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https://www.readbyqxmd.com/read/28916614/dysregulated-molecular-pathways-in-amyotrophic-lateral-sclerosis-frontotemporal-dementia-spectrum-disorder
#1
REVIEW
Fen-Biao Gao, Sandra Almeida, Rodrigo Lopez-Gonzalez
Frontotemporal dementia (FTD), the second most common form of dementia in people under 65 years of age, is characterized by progressive atrophy of the frontal and/or temporal lobes. FTD overlaps extensively with the motor neuron disease amyotrophic lateral sclerosis (ALS), especially at the genetic level. Both FTD and ALS can be caused by many mutations in the same set of genes; the most prevalent of these mutations is a GGGGCC repeat expansion in the first intron of C9ORF72 As shown by recent intensive studies, some key cellular pathways are dysregulated in the ALS-FTD spectrum disorder, including autophagy, nucleocytoplasmic transport, DNA damage repair, pre-mRNA splicing, stress granule dynamics, and others...
September 15, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28916533/sex-differences-in-the-prevalence-of-genetic-mutations-in-ftd-and-als-a-meta-analysis
#2
REVIEW
Ashley F Curtis, Mario Masellis, Ging-Yuek Robin Hsiung, Rahim Moineddin, Kathy Zhang, Bonnie Au, Geneva Millett, Ian Mackenzie, Ekaterina Rogaeva, Mary C Tierney
OBJECTIVE: To conduct a meta-analysis that investigates sex differences in the prevalence of mutations in the 3 most common genes that cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)-chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), or microtubule-associated protein tau (MAPT)-in patients clinically diagnosed with these conditions. METHODS: MEDLINE, EMBASE, and PsycINFO databases were searched (inception to June 30, 2016)...
September 15, 2017: Neurology
https://www.readbyqxmd.com/read/28889094/analysis-of-known-amyotrophic-lateral-sclerosis-and-frontotemporal-dementia-genes-reveals-a-substantial-genetic-burden-in-patients-manifesting-both-diseases-not-carrying-the-c9orf72-expansion-mutation
#3
Oriol Dols-Icardo, Alberto García-Redondo, Ricardo Rojas-García, Daniel Borrego-Hernández, Ignacio Illán-Gala, José Luís Muñoz-Blanco, Alberto Rábano, Laura Cervera-Carles, Alexandra Juárez-Rufián, Nino Spataro, Noemí De Luna, Lucía Galán, Elena Cortes-Vicente, Juan Fortea, Rafael Blesa, Oriol Grau-Rivera, Alberto Lleó, Jesús Esteban-Pérez, Ellen Gelpi, Jordi Clarimón
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum. OBJECTIVES: The purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion, the most important genetic cause in both diseases. METHODS: From an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in C9orf72...
September 9, 2017: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/28888721/tmem106b-and-apoe-polymorphisms-in-chmp2b-mediated-frontotemporal-dementia-ftd-3
#4
Nina Rostgaard, Peter Roos, Esben Budtz-Jørgensen, Peter Johannsen, Gunhild Waldemar, Anne Nørremølle, Suzanne G Lindquist, Susanne Gydesen, Jeremy M Brown, John Collinge, Adrian M Isaacs, Troels T Nielsen, Jørgen E Nielsen
Single-nucleotide polymorphisms in the TMEM106B gene have been identified as a risk factor in frontotemporal dementia (FTD). The major allele of SNP rs3173615 is a risk factor in sporadic FTD, whereas the minor allele seems protective in GRN- and C9orf72-mediated FTD. The role of apolipoprotein E (ApoE) in FTD is uncertain, though an established risk factor in Alzheimer's disease. In a unique Danish family, inherited FTD is caused by a mutation in the CHMP2B gene located on chromosome 3 (FTD-3). In this family, both risk factors TMEM106B and ApoE were analyzed and correlated to age at onset (AAO) and progression in terms of age at institutionalization (AAI) and age at death (AAD)...
