1,020 results match your criteria Acta neuropathologica communications[Journal]


Molecular identification of CNS NB-FOXR2, CNS EFT-CIC, CNS HGNET-MN1 and CNS HGNET-BCOR pediatric brain tumors using tumor-specific signature genes.

Acta Neuropathol Commun 2020 Jul 10;8(1):105. Epub 2020 Jul 10.

Department of Experimental and Clinical Neuropathology, Mossakowski Medical Research Centre, Polish Academy of Sciences, A. Pawińskiego 5 Street, 02-106, Warsaw, Poland.

Four molecular types of rare central nervous system (CNS) tumors have been recently identified by gene methylation profiling: CNS Neuroblastoma with FOXR2 activation (CNS NB-FOXR2), CNS Ewing Sarcoma Family Tumor with CIC alteration (CNS EFT-CIC), CNS high grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1) and CNS high grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR). Although they are not represented in 2016 updated WHO classification of CNS tumors, their diagnostic recognition is important because of clinical consequences. We have introduced a diagnostic method based on transcription profiling of tumor specific signature genes from formalin-fixed, paraffin-embedded tumor blocks using NanoString nCounter Technology. Read More

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http://dx.doi.org/10.1186/s40478-020-00984-9DOI Listing

Complex I reductions in the nucleus basalis of Meynert in Lewy body dementia: the role of Lewy bodies.

Acta Neuropathol Commun 2020 Jul 9;8(1):103. Epub 2020 Jul 9.

Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK.

Neurons of the nucleus basalis of Meynert (nbM) are vulnerable to Lewy body formation and neuronal loss, which is thought to underlie cognitive dysfunction in Lewy body dementia (LBD). There is continued debate about whether Lewy bodies exert a neurodegenerative effect by affecting mitochondria, or whether they represent a protective mechanism. Therefore, the present study sought to determine whether the nbM is subject to mitochondrial dysfunctional in LBD and the association of Lewy body formation with such changes. Read More

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http://dx.doi.org/10.1186/s40478-020-00985-8DOI Listing

High level MYCN amplification and distinct methylation signature define an aggressive subtype of spinal cord ependymoma.

Acta Neuropathol Commun 2020 Jul 8;8(1):101. Epub 2020 Jul 8.

Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

We report a novel group of clinically aggressive spinal cord ependymomas characterized by Grade III histology, MYCN amplification, an absence of NF2 alterations or other recurrent pathogenic mutations, and a unique methylation classifier profile. Seven cases were found to have MYCN amplification in the course of routine mutational profiling of 552 patients with central nervous system tumors between December 2016 and July of 2019 and an eighth patient was identified from an unrelated set of cases. Methylation array analysis revealed that none of the 8 cases clustered with any of the nine previously described ependymoma methylation subgroups, and 7 of 8 formed their own tight unique cluster. Read More

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http://dx.doi.org/10.1186/s40478-020-00973-yDOI Listing

Erythrocytic α-synuclein contained in microvesicles regulates astrocytic glutamate homeostasis: a new perspective on Parkinson's disease pathogenesis.

Acta Neuropathol Commun 2020 Jul 8;8(1):102. Epub 2020 Jul 8.

Department of Pathology, University of Washington School of Medicine, Seattle, Washington, USA.

Parkinson's disease is a neurodegenerative disorder characterized by the transmission and accumulation of toxic species of α-synuclein (α-syn). Extracellular vesicles (EVs) are believed to play a vital role in the spread of toxic α-syn species. Recently, peripheral α-syn pathology has been investigated, but little attention has been devoted to erythrocytes, which contain abundant α-syn. Read More

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http://dx.doi.org/10.1186/s40478-020-00983-wDOI Listing

In vivo evidence of exosome-mediated Aβ neurotoxicity.

Acta Neuropathol Commun 2020 Jul 6;8(1):100. Epub 2020 Jul 6.

Department of Physiology, University of Kentucky College of Medicine, 800 Rose Street Room MS519, Lexington, KY, USA.

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http://dx.doi.org/10.1186/s40478-020-00981-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339450PMC

Disturbed balance in the expression of MMP9 and TIMP3 in cerebral amyloid angiopathy-related intracerebral haemorrhage.

Acta Neuropathol Commun 2020 Jul 6;8(1):99. Epub 2020 Jul 6.

Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of the amyloid β (Aβ) protein in the cerebral vasculature and poses a major risk factor for the development of intracerebral haemorrhages (ICH). However, only a minority of patients with CAA develops ICH (CAA-ICH), and to date it is unclear which mechanisms determine why some patients with CAA are more susceptible to haemorrhage than others. We hypothesized that an imbalance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) contributes to vessel wall weakening. Read More

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http://dx.doi.org/10.1186/s40478-020-00972-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336459PMC

Quantitative patterns of motor cortex proteinopathy across ALS genotypes.

