Log in to search using one of your social media accounts:

 

Patterns and severity of vascular amyloid in Alzheimer ’s disease associated with duplications and missense mutations in APP gene, Down syndrome and sporadic Alzheimer’s disease
In this study, we have compared the severity of amyloid plaque formation and cerebral amyloid angiopathy (CAA), and the subtype pattern of CAA pathology itself, betweenAPP genetic causes of AD (APPdup,APP mutations), older individuals with Down syndrome (DS) showing the pathology of Alzheimer ’s disease (AD) and individuals with sporadic (early and late onset) AD (sEOAD and sLOAD, respectively). The aim of this was to elucidate important group differences and to provide mechanistic insights related to clinical and neuropathological phenotypes. Since lipid and cholesterol metabolism is implicated in AD as well as vasc...
Source: Acta Neuropathologica - May 16, 2018 Category: Neurology Source Type: research

Novel FGFR2 - INA fusion identified in two low-grade mixed neuronal-glial tumors drives oncogenesis via MAPK and PI3K/mTOR pathway activation
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 16, 2018 Category: Neurology Source Type: research

Molecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features
AbstractDiffuse leptomeningeal glioneuronal tumors (DLGNT) represent rare CNS neoplasms which have been included in the 2016 update of the WHO classification. The wide spectrum of histopathological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have afforded insight into key genetic alterations occurring in multiple types of brain tumors and provide unbiased, complementary tools to improve diagnostic accuracy. Through genome-wide DNA methylation screening of  >  25,000 tumors, we discovered a molecularly dis...
Source: Acta Neuropathologica - May 15, 2018 Category: Neurology Source Type: research

K27/G34 versus K28/G35 in histone H3-mutant gliomas: A note of caution
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 15, 2018 Category: Neurology Source Type: research

Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways
Conclusions drawn from the present study are that tracers injected into the CSF enter and leave the brain along separate periarterial bas ement membrane pathways. The exit route is along IPAD pathways in which Aβ accumulates in cerebral amyloid angiopathy (CAA) in Alzheimer’s disease. Results from this study suggest that CSF may be a suitable route for delivery of therapies for neurological diseases, including CAA. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 12, 2018 Category: Neurology Source Type: research

Tau seeding activity begins in the transentorhinal/entorhinal regions and anticipates phospho-tau pathology in Alzheimer ’s disease and PART
AbstractAlzheimer ’s disease (AD) is characterized by accumulation of tau neurofibrillary tangles (NFTs) and, according to the prion model, transcellular propagation of pathological “seeds” may underlie its progression. Staging of NFT pathology with phospho-tau antibody is useful to classify AD and primary age- related tauopathy (PART) cases. The locus coeruleus (LC) shows the earliest phospho-tau signal, whereas other studies suggest that pathology begins in the transentorhinal/entorhinal cortices (TRE/EC). The relationship of tau seeding activity, phospho-tau pathology, and progression of neurodegenerat...
Source: Acta Neuropathologica - May 11, 2018 Category: Neurology Source Type: research

Aging alters the immunological response to ischemic stroke
AbstractThe peripheral immune system plays a critical role in aging and in the response to brain injury. Emerging data suggest inflammatory responses are exacerbated in older animals following ischemic stroke; however, our understanding of these age-related changes is poor. In this work, we demonstrate marked differences in the composition of circulating and infiltrating leukocytes recruited to the ischemic brain of old male mice after stroke compared to young male mice. Blood neutrophilia and neutrophil invasion into the brain were increased in aged animals. Relative to infiltrating monocyte populations, brain-invading ne...
Source: Acta Neuropathologica - May 11, 2018 Category: Neurology Source Type: research

Collagen VI is required for the structural and functional integrity of the neuromuscular junction
AbstractThe synaptic cleft of the neuromuscular junction (NMJ) consists of a highly specialized extracellular matrix (ECM) involved in synapse maturation, in the juxtaposition of pre- to post-synaptic areas, and in ensuring proper synaptic transmission. Key components of synaptic ECM, such as collagen IV, perlecan and biglycan, are binding partners of one of the most abundant ECM protein of skeletal muscle, collagen VI (ColVI), previously never linked to NMJ. Here, we demonstrate that ColVI is itself a component of this specialized ECM and that it is required for the structural and functional integrity of NMJs. In vivo, Co...
Source: Acta Neuropathologica - May 11, 2018 Category: Neurology Source Type: research

Gadolinium-based contrast agents induce gadolinium deposits in cerebral vessel walls, while the neuropil is not affected: an autopsy study
AbstractRecent studies showed gadolinium depositions following serial administrations of gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging examinations in various parts of the brain with the dentate nucleus (DN) being most affected. Even though no clinical correlates of the deposits are known yet, an intensive debate developed if this might be harmful. The aim of the current study was to specify the gadolinium distribution in brain tissue of patients who received serial injections of GBCAs in the low- µm range and to explore any potential pathological tissue changes caused by gadolinium deposits...
Source: Acta Neuropathologica - May 10, 2018 Category: Neurology Source Type: research

