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Frontotemporal dementia progranulin

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https://www.readbyqxmd.com/read/27844039/increased-prevalence-of-autoimmune-disease-within-c9-and-ftd-mnd-cohorts-completing-the-picture
#1
Zachary A Miller, Virginia E Sturm, Gamze Balci Camsari, Anna Karydas, Jennifer S Yokoyama, Lea T Grinberg, Adam L Boxer, Howard J Rosen, Katherine P Rankin, Maria Luisa Gorno-Tempini, Giovanni Coppola, Daniel H Geschwind, Rosa Rademakers, William W Seeley, Neill R Graff-Radford, Bruce L Miller
OBJECTIVE: To determine the prevalence of autoimmune disease in symptomatic C9ORF72 (C9) mutation carriers and frontotemporal dementia with motor neuron disease (FTD/MND) cohorts. METHODS: In this case-control study, we reviewed the clinical histories of 66 patients with FTD/MND and 57 symptomatic C9 carriers (24 overlapping cases), a total of 99 charts, for history of autoimmune disease. The prevalence of autoimmune disease in C9 and FTD/MND cohorts was determined by χ(2) and Fisher exact comparisons between the combined C9 and FTD/MND group with normal control, Alzheimer disease, and progressive supranuclear palsy cohorts, as well as comparisons within C9 and FTD/MND cohorts...
December 2016: Neurology® Neuroimmunology & Neuroinflammation
https://www.readbyqxmd.com/read/27814992/a-cluster-of-progranulin-c157kfsx97-mutations-in-southern-italy-clinical-characterization-and-genetic-correlations
#2
Cinzia Coppola, Dario Saracino, Gianfranco Puoti, Giacomo Lus, Clemente Dato, Isabelle Le Ber, Jeremie Pariente, Paola Caroppo, Elena Piccoli, Fabrizio Tagliavini, Giuseppe Di Iorio, Giacomina Rossi
Frontotemporal lobar degeneration (FTLD) is a group of neurodegenerative diseases displaying high clinical, pathologic, and genetic heterogeneity. Several autosomal dominant progranulin (GRN) mutations have been reported, accounting for 5%-10% of FTLD cases worldwide. In this study, we described the clinical characteristics of 7 Italian patients, 5 with a diagnosis of frontotemporal dementia behavioral variant and 2 of corticobasal syndrome (CBS), carrying the GRN deletion g.101349_101355delCTGCTGT, resulting in the C157KfsX97 null mutation, and hypothesized the existence of a founder effect by means of haplotype sharing analysis...
October 11, 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/27767988/a-novel-loss-of-function-grn-mutation-p-tyr229-%C3%A2-clinical-and-neuropathological-features
#3
Liina Kuuluvainen, Minna Pöyhönen, Petra Pasanen, Maija Siitonen, Jaana Rummukainen, Pentti J Tienari, Anders Paetau, Liisa Myllykangas
Mutations in the progranulin (GRN) gene represent about 5-10% of frontotemporal lobar degeneration (FTLD). We describe a proband with a novel GRN mutation c.687T>A, p.(Tyr229*), presenting with dyspraxia, dysgraphia, and dysphasia at the age of 60 and a very severe FTLD neuropathological phenotype with TDP43 inclusions. The nephew of the proband had signs of dementia and personality changes at the age of 60 and showed similar but milder FTLD pathology. Three other family members had had early-onset dementia...
October 20, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27760429/cerebrospinal-fluid-progranulin-but-not-serum-progranulin-is-reduced-in-grn-negative-frontotemporal-dementia
#4
Carlo Wilke, Frank Gillardon, Christian Deuschle, Markus A Hobert, Iris E Jansen, Florian G Metzger, Peter Heutink, Thomas Gasser, Walter Maetzler, Cornelis Blauwendraat, Matthis Synofzik
BACKGROUND AND OBJECTIVE: Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene (GRN). However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to GRN mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in GRN-negative FTD. METHODS: Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls)...