Acta Neuropathol Commun 2020 Jul 2;8(1):98. Epub 2020 Jul 2.

Nuffield Department of Clinical Neurosciences, University of Oxford, Level 1, West Wing, John Radcliffe Hospital, Oxford, OX3 9DU, UK.

Degeneration of the primary motor cortex is a defining feature of amyotrophic lateral sclerosis (ALS), which is associated with the accumulation of microscopic protein aggregates in neurons and glia. However, little is known about the quantitative burden and pattern of motor cortex proteinopathies across ALS genotypes. We combined quantitative digital image analysis with multi-level generalized linear modelling in an independent cohort of 82 ALS cases to explore the relationship between genotype, total proteinopathy load and cellular vulnerability to aggregate formation. Read More

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http://dx.doi.org/10.1186/s40478-020-00961-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331195PMC

Excess Rab4 rescues synaptic and behavioral dysfunction caused by defective HTT-Rab4 axonal transport in Huntington's disease.

Acta Neuropathol Commun 2020 Jul 1;8(1):97. Epub 2020 Jul 1.

Department of Biological Sciences, The State University of New York at Buffalo, New York, 14260, USA.

Huntington's disease (HD) is characterized by protein inclusions and loss of striatal neurons which result from expanded CAG repeats in the poly-glutamine (polyQ) region of the huntingtin (HTT) gene. Both polyQ expansion and loss of HTT have been shown to cause axonal transport defects. While studies show that HTT is important for vesicular transport within axons, the cargo that HTT transports to/from synapses remain elusive. Read More

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http://dx.doi.org/10.1186/s40478-020-00964-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331280PMC

Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic Tauopathy.

Acta Neuropathol Commun 2020 Jul 1;8(1):96. Epub 2020 Jul 1.

Departments of Neurology and of Neuroscience, Program in Cellular Neuroscience, Neurodegeneration, Repair, Yale University School of Medicine, New Haven, CT, 06536, USA.

Accumulation of misfolded phosphorylated Tau (Tauopathy) can be triggered by mutations or by trauma, and is associated with synapse loss, gliosis, neurodegeneration and memory deficits. Fyn kinase physically associates with Tau and regulates subcellular distribution. Here, we assessed whether pharmacological Fyn inhibition alters Tauopathy. Read More

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http://dx.doi.org/10.1186/s40478-020-00976-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329553PMC

Diffuse leptomeningeal glioneuronal tumor: a double misnomer? A report of two cases.

Acta Neuropathol Commun 2020 Jun 30;8(1):95. Epub 2020 Jun 30.

APHM, CHU Timone, Service d'Anatomie Pathologique et de Neuropathologie, Marseille, France.

Diffuse leptomeningeal glioneuronal tumor (DLGNT) was introduced, for the first time, as a provisional entity in the 2016 WHO classification of central nervous system tumors. DLGNT mainly occur in children and characterized by a widespread leptomeningeal growth occasionally associated with intraspinal tumor nodules, an oligodendroglial-like cytology, glioneuronal differentiation and MAP-Kinase activation associated with either solitary 1p deletion or 1p/19q codeletion in the absence of IDH mutation.We report here two unexpected DLGNTs adult cases, characterized by a unique supratentorial circumscribed intraparenchymal tumor without leptomeningeal involvement in spite of long follow-up. Read More

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http://dx.doi.org/10.1186/s40478-020-00978-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325675PMC

A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy.

Acta Neuropathol Commun 2020 Jun 29;8(1):93. Epub 2020 Jun 29.

Mitochondrial dysfunctions in neurodegeneration Unit, Division of Neuroscience, Ospedale San Raffaele, Milan, Italy.

Autosomal dominant optic atrophy (ADOA) is a neuro-ophthalmic condition characterized by bilateral degeneration of the optic nerves. Although heterozygous mutations in OPA1 represent the most common genetic cause of ADOA, a significant number of cases remain undiagnosed.Here, we describe a family with a strong ADOA history with most family members spanning three generation having childhood onset of visual symptoms. Read More

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http://dx.doi.org/10.1186/s40478-020-00975-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325028PMC

de novo MAPT mutation G335A causes severe brain atrophy, 3R and 4R PHF-tau pathology and early onset frontotemporal dementia.

Acta Neuropathol Commun 2020 Jun 29;8(1):94. Epub 2020 Jun 29.

