Parkinsonism

• Tremor– resting

• Slowness– bradykinesia

• Stiffness– rigidity

• Loss of balance

Olanow. Neurology 2009

Dopa

Dopa Dopamine

Cause

Dopamine deficit

Dopamine replacement

Tremor, rigidity, bradykinesia, postural impairment

Golbe 1990

Parkinson’s – divergent causes, convergent mechanisms (Science

21 May 04)

Braak 2005

Cause

Dopamine deficit

Dopamine replacement

Tremor, rigidity, bradykinesia, postural impairment

Cause Cause Cause Cause Cause

Mechanism

Dopamine deficit Cortical Lewy bodies Other neurotransmitters

Parkinsonism Dementia

DepressionFalls

Autonomic dysfunction

Pain

Levodopa complications

Sleep disturbance

Dopaminergic

5 years 10 years

Parkinsonism Motor fluctuations and dyskinesia

Non-Dopaminergic

5 years 10 years

anosmiaRBD

anxiety depression

pain Fallsautonomic failuredementia

Dopaminergic

Non-Dopaminergic

Diagnosis and early treatment Motor complications General neurodegeneration

5 years 10 years

Parkinsonism Motor fluctuations and dyskinesia

anosmiaRBD

anxiety depression

pain Fallsautonomic failuredementia

Schwarz 2004

Hely 2008

Kempster Brain 2010

Kempster Brain 2010

Schenck et al 1986

REM Sleep behaviour disorder

• 5 patients (4 men)• 6 years of injuring themselves or spouses during

sleep• REM pathology with loss of chin atonia, increased

limb activity• Reaching and searching hand gestures, punches and

kicks• OPCA, GBS, SAH, atypical dementia• Excellent response to clonazepam• Replicates findings from cats with pontine

tegmental lesions

Schenck et al 1986

RBD clinical features

• Male gender predilection• Mean onset 50–65 years (childhood—80 years)• Vocalizations, swearing, screaming• Simple limb jerks to complex motor behaviour, with

injuries to patient or bedpartner• Dreams often involve chases or attacks by animals or

humans; exhibited behaviours mirror dream content• Behaviors tend to occur in latter half of the sleep period• When associated with neurodegenerative disease, RBD

often precedes dementia and/or parkinsonism by years or decades

Antonio Carnicero 1779

“…in his right hand he held his unsheathed sword, with which he was slashing about on all sides, uttering exclamations as if he were actually fighting some giant: and the best of it was his eyes were not open, for he was fast asleep, and dreaming that he was doing battle with the giant”.

Cervantes; Don Quixote 1605

RBD and PD

Schenck et al: • 29 patients with Idopathic-RBD

– 38% developed PD 12.7 yrs post RBD onset– 65% by 7 yrs later

• “Idiopathic” RBD– Olfactory deficits– Loss of striatal DA– impaired attention, executive function, and verbal

memory

RBD and prognosis of PD

• RBD more common in non-tremulous PD• Seldom occurs when PD develops <50 years• RBD is associated with visual hallucinations

– ?PD psychosis may represent a narcolepsy-like REM sleep disorder

• RBD is associated with worse and more rapidly developing PD– Vendette M, Gagnon J-F, Decary A, et al. REM sleep behavior

disorder predicts cognitive impairment in Parkinson disease without dementia. Neurology 2007; 69:1843-1849.

• RBD tends to wane with PD progression

The “wait and watch” option

modified from Grosset, D et al. J Neurol Neurosurg Psychiatry 2007;78:465-469

Self-reported health status deteriorated significantly over 18 months in untreated patients but not treated patients

n = 114

n = 61

n = 74n = 127

9/12

9/12

treated

untreated

*

*

The “wait and watch” option

modified from Asimakopoulos, P et al. J Neurol Neurosurg Psychiatry 2008;79:716-718

n = 16

n = 26

No significant deterioration over 2 years in health status score in either group even though motor status significantly worsened in the untreated group.

“……we believe a ‘‘wait and watch’’ strategy for the treatment of newly diagnosed PD remains a credible approach……..”

Change in Median UPDRS Motor Score

0

10

20

30

treated untreatedUP

DR

S (

Mo

tor)

Sco

re

baseline

year 2

In summary, it makes sense to treat patients early to improve early quality of life

However, the impact of early treatment on late quality of life has not been assessed

Does early treatment lead to better later PD status?

0

10

20

30

40

50

60

Levodopa Ropinirole

<70>70%

dys

kine

sia

Adapted from Rascol 054 Study

Initial treatment

• Young patients: dyskinesia– Dopamine agonists (ropinirole 3 mg tds)

• Old patients: dementia– Levodopa (100 mg tds)

RopiniroleAdverse Events (compared to levodopa)

Ropinirole Levodopa

Nausea 48.6% 36.7%

Somnolence 27.4 17.3

Hallucination 17.3 3.3

Edema 14.0 4.0

Agonists and disinhibition

• Gambling

• Impulsive sexual behaviour

• Shopping

• Eating

• Punding

Levodopa

Levodopa Dopamine

Miller. J Neurochem 1999;72:1516

Dopamine D1 receptor binding in dyskinetic rats

Aubert et al 2005

Nyholm. Clinical Neuropharmacology 2002;25:89

Levodopa Enzyme Inhibition

modified from Olanow et al. Neurology 2001;56(11 Suppl 5) S1-88)

carbidopa

selegiline

tolcapone

entacapone

rasagilinerasagiline

COMT inhibition: Entacapone

• 200mg with each dose of levodopa

• Easy to use

• Minimal diarrhoea 2.5%

• Not as powerful as tolcapone

COMT inhibition: Tolcapone

• 100-200 mg tds – do not adjust the dose

• Powerful

• More levodopa side effects

• More diarrhoea - 12%

• Need to monitor liver function

Who needs COMT inhibition?

• the patient with predictable fluctuations who has not responded to increases in dose or frequency of levodopa or slow-release levodopa

• the patient with unpredictable fluctuations. – But keep expectations low - difficult patients

with unpredictable fluctuations will stay difficult to treat

Apomorphine

• Morphine decomposition product by boiling with concentrated acid

• Occasionally used to enhance erectile function

• Non-selective dopamine agonist

• Suitable for parenteral use

Apomorphine

Nyholm. Clinical Neuropharmacology 2002;25:89

DUODOPA

Patient 03 Sinemetplasma levodopa

8 9 10 11 12 13 14 15 16 17

0

1

2

3

4

5

6

7

8

BaselineTest day 4Test day 5Test day 6

D D DM M

Time

g/m

l

Patient 03 Duodopaplasma levodopa

8 9 10 11 12 13 14 15 16 17

0

1

2

3

4

5

6

7

8

Test day 1Test day 2Test day 3

M M

Time g

/ml

Plasma Levodopa Concentrations

Olanow CW et al. (2006) Drug Insight: continuous dopaminergic stimulation in the treatment of Parkinson's disease Nat Clin Pract Neurol 2: 382–392 10.1038/ncpneuro0222

Figure 3 Effect of intraintestinal levodopa infusion on motor complications in Parkinson's disease

6 Months Follow Up: PDQ-39

PDQ-39(N=12)

0

5

10

15

20

25

30

35

40

Conventional TherapyBaseline

Duodopa Baseline Duodopa 6 months

*

*p<0.01

DIREQT

Deep Brain Stimulation

3387S-4X Electrodes 1.5mm apart; over 10.5mm3389S-4X Electrodes 0.5mm apart; over 7.5mmBody of Leads are 1.27mm diam.

Deuschl NEJM 2006

Selection of patients for DBS

•Diagnosis of Idiopathic Parkinson’s Disease Certain•On optimum drug treatment•Good L-Dopa “on” response (L-Dopa Challenge~50%)•Major fluctuations and/or dyskinesia•No significant dementia•No important psychiatric disorder or mood disorder•Age is relative contraindication; <70yrs•Hypertension well controlled•Not requiring long-term anticoagulation•No surgical contraindication found on MRI scan•Capable of tolerating the proceedure (takes a number of hours)•Patient well appraised of realistic expected outcome of the proceedure•[ No significant postural instability during best “on” period ]

