Methods and compositions for diagnosis, stratification, and monitoring of alzheimer's disease and other neurological disorders in body fluids

Inactive Publication Date: 2006-05-04
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0018] Further, the inventors have discovered methods of stratifying AD patients (i.e., sorting individuals with a probable diagnosis of AD or diagnosed with AD into different classes of AD) by obtaining measured values for brain derived neurotrophic factor (BDNF) and BB-homodimer platelet derived growth factor (PDGF-BB) levels in a peripheral biological fluid sample from an AD patient. The measured levels of these two biomarkers are compared with reference values. The information thus obtained may be used to aid in stratification of the AD diagnosis (or probable AD diagnosis) of the individual. Accordingly, the present invention provides methods for stratifying Alzheimer's disease (AD) in an individual, comprising comparing measured values for brain derived neurotrophic factor (BDNF) and BB homodimeric platelet derived growth factor (PDGF-BB) levels in a biological fluid sample from said patient with reference values for BDNF and PDGF-BB. In some examples, the bio

Problems solved by technology

Neither Medicare nor most private health insurance covers the long-term care most patients need.
In the early (mild) and moderate stages of the illness, recall of remote well-learned material may appear to be preserved, but new information cannot be adequately incorporated into memory.
These are often manifest first as word finding difficulty in spontaneous speech.
The language of the AD patient is often vague, lacking in specifics and may have increased automatic phrases and cliches.
Difficulty in naming everyday objects is often prominent.
Impairments of judgment and p

Method used

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  • Methods and compositions for diagnosis, stratification, and monitoring of alzheimer's disease and other neurological disorders in body fluids
  • Methods and compositions for diagnosis, stratification, and monitoring of alzheimer's disease and other neurological disorders in body fluids
  • Methods and compositions for diagnosis, stratification, and monitoring of alzheimer's disease and other neurological disorders in body fluids

Examples

Experimental program
Comparison scheme
Effect test

example 1

AD Diagnosis Biomarkers

[0182] We compared plasma protein expression levels for 120 proteins in 32 cases of serum collected from patients with Alzheimer's Disease (with a mean age of 74) to 19 cases of serum collected from control subjects (also with mean age of 74). Alzheimer's Disease subjects were clinically diagnosed with AD by a neurologist, and had Mini Mental State Exam (MMSE) scores ranging from 26-14.

[0183] Plasma samples were assayed using a sandwich-format ELISA on a nitrocellulose filter substrate. Plasma samples were diluted 1:10 in phosphate buffer and incubated with the capture substrate (a nitrocellulose membrane spotted with capture antibodies). The samples were incubated with the capture substrate for two hours at room temperature, then decanted from the capture substrate. The substrate was washed twice with 2 ml of washing buffer (1×PBS; 0.05% Tween-20) at room temp, then incubated with biotinylated detection antibodies for two hours at room temperature. The capt...

example 2

Decision Trees from AD Diagnosis Marker Data

[0186] Upon further analysis of the data from example 1, two different decision trees were formulated for diagnosis of AD using AD diagnosis biomarkers.

[0187] The first decision tree utilizes sIL-6R, IL-8, and TIMP-1 levels. The rules which make up the decision tree are: (1) If sIL-6R≦5.18 and IL-8 is ≦0.957, the indication is normal; (2) if sIL-6R≦5.18 and IL-8>0.957, the indication is AD; (3) if sIL-6R>5.18 and TIMP-1≦7.978, the indication is AD; and (4) if sIL-6R>5.18 and TIMP-1 is >7.978, the indication is normal, wherein the values expressed are relative concentrations.

[0188] Accuracy of this decision tree was measured using 10-fold cross-validation testing feature in CART to generate misclassification rates for learning samples and testing samples. Sensitivity was calculated from the testing scores as number of AD samples correctly predicted as AD / total number of AD samples (29 / 32=0.906). Specificity was calculated from the testin...

example 3

Diagnosis of MCI

[0190] Levels of RANTES and Leptin were measured in 18 samples from control subjects (mean age=74) and 6 samples from patients diagnosed with mild cognitive impairment (MCI). MCI patients had been clinically diagnosed by a neurologist, and had an AULT-A7 score of less than 5 and Mini Mental State Exam (MMSE) scores ranging from 30-28. Control subjects had an AULT-A7 score greater than or equal to 5 and MMSE score ranging from 30-28.

[0191] RANTES and Leptin levels were measured using an ELISA kit from R&D systems according to the manufacturer's instructions. The raw ELISA expressions values were normalized by dividing each value by the median of all the samples. Analysis of the data showed (a) Leptin is not decreased in MCI patients as compared to control subjects (in the six MCI samples, Leptin was actually 11% higher than the control subjects), and (b) a bimodal distribution of RANTES, where MCI patients had RANTES levels of between 1.043 and 1.183 (levels from co...

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Abstract

The inventors have discovered a collection of proteinaceous biomarkers (“AD biomarkers) which can be measured in peripheral biological fluid samples to aid in the diagnosis of neurodegenerative disorders, particularly Alzheimer's disease and mild cognitive impairment (MCI). The invention further provides methods of identifying candidate agents for the treatment of Alzheimer's disease by testing prospective agents for activity in modulating AD biomarker levels.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation in part application of U.S. patent application Ser. No. 10 / 993,813, filed Nov. 19, 2004 which claims benefit of U.S. Provisional Patent Application No. 60 / 523,796, filed Nov. 19, 2003, U.S. Provisional Patent Application Ser. No. 60 / 566,783, filed Apr. 30, 2004, and U.S. Provisional Patent Application No. 60 / 566,782, filed Apr. 30, 2004, all of which are incorporated by reference herein in their entireties.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] Not applicable. REFERENCE TO A COMPACT DISK APPENDIX [0003] Not applicable BACKGROUND OF THE INVENTION [0004] An estimated 4.5 million Americans have Alzheimer's Disease (“AD”). By 2050, the estimated range of AD prevalence will be 11.3 million to 16 million. Currently, the societal cost of AD to the U.S. is $100 billion per year, including $61 billion borne by U.S. businesses. Neither Medicare nor most private health insurance co...

Claims

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Application Information

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IPC IPC(8): G01N33/53G01N33/567C12Q1/68G01N33/68
CPCC12Q1/6883G01N33/6896G01N2800/28G01N2800/2821G01N2800/60
Inventor RAY, SANDIPWYSS-CORAY, ANTON
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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