July 11, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28887402/detection-of-long-repeat-expansions-from-pcr-free-whole-genome-sequence-data
#5
Egor Dolzhenko, Joke J F A van Vugt, Richard J Shaw, Mitchell A Bekritsky, Marka van Blitterswijk, Giuseppe Narzisi, Subramanian S Ajay, Vani Rajan, Bryan Lajoie, Nathan H Johnson, Zoya Kingsbury, Sean J Humphray, Raymond D Schellevis, William J Brands, Matt Baker, Rosa Rademakers, Maarten Kooyman, Gijs H P Tazelaar, Michael A van Es, Russell McLaughlin, William Sproviero, Aleksey Shatunov, Ashley Jones, Ahmad Al Khleifat, Alan Pittman, Sarah Morgan, Orla Hardiman, Ammar Al-Chalabi, Chris Shaw, Bradley Smith, Edmund J Neo, Karren Morrison, Pam Shaw, Catherine Reeves, Lara Winterkorn, Nancy S Wexler, David E Housman, Christopher W Ng, Alina L Li, Ryan J Taft, Leonard H van den Berg, David R Bentley, Jan H Veldink, Michael A Eberle
Identifying large expansions of short tandem repeats (STRs) such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome is challenging for short-read whole-genome sequencing (WGS) data. A solution to this problem is an important step towards integrating WGS into precision medicine. We have developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length...
September 8, 2017: Genome Research
https://www.readbyqxmd.com/read/28886177/inflammatory-and-non-inflammatory-monocytes-as-novel-prognostic-biomarkers-of-survival-in-sod1g93a-mouse-model-of-amyotrophic-lateral-sclerosis
#6
Samanta Gasco, Pilar Zaragoza, Alberto García-Redondo, Ana C Calvo, Rosario Osta
Amyotrophic Lateral Sclerosis (ALS) has lately become a suitable scenario to study the interplay between the hematopoietic system and disease progression. Recent studies in C9orf72 null mice have demonstrated that C9orf72 is necessary for the normal function of myeloid cells. In this study, we aimed to analyze in depth the connection between the hematopoietic system and secondary lymphoid (spleen) and non-lymphoid (liver and skeletal muscle) organs and tissues along the disease progression in the transgenic SOD1G93A mice...
2017: PloS One
https://www.readbyqxmd.com/read/28877758/neuron-loss-and-degeneration-in-the-progression-of-tdp-43-in-frontotemporal-lobar-degeneration
#7
Ahmed Yousef, John L Robinson, David J Irwin, Matthew D Byrne, Linda K Kwong, Edward B Lee, Yan Xu, Sharon X Xie, Lior Rennert, EunRan Suh, Vivianna M Van Deerlin, Murray Grossman, Virginia M-Y Lee, John Q Trojanowski
Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is associated with the accumulation of pathological neuronal and glial intracytoplasmic inclusions as well as accompanying neuron loss. We explored if cortical neurons detected by NeuN decreased with increasing TDP-43 inclusion pathology in the postmortem brains of 63 patients with sporadic and familial FTLD-TDP. Semi-automated quantitative algorithms to quantify histology in tissue sections stained with antibodies specific for pathological or phosphorylated TDP-43 (pTDP-43) and NeuN were developed and validated in affected (cerebral cortex) and minimally affected (cerebellar cortex) brain regions of FTLD-TDP cases...
September 6, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28872040/structural-magnetic-resonance-imaging-in-frontotemporal-lobar-dementia
#8
Anne Bertrand, Sebastian Stroër, Isabelle Le Ber, Marc Teichmann, Didier Dormont
Frontotemporal lobar dementia (FTLD) is a heterogeneous group of neurodegenerative diseases. FTLD encompass: 1) behavioral forms, sometimes associated with amyotrophic lateral sclerosis; 2) linguistic forms (semantic and non-fluent primary progressive aphasia); 3) atypical parkinsonian syndromes (progressive supranuclear palsy and corticobasal syndrome). Standard brain MRI allows for strengthening the clinical suspicion of FTLD, by showing a pattern of atrophy in relation with the patient's clinical symptoms: frontotemporal anterior atrophy in behavioral forms; temporopolar or inferior left frontal atrophy in the linguistic forms; mesencephalic or corticosubcortical hemispheric atrophy in forms with atypical pakinsonism...
September 1, 2017: Gériatrie et Psychologie Neuropsychiatrie du Vieillissement
https://www.readbyqxmd.com/read/28861032/mismatch-negativity-as-an-indicator-of-cognitive-sub-domain-dysfunction-in-amyotrophic-lateral-sclerosis
#9
Parameswaran Mahadeva Iyer, Kieran Mohr, Michael Broderick, Brighid Gavin, Tom Burke, Peter Bede, Marta Pinto-Grau, Niall P Pender, Russell McLaughlin, Alice Vajda, Mark Heverin, Edmund C Lalor, Orla Hardiman, Bahman Nasseroleslami
OBJECTIVE: To evaluate the utility of mismatch negativity (MMN), a neurophysiologic marker of non-motor cognitive processing, in amyotrophic lateral sclerosis (ALS). METHODS: 89 patients, stratified into 4 different phenotypic presentations of ALS (67 spinal-onset, 15 bulbar-onset, 7 ALS-FTD, 7 C9ORF72 gene careers), and 19 matched controls underwent 128-channel EEG data recording. Subjects were presented with standard auditory tones interleaved with pitch-deviant tones in three recording blocks...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28860970/failure-to-deliver-and-translate-new-insights-into-rna-dysregulation-in-als
#10
REVIEW
Alyssa N Coyne, Benjamin L Zaepfel, Daniela C Zarnescu
Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. The molecular mechanisms underlying disease pathogenesis remain largely unknown. Multiple genetic loci including genes involved in proteostasis and ribostasis have been linked to ALS providing key insights into the molecular mechanisms underlying disease. In particular, the identification of the RNA binding proteins TDP-43 and fused in sarcoma (FUS) as causative factors of ALS resulted in a paradigm shift centered on the study of RNA dysregulation as a major mechanism of disease...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28859526/increase-in-dna-methylation-in-patients-with-amyotrophic-lateral-sclerosis-carriers-of-not-fully-penetrant-sod1-mutations
#11
Fabio Coppedè, Andrea Stoccoro, Lorena Mosca, Roberta Gallo, Claudia Tarlarini, Christian Lunetta, Alessandro Marocchi, Lucia Migliore, Silvana Penco
OBJECTIVE: More than 180 different superoxide dismutase 1 (SOD1) mutations have been described to date in amyotrophic lateral sclerosis (ALS) patients, including not completely penetrant ones leading to phenotypic heterogeneity among carriers. We collected DNA samples from five ALS families with not fully penetrant SOD1 mutations (p.Asn65Ser, p.Gly72Ser, p.Gly93Asp, and p.Gly130_Glu133del) searching for epigenetic differences among ALS patients, asymptomatic/paucisymptomatic carriers and non-carrier family members...
September 1, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28859337/amygdala-tdp-43-pathology-in-frontotemporal-lobar-degeneration-and-motor-neuron-disease
#12
Takahiro Takeda, Danielle Seilhean, Isabelle Le Ber, Stéphanie Millecamps, Véronique Sazdovitch, Kazuo Kitagawa, Toshiki Uchihara, Charles Duyckaerts
TDP-43-positive inclusions are present in the amygdala in frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND) including amyotrophic lateral sclerosis. Behavioral abnormalities, one of the chief symptoms of FTLD, could be, at least partly, related to amygdala pathology. We examined TDP-43 inclusions in the amygdala of patients with sporadic FTLD/MND (sFTLD/MND), FTLD/MND with mutation of the C9ORF72 (FTLD/MND-C9) and FTLD with mutation of the progranulin (FTLD-GRN). TDP-43 inclusions were common in each one of these subtypes, which can otherwise be distinguished on topographical and genetic grounds...