•L-Dopa resistant symptoms not generally improved

Microarray Analysis of Choroid Plexus Neurotrophic Genes Expression

Name Expression Index Rank/24000TGFbeta 1 (HIGHEST) 12.6 240

IGF-2 11.8 528

VEGF (confirmed by ELISA) 10.29 2097

EGF 9.04 4947

IGF-1 7.92 8596

FGF-2 6.93 11758

Growth hormone 6.39 13317

BMPs 5.24 16628

Nerve growth factor 4.79 18152

BDNF (confirmed by ELISA) 4.31 19716

FGF-2 6.93 11758

TGFbeta 3 6.76 12272

FGF 5.267 16726

Nerve growth factor 4.79 18152

NT-3 (LOWEST) 3.98 20869

High Expression Genes

Detoxification Proteins Anti-Oxidant Enzymes Proteinase Inhibitors

TRANSTHYRETIN SOD-1 CYSTATIN B & C(confirmed - proteonomics)

Lipocalin-PGDS SOD-2 (Mn type) Neuroserpin(confirmed - proteonomics)

Retinol Binding Proteins Glutathione peroxidase(intracellular)

Glutathione peroxidase 4

Catalase

Glutathione reductase

Skinner 2009

Skinner 2009(calcein)

Rat brain at 6 Months

porcine endogenous retrovirus (PERV)

• highly prone to recombination events• capable of intracellularly moving within the pig genome as retrotransposons • remote possibility of recombination with human retroviruses, including human endogenous

retroviruses

• Cytomegalovirus• lymphotrophic herpes virus• encephalomyocarditis virus• hepatitis E • circo-viruses

Released 1807 by Captain Abraham Bristow of the Sarah

High Health Status Pigs: • US FDA Guidelines 2003• Low copy numbers for PERV• No gene marker for locus required for recombination PERV-C with

PERV-A• No demonstrated transmission of PERV

Molecular Diagnostic Laboratory• International Accreditation New Zealand certified

Manufacturing Plant: • GMP certification annual recertification and audit• Cell Processing• Encapsulation Technology• Toxicity data• Quality Certified Encapsulated Product

Preclinical Data• Safety and efficacy studies in animals:

Monitoring• Safety monitoring for donors and recipients

Human diabetes - NZ• John Baker, MMH• 14 brittle type I DM• Met US criteria for allograft. Intensive ministerial oversight• Dose escalation and de-escalation

– 10 ilets/kg…20…5• Peritoneal insertion, 20 min procedure• Most patients abdo pain and inflammation• One patient anaphylactoid response 6 days• First 4 patients, now 4 years• No long term AEs• Mild improvement

– 25% less insulin– Fewer hypos– 2 patients regained hypo awareness

Animal neurological studies

• Rat stroke

• Rat QA HD

• Monkey QA HD

• Rat 6OHD PD

• Monkey MPTP PD

1.Sheng L, Wang W, Yu XP, Mao J, Rong PF. Establishment of hemi-Parkinsonism model of rhesus induced by MPTP. Chin J Med Imaging Technology 2006; 3: 353-356.

0 2 4 6 8 10 12 14 16 18 20 22 240

20

40

60

80

100

120CP cell capsulesEmpty capsulesSham*

********* ***

***

Weeks post implant

% C

han

ge

of

turn

s

Hai Lin*, Wei Wang+, Xian-Ming Luo+, Marilyn S Geaney*, Shaun Wynyard*, Jian Guanx, Robert B Elliott*, Stephen JM Skinner*, Paul L-J Tan. Manuscript in preparation. 2012

Hai Lin*, Wei Wang+, Xian-Ming Luo+, Marilyn S Geaney*, Shaun Wynyard*, Jian Guanx, Robert B Elliott*, Stephen JM Skinner*, Paul L-J Tan. Manuscript in preparation. 2012

Pig cells for PDNot much new:• Many transplant studies (well developed assessment protocols)

– Adrenal– Foetal

• Previous Growth factor studies– GDNF

• Patients already accept burr holes and brain probes for DBS

• Sham surgery for PD established• Pig cells used before in PD• LCT encapsulated cells well tolerated in diabetes

Deep Brain Stimulation

Auckland Phase I safety Study with efficacy observations

Patients screened and selected for DBS

Offered recruitment to transplant study (n=4)

Unilateral putaminal transplant NT encapsulated cells

Observe 6 months

Excellent response Partial response No response

Keep observing Contralateral transplant DBS

Clinical assessmentVancouver PET

Clinical assessmentVancouver PET