Parkinson s Disease Treatment and Research: Today and Beyond

Transcription

1 Parkinson s Disease Treatment and Research: Today and Beyond Young Onset PD Symposium Portland, OR March 5, 2016 Matthew Brodsky, MD Associate Professor of Neurology Parkinson Center of Oregon Oregon Health & Science University

2 PD: What is it? A neurodegenerative syndrome Classically defined by the motor symptoms Rest tremor, slowed movement, muscle rigidity Nonmotor symptoms often predate motor symptoms Loss of sense of smell, constipation, changes in mood

3 PD: What is it? Dopamine depletion defines much of it This and other degenerative changes in the nervous system cause both motor and nonmotor symptoms Onset Diagnosis Dopaminergic neuron loss Nonmotor % Remaining Dopaminergic Neurons Sleep Olfactory* Mood Autonomic system Motor Presymptomatic phase Early nonmotor symptoms Time (years) Specific symptoms

4 Changes in the brain lead to an evolving picture of PD Braak H et al. Cell Tissue Res. 2004;318: Tolosa E et al. Neurology. 2009;72(suppl 2):S12-S20. Some scientists theorize that PD-related nerve cell damage begins in the lower brainstem and progresses to other parts of the brain Therefore, according to this theory, some nonmotor symptoms (like constipation and sleep problems) may appear before the motor symptoms that commonly lead to diagnosis Adaptation of figure reprinted with kind permission from Springer Science+Business Media: Cell Tissue Res, Stages in the development of Parkinson's disease-related pathology, 318, 2004, page 122, by Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K, Figure 1. Copyright 2004 Springer Berlin Heidelberg. 4

5 PD: Who has it? Affects ~5-6 million individuals worldwide ~1 million in the U.S. ~60,000 new cases each year diagnosed in U.S.

6 PD: What is it? -part of the challenge to finding a cure- The causes are varied likely complex interaction of genetic + environment Combination of symptoms and signs vary amongst affected individuals Progression rates vary Because of this, Syndrome is more appropriate than Disease Individual responses to different therapies also vary

7 PD: Recent Advances in Symptomatic Treatment Medical Surgical

8 PD: Recent Advances in Symptomatic Treatment Novel deliveries of dopaminergic therapies

9 PD: Recent Advances in Dopaminergic Therapies Available dopamine replacement therapies: MAO inhibitors Dopamine D2/D3 agonists Dopamine D1/D2 agonist (subcutaneous apomorphine) Levodopa (+/- COMT inhibitors) Amantadine New options: More effective long-acting levodopa (Rytary) Intrajejunal Levodopa (Duopa) In clinical trials: Sublingual Apomorphine Inhaled levodopa Novel D1 Dopamine agonist Transcutaneous levodopa Apomorphine pump (available in Europe, trial planned in US)

10 Motor Fluctuations in PD Symptoms adequately controlled ( on time ) Wearing off period Symptoms not adequately controlled ( off time ) PD Medication PD Medication PD Medication Time Typical Clinical Pattern of Wearing Off Adapted from Hauser RA. Geriatrics. 2006;61:14-20.

11 PD: Recent Advances in Dopaminergic Therapies New options: More effective long-acting levodopa (Rytary)

12 New options: PD: Recent Advances in Dopaminergic Therapies Intrajejunal Levodopa (Duopa)

13 PD: Recent Advances in Dopaminergic Therapies In clinical trials: Sublingual Apomorphine In phase III trial in the U.S.

14 PD: Recent Advances in Dopaminergic Therapies In clinical trials: Inhaled levodopa In phase III trial in the U.S.

15 In clinical trials: PD: Recent Advances in Dopaminergic Therapies Lu AE04621: A novel D1 dopamine receptor agonist More potent effect than conventional D2/D3 receptor agonists Longer acting than Levodopa Possibly less likely to induce dyskinesia Phase I trial getting underway (incl. at OHSU) Recruiting PD subjects with motor fluctuations

16 PD: Recent Advances in Symptomatic Treatment Dyskinesia treatment update: Avanir trial: Neudexta (dextromethorphan/qunidine) Phase II trial showed some promise Top-Dysk: Topiramate plus amantadine, in phase IIa trial Results end of this year BusPD: Buspirone, in phase I trial

17 PD: Surgical Advances Asleep DBS: Innovation at OHSU

18 What is Deep Brain Stimulation? An implanted pacemaker-type device for the brain, that emits a high-frequency, low voltage current in a targeted small region of the brain. This stimulation overrides abnormal rhythmic brain activity causing abnormal movements, and allows restoration of normal movement

