Lewy body dementia: Overcoming barriers and identifying solutions.

Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements.

MIJ821 (onfasprodil) in healthy volunteers: First-in-human, randomized, placebo-controlled study (single ascending dose and repeated intravenous dose).

This single-center study administered MIJ821 (onfasprodil) as an intravenous infusion to healthy volunteers and included two parts: a single ascending dose study (Part 1) and a repeated intravenous dose study (Part 2). Primary objective was to evaluate the safety and tolerability of single ascending intravenous doses infused over a 40-min period and of two repeated doses (1 week apart) of MIJ821 in healthy volunteers. Secondary objectives were to assess the pharmacokinetics of MIJ821 after intravenous infusion in Part 1 and Part 2 of the study.

Description of the Method for Evaluating Digital Endpoints in Alzheimer Disease Study: Protocol for an Exploratory, Cross-sectional Study.

Background: More sensitive and less burdensome efficacy end points are urgently needed to improve the effectiveness of clinical drug development for Alzheimer disease (AD). Although conventional end points lack sensitivity, digital technologies hold promise for amplifying the detection of treatment signals and capturing cognitive anomalies at earlier disease stages. Using digital technologies and combining several test modalities allow for the collection of richer information about cognitive and functional status, which is not ascertainable via conventional paper-and-pencil tests.

An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion.

Huntington's Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials.

Mavoglurant Augmentation in OCD Patients Resistant to Selective Serotonin Reuptake Inhibitors: A Proof-of-Concept, Randomized, Placebo-Controlled, Phase 2 Study.

Introduction: To determine if mavoglurant (modified release) as an augmentation therapy to selective serotonin reuptake inhibitors (SSRIs) could have beneficial effects reducing Yale-Brown Obsessive Compulsive Scale (Y-BOCS) total score in patients with obsessive-compulsive disorder (OCD) resistant to SSRI treatment.

Methods: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2 study. Patients remained on their SSRI treatment and mavoglurant or placebo was added on.

Assessment of the Abuse Potential of the Orexin Receptor Antagonist, Suvorexant, Compared With Zolpidem in a Randomized Crossover Study.

Suvorexant is a dual orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia at a maximum dose of 20 mg. This randomized double-blind crossover study evaluated the abuse potential of suvorexant in 36 healthy recreational polydrug users with a history of sedative and psychedelic drug use. Single doses of suvorexant (40, 80, and 150 mg: 2-7.

A randomized, crossover, placebo-controlled clinical trial to assess the sensitivity of the CRCDS Mini-Sim to the next-day residual effects of zopiclone.

Objectives: We sought to validate Cognitive Research Corporation's Driving Simulator (CRCDS Mini-Sim) for studies of drug safety with respect to driving ability.

Methods: A total of 30 healthy subjects were randomized to receive placebo or 7.5 mg zopiclone, a hypnotic known to impair driving, in random order during the 2 treatment periods of a 2 period crossover design.

MeCP2: a novel Huntingtin interactor.

Transcriptional dysregulation has been proposed to play a major role in the pathology of Huntington's disease (HD). However, the mechanisms that cause selective downregulation of target genes remain unknown. Previous studies have shown that mutant huntingtin (Htt) protein interacts with a number of transcription factors thereby altering transcription.

Feasibility and impact on surgical outcomes of modified double-stapling technique for patients undergoing laparoscopic anterior resection.

Background: Anastomotic leakage is a major cause of postoperative morbidity and mortality in the treatment of colorectal cancer. The aim of this study was to investigate the modified double-stapling technique (MDST), as an alternative for conventional double-stapling technique (DST), and whether it could reduce the anastomotic leakage rate in laparoscopic anterior resection (Lapa-AR).

Study Design: Between March 2009 and October 2010, a total of 189 patients who underwent Lapa-AR for the treatment of adenocarcinoma of the sigmoid colon or rectosigmoid colon were divided into the MDST group (n = 95) and the DST group (n = 94) according to the anastomotic technique.

Genome-wide increase in histone H2A ubiquitylation in a mouse model of Huntington's disease.

Background: Huntington's disease (HD) is a neurodegenerative disorder with selective vulnerability of striatal neurons and involves extensive transcriptional dysregulation early in the disease process. Previous work in cell and mouse models has shown that histone modifications are altered in HD. Specifically, monoubiquitylated histone H2A (uH2A) is present at the promoters of downregulated genes which led to the hypothesis that uH2A plays a role in transcriptional silencing in HD.

Genome-wide histone acetylation is altered in a transgenic mouse model of Huntington's disease.

In Huntington's disease (HD; MIM ID #143100), a fatal neurodegenerative disorder, transcriptional dysregulation is a key pathogenic feature. Histone modifications are altered in multiple cellular and animal models of HD suggesting a potential mechanism for the observed changes in transcriptional levels. In particular, previous work has suggested an important link between decreased histone acetylation, particularly acetylated histone H3 (AcH3; H3K9K14ac), and downregulated gene expression.

Increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area during cocaine abstinence is associated with increased histone acetylation at BDNF exon I-containing promoters.

Recent evidence suggests that the persistence of cocaine seeking during periods of protracted drug abstinence following chronic cocaine exposure is mediated, in part, by neuroadaptations in the mesolimbic dopamine system. Specifically, incubation of cocaine-seeking behavior coincides with increased brain-derived neurotrophic factor (BDNF) protein expression in the ventral tegmental area (VTA). However, the molecular mechanisms that regulate time-dependent changes in VTA BDNF protein expression during cocaine abstinence are unclear.

Molecular biology of Huntington's disease.

