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Early diagnosis of Alzheimer's disease and related dementia (DIADEM)

   
Project

QLK3-2001-02362

Cell factory area

3.1.1

EU Contribution

3 830 276 Euro

Duration

36 months

Type

Research project

Starting date

01-10-2001

Keywords
Alzheimer's disease
C.elegans
dementia
presinilins
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ABSTRACT
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AD and related dementia are irreversible, degenerative disorders of the brain characterised by progressive cognitive decline, the loss of personality and, finally, death. Because of the impact on individuals and owing to the enormous costs for health care and for society, these disorders present a major health problem to the EU. Treatment that can prevent, arrest and reverse degeneration and death of neurons is therefore urgently required. A prerequisite is the development of diagnostic tools that identify patients at an early pre-symptomatic stage. A consortium of 18 of the most experienced AD laboratories from Europe and beyond will carry out a research project integrating data from studies with tissue cultures and genetically modified animals into a clinical investigation of demented patients. A broad array of biotechnical methods will be used. Results of these studies will lead to diagnostic screening strategies combining genetic, pathophysiological and biomarker information.

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OBJECTIVES
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Increased knowledge of abnormal genes and proteins associated with AD and related dementia will yield candidate molecules for the development of novel diagnostic tests. Clinically identified molecules related to the genetics and pathogenesis of AD will be analysed for their neurobiological function in basic research study protocols, and vice versa, molecules identified in basic research studies will be tested in clinical settings for their pathophysiological relevance in the diagnosis, and possibly also therapy, of dementia. The combination of this approach with powerful developments in high throughput screening, chip technology and combinatorial chemistry will lead to products that will be useful in the diagnosis, prevention and, hopefully, the treatment of dementia. Our final goal is to develop a highly parallel assay device that can test simultaneously many biomarkers for dementia.

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DESCRIPTION OF THE WORK
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The research project is organised as 3 interdependent workpackages (WP), each addressing a research area that is currently amenable to investigation.

Quality control and assessment is assured in a 4th WP. Altogether, 18 research groups, the heads of which are leading neuroscientists in Europe and the USA, will contribute to the joint project. The criteria for quality research in the field of neurobiology are met: Proper study design, adequate study facilities and a multidisciplinary approach.

WP1 is designed to characterise molecular mechanisms involved in the pathophysiology of Alzheimer's disease and related dementia by analysing pathophysiological functions of genes and proteins associated with dementia. These include the presenilins, APP, beta-secretase (BACE), neprisylin (NEP), alpha-synuclein and Abeta-degrading enzymes. Knock-out and transgenic mice as well as C.elegans models will be used.

WP2 is designed to elucidate the interactions underlying synthesis, post translational processing, degradation and pathological build-up of abnormal proteins in the brain of affected patients using cultured cells and simple model organisms (C.elegans). A broad and synergistic spectrum of methods of molecular biology, cell biology, genetics, and biophysics will be applied.

WP3 is a clinical project designed to identify protein markers for early detection and to explore the applications for differential diagnosis, analysis of disease activity and therapy control. Genetic markers will be characterised for their contribution to the individual risk profile for dementia and used, together with protein markers, for phenotype-genotype associations and pharmaco-genetic assessment. In co-operation with two innovative biotechnology companies the results of the pre-clinical and clinical studies will be used to develop a diagnostic screening strategy that combines genetic, pathophysiological and biomarker information.

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DELIVERABLES
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The deliverables, which are based on studies with animal models, tissue cultures and human subjects, will elucidate the formation and degradation of amyloid plaques, probably the major cause of AD, and help to identify genes and gene products associated with AD or related dementia. Furthermore, they will reveal potential regulators of the early processes involved in the pathogenesis of these illnesses and, thus, allow the determination of marker molecules that are useful for the development of novel diagnostic tests at the beginning stage of dementia and for the differential diagnosis in later stages of the disease. The overall deliverable will be the DIADEM-chip integrating DNA-chip and protein-chip technologies that will enable us to demonstrate the dementia risk pattern in individual subjects. In addition to the early diagnosis, the results of the project will contribute to the detection of new therapeutic principles that are urgently needed, if the early diagnosis should not remain meaningless for subjects concerned and for society.

