TCF4 (E2-2) harbors tumor suppressive functions in SHH medulloblastoma
AbstractTheTCF4 gene encodes for the basic helix –loop–helix transcription factor 4 (TCF4), which plays an important role in the development of the central nervous system (CNS). Haploinsufficiency of TCF4 was found to cause Pitt-Hopkins syndrome (PTHS), a severe neurodevelopmental disorder. Recently, the screening of a large cohort of medullob lastoma (MB), a highly aggressive embryonal brain tumor, revealed almost 20% of adult patients with MB of the Sonic hedgehog (SHH) subtype carrying somaticTCF4 mutations. Interestingly, many of these mutations have previously been detected as germline mutations in patient...
Source: Acta Neuropathologica - March 4, 2019 Category: Neurology Source Type: research

Desmoplastic/nodular medulloblastomas (DNMB) and medulloblastomas with extensive nodularity (MBEN) disclose similar epigenetic signatures but different transcriptional profiles
AbstractDesmoplastic/nodular medulloblastomas (DNMB) and medulloblastomas with extensive nodularity (MBEN) were outlined in the current WHO classification of tumors of the nervous system as two distinct histological MB variants. However, they are often considered as cognate SHH MB entities, and it is a reason why some clinical MB trials do not separate the patients with DNMB or MBEN histology. In the current study, we performed an integrated DNA/RNA-based molecular analysis of 83 DNMB and 36 MBEN to assess the etiopathogenetic relationship between these SHH MB variants. Methylation profiling revealed “infant” a...
Source: Acta Neuropathologica - March 2, 2019 Category: Neurology Source Type: research

Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains
AbstractThe cytoplasmic accumulation of the nuclear TAR DNA-binding protein 43 (TDP-43) is a pathologic hallmark in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and other neurological disorders. However, most transgenic TDP-43 rodent models show predominant nuclear distribution of TDP-43 in the brain. By expressing mutant TDP-43 (M337V) in the brains of rhesus monkeys and mice, we verified that mutant TDP-43 is distributed in the cytoplasm of the monkey brain and that the majority of mutant TDP-43 remains in the nuclei of the mouse brain. The primate-specific caspase-4, but not mouse homologue caspase-...
Source: Acta Neuropathologica - February 27, 2019 Category: Neurology Source Type: research

Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology
AbstractDeposition of α-synuclein into Lewy bodies and Lewy neurites is the hallmark of Parkinson’s disease (PD). It is hypothesized that α-synuclein pathology spreads by a “prion-like” mechanism (i.e., by seeded aggregation or templated misfolding). Therefore, various extracellular α-synuclein conformers and/or posttranslational modifications may serve as biomarkers of disease or potential targets for novel interventions. To explore whether the antibody repertoires of PD patients contain anti-α-synuclein antibodies that can potentially be used as markers or immunotherapy, we inter...
Source: Acta Neuropathologica - February 25, 2019 Category: Neurology Source Type: research

α-Synuclein and astrocytes: tracing the pathways from homeostasis to neurodegeneration in Lewy body disease
Abstractα-Synuclein is a soluble protein that is present in abundance in the brain, though its normal function in the healthy brain is poorly defined. Intraneuronal inclusions of α-synuclein, commonly referred to as Lewy pathology, are pathological hallmarks of a spectrum of neurodegenerative disorders re ferred to as α-synucleinopathies. Though α-synuclein is expressed predominantly in neurons, α-synuclein aggregates in astrocytes are a common feature in these neurodegenerative diseases. How and why α-synuclein ends up in the astrocytes and the consequences of this dysfunctional proteos...
Source: Acta Neuropathologica - February 23, 2019 Category: Neurology Source Type: research

Demonstration of prion-like properties of mutant huntingtin fibrils in both in vitro and in vivo paradigms
AbstractIn recent years, evidence has accumulated to suggest that mutant huntingtin protein (mHTT) can spread into healthy tissue in a prion-like fashion. This theory, however, remains controversial. To fully address this concept and to understand the possible consequences of  mHTT spreading to Huntington’s disease pathology, we investigated the effects of exogenous human fibrillar mHTT (Q48) and huntingtin (HTT) (Q25) N-terminal fragments in three cellular models and three distinct animal paradigms. For in vitro experiments, human neuronal cells [induced pluripotent stem cell-derived GABA neurons (iGABA) and (S...
Source: Acta Neuropathologica - February 20, 2019 Category: Neurology Source Type: research

