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