USE CASE Parkinson‘s disease (UC-PD):Defining markers for PD progression: The LOC-PD study

Annual Symposium

Tübingen

10.10.2019

Parkinson Syndrome

• Second most common neurodegenerative disease

• > 1% of persons > 60 years affected

• 300.000 patients in Germany

• Expected to double by 2050

• Clinically and pathologically heterogenous

GENES and Parkinson‘s diseases

Mendelian

Parkinson‘s DiseasesFamily studies

Sporadic

(„idiopathic“)

Parkinson‘s diseases

Association studies

GWAS in PD

37.7K cases, 18.6K ‘proxy-cases’ and 1.4M controls

91 risk loci of genome-wide significance

Alpha-synucleinLRRK2

GBA

Nalls et al., Lancet Neurol, in press

GWAS: relative risk and disease prediction

Nalls et al., Lancet Neurol, in press

Gaucher disease and PDheterozygous GBA (glucocerebrosidase) mutations

Gaucher disease

• Hepatosplenomegaly

• Thrombocytopenia

• Cognitive decline

• Myoclonus

• Oculomotor disturbances

• Dementia

Gaucher

disease

Risk for PD

3 - 20

7 – 8 % of German PD patients carry a GBA mutation

7

Specific PDGBA phenotype

PDGBA:

More severe non-motor symptoms

- Cognitive Impairment / Dementia

Brockmann et al., Neurology 2011

Brockmann et al., Neurology 2012

Brockmann et al., Movement Disorders 2015

Srulijes et al. Parkinson‘s disease 2017

Diagnosis

PD

PDGBA

DIS

EA

SE

SE

VE

RIT

Y / P

HE

NO

TY

PE

DISEASE DURATION

Progression of sporadic PD

Maetzler et al. Lancet Neurology, 2009

Unified Parkinson‘sDisease Rating Scale

UPDRS-III

Risk factors

genetic markersPremotor markers

RBD

depression

hyposmia

autonomic

dysfunction

Early motor markers

reduced arm swing

Known markers

Adapted from DeKosky & Marek. Science 2003; 302 (5646): 830

Problem: clinical markers are relatively unspecific

Course and Treatement of Parkinson Syndromes

DiagnosisTreatment

decision

Disease course

today Treatment decision

Treatment decision

PS Benign course

iPS Intermediate course

Atypical course

iPS severe course

PS

Idiopathic PS

Atypical PS

Diagnosis

Treatment decision

Treatment decision

iPS

iPS

aPS

Treatment decision

future

LOC-DBS

36 mFU

LOC-EARLY

36 mFU

LOC-PD

AIMS of LOC-PD

Integration and analysis of all relevant clinical and paraclinical data to

• Predict natural disease course and progression in early and late phases

• Predict response to treatment across the course of disease

• Find markers for treatment response to allow personalized treatment decisions

• Generate stratified subcohorts for testing of novel treatments

• Clinical Data- Neurologic examination

- UPDRS-III/Hohen Yahr scale

- Montreal Cognitive Assessment, MoCA

- Schellong Test (Part III UMSARS)

- Levodopa equivalent dose

- Parkinson’s disease non-motor symptom Scale,

PD-NMSQ

- Beck Depression Inventory II, BDI-II &

Geriatric Depression Scale, GDS

- Parkinson’s disease questionnaire, PDQ-39

• DNA, Plasma, Serum

• MRT

• CSF

Design LOC-EARLY

Diagnose

Parkinson

Recruitment of patients within

first three years of diseaseMotor progression

Cognitive decline

MoCA ≤ 26

DD atypical

Parkinson syndrome

„Red Flags“-bulbar signs

-inspiratory stridor

-autonomic dysregulation

-frequent falls

-dystonic antecollis or contractures

-pyramidal signs

-cerebellar signs

-oculomotor disturbance

Onset postural InstabilityUPDRS-III Item 3.12

Clinically relevant milestones

• Non-motor symptoms like cognitve impairment and dementia, reduces quality of life

• Early recognition of dementia is essential, because dementia is mainreason for loosing independence

Course of disease

Loss of independence

Mild cognitive impairment(PD-MCI)

dementia(PDD)

High conversion

risk

Aarsland et al. Nature Review, 2017

Design LOC-EARLY

-preparation of study registration „Deutschen Register Klinischer Studien (DRKS)“(final registration after positive ethics votum)

Biosampling

Probenentnahme Bezeichnung Anzahl Firma; Artikelnr

Plasma / DNA

9 ml EDTA Röhrchen

2 Sarstedt; 02.1066.001

Serum

7.5 ml Serum Röhrchen

3 Sarstedt; 01.1601

Etikettierung bei Entnahme

LabID1-Etiketten 15 Wird von Tübingen bereit gestellt

Probenbegleitschein oder Blut-Versandschein

Formular zur Probenbegleitung

1 Siehe Anhang

Optional:

