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(12) Patent Application Publication (10) Pub. No.: US 2007/0254315 A1 Cox Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0254315 A1 Cox Et Al US 20070254315A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0254315 A1 Cox et al. (43) Pub. Date: Nov. 1, 2007 (54) SCREENING FOR NEUROTOXIC AMINO (60) Provisional application No. 60/494.686, filed on Aug. ACID ASSOCATED WITH NEUROLOGICAL 12, 2003. DSORDERS Publication Classification (75) Inventors: Paul A. Cox, Provo, UT (US); Sandra A. Banack, Fullerton, CA (US); Susan (51) Int. Cl. J. Murch, Cambridge (CA) GOIN 33/566 (2006.01) GOIN 33/567 (2006.01) Correspondence Address: (52) U.S. Cl. ............................................................ 435/721 PILLSBURY WINTHROP SHAW PITTMAN LLP (57) ABSTRACT ATTENTION: DOCKETING DEPARTMENT Methods for screening for neurological disorders are dis P.O BOX 105OO closed. Specifically, methods are disclosed for screening for McLean, VA 22102 (US) neurological disorders in a Subject by analyzing a tissue sample obtained from the subject for the presence of (73) Assignee: THE INSTITUTE FOR ETHNO elevated levels of neurotoxic amino acids or neurotoxic MEDICINE, Provo, UT derivatives thereof associated with neurological disorders. In particular, methods are disclosed for diagnosing a neu (21) Appl. No.: 11/760,668 rological disorder in a subject, or predicting the likelihood of developing a neurological disorder in a Subject, by deter (22) Filed: Jun. 8, 2007 mining the levels of B-N-methylamino-L-alanine (BMAA) Related U.S. Application Data in a tissue sample obtained from the subject. Methods for screening for environmental factors associated with neuro (63) Continuation of application No. 10/731,411, filed on logical disorders are disclosed. Methods for inhibiting, treat Dec. 8, 2003, now Pat. No. 7,256,002. ing or preventing neurological disorders are disclosed. concentration I maximum concentration Sa S 3 Sh 3 3 aS S as s root, non-coralloid root, coralold, non-infected " root, coralloid, rid infection root, coratoid, heavy fection roots, corallold, senscent stem, inner cortex stsm, oster core eaf nuclage raie sporophyll, miniature male sporangla, irrature male sporophyll, nature male sporangia, mature female sporophy seed gametophyte cotyledons seed sarcotesta seed sarcotesta, outer layer Eises Patent Application Publication Nov. 1, 2007 US 2007/0254315 A1 A. concentration I maximum concentration with asa asNo asto asa asu gie5 oN Oa O2 S.9 root, non-coralloid root, corallold, nonfected root, coralold, mild infection root, coralloid, heavy infection roots, coralloid, senscent A. stem, xylem stem, inner cortex stem, outer cortex leaf mucilage leaf male sporophyll, immature six male sporangla, nature male sporophyll, nature male sporangla, nature female sporophyll seed gametophyte cotyledons seed sarcotesta seed sarcotesta, outer layer FIG. US 2007/0254315 A1 Nov. 1, 2007 SCREENING FOR NEUROTOXC AMNO ACID bound and free neurotoxic amino acid or neurotoxic deriva ASSOCATED WITH NEUROLOGICAL tive thereof can be analyzed in a sample. In a tissue sample, DISORDERS protein-bound BMAA, free BMAA, or both protein-bound BMAA and free BMAA can be analyzed. The subject may RELATED APPLICATIONS have symptoms of a neurological disorder, or may be asymptomatic for a neurological disorder, or may have been 0001. This application is a continuation of U.S. patent identified as being at risk for developing a neurological application Ser. No. 10/731,411, filed Dec. 8, 2003, which disorder. The neurotoxic derivative may be any derivative claims the benefit of U.S. Provisional Patent Application No. having neurotoxic activity, Such as a carbamate adduct or 60/494.686, filed Aug. 13, 2003. metabolite of the neurotoxic amino acid. FIELD OF THE INVENTION 0005 The present invention provides methods of screen 0002 The present invention relates to screening for neu ing a subject having or at risk of having a neurological rological disorders. Specifically, the invention relates to disorder by analyzing a tissue sample from the Subject to screening for neurological disorders in a Subject by analyZ determine the presence of a neurotoxic amino acid or ing a tissue sample from the Subject to determine the neurotoxic derivative thereof associated with the neurologi presence of neurotoxic amino acids or neurotoxic deriva cal disorder, wherein the presence of a detectable level of a tives thereof associated with neurological disorders. In par neurotoxic amino acid or neurotoxic derivative thereof indi ticular, the present invention relates to methods for diag cates a neurological disorder. Methods of the invention can nosing a neurological disorder in a Subject, or predicting the be used to detect