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Frontotemporal degeneration

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https://www.readbyqxmd.com/read/28324764/enhancing-mitofusin-marf-ameliorates-neuromuscular-dysfunction-in-drosophila-models-of-tdp-43-proteinopathies
#1
Bilal Khalil, Marie-Jeanne Cabirol-Pol, Laetitia Miguel, Alexander J Whitworth, Magalie Lecourtois, Jean-Charles Liévens
Transactive response DNA-binding protein 43 kDa (TDP-43) is considered a major pathological protein in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The precise mechanisms by which TDP-43 dysregulation leads to toxicity in neurons are not fully understood. Using TDP-43-expressing Drosophila, we examined whether mitochondrial dysfunction is a central determinant in TDP-43 pathogenesis. Expression of human wild-type TDP-43 in Drosophila neurons results in abnormally small mitochondria...
February 27, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28301478/retrotransposon-activation-contributes-to-neurodegeneration-in-a-drosophila-tdp-43-model-of-als
#2
Lisa Krug, Nabanita Chatterjee, Rebeca Borges-Monroy, Stephen Hearn, Wen-Wei Liao, Kathleen Morrill, Lisa Prazak, Nikolay Rozhkov, Delphine Theodorou, Molly Hammell, Josh Dubnau
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders that exist on a symptomological spectrum and share both genetic underpinnings and pathophysiological hallmarks. Functional abnormality of TAR DNA-binding protein 43 (TDP-43), an aggregation-prone RNA and DNA binding protein, is observed in the vast majority of both familial and sporadic ALS cases and in ~40% of FTLD cases, but the cascade of events leading to cell death are not understood...
March 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28293793/ultrasensitive-and-selective-detection-of-3-repeat-tau-seeding-activity-in-pick-disease-brain-and-cerebrospinal-fluid
#3
Eri Saijo, Bernardino Ghetti, Gianluigi Zanusso, Adrian Oblak, Jennifer L Furman, Marc I Diamond, Allison Kraus, Byron Caughey
The diagnosis and treatment of diseases involving tau-based pathology such as Alzheimer disease and certain frontotemporal dementias is hampered by the inability to detect pathological forms of tau with sufficient sensitivity, specificity and practicality. In these neurodegenerative diseases, tau accumulates in self-seeding filaments. For example, Pick disease (PiD) is associated with frontotemporal degeneration and accumulation of 3-repeat (3R) tau isoforms in filaments constituting Pick bodies. Exploiting the self-seeding activity of tau deposits, and using a 3R tau fragment as a substrate, we have developed an assay (tau RT-QuIC) that can detect tau seeds in 2 µl aliquots of PiD brain dilutions down to 10(-7)-10(-9)...
March 14, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28288787/evolution-of-autobiographical-memory-impairments-in-alzheimer-s-disease-and-frontotemporal-dementia-a-longitudinal-neuroimaging-study
#4
Muireann Irish, Ramon Landin-Romero, Annu Mothakunnel, Siddharth Ramanan, Sharpley Hsieh, John R Hodges, Olivier Piguet
Compromised autobiographical memory (ABM) retrieval is well established in dementia, attributable to degeneration of a core memory brain network. It remains unclear, however, how the progressive spread of atrophy with advancing disease severity impacts ABM retrieval across life epochs. To this end, we conducted a longitudinal study of recent and remote ABM in Alzheimer's disease (AD, n =11), and a frontotemporal lobar degeneration group (FTD, n =13) comprising 7 behavioral variant FTD and 6 semantic dementia patients, in comparison with 23 healthy older Controls...
March 10, 2017: Neuropsychologia
https://www.readbyqxmd.com/read/28285794/missense-mutation-in-grn-gene-affecting-rna-splicing-and-plasma-progranulin-level-in-a-family-affected-by-frontotemporal-lobar-degeneration
#5
Simona Luzzi, Lara Colleoni, Paola Corbetta, Sara Baldinelli, Chiara Fiori, Francesca Girelli, Mauro Silvestrini, Paola Caroppo, Giorgio Giaccone, Fabrizio Tagliavini, Giacomina Rossi
Gene coding for progranulin, GRN, is a major gene linked to frontotemporal lobar degeneration. While most of pathogenic GRN mutations are null mutations leading to haploinsufficiency, GRN missense mutations do not have an obvious pathogenicity, and only a few have been revealed to act through different pathogenetic mechanisms, such as cytoplasmic missorting, protein degradation, and abnormal cleavage by elastase. The aim of this study was to disclose the pathogenetic mechanisms of the GRN A199V missense mutation, which was previously reported not to alter physiological progranulin features but was associated with a reduced plasma progranulin level...