October 20, 2016: Neuro-degenerative Diseases
https://www.readbyqxmd.com/read/27703466/progranulin-levels-in-plasma-and-cerebrospinal-fluid-in-granulin-mutation-carriers
#5
Lieke H H Meeter, Holger Patzke, Gordon Loewen, Elise G P Dopper, Yolande A L Pijnenburg, Rick van Minkelen, John C van Swieten
BACKGROUND: Pathogenic mutations in the granulin gene (GRN) are causative in 5-10% of patients with frontotemporal dementia (FTD), mostly leading to reduced progranulin protein (PGRN) levels. Upcoming therapeutic trials focus on enhancing PGRN levels. METHODS: Fluctuations in plasma PGRN (n = 41) and its relationship with cerebrospinal fluid (CSF, n = 32) and specific single nucleotide polymorphisms were investigated in pre- and symptomatic GRN mutation carriers and controls...
May 2016: Dementia and Geriatric Cognitive Disorders Extra
https://www.readbyqxmd.com/read/27625986/cerebral-blood-flow-in-presymptomatic-mapt-and-grn-mutation-carriers-a-longitudinal-arterial-spin-labeling-study
#6
Elise G P Dopper, Vicky Chalos, Eidrees Ghariq, Tom den Heijer, Anne Hafkemeijer, Lize C Jiskoot, Inge de Koning, Harro Seelaar, Rick van Minkelen, Matthias J P van Osch, Serge A R B Rombouts, John C van Swieten
OBJECTIVE: Frontotemporal dementia (FTD) is characterized by behavioral disturbances and language problems. Familial forms can be caused by genetic defects in microtubule-associated protein tau (MAPT), progranulin (GRN), and C9orf72. In light of upcoming clinical trials with potential disease-modifying agents, the development of sensitive biomarkers to evaluate such agents in the earliest stage of FTD is crucial. In the current longitudinal study we used arterial spin labeling MRI (ASL) in presymptomatic carriers of MAPT and GRN mutations to investigate early changes in cerebral blood flow (CBF)...
2016: NeuroImage: Clinical
https://www.readbyqxmd.com/read/27606344/neurofilament-light-chain-a-biomarker-for-genetic-frontotemporal-dementia
#7
Lieke H Meeter, Elise G Dopper, Lize C Jiskoot, Raquel Sanchez-Valle, Caroline Graff, Luisa Benussi, Roberta Ghidoni, Yolande A Pijnenburg, Barbara Borroni, Daniela Galimberti, Robert Jr Laforce, Mario Masellis, Rik Vandenberghe, Isabelle Le Ber, Markus Otto, Rick van Minkelen, Janne M Papma, Serge A Rombouts, Mircea Balasa, Linn Öijerstedt, Vesna Jelic, Katrina M Dick, David M Cash, Sophie R Harding, M Jorge Cardoso, Sebastien Ourselin, Martin N Rossor, Alessandro Padovani, Elio Scarpini, Chiara Fenoglio, Maria C Tartaglia, Foudil Lamari, Christian Barro, Jens Kuhle, Jonathan D Rohrer, Charlotte E Teunissen, John C van Swieten
OBJECTIVE: To evaluate cerebrospinal fluid (CSF) and serum neurofilament light chain (NfL) levels in genetic frontotemporal dementia (FTD) as a potential biomarker in the presymptomatic stage and during the conversion into the symptomatic stage. Additionally, to correlate NfL levels to clinical and neuroimaging parameters. METHODS: In this multicenter case-control study, we investigated CSF NfL in 174 subjects (48 controls, 40 presymptomatic carriers and 86 patients with microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72) mutations), and serum NfL in 118 subjects (39 controls, 44 presymptomatic carriers, 35 patients)...
