Neurological Predictors of Huntington’s Disease Clinical Professor Peter K Panegyres MD PhD FRACP PREDICT-HD Neurosciences Unit

PREDICT-HD Study Intervention model for HD

PREDICT-HD: Objectives Document natural history of premanifest HD Development of Markers Clinical Imaging Outcome measures Preventative Clinical Trials

PREDICT-HD N=1013 participants (premanifest) 32 sites International N=301 negative control > 35 CAG expansion repeats = cases < 36 gene mutation negative = controls 32 sites International Observational Premanifest HD Annual examination 2001-2014

PREDICT-HD 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

Premanifest Staging Group CAG-AGE product [CAP] score = CAPE = [age at entry] x [CAG -33.66] Estimate proximity to HD diagnosis CAPE can be used to estimate 5 year probability of motor diagnosis CAPE < 290 [low]  12.78 years 290  CAPE  368 [medium] 7.59-12.78 yrs > 368 [high] < 7.59 years

PREDICT-HD : Statistics 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

PREDICT-HD : Results 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

PREDICT-HD : Results

PREDICT-HD : Results Dystonia Stroop FAS SDMT TFC TMS Six variables significant acceleration of the slope of participants who converted: Dystonia Stroop FAS SDMT TFC TMS

PREDICT-HD : Results 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

PREDICT-HD Plots of key outcome variables for preventative clinical trials

Data derived model for disease progression PREDICT-HD Data derived model for disease progression

PREDICT-HD : Conclusions 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 a disease state chosen The effects of ageing Real natural history data

PREDICT-HD : Conclusions 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

PREDICT-HD : CSF Collection of CSF to analyse Huntingtin protein and other biomarkers as clues to disease progression

PREDICT-HD : Thank You 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