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Frontotemporal dementia

Jade-Emmanuelle Deshaies, Lulzim Shkreta, Alexander J Moszczynski, Hadjara Sidibé, Sabrina Semmler, Aurélien Fouillen, Estelle R Bennett, Uriya Bekenstein, Laurie Destroismaisons, Johanne Toutant, Quentin Delmotte, Kathryn Volkening, Stéphanie Stabile, Anaïs Aulas, Yousra Khalfallah, Hermona Soreq, Antonio Nanci, Michael J Strong, Benoit Chabot, Christine Vande Velde
The RNA binding proteins TDP-43 (encoded by TARDBP) and hnRNP A1 (HNRNPA1) are each mutated in certain amyotrophic lateral sclerosis cases and are often mislocalized in cytoplasmic aggregates within motor neurons of affected patients. Cytoplasmic inclusions of TDP-43, which are accompanied by a depletion of nuclear TDP-43, are observed in most amyotrophic lateral sclerosis cases and nearly half of frontotemporal dementia cases. Here, we report that TDP-43 binds HNRNPA1 pre-mRNA and modulates its splicing, and that depletion of nuclear TDP-43 results in increased inclusion of a cassette exon in the HNRNPA1 transcript, and consequently elevated protein levels of an isoform containing an elongated prion-like domain, referred to as hnRNP A1B...
March 19, 2018: Brain: a Journal of Neurology
Jan Kassubek, Hans-Peter Müller, Kelly Del Tredici, Michael Hornberger, Matthias L Schroeter, Karsten Müller, Sarah Anderl-Straub, Ingo Uttner, Murray Grossman, Heiko Braak, John R Hodges, Olivier Piguet, Markus Otto, Albert C Ludolph
Objective: Recently, the characteristic longitudinal distribution pattern of the underlying phosphorylated TDP-43 (pTDP-43) pathology in the behavioral variant of frontotemporal dementia (bvFTD) excluding Pick's disease (PiD) across specific brain regions was described. The aim of the present study was to investigate whether in vivo investigations of bvFTD patients by use of diffusion tensor imaging (DTI) were consistent with these proposed patterns of progression. Methods: Sixty-two bvFTD patients and 47 controls underwent DTI in a multicenter study design...
2018: Frontiers in Aging Neuroscience
Jakub Antczak, Katarzyna Kowalska, Aleksandra Klimkowicz-Mrowiec, Barbara Wach, Katarzyna Kasprzyk, Marta Banach, Karolina Rzeźnicka-Brzegowy, Jadwiga Kubica, Agnieszka Słowik
Background: Frontotemporal dementia (FTD) is one of the most frequent dementia types in patients under 65 years of age. Currently, no therapy can effectively improve the cognitive deficits associated with FTD. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method of inducing brain plasticity with therapeutic potential in neurodegenerative diseases. The purpose of this study was to evaluate the effect of rTMS on cognitive, behavioral, and emotional function in FTD...
2018: Neuropsychiatric Disease and Treatment
Ross W Paterson, Catherine F Slattery, Teresa Poole, Jennifer M Nicholas, Nadia K Magdalinou, Jamie Toombs, Miles D Chapman, Michael P Lunn, Amanda J Heslegrave, Martha S Foiani, Philip S J Weston, Ashvini Keshavan, Jonathan D Rohrer, Martin N Rossor, Jason D Warren, Catherine J Mummery, Kaj Blennow, Nick C Fox, Henrik Zetterberg, Jonathan M Schott
BACKGROUND: Cerebrospinal fluid (CSF) biomarkers are increasingly being used to support a diagnosis of Alzheimer's disease (AD). Their clinical utility for differentiating AD from non-AD neurodegenerative dementias, such as dementia with Lewy bodies (DLB) or frontotemporal dementia (FTD), is less well established. We aimed to determine the diagnostic utility of an extended panel of CSF biomarkers to differentiate AD from a range of other neurodegenerative dementias. METHODS: We used immunoassays to measure conventional CSF markers of amyloid and tau pathology (amyloid beta (Aβ)1-42, total tau (T-tau), and phosphorylated tau (P-tau)) as well as amyloid processing (AβX-38, AβX-40, AβX-42, soluble amyloid precursor protein (sAPP)α, and sAPPβ), large fibre axonal degeneration (neurofilament light chain (NFL)), and neuroinflammation (YKL-40) in 245 patients with a variety of dementias and 30 controls...
