8 th Annual UH Parkinson s Boot Camp What s New in Parkinson s Disease

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1 8 th Annual UH Parkinson s Boot Camp What s New in Parkinson s Disease Benjamin L. Walter M.D. Penni and Stephen Weinberg Master Clinician in Brain Health Director, Parkinson s and Movement Disorders Center Medical Director, Deep Brain Stimulation Program Associate Professor of Neurology

2 8th Annual Parkinson s Boot Camp Take Control of PD! September 10th, 2016

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6 Lewy bodies form in the brain

7 New findings in stem-cell transplant Transplanted tissue can also develop Lewy bodies (Hallmark of PD). 1. Li JY, Englund E, Holton JL, et al: Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nat Med 14: , Kordower JH, Chu Y, Hauser RA, et al: Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nat Med 14: , 2008

8 α-synuclein spreads in the Brain Braak H, Del Tredici K, Bratzke H, et al: Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages). J Neurol 249 Suppl 3:III/1-5, 2002

9 α-synuclein also spreads in the body 1. Beach TG, Adler CH, Lue L, et al. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta neuropathologica. Jun 2009;117(6): Beach TG, Adler CH, Sue LI, et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta neuropathologica. Jun 2010;119(6):

10 Loss of >70% of dopamine cells leads to symptoms of Parkinson s disease Striatum X Used with permission of Elsevier. All rights reserved. Dopamine cells in Substantia Nigra

11 Alpha-Synuclein Vaccine AFFITOPE PD01 Vaccine Made by AFFiRiS Following similar approaches being looked at for Alzheimer s Disease Also Evidence that alpha-synuclein induces spread of Lewy Bodies Some rare forms of PD are caused by extra gene copy (SNCA) for making alpha-synucein Positive results with vaccinating mice with alpha-synuclein 11

12 Alpha-Synuclein Vaccine AFFITOPE PD01 Phase I study: 32 subjects with early PD. 12 Low dose 12 High dose 8 Controls Not Powered to look for benefit Treatment groups did not deteriorate more than controls Booster Study to give additional booster vaccination Determined to be safe in 28 participants tested 14 % didn t respond with antibodies 42% of responders didn t have to increase meds during trial (average 3 years) 12

13 Cancer Drug for PD? - Nilotinib Tyrosine kinase inhibitor FDA approved for adult CML Dose daily Premise based on: Autophagy is impaired in PD TK inhibitors induce autophagy Lab evidence that drug promotes degradation of alpha-syn via autophagy & also increases dopamine levels 12 advanced PDD and DLB subjects randomized to one of 2 very low doses (150 mg and 300 mg) (~25% of dose used for CML) Not a controlled study Possible clinical benefit reported (reduced UPDRSIII 3.4 points, and 3. points in 150 and 300 mg doses), MMSE increased 3.85 & 3.5 pts CSF HVA levels were significantly increased at 24 weeks, Abl phosphorylation was reduced 30% in CSF SAEs ( 1 MI, 1 admission for UTI, 1 admission for pneumonia) Placebo-controlled trial planned 13

14 Awakenings

15 Therapeutic Window of Levodopa Obeso et al. Neurology 2000;55(11 Suppl 4):S13-20.

16 New Innovations in Drug Therapies for PD 16

17 Rytary ER Carbidopa/Levodopa extended release capsules Approved January 2015 Manufactured by IMPAX Maintains blood levels for 4-6 hours 2X reduction of off time as compared to IR Sinemet 2X increase in on time without troublesome dyskinesia

18 Apomorphine Pump Britannia / US World Meds Currently in phase III clinical Trial Continuous subcutaneous pump infusion of dopamine agonist 18

19 Xadago (Safinamide) To be Manufactured/Distributed by Newron/Zambon pharmaceuticals NDA resubmitted to FDA December 29, 2014 A monoamine oxidase B (MAO-B) inhibitor, reducing the degradation of dopamine, glutamate release inhibitor and inhibits dopamine reuptake. Additionally, safinamide blocks sodium and calcium channels. Various in vitro models showed that safinamide has neuroprotective and neurorescuing effects Significantly reduced dyskinesia in clinical trials

20 Extended Release Amantadine (ADS-5102) 23 % Reduction in Dyskinesia as compared to placebo 20

21 Pimavanserin (Nuplazid) First FDA Approved treatment for hallucinations and psychosis in Parkinson s disease Once-a-day medication Very selectively targets serotonin 5-HT 2A receptors

22 Northera (Droxidopa) Converts into Norepinephrine and Epinephrine Approved for the treatment of orthostatic hypotension (blood pressure drops when standing) 22

23 A Broken Circuit puts the break on movement in Parkinson s Disease Basal Ganglia Circuit Subthalamic Nucleus (STN) Used with permission of Elsevier. All rights reserved.