Laboratory of Histology, Neuroanatomy and Neuropathology, Faculty of Medicine, Université Libre de Bruxelles, ULB Neuroscience Institute, 808 route de Lennik, Bldg GE, B-1070, Brussels, Belgium.

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http://dx.doi.org/10.1186/s40478-020-00977-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325098PMC

Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis.

Acta Neuropathol Commun 2020 Jun 26;8(1):92. Epub 2020 Jun 26.

Department of Neurobiology, St. Joseph's Hospital and Medical Center and Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA.

The choroid plexus (CP) is a highly vascularized structure located in the ventricles that forms the blood-CSF barrier (BCSFB) and separates the blood from the cerebrospinal fluid (CSF). In addition to its role as a physical barrier, the CP functions in CSF secretion, transport of nutrients into the central nervous system (CNS) and a gated point of entry of circulating immune cells into the CNS. Aging and neurodegeneration have been reported to affect CP morphology and function and increase protein leakage from blood to the CSF. Read More

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http://dx.doi.org/10.1186/s40478-020-00968-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318439PMC

RBM45 associates with nuclear stress bodies and forms nuclear inclusions during chronic cellular stress and in neurodegenerative diseases.

Acta Neuropathol Commun 2020 Jun 26;8(1):91. Epub 2020 Jun 26.

Departments of Neurobiology and Neurology, Barrow Neurological Institute, Phoenix, AZ, USA.

The RNA binding protein (RBP) RBM45 forms nuclear and cytoplasmic inclusions in neurons and glia in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP), and Alzheimer's disease (AD). The normal functions of RBM45 are poorly understood, as are the mechanisms by which it forms inclusions in disease. To better understand the normal and pathological functions of RBM45, we evaluated whether the protein functions via association with several membraneless organelles and whether such an association could promote the formation of nuclear RBM45 inclusions. Read More

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http://dx.doi.org/10.1186/s40478-020-00965-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318465PMC

Ultrastructural and dynamic studies of the endosomal compartment in Down syndrome.

Acta Neuropathol Commun 2020 Jun 24;8(1):89. Epub 2020 Jun 24.

Paris Brain Institute (ICM), CNRS UMR7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, France.

Enlarged early endosomes have been visualized in Alzheimer's disease (AD) and Down syndrome (DS) using conventional confocal microscopy at a resolution corresponding to endosomal size (hundreds of nm). In order to overtake the diffraction limit, we used super-resolution structured illumination microscopy (SR-SIM) and transmission electron microscopies (TEM) to analyze the early endosomal compartment in DS.By immunofluorescence and confocal microscopy, we confirmed that the volume of Early Endosome Antigen 1 (EEA1)-positive puncta was 13-19% larger in fibroblasts and iPSC-derived neurons from individuals with DS, and in basal forebrain cholinergic neurons (BFCN) of the Ts65Dn mice modelling DS. Read More

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http://dx.doi.org/10.1186/s40478-020-00956-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315513PMC

Correction to: Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy.

Acta Neuropathol Commun 2020 Jun 24;8(1):90. Epub 2020 Jun 24.

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

An amendment to this paper has been published and can be accessed via the original article. Read More

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http://dx.doi.org/10.1186/s40478-020-00970-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315469PMC

Tau Ser208 phosphorylation promotes aggregation and reveals neuropathologic diversity in Alzheimer's disease and other tauopathies.

Acta Neuropathol Commun 2020 Jun 22;8(1):88. Epub 2020 Jun 22.

Department of Neuroscience, College of Medicine, University of Florida, 1275 Center Drive, Gainesville, Florida, 32610, USA.

Tau protein abnormally aggregates in tauopathies, a diverse group of neurologic diseases that includes Alzheimer's disease (AD). In early stages of disease, tau becomes hyperphosphorylated and mislocalized, which can contribute to its aggregation and toxicity. We demonstrate that tau phosphorylation at Ser208 (pSer208) promotes microtubule dysfunction and tau aggregation in cultured cells. Read More

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http://dx.doi.org/10.1186/s40478-020-00967-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310041PMC

A novel Cas9-targeted long-read assay for simultaneous detection of IDH1/2 mutations and clinically relevant MGMT methylation in fresh biopsies of diffuse glioma.

Acta Neuropathol Commun 2020 Jun 20;8(1):87. Epub 2020 Jun 20.

Department of Neurosurgery, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.

Molecular biomarkers provide both diagnostic and prognostic results for patients with diffuse glioma, the most common primary brain tumor in adults. Here, we used a long-read nanopore-based sequencing technique to simultaneously assess IDH mutation status and MGMT methylation level in 4 human cell lines and 8 fresh human brain tumor biopsies. Currently, these biomarkers are assayed separately, and results can take days to weeks. Read More

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http://dx.doi.org/10.1186/s40478-020-00963-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305623PMC

A novel mechanism of phenotypic heterogeneity in Creutzfeldt-Jakob disease.