H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo
AbstractHistone H3 K27M mutation is the defining molecular feature of the devastating pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). The prevalence of histone H3 K27M mutations indicates a critical role in DIPGs, but the contribution of the mutation to disease pathogenesis remains unclear. We show that knockdown of this mutation in DIPG xenografts restores K27M-dependent loss of H3K27me3 and delays tumor growth. Comparisons of matched DIPG xenografts with and without K27M knockdown allowed identification of mutation-specific effects on the transcriptome and epigenome. The resulting transcriptional changes ...
Source: Acta Neuropathologica - February 15, 2019 Category: Neurology Source Type: research

Papillary glioneuronal tumor (PGNT) exhibits a characteristic methylation profile and fusions involving PRKCA
AbstractPapillary glioneuronal tumor (PGNT) is a WHO-defined brain tumor entity that poses a major diagnostic challenge. Recently,SLC44A1–PRKCA fusions have been described in PGNT. We subjected 28 brain tumors from different institutions histologically diagnosed as PGNT to molecular and morphological analysis. Array-based methylation analysis revealed that 17/28 tumors exhibited methylation profiles typical for other tumor entities, mostly dysembryoplastic neuroepithelial tumor and hemispheric pilocytic astrocytoma. Conversely, 11/28 tumors exhibited a unique profile, thus constituting a distinct methylation class PG...
Source: Acta Neuropathologica - February 13, 2019 Category: Neurology Source Type: research

Tau drives translational selectivity by interacting with ribosomal proteins
AbstractThere is a fundamental gap in understanding the consequences of tau –ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. First, we performed microarrays and nascent proteomics to measure changes in protein synthesis. Using regulatable rTg4510 tau transgenic mice, we determined that tau expression differentially shifts both the transc...
Source: Acta Neuropathologica - February 13, 2019 Category: Neurology Source Type: research

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD
AbstractFrontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated thatC9orf72 repeat expansions andGRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations inTBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disea...
Source: Acta Neuropathologica - February 9, 2019 Category: Neurology Source Type: research

Translational control in brain pathologies: biological significance and therapeutic opportunities
AbstractMessenger RNA (mRNA) translation is the terminal step in protein synthesis, providing a crucial regulatory checkpoint for this process. Translational control allows specific cell types to respond to rapid changes in the microenvironment or to serve specific functions. For example, neurons use mRNA transport to achieve local protein synthesis at significant distances from the nucleus, the site of RNA transcription. Altered expression or functions of the various components of the translational machinery have been linked to several pathologies in the central nervous system. In this review, we provide a brief overview ...
Source: Acta Neuropathologica - February 9, 2019 Category: Neurology Source Type: research

Frontal cortex and striatal cellular and molecular pathobiology in individuals with Down syndrome with and without dementia
AbstractAlthough, by age 40, individuals with Down syndrome (DS) develop amyloid- β (Aβ) plaques and tau-containing neurofibrillary tangles (NFTs) linked to cognitive impairment in Alzheimer’s disease (AD), not all people with DS develop dementia. Whether Aβ plaques and NFTs are associated with individuals with DS with (DSD +) and without dementia (DSD −) is under-inve stigated. Here, we applied quantitative immunocytochemistry and fluorescent procedures to characterize NFT pathology using antibodies specific for tau phosphorylation (pS422, AT8), truncation (TauC3, MN423), and confo...
Source: Acta Neuropathologica - February 7, 2019 Category: Neurology Source Type: research

