WO2000068694A1 - Method for diagnosis of alzheimer's disease - Google Patents
Method for diagnosis of alzheimer's disease Download PDFInfo
- Publication number
- WO2000068694A1 WO2000068694A1 PCT/US2000/012167 US0012167W WO0068694A1 WO 2000068694 A1 WO2000068694 A1 WO 2000068694A1 US 0012167 W US0012167 W US 0012167W WO 0068694 A1 WO0068694 A1 WO 0068694A1
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- WIPO (PCT)
- Prior art keywords
- subject
- peptide
- disease
- plasma
- alzheimer
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Classifications
-
- 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 provides a method for diagnosing Alzheimer's disease (AD) in a subject. More particularly, a method for diagnosing AD by completely or nearly-completely releasing ⁇ -amyloid ⁇ -42 or A ⁇ 3pE from plasma or serum proteins and then analyzing the quantity of elevated levels of ⁇ -amyloid ⁇ -42 or A ⁇ 3pE found in AD patients, or those who are in the early stages of AD, or who will develop AD in the future.
- AD Alzheimer's disease
- AD Alzheimer's disease
- PD Parkinson's disease
- AD is characterized by neurofibrillary tangles, neuritic plaques, and neuronal cell death.
- AD appears as either the familial, early onset ( ⁇ 60 yrs) or late-onset (>60 yrs) forms, with the latter being more prevalent.
- AD is the major cause of age-related dementia and cognitive impairment (Wisniewski, T.; Ghiso, J.; Frangione, B. Neurobiol . of Disease 1997, 4, 313-328) .
- the amyloid various recently identified mutations accounting for certain types of inherited AD.
- a ⁇ 1 _ 40 is generally present to a much larger degree in the cerebrospinal fluid than A ⁇ x _ 42 , it is A ⁇ 1 _ 42 that is present to a greater degree in AD plaques.
- Another major amyloid related peptide found in plaques is an N- terminally truncated variant in which the two N-terminal amino acids are removed, and glutamic acid at position three has formed a pyroglutamyl residue.
- the A ⁇ 3pE has an increased tendency to form ⁇ -pleated sheets and aggregate than the parent amyloid peptides (He, W.; Barrow, C. J. Biochemistry 1999, 38 , 10871) .
- Another minor, related amyloid peptide is that m which the aspartic acid at residue one is present as the isoaspartic acid.
- the A ⁇ peptides can inhibit c olinergic neurotransmitter function independent of neurotoxicity (Auld, D. S . ; Kar, S . ; Qui ⁇ on, R. Trends Neurosci . 1998, 21 , 43) .
- a ⁇ peptides bind to a number of natural substances such as apoE3 , apoE4 , apoJ, transthyretin, and albumin.
- a ⁇ has been reported to interact with a membrane-bound receptor for advanced glycation end products and to the class A scavenger receptor (SR) associated with the production of reactive oxygen species .
- SR scavenger receptor
- the present invention incorporates a step involving the complete or nearly- complete dissociation of 42 , or related amyloid peptides such as A ⁇ 3pE, from serum or plasma samples obtained from humans, prior to analysis of ⁇ -amylo ⁇ d 142 or A ⁇ 3pE levels, as part of a diagnostic assay for the early detection of AD, or the propensity to develop AD m the future .
- the present invention is directed to a method of diagnosing Alzheimer's disease involving analysis of a plasma or serum sample in such a way that ⁇ -amylo ⁇ d 142 or A ⁇ 3pE is completely or nearly completely (ie., thoroughly) dissociated from binding proteins prior to the analysis of the levels of ⁇ -amyloidi 42 or A ⁇ 3pE .
- the procedure could be done at different times, and the relative increase m the levels of ⁇ -amyloid j ⁇ 42 or A ⁇ 3pE could be taken as a diagnostic component as to the presence of AD or the liability for developing AD m the future. Also, the relative increase m the levels of ⁇ - amyloid- L 42 or A ⁇ 3pE could be taken as a prognostic marker and a marker to monitor the progression of the disease. Levels of ⁇ amylo ⁇ d 1 42 or A ⁇ 3pE could be determined along with standard cognitive testing for additional assessment for prognosis and progression of the disease.
- the present invention provides a method of diagnosing
- Alzheimer's disease m a subject m need thereof comprising :
- the method may be further defined by adding a step to neutralize the dissociation reagent prior to analysis.
- This method is useful where the assay used to measure the quantity of A ⁇ peptide may be affected by the presence of an active dissociation reagent.
- a highly acidic or basic dissociation reagent may alter the pH of the plasma or serum sample such that an immunoassay technique is not possible.
- the present invention also provides a method of diagnosing Alzheimer's disease in a subject m need thereof comprising:
- subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation, biochemical screening, or experiment.
- a ⁇ peptide is a ⁇ -amyloid peptide- L 42 or enzymatically modified ⁇ -amyloid peptide, such as where aspartic acid at position one is modified to isoaspartic acid.