Acta Neuropathol Commun 2020 Jun 19;8(1):85. Epub 2020 Jun 19.

Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH, 44106, USA.

One of remarkable features of sporadic Creutzfeldt-Jakob disease (sCJD) is the great phenotypic variability. Understanding the molecular basis of this variability has important implications for the development of therapeutic approaches. It is well established that, in many cases, phenotypic heterogeneity of sCJD is under control of two determinants: the genotype at the methionine (M)/valine (V) polymorphic codon 129 of the human prion protein gene and the type, 1 or 2, of the pathogenic and disease-related form of the prion protein, PrP. Read More

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http://dx.doi.org/10.1186/s40478-020-00966-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304206PMC

Phosphorylation and oligomerization of α-synuclein associated with GSK-3β activation in the rTg4510 mouse model of tauopathy.

Acta Neuropathol Commun 2020 Jun 19;8(1):86. Epub 2020 Jun 19.

Laboratory of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, 113-8657, Japan.

Neurodegenerative diseases are characterized by the accumulation of specific phosphorylated protein aggregates in the brain, such as hyperphosphorylated tau (hp-tau) in tauopathies and phosphorylated α-synuclein (p-αSyn) in α-synucleinopathies. The simultaneous accumulation of different proteins is a common event in many neurodegenerative diseases. We herein describe the detection of the phosphorylation and dimerization of αSyn and activation of GSK-3β, a major kinase known to phosphorylate tau and αSyn, in the brains of rTg4510 mice that overexpress human P301L mutant tau. Read More

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http://dx.doi.org/10.1186/s40478-020-00969-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304163PMC

Transmission characteristics of heterozygous cases of Creutzfeldt-Jakob disease with variable abnormal prion protein allotypes.

Acta Neuropathol Commun 2020 Jun 9;8(1):83. Epub 2020 Jun 9.

Rocky Mountain Laboratories, Laboratory of Persistent Viral Diseases, National Institute of Allergy & Infectious Diseases, National Institutes of Health, 903 S. 4th Str, Hamilton, MT, 59840, USA.

In the human prion disease Creutzfeldt-Jakob disease (CJD), different CJD neuropathological subtypes are defined by the presence in normal prion protein (PrP) of a methionine or valine at residue 129, by the molecular mass of the infectious prion protein PrP, by the pattern of PrP deposition, and by the distribution of spongiform change in the brain. Heterozygous cases of CJD potentially add another layer of complexity to defining CJD subtypes since PrP can have either a methionine (PrP-M129) or valine (PrP-V129) at residue 129. We have recently demonstrated that the relative amount of PrP-M129 versus PrP-V129, i. Read More

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http://dx.doi.org/10.1186/s40478-020-00958-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285538PMC

Transplantation of induced neural stem cells (iNSCs) into chronically demyelinated corpus callosum ameliorates motor deficits.

Acta Neuropathol Commun 2020 Jun 9;8(1):84. Epub 2020 Jun 9.

Department of Anatomy, Physiology and Genetics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd, Bethesda, MD, 20814, USA.

Multiple Sclerosis (MS) causes neurologic disability due to inflammation, demyelination, and neurodegeneration. Immunosuppressive treatments can modify the disease course but do not effectively promote remyelination or prevent long term neurodegeneration. As a novel approach to mitigate chronic stage pathology, we tested transplantation of mouse induced neural stem cells (iNSCs) into the chronically demyelinated corpus callosum (CC) in adult mice. Read More

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http://dx.doi.org/10.1186/s40478-020-00960-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285785PMC

DNA methylation profiling demonstrates superior diagnostic classification to RNA-sequencing in a case of metastatic meningioma.

Acta Neuropathol Commun 2020 Jun 9;8(1):82. Epub 2020 Jun 9.

Department of Radiation Oncology, University of California San Francisco, California, 94143, USA.

Meningiomas are the most common primary intracranial tumors, but meningioma metastases are rare. Accordingly, the clinical workup, diagnostic testing, and molecular classification of metastatic meningioma is incompletely understood. Here, we present a case report of multiply recurrent meningioma complicated by liver metastasis. Read More

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http://dx.doi.org/10.1186/s40478-020-00952-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285578PMC

Characterization of the TNF and IL-1 systems in human brain and blood after ischemic stroke.

Acta Neuropathol Commun 2020 Jun 5;8(1):81. Epub 2020 Jun 5.

Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 21, st, DK-5000, Odense C, Denmark.

