Parkinson

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Parkinsons disease update

• Dr Jeff Kimber

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PD update

• new drugs - ? old problems
• DBS
• In the pipeline
• Drugs
• TMS
• Viral vectors

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• The old chestnut l-dopa v DA in early disease

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• Dopamine agonists
• Ergot
• Bromocriptine D2/NE/weak 5HT 3hrs
• Cabergoline D3gtD2/NE/5HT 60hrs
• Lisuride D2/NE/-5HT 12hrs
• Pergolide D3gtD2/D1/NE/5HT 15hrs
• Non ergot
• Apomorphine D3gtD2/D1 0.5hr
• Pirbedil D3gtD2 20hrs
• Pramipexole D3gtD2 10hrs
• Ropinirole D3gtD2 6hrs
• Rotigotine D3gtD2/D1 5hrs

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Main trials l-dopa v DA in early PD

• L dopa v ropinirole
• N 268 over 5 years, UPDRS reduction -4.8se 8
  v -0.8 se 10
• Dyskinesia 45 v 20, wearing off 34 v 23
• L-dopa v pramipexole
• N 301 over 2 years, UPDRS reduction -7se 8 v 3.4
  se 8
• Dyskinesia 30 v 10, wearing off 38 v 23
• Levodopa v pergolide
• N 294 over 3 years, UPDRS reduction -3se 8 v
  2.9se 10
• Dyskinesia 26 v 8, wearing off 43 v 30

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• Continuous motor stimulation and reduced risk of
  motor complications
• Mechanism not known
• Support from
• MPTP models
• Apomorphine
• Enteral L-dopa
• No studies to show continous l-dopa stimulation
  from early disease
• STRIDE PD and L-dopa SR failures
• Follow up of early treatment trials
• CALM PD (pramipexole) at 6 years and ropinirole
  at 10years when l-dopa used as adjunct continued
  to show reduced motor complications
• But 14 year (small numbers) from bromocriptine
  trial show equal complictions in long term but
  better initial treatment effect of l-dopa
• Suggest initial benefit of DA v l-dopa eventually
  diminishes

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Neuroprotection -1

• Key unmet need in PD
• Preclinical promise of many drugs unfounded in
  clinical trials
• REAL-PET study
• Ropinirole v l-dopa in early PD using PET
  scanning
• CALM-PD study
• Pramipexole v l-dopa in early PD using SPECT
• Both looked at decline in imaging uptake as
  surrogate marker of DA cell loss but neither
  included placebo arm.
• Both showed lower rates of decline for DA v
  l-dopa.
• While it remains possible that l-dopa could
  provide greater symptomatic benefit and be
  associated with faster loss of dopaminergic
  neurones, lack of clinical correlation suggests
  that imaging assessments should be interpreted
  cautiously.

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Neuroprotection -2

• Recent delayed start designs for DMT effects
• Rasigiline ADAGIO
• PROUD study with pramipexole -negative

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• Several clinical trials have attempted to assess
  the potential neuroprotective actions of
  selegiline in patients with PD
• DATATOP (Deprenyl and Tocopherol Antioxidative
  Therapy of Parkinsonism) study,
• Originally designed as a randomized,
  placebo-controlled trial of selegiline or
  tocopherol (vitamin E) or both in delaying
  clinical progression of early PD with the primary
  endpoint of time to need for levodopa.
• An early interim analysis demonstrated that
  selegiline significantly reduced the onset of
  disability and delayed the need for levodopa.
  However, subsequent analyses showed that
  selegiline had provided a small but significant
  symptomatic effect and raised the question of
  whether the results of the trial merely reflected
  this symptomatic relief rather than a
  neuroprotective benefit.
• The protocol was then modified such that all
  patients who had not reached the primary endpoint
  (requiring levodopa) discontinued study
  medication (selegiline or selegiline placebo) for
  2 months and were then administered open-label
  selegiline.
• After the addition of open-label selegiline,
  patients from the original selegiline placebo
  group caught up to the selegiline group, as
  assessed by UPDRS scores.
• Thus, there was no sustained benefit observed
  for initial therapy with selegiline compared with
  placebo.
• Additionally, the findings that the initial
  advantages of selegiline were not sustained and
  mortality was not reduced.

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• The SIN-DEP-PAR (Sinemet -Deprenyl-Parlodel)
  study also attempted to examine the
  neuroprotective effects of selegiline but used a
  washout design
• In this study, patients with early PD were
  randomized to receive selegiline or placebo and
  were also treated with levodopa or bromocriptine.
  After a 2-month washout of selegiline study
  medication (selegiline or placebo) and a 1-week
  washout of levodopa and bromocriptine, patients
  treated with selegiline had significantly better
  UPDRS scores compared with placebo. This is
  consistent with a potentially neuroprotective
  effect of selegiline, but it is not clear how
  long selegiline must be discontinued to wash out
  all of its symptomatic effects. Because its
  actions maybe longer lived
• In a long-term, 7-year, double-blind study
  conducted by the Swedish Parkinson Study Group,
  patients with early PD were randomly assigned to
  treatment with selegiline or placebo, and
  levodopa was added as necessary. Results showed
  that patients treated with selegiline experienced
  significantly less clinical progression of
  disability, as assessed by UPDRS scores, and
  required significantly less levodopa.
• In summary, the results of these studies are
  consistent with a potentially neuroprotective
  effect of selegiline. However, the DATATOP and
  SIN-DEP-PAR studies are confounded by potential
  symptomatic effects of selegiline.

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• To determine whether l-dopa is toxic,
  neuroprotective, or neither in patients with PD,
  the Parkinson Study Group conducted the ELLDOPA
  trial.
• Treatment with l-dopa reduced the severity of PD
  symptoms compared with placebo, as measured by
  UPDRS scores (even after a 2-week washout), but
  was associated with a greater decline in
  123Iß-CIT compared with placebo.
• Thus, the ELLDOPA study yielded conflicting
  results with regard to a possible neurotoxic
  versus neuroprotective effect for levodopa.

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• Other potential neuroprotective therapies have
  been described.
• N-methyl-D-aspartate (NMDA) receptor antagonists
  (eg, amantadine)
• Can protect neurons from hypoxia and
  excitotoxicity induced by NMDA and glutamate in
  vitro and in vivo,and a rat model of PD.
• To date, the only NMDA receptor antagonist to
  show clinical potential as a neuroprotective
  therapy is amantadine. A retrospective study
  identified increased survival in patients who
  received amantadine versus those who did
  not.Prospective studies are needed to explore
  possible neuroprotective effects of amantadine.
• Creatine, a dietary supplement, is well tolerated
  and was shown to be nonfutile in a NET-PD
  futility study
• Further, a randomized, placebo-controlled trial
  reported that creatine treatment led to a reduced
  need for dose increase of dopaminergic therapies
  over 2 years however, there was no improvement
  in UPDRS scores or results from imaging studies
  with creatine versus placebo.
• A phase 3 efficacy trial is currently under way
  to assess whether creatine improves global
  long-term clinical outcomes, whatever the
  mechanism of action.

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Risks associated with therapy

• L-dopa
• Dyskinesia
• Motor fluctutations
• Dopamine dysregulation syndrome

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Risks associated with therapy

• Dopamine agonists
• Oedema
• Somnolence
• Impulse control disorders
• Hallucinations
• Nausea
• Fibrosis (ergotgtgtnon ergot 5HT2b agonism of
  fibroblasts)
• Anaemia (apo)

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Behavioural disorders associated with treatment

• Dopamine dysregulation syndrome
• Mostly l-dopa and apomorphine
• Punding abnormal repetitive non goal orientated
  behaviours
• Impulse control disorders reward and incentive
  based compulsive actions (usually harmful)
• Hypersexuality
• Shopping
• Eating
• Gambling
• 6-7 lifetime risk in PD 13 in DA treated PD
• Neuroimaging suggests abnormal resting state of
  mesolimbic system suggesting drug induced
  overstimulation of reward circuits

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DBS

• DBS of the subthalamic nucleus has become
  relatively common as a therapy for advanced PD
• Subthalamic nucleus target established and
  benefits against existing medical therapy shown
  since 1990s
• Patient selection crucial still mostly younger
  cognitively intact patients with with good l-dopa
  response and motor fluctuations

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PD SURG trial

• Randomised open label trial
• DBS best medical therapy v best medical therapy
  alone
• N 366 mean age 58
• Quality of life score (PDQ-39)
• DBSBMT 5 v -0.3 (plt0.001)
• UPDRS improved and less dyskinesias
• Dopaminergic drug doses 33 less in DBS group
• No difference in cognition possible decline in
  verbal fluency subset in DBS group

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• Adverse effects (early)
• Surgery
• Haemorrhage 4 (I death)
• Infections 16
• Seizures 2
• Psychosis 1
• Urinary retention 4
• PE 2
• Subsequently equal adverse events rates compared
  to medical group