Beta-amyloid pathology in human brain microvessel extracts from the parietal cortex: relation with cerebral amyloid angiopathy and Alzheimer ’s disease
In this study, we validated by Western, ELISA and immunofluorescence analyses a procedure to generate microvasculature-enriched fractions from frozen samples of human cerebral cortex. We then investigated Aβ and proteins involved in its clearance or production in microvessel extract s generated from the parietal cortex of 60 volunteers in the Religious Orders Study. Volunteers were categorized as AD (n = 38) or controls (n = 22) based on the ABC scoring method presented in the revised guidelines for the neuropathological diagnosis of AD. Higher ELISA-determined concentrations of vascul...
Source: Acta Neuropathologica - February 7, 2019 Category: Neurology Source Type: research

Retinal α-synuclein deposits in Parkinson’s disease patients and animal models
AbstractDespite decades of research, accurate diagnosis of Parkinson ’s disease remains a challenge, and disease-modifying treatments are still lacking. Research into the early (presymptomatic) stages of Parkinson’s disease and the discovery of novel biomarkers is of utmost importance to reduce this burden and to come to a more accurate diagnosis at the very onse t of the disease. Many have speculated that non-motor symptoms could provide a breakthrough in the quest for early biomarkers of Parkinson’s disease, including the visual disturbances and retinal abnormalities that are seen in the majority of Par...
Source: Acta Neuropathologica - February 5, 2019 Category: Neurology Source Type: research

Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation
AbstractMultiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease that is characterized by varying degrees of cerebellar dysfunction and Parkinsonism. The neuropathological hallmark of MSA is alpha-synuclein (AS)-positive glial cytoplasmic inclusions (GCIs). Although severe neuronal loss (NL) is also observed in MSA, neuronal inclusions (NIs) are rare compared to GCIs, such that the pathological mechanism of NL in MSA is unclear. GCIs and NIs are late-stage pathology features relative to AS oligomers and may not represent early pathological changes in MSA. To reveal the early pathology of MSA, it is ne...
Source: Acta Neuropathologica - February 5, 2019 Category: Neurology Source Type: research

Aggregated Tau activates NLRP3 –ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo
AbstractBrains of Alzheimer ’s disease patients are characterized by the presence of amyloid plaques and neurofibrillary tangles, both invariably associated with neuroinflammation. A crucial role for NLRP3–ASC inflammasome [NACHT, LRR and PYD domains-containing protein 3 (NLRP3)–Apoptosis-associated speck-like protein co ntaining a CARD (ASC)] in amyloid-beta (Aβ)-induced microgliosis and Aβ pathology has been unequivocally identified. Aβ aggregates activate NLRP3–ASC inflammasome (Halle et al. in Nat Immunol 9:857–865,2008) and conversely NLRP3 –ASC inflammasome activatio...
Source: Acta Neuropathologica - February 5, 2019 Category: Neurology Source Type: research

Disrupted neuronal trafficking in amyotrophic lateral sclerosis
AbstractAmyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disease caused by degeneration of motor neurons in the brain and spinal cord leading to muscle weakness. Median survival after symptom onset in patients is 3 –5 years and no effective therapies are available to treat or cure ALS. Therefore, further insight is needed into the molecular and cellular mechanisms that cause motor neuron degeneration and ALS. Different ALS disease mechanisms have been identified and recent evidence supports a prominent role for defects in intracellular transport. Several different ALS-causing g...
Source: Acta Neuropathologica - February 5, 2019 Category: Neurology Source Type: research

Prognostic significance of NAB2 –STAT6 fusion variants and TERT promotor mutations in solitary fibrous tumors/hemangiopericytomas of the CNS: not (yet) clear
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - February 2, 2019 Category: Neurology Source Type: research

Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer ’s disease
AbstractLate-onset Alzheimer ’s disease (AD) is a complex age-related neurodegenerative disorder that likely involves epigenetic factors. To better understand the epigenetic state associated with AD, we surveyed 420,852 DNA methylation (DNAm) sites from neurotypical controls (N = 49) and late-onset AD patients (N = 24) across four brain regions (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex and cerebellum). We identified 858 sites with robust differential methylation collectively annotated to 772 possible genes (FDR 
Source: Acta Neuropathologica - February 2, 2019 Category: Neurology Source Type: research

ACTN2 mutations cause “Multiple structured Core Disease” (MsCD)
AbstractThe identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novoACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Morphological and ultrastructural analyses of muscle biopsies revealed a distinctive pattern with the presence of muscle fibers containing small structured cores and jagged Z-line...
Source: Acta Neuropathologica - January 30, 2019 Category: Neurology Source Type: research

