Longitudinal PD Biomarker Studies: DeNoPa and PPMI

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Longitudinal PD Biomarker Studies: DeNoPa and PPMI Prof. Dr. Brit Mollenhauer Paracelsus-Elena Klinik Kassel University Medical Center Göttingen, Germany

Transcript of Longitudinal PD Biomarker Studies: DeNoPa and PPMI

Longitudinal PD Biomarker Studies: DeNoPa and PPMI

Prof. Dr. Brit Mollenhauer

Paracelsus-Elena Klinik Kassel

University Medical Center Göttingen, Germany

CSF α-synuclein in independent cross sectional studies

and a cohort study

AD (n=4) HCO (n=5) DLB (n=6) PD (n=5)0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

ab

so

rba

nce

sig

na

l @

40

5 n

m

NCO (n=23) NPH (n=22) PSP (n=8) DLB (n=66) PD (n=273) MSA (n=15)0,8

1,0

1,2

1,4

1,6

1,8

2,0

2,2

2,4

2,6

2,8

CS

F α

-syn

ucle

in [

pg

l ]

AD (n=21) NDC (n=7) DLB (n=13)0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

CS

F a

lph

a-s

yn

ucle

in (

pg

/ul)

n=20 n=70 n=237

n=41 n=407

B

i

o

ti

n

p-Nitrophenyl Phosphat

α-

Syn

ucl

ein

pAb: Msa-1

ExtrAvidin-Alkalin

Phosphatase

mAb: syn-1

Remaining Questions

• Are CSF total α-synuclein levels decreased in

– early, de-novo PD

– Premotor PD

• Are CSF total α-synuclein levels helpful to monitor disease

progression?

• Are there any other (more accurate) biomarker, that can support

the clinical diagnosis and monitor progression

o Single-center

o National

o Observational

o 159 Early, at enrolment drug naive

PD subjects (UK Brain Bank)

o 110 matched (age, gender, education)

healthy controls

o FOCUS: non-motor symptoms, fluid biomarker

o Longitudinal

o Follow-up: every 24 months

o Autopsy verification of diagnoses ongoing

o EXPLORATION OF NEW MARKER

o Multi-center (24 sites)

o International

o Observational

o 423 Early, at enrolment drug naive

PD subjects (UK Brain Bank

/monosymptomatic tremor)

PLUS Dopaminergic deficit

o 196 matched (age, gender) healthy controls

o FOCUS: functional and structural imaging,

fluid biomarker

o Longitudinal

o Follow-up: every 6-12 months (V1/St visit)

o Autopsy verification of diagnoses planned

o Sharing of data and fluids (ppmi-info.org)

o VERIFICATION OF NEW MARKER

The long-term follow-up study of early

(drug-naïve) Parkinson’s Disease patients and

healthy controls

for non-motor symptoms and biomarkers

DeNoPa-Kassel

German Register for Clinical trials (DRKS00000540) according to the WHO Trial Registration Data Set.

Paracelsus-Elena Klinik, Kassel

Hospital for Movement Disorders

1937-2013

Linked to Göttingen University

Robert Wartenberg Preis 2013

• 36 patients follow-up after 20 years

• 48% orthostatic Hypotension

• 74% Hallucinations and/or Depression

• 78% Dysarthria

• 48% Dysphagia

• 87% Falls (Bone fractures 35%)

• 81% Freezing

• 70% Daytine sleepiness

• 83% Dementia

The emergence of non-motor symptoms

10 years before the onset of PD

Dr. M. Altenhain (Kassel), Dr. H. Baiker

(Detmold), Dr. M. Bauer (Minden), Dr. R.

Brodhuhn (Seesen), Dr. O. Erdmann

(Osterode), G. Falkenstein (Northeim), W.W.

Feldeisen (Hamm), Dr. A. Fetzer (Vellmar),

Dr. R. Flapper (Osnabrück), Dr. B.-J. Forsting

(Lippstadt), Dr. P. Gensicke (Göttingen), Dr.

E. Haacke (Paderborn), Dr. H. Hansal (Bad

Wildungen), Dr. F. Hellmann (Schwalmstadt),

W. Herschmann (Elsenfeld), Dr. O.

Hildenhagen (Kassel), Dr. T. Jörn

(Kassel/Baunatal), Dr. Z. Jakubovich

(Rotenburg a.d. Fulda), Dr. S. Kalok (Kassel),

J. Kleebach (Schwalmstadt), Dr. Klitsch

(Fulda), Dr. G. Knaak (Hann. Münden), Dr. H.

Kretzschmar (Bad Hersfeld), J. Köhler

(Northeim), Dr. J. Kühne (Detmold), Dr. G.

Kühnel (Göttingen), C. Lassek (Kassel), Dr. J.

