8,182 results match your criteria Acta neuropathologica[Journal]


H3.3 K27M depletion increases differentiation and extends latency of diffuse intrinsic pontine glioma growth in vivo.

Acta Neuropathol 2019 Feb 15. Epub 2019 Feb 15.

Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

Histone H3 K27M mutation is the defining molecular feature of the devastating pediatric brain tumor, diffuse intrinsic pontine glioma (DIPG). The prevalence of histone H3 K27M mutations indicates a critical role in DIPGs, but the contribution of the mutation to disease pathogenesis remains unclear. We show that knockdown of this mutation in DIPG xenografts restores K27M-dependent loss of H3K27me3 and delays tumor growth. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-019-01975-4DOI Listing
February 2019

Tau drives translational selectivity by interacting with ribosomal proteins.

Acta Neuropathol 2019 Feb 13. Epub 2019 Feb 13.

Department of Neuroscience and Center for Translational Research in Neurodegenerative Disease, University of Florida, 1275 Center Drive, BOX 100159, Gainesville, FL, 32610, USA.

There is a fundamental gap in understanding the consequences of tau-ribosome interactions. Tau oligomers and filaments hinder protein synthesis in vitro, and they associate strongly with ribosomes in vivo. Here, we investigated the consequences of tau interactions with ribosomes in transgenic mice, in cells, and in human brain tissues to identify tau as a direct modulator of ribosomal selectivity. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-019-01970-9DOI Listing
February 2019

Papillary glioneuronal tumor (PGNT) exhibits a characteristic methylation profile and fusions involving PRKCA.

Acta Neuropathol 2019 Feb 13. Epub 2019 Feb 13.

Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Papillary glioneuronal tumor (PGNT) is a WHO-defined brain tumor entity that poses a major diagnostic challenge. Recently, SLC44A1-PRKCA fusions have been described in PGNT. We subjected 28 brain tumors from different institutions histologically diagnosed as PGNT to molecular and morphological analysis. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-019-01969-2DOI Listing
February 2019

Translational control in brain pathologies: biological significance and therapeutic opportunities.

Acta Neuropathol 2019 Feb 9. Epub 2019 Feb 9.

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

Messenger RNA (mRNA) translation is the terminal step in protein synthesis, providing a crucial regulatory checkpoint for this process. Translational control allows specific cell types to respond to rapid changes in the microenvironment or to serve specific functions. For example, neurons use mRNA transport to achieve local protein synthesis at significant distances from the nucleus, the site of RNA transcription. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-019-01971-8DOI Listing
February 2019

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.

Authors:
Cyril Pottier Yingxue Ren Ralph B Perkerson Matt Baker Gregory D Jenkins Marka van Blitterswijk Mariely DeJesus-Hernandez Jeroen G J van Rooij Melissa E Murray Elizabeth Christopher Shannon K McDonnell Zachary Fogarty Anthony Batzler Shulan Tian Cristina T Vicente Billie Matchett Anna M Karydas Ging-Yuek Robin Hsiung Harro Seelaar Merel O Mol Elizabeth C Finger Caroline Graff Linn Öijerstedt Manuela Neumann Peter Heutink Matthis Synofzik Carlo Wilke Johannes Prudlo Patrizia Rizzu Javier Simon-Sanchez Dieter Edbauer Sigrun Roeber Janine Diehl-Schmid Bret M Evers Andrew King M Marsel Mesulam Sandra Weintraub Changiz Geula Kevin F Bieniek Leonard Petrucelli Geoffrey L Ahern Eric M Reiman Bryan K Woodruff Richard J Caselli Edward D Huey Martin R Farlow Jordan Grafman Simon Mead Lea T Grinberg Salvatore Spina Murray Grossman David J Irwin Edward B Lee EunRan Suh Julie Snowden David Mann Nilufer Ertekin-Taner Ryan J Uitti Zbigniew K Wszolek Keith A Josephs Joseph E Parisi David S Knopman Ronald C Petersen John R Hodges Olivier Piguet Ethan G Geier Jennifer S Yokoyama Robert A Rissman Ekaterina Rogaeva Julia Keith Lorne Zinman Maria Carmela Tartaglia Nigel J Cairns Carlos Cruchaga Bernardino Ghetti Julia Kofler Oscar L Lopez Thomas G Beach Thomas Arzberger Jochen Herms Lawrence S Honig Jean Paul Vonsattel Glenda M Halliday John B Kwok Charles L White Marla Gearing Jonathan Glass Sara Rollinson Stuart Pickering-Brown Jonathan D Rohrer John Q Trojanowski Vivianna Van Deerlin Eileen H Bigio Claire Troakes Safa Al-Sarraj Yan Asmann Bruce L Miller Neill R Graff-Radford Bradley F Boeve William W Seeley Ian R A Mackenzie John C van Swieten Dennis W Dickson Joanna M Biernacka Rosa Rademakers

