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

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...

AI Technical Summary

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 biological fluid sample is a peripheral fluid sample, including blood, serum or plasma. In other examples, the method further comprises comparing measured values for leptin and Rantes levels with reference values for leptin and Rantes, wherein reference values for BDNF, PDGF-BB, leptin and Rantes are for samples from individuals with MMSE scores from 25 to 28, wherein an increase in leptin and PDGF-BB levels and wherein levels of BDNF and RANTES stay substantially the same indicate mild AD as indicated by an MMSE score of 20-25. In additional examples, the method further comprises comparing measured values for leptin and Rantes levels with reference values for leptin and Rantes, wherein reference values for BDNF, PDGF-BB, leptin and Rantes are for samples from individuals with MMSE scores from 20-25, wherein a decrease in Rantes, BDNF, and PDGF levels and wherein levels of Leptin stays substantially the same indicate moderate AD as indicated by an MMSE score of 10-20.

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 problems solving are frequently seen.

These clinical diagnostic methods, however, are not foolproof.

One obstacle to diagnosis is pinpointing the type of dementia; AD is only one of seventy conditions that produce dementia.

Because of this, AD cannot be diagnosed with complete accuracy until after death, when autopsy reveals the disease's characteristic amyloid plaques and neurofibrillary tangles in a patient's brain.

In addition, clinical diagnostic procedures are only helpful after patients have begun displaying significant, abnormal memory loss or personality changes.

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