Preclinical and clinical proof-of-concept studies have suggested the effectiveness of pharmacological modulation of inflammatory cytokines in ischemic stroke. Experimental evidence shows that targeting tumor necrosis factor (TNF) and interleukin (IL)-1 holds promise, and these cytokines are considered prime targets in the development of new stroke therapies. So far, however, information on the cellular expression of TNF and IL-1 in the human ischemic brain is sparse. Read More

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http://dx.doi.org/10.1186/s40478-020-00957-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273684PMC

No symphony without bassoon and piccolo: changes in synaptic active zone proteins in Huntington's disease.

Acta Neuropathol Commun 2020 Jun 3;8(1):77. Epub 2020 Jun 3.

Institute of Neuroscience, College of Life and Health Sciences, Northeastern University, 110819, Shenyang, P. R. China.

Prominent features of HD neuropathology are the intranuclear and cytoplasmic inclusions of huntingtin and striatal and cortical neuronal cell death. Recently, synaptic defects have been reported on HD-related studies, including impairment of neurotransmitter release and alterations of synaptic components. However, the definite characteristics of synapse dysfunction and the underlying mechanisms remain largely unknown. Read More

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http://dx.doi.org/10.1186/s40478-020-00949-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268643PMC

Cerebrospinal fluid penetration of targeted therapeutics in pediatric brain tumor patients.

Acta Neuropathol Commun 2020 Jun 3;8(1):78. Epub 2020 Jun 3.

Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Treatment with small-molecule inhibitors, guided by precision medicine has improved patient outcomes in multiple cancer types. However, these compounds are often not effective against central nervous system (CNS) tumors. The failure of precision medicine approaches for CNS tumors is frequently attributed to the inability of these compounds to cross the blood-brain barrier (BBB), which impedes intratumoral target engagement. Read More

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http://dx.doi.org/10.1186/s40478-020-00953-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268320PMC

The lipid phosphatase Synaptojanin 1 undergoes a significant alteration in expression and solubility and is associated with brain lesions in Alzheimer's disease.

Acta Neuropathol Commun 2020 Jun 3;8(1):79. Epub 2020 Jun 3.

Laboratory of Histology, Neuroanatomy and Neuropathology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), 808, route de Lennik (Bldg G), 1070, Brussels, Belgium.

Synaptojanin 1 (SYNJ1) is a brain-enriched lipid phosphatase critically involved in autophagosomal/endosomal trafficking, synaptic vesicle recycling and metabolism of phosphoinositides. Previous studies suggest that SYNJ1 polymorphisms have significant impact on the age of onset of Alzheimer's disease (AD) and that SYNJ1 is involved in amyloid-induced toxicity. Yet SYNJ1 protein level and cellular localization in post-mortem human AD brain tissues have remained elusive. Read More

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http://dx.doi.org/10.1186/s40478-020-00954-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268631PMC

Transcriptional profiling of multiple system atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease.

Acta Neuropathol Commun 2020 Jun 3;8(1):76. Epub 2020 Jun 3.

Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.

Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n = 66) and healthy controls (HC; n = 66). Read More

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http://dx.doi.org/10.1186/s40478-020-00950-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268362PMC

Fusions involving BCOR and CREBBP are rare events in infiltrating glioma.

Acta Neuropathol Commun 2020 Jun 3;8(1):80. Epub 2020 Jun 3.

Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA.

BCOR has been recognized as a recurrently altered gene in a subset of pediatric tumors of the central nervous system (CNS). Here, we describe a novel BCOR-CREBBP fusion event in a case of pediatric infiltrating astrocytoma and further probe the frequency of related fusion events in CNS tumors. We analyzed biopsy samples taken from a 15-year-old male with an aggressive, unresectable and multifocal infiltrating astrocytoma. Read More

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http://dx.doi.org/10.1186/s40478-020-00951-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271411PMC

Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation.

Acta Neuropathol Commun 2020 May 29;8(1):74. Epub 2020 May 29.

Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pathology, Amsterdam Neuroscience, De Boelelaan, 1117, Amsterdam, The Netherlands.

Immunotherapies targeting pathological tau have recently emerged as a promising approach for treatment of neurodegenerative disorders. We have previously showed that the mouse antibody DC8E8 discriminates between healthy and pathological tau, reduces tau pathology in murine tauopathy models and inhibits neuronal internalization of AD tau species in vitro.Here we show, that DC8E8 and antibodies elicited against the first-in-man tau vaccine, AADvac1, which is based on the DC8E8 epitope peptide, both promote uptake of pathological tau by mouse primary microglia. Read More

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http://dx.doi.org/10.1186/s40478-020-00948-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257136PMC

Loss of homeostatic microglial phenotype in CSF1R-related Leukoencephalopathy.

Acta Neuropathol Commun 2020 May 19;8(1):72. Epub 2020 May 19.

Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.

Microglia are resident macrophages of the central nervous system, and their unique molecular signature is dependent upon CSF-1 signaling. Previous studies have demonstrated the importance of CSF-1R in survival and development of microglia in animal models, but the findings are of uncertain relevance to understanding the influence of CSF-1R on microglia in humans. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) [also known as adult onset leukoencephalopathy with spheroids and pigmented glia (ALSP)] is a neurodegenerative disorder primarily affecting cerebral white matter, most often caused by mutations of CSF1R. Read More

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http://dx.doi.org/10.1186/s40478-020-00947-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236286PMC

Meningomyeloencephalitis secondary to Mycobacterium haemophilum infection in AIDS.

Acta Neuropathol Commun 2020 May 19;8(1):73. Epub 2020 May 19.

Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, NY, 10032, USA.

Infections by opportunistic non-tuberculous mycobacteria (NTM) are rising in global incidence. One emerging, slowly growing NTM is Mycobacterium haemophilum, which can cause skin, lung, bone, and soft tissue infections in immunocompromised patients as well as lymphadenitis in immunocompetent individuals. Detection of this microorganism is difficult using conventional culture-based methods and few reports have documented involvement of this pathogen within the central nervous system (CNS). Read More

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http://dx.doi.org/10.1186/s40478-020-00937-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236527PMC

Correction to: Differential gene methylation and expression of HOX transcription factor family in orbitofacial neurofibroma.

Acta Neuropathol Commun 2020 May 14;8(1):69. Epub 2020 May 14.

Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

An amendment to this paper has been published and can be accessed via the original article. Read More

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http://dx.doi.org/10.1186/s40478-020-00944-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222592PMC

Restoration of miR-193a expression is tumor-suppressive in MYC amplified Group 3 medulloblastoma.

Acta Neuropathol Commun 2020 May 14;8(1):70. Epub 2020 May 14.

Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, 410210, India.

Medulloblastoma, a highly malignant pediatric brain tumor, consists of four molecular subgroups, namely WNT, SHH, Group 3, and Group 4. The expression of miR-193a, a WNT subgroup-specific microRNA, was found to be induced by MYC, an oncogenic target of the canonical WNT signaling. MiR-193a is not expressed in Group 3 medulloblastomas, despite MYC expression, as a result of promoter hypermethylation. Read More

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http://dx.doi.org/10.1186/s40478-020-00942-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227220PMC

Transcriptional analyses of adult and pediatric adamantinomatous craniopharyngioma reveals similar expression signatures regarding potential therapeutic targets.

Acta Neuropathol Commun 2020 May 13;8(1):68. Epub 2020 May 13.

Division of Pediatric Neurosurgery, Children's Hospital Colorado, Aurora, USA.

Adamantinomatous craniopharyngioma (ACP) is a biologically benign but clinically aggressive lesion that has a significant impact on quality of life. The incidence of the disease has a bimodal distribution, with peaks occurring in children and older adults. Our group previously published the results of a transcriptome analysis of pediatric ACPs that identified several genes that were consistently overexpressed relative to other pediatric brain tumors and normal tissue. Read More

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http://dx.doi.org/10.1186/s40478-020-00939-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222517PMC

Behavioral and electrophysiological evidence for a neuroprotective role of aquaporin-4 in the 5xFAD transgenic mice model.

Acta Neuropathol Commun 2020 May 12;8(1):67. Epub 2020 May 12.

Department of Pharmacology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Aquaporin-4 (AQP4) has been suggested to be involved in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), which may be due to the modulation of neuroinflammation or the impairment of interstitial fluid bulk flow system in the central nervous system. Here, we show an age-dependent impairment of several behavioral outcomes in 5xFAD AQP4 null mice. Twenty-four-hour video recordings and computational analyses of their movement revealed that the nighttime motion of AQP4-deficient 5xFAD mice was progressively reduced between 20 and 36 weeks of age, with a sharp deterioration occurring between 30 and 32 weeks. Read More

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http://dx.doi.org/10.1186/s40478-020-00936-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218576PMC

Persistent elevation of intrathecal pro-inflammatory cytokines leads to multiple sclerosis-like cortical demyelination and neurodegeneration.

Acta Neuropathol Commun 2020 May 12;8(1):66. Epub 2020 May 12.

Division of Neuroscience, Department of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, Burlington Danes Building, Du Cane Road, London, W12 0NN, UK.

