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

2. PREDICT-HD Study
Intervention model for HD

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

4. 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

5. 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

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

7. 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

8. 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

9. PREDICT-HD : Results

10. 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

11. 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

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

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

14. 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

15. 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

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

17. 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