Multiple system atrophy prions retain strain specificity after serial propagation in two different Tg( SNCA *A53T) mouse lines
AbstractPreviously, we reported that intracranial inoculation of brain homogenate from multiple system atrophy (MSA) patient samples produces neurological disease in the transgenic (Tg) mouse model TgM83+/ −, which uses the prion protein promoter to express human α-synuclein harboring the A53T mutation found in familial Parkinson’s disease (PD). In our studies, we inoculated MSA and control patient samples into Tg mice constructed using a P1 artificial chromosome to express wild-type (WT), A30P, and A53T human α-synuclein on a mouse α-synuclein knockout background [Tg(SNCA+/+)Nbm, Tg(SNCA*A30P...
Source: Acta Neuropathologica - January 28, 2019 Category: Neurology Source Type: research

Antisense RNA foci are associated with nucleoli and TDP-43 mislocalization in C9orf72-ALS/FTD: a quantitative study
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 21, 2019 Category: Neurology Source Type: research

Microglial nodules provide the environment for pathogenic T cells in human encephalitis
AbstractMicroglia nodule formation is a common feature in inflammatory brain diseases mediated by T lymphocytes such as viral and paraneoplastic encephalitis, multiple sclerosis, and Rasmussen encephalitis (RE). However, its role has not been fully understood yet. We hypothesized that, in RE, microglial nodules provide an environment for the initiation of the later dominating T-cell cytotoxicity. In RE stage 0, small primary microglia nodules could be identified in the absence of T cells. These primary nodules showed inflammasome activation and endosomal Toll-like receptor upregulation. In stage 1, T cells migrate into the...
Source: Acta Neuropathologica - January 20, 2019 Category: Neurology Source Type: research

Primary intracranial sarcomas with DICER1 mutation often contain prominent eosinophilic cytoplasmic globules and can occur in the setting of neurofibromatosis type 1
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - January 16, 2019 Category: Neurology Source Type: research

Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains
AbstractTDP-43 is present in a high proportion of aged brains that do not meet criteria for frontotemporal lobar degeneration (FTLD). We determined whether there are distinct TDP-43 types in non-FTLD brains. From a cohort of 553 brains (Braak neurofibrillary tangle (NFT) stage 0 –VI), excluding cases meeting criteria for FTLD, we identified those that had screened positive for TDP-43. We reviewed 14 different brain regions in these TDP-43 positive cases and classified them into those with “typical” TDP-43 immunoreactive inclusions (TDP type-α), and those in which TDP -43 immunoreactivity was adjacen...
Source: Acta Neuropathologica - January 2, 2019 Category: Neurology Source Type: research

C9orf72 arginine-rich dipeptide proteins interact with ribosomal proteins in vivo to induce a toxic translational arrest that is rescued by eIF1A
AbstractA GGGGCC hexanucleotide repeat expansion within theC9orf72 gene is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Sense and antisense repeat-containing transcripts undergo repeat-associated non-AUG-initiated translation to produce five dipeptide proteins (DPRs). The polyGR and polyPR  DPRs are extremely toxic when expressed in Drosophila neurons. To determine the mechanism that mediates this toxicity, we purified DPRs from the Drosophila brain and used mass spectrometry to identify the in vivo neuronal DPR interactome. PolyGR and p...
Source: Acta Neuropathologica - January 2, 2019 Category: Neurology Source Type: research

Amyloid- β pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo
AbstractNeuropathological analysis in Alzheimer ’s disease (AD) and experimental evidence in transgenic models overexpressing frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) mutant tau suggest that amyloid-β pathology enhances the development of tau pathology. In this work, we analyzed this interaction independently of the overexpression of an FTDP-17 mutant tau, by analyzing tau pathology in wild-type (WT), 5xFAD, APP−/− and tau−/− mice after stereotaxic injection in the somatosensory cortex of short-length native human AD-PHF. Gallyas and phosphotau-positive ...
Source: Acta Neuropathologica - January 1, 2019 Category: Neurology Source Type: research

