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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:
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.
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]
thor_uid=26711622> Buren C1,
cauthor_uid=26711622> Parsons MP2,
<> Smith-Dijak A1,
cauthor_uid=26711622> 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 cocultured 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.
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]
hor_uid=26685060> Pont L1,
&cauthor_uid=26685060> Benavente F1,
uthor_uid=26685060> Jaumot J2,
uthor_uid=26685060> Tauler R2,
author_uid=26685060> Alberch J3,4,5,
e&cauthor_uid=26685060> Ginés S3,4,5,
author_uid=26685060> 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.
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]
cauthor_uid=26666246> Sorolla MA1,
<> Rodríguez-Colman MJ2,
<> Vall-Llaura N2,
thor_uid=26666246> Vived C2,
<> Fernández-Nogales M3,
uthor_uid=26666246> Lucas JJ3,
uthor_uid=26666246> Ferrer I4,
cauthor_uid=26666246> 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.
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]
ue&cauthor_uid=26662373> Mikhaylova ER1,
cauthor_uid=26662373> Lazarev VF1,
&cauthor_uid=26662373> Nikotina AD1,
&cauthor_uid=26662373> Margulis BA1,
cauthor_uid=26662373> 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..
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]
rue&cauthor_uid=26660196> Miranda Â1,
cauthor_uid=26660196> Lavrador R1,
e&cauthor_uid=26660196> Júlio F1,
true&cauthor_uid=26660196> Januário C1,2,
<> Castelo-Branco M1,
author_uid=26660196> 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.
RNA Sequence Analysis of Human Huntington Disease Brain Reveals an
Extensive Increase in Inflammatory and Developmental Gene
PLoS One. 2015 Dec 4;10(12):e0143563. doi: 10.1371/journal.pone.0143563.
eCollection 2015.
cauthor_uid=26636579> Labadorf A1,2,
thor_uid=26636579> Hoss AG1,
ue&cauthor_uid=26636579> Lagomarsino V1,
ue&cauthor_uid=26636579> Latourelle JC1,
uthor_uid=26636579> Hadzi TC1,
thor_uid=26636579> Bregu J1,
e&cauthor_uid=26636579> MacDonald ME3,
cauthor_uid=26636579> Gusella JF3,
thor_uid=26636579> Chen JF1,
cauthor_uid=26636579> Akbarian S4,
hor_uid=26636579> Weng Z5,6,
uthor_uid=26636579> 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 antiinflammatory therapeutics may offer important opportunities in treating HD.
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]
author_uid=26626081> Rocher AB1,
&cauthor_uid=26626081> Gubellini P2,
cauthor_uid=26626081> Merienne N3,
ue&cauthor_uid=26626081> Boussicault L3,
thor_uid=26626081> Petit F3,
&cauthor_uid=26626081> Gipchtein P3,
or_uid=26626081> Jan C3,
cauthor_uid=26626081> Hantraye P3,
&cauthor_uid=26626081> Brouillet E3,
cauthor_uid=26626081> Bonvento G4. France
Abstract: None
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]
e&cauthor_uid=26626080> Ceccarelli I1,
uthor_uid=26626080> Fiengo P1,
author_uid=26626080> Remelli R1,
ue&cauthor_uid=26626080> Miragliotta V1,
author_uid=26626080> Rossini L1,
uthor_uid=26626080> Biotti I1,
cauthor_uid=26626080> Cappelli A1,
cauthor_uid=26626080> Petricca L1,
&cauthor_uid=26626080> La Rosa S1,
e&cauthor_uid=26626080> Caricasole A1,
uthor_uid=26626080> Pollio G1,
thor_uid=26626080> 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.
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]
true&cauthor_uid=26621114> Kolodziejczyk K1,
cauthor_uid=26621114> 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 miniexcitatory 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.
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.
&cauthor_uid=26604684> Squitieri F1,
true&cauthor_uid=26604684> de Yebenes JG2.
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-methanesulfonylphenyl]-1-propyl-piperidine; formerly known as ACR16) and OSU6162 ([S]-[-]-3-[3methane [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 brainderived 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.
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.
thor_uid=26652868> Mirek E1,
thor_uid=26652868> Filip M2,
true&cauthor_uid=26652868> Banaszkiewicz K3,
=true&cauthor_uid=26652868> Rudzinska M4,
author_uid=26652868> Szymura J5,
uthor_uid=26652868> Pasiut S5,
ue&cauthor_uid=26652868> Stozek J5,
&cauthor_uid=26652868> 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 PNFbased 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
There was a significant improvement in all measures of balance and
PNF-based physiotherapy is effective and safe in HD patients.
m%2Fcourses%2FPNF-to-enhance-gait-evidence-based-continuing-educationcourse.php&usg=AFQjCNHwkGtHcxS-Rc7CSVHZEw4LQLCZ_w&bvm=bv.110151844,d.dmo> PNF
and Functional Gait | OT-PT Evidenced Based ...
PNF Stretching - Stretching Exercises Guide
August 2015