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@predictPD
Alastair NoyceParkinson’s UK Doctoral Research Fellow, UCL Institute of NeurologySpecialist Registrar in Neurology, Barts Health NHS Trust
Pre-diagnostic Features & Markers of Parkinson’s
Web: www.predictpd.comBlog: www.predictpd.blogspot.com
@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
@predictPD
NO CURE & NO DRUGS THAT CHANGE THE UNDERLYING DISEASE COURSE
@predictPD
DelayedPresentation
Marked Heterogeneity
Sub-types
Measuring Disease
Wrong diagnosis
@predictPD
DelayedPresentation
Marked Heterogeneity
Sub-types
Measuring Disease
Wrong diagnosis
@predictPD
DelayedPresentation
Marked Heterogeneity
Sub-types
Measuring Disease
Wrong diagnosis
@predictPD
Marked Heterogeneity
Sub-types
DelayedPresentation
Measuring Disease
Wrong diagnosis
@predictPD
Genetic vs
Sporadic
Slow & stiffvs
Tremor
Fast vs
Slow
Sub-types
DelayedPresentation
Marked Heterogeneity
Measuring Disease
Wrong diagnosis
@predictPD
Measuring Disease
DelayedPresentation
Marked Heterogeneity
Sub-types
Wrong diagnosis
@predictPD
Measuring Disease
DelayedPresentation
Marked Heterogeneity
Sub-types
Wrong diagnosis
@predictPD
Measuring Disease
DelayedPresentation
Marked Heterogeneity
Sub-types
Wrong diagnosis
@predictPD
Measuring Disease
DelayedPresentation
Marked Heterogeneity
Sub-types
Wrong diagnosis
@predictPD
Measuring Disease
DelayedPresentation
Marked Heterogeneity
Sub-types
Wrong diagnosis
@predictPD
1) Late identification
2) Diluted group• Sub-types
• Wrong diagnosis
3) Poor measurement• Symptoms vs disease
• Heterogenous
Problems
@predictPD
1) Late identification
2) Diluted group• Sub-types
• Wrong diagnosis
3) Poor measurement• Symptoms vs disease
• Heterogenous
Problems
@predictPD
1) Late identification
2) Diluted group• Sub-types
• Wrong diagnosis
3) Poor measurement• Symptoms vs disease
• Heterogenous
4)Ineffective drugs
Problems
@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
@predictPD
Source: OECD Health Data April 2014
Between 1990 and 2013:
Global life expectancy increased from 65.3 years to 71.5 years
@predictPDSieber. Ann Neurol. 2014
@predictPD
Pre-diagnostic markers:
1. Specific for the disease
2. Sensitive to change over time
Requirements
Early identification – pre-diagnostic features
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PRE-DIAGNOSTIC FEATURES
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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 settingMeSH 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
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Case-control studies
Case-control studies
Case-control studies
Case-control studiesCohort studiesAll
Case-control studiesCohort studiesAll
Case-control studiesCohort studiesAll
Case-control studies
Case-control studiesCohort studiesAll
Case-control studies
Case-control studiesCohort studiesAll
Case-control studies
Family historyAny 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
112
112
13
362
38
19
181
19
3
241
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
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Case-control studiesCohort studiesAll
Case-control studiesCohort studiesAll
Case-control studiesCohort studiesAll
Case-control studiesCohort studiesAll
Case-control studiesCohort studiesAll
Case-control studiesCohort studiesAll
Case-control studiesCohort studiesAll
Case-control studiesCohort studiesAll
SmokingCurrent vs. never
Ever vs. never
Past vs. never
Coffee
Hypertension
NSAID's
CCB's
Alcohol
26733
61667
26531
13619
10212
549
415
22224
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
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Case-control studiesCohort studiesAll
Case-control studiesCohort studiesAll
Case-control studies
Case-control studiesCohort studiesAll
Case-control studiesCohort studiesAll
Case-control studiesCohort studiesAll
Case-control studies
Case-control studiesCohort studiesAll
Case-control studies
Case-control studiesCohort studiesAll
Case-control studies
Oral contraceptives
Oophorectomy
Statins
HRT
Diabetes
Tea
Cancer
Acetaminophen/Paracetamol
General anesthetic
Aspirin
Ulcers
213
415
5
729
94
13
516
7
112
6
426
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
@predictPD
Other factors with significant associations with later PDSmell 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
@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
@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
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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
@predictPD
Smell loss pre-PDEvidence 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).
@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)
@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
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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
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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
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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)
@predictPD
Constipation
Figure from Adams-Carr et al. 2015. Under review
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Pre-Motor Parkinson’s disease?
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Schrag et al. Lancet Neurol. 2015
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Pre-diagnostic Parkinson’s disease
@predictPD
• Bradykinesia
• Rigidity
• Tremor
• Reduced arm swing
• Gait disturbance
Early Motor Features?
@predictPD
58 PD patients, 93 controls, both hands testedAnalyses: • PD vs control• PD-only correlation with MDS-UPDRS
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• 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
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PRE-DIAGNOSTIC MARKERS
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@predictPD
@predictPD
In whom do we look?
Patients versus healthy people
Sub-types of Parkinson’s
Risk factor carriers
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Evidence for Lewy body pathology in salivary glands and ANS of patients with PD
Slide kindly donated by Joseph Masters
@predictPD
Evidence for Lewy pathology in the gut of PD subjects
Figures kindly donated by Sam Shribman
pAS in muscularis propria
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Imaging markers
For participants defined as being SN+ at baseline, the RR for developing PD by the end of 3 yearswas 17.37 (95% confidence interval, 3.71-81.34).
Arch. Neurol. 2011
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Imaging markers
@predictPD
Imaging markers
@predictPD
@predictPD
Motor
Non-motor
SmellGenes
Proteomics
Cognitive
Tissue bank enrolment
PREDICT
Imaging CSF Blood
Skin biopsySaliva
Tracking Parkinson’s
Clin
ical
PD
Early Identification
@predictPD
Other studies
PPMI and P-PPMI
TREND
Bruneck study
EPIPARK study
Various RBD cohorts
LRRK2 and GBA cohorts
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PREDICT–PD
@predictPD
PREDICT
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PREDICT
RISK KEY
High
Intermediate
Low
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The PREDICT-PD pilot studyOpened 11th April 2011Approx. 1500 individuals registered1323 eligible and included
Year 1 follow up – 1036 participantsYear 2 follow up – 934 participantsYear 3 follow up – 860 participants
@predictPD
Frequency of “intermediate” markers
Presence of motor abnormalities
Gene mutation differences
Imaging differences
CONVERSION TO PARKINSON’S
TIME
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2013
@predictPD
2013
@predictPD
Candidates for early intervention studies & Agents
De novo PD
RBD
Gene carriers
Higher risk PREDICT
AnosmicsNSAIDs
CCBsStatinsNicotine
Caffeine
LRRK2 inhibitors Ambroxol
ExenetidePXR002Inosine
Israpidine
@predictPD
AcknowledgementsUCL/QMUL/NHNNAndrew Lees Anette Schrag Gavin GiovannoniChris Hawkes John HardyJonathan BestwickNiccolo MencacciLaura Silveira-MoriyamaJoseph MastersKerala Adams-CarrSaiji NageshwaranCurtis OsborneTom WarnerSofia EriksonLea R’BiboAlan Pittman
University of East AngliaCarl Philpott
Guy’s HospitalGuy Leschziner
BRAIN testAnna NagyShami AcharyaJulian Fearnley
Transcranial Sonography (Innsbruck, Austria)Martin SojerHeike StocknerWerner PoeweKlaus Seppi
Industry SupportAndrew CartwrightConnor TreacySusan GoelzTed YednockKuldip Birdi
DeNDRoN/NIHR CRNSelina Paul
UCLHJohn Dickson
The Participants
Colleagues at Brain BankHelen LingEduardo FernandezPedro BarbosaNadia MagdalinouIliyana KomsiyskaKaren ShawLinda Parsons
Web: www.predictpd.comBlog: www.predictpd.blogspot.com