RNA

2,5 ml PAXgene Blood RNA Tubes

2 PreAnalytiX (Qiagen); 762165

RNA - Um-Etikettierung

LabID2-Etiketten 2 Wird von Tübingen bereit gestellt

Liquor

13ml PP Röhrchen

1 Bspw. Sarstedt; 60.540.500

Urin

10ml Urin Röhrchen

1 Sarstedt; 10.252.020

Tränenflüssigkeit

Schirmer-Teststreifen

2 Schirmer Tear Test Ophthalmic Strips; OptiTech Eyecare; Tarun Enterprises

Tränendflüssigkeit – Kryovials

Kryovials 2 Zentrum-spezifisch

Tränenflüssigkeit - Tütchen

Druckverschluss-Beutel

1 Bspw. neoLab; 1-7122

Stuhlentnahme-Paket

Versandpaket für Stuhlproben

1 Wird von Mikrobiologie Tübingen bereit gestellt

Stuhl-Versandschein

Formular zur Stuhlproben-begleitung

1 Siehe Anhang

- LMU will send DNA samples to Tübingen

- Standardized sample withdrawal andprocessing (SOP)

Add Ons:

- Tear fluid collection

- Cooperation for stool sample analysis withthe Institute for Medical Microbiology andHygiene, Univesity of Tübingen

Standardized MRI imaging

Imaging registration:

3D MPRAGE sag ≤1 mm³ isotrop

3D FLAIR sag ≤1 mm³ isotrop

SWI axial Schichtdicke max. 2 mm, falls lokal nicht verfügbar T2* axial

DTI mit 30 oder 32 Richtungen b1000 + b0 2 ≤mm isotrop - ca. 6 Minuten (mit SMS,

alternativ falls SMS nicht verfügbar DWI 4-weighted trace mit b = 0 und b = 1000, 2 mm

Schichten).

PD/T2 ax 3mm Basalganglien und hintere Schädelgrube

Optional:

Jedes Zentrum darf optional weitere Sequenzen ergänzen, z.B.: 3D T2 SPACE oder 2D T2 sag

Gesamtdauer: ~25 min Minuten

Vorschlag Felder des strukturierten Befunds: Vaskuläre Last: Fazekas-Score (numerischer Wert für PVWM und DWM), Anzahl Mikroblutungen (1,2,..,10, > 10) (numerische Werte) Atrophie supratentoriell visuell: nein/gering/mittelgradig/ausgeprägt NPH Aspekt: nein/fraglich/ja Diffusionsrestriktion: ja/nein + Freifeld: Lokalisation

Putamen: Atrophie: nein/gering/mittelgradig/ausgeprägt Signalveränderungen: ja/nein

GP: Signalveränderungen: ja/nein

Mittelhirn:

Midsagittale Midbrain-Area: mm² Midsagittale Pons-Area: mm² Coronarer Diameter oberer Kleinhirnstiel: mm Sagittaler Diameter Mittlerer Kleinhirnstiel: mm Swallow-Tail-Sign: normal, wahrscheinlich normal, wahrscheinlich pathologisch, pathologisch Signalveränderungen: ja/nein

Pons: Hot-Cross-Bun sign in PD: nein/wahrscheinlich/ja Andere Signalveränderungen: ja/nein

Cerbellum:

Visuell Atrophie: nein/gering/mittelgradig/ausgeprägt Nucleus dentatus signalverändert: ja/nein

Beurteilung:

V.a. atypisches Parkinsonsyndrom V.a. MSA V.a. PSP V.a. CBD V.a. NPH V.a. andere Genese (zusätzliches Freitextfeld – z.B. entzündlich, metablolisch

[Wilson], traumatisch, ... ) Kein Hinweis auf atypisches Parkinsonsyndrom, vereinbar mit M. Parkinson

Weitere Befunde (Freitextfeld)

Verlaufsbeurteilung: Nicht anwendbar / bildgebend Befund weiterhin mit Verdachtsdiagnose

vereinbar / bildgebend neue Verdachtsdiagnose

harmonised between centresStandardized diagnosis:

Use-Case implementation

• PMD implemented at all sites• Completness status of recend

PMD updates of all centers

Next Steps:

• Export of medication „bundeseinheitlichen Medikationsplan“ in study database

• Programming of study database (DIS)

Retrospective data analysis

276 PD patient‘s with disease duration ≤ 3 years

• 164 (59.4 %) male gender• 62 (23-80) years of age at PD diagnosis• at median assessed 2 years after PD diagnosis

used for sample size estimationof the prospective study part

Next Steps:

• Merging of center data-sets• calculation of prediction models• Integration of genetic and biomarker data

Monitoring

MSc. Patricia Sulzer

Off Site Monitoring On Site Monitoring• Informed consent process• Monitoring of study processes• Sample collection and handling in

accordance to protocol and SOP(s) • Review of data management procedure i.e.

data entry, handling of data discrepancies and data back-up.

• Study contact for sites

• Automated system monitoring• Monitoring of data and querie status

• Report of Metadata Design of monitoring

plan in cooperation with IT

Next Steps:

• Initiation of study sites