Acta Neuropathol 2019 Feb 9. Epub 2019 Feb 9.

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

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25. Read More

View Article

Download full-text PDF

Source
http://link.springer.com/10.1007/s00401-019-01962-9
Publisher Site
http://dx.doi.org/10.1007/s00401-019-01962-9DOI Listing
February 2019
3 Reads

Frontal cortex and striatal cellular and molecular pathobiology in individuals with Down syndrome with and without dementia.

Acta Neuropathol 2019 Feb 7. Epub 2019 Feb 7.

Department of Neurobiology and Neurology, Barrow Neurological Institute, 350 W. Thomas St, Phoenix, AZ, 85013, USA.

Although, by age 40, individuals with Down syndrome (DS) develop amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles (NFTs) linked to cognitive impairment in Alzheimer's disease (AD), not all people with DS develop dementia. Whether Aβ plaques and NFTs are associated with individuals with DS with (DSD +) and without dementia (DSD -) is under-investigated. Here, we applied quantitative immunocytochemistry and fluorescent procedures to characterize NFT pathology using antibodies specific for tau phosphorylation (pS422, AT8), truncation (TauC3, MN423), and conformational (Alz50, MC1) epitopes, as well as Aβ and its precursor protein (APP) to frontal cortex (FC) and striatal tissue from DSD + to DSD - cases. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-019-01965-6DOI Listing
February 2019
10.762 Impact Factor

Beta-amyloid pathology in human brain microvessel extracts from the parietal cortex: relation with cerebral amyloid angiopathy and Alzheimer's disease.

Acta Neuropathol 2019 Feb 7. Epub 2019 Feb 7.

Faculté de pharmacie, Université Laval, Quebec, QC, Canada.

Several pieces of evidence suggest that blood-brain barrier (BBB) dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD), exemplified by the frequent occurrence of cerebral amyloid angiopathy (CAA) and the defective clearance of Aβ peptides. However, the specific role of brain microvascular cells in these anomalies remains elusive. In this study, we validated by Western, ELISA and immunofluorescence analyses a procedure to generate microvasculature-enriched fractions from frozen samples of human cerebral cortex. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-019-01967-4DOI Listing
February 2019
3 Reads

Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo.

Acta Neuropathol 2019 Feb 5. Epub 2019 Feb 5.

Biomedical Research Institute, Hasselt University, 3500, Hasselt, Belgium.

Brains of Alzheimer's disease patients are characterized by the presence of amyloid plaques and neurofibrillary tangles, both invariably associated with neuroinflammation. A crucial role for NLRP3-ASC inflammasome [NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-Apoptosis-associated speck-like protein containing a CARD (ASC)] in amyloid-beta (Aβ)-induced microgliosis and Aβ pathology has been unequivocally identified. Aβ aggregates activate NLRP3-ASC inflammasome (Halle et al. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-01957-yDOI Listing
February 2019
2 Reads

Retinal α-synuclein deposits in Parkinson's disease patients and animal models.

Acta Neuropathol 2019 Feb 5. Epub 2019 Feb 5.

Research Group of Neural Circuit Development and Regeneration, Department of Biology, KU Leuven, Naamsestraat 61, Box 2464, Louvain, Belgium.

Despite decades of research, accurate diagnosis of Parkinson's disease remains a challenge, and disease-modifying treatments are still lacking. Research into the early (presymptomatic) stages of Parkinson's disease and the discovery of novel biomarkers is of utmost importance to reduce this burden and to come to a more accurate diagnosis at the very onset of the disease. Many have speculated that non-motor symptoms could provide a breakthrough in the quest for early biomarkers of Parkinson's disease, including the visual disturbances and retinal abnormalities that are seen in the majority of Parkinson's disease patients. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-01956-zDOI Listing
February 2019

Disrupted neuronal trafficking in amyotrophic lateral sclerosis.

Acta Neuropathol 2019 Feb 5. Epub 2019 Feb 5.

Department of Translational Neuroscience, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.

Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset neurodegenerative disease caused by degeneration of motor neurons in the brain and spinal cord leading to muscle weakness. Median survival after symptom onset in patients is 3-5 years and no effective therapies are available to treat or cure ALS. Therefore, further insight is needed into the molecular and cellular mechanisms that cause motor neuron degeneration and ALS. Read More

View Article

Download full-text PDF

Source
http://link.springer.com/10.1007/s00401-019-01964-7
Publisher Site
http://dx.doi.org/10.1007/s00401-019-01964-7DOI Listing
February 2019
3 Reads

Wide distribution of alpha-synuclein oligomers in multiple system atrophy brain detected by proximity ligation.

Acta Neuropathol 2019 Feb 5. Epub 2019 Feb 5.

Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.

Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease that is characterized by varying degrees of cerebellar dysfunction and Parkinsonism. The neuropathological hallmark of MSA is alpha-synuclein (AS)-positive glial cytoplasmic inclusions (GCIs). Although severe neuronal loss (NL) is also observed in MSA, neuronal inclusions (NIs) are rare compared to GCIs, such that the pathological mechanism of NL in MSA is unclear. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-019-01961-wDOI Listing
February 2019

Integrated DNA methylation and gene expression profiling across multiple brain regions implicate novel genes in Alzheimer's disease.

Acta Neuropathol 2019 Feb 2. Epub 2019 Feb 2.

Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 N Wolfe St, Suite 300, Baltimore, MD, 21205, USA.

Late-onset Alzheimer's disease (AD) is a complex age-related neurodegenerative disorder that likely involves epigenetic factors. To better understand the epigenetic state associated with AD, we surveyed 420,852 DNA methylation (DNAm) sites from neurotypical controls (N = 49) and late-onset AD patients (N = 24) across four brain regions (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex and cerebellum). We identified 858 sites with robust differential methylation collectively annotated to 772 possible genes (FDR < 5%, within 10 kb). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-019-01966-5DOI Listing
February 2019
1 Read

ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).

Acta Neuropathol 2019 Jan 30. Epub 2019 Jan 30.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.

The identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-019-01963-8DOI Listing
January 2019

Multiple system atrophy prions retain strain specificity after serial propagation in two different Tg(SNCA*A53T) mouse lines.

Acta Neuropathol 2019 Jan 28. Epub 2019 Jan 28.

Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.

Previously, we reported that intracranial inoculation of brain homogenate from multiple system atrophy (MSA) patient samples produces neurological disease in the transgenic (Tg) mouse model TgM83, which uses the prion protein promoter to express human α-synuclein harboring the A53T mutation found in familial Parkinson's disease (PD). In our studies, we inoculated MSA and control patient samples into Tg mice constructed using a P1 artificial chromosome to express wild-type (WT), A30P, and A53T human α-synuclein on a mouse α-synuclein knockout background [Tg(SNCA)Nbm, Tg(SNCA*A30P)Nbm, and Tg(SNCA*A53T)Nbm]. In contrast to studies using TgM83 mice, motor deficits were not observed by 330-400 days in any of the Tg(SNCA)Nbm mice after inoculation with MSA brain homogenates. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-019-01959-4DOI Listing
January 2019

Antisense RNA foci are associated with nucleoli and TDP-43 mislocalization in C9orf72-ALS/FTD: a quantitative study.

Acta Neuropathol 2019 Jan 21. Epub 2019 Jan 21.

Department of Neuroscience, University of California, San Diego, 9500 Gilman Drive, MS-0624, La Jolla, CA, 92093, USA.

View Article

Download full-text PDF

Source
http://link.springer.com/10.1007/s00401-018-01955-0
Publisher Site
http://dx.doi.org/10.1007/s00401-018-01955-0DOI Listing
January 2019
3 Reads

Microglial nodules provide the environment for pathogenic T cells in human encephalitis.

Acta Neuropathol 2019 Jan 20. Epub 2019 Jan 20.

Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, 1090, Vienna, Austria.

