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Parkinson's 2015 meeting 2nd July London
- 1. @predictPD Alastair Noyce Parkinson’s UK Doctoral Research Fellow, UCL Institute of Neurology Specialist Registrar in Neurology, Barts Health NHS Trust Pre-diagnostic Features & Markers of Parkinson’s Web: www.predictpd.com Blog: www.predictpd.blogspot.com
- 2. @predictPD Declarations Salary: Parkinson's UK, Barts and the London NHS Trust Grants: Parkinson's UK (F-1201, K-1006), GE Healthcare, Élan/Prothena Pharmaceuticals Honoraria: Henry Stewart Talks, Office Octopus
- 3. @predictPD NO CURE & NO DRUGS THAT CHANGE THE UNDERLYING DISEASE COURSE
- 10. @predictPD Measuring Disease Delayed Presentation Marked Heterogeneity Sub-types Wrong diagnosis
- 11. @predictPD Measuring Disease Delayed Presentation Marked Heterogeneity Sub-types Wrong diagnosis
- 12. @predictPD Measuring Disease Delayed Presentation Marked Heterogeneity Sub-types Wrong diagnosis
- 13. @predictPD Measuring Disease Delayed Presentation Marked Heterogeneity Sub-types Wrong diagnosis
- 14. @predictPD 1) Late identification 2) Diluted group • Sub-types • Wrong diagnosis 3) Poor measurement • Symptoms vs disease • Heterogenous Problems
- 15. @predictPD 1) Late identification 2) Diluted group • Sub-types • Wrong diagnosis 3) Poor measurement • Symptoms vs disease • Heterogenous Problems
- 16. @predictPD 1) Late identification 2) Diluted group • Sub-types • Wrong diagnosis 3) Poor measurement • Symptoms vs disease • Heterogenous 4) Ineffective drugs Problems
- 17. @predictPD Between 1990 and 2013: • Crude PD mortality has increased by ~140% • Age standardised PD mortality has increased ~30% (c.f. 3% for AD) Out of 240 causes of death only a few have increased to similar or greater extent than PD (and AD): • HIV • Liver Ca due to Hep C • Atrial fibrillation/flutter • Drug use • Chronic Kidney Disease • Pyoderma Between 1990 and 2010: • DALYs per 100,000 have increased 34.9% for PD (53.3% for AD) Out of 291 diseases only a few have increased in the disability they cause to similar or greater extent than PD (and AD): • HIV • Glaucoma & Macular degeneration • Trachoma • Hep C • PVD & Atrial fibrillation/flutter • Chronic Kidney Disease • Drug use • BPH
- 18. @predictPD Source: OECD Health Data April 2014 Between 1990 and 2013: Global life expectancy increased from 65.3 years to 71.5 years
- 19. @predictPD Sieber. Ann Neurol. 2014
- 20. @predictPD Pre-diagnostic markers: 1. Specific for the disease 2. Sensitive to change over time Requirements Early identification – pre-diagnostic features
- 22. @predictPD MEDLINE search using PUBMED Inclusion criteria: • Observational studies, English-language • Published between 1966 and 2011 (search date March 31st 2011) • Reported risk factors or early non-motor features • Amenable to screening in the primary care setting MeSH terms: Constipation OR Sleep Disorders OR Olfaction Disorders OR Smoking OR Color Vision OR Coffee OR Erectile Dysfunction OR Depression OR Anxiety OR Mood Disorders OR Hydroxymethylglutaryl-CoA Reductase Inhibitors OR Anti-Inflammatory Agents, Non-Steroidal OR Solvents OR Pesticides OR Body Mass Index OR Family OR Risk OR Risk Factors AND Parkinson Disease. Treatment of studies: • Meta-analysis (OR & RR combined using fixed & random effects) • Systematic review Noyce et al. Annals Neurol. 2012
- 23. @predictPD Case-control studies Case-control studies Case-control studies Case-control studies Cohort studies All Case-control studies Cohort studies All Case-control studies Cohort studies All Case-control studies Case-control studies Cohort studies All Case-control studies Case-control studies Cohort studies All Case-control studies Family history Any relative First degree relative Family history of tremor Constipation Mood disorder Pesticides Head injury Rural living Beta blockers Farming/agriculture Well water 19 26 10 1 1 2 11 2 13 36 2 38 19 18 1 19 3 24 1 25 28 4.45 (3.39 to 5.83) 3.23 (2.65 to 3.93) 2.74 (2.10 to 3.57) 2.18 (1.32 to 3.61) 2.70 (1.30 to 5.50) 2.34 (1.55 to 3.53) 1.90 (1.62 to 2.22) 1.79 (1.72 to 1.86) 1.86 (1.64 to 2.11) 1.77 (1.48 to 2.12) 1.78 (1.30 to 2.42) 1.78 (1.50 to 2.10) 1.58 (1.30 to 1.91) 1.43 (1.12 to 1.83) 1.37 (0.56 to 3.33) 1.43 (1.13 to 1.81) 1.28 (1.19 to 1.39) 1.26 (1.10 to 1.45) 1.24 (0.34 to 4.53) 1.26 (1.10 to 1.44) 1.21 (1.04 to 1.40) 0.25 0.5 1 2 4 8 Factor Number of studies OR/RR (95% CI) Decreased risk of PD Increased risk of PD Noyce et al. Annals Neurol. 2012
