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H D I N S I G H T S HD Research: Australia, cont... Figure 2. Environmental enrichment changes the temporal dynamics of the stress response and strikingly implies that adrenal cells maintain an in vitro epigenetic memory of their previous in vivo environmental enrichment; the first evidence that environmental enrichment can act on such a peripheral organ6 . My research team, led by Professor Julie Stout, uses tools for sensitive measurement of cognitive dysfunction to aid in the understanding and treatment of HD. Success in finding treatments to restore cognition or slow cognitive deterioration rests on the sensitivity of cognitive outcomes that can be tolerated during clinical trials and that are responsive to treatment. The Stoutlab recently developed and standardized a new Cognitive Assessment Battery, in conjunction with the CHDI Foundation, using a 20-site international study (unpublished data). Further, our group leads the cognitive component of the multinational longitudinal observational study, TrackHD8, in which we have been able to identify key cross-sectional and longitudinal markers of cognitive decline in large samples of HD patients. Within the Stoutlab, my own research addresses the social and emotional aspects of HD, and whether current medications impede socio-emotional outcomes9. I am currently leading an fMRI study in HD on whether intranasal oxytocin, a hormone associated with bonding, might improve neural responses to socialemotion cues, as has been observed in Conneally, PM. Huntington disease: genetics and epidemiology. Am J Hum Genet. 1984;36(3):506-26. other disorders. study, which followed a cohort of premanifest HD (pre-HD), early Professor Nellie Georgiou-Karistianis's symptomatic HD (symp-HD) and lab investigates motor and cognitive healthy controls at three time points over deficits in HD using a range of 30 months. To date, this study has experimental paradigms. Georgiouyielded cross-sectional and longitudinal Karistianis leads the IMAGE-HD project, reports on the impact of HD on an Australia-based longitudinal multimodal magnetic resonance multimodal biomarker development neuroimaging biomarkers of macrostructural, microstructural, and functional integrity10,11,12. Data from the 30-month functional imaging studies in working memory and set-shifting, although currently unpublished, shows dynamic changes in activity and connectivity in pre-HD and symp-HD, suggesting possible compensatory mechanisms occurring well in advance of disease onset (Figure 3). Figure 3. Longitudinal 30-month change in brain activity and functional connectivity in pre-HD during a working memory task (2-BACK). PreHD participants show an increased level of activation in corticostriatal networks over time (top images) despite the progressive loss of functional connectivity (bottom images) (unpublished data). 6 Du, 1 Olshina, MA, et al. Tracking mutant huntingtin aggregation kinetics in cells reveals three major populations that include an invariant oligomer pool. J Biol Chem. 2010;285(28):21807-16. 2 3 Hatters, DM. Putting huntingtin "aggregation" in view with windows into the cellular milieu. Curr Top Med Chem. 2012;12(22):2611-22. 4 Ramdzan, YM, et al. Tracking protein aggregation and mislocalization in cells with flow cytometry. Nat Methods. 2012;9(5):467-70. X, et al. Environmental enrichment rescues femalespecific hyperactivity of the hypothalamic-pituitary-adrenal axis in a model of Huntington's disease. Transl Psychiatry. 2012;2:133. TY, et al. Differential effects of voluntary physical exercise on behavioral and brain-derived neurotrophic factor expression deficits in Huntington's disease transgenic mice. Neurosci. 2006;141(2):569-84. Although I have highlighted the Melbourne, Victoria, research contribution, several colleagues in other states are making important contributions, notably Clement Loy and Elizabeth McCusker in New South Wales, and Peter Panegyres in Western Australia. And the kiwis in New Zealand are also punching above their weight, with collaborative projects in Adelaide, South Australia using a sheep model of HD, and other clinical research projects. Georgiou-Karistianis, N, et al. Automated differentiation of pre-diagnosis Huntington's disease from healthy control individuals based on quadratic discriminant analysis of the basal ganglia: The IMAGE-HD study. Neurobiol Dis. 2013;51:82-92. 10 7 Pang, SJ, et al. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol, 2013;12(7):637-49. 11 Poudel, GR, et al. Abnormal synchrony of resting-state networks in premanifest and symptomatic Huntington's disease: The IMAGE-HD Study. J Psychiatry Neurosci. Forthcoming 2013. 8 Tabrizi, Georgiou-Karistianis, N, et al. Functional magnetic resonance imaging of working memory in Huntington's disease: Cross-sectional data from the IMAGE-HD study. Hum Brain Mapp. Forthcoming 2013. 12 9 Labuschagne, van Dellen, A, et al. Delaying the onset of Huntington's in mice. Nature. 2000;404(6779):721-2. 5 10 I, et al. Emotional face recognition deficits and medication effects in pre-manifest through stage-II Huntington's disease. Psychiatry Res. 2013;207(1-2):118-26. Copyright © Huntington Study Group 2013. All rights reserved. HD Insights, Vol. 5