WO1992000521A1 - Procedes de diagnostic et de pronostic bases sur des derives solubles du precurseur de proteine beta amyloide - Google Patents

Procedes de diagnostic et de pronostic bases sur des derives solubles du precurseur de proteine beta amyloide Download PDF

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Publication number
WO1992000521A1
WO1992000521A1 PCT/US1991/004607 US9104607W WO9200521A1 WO 1992000521 A1 WO1992000521 A1 WO 1992000521A1 US 9104607 W US9104607 W US 9104607W WO 9200521 A1 WO9200521 A1 WO 9200521A1
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Prior art keywords
kilodalton
protein
soluble
patient
amino
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PCT/US1991/004607
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English (en)
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Steven G. Younkin
Mark R. Palmert
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Case Western Reserve University
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Publication of WO1992000521A1 publication Critical patent/WO1992000521A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer

Definitions

  • the present invention relates to methods which can be used to diagnose, prognose, and stage Alzheimer's disease, and monitor response to therapy of Alzheimer's disease. Such methods involve the measurement of the levels in cerebrospinal fluid of the -25 kDa, -105 kDa, and -125 kDa soluble derivatives of the beta amyloid precursor protein.
  • the invention also provides for evaluation and monitoring of neurologic aging.
  • the methods of the invention can also be used to diagnose Down's syndrome and prognose deleterious sequelae of amyloid deposition.
  • Alzheimer's disease is a progressive neurodegenerative disorder of the aged and is a major cause of adult-onset dementia. It is characterized by cerebral depositions of amyloid.
  • the principal proteinaceous component of the amyloid deposited in senile plaques and cerebral blood vessels in Alzheimer's disease is a 39-42 amino acid polypeptide ( ⁇ amyloid protein, /3AP) (Glenner G. G. and Wong, C. W. , 1984, Biochem. Biphys. Res. Commun. 122:1131-1135; Masters et al., 1985, Proc. Natl. Acad. Sci.
  • ⁇ amyloid protein precursor ⁇ APP
  • the 0APP gene produces at least three mRNAs (Kitaguchi et al., 1988, Nature 331:530-532; Ponte et al., 1988, Nature 331:525-527; Tanzi et al., 1988 Nature 331:528-530) through alternative splicing of two exons (Kitaguchi et al., 1988, Nature 331:530-532).
  • One these exons encodes a 19-amino acid domain; the other encodes.
  • a 56-amino acid domain that is highly homologous the Kunitz family of serine protease inhibitors.
  • the 39-to 42-residue / SAP occurs as an internal sequence which extends from the extracellular region into the putative membrane-spanning domain (Kang e al., 1987, Nature 325:733-736; Dyrks et al., 1988, EMBO J. 7:949-947).
  • the full-length forms of this precursor are truncated at their carboxyl-termini to produce -125 and -105 kDa (kilodalton) soluble derivatives (Schubert et al.
  • the -125 kDa derivative which appears to be the same protein as protease nexin-II (Oltersdorf et al., 1989, Nature 341:144-147 and Van Nostrand et al., 1989, Nature 341:546-549), contains the alternatively spliced (Kitaguch et al., 1988, Nature 331:530-532) Kunitz protease inhibito (KPI) domain, whereas the -105 kDa form lacks this insert (Palmert et al., 1989, Proc. Natl. Acad.
  • Alzheimer's type lesions containing amyloid protein are found in adult cases of Down's syndrome (Ball and Nuttall, 1981, Neuropathol. Appl. Neurobiol. 7:13).
  • the present invention relates to methods for the prognosis, diagnosis, and staging of AD. It further relates to methods for monitoring response to therapy in a patient with AD.
  • the methods of the invention involve the measurement of the levels in a sample of cerebrospinal fluid (CSF) of the -25 kDa, -105 kDa, and -125 kDa soluble derivatives of the APP.
