The importance of nerve microenvironment for schwannoma development
Abstract Schwannomas are predominantly benign nerve sheath neoplasms caused by Nf2 gene inactivation. Presently, treatment options are mainly limited to surgical tumor resection due to the lack of effective pharmacological drugs. Although the mechanistic understanding of Nf2 gene function has advanced, it has so far been primarily restricted to Schwann cell-intrinsic events. Extracellular cues determining Schwann cell behavior with regard to schwannoma development remain unknown. Here we show pro-tumourigenic microenvironmental effects on Schwann cells where an altered axonal microenvironment in cooperation with i...
Source: Acta Neuropathologica - May 28, 2016 Category: Neurology Source Type: research

Human-to-mouse prion-like propagation of mutant huntingtin protein
Abstract Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder of the central nervous system (CNS) that is defined by a CAG expansion in exon 1 of the huntingtin gene leading to the production of mutant huntingtin (mHtt). To date, the disease pathophysiology has been thought to be primarily driven by cell-autonomous mechanisms, but, here, we demonstrate that fibroblasts derived from HD patients carrying either 72, 143 and 180 CAG repeats as well as induced pluripotent stem cells (iPSCs) also characterized by 143 CAG repeats can transmit protein aggregates to genetically unrelated and ...
Source: Acta Neuropathologica - May 24, 2016 Category: Neurology Source Type: research

Full ablation of C9orf72 in mice causes immune system-related pathology and neoplastic events but no motor neuron defects
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 20, 2016 Category: Neurology Source Type: research

Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease
Abstract Cerebral amyloid angiopathy (CAA) often coexists with Alzheimer’s disease (AD). APOE4 is a strong genetic risk factor for both AD and CAA. Sex-dependent differences have been shown in AD as well as in cerebrovascular diseases. Therefore, we examined the effects of APOE4, sex, and pathological components on CAA in AD subjects. A total of 428 autopsied brain samples from pathologically confirmed AD cases were analyzed. CAA severity was histologically scored in inferior parietal, middle frontal, motor, superior temporal and visual cortexes. In addition, subgroups with severe CAA (n = 60) or w...
Source: Acta Neuropathologica - May 14, 2016 Category: Neurology Source Type: research

Comparative interactomics analysis of different ALS-associated proteins identifies converging molecular pathways
Abstract Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment available. An increasing number of genetic causes of ALS are being identified, but how these genetic defects lead to motor neuron degeneration and to which extent they affect common cellular pathways remains incompletely understood. To address these questions, we performed an interactomic analysis to identify binding partners of wild-type (WT) and ALS-associated mutant versions of ATXN2, C9orf72, FUS, OPTN, TDP-43 and UBQLN2 in neuronal cells. This analysis identified several known but also many novel bin...
Source: Acta Neuropathologica - May 10, 2016 Category: Neurology Source Type: research

IDH1 mutation can be present in diffuse astrocytomas and giant cell glioblastomas of young children under 10 years of age
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 9, 2016 Category: Neurology Source Type: research

Erratum to: Antibody-mediated neutralization of myelin-associated EphrinB3 accelerates CNS remyelination
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 9, 2016 Category: Neurology Source Type: research

The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary
Abstract The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, in...
Source: Acta Neuropathologica - May 9, 2016 Category: Neurology Source Type: research

Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology
We present a pathological loop in which the accumulation of C99 is both the effect and causality of impaired lysosomal-autophagic function. The deleterious effect of C99 was found to be linked to its aggregation within EAL-vesicle membranes leading to disrupted lysosomal proteolysis and autophagic impairment. This effect was Aβ independent and was even exacerbated when γ-secretase was pharmacologically inhibited. No effect was observed in inhibitor-treated wild-type animals suggesting that lysosomal dysfunction was indeed directly linked to C99 accumulation. In some brain areas, strong C99 expression also led to...
Source: Acta Neuropathologica - April 30, 2016 Category: Neurology Source Type: research

