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

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 influence of slat material, slat coverage and breeder age on broiler breeder reproduction and progeny growth

This study was conducted to examine the potential of plastic slats as flooring material for maintenance of broiler breeders. Although plastic slats are more expensive than wood slats, plastic slats are more durable and easier to clean. Wood and plastic slats were tested as full and partial flooring to determine the ideal proportion of slats for broiler breeder floors. Space allotment was 2040 cm²/bird on all floor treatments. . Arbor Acres broiler breeders, one of the more common strains in British Columbia, were raised to 58 weeks of age to monitor the influence of slat material and slat coverage on egg production and progeny growth over one production cycle. Since the pens were not set up to determine the number of eggs lost through slats, "egg production" values were actually egg recovery values. Over-all egg recovery was significantly higher on partial wood (PWS) and partial plastic slats (PPS) than on either of the full slat treatments. Breeders on full wood slats (FWS) had higher over-all egg production than those on full plastic slats (FPS). Differences were significant for three biweekly periods, but slats did not influence the over-all incidence of floor eggs and cracked floor eggs. The incidence of cracked nest eggs was significantly higher in FWS and FPS than in PWS and PPS pens during four lay periods and overall. The proportion of non-cracked nest eggs, which was taken as an approximation of the proportion of settable eggs, was higher for partial slat pens than full slat pens, and FWS pens had a higher proportion of non-cracked nest eggs than FPS pens. To monitor fertility and hatchability, eggs were incubated at 37, 42, 46, 50 and 56 weeks of breeder age. Fertility, hatchability of total eggs set and hatchability of fertile eggs was not affected by type of slats. Progeny from the hatch at 37, 46 and 56 week of breeder age were grown in Petersime battery cages to three weeks of age. The progeny of breeders on FPS had lower first week weight gain than the other progeny groups due to moisture loss when 7 FPS progeny were lost during the second growth trial. Weekly and over-all feed conversion of progeny was not affected by types of slats used by parents. The 56th week progeny were grown in Petersime battery cages to market age (six weeks). PWS and FPS progeny had higher third week weight gain than PPS progeny. During the sixth week, FWS and PWS progeny had higher weight gain than FPS and PPS progeny. The sixth week feed conversion of FPS progeny was higher than that of the other three progeny groups. No other differences were seen. As long as slats were used as partial flooring, there were no differences in egg production on wood or plastic slats. The proportion of "settable" eggs, fertility, and hatchability of eggs of plastic slat breeders were comparable with that of wood slat breeders regardless of slat coverage. There were significant differences in the 3-week growth of 37th, 46th and 56th week progeny and the 6-week growth of 56th week progeny on the different slat types, but the differences were not due to slat treatments. There was no interaction between breeder age and slat material, therefore the influence of slat material on egg production and progeny growth did not vary with breeder age. Although egg recovery and the number of settable eggs were lower for FPS breeders, breeders on plastic slats performed as well as those on wood slats in the present study.Land and Food Systems, Faculty ofGraduat

Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials.

IMPORTANCE: Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials. OBJECTIVE: To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS). DESIGN, SETTING, AND PARTICIPANTS: A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (\u3c37 \u3erepeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013. EXPOSURE: Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion. MAIN OUTCOMES AND MEASURES: Unified Huntington\u27s Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years. RESULTS: Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P \u3c .001), cognitive (P \u3c .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P \u3c .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P \u3c .001 for all); behavioral domain scores did not diverge significantly between groups. CONCLUSIONS AND RELEVANCE: Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion

MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1

Huntington’s disease and myotonic dystrophy type 1. A recent Huntington’s disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington’s disease. Using Illumina sequencing in Huntington’s disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAG CTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington’s disease and myotonic dystrophy type 1, and slower progression (P = 3.86 10 7) in Huntington’s disease. RNA-Seq of whole blood in the Huntington’s disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington’s disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington’s disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.UK DementiaResearch Institute/[]//Reino UnidoMedical Research Council/[MR/L010305/1]/MRC/Reino UnidoEuropean Union’s Seventh Framework Programme/[2012-305121]/FP7 2007-2013/Unión EuropeaRosetrees Trust/[JS16/M574]//Reino UnidoUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA