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05-Nov-15
1
Peter Silburn
Professor Clinical Neuroscience
University of Queensland
Queensland Brain Institute
Neurosciences Queensland
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• (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
The Nature of Parkinson’s disease21st Century
Basal Ganglia pathways
DA neuron loss and Lewy bodiesP
Dopaminergic circuitry
Many different neurones and
supporting cells
Many different
neurotransmitters
“ Prion Like “
Alpha Synuclein
PD: Threshold of degeneration for symptom emergence
Agid 1991
05-Nov-15
2
Parkinson’s DiseaseTHERE ARE MANY MANY MORE DEFICITS THAN JUST
DOPAMINE
Parkinson’s DiseaseNot a single phenotype
NOT just a Movement Disorder
• Motor features
Bradykinesia
Rigidity
Tremor
Postural instability
Levodopa responsive
• Non Motor Features
Behavioural
Autonomic
Sensory
Sleep Disorders
Nutritional Status
PD: Symptomatic treatment
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
Other– MAO-B inhibitor (selegiline and rasagiline )– Anticholinergics ( artane )
– amantadine
A Parkinson’s Disease Drug Regime
• Levodopa
• 6 12 6
• 6 10 2 6
• 6 9 12 3 6
• At bedtime
• Either madopar HBS or Sinemet CR
Find the dose that relieves the symptoms
Set that dose and then set the dose interval
Add a slow release formulation at night
Add an agonist
Add either rasagiline or amantadine
Add an anticholinergic if non responding tremor
Consider starting first a non ergot derived agonist if young
Sellbach A Silburn PA (2013 )
Australian Prescriber
Long-term challenges: Changes in levodopa response
Obeso et al. 2000
We need to keep the next half as smooth as the first
05-Nov-15
3
A Levodopa Drug Regime
• 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)
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
PD Symptomatic treatment when the drugs do not work all the time - these are known as
motor and non-motor fluctuations
“ 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
05-Nov-15
4
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
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
Right OpinionRight person
Right operationRight time
Right follow up
Patients for DBS
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
Best Medical Practice in Fluctuators
Braak staging based on
synuclein pathology
[Braak et al. (2003) Staging of brain pathology related to
sporadic Parkinson’s disease. Neurobiol Aging 24:197-211]
Many non-dopaminergic
nuclei are affected early
and throughout the course
of Parkinson’s disease.
Brain Connectivity
Exploration and DiscoverySt Andrews and University of Queensland
HELPING HUMANS
05-Nov-15
5
SPOKESPERSON Thank you for your attention
Long-term evolution of motor symptoms with STN-DBS
► 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
Med Off
0 2 4 6 8 10 120
20
40
60
time (years)
UP
DR
S II
I
Med On
0 2 4 6 8 10 120
20
40
60 Krack 2003
Schüpbach 2005
Fasano 2010
Zibetti 2011
Rizzone 2014
time (years)
UP
DR
S II
I
Therapeutic width
Residual motor symptoms
Stimulation
response
best ON
OFF+Stim
worst OFF
Complete references for this slide can be found on Slide 23 at the end of the presentation.
27
Parkinson’s disease: Pathology
PET scan showing
striatal fluorodopa
uptake
Gross pathology
of the mid brain
Normal PD
Substantia nigra
05-Nov-15
6
Peter Silburn
Professor Clinical Neuroscience
University of Queensland
Queensland Brain Institute
Neurosciences Queensland
Long-term challenges: Changes in levodopa response
Obeso et al. 2000
We need to keep the next half as smooth as the first
Deep Brain Stimulation
Terry Coyne Peter Silburn
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)
STN recordingBorder
STN
Border/SN
10sec
10sec
10sec
80ms
80ms
80ms
Sagittal Section through the Thalamus
05-Nov-15
7
(Illumina-based BeadChips arrays were used to conduct gene-expression studies in these cell lines).
Study -2 Expression differences in expanded neurospheres from PD
patients (n=19) compared to control subjects (n=14)
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
NCASCR, unpublished data
Differential expression of the “metabolism of xenobiotics by
CYP450” pathway between PD and control cell lines.
18 transcripts up-regulated in PD
16 transcripts down-regulated in PD
72 unchanged
208 “
xenobio
tic m
eta
bolism
” tr
anscri
pts
out
of
22,1
89 o
n c
hip
(102 n
ot
exp
ressed i
n h
um
an n
euro
sphere
s)
106 “xenobiotic
metabolism”
transcripts are
expressed in
neurospheres
EASE p-value for pathway p<0.000001
Proteins altered in Parkinson’s disease
2D gel electrophoresis and mass spectrometry
proteins down in PD
(left columns)
Proteins up in PD
(right column)
Functional alterations in PD
A Cook, G Sutherland, G Mellick , P Silburn, S Wood, N Matigian
PARK gene expression
0
2
4
6
8
10
12
14
PAR
K7
UCHL1
PIN
K1
HTR
A2
GBA
ATP13A
2
GIG
YF2
NR4A
2
Lo
g(2
) exp
ressio
n (
Illu
min
a)
cases
controls
Olfactory derived cultures express many PARK genes
Study - 6
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.
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)
PD
Control
Genes altered in Parkinson’s disease
05-Nov-15
8
Your BrainAs We Think We Know It
• 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 neuronesa day in adulthood :31 mill/ yr
• 8 million kilometers of tracts
Professor Peter Silburn
UQ Centre for Clinical Research
Long-term challenges: Changes in levodopa response
Obeso et al. 2000
A Levodopa Drug Regime
• 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 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
Duodopa Belly
The Nature of Parkinson’s disease21st Century
Basal Ganglia pathways
DA neuron loss and Lewy bodiesP
Dopaminergic circuitry
Many different neurones and
supporting cells
Many neurotransmitters
“ Prion Like “
Alpha Synuclein
Parkinson’s disease: What the deep brain looks like
PET scan showing striatal fluorodopa uptake
Gross pathology of the mid brain
Normal PD
Substantia nigra
05-Nov-15
9
Braak staging based on
synuclein pathology
[Braak et al. (2003) Staging of brain pathology related to
sporadic Parkinson’s disease. Neurobiol Aging 24:197-211]
Many non-dopaminergic
nuclei are affected early
and throughout the course
of Parkinson’s disease.
Parkinson’s Disease
We need to keep the next half as smooth as the first