Here are the abstract from some PubMed HD studies published in September, November and December.
Cognitive assessment strategies in Huntington's disease research.
J Neurosci Methods. 2015 Dec 21. pii: S0165-0270(15)00447-1. doi: 10.1016/j.jneumeth.2015.12.007.
Authors: Stout JC1, Glikmann-Johnston Y2, Andrews S3.
Abstract: The number of studies examining cognition in Huntington's disease (HD) has increased dramatically in recent decades, and cognitive research methods in HD have become much more sophisticated. In this review, we provide a summary of the advances in cognitive research in HD to date, and outline the key considerations for researchers planning to include cognitive assessment in their studies of HD. In particular, we discuss consideration of structure-function relationships, selection tests appropriate to the population, choice of materials and issues of intellectual property, consideration of variables which can confound studies of cognition in HD, practice effects, and specific issues for multi-site research. Finally, we discuss future directions for cognitive assessment in HD research.
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Impaired development of cortico-striatal synaptic connectivity in a cell culture model of Huntington's disease.
Neurobiol Dis. 2015 Dec 19. pii: S0969-9961(15)30112-1. doi: 10.1016/j.nbd.2015.12.009. [Epub ahead of print]
Authors: < Buren C1, < Parsons MP2, < Smith-Dijak A1, < Raymond LA3. Vancouver, BC, Canada.
Abstract: Huntington's disease (HD) is a genetically inherited neurodegenerative disease caused by a mutation in the gene encoding the huntingtin protein. This mutation results in progressive cell death that is particularly striking in the striatum. Recent evidence indicates that early HD is initially a disease of the synapse, in which subtle alterations in synaptic neurotransmission, particularly at the cortico-striatal (C-S) synapse, can be detected well in advance of cell death. Here, we used a cell culture model in which striatal neurons are co-cultured with cortical neurons, and monitored the development of C-S connectivity up to 21days in vitro (DIV) in cells cultured from either the YAC128 mouse model of HD or the background strain, FVB/N (wild-type; WT) mice. Our data demonstrate that while C-S connectivity in WT co-cultures develops rapidly and continuously from DIV 7 to 21, YAC128 C-S connectivity shows no significant growth from DIV 14 onward. Morphological and electrophysiological data suggest that a combination of pre- and postsynaptic mechanisms contribute to this effect, including a reduction in both the postsynaptic dendritic arborization and the size and replenishment rate of the presynaptic readily releasable pool of excitatory vesicles. Moreover, a chimeric culture strategy confirmed that the most robust impairment in C-S connectivity was only observed when mutant huntingtin was expressed both pre- and postsynaptically. In all, our data demonstrate a progressive HD synaptic phenotype in this co-culture system that may be exploited as a platform for identifying promising therapeutic strategies to prevent early HD-associated synaptopathy.
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Metabolic profiling for the identification of huntington biomarkers by on-line solid-phase extraction capillary electrophoresis mass spectrometry combined with advanced data analysis tools.
Published by Elsevier Inc. Electrophoresis. 2015 Dec 18. doi: 10.1002/elps.201500378. [Epub ahead of print]
Authors: < Pont L1, < Benavente F1, < Jaumot J2, < Tauler R2, < Alberch J3,4,5, < Ginés S3,4,5, < Barbosa J1, < Sanz-Nebot V1. Spain.
