Longitudinal PD Biomarker Studies: DeNoPa and PPMI
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
/μ
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
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
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)
12
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
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