  • CSF cerebrospinal fluid
  • detection of an increase in the percentage amount of the ⁇ 25 kDa protein and/or decrease in the percentage amount of the -105 kDa derivative and/or high absolute levels of all three soluble 0APP derivatives, relative to healthy individuals can be used to diagnose or prognose AD.
  • such detection can be used to diagnose Down's syndrome, and to prognose disorders in Down's syndrome patients associated with amyloid deposition.
  • the foregoing can also be used as an indication of neurologic aging.
  • determination of the percentage amounts of the -25 kDa protein and/or the -105 kDa protein can be used to stage AD, or to indicate the extent of mental dementia in a patient.
  • an increase in the percentage amount of -25 kDa protein and/or a decrease in the percentage amount of -105 kDa protein relative to such amount present prior to therapy or in healthy individuals can be deemed a poor response to therapy.
  • the invention is also directed to the soluble -25 kDa amino-ter inal form of the 0APP.
  • FIG. 1 Amino-terminal sequence (single letter code) of the -25 kDa soluble protein found in human CSF. X indicates that the signal was weak and did not permit an amino acid to be assigned. Note that the amino acid sequence predicted from 0APP cDNA (Kang et al., 1987, Nature 325:733-736) begins with a 17-residue signal sequence identified by Dyrks et al. (Dyrks et al., 1988, EMBO J. 7:949-957). Thus the amino-terminal residue of the mature protein is located at position 18 of the predicted sequence. ' FIG. 2. Standard curves from a protein A experiment.
  • FIGURE 3 Derivatives that may be produced when full-length 0APP is cleaved generating soluble forms (adapted from Palmert et al., 1989, Biochem. Biophys. Res. Commun. 165:182-188).
  • the solid bar in each schematic indicates the position of the / 3AP.
  • the relative sizes of the membrane-associated and soluble forms (Palmert et al., 1989, Proc. Natl. Acad. Sci. USA 86:6338-6342) and the observation that the soluble -125 and -105 kDa derivatives in CSF are labeled by antisera to the ⁇ AP (Palmert et al., 1989, Biochem. Biophys. Res. Commun. 165:182-188) indicates that cleavage normally occurs as shown in A or B. The cleavage shown in C may sometimes occur in normal individuals, and it could develop or be enhanced in AD.
  • the present invention is directed to methods of prognosis and diagnosis of AD. It also relates to methods of staging AD and to monitoring response to therapy in a patient with AD.
  • the invention is based upon the measurement-in cerebrospinal fluid (CSF) of a patient of the levels of soluble derivatives of the 0APP, in particular, the approximately (-) 25 kDa, -125 kDa, and -105 kDa soluble forms.
  • the invention is directed to the soluble. -25 kDa amino-terminal form of the APP.
  • the methods provided by the present invention also allow evaluation and monitoring of neurologic aging in an individual.
  • the invention further provides methods for diagnosis of Down's syndrome.
  • soluble as used herein shall mean th which is “not cell-associated, not due to any artificial intervention," as opposed to the term “solubilized,” whic refers to that which is artificially released from a cell surface into solution, e.g., by detergent cell lysis.
  • the methods provided by the present invention involve the measurement of the levels of soluble derivatives of the 0APP in cerebrospinal fluid of a patient.
  • soluble derivatives are selected from the group consisting of the -25 kDa, -105 kDa, and the -125 k ,9APP derivatives, which derivatives consist of a portion o the sequence of the 0APP starting with (as their amino- terminal residue) the amino acid at position 18 of the predicted 0APP sequence (see Kang, 1987, Nature 325:733- 736).
  • the levels of one o more of the above-mentioned soluble derivatives are measured in CSF from a patient.
  • CSF can be obtained by any procedures known in the art.
  • CSF can be obtained by lumbar puncture.
  • Dialysis into desired buffers and concentration before analysis can also be carried out.
  • Measurement of the soluble 3APP derivatives can be by any techniques known in the art.
  • an immunoblotting (Western blotting) procedure with appropriate antisera can be used to quantitate the soluble derivative(s) (see Examples sections, infra) .