24 Deep Brain Stimulation 24

25 Neuroimaging and neuromodulation

26 Relationship between contact distance and stimulation threshsold

27 fmri showing brain areas for smaller movements in PD A comparison of the individual group data for the PD and control groups during kinesthetic illusion 27

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29 Focused Ultrasound Ultrasound is used under MRI guidance to create a thermal lesion in the brain

30 Treatment of Parkinson s Disease: The Role of Exercise and Wellness 30

31 Exercise may enhance Motor & Cognitive Circuits in PD Petzinger G.M., Holschneider D.P., Fisher B.E., McEwen S., Kintz N., Halliday M., Toy W., Walsh J.W., Beeler J. and Jakowec M.W. (2015) The Effects of Exercise on Dopamine Neurotransmission in Parkinson's Disease: Targeting Neuroplasticity to Modulate Basal Ganglia Circuitry. Brain Plast 1:

32 Treadmill exercise elevates striatal dopamine D2 receptor binding potential in patients with early Parkinson's disease. Fisher, Beth; Li, Quanzheng; Nacca, Angelo; Salem, George; Song, Jooeun; Yip, Jeanine; Hui, Jennifer; Jakowec, Michael; Petzinger, Giselle Fig. 2. PET imaging using the dopamine D2/3 specific ligand [18F]fallypride. (a) Representative coregistration of MRI and PET imaging. PET imaging data were derived from subtraction of the postexercise from the preexercise [18F]fallypride binding potential (BP). Increased BP is indicated by red color within the basal ganglia. (b) BP for [18F]fallypride in the putamen for all participants including S1 and S2 [Parkinson's disease (PD) plus exercise], S3 and S4 (PD no exercise), and S5 (control plus exercise). Pre-exercise (black bar) and postexercise (gray bar) BPs were compared. The top graph shows a pre-exercise average BP for S1 in the putamen of 5.58+/-0.43 and postexercise BP of 11.0+/ For S2, the pre-exercise average BP in the putamen was 7.14+/ and the postexercise BP was 12.9+/ The middle graph shows a baseline BP of 5.94+/-0.18 for S3 (no exercise) in the putamen and an unchanged BP of 5.74+/-0.53 after 8 weeks. S4 had a baseline BP of 8.64+/-2.31, and after 8 weeks the BP was 6.64+/ The bottom graph shows a BP of /-1.31 at baseline for S5 (control) and a postexercise BP of19.92+/ Graphs show mean+/-sem. S1 and S2, exercise; S3 and S4, no exercise; S5, control. Ex, exercise; No Ex, no exercise. Neuroreport. 24(10): , July 10, DOI: /WNR.0b013e328361dc Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc.

33 Pilot Study of EXCEED (Enhanced EXerCisE ThErapy for Patients with PD) DAY 1 (ARMS) Seated Chest Press Wrap the middle of the tubing behind you at shoulder level. Grasp the handles at shoulderlevel and push forward, extending your elbows. Hold and slowly return. Keep your head and trunk upright. Seated Upright Row Place tubing under your feet. Grasp the handles with an overhand grip and pull upwards until your upper arms are parallel with the floor. Seated Bicep Curls Place tubing under your feet. Grasp the handles with an underhand grip and pull upwards until your fist touches your shoulder. Seated Tricep Extension Place tubing under your feet. Grasp the handle behind your head, reach your hand towards the sky by extending your elbow. DAY 1- EXCEED DAY 3 (ARM/LEGS) Seated Upright Row Place tubing under your feet. Grasp the handles with an overhand grip and pull upwards until your upper arms are parallel with the floor. Seated Leg Extensions Begin by looping the center of the band around the ankle of your exercising leg. Bring the ends of the band underneath the foot of the opposite leg. Slowly extend your leg against the band, pulling forwards. Seated Chest Press Wrap the middle of the tubing behind you at shoulder level. Grasp the handles at shoulderlevel and push forward, extending your elbows. Hold and slowly return. Keep your head and trunk upright. Standing Gluteal Hold onto the back of your chair with one hand. Wrap the band around your foot and hold onto the handles with the opposite hand. Kick your leg backward, keeping your knee straight. DAY 3- EXCEED