Gene expression, methylation and neuropathology correlations at progressive supranuclear palsy risk loci
Abstract To determine the effects of single nucleotide polymorphisms (SNPs) identified in a genome-wide association study of progressive supranuclear palsy (PSP), we tested their association with brain gene expression, CpG methylation and neuropathology. In 175 autopsied PSP subjects, we performed associations between seven PSP risk variants and temporal cortex levels of 20 genes in-cis, within ±100 kb. Methylation measures were collected using reduced representation bisulfite sequencing in 43 PSP brains. To determine whether SNP/expression associations are due to epigenetic modifications, CpG methylat...
Source: Acta Neuropathologica - April 26, 2016 Category: Neurology Source Type: research

Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 11, 2016 Category: Neurology Source Type: research

Granulovacuolar degeneration: a neurodegenerative change that accompanies tau pathology
Abstract Granule-containing vacuoles in the cytoplasm of hippocampal neurons are a neuropathological feature of Alzheimer’s disease. Granulovacuolar degeneration (GVD) is not disease-specific and can be observed in other neurodegenerative disorders and even in the brains of non-demented elderly people. However, several studies have reported much higher numbers of neurons undergoing GVD in the hippocampus of Alzheimer’s disease cases. Recently, a neuropathological staging system for GVD has facilitated neuropathological assessment. Data obtained by electron microscopy and immunolabeling suggest that GVD...
Source: Acta Neuropathologica - April 9, 2016 Category: Neurology Source Type: research

Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer’s disease
Abstract Vascular dementia (VaD) is recognised as a neurocognitive disorder, which is explained by numerous vascular causes in the general absence of other pathologies. The heterogeneity of cerebrovascular disease makes it challenging to elucidate the neuropathological substrates and mechanisms of VaD as well as vascular cognitive impairment (VCI). Consensus and accurate diagnosis of VaD relies on wide-ranging clinical, neuropsychometric and neuroimaging measures with subsequent pathological confirmation. Pathological diagnosis of suspected clinical VaD requires adequate postmortem brain sampling and rigorous asse...
Source: Acta Neuropathologica - April 9, 2016 Category: Neurology Source Type: research

Cerebrovascular pathology: the dark side of neurodegeneration
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 9, 2016 Category: Neurology Source Type: research

α-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy
In conclusion, this study defines the α-synuclein-induced myelination deficit as a novel and crucial pathomechanism in MSA. Importantly, the reversible nature of this oligodendrocytic dysfunction opens a novel avenue for an intervention in MSA. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 8, 2016 Category: Neurology Source Type: research

Risk stratification of childhood medulloblastoma in the molecular era: the current consensus
Abstract Historical risk stratification criteria for medulloblastoma rely primarily on clinicopathological variables pertaining to age, presence of metastases, extent of resection, histological subtypes and in some instances individual genetic aberrations such as MYC and MYCN amplification. In 2010, an international panel of experts established consensus defining four main subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) delineated by transcriptional profiling. This has led to the current generation of biomarker-driven clinical trials assigning WNT tumors to a favorable prognosis group in addition to c...
Source: Acta Neuropathologica - April 4, 2016 Category: Neurology Source Type: research

Brain imaging of neurovascular dysfunction in Alzheimer’s disease
Abstract Neurovascular dysfunction, including blood–brain barrier (BBB) breakdown and cerebral blood flow (CBF) dysregulation and reduction, are increasingly recognized to contribute to Alzheimer’s disease (AD). The spatial and temporal relationships between different pathophysiological events during preclinical stages of AD, including cerebrovascular dysfunction and pathology, amyloid and tau pathology, and brain structural and functional changes remain, however, still unclear. Recent advances in neuroimaging techniques, i.e., magnetic resonance imaging (MRI) and positron emission tomography (PET), of...
Source: Acta Neuropathologica - April 1, 2016 Category: Neurology Source Type: research

Histone H3 genotyping refines clinico-radiological diagnostic and prognostic criteria in DIPG
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - April 1, 2016 Category: Neurology Source Type: research