Abstract: In this work, an untargeted metabolomic approach based on sensitive analysis by on-line solid-phase extraction capillary electrophoresis mass spectrometry (SPE-CE-MS) in combination with multivariate data analysis is proposed as an efficient method for the identification of biomarkers of Huntington's disease (HD) progression in plasma. For this purpose, plasma samples from wild type (wt) and HD (R6/1) mice of different ages (8, 12 and 30 weeks), were analysed by C18 -SPE-CE-MS in order to obtain the characteristic electrophoretic profiles of low molecular mass compounds. Then, multivariate curve resolution alternating least squares (MCR-ALS) was applied to the multiple full scan MS data sets. This strategy permitted the resolution of a large number of metabolites being characterised by their electrophoretic peaks and their corresponding mass spectra. A total number of 29 compounds were relevant to discriminate between wt and HD plasma samples, as well as to follow-up the HD progression. The intracellular signalling was found to be the most affected metabolic pathway in HD mice after 12 weeks of birth, when mice already showed motor coordination deficiencies and cognitive decline. This fact agreed with the atrophy and dysfunction of specific neurons, loss of several types of receptors and changed expression of neurotransmitters.
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Impaired PLP-dependent metabolism in brain samples from Huntington disease patients and transgenic R6/1 mice.
Metab Brain Dis. 2015 Dec 14. [Epub ahead of print]
Authors: < Sorolla MA1, < Rodríguez-Colman MJ2, < Vall-Llaura N2, < Vived C2, < Fernández-Nogales M3, < Lucas JJ3, < Ferrer I4, < Cabiscol E2. Spain.
Abstract: Oxidative stress has been described as important to Huntington disease (HD) progression. In a previous HD study, we identified several carbonylated proteins, including pyridoxal kinase and antiquitin, both of which are involved in the metabolism of pyridoxal 5´-phosphate (PLP), the active form of vitamin B6. In the present study, pyridoxal kinase levels were quantified and showed to be decreased both in HD patients and a R6/1 mouse model, compared to control samples. A metabolomic analysis was used to analyze metabolites in brain samples of HD patients and R6/1 mice, compared to control samples using mass spectrometry. This technique allowed detection of increased concentrations of pyridoxal, the substrate of pyridoxal kinase. In addition, PLP, the product of the reaction, was decreased in striatum from R6/1 mice. Furthermore, glutamate and cystathionine, both substrates of PLP-dependent enzymes were increased in HD. This reinforces the hypothesis that PLP synthesis is impaired, and could explain some alterations observed in the disease. Together, these results identify PLP as a potential therapeutic agent.
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Glyceraldehyde 3-phosphate dehydrogenase augments the intercellular transmission and toxicity of polyglutamine aggregates in a cell model of Huntington disease.
J Neurochem. 2015 Dec 10. doi: 10.1111/jnc.13463. [Epub ahead of print]
Authors: < Mikhaylova ER1, < Lazarev VF1, < Nikotina AD1, < Margulis BA1, < Guzhova IV1. Russia.
Abstract: The common feature of Huntington disease is the accumulation of oligomers or aggregates of mutant huntingtin protein (mHTT), which causes the death of a subset of striatal neuronal populations. The cytotoxic species can leave neurons and migrate to other groups of cells penetrating and damaging them in a prion-like manner. We hypothesized that the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH), previously shown to elevate the aggregation of mHTT, is associated with an increased efficiency of intercellular propagation of mHTT. GAPDH, on its own or together with polyglutamine species, was shown to be released into the extracellular milieu mainly from dying cells as assessed by a novel enzyme immunoassay, Western blotting and ultrafiltration. The conditioned medium of cells with growing GAPDH-polyQ aggregates was toxic to naïve cells, while depletion of the aggregates from the medium lowered this cytotoxicity. The GAPDH component of the aggregates was found to increase their toxicity by 2-fold in comparison with polyQ alone. Furthermore, GAPDH-polyQ complexes were shown to penetrate acceptor cells and to increase the capacity of polyQ to prionize its intracellular homologue containing a repeat of 25 glutamine residues. Finally, inhibitors of intracellular transport showed that polyQ-GAPDH complexes, as well as GAPDH itself, penetrated cells using clathrin-mediated endocytosis. This suggested a pivotal role of the enzyme in the intercellular transmission of HD pathogenicity. In conclusion, GAPDH occurring in complexes with polyglutamine strengthens the prion-like activity and toxicity of the migrating aggregates..
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Classification of Huntington's disease stage with support vector machines: A study on oculomotor performance.
Behav Res Methods. 2015 Dec 10. [Epub ahead of print]
Authors: < Miranda Â1, < Lavrador R1, < Júlio F1, < Januário C1,2, < Castelo-Branco M1, < Caetano G3. Portugal.
Abstract: Alterations in oculomotor performance are among the first observable physical alterations during presymptomatic stages of Huntington's disease (HD). Quantifiable measurements of oculomotor performance have been studied as possible markers of disease status and progression in presymptomatic and early symptomatic stages of HD, on the basis of traditional analysis methods. Whether oculomotor performance can be used to classify individuals according to HD disease stage has yet to be explored via the application of machine-learning methods. In the present study, we report the application of the support vector machine (SVM) algorithm to oculomotor features pooled from a four-task psychophysical experiment. We were able to automatically distinguish control participants from presymptomatic HD (pre-HD) participants with an accuracy of 73.47 %, a sensitivity of 74.31 %, and a specificity of 72.64 %; to distinguish control participants from HD patients with an accuracy of 81.84 %, a sensitivity of 76.19 %, and a specificity of 87.48 %; and to distinguish pre-HD participants from HD patients with an accuracy of 83.54 %, a sensitivity of 92.62 %, and a specificity of 74.45 %. These results demonstrate that the application of supervised classification methods to oculomotor features is a valuable and promising approach to the automatic detection of disease stage in HD.
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RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression
PLoS One. 2015 Dec 4;10(12):e0143563. doi: 10.1371/journal.pone.0143563. eCollection 2015.
Authors: < Labadorf A1,2, < Hoss AG1, < Lagomarsino V1, < Latourelle JC1, < Hadzi TC1, < Bregu J1, < MacDonald ME3, < Gusella JF3, < Chen JF1, < Akbarian S4, < Weng Z5,6, < Myers RH1,2,7.
Author information: <
Abstract: Huntington's Disease (HD) is a devastating neurodegenerative disorder that is caused by an expanded CAG trinucleotide repeat in the Huntingtin (HTT) gene. Transcriptional dysregulation in the human HD brain has been documented but is incompletely understood. Here we present a genome-wide analysis of mRNA expression in human prefrontal cortex from 20 HD and 49 neuropathologically normal controls using next generation high-throughput sequencing. Surprisingly, 19% (5,480) of the 28,087 confidently detected genes are differentially expressed (FDR<0.05) and are predominantly up-regulated. A novel hypothesis-free geneset enrichment method that dissects large gene lists into functionally and transcriptionally related groups discovers that the differentially expressed genes are enriched for immune response, neuroinflammation, and developmental genes. Markers for all major brain cell types are observed, suggesting that HD invokes a systemic response in the brain area studied. Unexpectedly, the most strongly differentially expressed genes are a homeotic gene set (represented by Hox and other homeobox genes), that are almost exclusively expressed in HD, a profile not widely implicated in HD pathogenesis. The significance of transcriptional changes of developmental processes in the HD brain is poorly understood and warrants further investigation. The role of inflammation and the significance of non-neuronal involvement in HD pathogenesis suggest anti-inflammatory therapeutics may offer important opportunities in treating HD.
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November 2015
Synaptic scaling up in medium spiny neurons of aged BACHD mice: A slow-progression model of Huntington's disease.
Neurobiol Dis. 2015 Nov 25;86:131-139. doi: 10.1016/j.nbd.2015.10.016. [Epub ahead of print]
Authors: < Rocher AB1, < Gubellini P2, < Merienne N3, < Boussicault L3, < Petit F3, < Gipchtein P3, < Jan C3, < Hantraye P3, < Brouillet E3, < Bonvento G4. France
Abstract: None
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Recombinant Adeno Associated Viral (AAV) vector type 9 delivery of Ex1-Q138-mutant huntingtin in the rat striatum as a short-time model for in vivo studies in drug discovery.