  • blots e.g., nitrocellulose
  • denaturing e.g., sodium dodecyl sulfate-polyacrylamide
  • Such an appropriate antibody is one reactive with the soluble derivative being quantitated.
  • antibodies which can be used include but are not limited to an antiserum against amino acids 45-62 in the APP sequence described by Kang et al., 1987, Nature 325:733-736) (anti- ⁇ APP._ _ configure) , and an antiserum to residues 18-35 of the APP. It is expected that antibodies recognizing an epitope within a -25 kDa fragment of the y9APP starting at amino acid 18 should be suitable for such use.
  • the antibody thus employed can be labeled, or it can be reacted with a labeled binding partner of the antibody (e.g. 125I-labeled protein A) for detection and quantitation purposes.
  • a labeled binding partner of the antibody e.g. 125I-labeled protein A
  • assays suitable for use will be known to those skilled in the art, including but not limited to assays employing one or more of the following techniques: chromatography (e.g.; ion exchange, immunoaffinity, immunoabsorption, and sizing chromatography such as high pressure liquid chromatography) , centrifugation, electrophoretic procedures, differential solubility, competitive and non- competitive immunoassay systems using techniques such as radioimmunoassays, ELISA (enzyme linked immunosorbent assay) , "sandwich” immunoassays, precipitation reactions, gel diffusion precipitation reactions, immunodiffusion assays, agglutination assays, complement-fixation as
  • Antibodies against the soluble 0APP derivatives for use in immunodetection assays can be produced by methods known in the art. Such antibodies can be polyclonal or monoclonal.
  • various procedures known in the art may be used for the production of polyclonal antibodies to epitopes of a given soluble ,9APP derivative.
  • various host animals can be immunized by injection with 0APP, or a fragment thereof, or synthetic protein or peptide corresponding to the foregoing, including but not limited to rabbits, mice, rats, etc.
  • Various adjuvants may be used to increase the immunological response, depending on the host species.
  • a monoclonal antibody can be prepared by using any technique which provides for the production of antibody molecules by continuous cell lines in culture. These include but are not limited to the hybridoma technique originally described by Kohler and Milstein (1975, Nature 256:495-497), and the human B cell hybridoma technique (Kozbor et al., 1983, Immunology Today 4:72) and EBV- hybridoma technique (Cole et al., 1985, Monoclonal
  • Antibody fragments which contain the idiotype (binding region) of the molecule can also be used, and ca generated by known techniques.
  • fragmen include but are not limited to: the F(ab'j fragment whic can be produced by pepsin digestion of the antibody molec the Fab' fragments which can be generated by reducing the disulfide bridges of the F(ab')_ fragment, and the Fab fragments which can be generated by treating the antibody molecule with papain and a reducing agent.
  • the quantitation of the soluble 3APP derivative( in CSF according to the present invention can be used for diagnosis, staging and/or prognosis of AD. Such quantitat can also be used to monitor therapy of a patient with AD.
  • detection of an. increa in the percentage amount (% of total -25 kDa + -125 kDa + • -105 kDa soluble 0APP derivatives) of the -25 kDa derivati and/or a decrease in the percentage amount of the -105 kDa derivative, relative to healthy individuals can be used a an indication of the presence or impending onset of AD, or predicting the course of AD particularly when serial measurements are made.
  • Increased percentage of the -25 kD protein and/or decreased percentage of -105 kDa protein, and/or high absolute levels of all three soluble 0APP derivatives in non-demented individuals can be a significa risk factor such that a high percentage of the non 7 demente individuals who show such a profile eventually develop AD.
  • the percentage amount of the -25 kDa protein, and/or the percentage amount of the -105 kDa protein can be used to stage AD patients, and as an indication of the mental stat of the AD patients (see. Examples sections, infra) .