February 20, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28283675/amyotrophic-lateral-sclerosis-gene-deregulation-in-the-anterior-horn-of-the-spinal-cord-and-frontal-cortex-area-8-implications-in-frontotemporal-lobar-degeneration
#6
Pol Andrés-Benito, Jesús Moreno, Ester Aso, Mónica Povedano, Isidro Ferrer
Transcriptome arrays identifies 747 genes differentially expressed in the anterior horn of the spinal cord and 2,300 genes differentially expressed in frontal cortex area 8 in a single group of typical sALS cases without frontotemporal dementia compared with age-matched controls. Main up-regulated clusters in the anterior horn are related to inflammation and apoptosis; down-regulated clusters are linked to axoneme structures and protein synthesis. In contrast, up-regulated gene clusters in frontal cortex area 8 involve neurotransmission, synaptic proteins and vesicle trafficking, whereas main down-regulated genes cluster into oligodendrocyte function and myelin-related proteins...
March 9, 2017: Aging
https://www.readbyqxmd.com/read/28282387/the-essential-and-downstream-common-proteins-of-amyotrophic-lateral-sclerosis-a-protein-protein-interaction-network-analysis
#7
Yimin Mao, Su-Wei Kuo, Le Chen, C J Heckman, M C Jiang
Amyotrophic Lateral Sclerosis (ALS) is a devastative neurodegenerative disease characterized by selective loss of motoneurons. While several breakthroughs have been made in identifying ALS genetic defects, the detailed molecular mechanisms are still unclear. These genetic defects involve in numerous biological processes, which converge to a common destiny: motoneuron degeneration. In addition, the common comorbid Frontotemporal Dementia (FTD) further complicates the investigation of ALS etiology. In this study, we aimed to explore the protein-protein interaction network built on known ALS-causative genes to identify essential proteins and common downstream proteins between classical ALS and ALS+FTD (classical ALS + ALS/FTD) groups...
2017: PloS One
https://www.readbyqxmd.com/read/28281308/overlapping-but-distinct-tdp-43-and-tau-pathologic-patterns-in-aged-hippocampi
#8
Vanessa D Smith, Adam D Bachstetter, Eseosa Ighodaro, Kelly Roberts, Erin L Abner, David W Fardo, Peter T Nelson
Intracellular proteinaceous aggregates (inclusion bodies) are almost always detectable at autopsy in brains of elderly individuals. Inclusion bodies composed of TDP-43 and tau proteins often coexist in the same brain, and each of these pathologic biomarkers is associated independently with cognitive impairment. However, uncertainties remain about how the presence and neuroanatomical distribution of inclusion bodies correlate with underlying diseases including Alzheimer's disease (AD). To address this knowledge gap, we analyzed data from the University of Kentucky AD Center autopsy series (n = 247); none of the brains had frontotemporal lobar degeneration...
March 9, 2017: Brain Pathology
https://www.readbyqxmd.com/read/28271184/shared-genetic-risk-between-corticobasal-degeneration-progressive-supranuclear-palsy-and-frontotemporal-dementia
#9
Jennifer S Yokoyama, Celeste M Karch, Chun C Fan, Luke W Bonham, Naomi Kouri, Owen A Ross, Rosa Rademakers, Jungsu Kim, Yunpeng Wang, Günter U Höglinger, Ulrich Müller, Raffaele Ferrari, John Hardy, Parastoo Momeni, Leo P Sugrue, Christopher P Hess, A James Barkovich, Adam L Boxer, William W Seeley, Gil D Rabinovici, Howard J Rosen, Bruce L Miller, Nicholas J Schmansky, Bruce Fischl, Bradley T Hyman, Dennis W Dickson, Gerard D Schellenberg, Ole A Andreassen, Anders M Dale, Rahul S Desikan
Corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and a subset of frontotemporal dementia (FTD) are neurodegenerative disorders characterized by tau inclusions in neurons and glia (tauopathies). Although clinical, pathological and genetic evidence suggests overlapping pathobiology between CBD, PSP, and FTD, the relationship between these disorders is still not well understood. Using summary statistics (odds ratios and p values) from large genome-wide association studies (total n = 14,286 cases and controls) and recently established genetic methods, we investigated the genetic overlap between CBD and PSP and CBD and FTD...