August 2016: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/27581216/serum-neurofilament-light-chain-protein-is-a-measure-of-disease-intensity-in-frontotemporal-dementia
#8
Jonathan D Rohrer, Ione O C Woollacott, Katrina M Dick, Emilie Brotherhood, Elizabeth Gordon, Alexander Fellows, Jamie Toombs, Ronald Druyeh, M Jorge Cardoso, Sebastien Ourselin, Jennifer M Nicholas, Niklas Norgren, Simon Mead, Ulf Andreasson, Kaj Blennow, Jonathan M Schott, Nick C Fox, Jason D Warren, Henrik Zetterberg
OBJECTIVE: To investigate serum neurofilament light chain (NfL) concentrations in frontotemporal dementia (FTD) and to see whether they are associated with the severity of disease. METHODS: Serum samples were collected from 74 participants (34 with behavioral variant FTD [bvFTD], 3 with FTD and motor neuron disease and 37 with primary progressive aphasia [PPA]) and 28 healthy controls. Twenty-four of the FTD participants carried a pathogenic mutation in C9orf72 (9), microtubule-associated protein tau (MAPT; 11), or progranulin (GRN; 4)...
September 27, 2016: Neurology
https://www.readbyqxmd.com/read/27543771/survival-in-the-pre-senile-dementia-frontotemporal-lobar-degeneration-with-tdp-43-proteinopathy-effects-of-genetic-demographic-and-neuropathological-variables
#9
R A Armstrong
Factors associated with survival were studied in 84 neuropathologically documented cases of the pre-senile dementia frontotemporal dementia lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). Kaplan-Meier survival analysis estimated mean survival as 7.9 years (range: 1-19 years, SD = 4.64). Familial and sporadic cases exhibited similar survival, including progranulin (GRN) gene mutation cases. No significant differences in survival were associated with sex, disease onset, Braak disease stage, or disease subtype, but higher survival was associated with lower post-mortem brain weight...
2016: Folia Neuropathologica
https://www.readbyqxmd.com/read/27543298/what-we-know-about-tmem106b-in-neurodegeneration
#10
REVIEW
Alexandra M Nicholson, Rosa Rademakers
Frontotemporal lobar degeneration is a neurodegenerative disorder affecting over 50,000 people in the United States alone. The most common pathological subtype of FTLD is the presence of ubiquitinated TAR DNA binding protein 43 (TDP-43) accumulations in frontal and temporal brain regions at autopsy. While some cases of FTLD-TDP can be attributed to the inheritance of disease-causing mutations, the majority of cases arise with no known genetic cause. In 2010, the first genome-wide association study was conducted in patients with FTLD-TDP to determine potential genetic risk factors for this homogenous subgroup of dementia patients, leading to the identification of the TMEM106B locus on chromosome 7...
November 2016: Acta Neuropathologica
https://www.readbyqxmd.com/read/27435172/reduced-tau-protein-expression-is-associated-with-frontotemporal-degeneration-with-progranulin-mutation
#11
Anthony Papegaey, Sabiha Eddarkaoui, Vincent Deramecourt, Francisco-Jose Fernandez-Gomez, Pierre Pantano, Hélène Obriot, Camille Machala, Vincent Anquetil, Agnès Camuzat, Alexis Brice, Claude-Alain Maurage, Isabelle Le Ber, Charles Duyckaerts, Luc Buée, Nicolas Sergeant, Valérie Buée-Scherrer
Reduction of Tau protein expression was described in 2003 by Zhukareva et al. in a variant of frontotemporal lobar degeneration (FTLD) referred to as diagnosis of dementia lacking distinctive histopathology, then re-classified as FTLD with ubiquitin inclusions. However, the analysis of Tau expression in FTLD has not been reconsidered since then. Knowledge of the molecular basis of protein aggregates and genes that are mutated in the FTLD spectrum would enable to determine whether the "Tau-less" is a separate pathological entity or if it belongs to an existing subclass of FTLD...