Microglia nodule formation is a common feature in inflammatory brain diseases mediated by T lymphocytes such as viral and paraneoplastic encephalitis, multiple sclerosis, and Rasmussen encephalitis (RE). However, its role has not been fully understood yet. We hypothesized that, in RE, microglial nodules provide an environment for the initiation of the later dominating T-cell cytotoxicity. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-019-01958-5DOI Listing
January 2019
3 Reads

Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains.

Acta Neuropathol 2019 Feb 2;137(2):227-238. Epub 2019 Jan 2.

Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.

TDP-43 is present in a high proportion of aged brains that do not meet criteria for frontotemporal lobar degeneration (FTLD). We determined whether there are distinct TDP-43 types in non-FTLD brains. From a cohort of 553 brains (Braak neurofibrillary tangle (NFT) stage 0-VI), excluding cases meeting criteria for FTLD, we identified those that had screened positive for TDP-43. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1951-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358471PMC
February 2019
1 Read

C9orf72 arginine-rich dipeptide proteins interact with ribosomal proteins in vivo to induce a toxic translational arrest that is rescued by eIF1A.

Acta Neuropathol 2019 Jan 2. Epub 2019 Jan 2.

Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.

A GGGGCC hexanucleotide repeat expansion within the C9orf72 gene is the most common genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Sense and antisense repeat-containing transcripts undergo repeat-associated non-AUG-initiated translation to produce five dipeptide proteins (DPRs). The polyGR and polyPR DPRs are extremely toxic when expressed in Drosophila neurons. Read More

View Article

Download full-text PDF

Source
http://link.springer.com/10.1007/s00401-018-1946-4
Publisher Site
http://dx.doi.org/10.1007/s00401-018-1946-4DOI Listing
January 2019
9 Reads

Amyloid-β pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo.

Acta Neuropathol 2019 Jan 1. Epub 2019 Jan 1.

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

Neuropathological analysis in Alzheimer's disease (AD) and experimental evidence in transgenic models overexpressing frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) mutant tau suggest that amyloid-β pathology enhances the development of tau pathology. In this work, we analyzed this interaction independently of the overexpression of an FTDP-17 mutant tau, by analyzing tau pathology in wild-type (WT), 5xFAD, APP and tau mice after stereotaxic injection in the somatosensory cortex of short-length native human AD-PHF. Gallyas and phosphotau-positive tau inclusions developed in WT, 5xFAD, and APP but not in tau mice. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1953-5DOI Listing
January 2019
1 Read

The impact of histopathology and NAB2-STAT6 fusion subtype in classification and grading of meningeal solitary fibrous tumor/hemangiopericytoma.

Acta Neuropathol 2019 Feb 24;137(2):307-319. Epub 2018 Dec 24.

Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street, SW, Rochester, MN, 55905, USA.

Meningeal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) is a rare tumor with propensity for recurrence and metastasis. Although multiple classification schemes have been proposed, optimal risk stratification remains unclear, and the prognostic impact of fusion status is uncertain. We compared the 2016 WHO CNS tumor grading scheme (CNS-G), a three-tier system based on histopathologic phenotype and mitotic count, to the 2013 WHO soft-tissue counterpart (ST-G), a two-tier system based on mitotic count alone, in a cohort of 133 patients [59 female, 74 male; mean age 54 years (range 20-87)] with meningeal SFT/HPC. Read More

View Article

Download full-text PDF

Source
http://link.springer.com/10.1007/s00401-018-1952-6
Publisher Site
http://dx.doi.org/10.1007/s00401-018-1952-6DOI Listing
February 2019
7 Reads

Microglial cell loss after ischemic stroke favors brain neutrophil accumulation.

Acta Neuropathol 2019 Feb 22;137(2):321-341. Epub 2018 Dec 22.

Department of Brain Ischemia and Neurodegeneration, Institut d'Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Rossello 161 planta 6, Barcelona, 08036, España.

Stroke attracts neutrophils to the injured brain tissue where they can damage the integrity of the blood-brain barrier and exacerbate the lesion. However, the mechanisms involved in neutrophil transmigration, location and accumulation in the ischemic brain are not fully elucidated. Neutrophils can reach the perivascular spaces of brain vessels after crossing the endothelial cell layer and endothelial basal lamina of post-capillary venules, or migrating from the leptomeninges following pial vessel extravasation and/or a suggested translocation from the skull bone marrow. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1954-4DOI Listing
February 2019
1 Read

Seeding selectivity and ultrasensitive detection of tau aggregate conformers of Alzheimer disease.

Acta Neuropathol 2018 Dec 20. Epub 2018 Dec 20.

LPVD, Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, 59840, USA.

Alzheimer disease (AD) and chronic traumatic encephalopathy (CTE) involve the abnormal accumulation in the brain of filaments composed of both three-repeat (3R) and four-repeat (4R) (3R/4R) tau isoforms. To probe the molecular basis for AD's tau filament propagation and to improve detection of tau aggregates as potential biomarkers, we have exploited the seeded polymerization growth mechanism of tau filaments to develop a highly selective and ultrasensitive cell-free tau seed amplification assay optimized for AD (AD real-time quaking-induced conversion or AD RT-QuIC). The reaction is based on the ability of AD tau aggregates to seed the formation of amyloid fibrils made of certain recombinant tau fragments. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1947-3DOI Listing
December 2018
4 Reads

Circulating AQP4-specific auto-antibodies alone can induce neuromyelitis optica spectrum disorder in the rat.

Acta Neuropathol 2018 Dec 18. Epub 2018 Dec 18.

Department of Neuroimmunology, Center for Brain Research, Medical University Vienna, Spitalgasse 4, 1090, Vienna, Austria.

It is well established that the binding of pathogenic aquaporin-4 (AQP4)-specific autoantibodies to astrocytes may initiate a cascade of events culminating in the destruction of these cells and in the formation of large tissue-destructive lesions typical for patients with neuromyelitis optica spectrum disorders (NMOSD). To date, not a single experimental study has shown that the systemic presence of the antibody alone can induce any damage to the central nervous system (CNS), while pathological studies on brains of NMOSD patients suggested that there might be ways for antibody entry and subsequent tissue damage. Here, we systemically applied a highly pathogenic, monoclonal antibody with high affinity to AQP4 over prolonged period of time to rats, and show that AQP4-abs can enter the CNS on their own, via circumventricular organs and meningeal or parenchymal blood vessels, that these antibodies initiate the formation of radically different lesions with AQP4 loss, depending on their mode and site of entry, and that lesion formation is much more efficient in the presence of encephalitogenic T-cell responses. Read More

View Article

Download full-text PDF

Source
http://link.springer.com/10.1007/s00401-018-1950-8
Publisher Site
http://dx.doi.org/10.1007/s00401-018-1950-8DOI Listing
December 2018
2 Reads
10.762 Impact Factor

Novel tau fragments in cerebrospinal fluid: relation to tangle pathology and cognitive decline in Alzheimer's disease.

Acta Neuropathol 2019 Feb 13;137(2):279-296. Epub 2018 Dec 13.

Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Göteborgsvägen 31, House V3/SU, 43180, Mölndal, Sweden.

Tau is an axonal microtubule-binding protein. Tau pathology in brain and increased tau concentration in the cerebrospinal fluid (CSF) are hallmarks of Alzheimer's disease (AD). Most of tau in CSF is present as fragments. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1948-2DOI Listing
February 2019
10 Reads

The complexity of neuroinflammation consequent to traumatic brain injury: from research evidence to potential treatments.

Acta Neuropathol 2018 Dec 7. Epub 2018 Dec 7.

Wicking Dementia Research and Education Centre, College of Health and Medicine, University of Tasmania, Hobart, TAS, Australia.

This review recounts the definitions and research evidence supporting the multifaceted roles of neuroinflammation in the injured brain following trauma. We summarise the literature fluctuating from the protective and detrimental properties that cytokines, leukocytes and glial cells play in the acute and chronic stages of TBI, including the intrinsic factors that influence cytokine responses and microglial functions relative to genetics, sex, and age. We elaborate on the pros and cons that cytokines, chemokines, and microglia play in brain repair, specifically neurogenesis, and how such conflicting roles may be harnessed therapeutically to sustain the survival of new neurons. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1944-6DOI Listing
December 2018
1 Read

Enteric alpha-synuclein expression is increased in Crohn's disease.

Acta Neuropathol 2019 Feb 30;137(2):359-361. Epub 2018 Nov 30.

Inserm, U1235, Place Gaston Veil, 44035, Nantes, France.

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1943-7DOI Listing
February 2019
8 Reads
10.762 Impact Factor

Neurons selectively targeted in frontotemporal dementia reveal early stage TDP-43 pathobiology.

Acta Neuropathol 2019 Jan 3;137(1):27-46. Epub 2018 Dec 3.

Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.

TAR DNA-binding protein 43 (TDP-43) aggregation is the most common pathological hallmark in frontotemporal dementia (FTD) and characterizes nearly all patients with motor neuron disease (MND). The earliest stages of TDP-43 pathobiology are not well-characterized, and whether neurodegeneration results from TDP-43 loss-of-function or aggregation remains unclear. In the behavioral variant of FTD (bvFTD), patients undergo selective dropout of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1942-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339592PMC
January 2019
9 Reads

Current state of Alzheimer's fluid biomarkers.

Acta Neuropathol 2018 Dec 28;136(6):821-853. Epub 2018 Nov 28.

Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1932-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280827PMC
December 2018
1 Read

Post-stroke inflammation-target or tool for therapy?

Acta Neuropathol 2018 Nov 27. Epub 2018 Nov 27.

Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000, Odense, Denmark.

Inflammation is currently considered a prime target for the development of new stroke therapies. In the acute phase of ischemic stroke, microglia are activated and then circulating immune cells invade the peri-infarct and infarct core. Resident and infiltrating cells together orchestrate the post-stroke inflammatory response, communicating with each other and the ischemic neurons, through soluble and membrane-bound signaling molecules, including cytokines. Read More

View Article

Download full-text PDF

Source
http://link.springer.com/10.1007/s00401-018-1930-z
Publisher Site
http://dx.doi.org/10.1007/s00401-018-1930-zDOI Listing
November 2018
12 Reads

Renewed assessment of the risk of emergent advanced cell therapies to transmit neuroproteinopathies.

Acta Neuropathol 2018 Nov 27. Epub 2018 Nov 27.

Centre for Clinical Brain Sciences, University of Edinburgh, Chancellors Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.

The inadvertent transmission of long incubating, untreatable and fatal neurodegenerative prionopathies, notably iatrogenic Creutzfeldt-Jakob disease, following transplantation of cadaver-derived corneas, pituitary growth, hormones and dura mater, constitutes a historical precedent which has underpinned the application of precautionary principles to modern day advanced cell therapies. To date these have been reflected by geographic or medical history risk-based deferral of tissue donors. Emergent understanding of other prion-like proteinopathies, their potential independence from prions as a transmissible agent and the variable capability of scalably manufacturable stem cells and derivatives to take up and clear or to propagate prions, substantiate further commitment to qualifying neurodegenerative proteinopathy transmission risks. Read More

View Article

Download full-text PDF

Source
http://link.springer.com/10.1007/s00401-018-1941-9
Publisher Site
http://dx.doi.org/10.1007/s00401-018-1941-9DOI Listing
November 2018
10 Reads

The role of de novo mutations in adult-onset neurodegenerative disorders.

Acta Neuropathol 2019 Feb 26;137(2):183-207. Epub 2018 Nov 26.

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

The genetic underpinnings of the most common adult-onset neurodegenerative disorders (AOND) are complex in majority of the cases. In some families, however, the disease can be inherited in a Mendelian fashion as an autosomal-dominant trait. Next to that, patients carrying mutations in the same disease genes have been reported despite a negative family history. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1939-3DOI Listing
February 2019
2 Reads

TIA1 regulates the generation and response to toxic tau oligomers.

Acta Neuropathol 2019 Feb 21;137(2):259-277. Epub 2018 Nov 21.

Department of Pharmacology and Experimental Therapeutics, Boston University, School of Medicine, Boston, MA, 02118, USA.

RNA binding proteins (RBPs) are strongly linked to the pathophysiology of motor neuron diseases. Recent studies show that RBPs, such as TIA1, also contribute to the pathophysiology of tauopathy. RBPs co-localize with tau pathology, and reduction of TIA1 protects against tau-mediated neurodegeneration. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1937-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377165PMC
February 2019
18 Reads

Chromosome arm 1q gain is an adverse prognostic factor in localized and diffuse leptomeningeal glioneuronal tumors with BRAF gene fusion and 1p deletion.

