UPDATE ON RESEARCH IN PARKINSON S DISEASE

Transcription

1 UPDATE ON RESEARCH IN PARKINSON S DISEASE Charles H. Adler, M.D., Ph.D. Professor of Neurology Mayo Clinic College of Medicine Co-Principal Investigator Arizona Parkinson s Disease Consortium

2 Arizona Study of Aging and Neurodegenerative Disorders (AZSAND) Collaboration: Mayo, BSHRI, BNI Find biomarkers to predict who will develop PD and who will develop dementia in PD Correlation studies of brain and other tissue with PD and other movement disorders (essential tremor, restless legs syndrome, PSP, etc)

3 Biomarkers (Biological Markers) for PD Disease predictor: earlier diagnosis may lead to disease-modifying treatments Disease outcome measure: monitoring disease progression Diagnostic tissue biomarker may replace autopsy for confirming/validating diagnosis for genetic/epidemiology/biomarker/treatment

4 Natural History of Parkinson s Disease Dopamine Neuron Function Prediagnostic Motor Phase Diagnosis Time Adapted from Marek and Jennings Neurol 09

5 Initiate Treatment Dopamine Neuron Function Prediagnostic Motor Phase Diagnosis Treatment Time Adapted from Marek and Jennings Neurol 09

6 Prephysiologic PD Dopamine Neuron Function Genetic predisposition LRRK2, DJ-1, parkin, PINK1, GBA, SYN triplication Prediagnostic Motor PD Diagnosis Time

7 Preclinical PD Dopamine Neuron Function Prephysiologic Phase Genetic vulnerability Preclinical Phase Imaging Tissue test Prediagnostic Motor Phase Diagnosis Time

8 Premotor PD Dopamine Neuron Function Prephysiologic Phase Genetic vulnerability Preclinical Phase Imaging Tissue Premotor Phase Hyposmia RBD Autonomic Depression/anxiety Prediagnostic Motor Phase Diagnosis Time

9 High Risk Biomarker Identification and Drug Modifying Treatment Initiation Dopamine Neuron Function Prephysiologic Phase Premotor Phase Biomarker found treatment initiated Prediagnostic Motor Phase Diagnosis Time

10 AZSAND Evaluations Annual evaluations: Movement disorder exam Cognitive test battery General neurological exam/medical evaluation Sleep, autonomic, bowel movement questionnaires Every other year: EEG/EMG testing on a subset Every 3 rd year: Smell test (UPSIT-40)

11 So, what do we do with all this information?

12

13 Positive Predictive Value for ProbPD seen at First Visit ProbPD N 97 Female 32 (33%) Age at Visit 76.8 (7.5) Age at Death 80.6 (7.0) Duration of PD Symptoms at Visit 11.0 (6.6) Duration of PD Symptoms at Death 14.8 (6.9) Neuropathologically Confirmed PD 80 (82%) 95% CI 73% to 89% Adler et al. Neurol 14

14 PPV for ProbPD Divided by Disease Duration at First Visit ProbPD ProbPD <5 y ProbPD 5 y N Female 32 (33%) 4 (27%) 28 (34%) Age at Visit 76.8 (7.5) 78.4 (6.7) 76.6 (7.7) Age at Death 80.6 (7.0) 82.4 (6.0) 80.3 (7.1) Duration of PD Symptoms at Visit 11.0 (6.6) 2.4 (1.2) 12.6 (6.0) Duration of PD Symptoms at Death 14.8 (6.9) 6.4 (3.4) 16.3 (6.3) Neuropathologically Confirmed PD 80 (82%) 8 (53%) 72 (88%) 95% CI 73% to 89% 27% to 79% 79% to 94%

15 Conclusions An early clinical diagnosis of PD (pre-treatment or within 5 yrs. of onset) is inaccurate Important for RESEARCH on early PD including treatment trials, biomarker, genetic, and epidemiological studies Does NOT change what your doctor does for you!! Even if not PD most of the subjects had a neurologic disease that would need same Rx

16 Non-Motor Symptoms in PD Predate Motor Symptoms Hyposmia or Anosmia Visual Changes Sleep Disorders Neuropsychiatric Autonomic Dysfunction Cognitive Impairment Advanced PD Sleep Disorders Cognitive Impairment Neuropsychiatric Autonomic Dysfunction Sensory Disorders Impulse Control Disorders

17 Smell Test, Sleep Questionnaire, Autonomic Questionnaire We have performed tests on >1,200 subjects Multiple papers and presentations

18

19 Sense of Smell is Reduced in PD Mckinnon et al. Int l J Neurosci 10

20 Importance of Smell Testing Patients with PD lose their sense of smell before motor signs develop Smell testing may be used to identify of group of people that do not have PD but are increased risk for developing PD