- 24. @predictPD Case-control studies Cohort studies All Case-control studies Cohort studies All Case-control studies Cohort studies All Case-control studies Cohort studies All Case-control studies Cohort studies All Case-control studies Cohort studies All Case-control studies Cohort studies All Case-control studies Cohort studies All Smoking Current vs. never Ever vs. never Past vs. never Coffee Hypertension NSAID's CCB's Alcohol 26 7 33 61 6 67 26 5 31 13 6 19 10 2 12 5 4 9 4 1 5 22 2 24 0.46 (0.41 to 0.50) 0.47 (0.40 to 0.56) 0.44 (0.39 to 0.50) 0.64 (0.60 to 0.69) 0.63 (0.53 to 0.76) 0.64 (0.60 to 0.69) 0.80 (0.72 to 0.89) 0.75 (0.69 to 0.81) 0.78 (0.71 to 0.85) 0.68 (0.57 to 0.82) 0.66 (0.57 to 0.77) 0.67 (0.58 to 0.76) 0.69 (0.55 to 0.87) 0.98 (0.82 to 1.17) 0.74 (0.61 to 0.90) 0.86 (0.77 to 0.96) 0.86 (0.66 to 1.12) 0.83 (0.72 to 0.95) 0.89 (0.81 to 0.98) 1.18 (0.73 to 1.92) 0.90 (0.82 to 0.99) 0.92 (0.85 to 0.99) 0.79 (0.65 to 0.95) 0.90 (0.84 to 0.96) 0.25 0.5 1 2 4 8 Factor Number of studies OR/RR (95% CI) Decreased risk of PD Increased risk of PD Noyce et al. Annals Neurol. 2012
- 25. @predictPD Case-control studies Cohort studies All Case-control studies Cohort studies All Case-control studies Case-control studies Cohort studies All Case-control studies Cohort studies All Case-control studies Cohort studies All Case-control studies Case-control studies Cohort studies All Case-control studies Case-control studies Cohort studies All Case-control studies Oral contraceptives Oophorectomy Statins HRT Diabetes Tea Cancer Acetaminophen/Paracetamol General anesthetic Aspirin Ulcers 2 1 3 4 1 5 5 7 2 9 9 4 13 5 1 6 7 1 1 2 6 4 2 6 3 0.57 (0.37 to 0.89) 1.02 (0.77 to 1.36) 0.73 (0.43 to 1.25) 0.77 (0.42 to 1.43) 0.75 (0.56 to 0.99) 0.76 (0.52 to 1.13) 0.79 (0.61 to 1.02) 0.77 (0.60 to 0.99) 1.30 (1.09 to 1.54) 0.90 (0.67 to 1.21) 0.72 (0.54 to 0.97) 1.31 (1.10 to 1.57) 0.91 (0.72 to 1.15) 1.04 (0.66 to 1.65) 0.94 (0.69 to 1.26) 1.00 (0.72 to 1.38) 1.01 (0.94 to 1.09) 1.16 (1.00 to 1.35) 0.86 (0.66 to 1.10) 1.02 (0.76 to 1.36) 1.10 (0.77 to 1.58) 1.02 (0.74 to 1.40) 1.20 (1.04 to 1.39) 1.11 (0.93 to 1.32) 1.37 (0.36 to 5.31) 0.25 0.5 1 2 4 8 Factor Number of studies OR/RR (95% CI) Decreased risk of PD Increased risk of PD Noyce et al. Annals Neurol. 2012
- 26. @predictPD Other factors with significant associations with later PD Smell loss – 1 cohort study – positive association Erectile dysfunction – 1 cohort study – positive association Excessive daytime somnolence – 1 cohort study – positive association Serum urate/gout – 4 studies negative association, 2 studies no association Cholesterol/hyperlipidaemia – 3 studies negative association, 1 positive association, 3 no association BMI – 2 studies positive association, 1 negative association, 4 no association Physical activity – 1 study negative association, 1 study no association Education – 3 studies negative association, 1 positive association, 5 no association Occupation – positive association (health, legal, construction), negative association (service, sales, transport) Noyce et al. Annals Neurol. 2012
- 27. @predictPD Schrag et al. Lancet Neurol. 2015 • The Health Improvement Network primary care database: Jan 1st 1996 – Dec 31st 2012 • First diagnosis of PD (cases = 8166) versus those without (controls = 46,755) • Codes for pre-diagnostic features identified from systematic review and updated literature review • Reported incidence of symptoms per 1000 person-years if they affected >1% of cases (excl. RBD & anosmia) • Incidence risk ratios comparing cases and controls @ 2, 5 and 10 years
