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New Diagnostic Tools for Alzheimer Disease Neue Diagnostische Instrumente Für Morbus Alzheimer Nouveaux Outils Diagnostiques Pour La Maladie D’Alzheimer

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New Diagnostic Tools for Alzheimer Disease Neue Diagnostische Instrumente Für Morbus Alzheimer Nouveaux Outils Diagnostiques Pour La Maladie D’Alzheimer (19) TZZ _T (11) EP 2 459 742 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12Q 1/68 (2006.01) G01N 33/68 (2006.01) 06.04.2016 Bulletin 2016/14 (86) International application number: (21) Application number: 10739350.6 PCT/EP2010/061020 (22) Date of filing: 29.07.2010 (87) International publication number: WO 2011/012672 (03.02.2011 Gazette 2011/05) (54) NEW DIAGNOSTIC TOOLS FOR ALZHEIMER DISEASE NEUE DIAGNOSTISCHE INSTRUMENTE FÜR MORBUS ALZHEIMER NOUVEAUX OUTILS DIAGNOSTIQUES POUR LA MALADIE D’ALZHEIMER (84) Designated Contracting States: • RAY SANDIP ET AL: "Classification and AL AT BE BG CH CY CZ DE DK EE ES FI FR GB prediction of clinical Alzheimer’s diagnosis GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO based on plasma signaling proteins" NATURE PL PT RO SE SI SK SM TR MEDICINE, NATURE PUBLISHING GROUP, NEW YORK, NY, US LNKD- DOI:10.1038/NM1653, vol. (30) Priority: 29.07.2009 US 229356 P 13, no. 11, 1 November 2007 (2007-11-01), pages 1359-1362, XP002544276 ISSN: 1078-8956 (43) Date of publication of application: • SCHIPPER HYMAN M: "The role of biologic 06.06.2012 Bulletin 2012/23 markersin the diagnosis of Alzheimer’s disease." ALZHEIMER’S & DEMENTIA : THE JOURNAL OF (73) Proprietor: Pharnext THE ALZHEIMER’S ASSOCIATION OCT 2007 92130 Issy les Moulineaux (FR) LNKD- PUBMED:19595953, vol. 3, no. 4, October 2007 (2007-10), pages 325-332, XP002597524 (72) Inventors: ISSN: 1552-5279 •COHEN,Daniel • BRITSCHGI MARKUS ET AL: "Blood protein 92210 Saint Cloud (FR) signature for the early diagnosis of Alzheimer • CHUMAKOV, Ilya disease." ARCHIVES OF NEUROLOGY FEB 2009 F-77000 Vaux le Penil (FR) LNKD- PUBMED:19064741, vol. 66, no. 2, • NABIROCHKIN, Serguei February 2009 (2009-02), pages 161-165, F-92290 Chatenay Malabry (FR) XP002597525 ISSN: 1538-3687 • GUERASSIMENKO, Oxana • ROGELJB ET AL: "The X11/Mint family of adaptor 91490 Milly-la-Forêt (FR) proteins" BRAIN RESEARCH REVIEWS, • GRAUDENS, Esther ELSEVIER, NL LNKD- 75017 Paris (FR) DOI:10.1016/J.BRAINRESREV.2006.04.005, vol. 52, no. 2, 1 September 2006 (2006-09-01), pages (74) Representative: Becker, Philippe et al 305-315,XP024996732 ISSN: 0165-0173 [retrieved Cabinet Becker & Associés on 2006-09-01] 25, rue Louis Le Grand • JACOBS E H ET AL: "Cyclin-dependent kinase 5, 75002 Paris (FR) Munc18a and Munc18-interacting protein 1/X11alpha protein up-regulation in Alzheimer’s (56) References cited: disease", NEUROSCIENCE; [1068-7971], NEW EP-A1- 1 774 972 WO-A1-2009/133142 YORK, NY, US, vol. 138, no. 2, 1 January 2006 WO-A2-2009/068591 JP-A- 2000 321 274 (2006-01-01), pages511-522, XP024986566, ISSN: 0306-4522, DOI: 10.1016/J.NEUROSCIENCE.2005.11.017 [retrieved on 2006-01-01] Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 459 742 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 459 742 B1 • ANONYMOUS: ’Mouse Alzheimers Array Map • GUEDJ M ET AL: "A refined molecular taxonomy Assay List’ APPLIED BIOSYSTEMS, [Online] 16 of breast cancer.", ONCOGENE 1 MAR 2012, vol. February 2009, page 3PP, XP055108631 31, no. 9, 1 March 2012 (2012-03-01), pages Retrieved from the Internet: 1196-1206, ISSN: 1476-5594 <URL:www6.appliedbiosystems.com/support/m • HYE A ET AL: "Glycogen synthase kinase-3 is ou se_alzheimers.xls> [retrieved on 2014-03-18] increased in white cells early in Alzheimer’s • ANONYMOUS: ’TAQMAN HUMAN ALZHEIMER’S disease",NEUROSCIENCE LETTERS, LIMERICK, ARRAY’ APPLIED BIOSYSTEMS, [Online] 01 IE, vol. 373, no. 1, 3 January 2005 (2005-01-03), February 2008, page 2PP, XP055108635 pages 1-4, XP004651063, ISSN: 0304-3940, DOI: Retrieved from the Internet: 10.1016/J.NEULET.2004.10.031 <URL:http://tools.lifetechnologies.com/cont • MARKSTEINER J ET AL: ’Glycogen-synthase ent/sfs/brochures/cms_042810.pdf> [retrieved kinase-3beta is decreased in peripheral blood on 2014-03-18] mononuclear cells of patients with mild cognitive • Fiona Pickford ET AL: "The autophagy-related impairment’ EXPERIMENTAL GERONTOLOGY protein beclin 1 shows reduced expression in vol. 44, no. 6-7, 01 June 2009, ELSEVIER early Alzheimer disease and regulates amyloid SCIENCE, OXFORD, GB, pages 370 - 371, [beta] accumulation in mice", Journal of Clinical XP026160417DOI: 10.1016/J.EXGER.2009.02.007 Investigation, 1 May 2008 (2008-05-01), ISSN: 0531-5565 XP055108608, ISSN: 0021-9738, DOI: • Josef Marksteiner ET AL: "Five out of 16 plasma 10.1172/JCI33585 signaling proteins are enhanced in plasma of • Jake Yue Chen ET AL: "MINING ALZHEIMER patients with mild cognitive impairment and DISEASE RELEVANT PROTEINS FROM Alzheimer’s disease", Neurobiology of Aging, INTEGRATED PROTEIN INTERACTOME DATA", vol. 32, no. 3, 1 March 2011 (2011-03-01), pages