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Huntingtons disease

Asa Hatami, Chunni Zhu, Aroa Relaño-Gines, Chris Elias, Arpine Galstyan, Michael Jun, Ginger Milne, Charles R Cantor, Marie-Francoise Chesselet, Mikhail S Shchepinov
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease which has no effective treatment and is characterized by psychiatric disorders, motor alterations, and dementia, with the cognitive deficits representing a devastating aspect of the disorder. Oxidative stress and elevated levels of lipid peroxidation (LPO) products are found in mouse models and patients with HD, suggesting that strategies to reduce LPO may be beneficial in HD. In contrast to traditional antioxidants, substituting hydrogen with deuterium at bis-allylic sites in polyunsaturated fatty acids (D-PUFA) decreases the rate-limiting initiation step of PUFA autoxidation, a strategy that has shown benefits in other neurodegenerative diseases...
June 22, 2018: FEBS Journal
Ida Höijer, Yu-Chih Tsai, Tyson A Clark, Paul Kotturi, Niklas Dahl, Eva-Lena Stattin, Marie-Louise Bondeson, Lars Feuk, Ulf Gyllensten, Adam Ameur
Amplification of DNA is required as a mandatory step during library preparation in most targeted sequencing protocols. This can be a critical limitation when targeting regions that are highly repetitive or with extreme guanine-cytosine (GC) content, including repeat expansions associated with human disease. Here we used an amplification-free protocol for targeted enrichment utilizing the CRISPR/Cas9 system (No-Amp Targeted sequencing) in combination with Single Molecule, Real-Time (SMRT) sequencing for studying repeat elements in the huntingtin (HTT) gene, where an expanded CAG repeat is causative for Huntington disease...
June 22, 2018: Human Mutation
Flavio Nobili, Javier Arbizu, Femke Bouwman, Alexander Drzezga, Federica Agosta, Peter Nestor, Zuzana Walker, Marina Boccardi
BACKGROUND: Recommendations for using FDG-PET to support the diagnosis of dementing neurodegenerative disorders are sparse and poorly structured. METHODS: We defined 21 questions on diagnostic issues and on semi-automated analysis to assist visual reading. Literature was reviewed to assess study design, risk of bias, inconsistency, imprecision, indirectness and effect size. Critical outcomes were sensitivity, specificity, accuracy, positive/negative predictive value, area under the receiving operating characteristic curve, and positive/negative likelihood ratio of FDG-PET in detecting the target conditions...
June 22, 2018: European Journal of Neurology: the Official Journal of the European Federation of Neurological Societies
Jennifer A Ciarochi, Jingyu Liu, Vince Calhoun, Hans Johnson, Maria Misiura, H Jeremy Bockholt, Flor A Espinoza, Arvind Caprihan, Sergey Plis, Jessica A Turner, Jane S Paulsen
This study assessed how BDNF (brain-derived neurotrophic factor) and other genes involved in its signaling influence brain structure and clinical functioning in pre-diagnosis Huntington's disease (HD). Parallel independent component analysis (pICA), a multivariate method for identifying correlated patterns in multimodal datasets, was applied to gray matter concentration (GMC) and genomic data from a sizeable PREDICT-HD prodromal cohort ( N = 715). pICA identified a genetic component highlighting NTRK2 , which encodes BDNF's TrkB receptor, that correlated with a GMC component including supplementary motor, precentral/premotor cortex, and other frontal areas ( p < 0...
June 22, 2018: Brain Sciences
Abderrahmane Hedjoudje, Gaël Nicolas, Alice Goldenberg, Catherine Vanhulle, Clémentine Dumant-Forrest, Guillaume Deverrière, Pauline Treguier, Isabelle Michelet, Lucie Guyant-Maréchal, Didier Devys, Emmanuel Gerardin, Jean-Nicolas Dacher, Pierre-Hugues Vivier
BACKGROUND: The imaging features of Huntington disease are well known in adults, unlike in juvenile-onset Huntington disease. OBJECTIVE: To conduct a morphometric magnetic resonance imaging (MRI) analysis in three juvenile Huntington disease patients (ages 2, 4 and 6 years old) to determine whether quantitative cerebral and cerebellar morphological metrics may provide diagnostically interesting patterns of cerebellar and cerebellar atrophy. MATERIALS AND METHODS: We report the cases of three siblings with extremely early presentations of juvenile Huntington disease associated with dramatic expansions of the morbid paternal allele from 43 to more than 100 CAG trinucleotide repeats...
