synuclein. Based on the topographic distribution of Lewy bodies and neurites established after autopsy from PD patients, Braak and cowork ers hypothesized that PD pathology may start in the gastrointestinal tract then spread through the vagus nerve to the brain. This hypothesis has been reinforced by the discovery that alpha-synuclein may be capable of spreading transcellularly, thereby providing a mechanistic basis for Braak’s hypo th...
Source: Acta Neuropathologica - October 16, 2017 Category: Neurology Source Type: research

CASQ1 mutations impair calsequestrin polymerization and cause tubular aggregate myopathy
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 16, 2017 Category: Neurology Source Type: research

Rare ADAR and RNASEH2B variants and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis
AbstractIn search of novel germline alterations predisposing to tumors, in particular to gliomas, we studied a family with two brothers affected by anaplastic gliomas, and their father and paternal great-uncle diagnosed with prostate carcinoma. In this family, whole-exome sequencing yielded rare, simultaneously heterozygous variants in the Aicardi –Goutières syndrome (AGS) genesADAR andRNASEH2B co-segregating with the tumor phenotype. AGS is a genetically induced inflammatory disease particularly of the brain, which has not been associated with a consistently increased cancer risk to date. By targeted sequenci...
Source: Acta Neuropathologica - October 13, 2017 Category: Neurology Source Type: research

DNA-methylation profiling discloses significant advantages over NanoString method for molecular classification of medulloblastoma
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - October 13, 2017 Category: Neurology Source Type: research