parkinson's 2015 meeting 2nd july london

@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

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NO CURE & NO DRUGS THAT CHANGE THE UNDERLYING DISEASE COURSE

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DelayedPresentation

Marked Heterogeneity

Sub-types

Measuring Disease

Wrong diagnosis

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DelayedPresentation

Sub-types

Measuring Disease

Wrong diagnosis

@predictPD

DelayedPresentation

Sub-types

Measuring Disease

Wrong diagnosis

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Sub-types

DelayedPresentation

Measuring Disease

Wrong diagnosis

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Genetic vs

Sporadic

Slow & stiffvs

Tremor

Fast vs

Sub-types

DelayedPresentation

Measuring Disease

Wrong diagnosis

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Measuring Disease

DelayedPresentation

Sub-types

Wrong diagnosis

@predictPD

Measuring Disease

DelayedPresentation

Sub-types

Wrong diagnosis

@predictPD

Measuring Disease

DelayedPresentation

Sub-types

Wrong diagnosis

@predictPD

Measuring Disease

DelayedPresentation

Sub-types

Wrong diagnosis

@predictPD

Measuring Disease

DelayedPresentation

Sub-types

Wrong diagnosis

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1) Late identification

2) Diluted group• Sub-types

• Wrong diagnosis

3) Poor measurement• Symptoms vs disease

• Heterogenous

Problems

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• Wrong diagnosis

• Heterogenous

Problems

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• Wrong diagnosis

• Heterogenous

4)Ineffective drugs

Problems

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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

• 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

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Source: OECD Health Data April 2014

Global life expectancy increased from 65.3 years to 71.5 years

@predictPDSieber. Ann Neurol. 2014

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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 studiesCohort studiesAll

Family historyAny relative

First degree relative

Family history of tremor

Constipation

Mood disorder

Pesticides

Head injury

Rural living

Beta blockers

Farming/agriculture

Well water

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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SmokingCurrent vs. never

Ever vs. never

Past vs. never

Coffee

Hypertension

NSAID's

Alcohol

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

Decreased risk of PD Increased risk of PD

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Oral contraceptives

Oophorectomy

Statins

Diabetes

Cancer

Acetaminophen/Paracetamol

General anesthetic

Aspirin

Ulcers

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

Decreased risk of PD Increased risk of PD

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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)

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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

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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

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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).

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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)

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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)

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Constipation

Figure from Adams-Carr et al. 2015. Under review

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Pre-Motor Parkinson’s disease?

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Pre-diagnostic Parkinson’s disease

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• Bradykinesia

• Rigidity

• Tremor

• Reduced arm swing

• Gait disturbance

Early Motor Features?

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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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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

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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

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Imaging markers

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Non-motor

SmellGenes

Proteomics

Cognitive

Tissue bank enrolment

PREDICT

Imaging CSF Blood

Skin biopsySaliva

Tracking Parkinson’s

Early Identification

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Other studies

PPMI and P-PPMI

Bruneck study

EPIPARK study

Various RBD cohorts

LRRK2 and GBA cohorts

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PREDICT–PD

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PREDICT

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PREDICT

RISK KEY

Intermediate

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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

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Frequency of “intermediate” markers

Presence of motor abnormalities

Gene mutation differences

Imaging differences

CONVERSION TO PARKINSON’S

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Candidates for early intervention studies & Agents

De novo PD

Gene carriers

Higher risk PREDICT

AnosmicsNSAIDs

CCBsStatinsNicotine

Caffeine

LRRK2 inhibitors Ambroxol

ExenetidePXR002Inosine

Israpidine

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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

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