05-Nov-15
Peter Silburn
Professor Clinical Neuroscience
University of Queensland
Queensland Brain Institute
Neurosciences Queensland
The Nature of Parkinson’s disease
21st Century
Impact of Parkinson’s Disease in
Australia
• Second most common neurodegenerative
disorder
• Up to 64,000 individuals with PD
• Higher prevalence than other areas in the
Australian National Health Priority
• Cost of living with PD same as adult cancers
•
“ Prion Like “
Alpha Synuclein
DA neuron loss and Lewy bodies
P
Dopaminergic circuitry
(lymphoma, leukaemia, prostate, gynaecological malignancies, kidney- plus breast
and colorectal ca over 55’s)
• Net cost of burden of disease $ 8.3 billion in 2011
Access Economics Report 2011
Many different neurones and
Basal Ganglia supporting
pathways cells
Many different
neurotransmitters
PD: Threshold of degeneration
for symptom emergence
Agid 1991
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05-Nov-15
Parkinson’s Disease
Parkinson’s Disease
THERE ARE MANY MANY MORE DEFICITS THAN JUST
DOPAMINE
Not a single phenotype
NOT just a Movement Disorder
• Motor features
• Non Motor Features
Bradykinesia
Rigidity
Tremor
Postural instability
Behavioural
Autonomic
Sensory
Sleep Disorders
Nutritional Status
Levodopa responsive
PD: Symptomatic treatment
A Parkinson’s Disease
Drug Regime
Dopaminergic treatment:
– levodopa plus a DDC inhibitor
(carbidopa, benserazide)
– levodopa plus a DDC inhibitor and a
COMT inhibitor (entacapone )
– dopamine agonists : ergot derived- cabergoline, pergolide,
bromocriptine
– dopamine agonists : non ergot derived - pramipexole,
rotigotine transdermal patch
Find the dose that relieves the symptoms
Set that dose and then set the dose interval
Add a slow release formulation at night
– MAO-B inhibitor (selegiline and rasagiline )
– Anticholinergics ( artane )
– amantadine
• 6 12 6
• 6 10 2 6
• 6 9 12 3 6
Add an agonist
Add either rasagiline or amantadine
Other
• Levodopa
Add an anticholinergic if non responding tremor
Consider starting first a non ergot derived
agonist if young
• At bedtime
• Either madopar HBS
or Sinemet CR
Sellbach A Silburn PA (2013 )
Australian Prescriber
Long-term challenges:
Changes in levodopa response
We need to keep the next half as smooth as the first
Obeso et al. 2000
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05-Nov-15
PD Symptomatic treatment when the drugs do
not work all the time - these are known as
motor and non-motor fluctuations
A Levodopa Drug Regime
The dose
Start at 50 mg three times a day for 2
weeks
Then
100 mg three times a day
Then either
150 mg three times a day if not coming
“on”
or 100 mg four times a day if coming on
but not making it from dose to dose
or Stalevo 100mg three times a day if
not coming on or not making it from
dose to dose
•
Levodopa Preparations
•
•
Sinemet / Kinson- 100mg
Sinemet / Levohexal 250mg
Sinemet CR-200mg
•
Madopar - 100 or200mg
Madopar HBS-100mg
Madopar rapid-50 or 100 mg
•
•
Stalevo 50-200mg tabs
( essentially sinemet plus
entacapone in one tab)
“ Ons and Offs “
End dose
Sudden and unpredictable
Fail to come on at all
Dopaminergic therapy
Apomorphine injections or infusion pumps
Duodopa infusion thru a PEG tube
Neurosurgical treatments
– Deep brain stimulation
– Lesional surgery
Parkinson’s Disease
Existing and evolving
treatments for
Parkinson's disease
Drugs that are
available or in
development are
shown according to
their mechanism of
action, target
indication, and phase
of development.
(Schapira, et al. 2014 The Lancet, Volume 384, Issue 9942, 2014, 545 – 555)
External Pump
Therapies
Duodopa
Apomorphine
Deep Brain
Stimulation in
Parkinson’s Disease
Class 1 Evidence is basis
for
Best Medical Practice
Class 1 evidence is DBS
better than persisting with
drugs alone in Parkinson’s
Disease
Deutschel et al 2006 N Eng J Med
Schupbach et al 2013 N Eng J Med
Sooner and Later
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05-Nov-15
Right Opinion
Right person
Right operation
Right time
Right follow up
Deep Brain
Stimulation in
Parkinson’s Disease
Class 1 Evidence is basis
for
Best Medical Practice
Class 1 evidence is DBS
better than persisting with
drugs alone in Parkinson’s
Disease
Deutschel et al 2006 N Eng J Med
Schupbach et al 2013 N Eng J Med
Highly significant improvement in
Quality of Life
Superior
Motor scores
Activities of daily living
Drug induced complications
Levodopa reduction
Safety outcomes were similar in both
treatment groups
Sooner and Later
Patients for DBS
Braak staging based on
synuclein pathology
ADEQUATE TRIAL MEDICATIONS
Medications not maintaining Quality of Life
Core opinions from
Neurologist-Neurosurgeon–Psychiatrist
In an experienced and sufficiently active DBS
centre with dedicated team
Many non-dopaminergic
nuclei are affected early
and throughout the course
of Parkinson’s disease.
