Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
2001-03-16
2003-07-29
Lateef, Marvin M. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
C600S407000
Reexamination Certificate
active
06600947
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to methods and apparatus for detecting amyloid-containing lesions in tissue using autofluorescence. The invention also relates to methods of detecting the onset of cerebral amyloidosis by detecting the presence of amyloid-containing plaques and other related lesions in brain tissue.
2. Description of Related Art
The term “amyloidosis” encompasses a number of pathological conditions characterized by the deposition of abnormal fibrils (“amyloid fibrils”) in extracellular spaces. The amyloid fibril, in turn, represents a final common pathway for a diverse array of proteins. Regardless of their biochemical composition, however, all types of amyloid fibrils share (a) a &bgr;-pleated sheet structure, (b) staining similarities, such as green birefringence under polarized light after staining with Congo Red dye, (c) a fibrillar morphology that has a typical electron-microscopic appearance, and (d) other physicochemical properties well known in the art.
The deposition of amyloid fibrils can affect several organs in the systemic forms of the disorder, exemplified by familial Mediterranean fever, familial amyloid polyneuropathy and systemic amyloidosis, or it can be restricted to one organ in localized forms. Among the latter are conditions classified under the rubric “cerebral amyloidosis,” which covers the Alzheimer group of diseases, namely, Alzheimer's disease (pre-senile dementia, senile dementia); Alzheimer's disease associated with Down's syndrome; familial Alzheimer's Disease; genetic Alzheimer's disease due to mutations such as Presenilin 1, Presenilin 2, and others; Alzheimer's disease associated with other central-nervous-system diseases, such as Parkinson's disease, Lewy Body Disease, and cerebrovascular diseases; congophilic angiopathy (associated or not associated with Alzheimer's disease, familial or not familial), and other disorders and diseases such as those disclosed in U.S. Pat. No. 6,001,331, the disclosure of which is incorporated by reference herein in its entirety.
Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive impairments in memory, behavior, language, and visuo-spatial skills, ending ultimately in death. Hallmark pathologies within vulnerable regions include extracellular &bgr;-amyloid deposits, intracellular neurofibrillary tangles, synaptic loss, and extensive neuronal cell death. Research on the causes and treatments of Alzheimer's disease has led investigators down numerous avenues. Although many models have been proposed, no single model of AD satisfactorily accounts for all neuropathologic findings as well as the requirement of aging for disease onset, with the exception of that disclosed in Averback, WO 98/34643, the disclosure of which is incorporated by reference herein in its entirety. Considerable evidence has implicated alterations in production or processing of the human amyloid precursor protein (APP) in the etiology of the disease. However, intensive research has proven that AD is a multifactorial disease with many different, perhaps overlapping, etiologies.
Because of this, those in the field have conducted significant research studies and clinical investigations to study the structural deficiencies, chemical changes, and functional abnormalities both within the brain and within different populations of nerve cells. The depth of such investigations and studies are represented by the following publications, which represent only a handful of the vast reports in this arena:
Neurobiology of Alzheimer's Disease
(D. Dawbarn and S. J. Allen, Editors), Bios, Oxford 1995;
Dementia,
(J. Whitehouse, Ed.), F. A. Davis Company, Philadelphia, 1993;
Alzheimer's Disease: Senile Dementia and Related Disorders
(Katzman, R, and R. L. Bick, Eds), Raven Press, New York, 1994, pages 47-51;
Alzheimer's Disease and Related Disorders, Etiology, Pathogenesis and Therapeutics
(Iqbol, K., et al., Eds.), Wiley, Chichester, 1999;
Alzheimer's Disease: Advances in Clinical and Basic Research
(Corain, B, Ed.), Wiley, New York, 1993;
Alzheimer's Disease: Clinical and Treatment Perspectives
(Cutler, N. R., et al., Eds.), Wiley, Chichester, 1995;
Alzheimer's Disease: Therapeutic Strategies
(Giacobini, E., Becker, R., Eds.), Birkhauser, Boston, 1994; Paykel, et al.,
Arch. Gen. Psychiat.,
51:325-332 (1994); Amaducci, et al.,
Neurology,
36:922-931 (1986); McKhann, et al.,
Neurology
34:939-944 (1984), Heston et al.,
Arch. Gen. Psychiatry
38:1085-1090 (1981);
Aging of the Brain
(Gispen and Traber, editors), Elsevier Science Publishers, Amsterdam, 1983, pages 275-282; Heyman et al.,
Ann. Neurol
15:335-341 (1984); Brayne C. and P. Calloway, Lancet 1:1265-1267 (1988); Roth et al.,
Br. J. Psychiatry
149:698-709 (1986); Medical Research Council,
Report from the NRC Alzheimer's Disease Workshop,
London, England, 1987; Morris et al.,
Neurology
41:469-478 (1991); and the references cited within each of these publications.
To date, Alzheimer's disease is the third most expensive disease in the United States, costing society approximately $100 billion each year. It is one of the most prevalent illnesses in the elderly population, and with the aging of society, will become even more significant. Costs associated with AD include direct medical costs such as nursing home care, direct nonmedical costs such as in-home day care, and indirect costs such as lost patient and care giver productivity. Medical treatment and behavior modification may have economic benefits by slowing the rate of cognitive decline, delaying institutionalization, reducing care giver hours, and improving quality of life. Pharmacoeconomic evaluations have shown positive results regarding the effect of drug therapy and behavior modification on nursing home placement, cognition, and care giver time.
Despite the array of research investigations and studies undertaken to date, present clinical evaluations still have a difficult time establishing an unequivocal diagnosis of Alzheimer's Disease. Autopsy or biopsy is widely considered the gold standard method for AD diagnosis. Different criteria exists that assess and determine the presence of neurofibrillary tangles (NFT), cell loss and senile (amyloid) plaques in brain tissue. These criteria for the definite diagnosis of Alzheimer's Disease are met only by histologic evidence.
The research to date has been diverse insofar as the causes of various forms of cerebral amyloidosis. That is, the research has varied with respect to how the actual amyloid plaques and other similar lesions form in the brain. There is little disagreement in the scientific community, however, that a universally accepted indicator of cerebral amyloidosis is the accumulation of large numbers of amyloid-containing lesions, so-called “senile plaques,” that are comprised in large part of amyloid fibrils. Senile plaques are spherical, ranging from 10 to 200 &mgr;m in diameter, and are found occasionally in aged adult cerebral cortex, but are found in large numbers in Alzheimer-affected cerebral cortex. To date, the best means by which one can measure the presence of senile plaques in the brain is achieved by a brain biopsy or a postmortem examination, and subsequent detection of amyloid plaques.
In this context, various mechanisms have been described by which one can detect amyloid plaques and other amyloid-related lesions. Amyloid plaques and amyloid lesions can be visualized in histological sections by staining with many methods, such as silver impregnation, eosin, periodic acid Schiff, Congo red, thioflavins, and others. Amyloid plaques and amyloid lesions also can be visualized by immunohistochemical methods of staining the amyloid and other proteins in the plaques by antibodies to plaque proteins conjugated to enzymes, such as alkaline phosphatase or horseradish peroxidase and others, or to fluorophores such as fluorescein isothiocyanate, rhodamine, or o
Averback Paul A.
Dupuis Celine
Doody Patrick A.
Hunton & Williams
Lateef Marvin M.
Nymox Corporation
Shah Devaang
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