Analysis of isolated meninges and cerebrospinal fluid (CSF) of post-mortem MS cases has shown increased gene and protein expression for the pro-inflammatory cytokines: tumour necrosis factor (TNF) and interferon-γ (IFNγ). Here we tested the hypothesis that persistent production of these cytokines in the meningeal compartment and diffusion into underlying GM can drive chronic MS-like GM pathology. Lentiviral transfer vectors were injected into the sagittal sulcus of DA rats to deliver continuous expression of TNF + IFNγ transgenes in the meninges and the resulting neuropathology analysed after 1 and 2 months. Read More

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http://dx.doi.org/10.1186/s40478-020-00938-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218553PMC

Transmission of ALS pathogenesis by the cerebrospinal fluid.

Acta Neuropathol Commun 2020 May 7;8(1):65. Epub 2020 May 7.

CERVO Brain Research Centre, 2601 Chemin de la Canardière, Québec, Québec, G1J 2G3, Canada.

To test the hypothesis that the cerebrospinal fluid (CSF) could provide a spreading route for pathogenesis of amyotrophic lateral sclerosis (ALS), we have examined the effects of intraventricular infusion during 2 weeks of pooled CSF samples from sporadic ALS patients or control CSF samples into transgenic mice expressing human TDP43 which do not develop pathological phenotypes. Infusion of ALS-CSF, but not of control CSF, triggered motor and cognitive dysfunction, as well as ALS-like pathological changes including TDP43 proteinopathy, neurofilament disorganization and neuroinflammation. In addition, the neuron-specific translational profiles from peptide analyses of immunoprecipitated ribosomes revealed dysregulation of multiple protein networks in response to ALS-CSF altering cytoskeletal organization, vesicle trafficking, mitochondrial function, and cell metabolism. Read More

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http://dx.doi.org/10.1186/s40478-020-00943-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206749PMC

Genetic perspective on the synergistic connection between vesicular transport, lysosomal and mitochondrial pathways associated with Parkinson's disease pathogenesis.

Acta Neuropathol Commun 2020 May 6;8(1):63. Epub 2020 May 6.

Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, University of Antwerp - CDE, Universiteitsplein 1, 2610, Antwerpen, Belgium.

Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) are symptomatically characterized by parkinsonism, with the latter presenting additionally a distinctive range of atypical features. Although the majority of patients with PD and APS appear to be sporadic, genetic causes of several rare monogenic disease variants were identified. The knowledge acquired from these genetic factors indicated that defects in vesicular transport pathways, endo-lysosomal dysfunction, impaired autophagy-lysosomal protein and organelle degradation pathways, α-synuclein aggregation and mitochondrial dysfunction play key roles in PD pathogenesis. Read More

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http://dx.doi.org/10.1186/s40478-020-00935-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201634PMC

RNA modifications in brain tumorigenesis.

Acta Neuropathol Commun 2020 May 6;8(1):64. Epub 2020 May 6.

Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, V5Z 1L3, Canada.

RNA modifications are emerging as critical regulators in cancer biology, thanks to their ability to influence gene expression and the predominant protein isoforms expressed during cell proliferation, migration, and other pro-oncogenic properties. The reversibility and dynamic nature of post-transcriptional RNA modifications allow cells to quickly adapt to microenvironmental changes. Recent literature has revealed that the deregulation of RNA modifications can promote a plethora of developmental diseases, including tumorigenesis. Read More

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http://dx.doi.org/10.1186/s40478-020-00941-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204278PMC

Differential gene methylation and expression of HOX transcription factor family in orbitofacial neurofibroma.

Acta Neuropathol Commun 2020 May 4;8(1):62. Epub 2020 May 4.

Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Although most commonly benign, neurofibromas (NFs) can have devastating functional and cosmetic effects in addition to the possibility of malignant transformation. In orbitofacial neurofibromatosis type 1, NFs may cause progressive, disfiguring tumors of the lid, brow, temple, face and orbit. The purpose of this study was to identify biological differences between orbitofacial NFs and those occurring at other anatomic sites. Read More

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http://dx.doi.org/10.1186/s40478-020-00940-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197183PMC

Distinct molecular patterns of TDP-43 pathology in Alzheimer's disease: relationship with clinical phenotypes.

Acta Neuropathol Commun 2020 Apr 29;8(1):61. Epub 2020 Apr 29.

Department of Imaging and Pathology - Laboratory of Neuropathology, and Leuven Brain Institute, KU-Leuven, O&N IV, Herestraat 49, box 1032, 3000, Leuven, Belgium.

