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Clinical Professor Peter K Panegyres MD PhD FRACP PREDICT-HD Neurosciences Unit.

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Presentation on theme: "Clinical Professor Peter K Panegyres MD PhD FRACP PREDICT-HD Neurosciences Unit."— Presentation transcript:

1 Clinical Professor Peter K Panegyres MD PhD FRACP PREDICT-HD Neurosciences Unit

2 Intervention model for HD

3  Document natural history of premanifest HD  Development of Markers Clinical Imaging Outcome measures Preventative Clinical Trials

4  32 sites  International  Observational  Premanifest HD  Annual examination   N=1013 participants (premanifest)  N=301 negative control  > 35 CAG expansion repeats = cases  < 36 gene mutation negative = controls

5  Median duration in study = 6 years (range 1-10)  75% sample > 3 years data  15% - 2 years  <10% - 1 year  N=204 gene expanded participants received a motor diagnosis = converters  Dropout < 5% per year

6  CAG-AGE product [CAP] score = CAP E = [age at entry] x [CAG ] Estimate proximity to HD diagnosis  CAP E can be used to estimate 5 year probability of motor diagnosis  CAP E 368 [high]< 7.59 years

7  Change over time – controlling for covariates of age, gender, depressed mood, brain scanner field strength  Comparison of premanifest and control  LMER (linear mixed effects regression)  39 variables analysed separately  Graphical analysis to represent phenotypic characteristics of HD: Motor, cognitive, psychiatric + Biological (imaging) + Functional outcomes

8  Variables with largest effect sizes ◦ Regional brain volumes ◦ TMS [UHDRS], esp bradykinesia and chorea ◦ Decline in cognitive performance in every measrue examined, esp symbol digits modalities test ◦ Functional variables, every measure esp TFC ◦ Psychiatric variables, esp  Obsessive compulsive scale  Frontal systems behavioural scale  executive and apathy scales

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10  Six variables significant acceleration of the slope of participants who converted: Dystonia Stroop FAS SDMT TFC TMS

11  Estimated effect size for a two-arm Phase II randomised control trial  Effect size 20% ◦ Required sample for say TMS = 981  Dropout rate 20% ◦ Sample required TMS = 1131  CSF space ◦ 20% effect= 332 ◦ 20% dropout= 386

12 Plots of key outcome variables for preventative clinical trials

13 Data derived model for disease progression

14  Longitudinal change in 36 of 39 measures over 10 years of natural observation study  Effect sizes suggest a preventative RCT could be designed to detect treatment effects of 30%  Significant measures ◦ Clinical phenotype HD – motor, cognitive, psychiatric ◦ Biological ◦ Functional  Specific measure  disease state chosen  The effects of ageing  Real natural history data

15  1300 gene mutation tested individuals followed prospectively through actual motor diagnosis  Phenotypic and biological changes decade prior to, and just after, manifestations of disease  Biological progression in premanifest HD is ◦ Linear for imaging, cognitive and psychiatric ◦ Non-linear for motor and functional  Motor expression accelerates as the disease manifests over 15 years prior to motor onset  Worldwide collaboration  Relevant to clinical trials

16  Collection of CSF to analyse Huntingtin protein and other biomarkers as clues to disease progression

17 Patients and families Huntington’s Study Group PREDICT Team – Jane Paulsen & colleagues Rachel Zombor, Mark Woodman, Elizabeth Vuletich, Steve Andrews, Maria Tedesco, Carmela Pestell Staff at the Neurosciences Unit


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