Acta Neuropathol 2019 Jan 21;137(1):179-181. Epub 2018 Nov 21.

Cytogenetics Laboratory, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

View Article

Download full-text PDF

Source
http://link.springer.com/10.1007/s00401-018-1940-x
Publisher Site
http://dx.doi.org/10.1007/s00401-018-1940-xDOI Listing
January 2019
15 Reads
10.762 Impact Factor

Inflammation in ALS/FTD pathogenesis.

Acta Neuropathol 2018 Nov 21. Epub 2018 Nov 21.

Board of Governors Regenerative Medicine Institute, Los Angeles, USA.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that overlap in their clinical presentation, pathology and genetics, and likely represent a spectrum of one underlying disease. In ALS/FTD patients, neuroinflammation characterized by innate immune responses of tissue-resident glial cells is uniformly present on end-stage pathology, and human imaging studies and rodent models support that neuroinflammation begins early in disease pathogenesis. Additionally, changes in circulating immune cell populations and cytokines are found in ALS/FTD patients, and there is evidence for an autoinflammatory state. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1933-9DOI Listing
November 2018
4 Reads

Molecular profiling of tumors of the brainstem by sequencing of CSF-derived circulating tumor DNA.

Acta Neuropathol 2019 Feb 20;137(2):297-306. Epub 2018 Nov 20.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Nan Si Huan Xi Lu 119, Fengtai District, Beijing, 100070, China.

Brainstem gliomas are molecularly heterogeneous diseases, many of which are difficult to safely surgically resect and have limited treatment options due to their eloquent location. These constraints pose challenges to biopsy, which limits the use of routine molecular profiling and identification of personalized therapies. Here, we explored the potential of sequencing of circulating tumor DNA (ctDNA) isolated from the cerebrospinal fluid (CSF) of brainstem glioma patients as a less invasive approach for tumor molecular profiling. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1936-6DOI Listing
February 2019
24 Reads
10.762 Impact Factor

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology.

Acta Neuropathol 2019 Jan 19;137(1):47-69. Epub 2018 Nov 19.

Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Insoluble aggregates containing TDP-43 are widely observed in the diseased brain, and defined as "TDP-43 pathology" in a spectrum of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease and ALS with frontotemporal dementia. Here we report that Betz cells of patients with TDP-43 pathology display a distinct set of intracellular defects especially at the site of nuclear membrane, mitochondria and endoplasmic reticulum (ER). Numerous TDP-43 mouse models have been generated to discern the cellular and molecular basis of the disease, but mechanisms of neuronal vulnerability remain unknown. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1934-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6339587PMC
January 2019
2 Reads

Differential impact of pure glyphosate and glyphosate-based herbicide in a model of peripheral nervous system myelination.

Acta Neuropathol 2018 Dec 16;136(6):979-982. Epub 2018 Nov 16.

Department of Neurology, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1938-4DOI Listing
December 2018
1 Read

"When sex influences the brain: implications for Alzheimer disease".

Authors:
Matthew P Frosch

Acta Neuropathol 2018 Dec;136(6):855-856

C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1931-yDOI Listing
December 2018
1 Read

The metalloprotease ADAMTS4 generates N-truncated Aβ4-x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer's disease.

Acta Neuropathol 2019 Feb 13;137(2):239-257. Epub 2018 Nov 13.

Department of Neuropathology, Heinrich-Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany.

Brain accumulation and aggregation of amyloid-β (Aβ) peptides is a critical step in the pathogenesis of Alzheimer's disease (AD). Full-length Aβ peptides (mainly Aβ1-40 and Aβ1-42) are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. However, studies of autopsy brain samples from AD patients have demonstrated that a large fraction of insoluble Aβ peptides are truncated at the N-terminus, with Aβ4-x peptides being particularly abundant. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1929-5DOI Listing
February 2019
11 Reads

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease.

Acta Neuropathol 2019 Feb 9;137(2):209-226. Epub 2018 Nov 9.

Neuroradiology Section, L-352, Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 94143, USA.

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1928-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358498PMC
February 2019
16 Reads

Inner ear pathologies impair sodium-regulated ion transport in Meniere's disease.