Neurobiol Dis. 2015 Nov 25;86:41-51. doi: 10.1016/j.nbd.2015.11.019. [Epub ahead of print]
Authors: < Ceccarelli I1, < Fiengo P1, < Remelli R1, < Miragliotta V1, < Rossini L1, < Biotti I1, < Cappelli A1, < Petricca L1, < La Rosa S1, < Caricasole A1, < Pollio G1, < Scali C2. Italy
Abstract: Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by dyskinesia, cognitive impairment and emotional disturbances, presenting progressive neurodegeneration in the striatum and intracellular mutant Huntingtin (mHTT) aggregates in various areas of the brain. Recombinant Adeno Associated Viral (rAAV) vectors have been successfully used to transfer foreign genes to the brain of adult animals. In the present study we report a novel in vivo rat HD model obtained by stereotaxic injection of rAAV serotype2/9 containing Exon1-Q138 mHTT (Q138) and Exon1-Q17 wild type HTT (Q17; control), respectively in the right and in the left striatum, and expressed as C-terminal GFP fusions to facilitate detection of infected cells and aggregate production. Immunohistochemical analysis of brain slices from animals sacrificed twenty-one days after viral infection showed that Q138 injection resulted in robust formation of GFP-positive aggregates in the striatum, increased GFAP and microglial activation and neurodegeneration, with little evidence of any of these events in contralateral tissue infected with wild type (Q17) expressing construct. Differences in the relative metabolite concentrations (N-Acetyl Aspartate/Creatine and Myo-Inositol/Creatine) were observed by H1 MR Spectroscopy. By quantitative RT-PCR we also demonstrated that mHTT induced changes in the expression of genes previously shown to be altered in other rodent HD models. Importantly, administration of reference compounds previously shown to ameliorate the aggregation and neurodegeneration phenotypes in preclinical HD models was demonstrated to revert the mutant HTT-dependent effects in our model. In conclusion, the AAV2/9-Q138/Q17 exon 1 HTT stereotaxic injection represents a useful first-line in vivo preclinical model for studying the biology of mutant HTT exon 1 in the striatum and to provide early evidence of efficacy of therapeutic approaches.
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Differential changes in thalamic and cortical excitatory synapses onto striatal spiny projection neurons in a Huntington disease mouse model.
Neurobiol Dis. 2015 Nov 24;86:62-74. doi: 10.1016/j.nbd.2015.11.020. [Epub ahead of print]
Authors: < Kolodziejczyk K1, < Raymond LA2. Vancouver, British Columbia, Canada.
Abstract: Huntington disease (HD), a neurodegenerative disorder caused by CAG repeat expansion in the gene encoding huntingtin, predominantly affects the striatum, especially the spiny projection neurons (SPN). The striatum receives excitatory input from cortex and thalamus, and the role of the former has been well-studied in HD. Here, we report that mutated huntingtin alters function of thalamostriatal connections. We used a novel thalamostriatal (T-S) coculture and an established corticostriatal (C-S) coculture, generated from YAC128 HD and WT (FVB/NJ background strain) mice, to investigate excitatory neurotransmission onto striatal SPN. SPN in T-S coculture from WT mice showed similar mini-excitatory postsynaptic current (mEPSC) frequency and amplitude as in C-S coculture; however, both the frequency and amplitude were significantly reduced in YAC128 T-S coculture. Further investigation in T-S coculture showed similar excitatory synapse density in WT and YAC128 SPN dendrites by immunostaining, suggesting changes in total dendritic length or probability of release as possible explanations for mEPSC frequency changes. Synaptic N-methyl-d-aspartate receptor (NMDAR) current was similar, but extrasynaptic current, associated with cell death signaling, was enhanced in YAC128 SPN in T-S coculture. Employing optical stimulation of cortical versus thalamic afferents and recording from striatal SPN in brain slice, we found increased glutamate release probability and reduced AMPAR/NMDAR current ratios in thalamostriatal synapses, most prominently in YAC128. Enhanced extrasynaptic NMDAR current in YAC128 SPN was apparent with both cortical and thalamic stimulation. We conclude that thalamic afferents to the striatum are affected early, prior to an overt HD phenotype; however, changes in NMDAR localization in SPN are independent of the source of glutamatergic input.