The impact of histopathology and NAB2 – STAT6 fusion subtype in classification and grading of meningeal solitary fibrous tumor/hemangiopericytoma
AbstractMeningeal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) is a rare tumor with propensity for recurrence and metastasis. Although multiple classification schemes have been proposed, optimal risk stratification remains unclear, and the prognostic impact of fusion status is uncertain. We compared the 2016 WHO CNS tumor grading scheme (CNS-G), a three-tier system based on histopathologic phenotype and mitotic count, to the 2013 WHO soft-tissue counterpart (ST-G), a two-tier system based on mitotic count alone, in a cohort of 133 patients [59 female, 74 male; mean age 54  years (range 20–87)] with meni...
Source: Acta Neuropathologica - December 24, 2018 Category: Neurology Source Type: research

Microglial cell loss after ischemic stroke favors brain neutrophil accumulation
AbstractStroke attracts neutrophils to the injured brain tissue where they can damage the integrity of the blood –brain barrier and exacerbate the lesion. However, the mechanisms involved in neutrophil transmigration, location and accumulation in the ischemic brain are not fully elucidated. Neutrophils can reach the perivascular spaces of brain vessels after crossing the endothelial cell layer and endothelia l basal lamina of post-capillary venules, or migrating from the leptomeninges following pial vessel extravasation and/or a suggested translocation from the skull bone marrow. Based on previous observati...
Source: Acta Neuropathologica - December 22, 2018 Category: Neurology Source Type: research

Seeding selectivity and ultrasensitive detection of tau aggregate conformers of Alzheimer disease
AbstractAlzheimer disease (AD) and chronic traumatic encephalopathy (CTE) involve the abnormal accumulation in the brain of filaments composed of both three-repeat (3R) and four-repeat (4R) (3R/4R) tau isoforms. To probe the molecular basis for AD ’s tau filament propagation and to improve detection of tau aggregates as potential biomarkers, we have exploited the seeded polymerization growth mechanism of tau filaments to develop a highly selective and ultrasensitive cell-free tau seed amplification assay optimized for AD (AD real-time quaki ng-induced conversion or AD RT-QuIC). The reaction is based on the abili...
Source: Acta Neuropathologica - December 20, 2018 Category: Neurology Source Type: research

Circulating AQP4-specific auto-antibodies alone can induce neuromyelitis optica spectrum disorder in the rat
AbstractIt is well established that the binding of pathogenic aquaporin-4 (AQP4)-specific autoantibodies to astrocytes may initiate a cascade of events culminating in the destruction of these cells and in the formation of large tissue-destructive lesions typical for patients with neuromyelitis optica spectrum disorders (NMOSD). To date, not a single experimental study has shown that the systemic presence of the antibody alone can induce any damage to the central nervous system (CNS), while pathological studies on brains of NMOSD patients suggested that there might be ways for antibody entry and subsequent tissue damage. He...
Source: Acta Neuropathologica - December 18, 2018 Category: Neurology Source Type: research

Novel tau fragments in cerebrospinal fluid: relation to tangle pathology and cognitive decline in Alzheimer ’s disease
AbstractTau is an axonal microtubule-binding protein. Tau pathology in brain and increased tau concentration in the cerebrospinal fluid (CSF) are hallmarks of Alzheimer ’s disease (AD). Most of tau in CSF is present as fragments. We immunoprecipitated tau from CSF and identified several endogenous peptides ending at amino acid (aa) 123 or 224 using high-resolution mass spectrometry. We raised neo-epitope-specific antibodies against tau fragments specifically endi ng at aa 123 and 224, respectively. With these antibodies, we performed immunohistochemistry on brain tissue and designed immunoassays measuring N-123, N-22...
Source: Acta Neuropathologica - December 13, 2018 Category: Neurology Source Type: research