March 7, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28268100/intrafamilial-variable-phenotype-including-corticobasal-syndrome-in-a-family-with-p-p301l-mutation-in-the-mapt-gene-first-report-in-south-america
#10
Emilia M Gatto, Ricardo F Allegri, Gustavo Da Prat, Patricio Chrem Mendez, David S Hanna, Michael O Dorschner, Ezequiel I Surace, Cyrus P Zabetian, Ignacio F Mata
Frontotemporal lobar degeneration is a neuropathological disorder that causes a variety of clinical syndromes including frontotemporal dementia (FTD), progressive supranuclear palsy, and corticobasal syndrome (CBS). FTD associated with parkinsonism occurs frequently as a result of mutations in the C9orf72 gene and also in the genes coding for the protein associated with microtubule tau (MAPT) and progranulin (GRN) on chromosome 17 (FTDP-17). Herein, we report an Argentinean family, of Basque ancestry, with an extensive family history of behavioral variant of FTD...
February 10, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28264096/diagnostic-and-prognostic-biomarkers-in-amyotrophic-lateral-sclerosis-neurofilament-light-chain-levels-in-definite-subtypes-of-disease
#11
Alessandra Gaiani, Ilaria Martinelli, Luca Bello, Giorgia Querin, Marco Puthenparampil, Susanna Ruggero, Elisabetta Toffanin, Annachiara Cagnin, Chiara Briani, Elena Pegoraro, Gianni Sorarù
Importance: A clearer definition of the role of neurofilament light chain (NFL) as a biomarker in amyotrophic lateral sclerosis (ALS) is needed. Objectives: To assess the ability of NFL to serve as a diagnostic biomarker in ALS and the prognostic value of cerebrospinal fluid NFL in patients with ALS. Design, Setting, and Participants: In this single-center, retrospective, longitudinal study, disease progression was assessed by the ALS Functional Rating Score-Revised and the ALS Milano-Torino Staging system at baseline and 6, 12, 24, and 36 months...
March 6, 2017: JAMA Neurology
https://www.readbyqxmd.com/read/28256506/astrocyte-pathology-in-a-human-neural-stem-cell-model-of-frontotemporal-dementia-caused-by-mutant-tau-protein
#12
Anna-Lena Hallmann, Marcos J Araúzo-Bravo, Lampros Mavrommatis, Marc Ehrlich, Albrecht Röpke, Johannes Brockhaus, Markus Missler, Jared Sterneckert, Hans R Schöler, Tanja Kuhlmann, Holm Zaehres, Gunnar Hargus
Astroglial pathology is seen in various neurodegenerative diseases including frontotemporal dementia (FTD), which can be caused by mutations in the gene encoding the microtubule-associated protein TAU (MAPT). Here, we applied a stem cell model of FTD to examine if FTD astrocytes carry an intrinsic propensity to degeneration and to determine if they can induce non-cell-autonomous effects in neighboring neurons. We utilized CRISPR/Cas9 genome editing in human induced pluripotent stem (iPS) cell-derived neural progenitor cells (NPCs) to repair the FTD-associated N279K MAPT mutation...
March 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28247171/genetic-counseling-dilemmas-for-a-patient-with-sporadic-amyotrophic-lateral-sclerosis-frontotemporal-degeneration-parkinson-s-disease
#13
Vittorio Mantero, Claudia Tarlarini, Angelo Aliprandi, Giuseppe Lauria, Andrea Rigamonti, Lucia Abate, Paola Origone, Paola Mandich, Silvana Penco, Andrea Salmaggi
Amyotrophic lateral sclerosis (ALS), frontotemporal degeneration and Parkinson's disease may be different expressions of the same neurodegenerative disease. However, association between ALS and parkinsonism-dementia complex (ALS-PDC) has only rarely been reported apart from the cluster detected in Guam. We report a patient presenting with ALS-PDC in whom pathological mutations/expansions were investigated. No other family members were reported to have any symptoms of a neurological condition. Our case demonstrates that ALS-PDC can occur as a sporadic disorder, even though the coexistence of the three clinical features in one patient suggests a single underlying genetic cause...
March 1, 2017: Journal of Genetic Counseling
https://www.readbyqxmd.com/read/28229040/predicting-primary-progressive-aphasias-with-support-vector-machine-approaches-in-structural-mri-data
#14
Sandrine Bisenius, Karsten Mueller, Janine Diehl-Schmid, Klaus Fassbender, Timo Grimmer, Frank Jessen, Jan Kassubek, Johannes Kornhuber, Bernhard Landwehrmeyer, Albert Ludolph, Anja Schneider, Sarah Anderl-Straub, Katharina Stuke, Adrian Danek, Markus Otto, Matthias L Schroeter
Primary progressive aphasia (PPA) encompasses the three subtypes nonfluent/agrammatic variant PPA, semantic variant PPA, and the logopenic variant PPA, which are characterized by distinct patterns of language difficulties and regional brain atrophy. To validate the potential of structural magnetic resonance imaging data for early individual diagnosis, we used support vector machine classification on grey matter density maps obtained by voxel-based morphometry analysis to discriminate PPA subtypes (44 patients: 16 nonfluent/agrammatic variant PPA, 17 semantic variant PPA, 11 logopenic variant PPA) from 20 healthy controls (matched for sample size, age, and gender) in the cohort of the multi-center study of the German consortium for frontotemporal lobar degeneration...
2017: NeuroImage: Clinical
https://www.readbyqxmd.com/read/28181693/frontotemporal-lobar-degeneration-tdp-with-multiple-system-atrophy-phenocopy-syndrome
#15
Ana Luísa Sousa, Ricardo Taipa, Niall Quinn, Tamas Revesz, Manuel Melo Pires, Marina Magalhães
Multiple system atrophy (MSA) is a neurodegenerative disorder presenting with parkinsonism, cerebellar involvement, autonomic dysfunction and pyramidal signs (1). Two main clinical subtypes of MSA are recognized: a parkinsonian-type (MSA-P) associated with predominant nigrostriatal degeneration and a cerebellar-type (MSA-C) with predominant olivopontocerebellar atrophy. A 'definite' diagnosis requires pathological confirmation with demonstration of glial cytoplasmic inclusions comprising alpha-synuclein protein aggregates (1)...
February 9, 2017: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/28174682/glucose-deprivation-regulates-the-progranulin-sortilin-axis-in-pc12-cells
#16
Ken-Ichi Kawashima, Yuri Ishiuchi, Miki Konnai, Saori Komatsu, Hitoshi Sato, Hideo Kawaguchi, Nobumitsu Miyanishi, Jérôme Lamartine, Masugi Nishihara, Taku Nedachi
Progranulin (PGRN) is a growth factor implicated in several neurodegenerative diseases, such as frontotemporal lobar degeneration. Despite its important role in the central nervous system (CNS), the mechanisms controlling PGRN expression in the CNS are largely unknown. Recent evidence, however, suggested that several stressors, such as hypoxia, acidosis, or oxidative stress, induce PGRN expression. The present study was mainly aimed at determining whether and, if so, how glucose deprivation affects PGRN expression in PC12 cells...
