Feasibility of computerized working memory training in individuals with Huntington disease

<div><p>Objectives</p><p>Huntington disease (HD) is associated with a variety of cognitive deficits, with prominent difficulties in working memory (WM). WM deficits are notably compromised in early-onset and prodromal HD patients. This study aimed to determine the feasibility of a computerized WM training program (Cogmed QM), novel to the HD population.</p><p>Methods</p><p>Nine patients, aged 26–62, with early stage HD underwent a 25-session (5 days/week for 5 weeks) WM training program (Cogmed QM). Training exercises involved the manipulation and storage of verbal and visuospatial information, with difficulty adapted as a function of individual performance. Neuropsychological testing was conducted before and after training, and performance on criterion WM measures (Digit Span and Spatial Span), near-transfer WM measures (Symbol Span and Auditory WM), and control measures were evaluated. Post-training interviews about patient experience were thematically analyzed using NVivo software.</p><p>Results</p><p>Seven of nine patients demonstrated adherence to the training and completed all sessions within the recommended timeframe of 5 weeks. All adherent patients showed improvement on the Cogmed tasks as defined by the Improvement Index (<i>M</i> = 22.17, <i>SD</i> = 8.84, range = 13–36). All adherent patients reported that they found training helpful (<i>n = 7)</i>, and almost all felt that their memory improved (<i>n = 6)</i>. Participants also expressed that the training was difficult, sometimes frustrating, and time consuming.</p><p>Conclusions</p><p>This pilot study provides support for feasibility of computerized WM training in early-stage patients with HD. Results suggest that HD patients perceive benefits of intensive WM training, though a full-scale and controlled intervention project is needed to understand the size of the effect and reliability of changes over time.</p><p>Trial registration</p><p>ClinicalTrials.gov, Registry number <a href="https://clinicaltrials.gov/ct2/show/NCT02926820" target="_blank">NCT02926820</a></p></div

Flowchart of participant enrollment, inclusion, and involvement.

<p>Flowchart of participant enrollment, inclusion, and involvement.</p

Demographic and clinical characteristics for all participants (N = 9).

<p>Demographic and clinical characteristics for all participants (N = 9).</p

Neuropsychological outcomes for criterion, near-transfer, and far transfer tasks using raw scores.

<p>Neuropsychological outcomes for criterion, near-transfer, and far transfer tasks using raw scores.</p

Feasibility outcomes on Cogmed QM for all participants (N = 9).

<p>Feasibility outcomes on Cogmed QM for all participants (N = 9).</p

Participant inclusion and exclusion criteria.

<p>Participant inclusion and exclusion criteria.</p

Structure–Activity Studies Reveal the Molecular Basis for GABA_B‑Receptor Mediated Inhibition of High Voltage-Activated Calcium Channels by α‑Conotoxin Vc1.1

α-Conotoxins are disulfide-bonded peptides from cone snail venoms and are characterized by their affinity for nicotinic acetylcholine receptors (nAChR). Several α-conotoxins with distinct selectivity for nAChR subtypes have been identified as potent analgesics in animal models of chronic pain. However, a number of α-conotoxins have been shown to inhibit N-type calcium channel currents in rodent dissociated dorsal root ganglion (DRG) neurons <i>via</i> activation of G protein-coupled GABA_B receptors (GABA_BR). Therefore, it is unclear whether activation of GABA_BR or inhibition of α9α10 nAChRs is the analgesic mechanism. To investigate the mechanisms by which α-conotoxins provide analgesia, we synthesized a suite of Vc1.1 analogues where all residues, except the conserved cysteines, in Vc1.1 were individually replaced by alanine (A), lysine (K), and aspartic acid (D). Our results show that the amino acids in the first loop play an important role in binding of the peptide to the receptor, whereas those in the second loop play an important role for the selectivity of the peptide for the GABA_BR over α9α10 nAChRs. We designed a cVc1.1 analogue that is >8000-fold selective for GABA_BR-mediated inhibition of high voltage-activated (HVA) calcium channels over α9α10 nAChRs and show that it is analgesic in a mouse model of chronic visceral hypersensitivity (CVH). cVc1.1­[D11A,E14A] caused dose-dependent inhibition of colonic nociceptors with greater efficacy in <i>ex vivo</i> CVH colonic nociceptors relative to healthy colonic nociceptors. These findings suggest that selectively targeting GABA_BR-mediated HVA calcium channel inhibition by α-conotoxins could be effective for the treatment of chronic visceral pain

Air pollution during pregnancy and placental adaptation in the levels of global DNA methylation

<div><p>Background</p><p>Health in early life is crucial for health later in life. Exposure to air pollution during embryonic and early-life development can result in placental epigenetic modification and foetus reprogramming, which can influence disease susceptibility in later life. Objectives: The aim of this paper was to investigate the placental adaptation in the level of global DNA methylation and differential gene expression in the methylation cycle in new-borns exposed to high fine particulate matter in the foetal stage.</p><p>Study design</p><p>This is a nested case-control study. We enrolled pregnant healthy women attending prenatal care clinics in Tehran, Iran, who were residents of selected polluted and unpolluted regions, before the 14th week of pregnancy. We calculated the regional background levels of particle mass- particles with aerodynamics diameter smaller than 2.5 μm (PM2.5) and 10 μm (PM10)—of two regions of interest. At the time of delivery, placental tissue was taken for gene expression and DNA methylation analyses. We also recorded birth outcomes (the new-born’s sex, birth date, birth weight and length, head and chest circumference, gestational age, Apgar score, and level of neonatal care required).</p><p>Results</p><p>As regards PM2.5 and PM10 concentrations in different time windows of pregnancy, there were significantly independent positive correlations between PM10 and PM2.5 in the first trimester of all subjects and placental global DNA methylation levels (p-value = 0.01, p-value = 0.03, respectively). The gene expression analysis showed there was significant correlation between S-adenosylmethionine expression and PM2.5 (p = 0.003) and PM10 levels in the first trimester (p = 0.03).</p><p>Conclusion</p><p>Our data showed prenatal exposures to air pollutants in the first trimester could influence placental adaptation by DNA methylation.</p></div

Correlation between fine particulate matter concentrations and RNA expression levels of <i>DNMT-1 α</i> and <i>SAMe</i>.

<p>Correlation between fine particulate matter concentrations and RNA expression levels of <i>DNMT-1 α</i> and <i>SAMe</i>.</p

Differently expressed genes in placental tissues of mothers who lived in polluted region compared to those in non-polluted region.

<p>Not differentially expressed selected genes in placental samples from mothers in polluted compare to ones in non-polluted regions; with a fold change <1.5 (fold change values: DNMT-1 α = -1.2, and SAMe = 1.1).</p