Leferink (Kassel), Dr. S. Lefering (Kassel), Dr.

C. Lehmenkühler (Soest), M. Lorenz

(Minden), Dr. H.-J. Müller (Duderstadt), Dr. H.

Müller (Herford), Dr. A. Nachtmann

(Rotenburg a.d. Fulda), Dr. S. Niehaus

(Dortmund), Dr. I. Paseka (Kassel), Prof. Dr.

W. Paulus (Göttingen), Dr. H. Pausch

(Marburg), Dr. E. Petter (Detmold), Dr. R. Pfeil

(Göttingen), M. K. Quosigk (Witzenhausen),

Dr. M. Radau-Pfeil (Göttingen), Dr. R.

Ruppenthal (Meckenheim), Dr. B.

Schimmelpfenning (Melsungen), Dr. B.

Schirmer (Baunatal), M. Schorr (Heilbad

Heiligenstadt), Dr. M. Spillner (Osterode), Dr.

R. Sporleder (Bad Hersfeld), Dr. H. Steinberg

(Braunschweig), Dr. K-D. Toepfer (Einbeck),

G. van Nasse (Vellmar), Dr. C. Weber-Isele

(Frankenberg), Dr. F. Weinhold (Brilon), Prof.

Dr. F.-L. Welter (Bad Zwesten), Dr. B. Willeke

(Braunschweig), Dr. M. Wüstenhagen (Hann.

Münden).

Data are mean (SD, range)

HC

N=110

PD

n=159

p-value

age (years)

64·7

(6·83, 44·00-84·00)

65·3

(9·70, 40·00-85·00)

·610

sex

male/ female

(%)

67/ 43

(60/ 40)

105/ 54

(66/ 34)

·811

Number of

comorbidities

2·5

(1·53, 0-7)

2·3

(1·61, 0-8)

·333

PD

n=159

disease duration

[months] 26·9

(37·11, 2·00-240·00)

Hoehn & Yahr

score 1·8

(0·65, 1·00-3·00)

UPDRS total

score** 29·2

(14·67, 4·00-68·00)

UPDRS motor

score before

levodopa

n=158

18·9

(10·22, 3·00-53·00)

Tremor score $ 0·3

(0·34, 0-2·00)

PIGD Score § 0·7

(0·58, 0-2·50)

DeNoPa-Cohort

Mollenhauer et al., 2013

Recruitment and first Follow-up

* OND: MSA, PSP, DLB, Dystonia, unclear diagnosis

Study

population

400 de novo PD subjects (“possible PD” with

positive DaT and unmedicated)

200 age- and gender-matched healthy controls

Subjects will be followed for a minimum of 3 years

and a maximum of 5 years

Assessments

/ Clinical data

collection

Motor assessments

Neuropsychiatric/cognitive testing

Olfaction

DaTSCAN imaging, MRI

Biologic

collection

DNA collected at screening

Serum and plasma collected at each visit; urine

collected annually

CSF collected at baseline, 6 months, 12 months

and annually thereafter

Samples aliquotted and stored in central

biorepository

PD treatment De novo for ~6 months

Can participate in other clinical trials (including

interventional trials) after 12 months

Recruitment finalized May 2013

423 PD subjects

196 healthy controls (matched for age and gender)

64 SWEDD subjects

ANALYSES ONGOING

CSF BIOMARKERS REMAIN STABLE AT

1-YEAR FOLLOW-UP

Analyte/

Diagnosis Summary

Baseline

(0

months)

6

months

12

months

α-Syn

PD

N

Mean (SE)

412

1974 (38.7)

128

1838 (65.8)

166

1861 (62.1)

α-Syn

HC

N

Mean (SE)

189

2204 (79.2)

112

2201 (86.7)

111

2164 (91.1)

Analyte/

Diagnosis Summary

Baseline

(0

months)

6

months

12

months

Aβ1-42

PD

N

Mean (SD) 412

370 (4.95)

129

367 (8.57)

166

376 (8.07)

Aβ1-42

HC

N

Mean (SD) 180

377 ( 8.26)

112

374 (9.35)

111

389 (10.0)