Pacific Symposium on Biocomputing 2006, 1 539-540, XP055146990, ISSN: 0197-4580, DOI: January 2006 (2006-01-01), pages 367-378, 10.1016/j.neurobiolaging.2009.03.011 XP055108616, Singapore DOI: 10.1142/9789812701626_0034 ISBN: 978-9-81-256463-4 2 EP 2 459 742 B1 Description FIELD OF THE INVENTION 5 [0001] The present disclosure relates to development, validation and application of new sets of biomarkers for diagnosis of Alzheimer’s disease (AD) and related disorders including early diagnosis of MCI and early prodrome of AD, identification of disease sub types, prediction of their response to disease management procedures, drugs and their combinations and for monitoring response for these treatment, including validation of biomarkers for clinical trials. In particular, the present disclosure relates to the field of detection and of monitoring treatment of neurodegenerative disorders, including 10 Alzheimer’s disease, prodrome condition of Alzheimer disease or mild cognitive impairment (MCI). More specifically, the present disclosure relates to proteinaceous, lipid, glucidic and metabolite biomarkers that can be measured in biological fluids, which can be used to aid in the detection, subclassification, prediction of drug treatment and follow up of this treatment of neurodegenerative disorders, including Alzheimer’s disease, its prodrome and mild cognitive impair- ment. The invention provides a method for detecting the presence or risk of AD, and the use of a hit. 15 BACKGROUND OF THE INVENTION [0002] AD is at present the most common cause of dementia. It is clinically characterized by a global decline of cognitive function that progresses slowly and leaves end-stage patients bound to bed, incontinent and dependent on custodial 20 care. Death occurs, on average, 9 years after diagnosis (Citron et al., 2004). The incidence rate of AD increases dra- matically with age. United Nation population projections estimate that the number of people older than 80 years will approach 370 million by the year 2050. Currently, it is estimated that 50% of people older than age 85 years are afflicted with AD. Therefore, more than 100 million people worldwide w ill suffer from dementia in 50 years. The vast number of people requiring constant care and other services will severely affect medical, monetary and human resources (Suh & 25 Checler, 2002). [0003] Currently, clinical diagnosis of AD is based on structured interviews (patient histories), and neuropsychological examinations coupled with imaging or neurophysiological scans (CT, MRI, PET and/or SPECT scans and EEG) to rule out other explanations of memory loss including temporary (depression or vitamin B12 deficiency) or permanent condi- tions (stroke) and is based on NINCDS-ADRDA Work group criteria (McKhann et al., 1984) and the American Psychiatric 30 Association Diagnostic and Statistical Manual of Mental Disorders (4th Ed. Washington D.C., Am Psychiatric Assoc., 1997). [0004] Unfortunately, clinical diagnostic methods are not foolproof. Evidence based review of current literature shows clinical diagnostic accuracy of 65 to 90%. Higher accuracy rates are generally associated with specialized centers (memory disorder clinics) focused on memory disorders whereas lower rates are likely associated with primary care 35 physicians. Additionally, accuracyof the clinical diagnosisis likely lower duringearly stagesof thedisease when symptoms are difficult to differentiate from normal age-associated cognitive decline. More recently, studies suggest that a condition termed mild cognitive impairment (MCI) represents prodromal AD and if diagnosed early represents the best opportunity for pharmaceutical intervention. The clinical criteria used for diagnosis of MCI are those of Petersen et al. (1999) and include: 1) memory complaints corroborated by an informant, 2) objective memory impairment for age and education, 40 3) normal general cognitive function, 4) intact activities of daily living, and 5) the subject does not meet criteria for demen tia. [0005] Further complicating diagnosis and treatment of AD is the lack of a reliable biomarker that specifically identifies AD subjects, particularly early in the prodromal stage of the disease (MCI). In view of the magnitude of the public health problem posed by AD, considerable research efforts have been undertaken to elucidate the etiology of AD as well as to identify biomarkers, characteristic proteins or metabolites objectively measured as an indicator of pathogenic proc- 45 esses, that can be used to diagnose and/or predict whether a person is likely to develop AD. [0006] Most studies of biomarkers of AD have focused on measurement in the cerebrospinal fluid (CSF). Because of its intimate contact with the brain, pathogenic changes in the brain that result in alterations in proteins/peptides would likely be reflected in the CSF. [0007] A number of U.S. patents and published applications relate to methods for diagnosing AD, including U.S.
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