March 20, 2018: Alzheimer's Research & Therapy
Cyril Pottier, Evadnie Rampersaud, Matt Baker, Gang Wu, Joanne Wuu, Jacob L McCauley, Stephan Zuchner, Rebecca Schule, Christin Bermudez, Sumaira Hussain, Anne Cooley, Marielle Wallace, Jinghui Zhang, J Paul Taylor, Michael Benatar, Rosa Rademakers
Homozygous loss-of-function mutations in optineurin (OPTN) are a rare cause of amyotrophic lateral sclerosis (ALS), whereas heterozygous loss-of-function mutations have been suggested to increase ALS disease risk. We report a patient with ALS and frontotemporal dementia (FTD) from the Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium carrying compound heterozygous loss-of-function variants in OPTN. Quantitative real-time mRNA expression analyses revealed a 75-80% reduction in OPTN expression in blood in the OPTN carrier as compared to controls, suggesting at least partial nonsense-mediated decay of the mutant transcripts...
March 20, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Beata Peplonska, Mariusz Berdynski, Monika Mandecka, Anna Barczak, Magdalena Kuzma-Kozakiewicz, Maria Barcikowska, Cezary Zekanowski
Activation of the TREM2 receptor on microglia stimulates phagocytosis and decreases the microglial proinflammatory response. Mutations in exon 2 of the TREM2 gene have been reported to be associated with various neurodegenerative diseases characterized by chronic inflammation. The aim of our study was to evaluate exon 2 of TREM2 gene variants as a putative genetic risk factor for Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) in the Polish population. The results were interpreted using previously published data, especially highlighting differences in the prevalence of the variants among Caucasian subpopulations across different geographic regions...
March 20, 2018: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Matthew A White, Eosu Kim, Amanda Duffy, Robert Adalbert, Benjamin U Phillips, Owen M Peters, Jodie Stephenson, Sujeong Yang, Francesca Massenzio, Ziqiang Lin, Simon Andrews, Anne Segonds-Pichon, Jake Metterville, Lisa M Saksida, Richard Mead, Richard R Ribchester, Youssef Barhomi, Thomas Serre, Michael P Coleman, Justin Fallon, Timothy J Bussey, Robert H Brown, Jemeen Sreedharan
Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterized by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. Here we have created a TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene. TDP-43Q331K mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons. Critically, TDP-43 autoregulation is perturbed, leading to a gain of TDP-43 function and altered splicing of Mapt, another pivotal dementia-associated gene...
March 19, 2018: Nature Neuroscience
Stéphanie Philtjens, Sara Van Mossevelde, Julie van der Zee, Eline Wauters, Lubina Dillen, Mathieu Vandenbulcke, Rik Vandenberghe, Adrian Ivanoiu, Anne Sieben, Christiana Willems, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Barbara Borroni, Alessandro Padovani, Pau Pastor, Monica Diez-Fairen, Miquel Aguilar, Alexandre de Mendonça, Gabriel Miltenberger-Miltényi, Isabel Hernández, Merce Boada, Agustín Ruiz, Benedetta Nacmias, Sandro Sorbi, Maria Rosário Almeida, Isabel Santana, Jordi Clarimón, Alberto Lleó, Giovanni B Frisoni, Raquel Sanchez-Valle, Albert Lladó, Estrella Gómez-Tortosa, Ellen Gelpi, Marleen Van den Broeck, Karin Peeters, Patrick Cras, Peter P De Deyn, Sebastiaan Engelborghs, Marc Cruts, Christine Van Broeckhoven
We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is the neuronal receptor for granulin, encoded by the progranulin gene (GRN), a major causal gene for inherited FTD. In Belgian cohorts of 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants in SORT1. Rare variant burden analysis showed a significant increase in rare coding variants in patients compared to control individuals (p = 0.04), particularly in the β-propeller domain (p = 0...
February 17, 2018: Neurobiology of Aging
Stephanie Wong, Muireann Irish, Michael Hornberger
No abstract text is available yet for this article.