  • Such percentage amounts can also be used to monitor therapeutic strategies for AD, such as those aimed at reducing amyloid deposition. For example, an increase in the percentage amount of -25 kDa derivative, and/or decrease in the percentage amount of -105 kDa derivative relative to such amount present prior to therapy or in healthy individuals, can be deemed a poor response to therapy.
  • An increase in the percentage amount of the -25 kD protein, and/or a decrease in the percentage amount of the -105 kDa protein, and/or an increase in the absolute amount(s) of one or more of the soluble ,5APP derivatives ca also be used as an indication of neurologic aging.
  • detection of such an increase for t -25 kDa protein and/or decrease for the -105 kDa protein, o increased absolute amounts, relative to young individuals (e.g., those individuals under age 60), can indicate neurologic aging.
  • the ratios of the level(s) of one or more of the soluble 0APP derivative(s) to the level(s) of one or more different soluble 0APP derivatives can be calculated for use in the methods of the present invention.
  • the ratio o the amount of -25 kDa protein-to the amount of -105 kDa protein in a- sample of CSF can be determined for use in a method of diagnosis, prognosis, staging, or monitoring therapy, as provided by the present invention.
  • kits for use in practicing the methods of the invention comprise, in one or more containers, one or more antibodies directed against th soluble / 5APP derivative(s) being quantitated. 5.3. DIAGNOSIS OF DOWN'S SYNDROME
  • the invention further provides methods for diagnosis of Down's syndrome.
  • methods based on measurements of the soluble / 3APP derivatives including but not limited to detection of an increase in the percentage amount (% of total -25 kDa and
  • -25 kDa derivative and/or a decrease in the percentage amou in CSF of the -105 kDa derivative, relative to healthy individuals, can be used as an indication of the presence o
  • Down's syndrome or as an indication of the presence or impending onset in the Down's syndrome patient of disorders associated with amyloid deposition (e.g., mental dementia).
  • disorders associated with amyloid deposition e.g., mental dementia
  • CSF human cerebrospinal fluid
  • AD Alzheimer's disease
  • the -25 kDa protein was purified from CSF using ammonium sulfate fractionation, separation on a Mono-Q column (Pharmacia) , and preparative SDS/PAGE as previously described for the -125 and -105 kDa proteins (Palmert et al., 1989, Proc. Natl. Acad. Sci. USA 86:6338-6342). Briefly, the / 3APP derivative was separated from the bulk (75%) of the,CSF protein by fractionation at 62.5% of ammonium sulfate saturation (0.41 g/ml) .
  • the resulting pellet was resuspended in 20 mM sodium phosphate (monobasic) buffer ' (pH 6.8), desalted, and loaded onto a Mono Q column (Pharmacia) .
  • a linear 0 to 1 M NaCl gradient in 20 mM sodium phosphate (monobasic) buffer, pH 6 * 8, containing 0.05% Tween 20 was then applied to the column, and the -25 kDa derivative (along with -125 and -105 kDa derivatives) was eluted in a well defined peak at -60% (0.6 M NaCl) of the gradient.
  • Nitrocellulose blots were, then blocked with 5% nonfat dried milk diluted in TBS (10 mM Tris-HCl, pH 8 and 150 M NaCl) ; exposed overnight to anti- ⁇ APP.- g- (Palmert et al., 1988, Biochem. Biophys. Res. Commun. 156:432-437; Palmert et al., 1989, Proc. Natl. Acad. Sci.
  • the size of the excised area corresponded to the typical band size and was uniform from experiment to experiment.
  • CSF CSF was obtained by lumbar puncture 0 with removal of 20 ml of fluid which was then aliquoted into 2 ml containers. Patients were at bed rest for several hours before and after the examination. All psychotropic medications were withdrawn prior to the lumbar puncture. CSF (240 ⁇ l) from each case was exchanged into 1 g mM dibasic/monobasic (1.6/1) phosphate buffer (pH 6.9), concentrated, and analyzed as described above for the standards. Each experiment contained both AD and control samples, which were loaded into alternating.lanes of each gel. 0
  • the -25 kDa protein like the -125 and -105 kDa proteins, is an amino-terminal derivative of the 0APP.
  • the " ⁇ 25 kDa derivative” consists of a major band and 1 or 2 minor bands that migrate at -25 kDa on 5-15% SDS-polyacrylamide gels. All of these bands are specifically labeled by anti- / 3APP.__ 62 and by an antiserum to residues 18-35 of the 0APP.
  • Our sequence and the quantitative data shown below are from the.-.major protein within this complex.
  • AD patients (10 samples were obtained at autopsy and 14 were obtained conventionally from living patients) and 12 non-demented controls (including 3 non-demented patients with Parkinson's disease, 3 with multiple sclerosis, 1 with recurrent encephalitis, 1 with acute psychosis, 1 with hypersomnia, and 3 with no neurological disease) are summarized in Tables I and II.
  • Non-demented controls (30-60 yrs)
  • Non-demented controls (62-79 yrs)
  • Non-demented controls 55-79 yrs) 7 AD (52-73 yrs) 13
  • Non-demented controls (30-60 yrs) 7 45+4 1.5+0.6 6.2+1.6 1.3+0.4 9.0+2.5
  • Non-demented controls (55-79 yrs) 7 65+3 6.8+2.4 10.2+2.1 2.3+0.5 19.3+4.6 AD (52-73 yrs) 13 65+2 6.3+1.0 7.8+3.1 1.6+0.4 15.9+4.3
  • t APP derivatives in CSF indicate that both factors may contribute to amyloid deposition in AD.
  • the percentage of the -105 kDa form is decreased and the percentage of the -25 kDa form is increased in normal aging and, to a greater extent, in AD, indicating that APP processing is altered in these conditions.
  • the absolute levels of soluble 0APP derivatives are increased in elderly control subjects and, to a greater extent, in the least demented AD patients.
  • the altered relative amounts of the -25 and -105 kDa derivatives in CSF correlate remarkably well with amyloid deposition in the sense that they change modestly in the elderly population where there is limited amyloid deposition, show more marked alteration in AD patients where amyloid deposition is pronounced, and change progressively as the severity of dementia increases in the AD population.
  • the AD and age-matched control populations though significantly different, were overlapping with respect to the absolute and relative levels of 0APP derivatives measured in CSF. These measurements may be useful (i) as part of a series of tests aimed at diagnosing AD, (ii) in predicting the course of AD particularly when serial measurements are made, and (iii) in monitoring therapeutic strategies aimed at reducing amyloid deposition.
  • AD-like profile for these variables is a significant risk factor and that a high percentage of the non-demented individuals who show such a profile eventually develop AD.
  • Various references are cited herein, the disclosures of which are incorporated by reference in the entireties.

Abstract

Procédés de pronostic, de diagnostic et de détermination des stades de la maladie d'Alzheimer, et procédé de contrôle de la réponse à une thérapie chez un patient atteint de la maladie d'Alzheimer. Les procédés de l'invention consistent à mesurer le niveau dans un échantillon de liquide cérébrospinal (LCS) des dérivés solubles de ∩25 kDa, ∩105 kDa, et ∩125 kDa du précurseur de protéine bêta amyloïde βAPP). Dans des modes de réalisation spécifique, on peut utiliser la détection d'une augmentation du pourcentage de protéine ∩25 kDa et/ou l'augmentation du pourcentage du dérivé de ∩105 kDa et/ou des niveaux absolus élevés des trois dérivés de βAPP solubles, par rapport à des individus sains afin de diagnostiquer ou de pronostiquer la maladie d'Alzheimer. On peut également utiliser les éléments précités afin de diagnostiquer la trisomie 21, afin de pronostiquer chez des patients trisomiques 21 des troubles associés à un dépôt amyloïde, et comme indication de vieillissement neurologique. Dans d'autres modes de réalisation, on peut considérer que la détermination des quantités en pourcentage de la protéine de ∩25 kDa et/ou la protéine de ∩105 kDa par rapport à ladite quantité présente avant la thérapie ou chez des individus sains, est une faible réponse à la thérapie de la maladie d'Alzheimer. L'invention concerne également la forme terminale amino-soluble de ∩25 kDa du βPPA.
