Transcript No Slide Title

Parkinsonism
• Tremor
– resting
• Slowness
– bradykinesia
• Stiffness
– rigidity
• Loss of balance
Olanow. Neurology 2009
Dopa
Dopa
Dopamine
Cause
Dopamine deficit
Tremor, rigidity, bradykinesia, postural impairment
Dopamine replacement
Golbe 1990
Parkinson’s – divergent causes,
convergent mechanisms (Science
21 May 04)
Braak 2005
Cause
Dopamine deficit
Tremor, rigidity, bradykinesia, postural impairment
Dopamine replacement
Cause
Cause
Cause
Cause
Cause
Mechanism
Dopamine deficit
Parkinsonism
Cortical Lewy bodies
Dementia
Other neurotransmitters
Sleep
disturbance
Pain
Depression
Falls
Levodopa complications
Autonomic
dysfunction
Dopaminergic
Parkinsonism
Motor fluctuations
and dyskinesia
5 years
10 years
10 years
5 years
anosmia
RBD
anxiety
depression
Non-Dopaminergic
pain
Falls
autonomic failure
dementia
Dopaminergic
Motor fluctuations
and dyskinesia
Parkinsonism
Diagnosis and early treatment
Motor complications
10 years
5 years
anosmia
RBD
anxiety
depression
Non-Dopaminergic
General neurodegeneration
pain
Falls
autonomic failure
dementia
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
“…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
Antonio Carnicero 1779
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
Self-reported health status deteriorated significantly over
18 months in untreated patients but not treated patients
*
untreated
*
treated
n = 61
n = 114
n = 127
n = 74
modified from Grosset, D et al. J Neurol Neurosurg Psychiatry 2007;78:465-469
The “wait and watch” option
No significant deterioration over 2 years in health status
score in either group even though motor status significantly
worsened in the untreated group.
n = 16
UPDRS (Motor) Score
Change in Median UPDRS Motor Score
30
20
baseline
10
year 2
0
treated
untreated
n = 26
“……we believe a ‘‘wait and
watch’’ strategy for the
treatment of newly diagnosed PD
remains a credible approach……..”
modified from Asimakopoulos, P et al. J Neurol Neurosurg Psychiatry 2008;79:716-718
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?
60
% dyskinesia
50
40
<70
>70
30
20
10
0
Levodopa Ropinirole
Adapted from Rascol 054 Study
Initial treatment
• Young patients: dyskinesia
– Dopamine agonists (ropinirole 3 mg tds)
• Old patients: dementia
– Levodopa (100 mg tds)
Ropinirole
Adverse 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
entacapone
tolcapo
carbidopa
selegiline
rasagiline
modified from Olanow et al. Neurology 2001;56(11 Suppl 5) S1-88)
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
Blood dopa fraction
1.2
1
0.8
Fraction
Tol
0.6
0.4
0.2
0
0
50
100
150
Time (minutes)
200
250
300
1.2
1
Fraction
0.8
0.6
0.4
0.2
0
0
50
100
150
Time (minutes)
200
250
300
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
Plasma Levodopa Concentrations
Patient 03 Duodopa
plasma levodopa
Patient 03 Sinemet
plasma levodopa
8
8
Baseline
Test day 4
Test day 5
Test day 6
g/ml
6
5
4
7
6
g/ml
7
5
4
3
3
2
2
1
1
0
D
8
9
10
M
11
D
12
13
Time
0
DM
14
15
16
17
M
8
9
10
11
M
12
13
Time
14
15
16
Test day 1
Test day 2
Test day 3
17
Figure 3 Effect of intraintestinal levodopa infusion on motor complications in
Parkinson's disease
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
DIREQT
6 Months Follow Up: PDQ-39
PDQ-39
(N=12)
40
35
*
30
25
20
15
10
5
0
Conventional Therapy
Baseline
Duodopa Baseline
*p<0.01
Duodopa 6 months
Deep Brain Stimulation
3387S-4X Electrodes 1.5mm apart; over 10.5mm
3389S-4X Electrodes 0.5mm apart; over 7.5mm
Body 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/24000
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
3.98
20869
TGFbeta 1
NT-3
(HIGHEST)
(LOWEST)
High Expression Genes
Detoxification Proteins
Anti-Oxidant Enzymes
Proteinase Inhibitors
TRANSTHYRETIN
SOD-1
CYSTATIN B & C
SOD-2 (Mn type)
Neuroserpin
(confirmed - proteonomics)
Lipocalin-PGDS
(confirmed - proteonomics)
Retinol Binding Proteins
Glutathione peroxidase
(intracellular)
Glutathione peroxidase 4
Catalase
Glutathione reductase
Skinner 2009
Rat brain at 6 Months
(calcein)
Skinner 2009
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.
% Change of turns
120
CP cell capsules
Empty capsules
Sham
100
*
80
***
60
***
***
***
***
40
20
0
0
2
4
6
8 10 12 14 16 18 20 22 24
Weeks post implant
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 PD
Not 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)
Clinical assessment
Vancouver PET
Unilateral putaminal transplant NT encapsulated cells
Observe 6 months
Clinical assessment
Vancouver PET
Excellent response
Keep observing
Partial response
Contralateral transplant
No response
DBS