A comprehensive study of the genetic impact of rare variants in SORL1 in European early-onset Alzheimer’s disease
Abstract The sortilin-related receptor 1 (SORL1) gene has been associated with increased risk for Alzheimer’s disease (AD). Rare genetic variants in the SORL1 gene have also been implicated in autosomal dominant early-onset AD (EOAD). Here we report a large-scale investigation of the contribution of genetic variability in SORL1 to EOAD in a European EOAD cohort. We performed massive parallel amplicon-based re-sequencing of the full coding region of SORL1 in 1255 EOAD patients and 1938 age- and origin-matched control individuals in the context of the European Early-Onset Dementia (EOD) consortium, originating...
Source: Acta Neuropathologica - March 30, 2016 Category: Neurology Source Type: research

NG2, a common denominator for neuroinflammation, blood–brain barrier alteration, and oligodendrocyte precursor response in EAE, plays a role in dendritic cell activation
Abstract In adult CNS, nerve/glial-antigen 2 (NG2) is expressed by oligodendrocyte progenitor cells (OPCs) and is an early marker of pericyte activation in pathological conditions. NG2 could, therefore, play a role in experimental autoimmune encephalomyelitis (EAE), a disease associated with increased blood–brain barrier (BBB) permeability, inflammatory infiltrates, and CNS damage. We induced EAE in NG2 knock-out (NG2KO) mice and used laser confocal microscopy immunofluorescence and morphometry to dissect the effect of NG2 KO on CNS pathology. NG2KO mice developed milder EAE than their wild-type (WT) counter...
Source: Acta Neuropathologica - March 30, 2016 Category: Neurology Source Type: research

Commentary on “Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes”
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 30, 2016 Category: Neurology Source Type: research

Myelin-reactive antibodies initiate T cell-mediated CNS autoimmune disease by opsonization of endogenous antigen
Abstract In the pathogenesis of central nervous system (CNS) demyelinating disorders, antigen-specific B cells are implicated to act as potent antigen-presenting cells (APC), eliciting waves of inflammatory CNS infiltration. Here, we provide the first evidence that CNS-reactive antibodies (Ab) are similarly capable of initiating an encephalitogenic immune response by targeting endogenous CNS antigen to otherwise inert myeloid APC. In a transgenic mouse model, constitutive production of Ab against myelin oligodendrocyte glycoprotein (MOG) was sufficient to promote spontaneous experimental autoimmune encephalomyelit...
Source: Acta Neuropathologica - March 29, 2016 Category: Neurology Source Type: research

Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling
Abstract In neurons, microtubules form a dense array within axons, and the stability and function of this microtubule network is modulated by neurofilaments. Accumulation of neurofilaments has been observed in several forms of neurodegenerative diseases, but the mechanisms how elevated neurofilament levels destabilize axons are unknown so far. Here, we show that increased neurofilament expression in motor nerves of pmn mutant mice, a model of motoneuron disease, causes disturbed microtubule dynamics. The disease is caused by a point mutation in the tubulin-specific chaperone E (Tbce) gene, leading to an exchange o...
Source: Acta Neuropathologica - March 28, 2016 Category: Neurology Source Type: research

CSF biomarkers associated with disease heterogeneity in early Parkinson’s disease: the Parkinson’s Progression Markers Initiative study
Abstract The development of biomarkers to predict the progression of Parkinson’s disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson’s Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aβ1-42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline,...
Source: Acta Neuropathologica - March 28, 2016 Category: Neurology Source Type: research

Dura mater is a potential source of Aβ seeds
Abstract Deposition of amyloid-β (Aβ) in the brain parenchyma and vessels is one of the hallmarks of Alzheimer disease (AD). Recent observations of Aβ deposition in iatrogenic Creutzfeldt-Jakob disease (iCJD) after dural grafting or treatment with pituitary extracts raised concerns whether Aβ is capable of transmitting disease as seen in prion diseases by the disease-associated prion protein. To address this issue, we re-sampled and re-evaluated archival material, including the grafted dura mater of two cases with iCJD (28 and 33-years-old) without mutations in the AβPP, PSEN1 and PSEN2 ge...
Source: Acta Neuropathologica - March 25, 2016 Category: Neurology Source Type: research

Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer’s disease
Abstract Alzheimer’s disease (AD) is characterized by amyloid plaques composed of the β-amyloid (Aβ) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the β-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aβ generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Aβ may disrupt microtubules, which we hypothesize have a criti...
Source: Acta Neuropathologica - March 18, 2016 Category: Neurology Source Type: research

Neuropathological signs of inflammation correlate with mitochondrial DNA deletions in mesial temporal lobe epilepsy
Abstract Accumulation of mitochondrial DNA (mtDNA) deletions has been proposed to be responsible for the presence of respiratory-deficient neurons in several CNS diseases. Deletions are thought to originate from double-strand breaks due to attack of reactive oxygen species (ROS) of putative inflammatory origin. In epileptogenesis, emerging evidence points to chronic inflammation as an important feature. Here we aimed to analyze the potential association of inflammation and mtDNA deletions in the hippocampal tissue of patients with mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS). Hippocampal and...
Source: Acta Neuropathologica - March 18, 2016 Category: Neurology Source Type: research

Tau pathology-dependent remodelling of cerebral arteries precedes Alzheimer’s disease-related microvascular cerebral amyloid angiopathy
Abstract Alzheimer’s disease (AD) is characterised by pathologic cerebrovascular remodelling. Whether this occurs already before disease onset, as may be indicated by early Braak tau-related cerebral hypoperfusion and blood–brain barrier (BBB) impairment found in previous studies, remains unknown. Therefore, we systematically quantified Braak tau stage- and cerebral amyloid angiopathy (CAA)-dependent alterations in the alpha-smooth muscle actin (α-SMA), collagen, and elastin content of leptomeningeal arterioles, small arteries, and medium-sized arteries surrounding the gyrus frontalis medialis (G...
Source: Acta Neuropathologica - March 17, 2016 Category: Neurology Source Type: research

Vascular basement membranes as pathways for the passage of fluid into and out of the brain
The objective of this study is to differentiate the cerebral vascular basement membrane pathways by which fluid passes out of the brain from the pathway by which CSF enters the brain. Experiment 1: 0.5 µl of soluble biotinylated or fluorescent Aβ, or 1 µl 15 nm gold nanoparticles was injected into the mouse hippocampus and their distributions determined at 5 min by transmission electron microscopy. Aβ was distributed within the extracellular spaces of the hippocampus and within basement membranes of capillaries and tunica media of arteries. Nanoparticles did not enter capillary basement memb...
Source: Acta Neuropathologica - March 14, 2016 Category: Neurology Source Type: research

Glycolytic-to-oxidative fiber-type switch and mTOR signaling activation are early-onset features of SBMA muscle modified by high-fat diet
Abstract Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The mechanism by which expansion of polyglutamine in AR causes muscle atrophy is unknown. Here, we investigated pathological pathways underlying muscle atrophy in SBMA knock-in mice and patients. We show that glycolytic muscles were more severely affected than oxidative muscles in SBMA knock-in mice. Muscle atrophy was associated with early-onset, progressive glycolytic-to-oxidative fiber-type switch. Whole genome microarray and untargeted lipidomic analyses ...
Source: Acta Neuropathologica - March 12, 2016 Category: Neurology Source Type: research

The role of glial-specific Kir4.1 in normal and pathological states of the CNS
Abstract Kir4.1 is an inwardly rectifying K+ channel expressed exclusively in glial cells in the central nervous system. In glia, Kir4.1 is implicated in several functions including extracellular K+ homeostasis, maintenance of astrocyte resting membrane potential, cell volume regulation, and facilitation of glutamate uptake. Knockout of Kir4.1 in rodent models leads to severe neurological deficits, including ataxia, seizures, sensorineural deafness, and early postnatal death. Accumulating evidence indicates that Kir4.1 plays an integral role in the central nervous system, prompting many laboratories to study the p...
Source: Acta Neuropathologica - March 9, 2016 Category: Neurology Source Type: research

Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy
Abstract Germ cell tumors constitute a heterogeneous group that displays a broad spectrum of morphology. They often arise in testes; however, extragonadal occurrence, in particular brain, is not uncommon, and whether they share a common pathogenesis is unknown. We performed whole exome sequencing in 41 pairs of central nervous system germ cell tumors (CNS GCTs) of various histology and their matched normal tissues. We then performed targeted sequencing of 41 selected genes in a total of 124 CNS GCTs, 65 testicular germ cell tumors (tGCTs) and 8 metastatic GCTs to the CNS. The results showed that mutually exclusive...
Source: Acta Neuropathologica - March 8, 2016 Category: Neurology Source Type: research

Acknowledgement to referees
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - March 8, 2016 Category: Neurology Source Type: research

ECEL1 mutation implicates impaired axonal arborization of motor nerves in the pathogenesis of distal arthrogryposis
Abstract The membrane-bound metalloprotease endothelin-converting enzyme-like 1 (ECEL1) has been newly identified as a causal gene of a specific type of distal arthrogryposis (DA). In contrast to most causal genes of DA, ECEL1 is predominantly expressed in neuronal cells, suggesting a unique neurogenic pathogenesis in a subset of DA patients with ECEL1 mutation. The present study analyzed developmental motor innervation and neuromuscular junction formation in limbs of the rodent homologue damage-induced neuronal endopeptidase (DINE)-deficient mouse. Whole-mount immunostaining was performed in DINE-deficient limbs ...
Source: Acta Neuropathologica - March 7, 2016 Category: Neurology Source Type: research

Angiopoietin-2-induced blood–brain barrier compromise and increased stroke size are rescued by VE-PTP-dependent restoration of Tie2 signaling
Abstract The homeostasis of the central nervous system is maintained by the blood–brain barrier (BBB). Angiopoietins (Ang-1/Ang-2) act as antagonizing molecules to regulate angiogenesis, vascular stability, vascular permeability and lymphatic integrity. However, the precise role of angiopoietin/Tie2 signaling at the BBB remains unclear. We investigated the influence of Ang-2 on BBB permeability in wild-type and gain-of-function (GOF) mice and demonstrated an increase in permeability by Ang-2, both in vitro and in vivo. Expression analysis of brain endothelial cells from Ang-2 GOF mice showed a downregulation...
Source: Acta Neuropathologica - March 1, 2016 Category: Neurology Source Type: research

Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors
Abstract Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exo...
Source: Acta Neuropathologica - February 26, 2016 Category: Neurology Source Type: research

Peripheral monocytes are functionally altered and invade the CNS in ALS patients
Abstract Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease affecting primarily the upper and lower motor neurons. A common feature of all ALS cases is a well-characterized neuroinflammatory reaction within the central nervous system (CNS). However, much less is known about the role of the peripheral immune system and its interplay with CNS resident immune cells in motor neuron degeneration. Here, we characterized peripheral monocytes in both temporal and spatial dimensions of ALS pathogenesis. We found the circulating monocytes to be deregulated in ALS regarding subtype con...
Source: Acta Neuropathologica - February 24, 2016 Category: Neurology Source Type: research

Phosphorylation of the amyloid β-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity
Abstract Aggregation and toxicity of the amyloid β-peptide (Aβ) are considered as critical events in the initiation and progression of Alzheimer’s disease (AD). Recent evidence indicated that soluble oligomeric Aβ assemblies exert pronounced toxicity, rather than larger fibrillar aggregates that deposit in the forms of extracellular plaques. While some rare mutations in the Aβ sequence that cause early-onset AD promote the oligomerization, molecular mechanisms that induce the formation or stabilization of oligomers of the wild-type Aβ remain unclear. Here, we identified an Aβ va...
Source: Acta Neuropathologica - February 22, 2016 Category: Neurology Source Type: research

Monomethylated and unmethylated FUS exhibit increased binding to Transportin and distinguish FTLD-FUS from ALS- FUS
Abstract Deposition of the nuclear DNA/RNA-binding protein Fused in sarcoma (FUS) in cytosolic inclusions is a common hallmark of some cases of frontotemporal lobar degeneration (FTLD-FUS) and amyotrophic lateral sclerosis (ALS-FUS). Whether both diseases also share common pathological mechanisms is currently unclear. Based on our previous finding that FUS deposits are hypomethylated in FTLD-FUS but not in ALS-FUS, we have now investigated whether genetic or pharmacological inactivation of Protein arginine methyltransferase 1 (PRMT1) activity results in unmethylated FUS or in alternatively methylated forms of FUS....
Source: Acta Neuropathologica - February 19, 2016 Category: Neurology Source Type: research

The role of APOE in cerebrovascular dysfunction
Abstract The ε4 allele of the apolipoprotein E gene (APOE4) is associated with cognitive decline during aging, is the greatest genetic risk factor for Alzheimer’s disease and has links to other neurodegenerative conditions that affect cognition. Increasing evidence indicates that APOE genotypes differentially modulate the function of the cerebrovasculature (CV), with apoE and its receptors expressed by different cell types at the CV interface (astrocytes, pericytes, smooth muscle cells, brain endothelial cells). However, research on the role of apoE in CV dysfunction has not advanced as quickly as ot...
Source: Acta Neuropathologica - February 16, 2016 Category: Neurology Source Type: research

Resident microglia rather than peripheral macrophages promote vascularization in brain tumors and are source of alternative pro-angiogenic factors
Abstract Myeloid cells are an essential part of the glioblastoma microenvironment. However, in brain tumors the function of these immune cells is not sufficiently clarified. In our study, we investigated differential pro-angiogenic activities of resident microglia and peripheral macrophages and their impact on glioma vascularization and progression. Our data demonstrate stable accumulation of microglia/macrophages during tumor growth. These cells often interact with tumor blood vessels correlating with vascular remodeling. Here, we identified resident microglia as well as peripheral macrophages as part of the per...
Source: Acta Neuropathologica - February 14, 2016 Category: Neurology Source Type: research

Pathological α-synuclein distribution in subjects with coincident Alzheimer’s and Lewy body pathology
Abstract We investigated the distribution patterns of Lewy body-related pathology (LRP) and the effect of coincident Alzheimer disease (AD) pathology using a data-driven clustering approach that identified groups with different LRP pathology distributions without any diagnostic or researcher’s input in two cohorts including: Parkinson disease patients without (PD, n = 141) and with AD (PD-AD, n = 80), dementia with Lewy bodies subjects without AD (DLB, n = 13) and demented subjects with AD and LRP pathology (Dem-AD-LB, n = 308). The Dem-AD-LB group presented two LRP p...
Source: Acta Neuropathologica - February 14, 2016 Category: Neurology Source Type: research

Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke
Abstract Cell-based therapies are emerging as new promising treatments in stroke. However, their functional mechanism and therapeutic potential during early infarct maturation has so far received little attention. Here, we asked if cell-based delivery of the interleukin-1 receptor antagonist (IL-1Ra), a known neuroprotectant in stroke, can promote neuroprotection, by modulating the detrimental inflammatory response in the tissue at risk. We show by the use of IL-1Ra-overexpressing and IL-1Ra-deficient mice that IL-1Ra is neuroprotective in stroke. Characterization of the cellular and spatiotemporal production of ...
Source: Acta Neuropathologica - February 9, 2016 Category: Neurology Source Type: research

Methylation-based classification of benign and malignant peripheral nerve sheath tumors
Abstract The vast majority of peripheral nerve sheath tumors derive from the Schwann cell lineage and comprise diverse histological entities ranging from benign schwannomas and neurofibromas to high-grade malignant peripheral nerve sheath tumors (MPNST), each with several variants. There is increasing evidence for methylation profiling being able to delineate biologically relevant tumor groups even within the same cellular lineage. Therefore, we used DNA methylation arrays for methylome- and chromosomal profile-based characterization of 171 peripheral nerve sheath tumors. We analyzed 28 conventional high-grade...
Source: Acta Neuropathologica - February 8, 2016 Category: Neurology Source Type: research