September 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28855404/cognition-and-gray-and-white-matter-characteristics-of-presymptomatic-c9orf72-repeat-expansion
#13
Janne M Papma, Lize C Jiskoot, Jessica L Panman, Elise G Dopper, Tom den Heijer, Laura Donker Kaat, Yolande A L Pijnenburg, Lieke H Meeter, Rick van Minkelen, Serge A R B Rombouts, John C van Swieten
OBJECTIVE: To investigate cognitive function, gray matter volume, and white matter integrity in the presymptomatic stage of chromosome 9 open reading frame 72 repeat expansion (C9orf72RE). METHODS: Presymptomatic C9orf72RE carriers (n = 18) and first-degree family members without a pathogenic expansion (healthy controls [HC], n = 15) underwent a standardized protocol of neuropsychological tests, T1-weighted MRI, and diffusion tensor imaging within our cohort study of autosomal dominant frontotemporal dementia (FTD)...
August 30, 2017: Neurology
https://www.readbyqxmd.com/read/28827593/expansion-of-c9orf72-in-amyotrophic-lateral-sclerosis-correlates-with-brain-computer-interface-performance
#14
Andrew Geronimo, Kathryn E Sheldon, James R Broach, Zachary Simmons, Steven J Schiff
Abnormal expansion of hexanucleotide GGGGCC (G4C2) in the C9ORF72 gene has been associated with multiple neurodegenerative disorders, with particularly high prevalence in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat expansions of this type have been associated with altered pathology, symptom rate and severity, as well as psychological changes. In this study, we enrolled twenty-five patients with ALS and fifteen neurologically healthy controls in a P300 brain-computer interface (BCI) training procedure...
August 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28808785/conserved-dna-methylation-combined-with-differential-frontal-cortex-and-cerebellar-expression-distinguishes-c9orf72-associated-and-sporadic-als-and-implicates-serpina1-in-disease
#15
Mark T W Ebbert, Christian A Ross, Luc J Pregent, Rebecca J Lank, Cheng Zhang, Rebecca B Katzman, Karen Jansen-West, Yuping Song, Edroaldo Lummertz da Rocha, Carla Palmucci, Pamela Desaro, Amelia E Robertson, Ana M Caputo, Dennis W Dickson, Kevin B Boylan, Rosa Rademakers, Tamas Ordog, Hu Li, Veronique V Belzil
We previously found C9orf72-associated (c9ALS) and sporadic amyotrophic lateral sclerosis (sALS) brain transcriptomes comprise thousands of defects, among which, some are likely key contributors to ALS pathogenesis. We have now generated complementary methylome data and combine these two data sets to perform a comprehensive "multi-omic" analysis to clarify the molecular mechanisms initiating RNA misregulation in ALS. We found that c9ALS and sALS patients have generally distinct but overlapping methylome profiles, and that the c9ALS- and sALS-affected genes and pathways have similar biological functions, indicating conserved pathobiology in disease...
August 14, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28803727/elimination-of-toxic-microsatellite-repeat-expansion-rna-by-rna-targeting-cas9
#16
Ranjan Batra, David A Nelles, Elaine Pirie, Steven M Blue, Ryan J Marina, Harrison Wang, Isaac A Chaim, James D Thomas, Nigel Zhang, Vu Nguyen, Stefan Aigner, Sebastian Markmiller, Guangbin Xia, Kevin D Corbett, Maurice S Swanson, Gene W Yeo
Microsatellite repeat expansions in DNA produce pathogenic RNA species that cause dominantly inherited diseases such as myotonic dystrophy type 1 and 2 (DM1/2), Huntington's disease, and C9orf72-linked amyotrophic lateral sclerosis (C9-ALS). Means to target these repetitive RNAs are required for diagnostic and therapeutic purposes. Here, we describe the development of a programmable CRISPR system capable of specifically visualizing and eliminating these toxic RNAs. We observe specific targeting and efficient elimination of microsatellite repeat expansion RNAs both when exogenously expressed and in patient cells...
