national reference center for tse clinical dementia center ...survival age n, gender aksamit 200120...

advances in diagnostic and therapeutic approaches in CJD

Inga ZerrNational Reference Center for TSE

Clinical Dementia Center

University Medical School Göttingen

Donnerstag, 13. Juni 2013

1980 1990 20102000

EEG

14-3-3 CSF

MRI

Rt QuIC


MM MV VV

I

II

PRPSC

MEISSNER ET AL NEUROLOGY 2009 IN PRESS


ANSTIEG DER ATYPISCHEN ERKRANKUNGSFÄLLE?- CODON 129 GENOTYP


Biomarker based diagnosis of progressive dementias

Demtest


CSF requests 14-3-3 positiv sCJD Incidence

1993 17 11 25 0,7*1994 95 52 57 0,91995 99 60 69 1,11996 141 80 70 1,11997 305 75 82 1,31998 729 146 112 1,41999 806 150 99 1,32000 1248 270 110 1,32001 1724 306 125 1,52002 1876 283 97 1,22003 2164 466 117 1,42004 2387 597 136 1,72005 2408 274 145 1,82006 2440 417 143 1,72007 3113 406 137 1,72008 3701 498 137 1,7

2009 4434 415 125 1,5

2010 4720 466 139 1,7

2011 5206 628 152 1,82012 6008 555 149 1,82013 1874 275 33

30.4.2013


can we amlpfy misfolded proteins?

PMCA, QUIC, RT-‐QUIC


Real Time Quaking-Induced ConversionMethods

Schematic presentation of the RT-QuIC method

?

Real Time Quaking-Induced Conversion (RT-QuIC)

use of recombinant PrPC as a substrate to amplify PrPSc by repeated automated shaking

real-time monitoring by Thioflavin-T fluorescence dye analysis

FLUOstar OPTIMA – BMG Labtech


4000

12500

21000

29500

38000

0 5.0002810.000615.000820.001425.002230.002535.003140.003645.004250.005355.005860.006465.007270.008175.008680.009785.010390.011795.0128100.014105.015110.016115.017120.018

Detection of PrPSc in CSF using RT QuiC

ThT flu

orescence (relative flu

orescence un

its)

h

CJD (n=36)controls (n=23)


1980 1990 20102000

case reportsobservational reports

systematicrandomized trials

quinacrinedoxycycline

pentosane polysulphatequinacrine

flupirtine


ataxia

myoclonus

pyramidal

rigidity

0 10 20 30 40

age: 65 (35-89)

duration 30 months

Heinemann et al, Brain, 2007

rapid progressive AD

0

15

30

45

60

> 1 E4 E4/E4RP-AD ADcontrols


survival age N, genderAksamit 200120 n.a. n.a. 13van Everbroeck 2004 9 22m 71 30Collins 200021 n.a. n.a. 3Gelpi 200818 n.a. n.a. 6Huang 200322 n.a. n.a. 1, mJansen 200923 n.a. n.a. 54Jayaratnam 2008 24 4.5m 74 1, mJosephs 20096 3yrs

1.2yrs

72

74

1, m

1, m

Reinwald 200425 40d 69 1, mSchmidt 20108 26.4m 73 32 (15m,17f)Tschampa 200126 24m 76 19 (4m, 15f)

Neuropathologically confirmed rpAD cases mimicking CJD

...3 systematic studies on rapid progressive dementia....


Joint Programming Neurodegenerative Disease

"Neurodegenerative Diseases - a call for European research projects for the optimisation of biomarkers

and harmonisation of their use between clinical centres"

Multicenter study on rpAD

Nagasaki, JapanMadrid, SpainParis, FranceGöttingen, Germany

Santander, SpainBuenos Aires, Argentina

CJD Surveillance centers:

n=93


0

13

25

38

50

2/2 2/3 2/4 3/3 3/4 4/4

0

20

40

60

80

Apolipoprotein E


survival=22 Mo, no ApoE 4

defini6on „rapid“ MMSE decline = 6pt/year

no ApoE 4


OutlookRapid progressive Alzheimer’s disease (rpAD):

clinical and molecular characterization and determinants of disease progression

• neuropathological signature

• oligomer characterisation

• molecular predictors for disease progression

• neurotoxicity


KNDD Study Germany

Christian SchmidtHeiko Braak

Hans KretzschmarWalter Schulz-Schaeffer

Carsten KorthDieter Willbold

JPND multicenters study

Stephane HaikJean-Philippe BrandelJean-Lous LaplancheJean-Jaques Hauw

Miguel Calero LaraAlberto Rabano

Pablo Martinez MartinJesus de Pedro-Cuesta

Katsuya Satoh

Dr Jiri Safar


national reference center for tse clinical dementia center ...survival age n, gender aksamit 200120...

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