The co-existence of multiple pathologies and proteins is a common feature in the brains of cognitively impaired elderly individuals. Transactive response DNA-binding protein (TDP-43) has been discovered to accumulate in limbic brain regions of a portion of late-onset Alzheimer's disease (AD) patients, in addition to amyloid-β and τ protein. However, it is not yet known whether the TDP-43 species in the AD brain differ in their composition, when compared among different AD cases and to frontotemporal lobar degeneration cases with TDP-43 inclusions (FTLD-TDP). Read More

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http://dx.doi.org/10.1186/s40478-020-00934-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189555PMC

Association of Aβ with ceramide-enriched astrosomes mediates Aβ neurotoxicity.

Acta Neuropathol Commun 2020 Apr 28;8(1):60. Epub 2020 Apr 28.

Department of Physiology, University of Kentucky College of Medicine, 800 Rose Street Room MS519, Lexington, KY, 40536, USA.

Amyloid-β (Aβ) associates with extracellular vesicles termed exosomes. It is not clear whether and how exosomes modulate Aβ neurotoxicity in Alzheimer's disease (AD). We show here that brain tissue and serum from the transgenic mouse model of familial AD (5xFAD) and serum from AD patients contains ceramide-enriched and astrocyte-derived exosomes (termed astrosomes) that are associated with Aβ. Read More

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http://dx.doi.org/10.1186/s40478-020-00931-8DOI Listing

Validation of machine learning models to detect amyloid pathologies across institutions.

Acta Neuropathol Commun 2020 Apr 28;8(1):59. Epub 2020 Apr 28.

Department of Neurology, Emory University School of Medicine, 12 Executive Park Dr NE, Atlanta, GA, 30322, USA.

Semi-quantitative scoring schemes like the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) are the most commonly used method in Alzheimer's disease (AD) neuropathology practice. Computational approaches based on machine learning have recently generated quantitative scores for whole slide images (WSIs) that are highly correlated with human derived semi-quantitative scores, such as those of CERAD, for Alzheimer's disease pathology. However, the robustness of such models have yet to be tested in different cohorts. Read More

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http://dx.doi.org/10.1186/s40478-020-00927-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189549PMC

Enhanced accumulation of N-terminally truncated Aβ with and without pyroglutamate-11 modification in parvalbumin-expressing GABAergic neurons in idiopathic and dup15q11.2-q13 autism.

Acta Neuropathol Commun 2020 Apr 28;8(1):58. Epub 2020 Apr 28.

Department of Developmental Neurobiology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, New York, NY10314, USA.

Autism, the most frequent neurodevelopmental disorder of a very complex etiopathology, is associated with dysregulation of cellular homeostatic mechanisms, including processing of amyloid-β precursor protein (APP). Products of APP processing - N-terminally truncated amyloid-β peptide (N-tr-Aβ) species - are accumulated in autism in neurons and glia in the cortex, cerebellum, and subcortical structures of the brain. This process in neurons is correlated with increased oxidative stress. Read More

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http://dx.doi.org/10.1186/s40478-020-00923-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189730PMC

Clinical, imaging, and molecular analysis of pediatric pontine tumors lacking characteristic imaging features of DIPG.

Acta Neuropathol Commun 2020 Apr 23;8(1):57. Epub 2020 Apr 23.

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.

Diffuse intrinsic pontine glioma (DIPG) is most commonly diagnosed based on imaging criteria, with biopsy often reserved for pontine tumors with imaging features not typical for DIPG (atypical DIPG, 'aDIPG'). The histopathologic and molecular spectra of the clinical entity aDIPG remain to be studied systematically. In this study, thirty-three patients with newly diagnosed pontine-centered tumors with imaging inconsistent with DIPG for whom a pathologic diagnosis was subsequently obtained were included. Read More

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http://dx.doi.org/10.1186/s40478-020-00930-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181591PMC

Unilateral intranigral administration of β-sitosterol β-D-glucoside triggers pathological α-synuclein spreading and bilateral nigrostriatal dopaminergic neurodegeneration in the rat.

Acta Neuropathol Commun 2020 Apr 22;8(1):56. Epub 2020 Apr 22.

Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. Instituto Politécnico Nacional, No. 2508, 07360, Ciudad de México, Mexico.

The spreading and accumulation of α-synuclein and dopaminergic neurodegeneration, two hallmarks of Parkinson's disease (PD), have been faithfully reproduced in rodent brains by chronic, oral administration of β-sitosterol β-D-glucoside (BSSG). We investigated whether a single injection of BSSG (6 μg BSSG/μL DMSO) in the left substantia nigra of Wistar rats causes the same effects. Mock DMSO injections and untreated rats formed control groups. Read More

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http://dx.doi.org/10.1186/s40478-020-00933-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178762PMC