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Methods for detecting parenchymal plaques in vivo

Methods for detecting parenchymal plaques in vivo description/claims

This application is a divisional of U.S. patent application Ser. No. 10/351,777 filed Jan. 27, 2003, which claims benefit to U.S. Provisional Application 60/427,821 filed Nov. 20, 2002 and is a continuation-in-part of U.S. patent application Ser. No. 09/542,537, filed Apr. 4, 2000. These applications are incorporated by reference herein.

This invention relates to detecting extracellular deposits such as plaques in the brain of a living mammal, and more particularly to using a polyamine-modified, labeled polypeptide as a contrast agent which enables the plaques to imaged.

Alzheimer's disease is a devastating disease of the brain which results in progressive dementia, physical disability and death over a relatively long period of time. With the aging population in the United States and other countries, the number of Alzheimer's patients is rapidly rising and can accurately be characterized as a silent epidemic. Much research is being conducted to develop drugs that will slow or halt the progression of the disease, and there is hope that a vaccine or inhibitors of secretase may ultimately be developed.

One of the difficulties in managing this disease is the lack of means for its early detection and means for measuring its progression. Such means are needed to identify persons who should receive treatment and to measure the effectiveness of the treatment. An immediate problem is the need for a method which measures the progression of the disease in order to evaluate the effectiveness of the many drugs being developed.

Many techniques have been proposed for detecting and measuring the progress of Alzheimer's disease. These include cognitive tests which attempt to measure brain functions by having the patient perform different tasks. The problem with this approach is that it does not distinguish between dementia caused by Alzheimer's disease and dementia caused by other factors. In addition, the ability to measure the progression of the disease using cognitive tests is very limited.

Neurofibrillary tangles (NFTs) and neuritic plaques (NPs) are the classical neuropathological hallmarks of Alzheimer's disease. Numerous neuropathological studies indicate that the first appearance of NFTs and NPs in the hippocampal region of the brain marks the beginning of the degenerative process. Many studies have been done in which the structure of the brain has been imaged to determine structural changes that are linked to the presence and the progression of Alzheimer's disease. These include: 2-D estimates of size; measures of medical temporal lobe gray matter volume; the qualitative rating of the amount of CSF accumulating in the hippocampal fissures, the size of the suprasellar cistern; and the increased distance between the right and left uncus. None of have been particularly successful, and in fact, it has been found that profound structural changes can occur in the brain of some individuals with no cognitive impairment or other symptoms of the disease being evident.

Alzheimer's Disease (AD) is characterized neuropathologically by neuritic plaques and neurofibrillary tangles. Neuritic or senile plaques contain a dense core consisting largely of several species of amyloid-β (Aβ) peptide. Aβ is a 39-43 amino acid peptide derived from amyloid precursor protein. AP is highly hydrophobic and spontaneously aggregates in vitro to form D pleated sheets. Maggio, J. E. and Mantyh, P. W., Brain Pathol., 6:147-162 (1996). Aβ also has been reported to be neurotoxic in vitro and in vivo. The main link between AD and Aβ is based on genetic mutations that have been discovered in familial forms of AD and Down's syndrome that result in aberrant processing or increased levels and deposition of Aβ. Selkoe, D. J., Science, 275:630-631 (1997). Furthermore, transgenic mice overexpressing the same mutations have been shown to develop amyloid deposits like those in AD as well as significant behavioral deficits. Hsiao, K., et al., Science 274:99-102 (1996); and Holcomb, L., et al., Nature Med., 4:97-100 (1998). There also appears to be a significant correlation between amyloid burden and dementia in AD patients.

Currently, there is no definitive diagnosis for AD except by post-mortem observation of these deposits and a process of elimination of other neurodegenerative disorders.

In one embodiment, the present invention is a method for detecting parenchymal plaque deposits in the brain of a living mammal. The method comprises: a) administering an amount of a polypeptide to a mammal effective to detectably bind to parenchymal plaque deposits, wherein the polypeptide is labeled with a contrast agent and is polyamine modified, and wherein the polypeptide has specific binding affinity for said deposits; and b) detecting the polypeptide bound to the deposits. The detecting step comprises acquiring nuclear magnetic resonance image data and reconstructing an image therefrom.

In a preferred embodiment, the deposits are β-amyloid plaques and the polypeptide is a β-amyloid peptide, such as β-amyloid peptide1-40 or derivatives thereof.

In another preferred embodiment, the polyamine is putrescine.

In another embodiment, the present invention is a method for producing an image with a magnetic resonance imaging (MRI) system which indicates parenchymal plaques in the brain of a subject. Preferably, the steps comprise: a) acquiring a reference image data set of the brain with the MRI system; b) injecting into the subject's vascular system a contrast agent comprised of a labeled polypeptide having a specific binding affinity for said plaques and being polyamine modified to enhance transit through and exit from capillary endothelial cells to the brain parenchyma; c) waiting for a time period sufficient for the contrast agent to bind to said parenchymal plaques and for unbound contrast agent to diffuse in the subject; d) acquiring a contrast enhanced image data set of the brain with the MRI system; and e) reconstructing an image of the brain which indicates at each of its image pixels the difference in NMR signal magnitude between the contrast enhanced image data set and the reference image data set.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used to practice the invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Other features and advantages of the invention will be apparent from the following detailed description and from the claims.

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