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In the pipeline

• Safinamide
• Glutamate inhibitor and Na/Ca channel blockade
  and dopamine re-uptake inhibition
• Adjunctive treatment with DA trial positive
• Further phase III studies underway

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In the pipeline

• Methylphenidate
• NA and DA release enhancement
• Phase III positive of gait
• Phase IV underway

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In the pipeline

• Anti dyskinesia drugs
• Alpha adrenergic antagonists
• Idazoxan
• Fipamezole
• AMPA antagonists
• Perampanel
• Talampanel
• NMDA antagonists
• Eliprodil
• 5HT agonists
• pimavanserin

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In the pipelineputaminal gene vectors

• Recent development of viral vectors from
  adeno-associated virus (AAV), has translated gene
  therapy for Parkinson's disease (PD) from animal
  experiments into clinical trials. 
• The current gene therapy protocols used are based
  on three major strategies. 
• local production of dopamine via the introduction
  of dopamine-synthesizing enzyme genes into the
  putamen.  The aromatic L-amino acid decarboxylase
  (AADC) gene has been transferred in this manner
  in the aim of efficiently converting orally
  administered L-dopa. 
• The delivery of triple genes including tyrosine
  hydroxylase (TH), guanosine triphosphate
  cyclohydrolase I (GCH) and AADC can also be
  undertaken, and is aimed at continuously
  supplying dopamine into the putamen. 
• The second protocol involves the protection of
  nigrostriatal projections via the production of
  neurturin (GDNF), a trophic factor for
  dopaminergic neurons in the putamen. 
• The final method includes the modulation of
  neural activity along the output pathway of the
  basal ganglia by transducing the subthalamic
  nucleus with vectors expressing glutamic acid
  decarboxylase (GAD-65, GAD-67), a key enzyme
  required for the synthesis of the inhibitory
  transmitter ?-aminobutyric acid (GABA). 
• The initial results of phase 1 studies using AAV
  vectors have not only confirmed the safety of
  these vectors, but have also revealed the
  alleviation of motor symptoms associated with PD.

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18F-dopa PET images showing the effect of glial
neurotrophic factor (GDNF) infusion on dopamine
storage capacity in the brain of a patient with
Parkinson's disease. The image on the left was
taken pre-op, the image on the right is of the
same brain 24 months post-op
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Phase II study of intraputaminal neurturin

• Multicentre, double-blind, sham-surgery
  controlled trial in patients with advanced
  Parkinson's disease. Follow up to a phase one
  study (successful)
• Patients were randomly assigned (21) to either
  AAV2-neurturin (541011 vector genomes) injected
  bilaterally into the putamen or sham surgery.
• The primary endpoint was change from baseline to
  12 months in the motor subscore of the unified
  Parkinson's disease rating scale in the
  practically-defined off state.
• 58 patients
• No significant difference in the primary endpoint
  in patients treated with AAV2-neurturin compared
  with control individuals
• Serious adverse events occurred in 13 of 38
  patients treated with AAV2-neurturin and four of
  20 control individuals. Three patients in the
  AAV2-neurturin group and two in the sham surgery
  group developed tumours.

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In the pipeline TMS
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Principles of TMS. Current I(t) in the coil
generates a magnetic field B that induces an
electric field E. The lines of B go through the
coil the lines of E form closed circles. The
upper-right drawing illustrates schematically a
lateral view of the precentral gyrus in the right
hemisphere. Two pyramidal axons are shown,
together with a typical orientation of the
intracranial E. The electric field affects the
transmembrane potential, which may lead to local
membrane depolarisation and firing of the neurone
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• Safe and non invasive method of stimulating
  cortical neurones
• In animals can produce synaptic plasticity
• LTP high frequency stimulation
• LTD lower frequency stimulation or burst
• Relevance to PD?
• Disease affects processing in cortico-thalamus-cor
  tical loops
• Functional imaging shows SMA hypometabolism which
  is reversed by l-dopa
• Hence regular TMS (excitatory) may have similar
  effects
• rTMS can also increase DA release from striatum
  (PET) but bilateral so ? placebo

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• Several proof of concept studies showed
  inconsistent results
• Several studies using range of targets ( mostly
  M1 cortex handgtleg) and stimulation parameters
  some unilateral and bilateral.
• Shows can improve PD bradykinesia and gait speed
  and UPDRS score (15-50)
• Improvements up to 1 month
• Also low frequency stim to SMA may inhibit
  dyskinesia