- 28. @predictPD Schrag et al. Lancet Neurol. 2015 10 9 8 7 6 5 4 3 2 1 Years before index date 10 9 8 7 6 5 4 3 2 1 Years before index date
- 29. @predictPD Smell loss in PD Olfactory dysfunction - common finding (70-100%) Problems with being exact: • Definition of hyposmia – cut-off • Gender differences • Age dependence • Confounders • Subjective – most that score low, report normal smell
- 30. @predictPD Smell loss pre-PD Evidence from observational studies that hyposmia precedes motor PD: 1. First-degree relatives of patients with PD underwent smell identification testing. Hyposmic compared with normosmic using [123I] β-CIT SPECT. Only those with smell loss and abnormal SPECT got PD within 2 years – 4 subjects (Ponsen. Ann Neurol 2004) 2. Transcranial sonography (TCS) on 26 patients with idiopathic anosmia. 11 that had abnormal TCS, 10 had [123I] FP-CIT SPECT, which showed pathological appearances in 5 subjects (Sommer. Mov Disord 2004). 3. 2267 subjects in HAAS tested with B-SIT, and followed up for 8 years. 35 incident PD cases. Relative odds of 5.2 (CI 1.5, 25.6) for developing PD over 4 years if the lowest smell quartile was compared to the reference group (the highest two quartiles) (Ross. Ann Neurol 2008).
- 31. @predictPD REM Sleep Behaviour Disorder (RBD) Distinct parasomnia characterised by abnormal REM sleep electrophysiology and abnormal REM sleep behaviour (Boeve 2011) More common in males Background prevalence: • approximately 0.5% subjectively (Ohayon 1997) • PSG confirmed 0.02% (Boeve 2011) Prevalence in established PD: • 32.8%, mean PD duration 8.1yrs (Scaglione 2005) • 27%, newly diagnosed/untreated PD (PPMI data, Mahajan 2014) NB. Some patients have improvement in RBD symptoms with pramipexole and levodopa (Fantini 2003, Tan 1996)
- 32. @predictPD RBD pre-PD Observational studies demonstrate that RBD can precede onset of parkinsonism 1. 29 patients with RBD, 11 (38%) had developed parkinsonism at 4 years follow-up (Schenk. Neurology 1996). 2. 93 patients RBD - 5-year risk of developing a neurodegenerative disorder was 17.7%. The 10-year and 12-year risks were 40.6% and 52.4%, respectively (Postuma. Neurology 2009). 3. 44 patients with RBD - 20 (45%) developed neurodegenerative disorder after mean time of 11.5 years from symptom onset (Iranzo. Lancet Neurol 2006). Figure from Postuma et al. Annals Neurol 2015
- 33. @predictPD RBD +/- hyposmia Figure from Mahlknecht et al. Neurology 2015 • 34 PSG confirmed iRBD subjects • Followed for 4.9 years • After 2.4 ± 1.7 years (mean ± SD), 9 patients (26.5%) converted (6 PD and 3 DLB) • Full Sniffin' Sticks test and identification subtest had overall diagnostic accuracy of 82.4% (95% CI: 66.1%–92.0%) in predicting conversion • Similar findings from Postuma et al 2011, Annals Neurol
- 34. @predictPD RBD +/- hyposmia Figure from Mahlknecht et al. Neurology 2015 • 34 PSG confirmed iRBD subjects • Followed for 4.9 years • After 2.4 ± 1.7 years (mean ± SD), 9 patients (26.5%) converted (6 PD and 3 DLB) • Full Sniffin' Sticks test and identification subtest had overall diagnostic accuracy of 82.4% (95% CI: 66.1%–92.0%) in predicting conversion • Similar findings from Postuma et al 2011, Annals Neurol
- 35. @predictPD RBD – is it the answer? Little doubt that case finding of RBD will help explore the prodrome of PD and may yield a homogenous group for neuroprotective trials, but: • Cases are rare! • PSG is expensive! • Questionnaires are inaccurate – May overestimate: PPMI and PREDICT-PD (20% and 15% of healthy older people respectively score ≥5) – May underestimate: in those without a bed partner Most studies refer to Parkinsonism rather than PD (Postuma 2012) Motor features (Postuma 2008): • Less tremor • More freezing and falls • Less % change on/off medication Non-motor features: • orthostatic hypotension (Postuma 2008) • cognitive impairment (Olson 2000) • hallucinations (Pacchetti 2005)
- 36. @predictPD Constipation Figure from Adams-Carr et al. 2015. Under review
- 38. @predictPD Schrag et al. Lancet Neurol. 2015
- 40. @predictPD • Bradykinesia • Rigidity • Tremor • Reduced arm swing • Gait disturbance Early Motor Features?