Acta Neuropathol 2019 Feb 2;137(2):343-357. Epub 2018 Nov 2.

Otopathology Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA, USA.

Meniere's disease (MD), a syndromal inner ear disease, is commonly associated with a pathological accumulation of endolymphatic fluid in the inner ear, termed "idiopathic" endolymphatic hydrops (iEH). Although numerous precipitating/exacerbating factors have been proposed for MD, its etiology remains elusive. Here, using immunohistochemistry and in situ protein-protein interaction detection assays, we demonstrate mineralocorticoid-controlled sodium transport mechanisms in the epithelium of the extraosseous portion of the endolymphatic sac (eES) in the murine and human inner ears. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1927-7DOI Listing
February 2019
12 Reads

Rare variants in the neuronal ceroid lipofuscinosis gene MFSD8 are candidate risk factors for frontotemporal dementia.

Acta Neuropathol 2019 Jan 31;137(1):71-88. Epub 2018 Oct 31.

Department of Neurology, Memory and Aging Center, University of California, San Francisco, 675 Nelson Rising Lane, Suite 190, San Francisco, CA, 94158, USA.

Pathogenic variation in MAPT, GRN, and C9ORF72 accounts for at most only half of frontotemporal lobar degeneration (FTLD) cases with a family history of neurological disease. This suggests additional variants and genes that remain to be identified as risk factors for FTLD. We conducted a case-control genetic association study comparing pathologically diagnosed FTLD patients (n = 94) to cognitively normal older adults (n = 3541), and found suggestive evidence that gene-wide aggregate rare variant burden in MFSD8 is associated with FTLD risk. Read More

View Article

Download full-text PDF

Source
http://link.springer.com/10.1007/s00401-018-1925-9
Publisher Site
http://dx.doi.org/10.1007/s00401-018-1925-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371791PMC
January 2019
3 Reads

The aftermath of boxing revisited: identifying chronic traumatic encephalopathy pathology in the original Corsellis boxer series.

Acta Neuropathol 2018 Dec 30;136(6):973-974. Epub 2018 Oct 30.

Division of Brain Sciences, Department of Medicine, Imperial College London, 4th Floor Burlington Danes Building, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK.

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-018-1926-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280830PMC
December 2018
2 Reads

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies.

Acta Neuropathol 2019 Jan 27;137(1):1-26. Epub 2018 Oct 27.

Memory and Aging Center, Department of Neurology, University of California, San Francisco, USA.

What are the most important and treatable pathogenic mechanisms in C9orf72-FTD/ALS? Model-based efforts to address this question are forging ahead at a blistering pace, often with conflicting results. But what does the human neuropathological literature reveal? Here, we provide a critical review of the human studies to date, seeking to highlight key gaps or uncertainties in our knowledge. First, we engage the C9orf72-specific mechanisms, including C9orf72 haploinsufficiency, repeat RNA foci, and dipeptide repeat protein inclusions. Read More

View Article

Download full-text PDF

Source
http://link.springer.com/10.1007/s00401-018-1921-0
Publisher Site
http://dx.doi.org/10.1007/s00401-018-1921-0DOI Listing
January 2019
5 Reads

Evidence of intraneuronal Aβ accumulation preceding tau pathology in the entorhinal cortex.

Acta Neuropathol 2018 Dec 25;136(6):901-917. Epub 2018 Oct 25.

Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Growing evidence gathered from transgenic animal models of Alzheimer's disease (AD) indicates that the intraneuronal accumulation of amyloid-β (Aβ) peptides is an early event in the AD pathogenesis, producing cognitive deficits before the deposition of insoluble plaques. Levels of soluble Aβ are also a strong indicator of synaptic deficits and concurrent AD neuropathologies in post-mortem AD brain; however, it remains poorly understood how this soluble amyloid pool builds within the brain in the decades leading up to diagnosis, when a patient is likely most amenable to early therapeutic interventions. Indeed, characterizing early intracellular Aβ accumulation in humans has been hampered by the lack of Aβ-specific antibodies, variability in the quality of available human brain tissue and the limitations of conventional microscopy. Read More

View Article

Download full-text PDF

Source
http://link.springer.com/10.1007/s00401-018-1922-z
Publisher Site
http://dx.doi.org/10.1007/s00401-018-1922-zDOI Listing
December 2018
7 Reads