- Particularly preferred A ⁇ peptides are selected from the group consisting of ⁇ -amylo ⁇ d 142 and A ⁇ 3pE.
- binding protein is any protein to which ⁇ -amyloid peptides naturally bind, such as apoE3 , apoE4 , apoJ, transthyretm, and albumin.
- dissociation reagent is a material, preferably a solution, that causes A ⁇ peptide to dissociate from the binding protein, and optionally causes denaturation of the binding protein.
- Preferred dissociation reagents include acids, including formic acid, hydrochloric acid, acetic acid, sulfuric acid, bases, including sodium hydroxide, miscible organic solvents, including ethanol , methanol, DMSO, and DMF .
- the dissociation reagent may also be a detergent or surfactant including Triton X-100, Tween 20, Tween 80, and sodium dodecyl sulfate ("SDS") or a chaotropic agent lcludmg urea, and guanidimum chloride.
- a detergent or surfactant including Triton X-100, Tween 20, Tween 80, and sodium dodecyl sulfate ("SDS”) or a chaotropic agent lcludmg urea, and guanidimum chloride.
- SDS sodium dodecyl sulfate
- a chaotropic agent lcludmg urea guanidimum chloride
- Yet another type of dissociation reagent is a compound that inhibits ⁇ -amyloid aggregation, such as raloxifene and those compounds described m Curr . Med . Chem . 1997, 4, 159; and
- neutralizing reagent is a material, preferably a solution, that counteracts the dissociation reagents so that the final plasma or serum sample composition is suitable for an assay to measure the dissociated A ⁇ peptide.
- the dissociation reagent is an acid
- a suitable amount of a base as the neutralizing reagent
- the neutralizing reagent may be added to the plasma or serum sample to prepare it for an assay.
- a suitable amount of acid as the neutralizing reagent, may be added to the plasma or serum sample.
- a neutralizing reagent including miscible organic solvents or compounds that inhibit ⁇ -amyloid aggregation.
- thoroughly dissociated and/or “thoroughly dissociating” as used herein when referring to dissociation of A ⁇ peptide from binding protein means that the A ⁇ peptide is completely or nearly completely dissociated from the binding protein; that is, greater than 80% (preferably, >90%, more preferably, >95%) .
- the levels of A ⁇ peptide are measured by methods known in the art including, but not limited to, lmmunoassay techniques, HPLC analysis, HPLC/MS (mass spectral) analysis, MALDI/TOF (matrix-assisted laser desorption / time-of-flight ) mass spectral analysis, size exclusion chromatography, thioflavm-T or Congo Red staining, or
- ES/MS electrospray lonization mass spectral
- a particularly preferred assay format is the immunoassay format, wherein the A ⁇ peptide is isolated from the plasma or serum sample using one affinity capture reagent, and is detected with a affinity label reagent.
- the affinity capture or affinity label reagents comprise compounds capable of specific interaction with the A ⁇ peptide to the exclusion of similar compounds . These compounds include, for example, synthetic or natural ammo acid polypeptides, proteins (including antibodies), small synthetic organic molecules, or deoxy- or ribo- nucleic acid sequences with about 20-fold or greater affinity for the A ⁇ peptide compared to other proteins or peptides.
- the labeled compounds useful m the present invention may be labeled compounds, with means of direct detection, or may be detected by an indirect means, for example by a second labeled compound.
- labeled compound refers to moieties capable of measurement comprising radioactive atoms, enzymes, fluorescent molecules, or alternative tags, for example biotm.
- radioactive atoms particularly atoms, enzymes, fluorescent molecules, or alternative tags, for example biotm.
- radioisotopes useful as a label the present invention are 3 H, 125 I, 13 I, 35 S, 32 P, or 33 P.
- enzymes suitable for use m the present invention are horseradish peroxidase, alkaline phosphatase, or luciferase.
- a preferred example of a detectable label is an enzyme that cleaves a substrate to yield a chromogenic or luminescent product.
- fluorescent molecules are fluorescein (FITC) , rhodamme, R-phycoeryth ⁇ n (PE) or AlexaTM dyes (Molecular Probes) .
- Direct measurement is conducted by observing the presence of the radioactive atom or flourogenic molecule, or by observation of enzymatic activity of a colorimetric or luminescent substrate.
- Indirect measurement is conducted by adding an additional compound including a label to the plasma or serum sample so that it can interact with the compound bound to the plasma or serum sample.
- the labeled compound comprises biotin
- a second compound comprises avidin or streptavid and a detectable label .
- a second well-known example is when a first antibody is used to bind to the A ⁇ peptide and is detected with an anti-antibody comprising a detectable label.
- the first antibody comprises a label m that there are specific regions capable of detection within the structure of the first antibody.