21 REM Sleep Behavior Disorder

22 REM Sleep Behavior Disorder Adler et al. Park Rel Dis 11

23 Autonomic Symptoms

24 Autonomic Symptoms Damian et al. Park Rel Dis 12

25 EEG and EMG Testing

26 TISSUE DIAGNOSIS OF PARKINSON S DISEASE

27

28 GI regions assessed for phosphorylated a-synuclein staining Beach et al. Acta Neuropathol 10

29 Submandibular Gland

30 Background Lewy-type phosphorylated a-synuclein (LTS) staining is found in submandibular glands of autopsied PD cases 1,2 28/28 PD post-mortem whole submandibular glands were found to have LTS, none found in control, PSP, incidental Lewy Body cases 3 17/19 needle core biopsies of thawed PD postmortem submandibular gland had LTS 3 1 Beach et al. Acta Neuropathol 10; 2 Del Tredici et al. Acta Neuropathol 10; 3 Beach et al. J Neuropathol Exp Neurol 13

31 Two SMG Needle Core Biopsy Studies 1 st study: 15 PD > 5 year disease duration, responsive to dopaminergic medications 2 nd study: 25 PD < 5 yrs disease duration and 10 controls. All PD DaTscan positive Outpatient needle biopsy of the submandibular gland using local anesthetic and palpation to identify gland 3-6 needle cores Adler et al. Neurology 14; Adler et al. Mov Disorders 16

32 Demographics PD > 5 yrs N=15 PD < 5 yrs N=25 Control N=10 Age at biopsy, yrs Disease duration, yrs Mean = 11.8 (6-17) Mean = 2.6 ( ) Male 6 (40%) 16 (64%) 3 (30%) N/A UPDRS motor score, mean Motor fluctuations 13 0 Adler et al. Neurology 14; Adler et al. Mov Disorders 16

33 Results PD > 5 yrs N=15 PD < 5 yrs N=25 Control N=10 Insufficient Tissue LTS positive 9/12 (75%) 14/19 (74%) 2/9 (22%) Side effects 5/15 (33%) Mainly swelling or bruising 27/35 (77%) 22-swelling, 5- bruising 3- sore throat Adler et al. Neurology 14; Adler et al. Mov Disorders 16

34 SMG biopsy in RBD and PD 21 irbd, 24 PD, 26 controls Ultrasound guidance of 45 cases and 7 controls- still < 50% had glandular tissue 8/9 (89%) RBD and 8/12 (67%) PD positive No controls were positive SE: 11/52 pain, 9/52 subcutaneous hematoma Vilas et al. Lancet Neurol 16

35 Conclusions- SMG Biopsy Submandibular gland biopsies may be useful as a diagnostic test for LTS in living PD patients with early and advanced disease The lack of 100% positivity may be 2 o to insufficient tissue acquisition with a needle biopsy, as found in our autopsy study inaccuracy of a clinical diagnosis of PD Biopsies are safe and well tolerated

36 Value of Submandibular Gland Biopsy Given inaccuracy of clinical dx, especially early, PD tissue bx would confirm dx Improve clinical trial entry, higher observed effect size, reduce number of patients needed Serve as gold standard, short of autopsy, for validation of other candidate biomarkers

37 Current Studies

38 S4 Systemic Synuclein Sampling Study Biopsies of SMG, skin, colon Spinal tap, blood, saliva One time for each of these Determine what biopsy or tissue would be best to make the diagnosis of PD and/or follow the progress of PD MJFF funded, multi-site Amy Duffy (Research Coordinator) ;

39 Weight Loss in PD Examine factors that may lead to weight loss Mainly interested in possible bacteria in the small intestine Must have had at least a 10% weight loss since developed PD One time visit for a breath test Amy Duffy (Research Coordinator) ; duffy.amy@mayo.edu

40 JZP-110 for Daytime Sleepiness Crossover study All patients will receive the experimental drug and the placebo Details are to come Amy Duffy (Research Coordinator) ;

41 Sanofi ACT for Early PD Must be a carrier of a GBA mutation GZ/SAR vs placebo given for 1 year then a 2 year follow-up study where all will get the study drug Study should be starting soon Galasky.Irene@mayo.edu

42 Other Trials in the Valley SURE-PD3 at BNI Oral inosine to slow PD. PD < 3 yrs on no dopamine meds PF for early and advanced at BNI Freezing and the 6 minute walk test at A.T.Still Univ

43 What Can You Do? Volunteers from Maricopa County, AZ are leading the way to finding these answers!!! Call Amy Duffy at Mayo Clinic Call Kathy Jo Davis at BSHRI

44 National Brain and Tissue Resource for Parkinson s Disease and Related Disorders Funded by NINDS, Michael J. Fox Foundation, Arizona Biomedical Research Commission, International Essential Tremor Foundation BANNER SUN HEALTH RESEARCH INSTITUE MAYO CLINIC ARIZONA Tom Beach, MD, PhD Charles Adler, MD, PhD David Shprecher, DO Ed Zamrini, MD Erika Driver-Dunckley, MD John Caviness, MD Kathy Jo Davis Lucia Sue BARROW NEUROLOGIC Christi Belden, PhD Geidy Serrano, PhD Marwan Sabbagh, MD Holly Shill, MD Bruce Peterson Shyamal Mehta, MD, PhD Joe Hentz, MS