February 27, 2018: Cortex; a Journal Devoted to the Study of the Nervous System and Behavior
Hanna Cho, Sang Won Seo, Jae Yong Choi, Hye Sun Lee, Young Hoon Ryu, Myung Sik Lee, Duk L Na, Hee Jin Kim, Chul Hyoung Lyoo
Behavioral variant frontotemporal dementia (bvFTD) is the most common form of frontotemporal dementia, and tau pathology can be found in 40%-50% of bvFTD patients. In this study, we sought to investigate18 F-flortaucipir-binding patterns and their correlates in clinically diagnosed bvFTD patients by comparing with results for Alzheimer's disease (AD) patients. We enrolled 20 bvFTD, 20 AD, and 20 age-matched healthy subjects who underwent neuropsychological tests, magnetic resonance imaging, and tau positron emission tomography scans with18 F-flortaucipir...
February 21, 2018: Neurobiology of Aging
Jackie M Poos, Lize C Jiskoot, Janne M Papma, John C van Swieten, Esther van den Berg
OBJECTIVES: A meta-analysis of the extent, nature and pattern of memory performance in behavioral variant frontotemporal dementia (bvFTD). Multiple observational studies have challenged the relative sparing of memory in bvFTD as stated in the current diagnostic criteria. METHODS: We performed a meta-analytic review covering the period 1967 to February 2017 of case-control studies on episodic memory in bvFTD versus control participants (16 studies, 383 patients, 603 control participants), and patients with bvFTD versus those with Alzheimer's disease (AD) (20 studies, 452 bvFTD, 874 AD)...
March 19, 2018: Journal of the International Neuropsychological Society: JINS
Jana Janssens, Yannick Vermeiren, Erik Fransen, Tony Aerts, Debby Van Dam, Sebastiaan Engelborghs, Peter P De Deyn
Introduction: Given the challenges concerning the differential diagnosis of dementia, we investigated the possible added value of monoaminergic compounds to the standard cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. Particularly, regarding the AD versus dementia with Lewy bodies (DLB) comparison, monoamines or their metabolites might have added discriminative value as there is a more severe neuropathological burden in the locus coeruleus of DLB patients, the principal site of noradrenaline synthesis...
2018: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Silvana Konermann, Peter Lotfy, Nicholas J Brideau, Jennifer Oki, Maxim N Shokhirev, Patrick D Hsu
Class 2 CRISPR-Cas systems endow microbes with diverse mechanisms for adaptive immunity. Here, we analyzed prokaryotic genome and metagenome sequences to identify an uncharacterized family of RNA-guided, RNA-targeting CRISPR systems that we classify as type VI-D. Biochemical characterization and protein engineering of seven distinct orthologs generated a ribonuclease effector derived from Ruminococcus flavefaciens XPD3002 (CasRx) with robust activity in human cells. CasRx-mediated knockdown exhibits high efficiency and specificity relative to RNA interference across diverse endogenous transcripts...
March 8, 2018: Cell
Bita Zamiri, Mila Mirceta, Rashid Abu-Ghazalah, Marc S Wold, Christopher E Pearson, Robert B Macgregor
BACKGROUND: Expansion of the C9orf72 hexanucleotide repeat (GGGGCC)n •(GGCCCC)n is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Both strands of the C9orf72 repeat have been shown to form unusual DNA and RNA structures that are thought to be involved in mutagenesis and/or pathogenesis. We previously showed that the C-rich DNA strands from the C9orf72 repeat can form four-stranded quadruplexes at neutral pH. The cytosine residues become protonated under slightly acidic pH (pH 4...
March 14, 2018: Biochimica et Biophysica Acta
Shannon N Rhoads, Zachary T Monahan, Debra S Yee, Frank P Shewmaker
Subcellular mislocalization and aggregation of the human FUS protein occurs in neurons of patients with subtypes of amyotrophic lateral sclerosis and frontotemporal dementia. FUS is one of several RNA-binding proteins that can functionally self-associate into distinct liquid-phase droplet structures. It is postulated that aberrant interactions within the dense phase-separated state can potentiate FUS's transition into solid prion-like aggregates that cause disease. FUS is post-translationally modified at numerous positions, which affect both its localization and aggregation propensity...