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Description of sub-

species

Peptide Modification Peptide Sequence LOQ

(fmol/m

L)

aSyn_13-21.2 WT EGVVAAAEK 1

aSyn_33-43.2 WT, missed cleavage TKEGVLYVGSK 2.5

aSyn_35-43_pY39 pY39 EGVLpYVGSK 0.5

aSyn_35-43_nY39 nY39 EGVLnYVGSK 0.1

aSyn_35-43.2 WT EGVLYVGSK 0.1

aSyn_46-58 (unique) WT EGVVHGVATVAEK 0.5

aSyn_81-96 (unique) WT TVEGAGSIAAATGFVK 10

aSyn_81-96_pS87 WT, pS87 TVEGAGpSIAAATGFVK 10

WT AspN peptide MeO DNEAYEMPSEEGYQ 25

WT AspN peptide DNEAYEMPSEEGYQ 2.5

WT AspN peptide MeO,

pS129

DNEAYEMPpSEEGYQ 100

WT AspN peptide, pS129 DNEAYEMPpSEEGYQ 50

aSyn112_131-140 Isoform 2-5 EGYQDYEPEA 5

aSyn126_35-40+55-58 Isoform 2-4 EGVLYVVAEK 0.1

aSyn119_103-

119_m116

Trunc @ 119, MeO NEEGAPQEGILEDMPVD 10

aSyn119_103-119 Trunc @ 119 NEEGAPQEGILEDMPVD 5

aSyn120_103-

120_m116

Trunc @ 120, MeO NEEGAPQEGILEDMPVDP 25

aSyn120_103-120 Trunc @ 120 NEEGAPQEGILEDMPVDP 2.5

aSyn122_103-

122_m116

Trunc @ 122, MeO NEEGAPQEGILEDMPVDPDN 10

aSyn122_103-122 Trunc @ 122 NEEGAPQEGILEDMPVDPDN 10

aSyn123_103-

123_m116

Trunc @ 123, MeO NEEGAPQEGILEDMPVDPDNE 5

aSyn123_103-123 Trunc @ 123 NEEGAPQEGILEDMPVDPDNE 5

aSyn124_103-

124_m116

Trunc @ 124, MeO NEEGAPQEGILEDMPVDPDNEA 5

aSyn124_103-124 Trunc @ 124 NEEGAPQEGILEDMPVDPDNEA 5

WT, pT81a pTVEGAGSIAAATGFVK N/A

WT, pT92a TVEGAGSIAAApTGFVK N/A

Mutation A30P QGVAEAPGK 0.1

aSyn_46-58_A53T Mutation A53T EGVVHGVTTVAEK 0.5

PI: Brit Mollenhauer

Peggy Taylor

Peter Juhasz

Hilal Lashuel

Michael Ahlijanian,

Henrik Zetterberg,

Andreas Jeromin

Assay

development

and validation for

3-5 relevant

for PD progression

aSyn species

Funded MJFF LEAPS academic-industry TEAM

Charakterisation of progression specific

α-Synuklein Species in CSF of PD patients

Natural History of Parkinson disease N

eu

ro

n F

un

cti

on

Pre-diagnostic

Symptomatic

Diagnosis

P-PPMI RBD Hyposmics LRRK-2 ….

PPMI

Current

Biomarker

Studies

DeNoPa

RBD Hyposmia

SINBAR

PARS

Honolulu

Asia

Aging

Study

EPIPARK

PRIPS

DeNoPa substudy

TREND

Clinical course

heterogeinity

www.ppmi-info.org

Clinic (KS)

Claudia Trenkwalder

Friederike Sixel-Döring

Jens Ebentheuer

Monica Canelo

Lab

Niels Kruse (Gö)

Birgit Otte (Gö/KS)

Olivia Steuer (KS)

Sleep Lab

Friederike Sixel-Döring (KS)

Andrea Wegener (KS)

Norbert Drescher (KS)

MRI/Imaging

Niels Focke (Gö)

Neuropsychology

Martina Schaumburg (KS)

Statistical analysis

Johannes Zimmermann (KS)

Joe J. Locascio (Boston)

Study coordinators

Tamara Wicke (KS)

Diana Willeke (KS)

Sandra Gesse (KS)

Elisabeth Lang (KS)

IITs from TEVA Pharma,

Boehringer-Ingelheim,

GE, DiaGenics

COLLABORATION PARTNERS: Rudi Balling, LCSB Luxemburg Wolfgang Brück/ Walter J Schulz-Schaeffer, Univ. Göttingen Christian Czech, Thomas Kremer, Roche, Switzerland

Omar El-Agnaf, Al-Ain, United Arab Emirates Karsten Hiller, Luxemburg Christine Klein/Katja Lohmann, Univ. Lübeck

Ralf Kohnen†, RPS, Nürnberg Hilal Lashuel, Adrian Schmid, Lausanne, Switzerland

Katrin Marcus, Medical Proteomcenter Bochum Tiago Outeiro, Univ. Göttingen

Michael Schlossmacher, OHRI, Ottawa, Canada Anja Schneider, Univ. Göttingen Peggy Taylor, BioLegend, USA

Eugeen Vanmechelen und Hugo Vanstichelen, ADx Neurosciences, Ghent, Belgium Heike Wersching, Klaus Berger, Münster University Juliane Winkelmann, Center of Human Genetics, Munich /Stanford University Henrik Zetterberg, Gothenborg University, Sweden

Acknowledgement