- 41. @predictPD 58 PD patients, 93 controls, both hands tested Analyses: • PD vs control • PD-only correlation with MDS-UPDRS
- 42. @predictPD • Commonest risk factor and commonest AD cause of PD • GBA: • Encodes glucocerebrosidase, homozygotes – Gaucher’s disease • Present in 3.5% of UK PD subjects (Winder-Rhodes 2013), variants more common • OR for N370S ~ 3.5 (Nalls 2014) • Up to 30% get PD by age 80yo • Impaired olfaction, motor function and cognition, RBD in GD and GBA hets compared with controls (Beavan et al. JAMA Neurol 2014) • LRRK2: • Multiple possible mechanisms – protein clearance, oxidative stress • Age-dependent penetrance (Healy. Lancet Neurol 2008) • OR for G2019S mutation ~ 9.0 (Nalls 2014) • Predominantly motor phenotype, less cognitively impaired, better smell • Otherwise may have similar prodromal features as iPD (Gaig. PLoS One 2014) GBA and LRRK2
- 44. @predictPD
- 45. @predictPD
- 46. @predictPD In whom do we look? Patients versus healthy people Sub-types of Parkinson’s Risk factor carriers
- 47. @predictPD Evidence for Lewy body pathology in salivary glands and ANS of patients with PD Slide kindly donated by Joseph Masters
- 48. @predictPD Evidence for Lewy pathology in the gut of PD subjects Figures kindly donated by Sam Shribman pAS in muscularis propria
- 49. @predictPD Imaging markers For participants defined as being SN+ at baseline, the RR for developing PD by the end of 3 years was 17.37 (95% confidence interval, 3.71-81.34). Arch. Neurol. 2011
- 52. @predictPD
- 53. @predictPD Motor Non-motor SmellGenes Proteomics Cognitive Tissue bank enrolment ntory, Epworth Sleep Scale, RBD Q’aire, EQ-5D ntory-II, QUIP-anytime-short, IQ-CODE, NART, ion Cognitive Assessment, Phonemic/Semantic ca nd serum proteomics sample (each visit) PREDICT Imaging CSF Blood Skin biopsy Saliva Tracking Parkinson’s ClinicalPD EarlyIdentification
- 54. @predictPD Other studies PPMI and P-PPMI TREND Bruneck study EPIPARK study Various RBD cohorts LRRK2 and GBA cohorts
- 58. @predictPD The PREDICT-PD pilot study Opened 11th April 2011 Approx. 1500 individuals registered 1323 eligible and included Year 1 follow up – 1036 participants Year 2 follow up – 934 participants Year 3 follow up – 860 participants
- 59. @predictPD Frequency of “intermediate” markers Presence of motor abnormalities Gene mutation differences Imaging differences CONVERSION TO PARKINSON’S T I M E
- 60. @predictPD 2013
- 61. @predictPD 2013
- 62. @predictPD Candidates for early intervention studies & Agents De novo PD RBD Gene carriers Higher risk PREDICT Anosmics NSAIDs CCBs Statins Nicotine Caffeine LRRK2 inhibitors Ambroxol Exenetide PXR002Inosine Israpidine
- 63. @predictPD Acknowledgements UCL/QMUL/NHNN Andrew Lees Anette Schrag Gavin Giovannoni Chris Hawkes John Hardy Jonathan Bestwick Niccolo Mencacci Laura Silveira-Moriyama Joseph Masters Kerala Adams-Carr Saiji Nageshwaran Curtis Osborne Tom Warner Sofia Erikson Lea R’Bibo Alan Pittman University of East Anglia Carl Philpott Guy’s Hospital Guy Leschziner BRAIN test Anna Nagy Shami Acharya Julian Fearnley Transcranial Sonography (Innsbruck, Austria) Martin Sojer Heike Stockner Werner Poewe Klaus Seppi Industry Support Andrew Cartwright Connor Treacy Susan Goelz Ted Yednock Kuldip Birdi DeNDRoN/NIHR CRN Selina Paul UCLH John Dickson The Participants Colleagues at Brain Bank Helen Ling Eduardo Fernandez Pedro Barbosa Nadia Magdalinou Iliyana Komsiyska Karen Shaw Linda Parsons Web: www.predictpd.com Blog: www.predictpd.blogspot.com