Transcript Neurological Predictors of Huntington’s Disease

Clinical Professor Peter K Panegyres
MD PhD FRACP
PREDICT-HD
Neurosciences Unit
Intervention model for HD
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Document natural history of premanifest HD
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Development of Markers
Clinical
Imaging
Outcome measures
Preventative
Clinical Trials
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32 sites
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International
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Observational
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Premanifest HD
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Annual examination
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2001-2014
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N=1013 participants
(premanifest)
N=301 negative control
> 35 CAG expansion
repeats = cases
< 36 gene mutation
negative = controls
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Median duration in study = 6 years
(range 1-10)
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75% sample > 3 years data
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15% - 2 years
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<10% - 1 year
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N=204 gene expanded participants received
a motor diagnosis = converters
Dropout < 5% per year
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CAG-AGE product [CAP] score =
CAPE = [age at entry] x [CAG -33.66]
Estimate proximity to HD diagnosis
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CAPE can be used to estimate 5 year
probability of motor diagnosis
CAPE < 290
290  CAPE  368
> 368
[low]  12.78 years
[medium] 7.59-12.78 yrs
[high]
< 7.59 years
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Change over time – controlling for covariates of
age, gender, depressed mood, brain scanner field
strength
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Comparison of premanifest and control
 LMER (linear mixed effects regression)
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39 variables analysed separately
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Graphical analysis to represent phenotypic
characteristics of HD:
Motor, cognitive, psychiatric
+
Biological (imaging)
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Functional outcomes
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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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Six variables significant acceleration of the
slope of participants who converted:
Dystonia
Stroop
FAS
SDMT
TFC
TMS
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Estimated effect size for a two-arm Phase II
randomised control trial
Effect size 20%
◦ Required sample for say TMS = 981
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Dropout rate 20%
◦ Sample required TMS = 1131
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CSF space
◦ 20% effect
◦ 20% dropout
= 332
= 386
Plots of key
outcome variables
for preventative
clinical trials
Data derived model for disease progression
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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
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Specific measure a disease state chosen
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The effects of ageing
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Real natural history data
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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
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Motor expression accelerates as the disease
manifests over 15 years prior to motor onset
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Worldwide collaboration
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Relevant to clinical trials
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Collection of CSF to analyse Huntingtin
protein and other biomarkers as clues to
disease progression
• 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