05-Nov-15. Impact of Parkinson s Disease in Australia. The Nature of Parkinson s disease 21st Century

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1 Peter Silburn Professor Clinical Neuroscience University of Queensland Queensland Brain Institute Neurosciences Queensland Impact of 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 Dopaminergic circuitry The Nature of Parkinson s disease 21st Century Prion Like Alpha Synuclein DA neuron loss and Lewy bodies P Many different neurones and Basal Ganglia supporting pathways cells Many different neurotransmitters PD: Threshold of degeneration for symptom emergence Agid

2 THERE ARE MANY MANY MORE DEFICITS THAN JUST DOPAMINE Not a single phenotype NOT just a Movement Disorder Motor features Non Motor Features Bradykinesia Rigidity Tremor Postural instability Levodopa responsive 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 A Drug Regime 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 Levodopa Other MAO-B inhibitor (selegiline and rasagiline ) Anticholinergics ( artane ) amantadine Add either rasagiline or amantadine Add an anticholinergic if non responding tremor At bedtime Either madopar HBS or Sinemet CR Consider starting first a non ergot derived agonist if young Sellbach A Silburn PA (2013 ) Australian Prescriber Long-term challenges: Changes in levodopa response We need to keep the next half as smooth as the first Obeso et al

3 A Levodopa Drug Regime 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 Levodopa Preparations Sinemet / Kinson- 100mg Sinemet / Levohexal 250mg Sinemet CR-200mg Madopar or200mg Madopar HBS-100mg Madopar rapid-50 or 100 mg Stalevo mg tabs ( essentially sinemet plus entacapone in one tab) 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 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 The Lancet, Volume 384, Issue 9942, 2014, ) External Pump Therapies Duodopa Apomorphine Deep Brain Stimulation in 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 3

4 Deep Brain Stimulation in Right Opinion Right person Right operation Right time Right follow up 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 Patients for DBS ADEQUATE TRIAL MEDICATIONS Medications not maintaining Quality of Life Braak staging based on synuclein pathology Core opinions from Neurologist-Neurosurgeon Psychiatrist Many non-dopaminergic nuclei are affected early and throughout the course of Parkinson s disease. In an experienced and sufficiently active DBS centre with dedicated team [Braak et al. (2003) Staging of brain pathology related to sporadic Parkinson s disease. Neurobiol Aging 24: ] Best Medical Practice in Fluctuators Exploration and Discovery St Andrews and University of Queensland Brain Connectivity HELPING HUMANS 4

5 SPOKESPERSON Thank you for your attention Long-term evolution of motor symptoms with STN-DBS Med Off UPDRS III time (years) 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 UPDRS III Med On 60 Krack 2003 Schüpbach 2005 Fasano Zibetti 2011 Rizzone Therapeutic Stimulation width response Residual motor symptoms worst OFF OFF+Stim best ON time (years) Complete references for this slide can be found on Slide 23 at the end of the presentation. 27 Parkinson s disease: Pathology Normal PD PET scan showing striatal fluorodopa uptake Gross pathology of the mid brain Substantia nigra 5

6 Long-term challenges: Changes in levodopa response Peter Silburn Professor Clinical Neuroscience University of Queensland Queensland Brain Institute Neurosciences Queensland Obeso et al Deep Brain Stimulation We need to keep the next half as smooth as the first Terry Coyne Peter Silburn Border STN recording 10sec Sagittal Section through the Thalamus 80ms 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. STN 10sec 80ms Border/SN 10sec 80ms (Schapira, et al The Lancet, Volume 384, Issue 9942, 2014, ) 6

7 208 xenobiotic metabolism transcripts out of 22,189 on chip (102 not expressed in human neurospheres) 05-Nov-15 Study -2 Expression differences in expanded neurospheres from PD patients (n=19) compared to control subjects (n=14) Differential expression of the metabolism of xenobiotics by CYP450 pathway between PD and control cell lines. (Illumina-based BeadChips arrays were used to conduct gene-expression studies in these cell lines). Unsupervised clustering 18 transcripts up-regulated in PD Unbiased pathway examination of differentially expressed transcripts using Database for Annotation, Visualization and Integrated Discovery (DAVID) Bioinformatics Resources. 72 unchanged 106 xenobiotic metabolism transcripts are expressed in neurospheres NCASCR, unpublished data We have uncovered some interesting differentially expressed pathways 16 transcripts down-regulated in PD EASE p-value for pathway p< Proteins altered in Parkinson s disease Functional alterations in PD 2D gel electrophoresis and mass spectrometry proteins down in PD (left columns) Proteins up in PD (right column) Study - 6 Olfactory derived cultures express many PARK genes PARK gene expression Genes altered in Parkinson s disease 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) Log(2) expression (Illumina) cases controls PD PARK7 UCHL1 PINK1 HTRA2 GBA ATP13A2 GIGYF2 NR4A2 Control 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. A Cook, G Sutherland, G Mellick, P Silburn, S Wood, N Matigian 7

8 Your Brain As We Think We Know It 1.4 kilograms 2% body weight Surface area 2,500 cm squared Long-term challenges: Changes in levodopa response Professor Peter Silburn UQ Centre for Clinical Research 100 billion neurones 1000 billion glia Make 250,000 neurones a minute during development Lose 85,000 neurones a day in adulthood :31 mill/ yr 8 million kilometers of tracts Obeso et al A Levodopa Drug Regime The dose Duodopa Belly 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 Levodopa Preparations Sinemet / Kinson- 100mg Sinemet / Levohexa-l250mg Sinemet CR-200mg Madopar or200mg Madopar HBS-100mg Madopar rapid-50 or 100 mg Stalevo mg tabs ( essentially sinemet plus entacapone in one tab) The Nature of Parkinson s disease 21st Century Prion Like Alpha Synuclein Parkinson s disease: What the deep brain looks like Normal PD PET scan showing striatal fluorodopa uptake DA neuron loss and Lewy bodies P Dopaminergic circuitry Many different neurones and Basal Ganglia supporting pathways cells Many neurotransmitters Substantia nigra Gross pathology of the mid brain 8

9 Braak staging based on synuclein pathology Many non-dopaminergic nuclei are affected early and throughout the course of Parkinson s disease. [Braak et al. (2003) Staging of brain pathology related to sporadic Parkinson s disease. Neurobiol Aging 24: ] We need to keep the next half as smooth as the first 9