March 16, 2018: International Journal of Molecular Sciences
Hilary C Archbold, Kasey L Jackson, Ayush Arora, Kaitlin Weskamp, Elizabeth M-H Tank, Xingli Li, Roberto Miguez, Robert D Dayton, Sharon Tamir, Ronald L Klein, Sami J Barmada
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders marked in most cases by the nuclear exclusion and cytoplasmic deposition of the RNA binding protein TDP43. We previously demonstrated that ALS-associated mutant TDP43 accumulates within the cytoplasm, and that TDP43 mislocalization predicts neurodegeneration. Here, we sought to prevent neurodegeneration in ALS/FTD models using selective inhibitor of nuclear export (SINE) compounds that target exportin-1 (XPO1)...
March 15, 2018: Scientific Reports
Maria Garranzo-Asensio, Pablo San Segundo-Acosta, Javier Martínez-Useros, Ana Montero-Calle, María Jesús Fernández-Aceñero, Anna Häggmark-Månberg, Alberto Pelaez-Garcia, Mayte Villalba, Alberto Rabano, Peter Nilsson, Rodrigo Barderas
Alzheimer's disease (AD) is the most common form of dementia in developed countries. A better understanding of the events taking place at the molecular level would help to identify novel protein alterations, which might be used in diagnosis or for treatment development. In this study, we have performed the high-throughput analysis of 706 molecules mostly implicated in cell-cell communication and cell signaling processes by using two antibody microarray platforms. We screened three AD pathological groups -each one containing four pooled samples- from Braak stages IV, V and VI, and three control groups from two healthy subjects, five frontotemporal and two vascular dementia patients onto Panorama and L-Series antibody microarrays to identify AD-specific alterations not common to other dementias...
February 16, 2018: Oncotarget
Woojin Scott Kim, Eve Jary, Russell Pickford, Ying He, Rebekah M Ahmed, Olivier Piguet, John R Hodges, Glenda M Halliday
Behavioral variant frontotemporal dementia (bvFTD) is the most prevalent form of FTD syndromes. bvFTD is characterized clinically by changes in behavior and cognition and pathologically by focal brain atrophy and concomitant loss of lipids. bvFTD is further characterized by eating abnormalities that result in dyslipidemia. Although dyslipidemia is apparent in bvFTD, very little is known about global lipid changes in bvFTD and lipid dysregulation underlying bvFTD. Here, we undertook a comprehensive lipidomics analysis of blood plasma from patients with bvFTD, patients with Alzheimer's disease (AD) and controls, using liquid chromatography-tandem mass spectrometry, with the aim of understanding lipid dysregulation in bvFTD...
2018: Frontiers in Neurology
Wouter I Schievink, M Marcel Maya, Zachary R Barnard, Franklin G Moser, Stacey Jean-Pierre, Alan D Waxman, Miriam Nuño
BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is a devastating early onset dementia. Symptoms of bvFTD may be caused by spontaneous intracranial hypotension (SIH), a treatable disorder, but no comprehensive study of such patients has been reported. OBJECTIVE: To describe detailed characteristics of a large cohort of patients with SIH and symptoms of bvFTD. METHODS: We identified patients with SIH who met clinical criteria for bvFTD...
March 8, 2018: Operative Neurosurgery (Hagerstown, Md.)
Kuo-Hsuan Chang, Guan-Chiun Lee, Chin-Chang Huang, Hung-Chou Kuo, Chiung-Mei Chen, Ya-Chin Hsiao, Hsuan-Chu Hsu, Ke-Jen Hsu, Chih-Hsin Lin, Chia Wen Chang, Guey-Jen Lee-Chen, Yih-Ru Wu
BACKGROUND: Mutations in the GRN (granulin precursor) are a frequent cause of frontotemporal dementia (FTD) and other atypical parkinsonian disorders. However, the frequency of GRN mutations in Asian patients with atypical parkinsonian disorders is still uncertain. METHODS: We screened GRN mutations by sequencing cDNA from 98 patients with FTD or atypical parkinsonian disorders. The functional properties of the identified mutation were evaluated by overexpression in human embryonic kidney (HEK)-293 cells...
February 28, 2018: Parkinsonism & related Disorders
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