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

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  • Longitudinal PD Biomarker Studies: DeNoPa and PPMI

    Prof. Dr. Brit Mollenhauer

    Paracelsus-Elena Klinik Kassel

    University Medical Center Gttingen, Germany

  • CSF -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

    -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

    -

    Syn

    ucl

    ein

    pAb: Msa-1

    ExtrAvidin-Alkalin

    Phosphatase

    mAb: syn-1

  • Remaining Questions

    Are CSF total -synuclein levels decreased in

    early, de-novo PD

    Premotor PD

    Are CSF total -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-nave) Parkinsons 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 Gttingen 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 (Osnabrck), Dr. B.-J. Forsting

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

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

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

    W. Herschmann (Elsenfeld), Dr. O.

    Hildenhagen (Kassel), Dr. T. Jrn

    (Kassel/Baunatal), Dr. Z. Jakubovich

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

    J. Kleebach (Schwalmstadt), Dr. Klitsch

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

    Kretzschmar (Bad Hersfeld), J. Khler

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

    Khnel (Gttingen), C. Lassek (Kassel), Dr. J.

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

    C. Lehmenkhler (Soest), M. Lorenz

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

    Mller (Herford), Dr. A. Nachtmann

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

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

    W. Paulus (Gttingen), Dr. H. Pausch

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

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

    Dr. M. Radau-Pfeil (Gttingen), 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. Wstenhagen (Hann.

    Mnden).

    Data are mean (SD, range)

    HC

    N=110

    PD

    n=159

    p-value

    age (years)

    647

    (683, 4400-8400)

    653

    (970, 4000-8500)

    610

    sex

    male/ female

    (%)

    67/ 43

    (60/ 40)

    105/ 54

    (66/ 34)

    811

    Number of

    comorbidities

    25

    (153, 0-7)

    23

    (161, 0-8)

    333

    PD

    n=159

    disease duration

    [months] 269

    (3711, 200-24000)

    Hoehn & Yahr

    score 18

    (065, 100-300)

    UPDRS total

    score** 292

    (1467, 400-6800)

    UPDRS motor

    score before

    levodopa

    n=158

    189

    (1022, 300-5300) Tremor score $ 03

    (034, 0-200)

    PIGD Score 07

    (058, 0-250)

    DeNoPa-Cohort

    Mollenhauer et al., 2013

    http://www.google.de/imgres?imgurl=http://www.digifunk.info/df_d/PublishingImages/Deutschland.png&imgrefurl=http://www.digifunk.info/df_d/Seiten/default.aspx&usg=__tGu4VsoaMI8NtDWjjHr1yVi9D78=&h=599&w=443&sz=71&hl=de&start=6&itbs=1&tbnid=PQ2wnnb2FfTvkM:&tbnh=135&tbnw=100&prev=/images%3Fq%3Ddeutschland%2BKarte%26hl%3Dde%26sa%3DN%26tbs%3Disch:1

  • 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

    -Syn

    PD

    N

    Mean (SE)

    412

    1974 (38.7)

    128

    1838 (65.8)

    166

    1861 (62.1)

    -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

    A1-42 PD

    N

    Mean (SD) 412

    370 (4.95)

    129

    367 (8.57)

    166

    376 (8.07)

    A1-42 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

    -Synuklein Species in CSF of PD patients

    https://www.michaeljfox.org/http://4.bp.blogspot.com/-rX0ZZHTuwpI/U6JH8S8g75I/AAAAAAAAgZQ/YZftGLqVkOY/s1600/bristol-myers+squibb.png

  • 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-Dring

    Jens Ebentheuer

    Monica Canelo

    Lab

    Niels Kruse (G)

    Birgit Otte (G/KS)

    Olivia Steuer (KS)

    Sleep Lab

    Friederike Sixel-Dring (KS)

    Andrea Wegener (KS)

    Norbert Drescher (KS)

    MRI/Imaging

    Niels Focke (G)

    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 Brck/ Walter J Schulz-Schaeffer, Univ. Gttingen Christian Czech, Thomas Kremer, Roche, Switzerland Omar El-Agnaf, Al-Ain, United Arab Emirates Karsten Hiller, Luxemburg Christine Klein/Katja Lohmann, Univ. Lbeck Ralf Kohnen, RPS, Nrnberg Hilal Lashuel, Adrian Schmid, Lausanne, Switzerland Katrin Marcus, Medical Proteomcenter Bochum Tiago Outeiro, Univ. Gttingen Michael Schlossmacher, OHRI, Ottawa, Canada Anja Schneider, Univ. Gttingen Peggy Taylor, BioLegend, USA Eugeen Vanmechelen und Hugo Vanstichelen, ADx Neurosciences, Ghent, Belgium Heike Wersching, Klaus Berger, Mnster University Juliane Winkelmann, Center of Human Genetics, Munich /Stanford University Henrik Zetterberg, Gothenborg University, Sweden

    Acknowledgement