The lysosomal function of progranulin,  a guardian against neurodegeneration
AbstractProgranulin (PGRN), encoded by theGRN gene in humans, is a secreted growth factor implicated in a multitude of processes ranging from regulation of inflammation to wound healing and tumorigenesis. The clinical importance of PGRN became especially evident in 2006, when heterozygous mutations in theGRN gene, resulting in haploinsufficiency, were found to be one of the main causes of frontotemporal lobar degeneration (FTLD). FTLD is a clinically heterogenous disease that results in the progressive atrophy of the frontal and temporal lobes of the brain. Despite significant research, the exact function of PGRN and its m...
Source: Acta Neuropathologica - May 9, 2018 Category: Neurology Source Type: research

DNA methylation-based reclassification of olfactory neuroblastoma
In conclusion, we demonstrate that institutionally diagnosed ONB are a heterogeneous group of tumors. Expression of cytokeratin, chromogranin A, the mutational status ofIDH2 as well as DNA methylation patterns may greatly aid in the precise classification of ONB. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 5, 2018 Category: Neurology Source Type: research

CADASIL brain vessels show a HTRA1 loss-of-function profile
AbstractCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and a phenotypically similar recessive condition (CARASIL) have emerged as important genetic model diseases for studying the molecular pathomechanisms of cerebral small vessel disease (SVD). CADASIL, the most frequent and intensely explored monogenic SVD, is characterized by a severe pathology in the cerebral vasculature including the mutation-induced aggregation of the Notch3 extracellular domain (Notch3ECD) and the formation of protein deposits of insufficiently determined composition in vessel walls. To identify ...
Source: Acta Neuropathologica - May 3, 2018 Category: Neurology Source Type: research

Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients
AbstractAmyotrophic lateral sclerosis type 4 (ALS4) is a rare, early-onset, autosomal dominant form of ALS, characterized by slow disease progression and sparing of respiratory musculature. Dominant, gain-of-function mutations in the senataxin gene (SETX) cause ALS4, but the mechanistic basis for motor neuron toxicity is unknown. SETX is a RNA-binding protein with a highly conserved helicase domain, but does not possess a low-complexity domain, making it unique among ALS-linked disease proteins. We derived ALS4 mouse models by expressing two different senataxin gene mutations (R2136H and L389S) via transgenesis and knock-i...
Source: Acta Neuropathologica - May 3, 2018 Category: Neurology Source Type: research

The relationship between neurosurgical instruments and disease transmission: Society of British Neurological Surgeons perspective
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 3, 2018 Category: Neurology Source Type: research

Somatic mutations in neurons during aging and neurodegeneration
AbstractThe nervous system is composed of a large variety of neurons with a diverse array of morphological and functional properties. This heterogeneity is essential for the construction and maintenance of a distinct set of neural networks with unique characteristics. Accumulating evidence now indicates that neurons do not only differ at a functional level, but also at the genomic level. These genomic discrepancies seem to be the result of somatic mutations that emerge in nervous tissue during development and aging. Ultimately, these mutations bring about a genetically heterogeneous population of neurons, a phenomenon that...
Source: Acta Neuropathologica - April 28, 2018 Category: Neurology Source Type: research

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology
AbstractNeurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer ’s disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodege nerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnos...
Source: Acta Neuropathologica - April 26, 2018 Category: Neurology Source Type: research

Evidence for altered dendritic spine compartmentalization in Alzheimer ’s disease and functional effects in a mouse model
AbstractAlzheimer ’s disease (AD) is associated with a progressive loss of synapses and neurons. Studies in animal models indicate that morphological alterations of dendritic spines precede synapse loss, increasing the proportion of large and short (“stubby”) spines. Whether similar alterations occur in human p atients, and what their functional consequences could be, is not known. We analyzed biopsies from AD patients and APP x presenilin 1 knock-in mice that were previously shown to present a loss of pyramidal neurons in the CA1 area of the hippocampus. We observed that the proportion of stubby spines a...
Source: Acta Neuropathologica - April 25, 2018 Category: Neurology Source Type: research

Diffusible, highly bioactive oligomers represent a critical minority of soluble A β in Alzheimer’s disease brain
AbstractSignificant data suggest that soluble A β oligomers play an important role in Alzheimer’s disease (AD), but there is great confusion over what exactly constitutes an Aβ oligomer and which oligomers are toxic. Most studies have utilized synthetic Aβ peptides, but the relevance of these test tube experiments to the conditions that prev ail in AD is uncertain. A few groups have studied Aβ extracted from human brain, but they employed vigorous tissue homogenization which is likely to release insoluble Aβ that was sequestered in plaques during life. Several studies have found such extracts...
Source: Acta Neuropathologica - April 23, 2018 Category: Neurology Source Type: research

Novel, improved grading system(s) for IDH-mutant astrocytic gliomas
AbstractAccording to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AIIIDHmut), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIIIIDHmut), and WHO grade IV glioblastoma, IDH-mutant (GBMIDHmut). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognosti...
Source: Acta Neuropathologica - April 23, 2018 Category: Neurology Source Type: research

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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