Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy.

TRACK-HD is a multicentre longitudinal observational study investigating the use of clinical assessments and 3-Tesla magnetic resonance imaging as potential biomarkers for future therapeutic trials in Huntington's disease (HD). The cross-sectional data from this large well-characterized dataset provide the opportunity to improve our knowledge of how the underlying neuropathology of HD may contribute to the clinical manifestations of the disease across the spectrum of premanifest (PreHD) and early HD. Two hundred and thirty nine gene-positive subjects (120 PreHD and 119 early HD) from the TRACK-HD study were included. Using voxel-based morphometry (VBM), grey and white matter volumes were correlated with performance in four domains: quantitative motor (tongue force, metronome tapping, and gait); oculomotor [anti-saccade error rate (ASE)]; cognition (negative emotion recognition, spot the change and the University of Pennsylvania smell identification test) and neuropsychiatric measures (apathy, affect and irritability). After adjusting for estimated disease severity, regionally specific associations between structural loss and task performance were found (familywise error corrected, P < 0.05); impairment in tongue force, metronome tapping and ASE were all associated with striatal loss. Additionally, tongue force deficits and ASE were associated with volume reduction in the occipital lobe. Impaired recognition of negative emotions was associated with volumetric reductions in the precuneus and cuneus. Our study reveals specific associations between atrophy and decline in a range of clinical modalities, demonstrating the utility of VBM correlation analysis for investigating these relationships in HD

WUDAPT: an urban weather, climate and environmental modeling infrastructure for the Anthropocene

WUDAPT is an international community-based initiative to acquire and disseminate climate relevant data on the physical geographies of cities for modeling and analyses purposes. The current lacuna of globally consistent information on cities is a major impediment to urban climate science towards informing and developing climate mitigation and adaptation strategies at urban scales. WUDAPT consists of a database and a portal system; its database is structured into a hierarchy representing different levels of detail and the data are acquired using innovative protocols that utilize crowdsourcing approaches, Geowiki tools, freely accessible data, and building typology archetypes. The base level of information (L0) consists of Local Climate Zones (LCZ) maps of cities; each LCZ category is associated with range of values for model relevant surface descriptors (e.g. roughness, impervious surface cover, roof area, building heights, etc.). Levels 1 (L1) and 2 (L2) will provide specific intraurban values for other relevant descriptors at greater precision, such as data morphological forms, material composition data and energy usage. This article describes the status of the WUDAPT project and demonstrates its potential value using observations and models. As a community-based project, other researchers are encouraged to participate to help create a global urban database of value to urban climate scientists

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

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Effects of gestational age on brain volume and cognitive functions in generally healthy very preterm born children during school-age : a Voxel-based morphometry study

Objective To determine whether the relationship of gestational age (GA) with brain volumes and cognitive functions is linear or whether it follows a threshold model in preterm and term born children during school-age. Study design We studied 106 children (M = 10 years 1 month, SD = 16 months; 40 females) enrolled in primary school: 57 were healthy very preterm children (10 children born 24–27 completed weeks’ gestation (extremely preterm), 14 children born 28–29 completed weeks’ gestation, 19 children born 30–31 completed weeks’ gestation (very preterm), and 14 born 32 completed weeks’ gestation (moderately preterm)) all born appropriate for GA (AGA) and 49 term-born children. Neuroimaging involved voxel-based morphometry with the statistical parametric mapping software. Cognitive functions were assessed with the WISC-IV. General Linear Models and multiple regressions were conducted controlling age, sex, and maternal education. Results Compared to groups of children born 30 completed weeks’ gestation and later, children born <28 completed weeks’ gestation had less gray matter volume (GMV) and white matter volume (WMV) and poorer cognitive functions including decreased full scale IQ, and processing speed. Differences in GMV partially mediated the relationship between GA and full scale IQ in preterm born children. Conclusions In preterm children who are born AGA and without major complications GA is associated with brain volume and cognitive functions. In particular, decreased brain volume becomes evident in the extremely preterm group (born <28 completed weeks’ gestation). In preterm children born 30 completed weeks’ gestation and later the relationship of GA with brain volume and cognitive functions may be less strong as previously thought

Mediation of the relationship between gestational age and IQ by GMV in preterm children (gestational age range: 24–32 completed weeks’ gestation).

<p>The direct effect predicting full scale IQ by GA controlling GMV volume is displayed in brackets. Coefficients are standardized regression coefficients controlled for age, sex, and maternal education. Explained variance (Δ<i>r</i>) is derived from a model that entered the predictor in a separate step holding covariates constant. * P < 0.05, ** P < 0.01.</p

Brain volumes and cognitive functions by gestational age groups.

<p><b>A)</b> Mean values and standard errors of Gray Matter Volume (GMV) and White Matter Volume (WMV) based on 1000 bootstrap samples by five gestational age groups (children born 24–27 completed weeks’ gestation, 28–29 completed weeks’ gestation, 30–31 completed weeks’ gestation, 32 completed weeks’ gestation and term born children) controlling age, sex, and maternal education. <b>B)</b> Mean values and standard errors of cognitive functions (IQ score normative mean = 100, SD = 15) based on 1000 bootstrap samples by five gestational age groups (children born 24–27 completed weeks’ gestation, 28–29 completed weeks’ gestation, 30–31 completed weeks’ gestation, 32 completed weeks’ gestation and term born children) controlling age, sex, and maternal education. * P < 0.05, ** P < 0.01, *** P < 0.001.</p

Means and bias corrected bootstrap confidence intervals for five gestational age groups adjusted for age, sex, and maternal education.

<p>Means and bias corrected bootstrap confidence intervals for five gestational age groups adjusted for age, sex, and maternal education.</p

Regional differences of gray matter volume.

<p>Significant difference of GMV A) Contrast between children born 24–27 completed weeks’ gestation and term born children showing significantly decreased cortical GMV in one cluster in the right middle and superior temporal gyrus (MNI-coordinates: 56–6–15) with a cluster size of 542 voxel in the preterm group. B) Contrast between children born 28–29 completed weeks’ gestation and term born children showing significantly decreased cortical GMV in one cluster in the right middle and superior temporal gyrus (MNI-coordinates: 57–16–12), with a cluster size of 1487 voxel in the preterm group. C) Contrast between children born 32 completed weeks’ gestation and term born children showing significantly decreased cortical GMV in the left insula (MNI-coordinates: -32 6–15), with a cluster size of 145 voxel in the preterm group. The color bars represent the t-scores.</p

Descriptive statistics for study variables (<i>N</i> = 106).

<p>Descriptive statistics for study variables (<i>N</i> = 106).</p