34 Pilot Study of EXCEED (Enhanced EXerCisE ThErapy for Patients with PD)

35 The problem with reimbursement for in neurodegeneration Mismatch between therapy and disease Reimbursement for short 2-6 week blocks ideal for orthopedic or sports injury Neurodegeneration is progressive 2013 Jimmeo vs. Sebelius: Class action suit in Vermont against HHS won the right to have therapy to maintain or reduce loss of function

36 Parkfit Study Study in Netherlands showing efficacy of nationwide comprehensive exercise program for Parkinson s Disease

37 Parkinson s Wellness Program Currently 1 site, 9 classes a week, 1 monthly education program 70 participants, representing 23 cities in NE Ohio Vision to develop 2+ more sites to serve community Integrating with clinical program and Rehab therapies (Physical Therapy, Speech and Occupational Therapy

38 Innovating Healthcare: Changing the paradigm 38

39 Inpatient Medication Errors 17.4% of all PD medication events Affecting 89.9% of PD patients ~50% of these were missing doses 21.3% received contraindicated medications Hou JG, Wu LJ, Moore S, et al. Assessment of appropriate medication administration for hospitalized patients with Parkinson's disease. Parkinsonism Relat Disord. May 2012;18(4):

40 Levodopa Compounds Carbidopa/levodopa (Sinemet) Controlled Release Carbidopa/levodopa (Sinemet CR) Carbidopa/levodopa/ entacapone (Stalevo) Dopamine Agonists Pramipexole (Mirapex) Ropinerole (Requip) Pergolide (Permax) Apomorpine (Apokyn) Rotigitine (Neupro) Patch Anticholinergics Trihexaphenedyl (Artane) Benztropine (Cogentin) Parsitan Kemadrin NMDA Antagonists Amantadine (Symmetrel) MAOB Inhibitors Selegeline (Eldepryl) Zelopar (Eldepryl Zydis) Rasagaline (Azilect) COMT Inhibitors Entacapone (Comtan) Tolcapone (Tasmar)

41 Example PD Medication Schedule 8AM 12PM 4PM 8PM HS Sinemet 25/100 IR Sinemet 25/100 CR 1 Comtan 200 mg Azilect 0.5 mg 1 Potential problems when hospitalized 1. Sinemet 25/100 Q4 but.. How many doses? 2. Sinemet 25/100 4 times a day but not QID 3. Comtan not TID---should be paired with particular Levodopa dose

42 Avoiding Medication Problems with PD Patients List of Medications to avoid for Parkinson s Patients 1. Neuroleptics except Seroquel or Clozaril 2. Phenergan 3. Reglan

43 Issues for Cognitive Fragile PD Patients Caution with: Anticholinergics Narcotics Benzodiazepines

44 Sudden Parkinson s Exacerbation possible causes PD Medications are wrong Inappropriate medications given for other problem Infection Especially UTI or Pneumonia Metabolic Problem Other Problem other than PD

45 University Hospitals Case Medical Center PD Nurse Inpatient Liaison Catch all PD patients as they are admitted Communicate with MDS, and reconcile MDS plan, Patients medication list, inpatient PD medications Educate and prevent against contraindicated medications Improve care and satisfaction, decrease LOS and unnecessary complications

46 Evolving from wellness to integrated comprehensive care Development of Exercise & Wellness Programs for PD Improving Care at the population level at all Points of Care Comprehensive Care Integrating Clinical Care, Wellness, Inpatient and Outpatient Programs Traditional Parkinson s Care 46

47 Parkinson s & Movement Disorders Center

48 Parkinson s & Movement Disorders Center Translational Research Neuromodulation Program Comprehensive Care

49 Very special thanks to all of those who have supported our efforts Our Sponsors/Vendors Parkinson s Disease Foundation- Northeast Region National Parkinson s Foundation Spitz Foundation Penni & Steven Weinberg Sheila & Sandy Fox Alan Woll Kim Ganley and Courageous Steps for Parkinson s Disease Dick Nicely William O. and Gertrude Frohring Foundation All of you who come to Parkinson s Boot Camp every year to give PD the Boot 49

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