HD Down Under
By: Izelle Labuschagne, PhD
Approximately 1,200 Australians have HD and 6,000 people are at risk1. HD got its start in our island state of Tasmania, where it was first introduced in 1842 by a woman from Somerset, England, who had 13 children, 11 of whom carried the HD gene.
The 1970s in Australia saw significant early developments for HD, thanks to psychiatrist and educator Professor Edmond Yu-Kuen Chiu. In 1972, Professor Chiu envisioned a plan that would eventually result in the opening of the first HD clinic in Australia at the Royal Melbourne Hospital, followed by his establishment in 1973 of the Australian HD Association. Since then, many more clinical services for HD have been established in other Australian states.
Our largest HD research efforts come from Melbourne-based researchers. Biochemist Dr. Danny Hatters from the University of Melbourne’s Bio21 Institute leads a team studying how clumps of huntingtin (Htt) form, and their role in disease pathogenesis. Dr Hatters’ group has developed tools for dissecting how Htt clumps accumulate at the molecular level. For example, sedimentation velocity analysis can measure the size and heterogeneity of all Htt molecules in a cell extract2, 3. Another more recently developed method can, for the first time, separate and recover cells enriched with mutant Htt in dispersed patterns relative to Htt in inclusions4, which allows detailed study of the aggregation and clumping process and how it relates to biological functioning of the cells that contain mutant Htt (Figure 1).
Professor Anthony Hannan and his team at the Florey Institute of Neuroscience and Mental Health in Melbourne have made exciting discoveries using the R6/1 transgenic mouse model of HD. A key discovery from their work was the finding that environmental enrichment has beneficial effects on the development of HD in the transgenic mice. Environmental enrichment resulted in a delay in onset and a slowing of disease progression in the mice5, and it also resulted in the rescue of abnormal stress response in the adrenal cells6 (Figure 2). Furthermore, increased physical activity delayed motor onset and slowed cognitive decline7. Hannan’s team was the first to demonstrate the beneficial effects of environmental stimulation in a genetic model of a brain disorder. These, and other findings from Hannan’s lab, provide a biological foundation for the potential of environmental enrichment as a treatment option for HD.
Our focus at Monash University in Melbourne is on clinical studies assessing cognition and structural brain changes in HD. Our work is well-integrated with the largest HD clinic in the state, run by Dr. Andrew Churchyard at the Calvary-Bethlehem Hospital.
My research team, led by Professor Julie Stout, uses tools for sensitive measurement of cognitive dysfunction to aid in the understnding 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 Stout lab, 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 social-emotion cues, as has been observed in other disorders.
Professor Nellie Georgiou-Karistianis’s lab investigates motor and cognitive deficits in HD using a range of experimental paradigms. Georgiou-Karistianis leads the IMAGE-HD project, an Australia-based longitudinal multimodal biomarker development study, which followed a cohort of premanifest HD (pre-HD), early symptomatic HD (symp-HD) and healthy controls at three time points over 30 months. To date, this study has yielded cross-sectional and longitudinal reports on the impact of HD on multimodal magnetic resonance 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).
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.
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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.
5 van Dellen, A, et al. Delaying the onset of Huntington’s in mice. Nature. 2000;404(6779):721-2.
6 Du, 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.
7 Pang, 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.
8 Tabrizi, 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.
9 Labuschagne, 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.
10 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.
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.
12 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.