Targeting pericytes for therapeutic approaches to neurological disorders
AbstractMany  central nervous system diseases currently lack effective treatment and are often associated with defects in microvascular function, including a failure to match the energy supplied by the blood to the energy used on neuronal computation, or a breakdown of the blood–brain barrier. Pericytes, an u nder-studied cell type located on capillaries, are of crucial importance in regulating diverse microvascular functions, such as angiogenesis, the blood–brain barrier, capillary blood flow and the movement of immune cells into the brain. They also form part of the “glial” scar isolating dam...
Source: Acta Neuropathologica - August 10, 2018 Category: Neurology Source Type: research

Correction to: DNA methylation-based reclassification of olfactory neuroblastoma
In the original publication, the second name of the twentieth author was incorrect. It should read as ‘Miguel Sáinz-Jaspeado’. The original publication of the article has been updated to reflect the change. This correction was authored by Ulrich Schüller on behalf of all authors of the original publication. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 9, 2018 Category: Neurology Source Type: research

Different patterns of hippocampal tau pathology in Alzheimer ’s disease and PART
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - August 7, 2018 Category: Neurology Source Type: research

Physiological clearance of tau in the periphery and its therapeutic potential for tauopathies
AbstractAccumulation of pathological tau is the hallmark of Alzheimer ’s disease and other tauopathies and is closely correlated with cognitive decline. Clearance of pathological tau from the brain is a major therapeutic strategy for tauopathies. The physiological capacity of the periphery to clear brain-derived tau and its therapeutic potential remain largely unkno wn. Here, we found that cisterna magna injected131I-labelled synthetic tau dynamically effluxed from the brain and was mainly cleared from the kidney, blood, and liver in mice; we also found that plasma tau levels in inferior vena cava were lower than tho...
Source: Acta Neuropathologica - August 3, 2018 Category: Neurology Source Type: research

Synapsin III deficiency hampers α-synuclein aggregation, striatal synaptic damage and nigral cell loss in an AAV-based mouse model of Parkinson’s disease
AbstractParkinson ’s disease (PD), the most common neurodegenerative movement disorder, is characterized by the progressive loss of nigral dopamine neurons. The deposition of fibrillary aggregated α-synuclein in Lewy bodies (LB), that is considered to play a causative role in the disease, constitutes another key n europathological hallmark of PD. We have recently described that synapsin III (Syn III), a synaptic phosphoprotein that regulates dopamine release in cooperation with α-synuclein, is present in the α-synuclein insoluble fibrils composing the LB of patients affected by PD. Moreover, we obse...
Source: Acta Neuropathologica - July 25, 2018 Category: Neurology Source Type: research

On the origin of tau seeding activity in Alzheimer ’s disease
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 23, 2018 Category: Neurology Source Type: research

HEIRECA! The HEIdelberg REvolution of CAncer classification and what it means for neurooncology and neuropathology
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 20, 2018 Category: Neurology Source Type: research

Microglia control the spread of neurotropic virus infection via P2Y12 signalling and recruit monocytes through P2Y12-independent mechanisms
AbstractNeurotropic herpesviruses can establish lifelong infection in humans and contribute to severe diseases including encephalitis and neurodegeneration. However, the mechanisms through which the brain ’s immune system recognizes and controls viral infections propagating across synaptically linked neuronal circuits have remained unclear. Using a well-established model of alphaherpesvirus infection that reaches the brain exclusively via retrograde transsynaptic spread from the periphery, and in v ivo two-photon imaging combined with high resolution microscopy, we show that microglia are recruited to and isolate inf...
Source: Acta Neuropathologica - July 19, 2018 Category: Neurology Source Type: research

Heterogeneity within the PF-EPN-B ependymoma subgroup
AbstractPosterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsuperv...
Source: Acta Neuropathologica - July 17, 2018 Category: Neurology Source Type: research

Myxoid glioneuronal tumor of the septum pellucidum and lateral ventricle is defined by a recurrent PDGFRA p.K385 mutation and DNT-like methylation profile
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 13, 2018 Category: Neurology Source Type: research

Bidirectional modulation of Alzheimer phenotype by alpha-synuclein in mice and primary neurons
Abstractα-Synuclein (αSyn) histopathology defines several neurodegenerative disorders, including Parkinson’s disease, Lewy body dementia, and Alzheimer’s disease (AD). However, the functional link between soluble αSyn and disease etiology remains elusive, especially in AD. We, therefore, genetically targeted αSyn in APP transgenic mice modeling AD and mouse primary neurons. Our results demonstrate bidirectional modulation of behavioral deficits and pathophysiology by αSyn. Overexpression of human wild-type αSyn in APP animals markedly reduced amyloid deposition but, counter-i...
Source: Acta Neuropathologica - July 11, 2018 Category: Neurology Source Type: research

MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways
AbstractMicroRNAs (miRNA) regulate fundamental biological processes, including neuronal plasticity, stress response, and survival. Here, we describe a neuroprotective function of miR-132, the miRNA most significantly downregulated in neurons in Alzheimer ’s disease. We demonstrate that miR-132 protects primary mouse and human wild-type neurons and more vulnerable Tau-mutant neurons against amyloid β-peptide (Aβ) and glutamate excitotoxicity. It lowers the levels of total, phosphorylated, acetylated, and cleaved forms of Tau implicated in tauopat hies, promotes neurite elongation and branching, and reduces n...
Source: Acta Neuropathologica - July 7, 2018 Category: Neurology Source Type: research

FGFR1:TACC1 fusion is a frequent event in molecularly defined extraventricular neurocytoma
In conclusion, our data demonstrate a specific epigenetic signature of EVN suitable for characterization of these tumors as a molecularly distinct entity, and reveal a high frequency of potentially druggable FGFR pathway activation in this tumor group. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 5, 2018 Category: Neurology Source Type: research

Practical implementation of DNA methylation and copy-number-based CNS tumor diagnostics: the Heidelberg experience
We describe our current approach to the integrated diagnosis of CNS tumors with a focus on constellations with conflicts between morphological and molecular genetic findings. We further describe the benefit of integrating DNA copy-number alterations into diagnostic considerations and provide a catalog of copy-number changes for individual DNA methylation classes. We also point to several pitfalls accompanying the diagnostic implementation of DNA methylation profiling and give practical suggestions for recurring diagnostic scenarios. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - July 2, 2018 Category: Neurology Source Type: research

Sex-specific genetic predictors of Alzheimer ’s disease biomarkers
AbstractCerebrospinal fluid (CSF) levels of amyloid- β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer’s disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify se...
Source: Acta Neuropathologica - July 2, 2018 Category: Neurology Source Type: research

Nucleo-cytoplasmic transport of TDP-43 studied in real time: impaired microglia function leads to axonal spreading of TDP-43 in degenerating motor neurons
We report the formation of mobile TDP-43 deposits within degenerating motor neurons, which are normally phagocytosed by microglia. However, when microglial cells were depleted, injury-induced motor neuron degeneration follows a characteristic process that includes TDP-43 redistribution into the cytoplasm, axon and extracellular space. This is the first demonstration of perturbed TDP-43 nucleocytoplasmic transport in vivo, and suggests that impairment in microglial phagocytosis of dying neurons may contribute towards the formation of pathological TDP-43 presentations in ALS and FTLD. (Source: Acta Neuropathologica)
Source: Acta Neuropathologica - June 25, 2018 Category: Neurology Source Type: research

Corticobasal degeneration with TDP-43 pathology presenting with progressive supranuclear palsy syndrome: a distinct clinicopathologic subtype
This study aimed to elucidate whether transactive response DNA-binding protein of 43  kDa (TDP-43) pathology contributes to clinicopathologic heterogeneity of CBD. Paraffin-embedded sections of the midbrain, pons, subthalamic nucleus, and basal forebrain from 187 autopsy-confirmed CBD cases were screened with immunohistochemistry for phospho-TDP-43. In cases with TDP-43 pathology, additional brain regions (i.e., precentral, cingulate, and superior frontal gyri, hippocampus, medulla, and cerebellum) were immunostained. Hierarchical clustering analysis was performed based on the topographical distribution and severity o...
Source: Acta Neuropathologica - June 20, 2018 Category: Neurology Source Type: research

Non-Alzheimer ’s contributions to dementia and cognitive resilience in The 90+ Study
AbstractThe diagnosis of Alzheimer ’s disease (AD) in the oldest-old is complicated by the increasing prevalence of age-related neurofibrillary tangles, plaques and non-AD pathologies such as cerebrovascular disease (CVD), hippocampal sclerosis (HS), aging-related tau astrogliopathy (ARTAG), as well as TDP-43 and Lewy pathology. Th e contribution of these non-AD pathologies to dementia and cognitive resilience is unclear. We assessed the level of AD neuropathologic change (ADNPC) and non-AD pathology in 185 participants enrolled in The 90+ Study with available cognitive assessments and brain tissue. Logistic r...
Source: Acta Neuropathologica - June 18, 2018 Category: Neurology Source Type: research

Small fiber pathology parallels disease progression in Parkinson disease: a longitudinal study
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - June 18, 2018 Category: Neurology Source Type: research

Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas
AbstractOf nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a ...
Source: Acta Neuropathologica - June 16, 2018 Category: Neurology Source Type: research

Pediatric low-grade gliomas can be molecularly stratified for risk
In this study, we evaluated in a large cohort of 289 PLGGs a list of biomarkers and examined their clinical relevance. TERT promoter (TERTp), H3F3A and BRAF V600E mutations were detected by direct sequencing. ATRX nuclear loss was examined by immunohistochemistry. CDKN2A deletion, KIAA1549-BRAF fusion, and MYB amplification were determined by fluorescence in situ hybridization (FISH). TERTp, H3F3A, and BRAF V600E mutations were identified in 2.5, 6.4, and 7.4% of PLGGs, respectively. ATRX loss was found in 4.9% of PLGGs. CDKN2A deletion, KIAA1549-BRAF fusion and MYB amplification were detected in 8.8, 32.0 and 10.6% of PLG...
Source: Acta Neuropathologica - June 14, 2018 Category: Neurology Source Type: research

Selective targeting of 3 repeat Tau with brain penetrating single chain antibodies for the treatment of neurodegenerative disorders
AbstractAlzheimer ’s disease (AD) is the most common form of dementia in the elderly affecting more than 5 million people in the U.S. AD is characterized by the accumulation of β-amyloid (Aβ) and Tau in the brain, and is manifested by severe impairments in memory and cognition. Therefore, removing tau pathology h as become one of the main therapeutic goals for the treatment of AD. Tau (tubulin-associated unit) is a major neuronal cytoskeletal protein found in the CNS encoded by the geneMAPT. Alternative splicing generates two major isoforms of tau containing either 3 or 4 repeat (R) segments. These 3R or 4R...
Source: Acta Neuropathologica - June 14, 2018 Category: Neurology Source Type: research

Alzheimer ’s disease pathology propagation by exosomes containing toxic amyloid-beta oligomers
AbstractThe gradual deterioration of cognitive functions in Alzheimer ’s disease is paralleled by a hierarchical progression of amyloid-beta and tau brain pathology. Recent findings indicate that toxic oligomers of amyloid-beta may cause propagation of pathology in a prion-like manner, although the underlying mechanisms are incompletely understood. Here we show that small extracellular vesicles, exosomes, from Alzheimer patients’ brains contain increased levels of amyloid-beta oligomers and can act as vehicles for the neuron-to-neuron transfer of such toxic species in recipient neurons in culture. Moreover, blo...
Source: Acta Neuropathologica - June 13, 2018 Category: Neurology Source Type: research

Alpha-synuclein delays mitophagy and targeting Miro rescues neuron loss in Parkinson ’s models
AbstractAlpha-synuclein is a component of Lewy bodies, the pathological hallmark of Parkinson ’s disease (PD), and is also mutated in familial PD. Here, by extensively analyzing PD patient brains and neurons, and fly models, we show that alpha-synuclein accumulation results in upregulation of Miro protein levels. Miro is a motor/adaptor on the outer mitochondrial membrane that mediates mit ochondrial motility, and is removed from damaged mitochondria to facilitate mitochondrial clearance via mitophagy. PD patient neurons abnormally accumulate Miro on the mitochondrial surface leading to delayed mitophagy. Partial red...
Source: Acta Neuropathologica - June 9, 2018 Category: Neurology Source Type: research

Transcriptome –pathology correlation identifies interplay between TDP-43 and the expression of its kinase CK1E in sporadic ALS
AbstractSporadic amyotrophic lateral sclerosis (sALS) is the most common form of ALS, however, the molecular mechanisms underlying cellular damage and motor neuron degeneration remain elusive. To identify molecular signatures of sALS we performed genome-wide expression profiling in laser capture microdissection-enriched surviving motor neurons (MNs) from lumbar spinal cords of sALS patients with rostral onset and caudal progression. After correcting for immunological background, we discover a highly specific gene expression signature for sALS that is associated with phosphorylated TDP-43 (pTDP-43) pathology. Transcriptome ...
Source: Acta Neuropathologica - June 7, 2018 Category: Neurology Source Type: research

Primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features share a highly distinct methylation profile and DICER1 mutations
In this study, we identified 22 primary intracranial sarcomas, including 18 in pediatric patients, with a distinct methylation signature detected by array-based DNA-methylation profiling. In addition, two uterine rhabdomyosarcomas sharing identical features were identified. Gene panel sequencing of the 22 intracranial sarcomas revealed the almost unifying feature ofDICER1 hotspot mutations (21/22; 95%) and a high frequency of co-occurringTP53 mutations (12/22; 55%). In addition, 17/22 (77%) sarcomas exhibited alterations in the mitogen-activated protein kinase pathway, most frequently affecting the mutational hotspots ofKR...
Source: Acta Neuropathologica - June 7, 2018 Category: Neurology Source Type: research

Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases?
AbstractNeurological diseases, such as Parkinson ’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis, are often associated with functional gastrointestinal disorders. These gastrointestinal disturbances may occur at all stages of the neurodegenerative diseases, to such an extent that they are now consi dered an integral part of their clinical picture. Several lines of evidence support the contention that, in central neurodegenerative diseases, changes in gut microbiota and enteric neuro-immune system alterations could contribute to gastrointesinal dysfuncti...
Source: Acta Neuropathologica - May 24, 2018 Category: Neurology Source Type: research

A suggestion to introduce the diagnosis of “diffuse midline glioma of the pons, H3 K27 wildtype (WHO grade IV)”
(Source: Acta Neuropathologica)
Source: Acta Neuropathologica - May 21, 2018 Category: Neurology Source Type: research

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