Rapid and Progressive Regional Brain Atrophy in CLN6 Batten Disease Affected Sheep Measured with Longitudinal Magnetic Resonance Imaging.

Variant late-infantile Batten disease is a neuronal ceroid lipofuscinosis caused by mutations in CLN6. It is a recessive genetic lysosomal storage disease characterised by progressive neurodegeneration. It starts insidiously and leads to blindness, epilepsy and dementia in affected children. Sheep that are homozygous for a natural mutation in CLN6 have an ovine form of Batten disease Here, we used in vivo magnetic resonance imaging to track brain changes in 4 unaffected carriers and 6 affected Batten disease sheep. We scanned each sheep 4 times, between 17 and 22 months of age. Cortical atrophy in all sheep was pronounced at the baseline scan in all affected Batten disease sheep. Significant atrophy was also present in other brain regions (caudate, putamen and amygdala). Atrophy continued measurably in all of these regions during the study. Longitudinal MRI in sheep was sensitive enough to measure significant volume changes over the relatively short study period, even in the cortex, where nearly 40% of volume was already lost at the start of the study. Thus longitudinal MRI could be used to study the dynamics of progression of neurodegenerative changes in sheep models of Batten disease, as well as to assess therapeutic efficacy

Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants

This is the final version of the article. Available from the publisher via the DOI in this record.Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus(CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7x10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.This work was generously funded by an award to DM, TF, AM, LH and CB by the Medical Research Council MR/M023095/1. This research has been conducted using the UK Biobank Resource, under application 1417. The authors wish to thank the UK Biobank participants and coordinators for this unique dataset. S.E.J. is funded by the Medical Research Council (grant: MR/M005070/1). J.T. is funded by a Diabetes Research and Wellness Foundation Fellowship. R.B. is funded by the Wellcome Trust and Royal Society grant: 104150/Z/14/Z. M.A.T., M.N.W. and A.M. are supported by the Wellcome Trust Institutional Strategic Support Award (WT097835MF). R.M.F. is a Sir Henry Dale Fellow (Wellcome Trust and Royal Society grant: 104150/Z/14/Z). A.R.W. H.Y., and T.M.F. are supported by the European Research Council grant: 323195:GLUCOSEGENES-FP7-IDEAS-ERC. The funders had no influence on study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Framingham Heart Study is supported by Contract No. N01-HC-25195 and HHSN268201500001I and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). The phenotypegenotype association analyses were supported by National Institute of Aging R01AG29451. This work has made use of the resources provided by the University of Exeter Science Strategy and resulting Systems Biology initiative. Primarily these include high-performance computing facilities managed by Konrad Paszkiewicz of the College of Environmental and Life Sciences and Pete Leggett of the University of Exeter Academics services unit

Feasibility, safety and pharmacokinetic study of hepatic administration of drug-eluting beads loaded with irinotecan (DEBIRI) followed by intravenous administration of irinotecan in a porcine model

Irinotecan eluting embolization beads (DEBIRI) are currently being evaluated in the clinic for the treatment of colorectal cancer metastases to the liver. The aim of this study was to determine the safety and pharmacokinetics associated with two cycles of hepatic embolization using DEBIRI followed by intravenous administration of irinotecan. Pigs were embolized with DEBIRI (100–300 μm, 100 mg dose, n = 6) and blood samples taken over 24 h to determine plasma levels of irinotecan and SN-38 metabolite and for haematology and biochemistry. At 24 h an IV infusion of 250 mg/m2 of irinotecan was administered and the plasma levels taken again. This cycle was repeated 3 weeks later. A single animal was subjected to a more aggressive regimen of embolization with 200 mg bead dose and IV of 350 mg/m2 for two cycles. Three animals were sacrificed at 6 weeks and the remaining four (n = 3 standard dose, n = 1 high dose) animals at 12 weeks and detailed histopathology performed. All animals tolerated the treatments well, with only minor changes in haematological and biochemical parameters. There was no overlap in drug plasma levels observed from the bead and IV treatments when given 24 h apart and no difference between the pharmacokinetic profiles of the two cycles separated by 3 weeks. Irinotecan plasma AUC values were similar in both the embolization and IV arms of the study. Cmax values obtained during the IV arms of the study are approximately double that of the embolization arms whilst Tmax times are shorter in the IV arms, supporting extended release of drug from the beads. Bioavailability for bead-based delivery was double that for IV administration, which was attributed to reduced clearance of the drug when delivered by this route. No additive toxicity was observed as a consequence of the combined treatments. The combination of irinotecan delivery via drug eluting bead and IV was well-tolerated with no significant clinical effects. Pharmacokinetic analyses suggest the bioavailability from bead-based delivery of drug is double that of IV infusion, attributable to reduced drug clearance for the former.Andrew L. Lewis, Rachel R. Holden, S. Ting Chung, Peter Czuczman, Timothy Kuchel, John Finnie, Susan Porter, David Foste

Increased plasma melatonin in presymptomatic Huntington disease sheep ( Ovis aries ): Compensatory neuroprotection in a neurodegenerative disease?

Melatonin is a pleiotrophic hormone, synthesised primarily by the pineal gland under the control of the suprachiasmatic nuclei (SCN). It not only provides a hormonal signal of darkness but also has neuroprotective properties. Huntington's disease (HD) is a progressive neurodegenerative disorder characterised by abnormal motor, cognitive and psychiatric symptoms. There is growing evidence, particularly from animal models, that circadian rhythms may also be disturbed in HD. We measured two circadian‐regulated hormones, melatonin and cortisol, in plasma samples collected around‐the‐clock from normal and presymptomatic transgenic HD sheep (Ovis aries) at 5 and 7 years of age, to assess SCN‐driven rhythms and the effect of genotype, sex and age. Melatonin‐related precursors and metabolites (tryptophan, serotonin, kynurenine) were also measured by liquid chromatography (LC)‐mass spectrometry (MS). At 5 years of age in both rams and ewes, plasma melatonin levels were significantly elevated in HD sheep. In ewes measured 2 years later, there was still a significant elevation of nocturnal melatonin. Furthermore, the daytime baseline levels of melatonin were significantly higher in HD sheep. Since increased melatonin could have global beneficial effects on brain function, we suggest that the increased melatonin measured in presymptomatic HD sheep is part of an autoprotective response to mutant huntingtin toxicity that may account, at least in part, for the late onset of disease that characterises HD

Increased plasma melatonin in presymptomatic Huntington disease sheep ( Ovis aries

Melatonin is a pleiotrophic hormone, synthesised primarily by the pineal gland under the control of the suprachiasmatic nuclei (SCN). It not only provides a hormonal signal of darkness but also has neuroprotective properties. Huntington's disease (HD) is a progressive neurodegenerative disorder characterised by abnormal motor, cognitive and psychiatric symptoms. There is growing evidence, particularly from animal models, that circadian rhythms may also be disturbed in HD. We measured two circadian‐regulated hormones, melatonin and cortisol, in plasma samples collected around‐the‐clock from normal and presymptomatic transgenic HD sheep (Ovis aries) at 5 and 7 years of age, to assess SCN‐driven rhythms and the effect of genotype, sex and age. Melatonin‐related precursors and metabolites (tryptophan, serotonin, kynurenine) were also measured by liquid chromatography (LC)‐mass spectrometry (MS). At 5 years of age in both rams and ewes, plasma melatonin levels were significantly elevated in HD sheep. In ewes measured 2 years later, there was still a significant elevation of nocturnal melatonin. Furthermore, the daytime baseline levels of melatonin were significantly higher in HD sheep. Since increased melatonin could have global beneficial effects on brain function, we suggest that the increased melatonin measured in presymptomatic HD sheep is part of an autoprotective response to mutant huntingtin toxicity that may account, at least in part, for the late onset of disease that characterises HD

Voxel-based morphometry results showing differences between control sheep and Batten affected sheep, at the baseline scan.

<p>Coronal sections are pseudocoloured to show changes in grey matter (A), or white matter (B). The colour bar shows Student’s t-score with 8 degrees of freedom. The position of the sequential coronal sections indicated by the lines on the accompanying sagittal section.</p

Map of mean volume changes in Batten disease affected sheep.

<p>Volume changes are shown for control sheep (A, C, E, G) and Batten disease affected sheep (B, D, F, H) in sagittal (A, B)), horizontal (C, D) and two coronal planes (E-H), one at the level of the striatum (E, F), the other at the level of the thalamus (G,H). Scale bar in G is 1cm and the colour scale indicates volume change as ml/year.</p

Batten disease affected sheep body weight changes and <i>post mortem</i> brain appearance.

<p>(A) Mean (± SEM) body weight of control (blue) and Batten disease affected sheep (red) from birth to 20 months of age shows that growth of Batten disease affected animals stopped at around 14 months. The dotted line indicates the time of transfer from the home farm to the MRI facility. (B) Comparison of gross anatomy of brains from a control sheep (left) and the least affected wether (male, 939), and least affected ewe (female, 937) (centre and right respectively) shows pronounced atrophy of the cerebral cortex (Co) with relative sparing of the cerebellum (Cb). Brains were fixed with 4% paraformaldehyde. Size bar in B represents 3cm.</p

Red blood cell distribution width: Genetic evidence for aging pathways in 116,666 volunteers

<div><p>Introduction</p><p>Variability in red blood cell volumes (distribution width, RDW) increases with age and is strongly predictive of mortality, incident coronary heart disease and cancer. We investigated inherited genetic variation associated with RDW in 116,666 UK Biobank human volunteers.</p><p>Results</p><p>A large proportion RDW is explained by genetic variants (29%), especially in the older group (60+ year olds, 33.8%, <50 year olds, 28.4%). RDW was associated with 194 independent genetic signals; 71 are known for conditions including autoimmune disease, certain cancers, BMI, Alzheimer’s disease, longevity, age at menopause, bone density, myositis, Parkinson’s disease, and age-related macular degeneration. Exclusion of anemic participants did not affect the overall findings. Pathways analysis showed enrichment for telomere maintenance, ribosomal RNA, and apoptosis. The majority of RDW-associated signals were intronic (119 of 194), including SNP rs6602909 located in an intron of oncogene <i>GAS6</i>, an eQTL in whole blood.</p><p>Conclusions</p><p>Although increased RDW is predictive of cardiovascular outcomes, this was not explained by known CVD or related lipid genetic risks, and a RDW genetic score was not predictive of incident disease. The predictive value of RDW for a range of negative health outcomes may in part be due to variants influencing fundamental pathways of aging.</p></div