February 2017: FEBS Open Bio
https://www.readbyqxmd.com/read/28167528/heat-shock-induced-phosphorylation-of-tar-dna-binding-protein-43-tdp-43-by-mapk-erk-kinase-regulates-tdp-43-function
#17
Wen Li, Ashley N Reeb, Binyan Lin, Praveen Subramanian, Erin E Fey, Catherine R Knoverek, Rachel L French, Eileen H Bigio, Yuna M Ayala
TAR DNA binding protein (TDP-43) is a highly conserved and essential DNA- and RNA-binding protein that controls gene expression through RNA processing, in particular, regulation of splicing. Intracellular aggregation of TDP-43 is a hallmark of amyotrophic lateral sclerosis and ubiquitin-positive frontotemporal lobar degeneration. This TDP-43 pathology is also present in other types of neurodegeneration including Alzheimer's disease. We report here that TDP-43 is a substrate of MEK, a central kinase in the MAPK/ERK signaling pathway...
February 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28165465/apical-dendrite-degeneration-a-novel-cellular-pathology-for-betz-cells-in-als
#18
Barış Genç, Javier H Jara, Amiko K B Lagrimas, Peter Pytel, Raymond P Roos, M Marsel Mesulam, Changiz Geula, Eileen H Bigio, P Hande Özdinler
Apical dendrites of Betz cells are important sites for the integration of cortical input, however their health has not been fully assessed in ALS patients. We investigated the primary motor cortices isolated from post-mortem normal control subjects, patients with familial ALS (fALS), sporadic ALS (sALS), ALS with frontotemporal dementia (FTD-ALS), and Alzheimer's disease (AD), and found profound apical dendrite degeneration of Betz cells in both fALS and sALS, as well as FTD-ALS patients. In contrast, Betz cells of AD patients and normal controls retain cellular integrity in the motor cortex, and CA1 pyramidal neurons show abnormalities predominantly within their soma, rather than the apical dendrite...
February 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28147269/altered-tau-isoform-ratio-caused-by-loss-of-fus-and-sfpq-function-leads-to-ftld-like-phenotypes
#19
Shinsuke Ishigaki, Yusuke Fujioka, Yohei Okada, Yuichi Riku, Tsuyoshi Udagawa, Daiyu Honda, Satoshi Yokoi, Kuniyuki Endo, Kensuke Ikenaka, Shinnosuke Takagi, Yohei Iguchi, Naruhiko Sahara, Akihiko Takashima, Hideyuki Okano, Mari Yoshida, Hitoshi Warita, Masashi Aoki, Hirohisa Watanabe, Haruo Okado, Masahisa Katsuno, Gen Sobue
Fused in sarcoma (FUS) and splicing factor, proline- and glutamine-rich (SFPQ) are RNA binding proteins that regulate RNA metabolism. We found that alternative splicing of the Mapt gene at exon 10, which generates 4-repeat tau (4R-T) and 3-repeat tau (3R-T), is regulated by interactions between FUS and SFPQ in the nuclei of neurons. Hippocampus-specific FUS- or SFPQ-knockdown mice exhibit frontotemporal lobar degeneration (FTLD)-like behaviors, reduced adult neurogenesis, accumulation of phosphorylated tau, and hippocampal atrophy with neuronal loss through an increased 4R-T/3R-T ratio...
January 31, 2017: Cell Reports
https://www.readbyqxmd.com/read/28133816/typical-and-atypical-pathology-in-primary-progressive-aphasia-variants
#20
Edoardo G Spinelli, Maria Luisa Mandelli, Zachary A Miller, Miguel A Santos-Santos, Stephen M Wilson, Federica Agosta, Lea T Grinberg, Eric J Huang, John Q Trojanowski, Marita Meyer, Maya L Henry, Giancarlo Comi, Gil Rabinovici, Howard J Rosen, Massimo Filippi, Bruce L Miller, William W Seeley, Maria Luisa Gorno-Tempini
OBJECTIVE: To characterize in vivo signatures of pathological diagnosis in a large cohort of patients with primary progressive aphasia (PPA) variants defined by current diagnostic classification. METHODS: Extensive clinical, cognitive, neuroimaging, and neuropathological data were collected from 69 patients with sporadic PPA, divided into 29 semantic (svPPA), 25 non-fluent (nfvPPA), 11 logopenic (lvPPA), and 4 mixed PPA. Patterns of grey matter (GM) and white matter (WM) atrophy at presentation were assessed and tested as predictors of pathological diagnosis using support vector machine (SVM) algorithms...
January 30, 2017: Annals of Neurology
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