The complexity of neuroinflammation consequent to traumatic brain injury: from research evidence to potential treatments
AbstractThis review recounts the definitions and research evidence supporting the multifaceted roles of neuroinflammation in the injured brain following trauma. We summarise the literature fluctuating from the protective and detrimental properties that cytokines, leukocytes and glial cells play in the acute and chronic stages of TBI, including the intrinsic factors that influence cytokine responses and microglial functions relative to genetics, sex, and age. We elaborate on the pros and cons that cytokines, chemokines, and microglia play in brain repair, specifically neurogenesis, and how such conflicting roles may be harn...
Source: Acta Neuropathologica - December 7, 2018 Category: Neurology Source Type: research

Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology
AbstractTAR DNA-binding protein 43 (TDP-43) aggregation is the most common pathological hallmark in frontotemporal dementia (FTD) and characterizes nearly all patients with motor neuron disease (MND). The earliest stages of TDP-43 pathobiology are not well-characterized, and whether neurodegeneration results from TDP-43 loss-of-function or aggregation remains unclear. In the behavioral variant of FTD (bvFTD), patients undergo selective dropout of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices. Here, we examined TDP-43 pathobiology within these vulnerable neurons in t...
Source: Acta Neuropathologica - December 3, 2018 Category: Neurology Source Type: research

Enteric alpha-synuclein expression is increased in Crohn ’s disease
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 30, 2018 Category: Neurology Source Type: research

Current state of Alzheimer ’s fluid biomarkers
AbstractAlzheimer ’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical tria ls. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific conte xt of ...
Source: Acta Neuropathologica - November 28, 2018 Category: Neurology Source Type: research

Renewed assessment of the risk of emergent advanced cell therapies to transmit neuroproteinopathies
AbstractThe inadvertent transmission of long incubating, untreatable and fatal neurodegenerative prionopathies, notably iatrogenic Creutzfeldt –Jakob disease, following transplantation of cadaver-derived corneas, pituitary growth, hormones and dura mater, constitutes a historical precedent which has underpinned the application of precautionary principles to modern day advanced cell therapies. To date these have been reflected by geograph ic or medical history risk-based deferral of tissue donors. Emergent understanding of other prion-like proteinopathies, their potential independence from prions as a transmissible ag...
Source: Acta Neuropathologica - November 27, 2018 Category: Neurology Source Type: research

Post-stroke inflammation —target or tool for therapy?
AbstractInflammation is currently considered a prime target for the development of new stroke therapies. In the acute phase of ischemic stroke, microglia are activated and then circulating immune cells invade the peri-infarct and infarct core. Resident and infiltrating cells together orchestrate the post-stroke inflammatory response, communicating with each other and the ischemic neurons, through soluble and membrane-bound signaling molecules, including cytokines. Inflammation can be both detrimental and beneficial at particular stages after a stroke. While it can contribute to expansion of the infarct, it is also responsi...
Source: Acta Neuropathologica - November 27, 2018 Category: Neurology Source Type: research

The role of de novo mutations in adult-onset neurodegenerative disorders
AbstractThe genetic underpinnings of the most common adult-onset neurodegenerative disorders (AOND) are complex in majority of the cases. In some families, however, the disease can be inherited in a Mendelian fashion as an autosomal-dominant trait. Next to that, patients carrying mutations in the same disease genes have been reported despite a negative family history. Although challenging to demonstrate due to the late onset of the disease in most cases, the occurrence of de novo mutations can explain this sporadic presentation, as demonstrated for severe neurodevelopmental disorders. Exome or genome sequencing of patient ...
Source: Acta Neuropathologica - November 26, 2018 Category: Neurology Source Type: research

Inflammation in ALS/FTD pathogenesis
AbstractAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that overlap in their clinical presentation, pathology and genetics, and likely represent a spectrum of one underlying disease. In ALS/FTD patients, neuroinflammation characterized by innate immune responses of tissue-resident glial cells is uniformly present on end-stage pathology, and human imaging studies and rodent models support that neuroinflammation begins early in disease pathogenesis. Additionally, changes in circulating immune cell populations and cytokines are found in ALS/FTD patients, and there is evide...
Source: Acta Neuropathologica - November 21, 2018 Category: Neurology Source Type: research