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October 2015
Profile of pridopidine and its potential in the treatment of Huntington disease: the evidence to date.
Drug Des Devel Ther. 2015 Oct 28;9:5827-33. doi: 10.2147/DDDT.S65738. eCollection 2015.
Authors: < Squitieri F1, < de Yebenes JG2. Italy/Spain
Abstract: Huntington disease (HD) is a chronic, genetic, neurodegenerative disease for which there is no cure. The main symptoms of HD are abnormal involuntary movements (chorea and dystonia), impaired voluntary movements (ie, incoordination and gait balance), progressive cognitive decline, and psychiatric disturbances. HD is caused by a CAG-repeat expanded mutation in the HTT gene, which encodes the huntingtin protein. The inherited mutation results in the production of an elongated polyQ mutant huntingtin protein (mHtt). The cellular functions of the Htt protein are not yet fully understood, but the functions of its mutant variant are thought to include alteration of gene transcription and energy production, and dysregulation of neurotransmitter metabolism, receptors, and growth factors. The phenylpiperidines pridopidine (4-[3-methanesulfonyl-phenyl]-1-propyl-piperidine; formerly known as ACR16) and OSU6162 ([S]-[-]-3-[3-methane [sulfonyl-phenyl]-1-propyl-piperidine) are members of a new class of pharmacologic agents known as "dopamine stabilizers". Recent clinical trials have highlighted the potential of pridopidine for symptomatic treatment of patients with HD. More recently, the analysis of HD models (ie, in vitro and in mice) highlighted previously unknown effects of pridopidine (increase in brain-derived neurotrophic factor, reduction in mHtt levels, and s-1 receptor binding and modulation). These additional functions of pridopidine suggest it might be a neuroprotective and disease-modifying drug. Data from ongoing clinical trials of pridopidine will help define its place in the treatment of HD. This commentary examines the available preclinical and clinical evidence regarding the use of pridopidine in HD.
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September 2015
The effects of physiotherapy with PNF concept on gait and balance of patients with Huntington's disease - pilot study.
Neurol Neurochir Pol. 2015;49(6):354-7. doi: 10.1016/j.pjnns.2015.09.002. Epub 2015 Sep 15.
Authors: < Mirek E1, < Filip M2, < Banaszkiewicz K3, < Rudzinska M4, < Szymura J5, < Pasiut S5, < Stozek J5, < Szczudlik A6. Poland.
BACKGROUND AND PURPOSE: Huntington's disease (HD) is a neurodegenerative, progressive disorder of the central nervous system which causes significant gait and balance disturbances. This is a pilot study which aims to determine the effects of a physiotherapy programme with use of Proprioceptive Neuromuscular Facilitation (PNF) on gait and balance in HD patients.
MATERIAL AND METHODS: 30 HD patients aged 21-60 with genetically confirmed diagnosis participated in the study. Participants followed a 3-week-long PNF-based physiotherapy programme. Gait and balance were evaluated twice in each participant: first at baseline and then after the course of physiotherapy. The following methods were used for gait disturbances: Tinetti Gait Assessment Tool, Up and Go Test, Timed Walking Tests for 10m and 20m (TWT10m, TWT20m). Balance was assessed with use of Berg Balance Scale, Pastor Test and Functional Reach Test.
RESULTS: There was a significant improvement in all measures of balance and gait.
CONCLUSION: PNF-based physiotherapy is effective and safe in HD patients.
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< PNF Stretching - Stretching Exercises Guide
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August 2015