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CONSORTIUM
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COORDINATOR
  Prof. Dr. Adlkofer Franz
Prof. Dr. Haass Christian
VERUM Foundation
80336 München, Germany
Tel: +49 895309880
Fax: +49 8953098829
prof.adlkofer@verum-foundation.de

CONTRACTOR
  Prof. Dr. Aguzzi Adriano
Institute of Neuropathology
University of Zürich
8091 Zürich, Switzerland
Tel: +41 12552107
Fax: +41 12554402
adriano@pathol.unizh.ch

Prof. Dr. Baumeister Ralf
Adolf Butenandt Institute
University of Munich
80336 München, Germany
Tel: +49 8921806927
Fax: +49 8921806946
bmeister@lmb.uni-muenchen.de

Prof. Dr. da Cruz e Silva Odete
Centro de Biologia Celular
Universidade de Aveiro
3810-193 Aveiro, Portugal
Tel: +35 1234370350
Fax: +35 1234426408
odetecs@bio.ua.pt

Prof. Dr. De Strooper Bart
Department of Human Genetics
Flanders Interuniversitary
Institute for Biotechnology
3000 Leuven, Belgium
Tel: +32 16346227
Fax: +32 16347181
Bart.DeStrooper@med.kuleuven.ac.be

Dr. Dotti Carlos G.
Cavalieri Ottolenghi Scientific Institute
10043 Orbassano (TO), Italy
Tel: +39 0116708149
Fax: +39 0116708151
carlos.dotti@sluigi.unito.it

Dr. Efthimiopoulos Spiros
Department of Animal and
Human Physiology
University of Athens
15771 Athens, Greece
Tel: +30 17274244
Fax: +30 17274635
efthis@biol.uoa.gr

Dr. Gomez-Isla Teresa
Departamento de Neurosciencias
Universidad de Navarra
31008 Pamplona, Spain
Tel: +34 948296280
Fax: +34 948255400
tgisla@unav.es

Prof. Dr. Growdon John H.
Department of Neurology
Harvard Medical School
Boston, Massachusetts 02114, USA
Tel: +1 6177261728
Fax: +1 6177264101
growdon@hellix.mgh.harvard.edu

Prof. Dr. Haass Christian
Adolf-Butenandt-Institut
Universitaet München
80336 München, Germany
Tel: +49 895996471
Fax: +49 895996415
chaass@pbm.med.uni-muenchen.de

Prof. Dr. Hardy John
Center for Neuroscience
Mayo Clinic Jacksonville
Jacksonville, Florida 32224, USA
Tel: +1 904 9537356
Fax: +1 904 9537370
hardy.john@mayo.edu

Prof. Dr. Hock Christoph
Department of Psychiatric Research
University of Zürich
8029 Zürich, Switzerland
Tel: +41 13842271
Fax: +41 13842275
chock@bli.unizh.ch

Dr. Lannfelt Lars
Department of Clinical Neuroscience
Karolinska Institutet
14186 Stockholm, Sweden
Tel: +46 858586472
Fax: +46 858583880
Lars.Lannfelt@neurotec.ki.se

Prof. Dr. Nitsch Roger
Division of Psychiatric Research
University of Zürich
8008 Zürich, Switzerland
Tel: +41 16348871
Fax: +41 16348876
nitsch@bli.unizh.de

Prof. Dr. Rossor Martin N.
Institute of Neurology
University College London
WC1N 3BG London, United Kingdom
Tel: +44 2078298773
Fax: +44 8701320447
m.rossor@dementia.ion.ucl.ac.uk

Dr. Wiltfang Jens PD
Psychiatrische Klinik
Universitaet Goettingen
37075 Goettingen, Germany
Tel: +49 551392241
Fax: +49 551392241
jwiltfa@gwdg.de

Prof. Dr. Unsicker Klaus
Institute for Anatomy and Cell Biology
University of Heidelberg
69120 Heidelberg, Germany
Tel: +49 6221548227
Fax: +49 6221545604
klaus.unsicker@urz.uni-heidelberg.de

Dr. Tovar Karlheinz
leGene GmbH
82152 Martinsried, Germany
Tel: +49 8970076512
Fax: +49 8970076522
k.tovar@elegene.de

PD Dr. Pohlner John
EVOTEC Neurosciences GmbH
22525 Hamburg, Germany
Tel: +49 4056081273
Fax: +49 4056081222
john-pohlner@evotec.de
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