2016: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/27356620/prosaposin-is-a-regulator-of-progranulin-levels-and-oligomerization
#12
Alexandra M Nicholson, NiCole A Finch, Marcio Almeida, Ralph B Perkerson, Marka van Blitterswijk, Aleksandra Wojtas, Basar Cenik, Sergio Rotondo, Venette Inskeep, Laura Almasy, Thomas Dyer, Juan Peralta, Goo Jun, Andrew R Wood, Timothy M Frayling, Christian Fuchsberger, Sharon Fowler, Tanya M Teslovich, Alisa K Manning, Satish Kumar, Joanne Curran, Donna Lehman, Goncalo Abecasis, Ravindranath Duggirala, Cyril Pottier, Haaris A Zahir, Julia E Crook, Anna Karydas, Laura Mitic, Ying Sun, Dennis W Dickson, Guojun Bu, Joachim Herz, Gang Yu, Bruce L Miller, Shawn Ferguson, Ronald C Petersen, Neill Graff-Radford, John Blangero, Rosa Rademakers
Progranulin (GRN) loss-of-function mutations leading to progranulin protein (PGRN) haploinsufficiency are prevalent genetic causes of frontotemporal dementia. Reports also indicated PGRN-mediated neuroprotection in models of Alzheimer's and Parkinson's disease; thus, increasing PGRN levels is a promising therapeutic for multiple disorders. To uncover novel PGRN regulators, we linked whole-genome sequence data from 920 individuals with plasma PGRN levels and identified the prosaposin (PSAP) locus as a new locus significantly associated with plasma PGRN levels...
2016: Nature Communications
https://www.readbyqxmd.com/read/27341800/trehalose-upregulates-progranulin-expression-in-human-and-mouse-models-of-grn-haploinsufficiency-a-novel-therapeutic-lead-to-treat-frontotemporal-dementia
#13
Christopher J Holler, Georgia Taylor, Zachary T McEachin, Qiudong Deng, William J Watkins, Kathryn Hudson, Charles A Easley, William T Hu, Chadwick M Hales, Wilfried Rossoll, Gary J Bassell, Thomas Kukar
BACKGROUND: Progranulin (PGRN) is a secreted growth factor important for neuronal survival and may do so, in part, by regulating lysosome homeostasis. Mutations in the PGRN gene (GRN) are a common cause of frontotemporal lobar degeneration (FTLD) and lead to disease through PGRN haploinsufficiency. Additionally, complete loss of PGRN in humans leads to neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Importantly, Grn-/- mouse models recapitulate pathogenic lysosomal features of NCL...
June 24, 2016: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/27258413/a-novel-splice-acceptor-site-mutation-in-grn-c-709-2-a-t-causes-frontotemporal-dementia-spectrum-in-a-large-family-from-southern-italy
#14
Celeste Sassi, Rosa Capozzo, Raphael Gibbs, Cynthia Crews, Chiara Zecca, Simona Arcuti, Massimiliano Copetti, Maria R Barulli, Vincenzo Brescia, Andrew B Singleton, Giancarlo Logroscino
Heterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degeneration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c.709-2 A>T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c.709-2 A>T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c.709-2 A>T carriers were significantly lower (24 ng/ml) compared to controls (142...
May 30, 2016: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/27213486/progranulin-haploinsufficiency-causes-biphasic-social-dominance-abnormalities-in-the-tube-test
#15
A E Arrant, A J Filiano, B A Warmus, A M Hall, E D Roberson
Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia (FTD), a neurodegenerative disorder in which social behavior is disrupted. Progranulin-insufficient mice, both Grn(+/-) and Grn(-/-) , are used as models of FTD due to GRN mutations, with Grn(+/-) mice mimicking the progranulin haploinsufficiency of FTD patients with GRN mutations. Grn(+/-) mice have increased social dominance in the tube test at 6 months of age, although this phenotype has not been reported in Grn(-/-) mice...
July 2016: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/27199656/reduced-mir-659-3p-levels-correlate-with-progranulin-increase-in-hypoxic-conditions-implications-for-frontotemporal-dementia
#16
Paola Piscopo, Margherita Grasso, Francesca Fontana, Alessio Crestini, Maria Puopolo, Valerio Del Vescovo, Aldina Venerosi, Gemma Calamandrei, Sebastian F Vencken, Catherine M Greene, Annamaria Confaloni, Michela A Denti
Progranulin (PGRN) is a secreted protein expressed ubiquitously throughout the body, including the brain, where it localizes in neurons and is activated microglia. Loss-of-function mutations in the GRN gene are an important cause of familial frontotemporal lobar degeneration (FTLD). PGRN has a neurotrophic and anti-inflammatory activity, and it is neuroprotective in several injury conditions, such as oxygen or glucose deprivation, oxidative injury, and hypoxic stress. Indeed, we have previously demonstrated that hypoxia induces the up-regulation of GRN transcripts...
2016: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/27144467/the-clinical-spectrum-of-sporadic-and-familial-forms-of-frontotemporal-dementia
#17
REVIEW
Ione O C Woollacott, Jonathan D Rohrer
The term frontotemporal dementia (FTD) describes a clinically, genetically and pathologically diverse group of neurodegenerative disorders. Symptoms of FTD can present in individuals in their 20s through to their 90s, but the mean age at onset is in the sixth decade. The most common presentation is with a change in personality and impaired social conduct (behavioural variant FTD). Less frequently patients present with language problems (primary progressive aphasia). Both of these groups of patients can develop motor features consistent with either motor neuron disease (usually the amyotrophic lateral sclerosis variant) or parkinsonism (most commonly a progressive supranuclear palsy or corticobasal syndrome)...
August 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27143419/suberoylanilide-hydroxamic-acid-increases-progranulin-production-in-ipsc-derived-cortical-neurons-of-frontotemporal-dementia-patients
#18
Sandra Almeida, Fuying Gao, Giovanni Coppola, Fen-Biao Gao
Mutations in the granulin (GRN) gene cause frontotemporal dementia (FTD) due to progranulin haploinsufficiency. Compounds that can increase progranulin production and secretion may be considered as potential therapeutic drugs; however, very few of them have been directly tested on human cortical neurons. To this end, we differentiated 9 induced pluripotent stem cell lines derived from a control subject, a sporadic FTD case and an FTD patient with progranulin S116X mutation. Treatment with 1 μM suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, increased the production of progranulin in cortical neurons of all subjects at both the mRNA and protein levels without affecting their viability...
June 2016: Neurobiology of Aging
https://www.readbyqxmd.com/read/27138926/targeting-tdp-43-phosphorylation-by-casein-kinase-1%C3%AE-inhibitors-a-novel-strategy-for-the-treatment-of-frontotemporal-dementia
#19
Carolina Alquezar, Irene G Salado, Ana de la Encarnación, Daniel I Pérez, Fermín Moreno, Carmen Gil, Adolfo López de Munain, Ana Martínez, Ángeles Martín-Requero
BACKGROUND: Mutations in the progranulin gene (GRN) are the most common cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). TDP-43 pathology is characterized by the hyperphosphorylation of the protein at Serine 409/410 residues. Casein kinase-1δ (CK-1δ) was reported to phosphorylate TDP-43 directly. Previous works from our laboratory described the presence of CDK6/pRb-dependent cell cycle alterations, and cytosolic accumulation of TDP-43 protein in lymphoblast from FTLD-TDP patients carriers of a loss-of function mutation in GRN gene (c...
2016: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/27114033/progranulin-deficiency-promotes-circuit-specific-synaptic-pruning-by-microglia-via-complement-activation
#20
Hansen Lui, Jiasheng Zhang, Stefanie R Makinson, Michelle K Cahill, Kevin W Kelley, Hsin-Yi Huang, Yulei Shang, Michael C Oldham, Lauren Herl Martens, Fuying Gao, Giovanni Coppola, Steven A Sloan, Christine L Hsieh, Charles C Kim, Eileen H Bigio, Sandra Weintraub, Marek-Marsel Mesulam, Rosa Rademakers, Ian R Mackenzie, William W Seeley, Anna Karydas, Bruce L Miller, Barbara Borroni, Roberta Ghidoni, Robert V Farese, Jeanne T Paz, Ben A Barres, Eric J Huang
Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn(-/-) mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors...
May 5, 2016: Cell
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