19 DBS vs Best Medical Therapy for Advanced PD: Motor Results BMT DBS Increase ON time w/o dyskinesia Reduction OFF time Reduction ON time w/dyskinesia mupdrs improvement Stand/Walk/Sit improvement (sec) P=.05 P<.001 CSP 468 Study Group. JAMA (1):

20 DBS for PD: Making it a safer and more pleasant experience Intraoperative Imaging with Ceretom versus traditional microelectrode recording guidance OHSU outcomes trial

21 Traditional approach to DBS Frame Placement

22 Traditional approach to DBS MRI Stereotaxis

23 Traditional approach to DBS Stereotactic Planning

24 Traditional approach to DBS Microelectrode Recording

25 Traditional approach to DBS Microelectrode Recording

26 OHSU Innovations: Asleep DBS Uses intraoperative imaging to localize the target for the electrode Removes need for stereotactic frame being screwed into skull Allows the patient to be under general anesthesia for the entire procedure Reduces operative time Reduces the number of brain penetrations to find the target These two factors likely reduce the risk of complications such as a bleed or an infection May also improve outcomes such as speech impairment or other compromises in cognitive function

27 Surgical Positioning

28 Surgical Positioning

29 Surgical Positioning

30 Frameless Sterotactic Approach with Intraoperative CT

31 Frameless Sterotactic Approach with Intraoperative CT

32 Frameless Sterotactic Approach with Intraoperative CT

33 Frameless Sterotactic Approach with Intraoperative CT

34 PD: Finding a cure

35 PD: Finding a cure Neuroprotection: tailoring therapy to causality Mitochondrial enhancers Protein clearance Kinase inhibitors Neurorestoration Pre-motor detection Independent Biomarkers of pathology and progression

36 Efforts at neuroprotection Dopamine agonists; MAO inhibitors Pioglitazone Coenzyme Q10 Creatine Inosine Isradipine Alpha Synuclein Immunotherapy Exercise

37 Dopamine agonists as disease-modifying agents

38 MAO inhibitors as diseasemodifying agents: ADAGIO (Attenuation of Disease Progression with Azilect Given Once-daily) Olanow CW et al. N Engl J Med 2009;361:

39 Failed efforts at neuroprotection in PD

40 Efforts at neuroprotection CoQ10, Creatine, Pioglitazone phase III trials all failed: Why? - Subjects enrolled too late - Outcome measures not sensitive enough to change - Too heterogeneous of a population of PD subjects enrolled, and therapy not targeted to cause of PD in each subject

41 Ongoing Efforts at neuroprotection Inosine increasing levels of Uric Acid UA is a natural antioxidant Free radical scavenger Orally bioavailable Good CNS penetrance Risks include kidney stones, gout (and related arthritis)

42 Data on PD progression from PRECEPT trial (Parkinson Research Examination of CEP-1347 Trial Lowest vs Highest Quintile of Serum Urate: Progression rate of motor signs/symptoms fastest in lowest quintile, slowest in highest quintile Schwarzchild M et al Arch Neurology 2008;65(6):

43 SURE-PD: Safety of URate Elevation in Parkinson s Disease Phase II placebo controlled trial, 90 subjects, 2 year duration

44 SURE-PD III: Efficacy of URate Elevation in Parkinson s Disease SURE-PD III (Phase III) trial getting underway

45 Ongoing Efforts at neuroprotection Isradipine Ca channel blocker approved for treatment of hypertension Shown to be neuroprotective in preclinical models of parkinsonism Reduced risk of development of PD in people treated with Ca blockers vs other anti-htn agents

46 Isradipine STEADY-PD (Safety, Tolerability and Efficacy Assessment of DYnacirc in Parkinson Disease) Phase II trial showed safety at two dose levels Phase III trial fully recruited, ongoing

47 Ongoing Efforts at neuroprotection Immunotherapy as neuroprotection for PD

48 Why antibodies against alpha synuclein? Brain autopsy in PD shows Lewy bodies The chief component of the lewy body is alpha synuclein. Can we arrest PD by arresting alphasynuclein?

49 Antibody therapy for PD:

50 Prothena clinical trial: Patients with mild to moderate Parkinson s disease. Get injected with antibody vs placebo each month for 6 months. Examinations, MRI scans, etc Recruiting last patients for Phase 1 anticipating Phase 2 to follow

51 Efforts at neurorestoration Increasing neurotrophic activity in the brain

52 Gene Therapy for PD

53 Gene Therapy for PD

54 Gene Therapy for PD GDNF (neurturin) Glutamic Acid Decarboxylase (GAD) human aromatic l-amino acid decarboxylase (haadc)