[Braak et al. (2003) Staging of brain pathology related to
sporadic Parkinson’s disease. Neurobiol Aging 24:197-211]
Best Medical Practice in Fluctuators
Exploration and Discovery
St Andrews and University of Queensland
Brain Connectivity
HELPING HUMANS
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Thank you for your attention
SPOKESPERSON
Long-term evolution of motor symptoms with STN-DBS
Med Off
UPDRS III
60
►
40
►
20
►
0
0
2
4
6
8
10
12
time (years)
Slow worsening of On-period motor
symptoms 5-10 years after surgery
Parallel decline of motor score in Med
Off/Stim ON
But: 40-50% reduction of off-period
motor score by DBS 5-10 years after
surgery
worst OFF
Med On
UPDRS III
60
Stimulation width
Therapeutic
response
Krack 2003
Schüpbach 2005
Fasano 2010
Zibetti 2011
Rizzone 2014
40
OFF+Stim
best ON
Residual motor symptoms
20
0
0
2
4
6
8
time (years)
10
12
Complete references for this slide can be found on Slide 23 at
the end of the presentation.
27
Parkinson’s disease: Pathology
Normal
PD
PET scan showing
striatal fluorodopa
uptake
Gross pathology
of the mid brain
Substantia nigra
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05-Nov-15
Long-term challenges:
Changes in levodopa response
Peter Silburn
Professor Clinical Neuroscience
University of Queensland
Queensland Brain Institute
Neurosciences Queensland
Obeso et al. 2000
Deep Brain Stimulation
We need to keep the next half as smooth as the first
Terry Coyne Peter Silburn
STN recording
Border
10sec
Sagittal Section through the Thalamus
80ms
Existing and evolving
treatments for
Parkinson's disease
Drugs that are available
or in development are
shown according to their
mechanism of action,
target indication, and
phase of development.
STN
10sec
80ms
Border/SN
10sec
80ms
(Schapira, et al. 2014 The Lancet, Volume 384, Issue 9942, 2014, 545 – 555)
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Study -2
Differential expression of the “metabolism of xenobiotics by
CYP450” pathway between PD and control cell lines.
(Illumina-based BeadChips arrays were used to conduct gene-expression studies in these cell lines).
Unsupervised clustering
Unbiased pathway examination of differentially
expressed transcripts using Database for
Annotation, Visualization and Integrated
Discovery (DAVID) Bioinformatics Resources.
We have uncovered some interesting
differentially expressed pathways
208 “xenobiotic metabolism” transcripts out of 22,189 on chip
(102 not expressed in human neurospheres)
Expression differences in expanded neurospheres from PD
patients (n=19) compared to control subjects (n=14)
18 transcripts up-regulated in PD
106 “xenobiotic
metabolism”
transcripts are
expressed in
neurospheres
72 unchanged
16 transcripts down-regulated in PD
EASE p-value for pathway p<0.000001
NCASCR, unpublished data
Proteins altered in Parkinson’s disease
Functional alterations in PD
2D gel electrophoresis and
mass spectrometry
proteins down in PD
(left columns)
Proteins up in PD
(right column)
Study - 6
Olfactory derived cultures express many PARK genes
Genes altered in Parkinson’s disease
PD Vs Controls
– 904 gene significantly (≤0.05) differentially expressed (Welch t-test)
– 435 Up-regulated (36 at 2-fold)
– 469 Down-regulated (12 at 2- fold)
PARK gene expression
Log(2) expression (Illumina)
14
12
10
8
cases
6
controls
4
PD
2
4A
2
P1
3A
2
NR
A2
G
BA
G
IG
YF
2
AT
K1
PIN
K7
HT
R
UC
PA
R
HL
1
0
Control
Conclusion- These cultures may be directly suitable to study several of the
PARK gene products but might require manipulation from baseline to
stimulate expression of others such as SNCA and LRRK2.
A Cook, G Sutherland, G Mellick , P Silburn, S Wood, N Matigian
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Your Brain
As We Think We Know It
Long-term challenges:
Changes in levodopa response
• 1.4 kilograms
• 2% body weight
• Surface area 2,500 cm
squared
• 100 billion neurones
• 1000 billion glia
• Make 250,000
neurones a minute
during development
• Lose 85,000 neurones
a day in adulthood :31
mill/ yr
• 8 million kilometers of
tracts
Professor Peter Silburn
UQ Centre for Clinical Research
Obeso et al. 2000
A Levodopa Drug Regime
Duodopa Belly
The dose
Start at 50 mg three times a day for 2
weeks
Then
100 mg three times a day
Then either
150 mg three times a day if not coming
“on”
or 100 mg four times a day if coming on
but not making it from dose to dose
or Stalevo 100mg three times a day if
not coming on or not making it from
dose to dose
•
Levodopa Preparations
•
•
Sinemet / Kinson- 100mg
Sinemet / Levohexa-l250mg
Sinemet CR-200mg
•
Madopar - 100 or200mg
Madopar HBS-100mg
Madopar rapid-50 or 100 mg
•
•
Stalevo 50-200mg tabs
( essentially sinemet plus
entacapone in one tab)
The Nature of Parkinson’s disease
21st Century
Parkinson’s disease: What the deep
brain looks like
Normal
PD
“ Prion Like “
Alpha Synuclein
PET scan showing
striatal fluorodopa
uptake
DA neuron loss and Lewy bodies
P
Dopaminergic circuitry
Many different neurones and
Basal Ganglia supporting
pathways cells
Many neurotransmitters
Gross pathology of
the mid brain
Substantia nigra
8
05-Nov-15
Braak staging based on
synuclein pathology
Parkinson’s Disease
Many non-dopaminergic
nuclei are affected early
and throughout the course
of Parkinson’s disease.
[Braak et al. (2003) Staging of brain pathology related to
sporadic Parkinson’s disease. Neurobiol Aging 24:197-211]
We need to keep the next half as smooth as the first
9