It has been more than 17 years since the causative mutation for Huntington's disease was discovered as the expansion of the triplet repeat in the N-terminal portion of the Huntingtin (HTT) gene. In the intervening time, researchers have discovered a great deal about Huntingtin's involvement in a number of cellular processes. However, the role of Huntingtin in the key pathogenic mechanism leading to neurodegeneration in the disease process has yet to be discovered.

Cocaine-induced chromatin remodeling increases brain-derived neurotrophic factor transcription in the rat medial prefrontal cortex, which alters the reinforcing efficacy of cocaine.

Cocaine self-administration alters patterns of gene expression in the brain that may underlie cocaine-induced neuronal plasticity. In the present study, male Sprague Dawley rats were allowed to self-administer cocaine (0.25 mg/infusion) 2 h/d for 14 d, followed by 7 d of forced abstinence.

Environmental enrichment reduces neuronal intranuclear inclusion load but has no effect on messenger RNA expression in a mouse model of Huntington disease.

Huntington disease (HD) is a fatal neurodegenerative disease with no effective treatment. In the R6/1 mouse model of HD, environmental enrichment delays the neurologic phenotype onset and prevents cerebral volume loss by unknown molecular mechanisms. We examined the effects of environmental enrichment on well-characterized neuropathological parameters in a mouse model of HD.

Altered white matter microstructure in the corpus callosum in Huntington's disease: implications for cortical "disconnection".

The corpus callosum (CC) is the major conduit for information transfer between the cerebral hemispheres and plays an integral role in relaying sensory, motor and cognitive information between homologous cortical regions. The majority of fibers that make up the CC arise from large pyramidal neurons in layers III and V, which project contra-laterally. These neurons degenerate in Huntington's disease (HD) in a topographically and temporally selective way.

Phosphorylation-dependent trafficking of GluR2-containing AMPA receptors in the nucleus accumbens plays a critical role in the reinstatement of cocaine seeking.

A growing body of evidence indicates that enhanced AMPA-mediated glutamate transmission in the core of the nucleus accumbens is critically involved in cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. However, the extent to which increased glutamate transmission in the other major subregion of the nucleus accumbens, the shell, contributes to the reinstatement of cocaine seeking remains unclear. In the present experiments, administration of the AMPA/kainate receptor antagonist CNQX (0, 0.

Linking SNPs to CAG repeat length in Huntington's disease patients.

Allele-specific silencing using small interfering RNAs targeting heterozygous single-nucleotide polymorphisms (SNPs) is a promising therapy for human trinucleotide repeat diseases such as Huntington's disease. Linking SNP identities to the two HTT alleles, normal and disease-causing, is a prerequisite for allele-specific RNA interference. Here we describe a method, SNP linkage by circularization (SLiC), to identify linkage between CAG repeat length and nucleotide identity of heterozygous SNPs using Huntington's disease patient peripheral blood samples.

Huntingtin modulates transcription, occupies gene promoters in vivo, and binds directly to DNA in a polyglutamine-dependent manner.

Transcriptional dysregulation is a central pathogenic mechanism in Huntington's disease, a fatal neurodegenerative disorder associated with polyglutamine (polyQ) expansion in the huntingtin (Htt) protein. In this study, we show that mutant Htt alters the normal expression of specific mRNA species at least partly by disrupting the binding activities of many transcription factors which govern the expression of the dysregulated mRNA species. Chromatin immunoprecipitation (ChIP) demonstrates Htt occupation of gene promoters in vivo in a polyQ-dependent manner, and furthermore, ChIP-on-chip and ChIP subcloning reveal that wild-type and mutant Htt exhibit differential genomic distributions.

50bp deletion in the promoter for superoxide dismutase 1 (SOD1) reduces SOD1 expression in vitro and may correlate with increased age of onset of sporadic amyotrophic lateral sclerosis.

The objective was to test the hypothesis that a described association between homozygosity for a 50bp deletion in the SOD1 promoter 1684bp upstream of the SOD1 ATG and an increased age of onset in SALS can be replicated in additional SALS and control sample sets from other populations. Our second objective was to examine whether this deletion attenuates expression of the SOD1 gene. Genomic DNA from more than 1200 SALS cases from Ireland, Scotland, Quebec and the USA was genotyped for the 50bp SOD1 promoter deletion.

Altered histone monoubiquitylation mediated by mutant huntingtin induces transcriptional dysregulation.

Although transcriptional dysregulation is a critical pathogenic mechanism in Huntington's disease (HD), it is still not known how mutant huntingtin causes it. Here we show that alteration of histone monoubiquitylation is a key mechanism. Disrupted interaction of huntingtin with Bmi-1, a component of the hPRC1L E3 ubiquitin ligase complex, increases monoubiquityl histone H2A (uH2A) levels in a cell culture model of HD.

CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking.

Increases in dopamine and glutamate transmission in the nucleus accumbens independently promote the reinstatement of cocaine seeking, an animal model of relapse. Here we have tested whether cocaine reinstatement in rats depends on interactions between accumbal dopamine and glutamate systems that are mediated by Ca(2+)/calmodulin-mediated kinase II (CaMKII). We show that stimulation of D1-like dopamine receptors in the nucleus accumbens shell reinstates cocaine seeking by activating L-type Ca(2+) channels and CaMKII.

Dopamine release is impaired in a mouse model of DYT1 dystonia.

Early onset torsion dystonia, the most common form of hereditary primary dystonia, is caused by a mutation in the TOR1A gene, which codes for the protein torsinA. This form of dystonia is referred to as DYT1. We have used a transgenic mouse model of DYT1 dystonia [human mutant-type (hMT)1 mice] to examine the effect of the mutant human torsinA protein on striatal dopaminergic function.

Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage.

To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2(Q150/Q150), 18-month Hdh(Q92/Q92) and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures.