WO2001040261A1 - Method of diagnosing neurodegenerative disease - Google Patents
Method of diagnosing neurodegenerative disease Download PDFInfo
- Publication number
- WO2001040261A1 WO2001040261A1 PCT/US2000/031467 US0031467W WO0140261A1 WO 2001040261 A1 WO2001040261 A1 WO 2001040261A1 US 0031467 W US0031467 W US 0031467W WO 0140261 A1 WO0140261 A1 WO 0140261A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acetylcholine receptor
- nicotinic acetylcholine
- test sample
- receptor protein
- cell
- Prior art date
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Classifications
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- 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
- G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
- G01N33/9406—Neurotransmitters
- G01N33/944—Acetylcholine
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/286—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against neuromediator receptors, e.g. serotonin receptor, dopamine receptor
-
- 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
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
- G01N2333/4709—Amyloid plaque core protein
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/70571—Assays involving receptors, cell surface antigens or cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor
-
- 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
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Definitions
- 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 or late-onset 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 only effective diagnostic method consists of cognitive function of the patient. There is a need to develop sensitive, biochemical methods to determine the prognosis, progression, and monitor therapeutic efficacy of subjects likely to develop or suffering from Alzheimer's disease.
- the neurotoxic ⁇ -amyloid peptide 1-4 [A ⁇ _4 2 ] is abundantly present in the amyloid plaques of Alzheimer's disease (AD) brains and also modulates cholinergic functions which are critical in memory and cognitive neurophysiology (Auld, D.S., Kar, S., Quirion, R. Trends Neurosci 1998; 21: 43-49).
- a ⁇ ,. ⁇ interacts selectively and with high affinity to the neuronal pentameric cation channel ⁇ 7 nicotinic acetylcholine receptor (Wang, H.-Y. et al . J. Biol . Chem. 2000, in press) .
- nAChRs nicotinic acetylcholine receptors
- compounds that activate nAChRs, especially of the alpha-7 subtype have been found to have in vivo activity in models of cognition enhancement (US Patent No. 5,741,802, issued April 21, 1998).
- Amyloid precursor protein can be induced on the cell surface of human lymphocytes upon stimulation (Bullido et al . , Biochim Biophys Acta 1996 Aug 21;1313 (1) :54-62) and increased APP-770 isoform occurs in lymphocytes from AD patients (Ebstein et al., Brain Res Mol Brain
- ⁇ 7 nicotinic acetylcholine receptor mRNA was equally distributed in all areas of the brain except the hippocampus, where AD subjects exhibited higher mRNA levels than the control population.
- lymphocytes from AD patients exhibit an increased mRNA level for ⁇ 7 nicotinic acetylcholine receptor (Hellstrom-Lindahl et al.. Brain Res Mol Brain Res 1999 Mar 20;66 (1-2) : 94-103) .
- nicotinic acetylcholine receptor binding in brains of AD and control subjects showed no significant difference (Lang, W. and Henke, H. Brain Res 1983; 267: 271-280).
- the present invention provides the unexpected observation that ⁇ 7 nicotinic acetylcholine receptor protein levels are decreased in neuronal tissue, thus forming the basis of a biochemical assay to diagnose Alzheimer's disease. Summary of the invention
- the present invention provides methods for diagnosing Alzheimer's disease, monitoring the progression and prognosis of Alzheimer's disease and/or monitoring the therapeutic efficacy of any intervention or treatment of Alzheimer's disease comprising:
- test sample comprises a cell, said cell expressing ⁇ 7 nicotinic acetylcholine receptor protein;
- test sample comprises a cell, said cell expressing ⁇ 7 nicotinic acetylcholine receptor protein;
- FIG. 1 ⁇ 7 nicotinic acetylcholine receptor protein levels in Alzheimer's disease (AD) brains are reduced. Equal amounts of hippocampal proteins from AD or control subjects were subjected to electrophoresis and Western blot analysis using anti- ⁇ 7 nicotinic acetylcholine receptor antibodies . The intensity of the bands was measured by densitometry . Representative data from three AD [Al-3] and control [Cl-3] are shown. Molecular weight markers in kiloDalton are shown.
- the present invention also provides tools useful for diagnosing
- Alzheimer's disease exhibits neuropathological abnormalities in the olfactory system located in the nasal cavity. These include the presence of dystrophic neurites that exhibit i munoreactivity for tau, neurofilaments, apolipoprotein E and other proteins, abnormal tau protein, increase in superoxide dismutase, and ⁇ amyloid deposition in the primary sensory (olfactory receptor) cells and nerve fibres of the nasal ucosa tissue (Arnold et al., Ann N Y Acad Sci 1998 Nov 30;855:762-75; Hock et al .
- Olfactory neuroblasts olfactory neurons obtained by biopsy and placed in primary cell culture
- AD patients produce carboxyl terminal amyloid precursor protein (APP) fragments that contain ⁇ amyloid (A ⁇ )
- APP carboxyl terminal amyloid precursor protein
- a ⁇ ⁇ amyloid
- Crino et al . showed labeling of A ⁇ in the basal third of the olfactory neuroepithelium and in axons projecting through the lamina intestinal of AD patients .
- Thioflavin-S staining that detects amyloid deposition was also observed in the basal third of the olfactory neuroepithelium from AD patients.
- ⁇ 7 nicotinic acetylcholine receptors are present in olfactory neurons probably including olfactory receptor cells in the nasal cavity (Alkondon et al., Neurosci Lett 1994 Aug 1; 176 (2) : 152-6; Alkondon et al . , Eur J Neurosci 1997 Dec; 9 (12) :2734-42 ; Bouvet et al . , Neurosci Res 1988 Feb;5 (3) :214-23; Edwards et al .
- Lymphocytes including B cells, T cells and neutrophils
- Lymphocytes also likely express ⁇ 7 nicotinic acetylcholine receptor protein, though evidence of such expression is indirect via the observation of Beta- amyloid peptide functional activity in AD patients (Ibarreta et al, Ekert et al) or by measurement of mRNA (Hellstom-Lindahl et al) .
- test sample comprises a cell
- Alzheimer's disease monitoring the prognosis and progression of Alzheimer's disease and monitoring the therapeutic efficacy of any intervention or treatment of Alzheimer's disease comprising:
- test sample comprises a cell, said cell expressing ⁇ 7 nicotinic acetylcholine receptor protein;
- sample refers to any substance that may contain ⁇ 7 nicotinic acetylcholine receptor protein.
- a sample can be biological fluid, such as whole blood or whole blood components including red blood cells, white blood cells, platelets, serum and plasma, ascites, urine, cerebrospinal fluid, and other constituents of the body that may contain the cell or fragment containing ⁇ 7 nicotinic acetylcholine receptor protein.
- a sample may be a component in a larger composition, for example in a tissue section of a biopsy, where the cells of interest may belong to one or more cellular subtypes amongst a field of different cell types.
- cell refers to at least one cell, but includes a plurality of cells, or fractions of cells appropriate for the sensitivity of the detection method.
- Cells suitable for the present invention may be present as isolated, purified cell populations or as a fraction of an organized tissue biopsy. Fractions of cells, including the axon or dendrites of a neuron are also suitable for use in the present invention, and may be isolated, for example in a tissue section of a biopsy.
- Preferred cells suitable for use in the present invention are selected from the group consisting of circulating lymphocytes, olfactory neuroepithelial neuronal cell bodies or their neuronal processes, or hippocampal cells.
- compound capable of specific interaction with the ⁇ 7 nicotinic acetylcholine receptor refers to, for example, synthetic or natural amino acid polypeptides, proteins, small synthetic organic molecules, or deoxy- or ribo- nucleic acid sequences that bind to the ⁇ 7 nicotinic acetylcholine receptor with about 20-fold or greater affinity compared to other proteins.
- a ⁇ 1-40 , A ⁇ 1-42 , A ⁇ - 3 , peptides, purified from natural sources or created synthetically using peptide synthetic methods, polyclonal or monoclonal antibodies raised against the ⁇ 7 nicotinic acetylcholine receptor, or a peptide fragment thereof, or small organic molecules that block A ⁇ 1-40 ⁇ A ⁇ 1-42 , A ⁇ ⁇ - « peptide interaction with the receptor are suitable for use in the present invention.
- Preferred compounds of the present invention include A ⁇ 1-40 ⁇ A ⁇ 1-42 , A ⁇ 1-43 peptides, or antibodies that bind to the a7 nicotinic acetylcholine receptor.
- 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) , rhodamine, 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 test sample so that it can interact with the compound bound to the test sample.
- the labeled compound comprises biotin
- a second compound comprises avidin or streptavidin and a detectable label.
- a second well-known example is when a first antibody is used to bind to the ⁇ 7 nicotinic acetylcholine receptor and is detected with a second anti-antibody comprising a detectable label.
- the first antibody comprises a label in that there are specific regions capable of detection within the structure of the first antibody.
- the method of the present invention can be further defined by adding a step (d) of comparing changes in the level of ⁇ 7 acetylcholine protein in the test sample with an established normal level determined by measuring the ct7 nicotinic acetylcholine receptor protein in an normal samples.
- Normal sample refers to a sample from a subject who demonstrates no detectable neurodegenerative disease, for example, Alzheimer's disease, by known cognitive diagnostic methods, and may include preserved tissue sections from tissue archives.
- the measurement means of step (c) suitable for the method of the present invention comprises measuring changes in the quantity of intracellular protein, or cell surface protein. Immunoaffinity or ligand affinity measurement quantitates levels of protein in or on the surface of host cells.
- Unlabelled ⁇ 7 nicotinic acetylcholine receptor protein is detected by Western blotting, cell surface detection by fluorescent cell sorting, cell image analysis, and immunoassay employing compounds specific for ⁇ 7 nicotinic acetylcholine receptor protein.
- Preferred detection means for cell surface protein include flow cytometry or statistical cell imaging. In both techniques the protein of interest is localized at the cell surface, labeled with a specific fluorescent probe, and detected via the degree of cellular fluorescence. In flow cytometry, the cells are analyzed in a solution, whereas in cellular imaging techniques, a field of cells is compared for relative fluorescence.
- the methods of the present invention may be used to measure intracellular ⁇ 7 nicotinic acetylcholine receptor protein contained within the entoplasmic reticulum, Golgi complex, or vesicles.
- This method provides that the test sample be pretreated to perforate the cell membranes or to solubilize the cell, for example with a detergent containing solution, both techniques are well known in the art.
- the compound enters the cell and specifically interacts with the cc7 nicotinic acetylcholine receptor in the compartments previously described.
- Membrane perforating agents are well known in the art, and are used, for instance to perforate lymphocytic cells to analyze intracellular components using flow cytometry. These agents are commercially available, for example, by Ortho Clinical
- a particular assay of the present invention comprises binding protein assay methods using a compound capable of specific interaction with ⁇ 7 nicotinic acetylcholine receptor protein to detect changes in the level of 7 nicotinic acetylcholine receptor protein.
- the compound is an antibody to ⁇ 7 nicotinic acetylcholine receptor protein.
- the preferred method to detect ⁇ 7 nicotinic acetylcholine receptor protein comprises the steps: (a) obtaining a test sample from a subject wherein the test sample comprises a cell, said cell expressing ⁇ 7 nicotinic acetylcholine receptor protein in healthy individuals;
- Figure 1 shows that the amount of ⁇ 7 nicotinic acetylcholine receptor protein was reduced. The extent of the reduction was measured by densitometry and indicated that the ⁇ 7 acetylcholine receptor was reduced by 57+5% compared to controls (Table 1, p ⁇ 0.04). A reduction was observed in all twelve AD brain samples tested.
- Postmortem brains were obtained from Harvard Brain Tissue Resource Center at McLean Hospital (Belmont, MA) and Analytical Biological Services, Inc. (Wilmington, DE).
- the mean ages of the subjects for AD and controls were 73.9 ⁇ 1.5 and 71.6 ⁇ 1.4, respectively.
- the postmortem interval for AD and control subjects were 11.7 ⁇ 1.4 hr and 10.0 ⁇ 2.0 hr, respectively.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2001541016A JP2003530542A (en) | 1999-12-01 | 2000-11-16 | Diagnostic methods for neurodegenerative diseases |
AU19204/01A AU1920401A (en) | 1999-12-01 | 2000-11-16 | Method of diagnosing neurodegenerative disease |
CA002393004A CA2393004A1 (en) | 1999-12-01 | 2000-11-16 | Method of diagnosing neurodegenerative disease |
EP00982134A EP1233979A1 (en) | 1999-12-01 | 2000-11-16 | Method of diagnosing neurodegenerative disease |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16823899P | 1999-12-01 | 1999-12-01 | |
US60/168,238 | 1999-12-01 |
Publications (1)
Publication Number | Publication Date |
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WO2001040261A1 true WO2001040261A1 (en) | 2001-06-07 |
Family
ID=22610681
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US2000/031467 WO2001040261A1 (en) | 1999-12-01 | 2000-11-16 | Method of diagnosing neurodegenerative disease |
Country Status (5)
Country | Link |
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EP (1) | EP1233979A1 (en) |
JP (1) | JP2003530542A (en) |
AU (1) | AU1920401A (en) |
CA (1) | CA2393004A1 (en) |
WO (1) | WO2001040261A1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004095031A1 (en) * | 2003-04-24 | 2004-11-04 | Universität Zürich | Method of monitoring immunotherapy |
US8436145B2 (en) | 2008-12-04 | 2013-05-07 | Yeda Research And Development Co. Ltd. | Compositions and methods for diagnosing and treating cancer and neurodegenerative diseases related to Beclin-1 |
WO2014012054A1 (en) | 2012-07-13 | 2014-01-16 | Pain Therapeutics, Inc. | Alzheimer's disease assay in a living patent |
US8987453B2 (en) | 2006-11-06 | 2015-03-24 | Abbvie Inc. | Azaadamantane derivatives and methods of use |
US9464078B2 (en) | 2010-09-23 | 2016-10-11 | Abbvie Inc. | Monohydrate of azaadamantane derivatives |
US10282875B2 (en) | 2015-12-11 | 2019-05-07 | International Business Machines Corporation | Graph-based analysis for bio-signal event sensing |
US11862337B2 (en) | 2019-03-19 | 2024-01-02 | Cambridge Cognition Limited | Method and uses of diagnosing and recommending treatment for a psychotic disorder |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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DE10164139A1 (en) | 2001-12-27 | 2003-07-10 | Bayer Ag | 2-heteroaryl carboxamides |
TR201807944T4 (en) | 2008-11-19 | 2018-06-21 | Forum Pharmaceuticals Inc | (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide, and pharmaceutically acceptable salts thereof, and treatment of negative symptoms of schizophrenia. |
US20110229905A1 (en) | 2008-12-04 | 2011-09-22 | Yeda Research And Development Co. Ltd. At The Weizmann Institute Of Science | Compositions and methods for diagnosing and treating cancer and neurodegenerative diseases rlated to beclin-1 |
ES2746850T3 (en) | 2010-05-17 | 2020-03-09 | Forum Pharmaceuticals Inc | Pharmaceutical formulations comprising crystalline forms of (R) -7-chloro-N- (quinuclidin-3-yl) benzo (b) thiophene-2-carboxamide monohydrate hydrochloride |
MX358512B (en) | 2012-05-08 | 2018-08-24 | Forum Pharmaceuticals Inc | Methods of maintaining, treating or improving cognitive function. |
KR102246021B1 (en) * | 2019-10-10 | 2021-04-29 | 연세대학교 산학협력단 | A composition for diagnosing of fibrosis and using thereof |
-
2000
- 2000-11-16 WO PCT/US2000/031467 patent/WO2001040261A1/en not_active Application Discontinuation
- 2000-11-16 EP EP00982134A patent/EP1233979A1/en not_active Withdrawn
- 2000-11-16 JP JP2001541016A patent/JP2003530542A/en active Pending
- 2000-11-16 CA CA002393004A patent/CA2393004A1/en not_active Abandoned
- 2000-11-16 AU AU19204/01A patent/AU1920401A/en not_active Abandoned
Non-Patent Citations (6)
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004095031A1 (en) * | 2003-04-24 | 2004-11-04 | Universität Zürich | Method of monitoring immunotherapy |
US8987453B2 (en) | 2006-11-06 | 2015-03-24 | Abbvie Inc. | Azaadamantane derivatives and methods of use |
US8436145B2 (en) | 2008-12-04 | 2013-05-07 | Yeda Research And Development Co. Ltd. | Compositions and methods for diagnosing and treating cancer and neurodegenerative diseases related to Beclin-1 |
US9464078B2 (en) | 2010-09-23 | 2016-10-11 | Abbvie Inc. | Monohydrate of azaadamantane derivatives |
WO2014012054A1 (en) | 2012-07-13 | 2014-01-16 | Pain Therapeutics, Inc. | Alzheimer's disease assay in a living patent |
EP2872899A4 (en) * | 2012-07-13 | 2015-12-30 | Pain Therapeutics Inc | Alzheimer's disease assay in a living patient |
US9354223B2 (en) | 2012-07-13 | 2016-05-31 | Pain Therapeutics Inc. | Alzheimer's disease assay in a living patient |
US9500640B2 (en) | 2012-07-13 | 2016-11-22 | Pain Therapeutics, Inc. | Alzheimer's disease assay in a living patient |
US10222368B2 (en) | 2012-07-13 | 2019-03-05 | Pain Therapeutics, Inc. | Alzheimer's disease assay in a living patient |
US11385221B2 (en) | 2012-07-13 | 2022-07-12 | Pain Therapeutics, Inc. | Alzheimer's disease assay in a living patient |
US10282875B2 (en) | 2015-12-11 | 2019-05-07 | International Business Machines Corporation | Graph-based analysis for bio-signal event sensing |
US11862337B2 (en) | 2019-03-19 | 2024-01-02 | Cambridge Cognition Limited | Method and uses of diagnosing and recommending treatment for a psychotic disorder |
Also Published As
Publication number | Publication date |
---|---|
AU1920401A (en) | 2001-06-12 |
EP1233979A1 (en) | 2002-08-28 |
JP2003530542A (en) | 2003-10-14 |
CA2393004A1 (en) | 2001-06-07 |
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