June 20, 2018: Pediatric Radiology
Dan P Covey, Hannah M Dantrassy, Samantha E Yohn, Alberto Castro, P Jeffrey Conn, Yolanda Mateo, Joseph F Cheer
Prominent motor deficits (e.g., chorea) that typify Huntington's disease (HD) arise following a prolonged prodromal stage characterized by psychiatric disturbances. Apathy, a disorder of motivation characterized by diminished goal-directed behavior, is one of the earliest and most common psychiatric symptoms in HD, but the underlying neurobiology is unclear and treatment options are limited. Alterations in the endocannabinoid (eCB) and dopamine systems represent prominent pathophysiological markers in HD that-similar to motivational deficits-present early and decline across disease progression...
June 1, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Jordan L Schultz, Annie Killoran, Peg C Nopoulos, Chloe C Chabal, David J Moser, John A Kamholz
OBJECTIVE: To determine whether tetrabenazine (TBZ) use is associated with an increased incidence of depression and/or suicidal ideation. METHODS: In this retrospective cross-sectional study of the Enroll-HD database, we used multiple logistic regression analyses to determine whether TBZ use is associated with an increased incidence of depression and/or suicidal ideation. For both dependent variables (depression and suicidality), separate analyses were conducted on (1) all participants, (2) only participants with a history of depression, and (3) only participants with no history of depression...
June 20, 2018: Neurology
Yuxia Zhang, Jovana Maksimovic, Bing Huang, David Peter De Souza, Gaetano Naselli, Huan Chen, Li Zhang, Kai Weng, Hanquan Liang, Yanhui Xu, John M Wentworth, Nicholas D Huntington, Alicia Oshlack, Sitang Gong, Axel Kallies, Peter Vuillermin, Min Yang, Leonard C Harrison
How T cells differentiate in the neonate may critically determine the ability of the infant to cope with infections, respond to vaccines and avert allergies. Previously, we found that naïve cord blood CD4+ T cells differentiated toward an IL-4-expressing phenotype when activated in the presence of TGF-β and monocyte-derived inflammatory cytokines, the latter are more highly secreted by infants who developed food allergy. Here, we show that in the absence of IL-2 or IL-12, naïve cord blood CD8+ T cells have a natural propensity to differentiate into IL-4-producing non-classic TC 2 cells when they are activated alone, or in the presence of TGF-β and/or inflammatory cytokines...
2018: Frontiers in Immunology
Filipe B Rodrigues, Joaquim J Ferreira, Edward J Wild
No abstract text is available yet for this article.
June 19, 2018: Current Medical Research and Opinion
Erik M Lehmkuhl, Daniela C Zarnescu
Cells utilize a complex network of proteins to regulate translation, involving post-transcriptional processing of RNA and assembly of the ribosomal unit. Although the complexity provides robust regulation of proteostasis, it also offers several opportunities for translational dysregulation, as has been observed in many neurodegenerative disorders. Defective mRNA localization, mRNA sequatration, inhibited ribogenesis, mutant tRNA synthetases, and translation of hexanucleotide expansions have all been associated with neurodegenerative disease...
2018: Advances in Neurobiology
Ashley Boehringer, Robert Bowser
In eukaryotic cells, transcription and translation are compartmentalized by the nuclear membrane, requiring an active transport of RNA from the nucleus into the cytoplasm. This is accomplished by a variety of transport complexes that contain either a member of the exportin family of proteins and translocation fueled by GTP hydrolysis or in the case of mRNA by complexes containing the export protein NXF1. Recent evidence indicates that RNA transport is altered in a number of different neurodegenerative diseases including Huntington's disease, Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis...
2018: Advances in Neurobiology
Jacob Lahr, Lora Minkova, Sarah J Tabrizi, Julie C Stout, Stefan Klöppel, Elisa Scheller
Huntington's disease (HD) is a genetically caused neurodegenerative disorder characterized by heterogeneous motor, psychiatric, and cognitive symptoms. Although motor symptoms may be the most prominent presentation, cognitive symptoms such as memory deficits and executive dysfunction typically co-occur. We used functional magnetic resonance imaging (fMRI) and task fMRI-based dynamic causal modeling (DCM) to evaluate HD-related changes in the neural network underlying working memory (WM). Sixty-four pre-symptomatic HD mutation carriers (preHD), 20 patients with early manifest HD symptoms (earlyHD), and 83 healthy control subjects performed an n -back fMRI task with two levels of WM load...
2018: Frontiers in Neurology
Sonia Marco, Alvaro Murillo, Isabel Pérez-Otaño
Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. HD symptoms include severe motor, cognitive, and psychiatric impairments that result from dysfunction and later degeneration of medium-sized spiny neurons (MSNs) in the striatum. A key early pathogenic mechanism is dysregulated synaptic transmission due to enhanced surface expression of juvenile NMDA-type glutamate receptors containing GluN3A subunits, which trigger the aberrant pruning of synapses formed by cortical afferents onto MSNs...
June 15, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Emilia Gatto, Virginia Parisi, Gabriel Persi, Estela Fernandez Rey, Martin Cesarini, José Luis Etcheverry, Pablo Rivera, Ferdinando Squitieri
BACKGROUND: Huntington's disease (HD) is a genetic, rare and progressive neurodegenerative disorder that causes motor and cognitive impairment in midlife patients. Although retinal damage was observed in animal HD models and in patients with other neurodegenerative diseases, we still need confirmation of impairment in HD patients. Optical Coherence Tomography (OCT) is a non-invasive methodology that analyzes the retinal nerve fiber layers (RNFL) and could reflect processes of neurodegeneration...
June 18, 2018: International Journal of Neuroscience
Rita L Vaz, Tiago F Outeiro, Joaquim J Ferreira
Movement disorders can be primarily divided into hypokinetic and hyperkinetic. Most of the hypokinetic syndromes are associated with the neurodegenerative disorder Parkinson's disease (PD). By contrast, hyperkinetic syndromes encompass a broader array of diseases, including dystonia, essential tremor, or Huntington's disease. The discovery of effective therapies for these disorders has been challenging and has also involved the development and characterization of accurate animal models for the screening of new drugs...
2018: Frontiers in Neurology
N E Carlozzi, S Schilling, A L Kratz, J S Paulsen, S Frank, J C Stout
PURPOSE: Symptom progression in Huntington disease (HD) is associated with cognitive decline which may interfere with the self-report of symptoms. Unfortunately, data to support or refute the psychometric reliability of patient-reported outcomes (PROs) as HD progresses are limited. This is problematic given that PROs are increasingly recognized as important measures of efficacy for new treatments. METHODS: We examined PRO data from the HDQLIFE Measurement System (Speech Difficulties; Swallowing Difficulties; Chorea) in 509 individuals with premanifest, early-stage, or late-stage HD...
June 16, 2018: Quality of Life Research
He-Jin Lee, Ye-Seul Yoon, Seung-Jae Lee
Trehalose is a non-reducing disaccharide with two glucose molecules linked through an α, α-1,1-glucosidic bond. Trehalose has received attention for the past few decades for its role in neuroprotection especially in animal models of various neurodegenerative diseases, such as Parkinson and Huntington diseases. The mechanism underlying the neuroprotective effects of trehalose remains elusive. The prevailing hypothesis is that trehalose protects neurons by inducing autophagy, thereby clearing protein aggregates...
June 15, 2018: Cell Death & Disease
Bor Luen Tang
The mechanism of intercellular transmission of pathological agents in neurodegenerative diseases has received much recent attention. Huntington's disease (HD) is caused by a monogenic mutation in the gene encoding Huntingtin (HTT). Mutant HTT (mHTT) harbors a CAG repeat extension which encodes an abnormally long polyglutamine (polyQ) repeat at HTT's N-terminus. Neuronal pathology in HD is largely due to the toxic gain-of-function by mHTT and its proteolytic products, which forms both nuclear and cytoplasmic aggregates that perturb nuclear gene transcription, RNA splicing and transport as well cellular membrane dynamics...
June 14, 2018: Cells
Robert H Scannevin
Neurodegenerative diseases can arise from a multitude of different pathological drivers, however protein misfolding appears to be a common molecular feature central to several disorders. Protein folding, and attainment of correct secondary and tertiary structure, is essential for proper protein function. Protein misfolding gives rise to structural perturbations that can result in loss of protein function or a gain of toxic function, such as through aggregation, either of which can initiate and propagate biological responses that are deleterious to cells...
June 11, 2018: Current Opinion in Chemical Biology
Shu-Ying Liu, Xiao-Lin Yu, Jie Zhu, Xiang-Meng Liu, Yue Zhang, Quan-Xiu Dong, Shan Ma, Rui-Tian Liu
Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive movement disorders and cognitive deficits, which is caused by a CAG-repeat expansion encoding an extended polyglutamine (polyQ) tract in the huntingtin protein (HTT). Reduction of mutant HTT levels and inhibition of neuroinflammation has been proposed as a major therapeutic strategy in treating HD. Intravenous immunoglobulin (IVIg) therapy has been firmly established for the treatment of several autoimmune or inflammatory neurological diseases, either as adjunctive treatment or as first-line therapy...
June 11, 2018: Brain Research
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