55 Ceregene Neurturin Trials A neurotrophic factor Should enable viable dopamine producing neurons to survive longer Phase I open label trial 12 patients, PD > 5 years Bilateral stereotactic intraputamenal injections 6 low dose, 6 high dose Improvement in mupdrs (14 pts) and increase in ON time w/o dyskinesia (2.3 h) No clinically significant adverse events over 1 year

56 Ceregene Phase IIa Trial: Placebo-controlled and blinded 37 subjects received neurturin Putamen injections 20 subjects received placebo Primary analysis at 1 year Secondary analysis at 1.5 years Marks et al. Lancet Neurol 2010; 9:

57 Injection into SN 4-fold higher dose injected into Putamen Enrollment completed Dec centers Analysis at 6-24 months post-treatment CERE-120 Phase 2b Olanow et al. ANN NEUROL 2015;78:

58 Exercise neuroprotection and neurorestoration? Basic science evidence Clinical evidence

59 Exercise Basic Science Update: OHSU Meshul Lab Effect of 3-weeks of treadmill exercise on tyrosine hydroxylase labeled dopamine cells within the substantia nigra pars compacta following MPTP

60 Social Enrichment Basic Science Update: OHSU Meshul Lab Mice were placed 4/cage while injected with 4 mg/kg and then 8 mg/kg MPTP during weeks 1 and 2, respectively. Mice were then placed either 2 mice/cage (socially limited environment/sle) or 12 mice/cage (social enrichment/soce) and increasing doses of MPTP (16 and 32 mg/kg) administered over the next 2 weeks.

61 Effect of social enrichment on tyrosine hydroxylase immunolabeling in the substantia nigra and the striatum.

62 Experimental research has produced evidence in recent years underlying the beneficial effects that exercise can have in preventing and deceleration of the development of Parkinson disease. These beneficial effects are exerted through various mechanisms such as neuroprotection, neurotransmission, plasticity, neurogenesis, homeostasis, and neurotrophic factors. A rich vein of bench and translational research now suggest non-pharmacological approaches, such as exercise or physiotherapy, have a far greater effect on the cardinal features of PD than previously believed.

63 Exercise and brain health Promotes Neurogenesis and Synaptogenesis Enhances glucose utiliztion Promotes Angiogenesis Reduces inflammation Suppresses oxidative stress Stabilizes calcium homeostasis Promotes release of endogenous neurotrophins such as brain derived neurotrophin (BDNF), glia derived neurtrophin (GDNF) and nerve growth factor (NGF) Enhances cognitive ability, learning and memory Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 2002;25: Dishman RK, Berthoud HR, Booth FW, CottmanCW, Edgerton VR, FleshnerMR et al. Neurobiology of exercise. Obesity 2006;14: Colcombe S, Kramer AF. Fitness effects on the cognitive function of older adults: A meta-analytic study. Psychological Science. 2003;14(2):

64 HOME INDIVIDUAL CLASS Compared success of exercise when administered by (1) home exercise program, (2) individualized physical therapy, or (3) a group class 58 people with PD were randomized into (1) home exercise program, (2) individual physical therapy, or (3) group class intervention, based on the Agility Boot Camp exercise program for PD, 3 times per week for 4 weeks. The primary outcome measure was the 7-item Physical Performance Test. Results: Only the individual group significantly improved in the Physical Performance Test. The individual exercise showed the most improvements in functional and balance measures, whereas the group class showed the most improvements in gait. The home exercise program improved the least across all outcomes.

65 Exercise-Induced Neural Plasticity! Right PPN - SMA Fling et al., In prep FoG+ N = 11 Baseline FoG+ N = 11 Post-Exercise HC N = 14 Baseline Z-score

66 Exercise + Social Enrichment: A winning combination, and side-effect free!

67 Premotor Biomarkers

68 Finding a Cure for PD The Other Part of the Challenge: Premotor Detection Clinical motor signs of PD present when ~70% of dopamine producing cells in the midbrain have already lost normal function Onset Diagnosis Dopaminergic neuron loss Nonmotor % Remaining Dopaminergic Neurons Sleep Olfactory* Mood Autonomic system Motor Presymptomatic phase Early nonmotor symptoms Time (years) Specific symptoms Fearnley JM, Lees AJ. Ageing and Parkinson s disease: substantia nigra regional selectivity. Brain 1991; 114:

69 Finding a Cure for PD The Other Part of the Challenge: Premotor Detection Effective neuroprotective and neurorestorative therapies of the future may only be effective if started before motor symptoms begin Testing possible neuroprotective interventions earlier than we are currently able to, in order to prevent onset of PD A need to identify who is at risk, and develop more accurate biomarkers of diagnosis and progression Fearnley JM, Lees AJ. Ageing and Parkinson s disease: substantia nigra regional selectivity. Brain 1991; 114:

70 Biomarker Sources for Parkinsonism

71 Current Biomarker Research: Most Promising Avenues Genetic biomarkers Blood biomarkers Glandular biomarkers Imaging biomarkers

72 Biomarkers of Premotor Detection: Genomics of Parkinsonian Syndrome Only represent ~10% of all idiopathic forms May be instructive to test other premotor markers in asymptomatic gene carriers (esp LRRK2) but may not apply to majority of idiopathic PD in global population

73

74

75 The mean (SD) duration of PD was 2.6 (1.1) years at the time of biopsy.

76

77

78 OHSU Imaging Biomarker Research Prospective case-control study 3 cohorts: Subjects with early PD (<1 year duration motor sxs) Subjects with idiopathic RBD (without PD symptoms) Age-matched controls

79 REM- Sleep Behavior Disorder as a Risk Factor for PD: A valuable at-risk cohort to follow Posthuma et al Neurology 2009;72:

80 Identifying Pre-motor PD: High Risk Cohorts Population PD incidence (cases/100,000 person-yrs) Subjects to screen to identify 100 at risk General population 40 62,500 1 st degree relatives of PD patients 1 st degree relatives of PD patients with multiple risk factors 1 st degree relatives of LRRK2 carriers , ,944 1,000 2,500 Diagnosed with RBD 4, courtesy Andrew Siderowf MD

81 60% of DA neurons in SNpc located within calbindin-rich zone: nigral matrix Calbindin is a calcium-binding protein: Ca buffer and sensor 40% DA neurons packed within calbindin-poor zones: nigrosomes 5 nigrosomes identified Nigrosome 1 is largest lens shaped with dorsal concavity and main axis parallel to rostrocaudal axis of SN 6 x 6 x 1 mm ~22,000 DA neurons

82 Depletion maximum in nigrosome 1 Nigrosome 1 Comparing mean numbers of THpositive neurons in each group of 5 PD midbrains (disease duration 7-32 years) with means for 5 control midbrains

83 Nigrosome quantification: 12 Tesla MRI Asymmetry index of nigrosomal volumes in controls (N=7; mean age 77 (±14) y) and PD (N=4; mean age 77 (±13) y) control PD control PD courtesy William Rooney PhD

84 OHSU Study: Ultra-High Field (7T) Magnetic Resonance Imaging of PD and RBD Methods: 16 subjects have thus far been recruited, 6 with idiopathic PD, 5 with idiopathic RBD, and 5 age-matched healthy controls (HCs) All subjects underwent clinical histories and exams, completed the SCOPA-AUT questionnaire of autonomic dysfunction, and the 40-item University of Pennsylvania Smell Identification Test (UPSIT). All subjects underwent 7T MRI with a specific protocol including T2* gradient echo sequences, with a voxel resolution of 0.28 x 0.28 x 0.8mm.

85 OHSU Study: Ultra-High Field (7T) Magnetic Resonance Imaging of PD and RBD Methods: Qualitative analysis of N1 signal was performed by two trained neuroradiologists blinded to subject status. Quantitative analysis of N1 signal was performed in 6 serial axial slices, the most rostral two slices containing the two most caudal slices of the red nucleus.

86 OHSU Study: Ultra-High Field (7T) Magnetic Resonance Imaging of PD and RBD Results: Qualitative analysis of a predefined N1 region of interest by two blinded neuroradiologists was able to separate out PD subjects from HCs with 100% accuracy. Intraclass correlation between the blinded readers was perfect. Quantitative analyses of N1 image signal strength in PD and RBD subjects showed significant degradation in signal in the most rostral and two most caudal slices.

87 Hope for the future

88 I ve just been diagnosed with PD What can I do now? Get well informed Find a good peer group Exercise Healthy Diet Consider participating in a research study Treat symptoms when they need treating!

89 Reasons for a Hopeful Future: Research(ers) in the field of PD NIH spends ~ $160 million on PD research each year 7175 abstracts related to Parkinson s Disease published in the past year Membership, MDS: >4000 members from 90 countries

90 International Congress on Parkinson s Disease

91 International Congress on Parkinson s Disease

92 More Reasons for a Hopeful Future: Socio-economic drive to find a cure for PD Age remains main RF for PD 65 yrs old is mean age of onset In USA, baby-boom population is just reaching mid-60 s # of individuals with PD expected to double by 2030 Annual economic impact of PD in the U.S. is ~$10.8 billion Major impact on health-care costs in next decade Chen J, American J Managed Care :S87 (4)

93 You are not alone

94 You are not alone 47 yrs old 29 yrs old 42 yrs old 57 yrs old 52 yrs old

95 You are not alone