Intellectual enrichment and genetic modifiers of cognition and brain volume in Huntington's disease

An important step towards the development of treatments for cognitive impairment in ageing and neurodegenerative diseases is to identify genetic and environmental modifiers of cognitive function and understand the mechanism by which they exert an effect. In Huntington’s disease, the most common autosomal dominant dementia, a small number of studies have identified intellectual enrichment, i.e. a cognitively stimulating lifestyle and genetic polymorphisms as potential modifiers of cognitive function. The aim of our study was to further investigate the relationship and interaction between genetic factors and intellectual enrichment on cognitive function and brain atrophy in Huntington’s disease. For this purpose, we analysed data from Track-HD, a multi-centre longitudinal study in Huntington’s disease gene carriers and focused on the role of intellectual enrichment (estimated at baseline) and the genes FAN1, MSH3, BDNF, COMT and MAPT in predicting cognitive decline and brain atrophy. We found that carrying the 3a allele in the MSH3 gene had a positive effect on global cognitive function and brain atrophy in multiple cortical regions, such that 3a allele carriers had a slower rate of cognitive decline and atrophy compared with non-carriers, in agreement with its role in somatic instability. No other genetic predictor had a significant effect on cognitive function and the effect of MSH3 was independent of intellectual enrichment. Intellectual enrichment also had a positive effect on cognitive function; participants with higher intellectual enrichment, i.e. those who were better educated, had higher verbal intelligence and performed an occupation that was intellectually engaging, had better cognitive function overall, in agreement with previous studies in Huntington’s disease and other dementias. We also found that intellectual enrichment interacted with the BDNF gene, such that the positive effect of intellectual enrichment was greater in Met66 allele carriers than non-carriers. A similar relationship was also identified for changes in whole brain and caudate volume; the positive effect of intellectual enrichment was greater for Met66 allele carriers, rather than for non-carriers. In summary, our study provides additional evidence for the beneficial role of intellectual enrichment and carrying the 3a allele in MSH3 in cognitive function in Huntington’s disease and their effect on brain structure

The James Webb Space Telescope Mission: Optical Telescope Element Design, Development, and Performance

The James Webb Space Telescope (JWST) is a large, infrared space telescope that has recently started its science program which will enable breakthroughs in astrophysics and planetary science. Notably, JWST will provide the very first observations of the earliest luminous objects in the Universe and start a new era of exoplanet atmospheric characterization. This transformative science is enabled by a 6.6 m telescope that is passively cooled with a 5-layer sunshield. The primary mirror is comprised of 18 controllable, low areal density hexagonal segments, that were aligned and phased relative to each other in orbit using innovative image-based wavefront sensing and control algorithms. This revolutionary telescope took more than two decades to develop with a widely distributed team across engineering disciplines. We present an overview of the telescope requirements, architecture, development, superb on-orbit performance, and lessons learned. JWST successfully demonstrates a segmented aperture space telescope and establishes a path to building even larger space telescopes.Comment: accepted by PASP for JWST Overview Special Issue; 34 pages, 25 figure

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

A Comparison of Depressive Symptom Self-Reported Measures in the Texas Youth Depression and Suicide Research Network (TX-YDSRN)

Objective: To evaluate psychometrically and provide crosswalks between 3 self-report measures of depressive symptomatology in youth in psychiatric care settings. Ratings included the Patient Health Questionnaire for Adolescents (PHQ-A), a widely used 9-item self-report; the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR16); and the 5-item Very Quick Inventory of Depressive Symptomatology–Self-Report (VQIDS-SR5), a recent effort to create a bridge from the QIDS-SR16 to clinical practice. Methods: Data from the Texas Youth Depression and Suicide Research Network Registry (August 26, 2020–May 11, 2022) were included in this work. At first visit, 795 depressed or suicidal adolescent (12–20 years of age) psychiatric outpatients completed the PHQ-A, QIDS-SR16, and VQIDS-SR5. Classical test theory and item-response theory (IRT) analyses were conducted. Crosswalks among total scales were created. Sensitivity to change over 1-month follow-up was assessed for all 3 scales (n = 682). Results: Cronbach alphas were 0.86 (PHQ-A), 0.80 (QIDS-SR16), and 0.76 (VQIDS-SR5). Item total correlations were 0.49–0.72, 0.29–0.64, and 0.43–0.61, respectively. All 3 scales were unidimensional and sensitive to change over a 1-month period. IRT analyses revealed satisfactory item performance. Modest but significant associations were found between baseline to 1-month changes in PHQ-A and VQIDS-SR5 total scores (r = 0.50, P \u3c .0001) and between PHQ-A and QIDS-SR16 total scores (r = 0.56; P \u3c .0001). Categorical thresholds of severity (ie, mild, moderate, severe, and very severe) were comparable between PHQ-A and QIDS-SR16. Conclusions: The PHQ-A, QIDS-SR16, and VQIDS-SR5 are unidimensional, psychometrically acceptable self-reports of depressive prevalence or severity in adolescents and young adults in this sample. Total scale scores on any measure can be converted reliably to those on any other

Assessment of motor symptoms and functional impact in prodromal and early Huntington disease.

The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal of developing a data-driven, comprehensive, psychometrically sound, rating scale for assessing symptoms and functional ability in prodromal and early Huntington disease (HD) gene expansion carriers. The process involves input from numerous sources to identify relevant symptom domains, including HD individuals, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing large-scale studies in HD using existing clinical scales. This is an iterative process in which an ongoing series of field tests in prodromal (prHD) and early HD individuals provides the team with data on which to make decisions regarding which questions should undergo further development or testing and which should be excluded. We report here the development and assessment of the first iteration of interview questions aimed to assess functional impact of motor manifestations in prHD and early HD individuals

Structure of the antisaccade task.

<p>Participants first fixated on the center of the screen. Afterwards, a blank screen was presented followed by either a green or red central cue instructing participants to either make a pro or antisaccade, respectively.</p

Results of multiple linear regression of model parameters on total motor score (TMS)—higher scores indicate worse motor problems.

<p>Results of multiple linear regression of model parameters on total motor score (TMS)—higher scores indicate worse motor problems.</p

Results of multiple linear regression of model parameters on total functional capacity (TFC).

<p>Higher TFC indicates better functioning than lower scores.</p