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    8049 results match your criteria Acta neuropathologica[Journal]

    1 OF 161

    Energy metabolism in ALS: an underappreciated opportunity?
    Acta Neuropathol 2018 Mar 16. Epub 2018 Mar 16.
    Department of Neurosciences, Experimental Neurology, KU Leuven-University of Leuven, Campus Gasthuisberg O&N 4, Herestraat 49, PB 602, 3000, Leuven, Belgium.
    Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disorder that primarily affects motor neurons. Despite our increased understanding of the genetic factors contributing to ALS, no effective treatment is available. A growing body of evidence shows disturbances in energy metabolism in ALS. Read More

    Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target.
    Acta Neuropathol 2018 Mar 14. Epub 2018 Mar 14.
    Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
    Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. Read More

    Aberrant cerebellar Purkinje cell function repaired in vivo by fusion with infiltrating bone marrow-derived cells.
    Acta Neuropathol 2018 Mar 14. Epub 2018 Mar 14.
    Multiple Sclerosis and Stem Cell Group, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
    Bone marrow-derived cells are known to infiltrate the adult brain and fuse with cerebellar Purkinje cells. Histological observations that such heterotypic cell fusion events are substantially more frequent following cerebellar injury suggest they could have a role in the protection of mature brain neurons. To date, the possibility that cell fusion can preserve or restore the structure and function of adult brain neurons has not been directly addressed; indeed, though frequently suggested, the possibility of benefit has always been rather speculative. Read More

    Interaction of amyloidogenic proteins in pancreatic β cells from subjects with synucleinopathies.
    Acta Neuropathol 2018 Mar 13. Epub 2018 Mar 13.
    Neurology Department, Clinica Universidad de Navarra, Avenida de Pio XII 36, 31008, Pamplona, Navarra, Spain.
    Parkinson's disease patients experience a wide range of non-motor symptoms that may be provoked by deposits of phosphorylated α-synuclein in the peripheral nervous system. Pre-existing diabetes mellitus might be a risk factor for developing Parkinson's disease, and indeed, nearly 60% of Parkinson's disease patients are insulin resistant. Thus, we have investigated whether phosphorylated α-synuclein is deposited in pancreatic tissue of subjects with synucleinopathies. Read More

    Fatal Aβ cerebral amyloid angiopathy 4 decades after a dural graft at the age of 2 years.
    Acta Neuropathol 2018 Mar 5. Epub 2018 Mar 5.
    Département de Neuropathologie Raymond Escourolle, GH Pitié-Salpêtrière, Faculté de médecine Sorbonne Université, Paris, France.

    Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity.
    Acta Neuropathol 2018 Mar 3. Epub 2018 Mar 3.
    Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Philadelphia, PA, 19104-4283, USA.
    The accumulation of misfolded α-synuclein (aSyn) and neuron loss define several neurodegenerative disorders including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the precise relationship between pathology and neurotoxicity and why these processes disproportionately affect certain neuron subpopulations are poorly understood. We show here that Math2-expressing neurons in the hippocampal Cornu ammonis (CA), a region significantly affected by aSyn pathology in advanced PD and DLB, are highly susceptible to pathological seeding with pre-formed fibrils (PFFs), in contrast to dentate gyrus neurons, which are relatively spared. Read More

    Diffuse gliomas classified by 1p/19q co-deletion, TERT promoter and IDH mutation status are associated with specific genetic risk loci.
    Acta Neuropathol 2018 Feb 19. Epub 2018 Feb 19.
    Sorbonne Universités UPMC Univ Paris 06, INSERM CNRS, U1127, UMR 7225, ICM, 75013, Paris, France.
    Recent genome-wide association studies of glioma have led to the discovery of single nucleotide polymorphisms (SNPs) at 25 loci influencing risk. Gliomas are heterogeneous, hence to investigate the relationship between risk SNPs and glioma subtype we analysed 1659 tumours profiled for IDH mutation, TERT promoter mutation and 1p/19q co-deletion. These data allowed definition of five molecular subgroups of glioma: triple-positive (IDH mutated, 1p/19q co-deletion, TERT promoter mutated); TERT-IDH (IDH mutated, TERT promoter mutated, 1p/19q-wild-type); IDH-only (IDH mutated, 1p/19q wild-type, TERT promoter wild-type); triple-negative (IDH wild-type, 1p/19q wild-type, TERT promoter wild-type) and TERT-only (TERT promoter mutated, IDH wild-type, 1p/19q wild-type). Read More

    Mechanical disruption of the blood-brain barrier following experimental concussion.
    Acta Neuropathol 2018 Feb 19. Epub 2018 Feb 19.
    Department of Neurosurgery, Penn Center for Brain Injury and Repair, Perelman School of Medicine, University of Pennsylvania, 105 Hayden Hall, 3320 Smith Walk, Philadelphia, PA, 19104, USA.
    Although concussion is now recognized as a major health issue, its non-lethal nature has limited characterization of the underlying pathophysiology. In particular, potential neuropathological changes have typically been inferred from non-invasive techniques or post-mortem examinations of severe traumatic brain injury (TBI). Here, we used a swine model of head rotational acceleration based on human concussion to examine blood-brain barrier (BBB) integrity after injury in association with diffuse axonal injury and glial responses. Read More

    Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery.
    Acta Neuropathol 2018 Feb 15. Epub 2018 Feb 15.
    Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, Queen Square, London, WC1N 3BG, UK.
    Amyloid-β (Aβ) is a peptide deposited in the brain parenchyma in Alzheimer's disease and in cerebral blood vessels, causing cerebral amyloid angiopathy (CAA). Aβ pathology is transmissible experimentally in animals and through medical procedures in humans, such as contaminated growth hormone or dura mater transplantation in the context of iatrogenic prion disease. Here, we present four patients who underwent neurosurgical procedures during childhood or teenage years and presented with intracerebral haemorrhage approximately three decades later, caused by severe CAA. Read More

    Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis.
    Acta Neuropathol 2018 Feb 13. Epub 2018 Feb 13.
    Laboratory of Neuroimmunology, Netherlands Institute for Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA, Amsterdam, The Netherlands.
    Multiple sclerosis (MS) is a highly heterogeneous disease with large inter-individual differences in disease course. MS lesion pathology shows considerable heterogeneity in localization, cellular content and degree of demyelination between patients. In this study, we investigated pathological correlates of disease course in MS using the autopsy cohort of the Netherlands Brain Bank (NBB), containing 182 MS brain donors. Read More

    5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma.
    Acta Neuropathol 2018 Feb 10. Epub 2018 Feb 10.
    MacFeeters-Hamilton Centre for Neuro-Oncology Research, University Health Network, Toronto, Canada.
    Gliomas demonstrate epigenetic dysregulation exemplified by the Glioma CpG Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. 5-Hydroxymethylcytosine (5hmC) is implicated in glioma pathogenesis; however, its role in IDH1 mutant gliomas is incompletely understood. To characterize 5hmC in IDH1 mutant gliomas further, we examine 5hmC in a cohort of IDH1 mutant and wild-type high-grade gliomas (HGG) using a quantitative locus-specific approach. Read More

    Malignant rhabdoid tumors originating within and outside the central nervous system are clinically and molecularly heterogeneous.
    Acta Neuropathol 2018 Feb 10. Epub 2018 Feb 10.
    Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
    Multifocal synchronous or metachronous atypical teratoid rhabdoid tumors (ATRTs) and non-central nervous system malignant rhabdoid tumors (extra-CNS MRTs) are rare cancers. We reviewed the clinical and radiologic characteristics of affected patients seen at our institution. Genotyping and analysis of copy number abnormalities (CNAs) in SMARCB1 were performed in germline and tumor samples. Read More

    The role of brain barriers in fluid movement in the CNS: is there a 'glymphatic' system?
    Acta Neuropathol 2018 Mar 10;135(3):387-407. Epub 2018 Feb 10.
    Division of Pharmaceutical Sciences, University of Wisconsin-Madison School of Pharmacy, Madison, WI, USA.
    Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K, Ca, and protein to optimise signalling and minimise neurotoxicity. Read More

    NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA): characterisation of a novel cerebropulmonary disease.
    Acta Neuropathol 2018 Feb 8. Epub 2018 Feb 8.
    PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, PO Box 5000, 90014, Oulu, Finland.
    A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. Read More

    Functional morphology of the blood-brain barrier in health and disease.
    Acta Neuropathol 2018 Mar 6;135(3):311-336. Epub 2018 Feb 6.
    Department of Medicine, Section of General Pathology, University of Verona, Verona, Italy.
    The adult quiescent blood-brain barrier (BBB), a structure organised by endothelial cells through interactions with pericytes, astrocytes, neurons and microglia in the neurovascular unit, is highly regulated but fragile at the same time. In the past decade, there has been considerable progress in understanding not only the molecular pathways involved in BBB development, but also BBB breakdown in neurological diseases. Specifically, the Wnt/β-catenin, retinoic acid and sonic hedgehog pathways moved into the focus of BBB research. Read More

    Activin receptors regulate the oligodendrocyte lineage in health and disease.
    Acta Neuropathol 2018 Feb 3. Epub 2018 Feb 3.
    Medical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK.
    The most prevalent neurological disorders of myelin include perinatal brain injury leading to cerebral palsy in infants and multiple sclerosis in adults. Although these disorders have distinct etiologies, they share a common neuropathological feature of failed progenitor differentiation into myelin-producing oligodendrocytes and lack of myelin, for which there is an unmet clinical need. Here, we reveal that a molecular pathology common to both disorders is dysregulation of activin receptors and that activin receptor signaling is required for the majority of myelin generation in development and following injury. Read More

    Correction to: Paragangliomas arise through an autonomous vasculo-angio-neurogenic program inhibited by imatinib.
    Acta Neuropathol 2018 Feb 1. Epub 2018 Feb 1.
    Laboratory of General Pathology, Center of Aging Science and Translational Medicine (CeSI-MeT), Gabriele d'Annunzio University, Via Luigi Polacchi 11, 66100, Chieti, Italy.
    The given and family names of two co-authors were incorrect in the published article. The correct spelling should read as: Sampath Chandra Prasad and Vinagolu K Rajasekhar. Read More

    Sense and antisense RNA are not toxic in Drosophila models of C9orf72-associated ALS/FTD.
    Acta Neuropathol 2018 Mar 29;135(3):445-457. Epub 2018 Jan 29.
    Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK.
    A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Neurodegeneration may occur via transcription of the repeats into inherently toxic repetitive sense and antisense RNA species, or via repeat-associated non-ATG initiated translation (RANT) of sense and antisense RNA into toxic dipeptide repeat proteins. We have previously demonstrated that regular interspersion of repeat RNA with stop codons prevents RANT (RNA-only models), allowing us to study the role of repeat RNA in isolation. Read More

    The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS.
    Acta Neuropathol 2018 Mar 24;135(3):363-385. Epub 2018 Jan 24.
    Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark.
    Meninges that surround the CNS consist of an outer fibrous sheet of dura mater (pachymeninx) that is also the inner periosteum of the skull. Underlying the dura are the arachnoid and pia mater (leptomeninges) that form the boundaries of the subarachnoid space. In this review we (1) examine the development of leptomeninges and their role as barriers and facilitators in the foetal CNS. Read More

    Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease.
    Acta Neuropathol 2018 Mar 24;135(3):337-361. Epub 2018 Jan 24.
    Theodor Kocher Institute, University of Bern, Bern, Switzerland.
    The barrier between the blood and the ventricular cerebrospinal fluid (CSF) is located at the choroid plexuses. At the interface between two circulating fluids, these richly vascularized veil-like structures display a peculiar morphology explained by their developmental origin, and fulfill several functions essential for CNS homeostasis. They form a neuroprotective barrier preventing the accumulation of noxious compounds into the CSF and brain, and secrete CSF, which participates in the maintenance of a stable CNS internal environment. Read More

    The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033.
    Acta Neuropathol 2018 Jan 24. Epub 2018 Jan 24.
    Laboratory of Brain Tumor Biology and Genetics, Neuroscience Research Center, Lausanne University Hospital, Chemin des Boveresses 155, CLE-C306, 1066 Epalinges, Lausanne, Switzerland.
    The optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk-adjusted treatments are required for optimizing outcome and quality of life. Read More

    T lymphocytes facilitate brain metastasis of breast cancer by inducing Guanylate-Binding Protein 1 expression.
    Acta Neuropathol 2018 Jan 19. Epub 2018 Jan 19.
    Department of Pathology, Erasmus Medical Center, Wytemaweg 80, 3000 DR, Rotterdam, The Netherlands.
    The discovery of genes and molecular pathways involved in the formation of brain metastasis would direct the development of therapeutic strategies to prevent this deadly complication of cancer. By comparing gene expression profiles of Estrogen Receptor negative (ER-) primary breast tumors between patients who developed metastasis to brain and to organs other than brain, we found that T lymphocytes promote the formation of brain metastases. To functionally test the ability of T cells to promote brain metastasis, we used an in vitro blood-brain barrier (BBB) model. Read More

    BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology.
    Acta Neuropathol 2018 Jan 11. Epub 2018 Jan 11.
    German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen Str. 17, 81377, Munich, Germany.
    BACE1 is the rate-limiting protease in the production of synaptotoxic β-amyloid (Aβ) species and hence one of the prime drug targets for potential therapy of Alzheimer's disease (AD). However, so far pharmacological BACE1 inhibition failed to rescue the cognitive decline in mild-to-moderate AD patients, which indicates that treatment at the symptomatic stage might be too late. In the current study, chronic in vivo two-photon microscopy was performed in a transgenic AD model to monitor the impact of pharmacological BACE1 inhibition on early β-amyloid pathology. Read More

    Paragangliomas arise through an autonomous vasculo-angio-neurogenic program inhibited by imatinib.
    Acta Neuropathol 2018 Jan 5. Epub 2018 Jan 5.
    Laboratory of General Pathology, Center of Aging Science and Translational Medicine (CeSI-MeT), Gabriele d'Annunzio University, Via Luigi Polacchi 11, 66100, Chieti, Italy.
    Tumours can be viewed as aberrant tissues or organs sustained by tumorigenic stem-like cells that engage into dysregulated histo/organogenetic processes. Paragangliomas, prototypical organoid tumours constituted by dysmorphic variants of the vascular and neural tissues found in normal paraganglia, provide a model to test this hypothesis. To understand the origin of paragangliomas, we built a biobank comprising 77 cases, 18 primary cultures, 4 derived cell lines, 80 patient-derived xenografts and 11 cell-derived xenografts. Read More

    Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations.
    Acta Neuropathol 2018 Jan 4. Epub 2018 Jan 4.
    CNR Institute of Neuroscience, via Vanvitelli 32, 20129, Milan, Italy.
    Recent evidence indicates synaptic dysfunction as an early mechanism affected in neuroinflammatory diseases, such as multiple sclerosis, which are characterized by chronic microglia activation. However, the mode(s) of action of reactive microglia in causing synaptic defects are not fully understood. In this study, we show that inflammatory microglia produce extracellular vesicles (EVs) which are enriched in a set of miRNAs that regulate the expression of key synaptic proteins. Read More

    A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism.
    Acta Neuropathol 2018 Mar 4;135(3):427-443. Epub 2018 Jan 4.
    Department of Neurosciences, Experimental Neurology, KU Leuven-University of Leuven, 3000, Leuven, Belgium.
    The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGGGCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Read More

    Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration.
    Acta Neuropathol 2018 Jan 3. Epub 2018 Jan 3.
    Institut NeuroMyogène, Equipe Synaptopathies et Autoanticorps (SynatAc), INSERM U1217/UMR CRS 5310, Lyon, France.
    Paraneoplastic cerebellar degenerations with anti-Yo antibodies (Yo-PCD) are rare syndromes caused by an auto-immune response against neuronal antigens (Ags) expressed by tumor cells. However, the mechanisms responsible for such immune tolerance breakdown are unknown. We characterized 26 ovarian carcinomas associated with Yo-PCD for their tumor immune contexture and genetic status of the 2 onconeural Yo-Ags, CDR2 and CDR2L. Read More

    Functional requirement of a wild-type allele for mutant IDH1 to suppress anchorage-independent growth through redox homeostasis.
    Acta Neuropathol 2018 Feb 29;135(2):285-298. Epub 2017 Dec 29.
    Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, 175 North Medical Drive East, Salt Lake City, UT, 84132, USA.
    Mutations of isocitrate dehydrogenase 1 (IDH1) gene are most common in glioma, arguably preceding all known genetic alterations during tumor development. IDH1 mutations nearly invariably target the enzymatic active site Arg132, giving rise to the predominant IDH1. Cells harboring IDH1-heterozygous mutation produce 2-hydroxyglutarate (2-HG), which results in histone and DNA hypermethylation. Read More

    Synapse loss in the prefrontal cortex is associated with cognitive decline in amyotrophic lateral sclerosis.
    Acta Neuropathol 2018 Feb 22;135(2):213-226. Epub 2017 Dec 22.
    Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, Scotland, UK.
    In addition to motor neurone degeneration, up to 50% of amyotrophic lateral sclerosis (ALS) patients present with cognitive decline. Understanding the neurobiological changes underlying these cognitive deficits is critical, as cognitively impaired patients exhibit a shorter survival time from symptom onset. Given the pathogenic role of synapse loss in other neurodegenerative diseases in which cognitive decline is apparent, such as Alzheimer's disease, we aimed to assess synaptic integrity in the ALS brain. Read More

    Neuronal complex I deficiency occurs throughout the Parkinson's disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage.
    Acta Neuropathol 2018 Mar 21;135(3):409-425. Epub 2017 Dec 21.
    Department of Neurology, Haukeland University Hospital, 5021, Bergen, Norway.
    Mitochondrial complex I deficiency occurs in the substantia nigra of individuals with Parkinson's disease. It is generally believed that this phenomenon is caused by accumulating mitochondrial DNA damage in neurons and that it contributes to the process of neurodegeneration. We hypothesized that if these theories are correct, complex I deficiency should extend beyond the substantia nigra to other affected brain regions in Parkinson's disease and correlate tightly with neuronal mitochondrial DNA damage. Read More

    Distinguishing features of microglia- and monocyte-derived macrophages after stroke.
    Acta Neuropathol 2017 Dec 16. Epub 2017 Dec 16.
    Center for Stroke Research, Klinik für Neurologie, and Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Charitéplatz 1, 10117, Berlin, Germany.
    After stroke, macrophages in the ischemic brain may be derived from either resident microglia or infiltrating monocytes. Using bone marrow (BM)-chimerism and dual-reporter transgenic fate mapping, we here set out to delimit the responses of either cell type to mild brain ischemia in a mouse model of 30 min transient middle cerebral artery occlusion (MCAo). A discriminatory analysis of gene expression at 7 days post-event yielded 472 transcripts predominantly or exclusively expressed in blood-derived macrophages as well as 970 transcripts for microglia. Read More

    Spread of aggregates after olfactory bulb injection of α-synuclein fibrils is associated with early neuronal loss and is reduced long term.
    Acta Neuropathol 2018 Jan 5;135(1):65-83. Epub 2017 Dec 5.
    Center for Neurodegenerative Science, Van Andel Research Institute, 333 Bostwick Avenue N.E., Grand Rapids, MI, 49503, USA.
    Parkinson's disease is characterized by degeneration of substantia nigra dopamine neurons and by intraneuronal aggregates, primarily composed of misfolded α-synuclein. The α-synuclein aggregates in Parkinson's patients are suggested to first appear in the olfactory bulb and enteric nerves and then propagate, following a stereotypic pattern, via neural pathways to numerous regions across the brain. We recently demonstrated that after injection of either mouse or human α-synuclein fibrils into the olfactory bulb of wild-type mice, α-synuclein fibrils recruited endogenous α-synuclein into pathological aggregates that spread transneuronally to over 40 other brain regions and subregions, over 12 months. Read More

    Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Abeta pathology.
    Acta Neuropathol 2018 Feb 22;135(2):201-212. Epub 2017 Nov 22.
    Inserm U1127, CNRS UMR 7225, UPMC Univ Paris VI UMR S 1127, Institut du Cerveau et de la Moelle épinière, Sorbonne Universités, 47 boulevard de l'Hôpital, 75013, Paris, France.
    Abeta deposits and tau pathology were investigated in 24 French patients that died from iatrogenic Creutzfeldt-Jakob disease after exposure to cadaver-derived human growth hormone (c-hGH) in the 1980s. Abeta deposits were found only in one case that had experienced one of the longest incubation periods. Three cases had also intracellular tau accumulation. Read More

    Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis.
    Acta Neuropathol 2018 Mar 1;135(3):459-474. Epub 2017 Dec 1.
    Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0624, USA.
    Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (C9 ALS). The main hypothesized pathogenic mechanisms are C9orf72 haploinsufficiency and/or toxicity from one or more of bi-directionally transcribed repeat RNAs and their dipeptide repeat proteins (DPRs) poly-GP, poly-GA, poly-GR, poly-PR and poly-PA. Recently, nuclear import and/or export defects especially caused by arginine-containing poly-GR or poly-PR have been proposed as significant contributors to pathogenesis based on disease models. Read More

    Polygenic hazard score: an enrichment marker for Alzheimer's associated amyloid and tau deposition.
    Acta Neuropathol 2018 Jan 24;135(1):85-93. Epub 2017 Nov 24.
    Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.
    There is an urgent need for identifying nondemented individuals at the highest risk of progressing to Alzheimer's disease (AD) dementia. Here, we evaluated whether a recently validated polygenic hazard score (PHS) can be integrated with known in vivo cerebrospinal fluid (CSF) or positron emission tomography (PET) biomarkers of amyloid, and CSF tau pathology to prospectively predict cognitive and clinical decline in 347 cognitive normal (CN; baseline age range = 59.7-90. Read More

    The function of the cellular prion protein in health and disease.
    Acta Neuropathol 2018 Feb 18;135(2):159-178. Epub 2017 Nov 18.
    Department of Biochemistry, Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Krembil Discovery Tower, Rm. 4KD481, 60 Leonard Ave., Toronto, ON, M5T 2S8, Canada.
    The essential role of the cellular prion protein (PrP) in prion disorders such as Creutzfeldt-Jakob disease is well documented. Moreover, evidence is accumulating that PrPmay act as a receptor for protein aggregates and transduce neurotoxic signals in more common neurodegenerative disorders, such as Alzheimer's disease. Although the pathological roles of PrPhave been thoroughly characterized, a general consensus on its physiological function within the brain has not yet been established. Read More

    Parkinson's disease: experimental models and reality.
    Acta Neuropathol 2018 Jan 18;135(1):13-32. Epub 2017 Nov 18.
    Neuropathology Laboratory, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
    Parkinson's disease (PD) is a chronic, progressive movement disorder of adults and the second most common neurodegenerative disease after Alzheimer's disease. Neuropathologic diagnosis of PD requires moderate-to-marked neuronal loss in the ventrolateral substantia nigra pars compacta and α-synuclein (αS) Lewy body pathology. Nigrostriatal dopaminergic neurodegeneration correlates with the Parkinsonian motor features, but involvement of other peripheral and central nervous system regions leads to a wide range of non-motor features. Read More

    Changes in chromatin state reveal ARNT2 at a node of a tumorigenic transcription factor signature driving glioblastoma cell aggressiveness.
    Acta Neuropathol 2018 Feb 17;135(2):267-283. Epub 2017 Nov 17.
    CNRS UMR8246, Inserm U1130, Neuroscience Paris Seine-IBPS, UPMC, Sorbonne Universités, Paris, France.
    Although a growing body of evidence indicates that phenotypic plasticity exhibited by glioblastoma cells plays a central role in tumor development and post-therapy recurrence, the master drivers of their aggressiveness remain elusive. Here we mapped the changes in active (H3K4me3) and repressive (H3K27me3) histone modifications accompanying the repression of glioblastoma stem-like cells tumorigenicity. Genes with changing histone marks delineated a network of transcription factors related to cancerous behavior, stem state, and neural development, highlighting a previously unsuspected association between repression of ARNT2 and loss of cell tumorigenicity. Read More

    Co-occurrence of mixed proteinopathies in late-stage Huntington's disease.
    Acta Neuropathol 2018 Feb 13;135(2):249-265. Epub 2017 Nov 13.
    Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval, CHUL, 2705 Boul. Laurier, P0-9800, Québec, QC, G1V 4G2, Canada.
    Accumulating evidence highlights the potential role of mixed proteinopathies (i.e., abnormal protein aggregation) in the development of clinical manifestations of neurodegenerative diseases (NDD). Read More

    Artificial intelligence in neurodegenerative disease research: use of IBM Watson to identify additional RNA-binding proteins altered in amyotrophic lateral sclerosis.
    Acta Neuropathol 2018 Feb 13;135(2):227-247. Epub 2017 Nov 13.
    Department of Neurobiology, Barrow Neurological Institute, 350 W Thomas Road, Phoenix, AZ, 85013, USA.
    Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no effective treatments. Numerous RNA-binding proteins (RBPs) have been shown to be altered in ALS, with mutations in 11 RBPs causing familial forms of the disease, and 6 more RBPs showing abnormal expression/distribution in ALS albeit without any known mutations. RBP dysregulation is widely accepted as a contributing factor in ALS pathobiology. Read More

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