PCT/US1991/004607 1990-06-29 1991-06-27 Procedes de diagnostic et de pronostic bases sur des derives solubles du precurseur de proteine beta amyloide WO1992000521A1 (fr)

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US6300540B1 (en) 1991-01-21 2001-10-09 Elan Pharmaceuticals, Inc. Transgenic mouse expressing an APP-FAD DNA sequence
US5877015A (en) * 1991-01-21 1999-03-02 Imperial College Of Science, Technology Of Medicine APP770 mutant in alzheimer's disease
US5705401A (en) * 1991-11-12 1998-01-06 The University Of Melbourne Method of assaying for alzheimer's disease
US5721130A (en) * 1992-04-15 1998-02-24 Athena Neurosciences, Inc. Antibodies and fragments thereof which bind the carboxyl-terminus of an amino-terminal fragment of βAPP
US5441870A (en) * 1992-04-15 1995-08-15 Athena Neurosciences, Inc. Methods for monitoring cellular processing of β-amyloid precursor protein
US6018024A (en) * 1992-04-15 2000-01-25 Elan Pharmaceuticals Methods and compositions for monitoring cellular processing of beta-amyloid precursor protein
US5604102A (en) * 1992-04-15 1997-02-18 Athena Neurosciences, Inc. Methods of screening for β-amyloid peptide production inhibitors
EP0638172A1 (fr) * 1992-04-15 1995-02-15 Athena Neurosciences, Inc. PROCEDES ET COMPOSITION DE CONTROLE DU TRAITEMENT CELLULAIRE DE LA PROTEINE PRECURSEUR $g(b)-AMYLOIDE
EP0638172A4 (fr) * 1992-04-15 1997-03-19 Athena Neurosciences Inc PROCEDES ET COMPOSITION DE CONTROLE DU TRAITEMENT CELLULAIRE DE LA PROTEINE PRECURSEUR -g(b)-AMYLOIDE.
US7993627B2 (en) 1992-07-10 2011-08-09 Elan Pharmaceuticals, Inc. Methods for determining whether a compound alters the amount of at least one αβ (X-41) peptide and the amount of either total αβ or at least one αβ (X-40) peptide produced by a non-human mammal
US5605811A (en) * 1992-10-26 1997-02-25 Athena Neurosciences, Inc. Methods and compositions for monitoring cellular processing of beta-amyloid precursor protein
EP0667959A4 (fr) * 1992-10-26 1998-07-08 Dale B Schenk PROCEDES ET COMPOSITIONS VISANT A DETECTER UN PEPTIDE -g(b)-AMYLOIDE SOLUBLE.
EP1298436A3 (fr) * 1992-10-26 2003-07-09 Elan Pharmaceuticals, Inc. Composés inhibiteurs de la libération du peptide beta-amyloide (BAP) pour le traitement de maladies associées au BAP et procédés de leur identification
EP1298436A2 (fr) * 1992-10-26 2003-04-02 Elan Pharmaceuticals, Inc. Composés inhibiteurs de la libération du peptide beta-amyloide (BAP) pour le traitement de maladies associées au BAP et procédés de leur identification
EP0667959A1 (fr) * 1992-10-26 1995-08-23 SCHENK, Dale, B. PROCEDES ET COMPOSITIONS VISANT A DETECTER UN PEPTIDE $g(b)-AMYLOIDE SOLUBLE
WO1995005604A2 (fr) * 1993-08-13 1995-02-23 Molecular Geriatrics Corporation Procedes de diagnostic de la maladie d'alzheimer
WO1995005604A3 (fr) * 1993-08-13 2001-09-13 Molecular Geriatrics Corp Procedes de diagnostic de la maladie d'alzheimer
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