TIA1 regulates the generation and response to toxic tau oligomers
AbstractRNA binding proteins (RBPs) are strongly linked to the pathophysiology of motor neuron diseases. Recent studies show that RBPs, such as TIA1, also contribute to the pathophysiology of tauopathy. RBPs co-localize with tau pathology, and reduction of TIA1 protects against tau-mediated neurodegeneration. The mechanism through which TIA1 reduction protects against tauopathy, and whether TIA1 modulates the propagation of tau, are unknown. Previous studies indicate that the protective effect of TIA1 depletion correlates with both the reduction of oligomeric tau and the reduction of pathological TIA1 positive tau inclusio...
Source: Acta Neuropathologica - November 21, 2018 Category: Neurology Source Type: research

Chromosome arm 1q gain is an adverse prognostic factor in localized and diffuse leptomeningeal glioneuronal tumors with BRAF gene fusion and 1p deletion
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 21, 2018 Category: Neurology Source Type: research

Molecular profiling of tumors of the brainstem by sequencing of CSF-derived circulating tumor DNA
AbstractBrainstem gliomas are molecularly heterogeneous diseases, many of which are difficult to safely surgically resect and have limited treatment options due to their eloquent location. These constraints pose challenges to biopsy, which limits the use of routine molecular profiling and identification of personalized therapies. Here, we explored the potential of sequencing of circulating tumor DNA (ctDNA) isolated from the cerebrospinal fluid (CSF) of brainstem glioma patients as a less invasive approach for tumor molecular profiling. CSF was obtained from patients either intraoperatively (91.2%, 52/57), from ventricular...
Source: Acta Neuropathologica - November 20, 2018 Category: Neurology Source Type: research

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology
AbstractInsoluble aggregates containing TDP-43 are widely observed in the diseased brain, and defined as “TDP-43 pathology” in a spectrum of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease and ALS with frontotemporal dementia. Here we report that Betz cells of patients with TDP-43 pathology display a distinct set of intracellular defects especially at the site of nuclear membrane, mitochondria and endoplasmic reticulum (ER). Numerous TDP-43 mouse models have been generated to discern the cellular and molecular basis of the disease, but mechanisms of neuronal vu...
Source: Acta Neuropathologica - November 19, 2018 Category: Neurology Source Type: research

ETMR-like infantile cerebellar embryonal tumors in the extended morphologic spectrum of DICER1 -related tumors
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 16, 2018 Category: Neurology Source Type: research

Differential impact of pure glyphosate and glyphosate-based herbicide in a model of peripheral nervous system myelination
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 16, 2018 Category: Neurology Source Type: research

“When sex influences the brain: implications for Alzheimer disease”
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - November 15, 2018 Category: Neurology Source Type: research

The metalloprotease ADAMTS4 generates N-truncated A β4–x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease
AbstractBrain accumulation and aggregation of amyloid- β (Aβ) peptides is a critical step in the pathogenesis of Alzheimer’s disease (AD). Full-length Aβ peptides (mainly Aβ1–40 and Aβ1–42) are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. However, studies of autopsy brain sa mples from AD patients have demonstrated that a large fraction of insoluble Aβ peptides are truncated at the N-terminus, with Aβ4–x peptides being particularly abundant. Aβ4–x peptides are highly aggregatio...
Source: Acta Neuropathologica - November 13, 2018 Category: Neurology Source Type: research

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer ’s disease
AbstractCardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer ’s disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated  tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs)jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist ...
Source: Acta Neuropathologica - November 9, 2018 Category: Neurology Source Type: research

Inner ear pathologies impair sodium-regulated ion transport in Meniere ’s disease
AbstractMeniere ’s disease (MD), a syndromal inner ear disease, is commonly associated with a pathological accumulation of endolymphatic fluid in the inner ear, termed “idiopathic” endolymphatic hydrops (iEH). Although numerous precipitating/exacerbating factors have been proposed for MD, its etiology remains elusive. Here, using immunohistochemistry and in situ protein–protein interaction detection assays, we demonstrate mineralocorticoid-controlled sodium transport mechanisms in the epithelium of the extraosseous portion of the endolymphatic sac (eES) in the murine and human inner ears. Histologic...
Source: Acta Neuropathologica - November 2, 2018 Category: Neurology Source Type: research