Proaggregant nuclear factor(s) trigger rapid formation of α-synuclein aggregates in apoptotic neurons
In this study we demonstrate that filamentous αS aggregates form in neurons in response to apoptosis induced by staurosporine or other toxins-6-hydroxy-dopamine and 1-methyl-4-phenylpyridinium (MPP+). Interaction between αS and proaggregant nuclear factor(s) is associated with disruption of nuclear envelope integrity. Knocking down a key nuclear envelop constituent protein, lamin B1, enhances αS aggregation. Moreover, in vitro and in vivo experimental models demonstrate that aggregates released upon cell breakdown can be taken up by surrounding cells. Accordingly, we suggest that at least some αS ag...
Source: Acta Neuropathologica - February 2, 2016 Category: Neurology Source Type: research

Human spinal autografts of olfactory epithelial stem cells recapitulate donor site histology, maintaining proliferative and differentiation capacity many years after transplantation
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - February 2, 2016 Category: Neurology Source Type: research

Axonal transport and secretion of fibrillar forms of α-synuclein, Aβ42 peptide and HTTExon 1
Abstract Accruing evidence suggests that prion-like behavior of fibrillar forms of α-synuclein, β-amyloid peptide and mutant huntingtin are responsible for the spread of the lesions that characterize Parkinson disease, Alzheimer disease and Huntington disease, respectively. It is unknown whether these distinct protein assemblies are transported within and between neurons by similar or distinct mechanisms. It is also unclear if neuronal death or injury is required for neuron-to-neuron transfer. To address these questions, we used mouse primary cortical neurons grown in microfluidic devices to measure the...
Source: Acta Neuropathologica - January 28, 2016 Category: Neurology Source Type: research

Updated TDP-43 in Alzheimer’s disease staging scheme
In this study, we update the TDP-43 in Alzheimer’s disease staging scheme by assessing the topography of TDP-43 in 193 cases of Alzheimer’s disease, in 14 different brain regions (eight previously described plus six newly reported) and use conditional probability to model the spread of TDP-43 across the 14 brain regions. We show that in addition to the eight original regions we previously reported [amygdala, entorhinal cortex, subiculum, dentate gyrus of the hippocampus, occipitotemporal cortex, inferior temporal cortex, middle frontal cortex and basal ganglia (putamen/globus pallidum)] that TDP-43 is also depo...
Source: Acta Neuropathologica - January 25, 2016 Category: Neurology Source Type: research

Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF , FGFR1 , and MYB mutations occur at high frequency and align with morphology
In this study, we have used massively parallel sequencing and various targeted molecular genetic approaches to study alterations in 91 LGNTs, mostly from children but including young adult patients. These tumors comprise dysembryoplastic neuroepithelial tumors (DNETs; n = 22), diffuse oligodendroglial tumors (d-OTs; n = 20), diffuse astrocytomas (DAs; n = 17), angiocentric gliomas (n = 15), and gangliogliomas (n = 17). Most LGNTs (84 %) analyzed by whole-genome sequencing (WGS) were characterized by a single driver genetic alteration. Alterations of FGFR1 occurred freq...
Source: Acta Neuropathologica - January 25, 2016 Category: Neurology Source Type: research

Genomic characterization of primary central nervous system lymphoma
Abstract Primary central nervous system lymphoma (PCNSL) is a rare malignancy confined to the central nervous system (CNS), and majority of PCNSL is pathologically classified as diffuse large B-cell lymphoma (DLBCL). We have now performed whole-exome sequencing for 41 tumor tissues of DLBCL-type PCNSL and paired normal specimens and also RNA-sequencing for 30 tumors, revealing a very high frequency of nonsynonymous somatic mutations in PIM1 (100 %), BTG2 (92.7 %), and MYD88 (85.4 %). Many genes in the NF-κB pathway are concurrently mutated within the same tumors. Further, focal deletion or som...
Source: Acta Neuropathologica - January 12, 2016 Category: Neurology Source Type: research