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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