- an immunoassay diagnostic kit which all of the components required for a viable diagnostic determination are packaged together sufficient for complete or nearly-complete dissociation of A ⁇ peptide from a plasma or serum sample and subsequent analysis of the levels of the A ⁇ peptide such as by an ELISA (enzyme linked immunosorbant assay) .
- the components of an immunoassay diagnostic kit include a dissociation reagent, optionally a neutralizing reagent, and an affinity capture reagent, for instance, an affinity coated resin, an affinity label reagent, and optionally immunoassay control reagents.
- Immunoassay control reagents are those that confirm proper function of the assay system and serve to validate interpretation of the sample.
- a negative control is one that yields no signal from the affinity label reagent, and is often used to determine the background noise of an assay system or used to calculate the signal to noise ratio for a positive sample using calculations well known m the art.
- a positive control is one that yields a signal from the affinity label reagent, and is often used to validate the assay system or to compare to a sample to interpret the status of the sample. This can be done empirically using a "yes/no" system or can be made quantitative by comparing the signal generated by control samples containing known quantities of AD peptide with a test sample.
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU49844/00A AU4984400A (en) | 1999-05-07 | 2000-05-05 | Method for diagnosis of alzheimer's disease |
EP00932062A EP1177447A1 (en) | 1999-05-07 | 2000-05-05 | Method for diagnosis of alzheimer's disease |
CA002373150A CA2373150A1 (en) | 1999-05-07 | 2000-05-05 | Method for diagnosis of alzheimer's disease |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13316199P | 1999-05-07 | 1999-05-07 | |
US60/133,161 | 1999-05-07 | ||
US17997500P | 2000-02-03 | 2000-02-03 | |
US60/179,975 | 2000-02-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000068694A1 true WO2000068694A1 (en) | 2000-11-16 |
Family
ID=26831109
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/012167 WO2000068694A1 (en) | 1999-05-07 | 2000-05-05 | Method for diagnosis of alzheimer's disease |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1177447A1 (en) |
AU (1) | AU4984400A (en) |
CA (1) | CA2373150A1 (en) |
WO (1) | WO2000068694A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001057537A2 (en) * | 2000-02-03 | 2001-08-09 | Ortho-Mcneil Pharmaceutical, Inc. | Methods for diagnosis of alzheimer's disease |
CN105339798A (en) * | 2013-04-26 | 2016-02-17 | 韩国科学技术研究院 | Diagnostic kit for diagnosing disorders or diseases related to abnormal protein aggregation or misfolding of protein using dissolution of protein aggregates |
-
2000
- 2000-05-05 WO PCT/US2000/012167 patent/WO2000068694A1/en not_active Application Discontinuation
- 2000-05-05 AU AU49844/00A patent/AU4984400A/en not_active Abandoned
- 2000-05-05 CA CA002373150A patent/CA2373150A1/en not_active Abandoned
- 2000-05-05 EP EP00932062A patent/EP1177447A1/en not_active Withdrawn
Non-Patent Citations (2)
Title |
---|
KUO, Y-M ET AL.: "Amyloid - beta peptides interact with plasma proteins and erythrocytes: implications for their quantitation in plasma.", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS., vol. 268, February 2000 (2000-02-01), ACADEMIC PRESS INC. ORLANDO, FL., US, pages 750 - 756, XP002148039, ISSN: 0006-291X * |
KUO, Y-M ET AL.: "High levels of circulating Abeta42 are sequestered by plasma proteins in Alzheimer's disease", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS., vol. 257, no. 3, 21 April 1999 (1999-04-21), ACADEMIC PRESS INC. ORLANDO, FL., US, pages 787 - 791, XP002148038, ISSN: 0006-291X * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001057537A2 (en) * | 2000-02-03 | 2001-08-09 | Ortho-Mcneil Pharmaceutical, Inc. | Methods for diagnosis of alzheimer's disease |
WO2001057537A3 (en) * | 2000-02-03 | 2002-02-21 | Ortho Mcneil Pharm Inc | Methods for diagnosis of alzheimer's disease |
CN105339798A (en) * | 2013-04-26 | 2016-02-17 | 韩国科学技术研究院 | Diagnostic kit for diagnosing disorders or diseases related to abnormal protein aggregation or misfolding of protein using dissolution of protein aggregates |
EP2990801A4 (en) * | 2013-04-26 | 2016-11-30 | Korea Inst Sci & Tech | Diagnostic kit for diagnosing disorders or diseases related to abnormal protein aggregation or misfolding of protein using dissolution of protein aggregates |
US10006920B2 (en) | 2013-04-26 | 2018-06-26 | Korea Institute Of Science And Technology | Diagnostic kit for diagnosis of abnormal protein aggregation- or misfolding-related diseases using dissociation of protein aggregates |
Also Published As
Publication number | Publication date |
---|---|
AU4984400A (en) | 2000-11-21 |
CA2373150A1 (en) | 2000-11-16 |
EP1177447A1 (en) | 2002-02-06 |
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