August 24, 2017: Cell
https://www.readbyqxmd.com/read/28803444/atypical-parkinsonian-syndromes-a-general-neurologist-s-perspective
#17
REVIEW
Angela B Deutschländer, Owen A Ross, Dennis W Dickson, Zbigniew K Wszolek
The differential diagnosis of atypical parkinsonian syndromes is challenging. These severe and often rapidly progressive neurodegenerative disorders are clinically heterogeneous and show significant phenotypic overlap. Here we review clinical, imaging, neuropathologic and genetic features of multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal lobar degeneration (FTLD). The terms CBD and FTLD refer to pathologically confirmed cases of corticobasal syndrome (CBS) and frontotemporal dementia (FTD)...
August 12, 2017: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
https://www.readbyqxmd.com/read/28792508/dctn1-gene-analysis-in-chinese-patients-with-sporadic-amyotrophic-lateral-sclerosis
#18
Xiangyi Liu, Lipeng Yang, Lu Tang, Lu Chen, Xiaolu Liu, Dongsheng Fan
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. Missense mutations of DCTN1 have been identified as a possible genetic risk factor for ALS. Here, we tested the DCTN1 protein-coding exons in 510 sporadic ALS patients in whom SOD1, TARDBP, FUS, and C9orf72 genes were screened before. Polymerase chain reaction and Sanger sequencing were used for mutation discovery. The results revealed two rare heterozygous missense variants, c.1867C>T (p.R623W) and c.2798C>T (p.A933V). These two patients exhibited spinal disease onset without cognitive impairment, and their onset age and diagnosis delay was within the average range of Chinese ALS patients...
2017: PloS One
https://www.readbyqxmd.com/read/28782342/-hummingbird-sign-in-a-patient-with-guam-parkinsonism-dementia-complex
#19
Tianrong Yeo, Louis Cs Tan
We present a case of a 71-year-old male Chamorro patient from Guam who presented with progressive supranuclear palsy (PSP)-Richardson's syndrome. Considering his strong family history of parkinsonism and a PSP phenotype, he was clinically diagnosed with Guam parkinsonism-dementia complex (PDC). Magnetic resonance imaging (MRI) of the brain revealed prominent midbrain atrophy with preserved pontine volume, forming the 'hummingbird' sign, which has not been described before in Guam PDC. Molecular analysis of the chromosome 9 open reading frame 72 gene (C9orf72) showed only 6 GGGGCC repeats...
August 8, 2017: Journal of Movement Disorders
https://www.readbyqxmd.com/read/28766957/immunohistochemical-detection-of-c9orf72-protein-in-frontotemporal-lobar-degeneration-and-motor-neurone-disease-patterns-of-immunostaining-and-an-evaluation-of-commercial-antibodies
#20
Yvonne S Davidson, Andrew C Robinson, Sara Rollinson, Stuart Pickering-Brown, Shangxi Xiao, Janice Robertson, David M A Mann
We have employed as 'gold standards' two in-house, well-characterised and validated polyclonal antibodies, C9-L and C9-S, which detect the longer and shorter forms of C9orf72, and have compared seven other commercially available antibodies with these in order to evaluate the utility of the latter as credible tools for the demonstration of C9orf72. C9-L and C9-S antibodies immunostained cytoplasmic 'speckles', and the nuclear membrane, respectively, in cerebellar Purkinje cells of the cerebellum in patients with behavioural variant frontotemporal dementia (bvFTD) with amyotrophic lateral sclerosis (ALS), and in patients with ALS alone...
August 2, 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
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