neurological disorders including a neu likelihood of developing a neurological disorder in a Subject, rofibrillary tangle disorder (NFT disorder) such as amyo by determining the levels of B-N-methylamino-L-alanine trophic lateral sclerosis-Parkinsonism dementia complex (BMAA) or a neurotoxic derivative thereof, in a tissue (ALS-PDC), Alzheimer's disease, or progressive supra sample obtained from the subject. Further, the invention nuclear palsy (PSP), a movement disorder such as Parkin relates to screening environmental samples for a neurotoxic son's disease, or a motor neuron disease Such as amyo amino acid or neurotoxic derivative thereof associated with trophic lateral sclerosis (ALS). neurological disorders. Further, the invention relates to 0006 The present invention provides methods of screen inhibiting neurological disorders. ing a subject having or at risk of having a neurological BACKGROUND OF THE INVENTION disorder by analyzing a tissue sample from the subject to determine the presence of a neurotoxic amino acid or 0003. A unique neurological disease initially identified neurotoxic derivative thereof associated with the neurologi among the Chamorro people of Guam by Kurland and cal disorder, wherein the methods can be used to predict the Mulder (1954) is characterized by a combination of symp likelihood of developing a neurological disease, and/or to toms including Stooped posture, a blank expressionless face, predict the latency period prior to onset of the neurological dementia, slow shuffling movement, a resting tremor that disorder, and/or to predict the severity of the neurological stops upon deliberate action, slow movements, and muscle disorder. Methods of the present invention can be practiced atrophy that results in muscles dipping down in the hand. In using tissue samples including, but not limited to, neuro Some clinical manifestations, patients have clinical Symp logical tissue or non-neurological tissue. Neurological tissue toms indistinguishable from amyotrophic lateral sclerosis can be associated with the central nervous system (CNS), (ALS). Other patients have Parkinsonism features combined including brain tissue or cerebral-spinal fluid (CSF), or may with dementia (Parkinsonism Dementia Complex, PDC). In be associated with the peripheral nervous system (PNS). still others, only dementia is observed. Some patients also Non-neurological tissue can be keratinous tissue including have both ALS and PDC. Neuropathologically, all clinical but not limited to, hair, skin, nail, including fingernail or forms of the disease result in a specific feature, neurofibril toenail, feather, claw, hoof, or horn. Non-neurological tissue lary tangles, found in the cortex and in the spinal cord. can be non-keratinous tissue including but not limited to, Because the disease has aspects that resemble amyotrophic bood, serum, Saliva, or urine. lateral sclerosis (ALS), Parkinson's disease (PD) and Alzhe imer's disease (AD), this disease is known as amyotrophic 0007. The present invention provides methods for screen lateral Sclerosis-Parkinsonism dementia complex of Guam ing an environmental sample to determine if the environ (ALS-PDC) and is also known as lytico-bodig. mental sample is associated with a neurological disorder, by analyzing the environmental sample to determine the pres SUMMARY OF THE INVENTION ence of a neurotoxic amino acid or neurotoxic derivative thereof associated with the neurological disorder. The neu 0004 The present invention provides methods of screen rotoxic amino acid or neurotoxic derivative thereof can be a ing a Subject having or at risk of having a neurological glutamate receptor agonist Such as a methylated alanine, in disorder by analyzing a tissue sample from the Subject to particular, BMAA. Suitable environmental samples include determine the presence of a neurotoxic amino acid, or water and/or food items or sources. neurotoxic derivative thereof, associated with the neurologi cal disorder. The neurotoxic amino acid or neurotoxic 0008. The present invention provides methods for screen derivative thereof can be a glutamate receptor agonist Such ing an environmental sample to determine if the sample is as B-N-methylamino-L-alanine (BMAA), or B-N-oxalyl associated with a neurological disorder, by detecting neu amino-L-alanine (BOAA). In a tissue sample, protein-bound rotoxic amino acid or neurotoxic derivative thereof produc neurotoxic amino acid or neurotoxic derivative thereof can ing cyanobacteria in the environmental sample. The neuro be analyzed, free (unbound) neurotoxic amino acid or neu toxic amino acid or neurotoxic derivative thereof can be a rotoxic derivative thereof can be analyzed, or both protein glutamate receptor agonist Such as a methylated alanine, in US 2007/0254315 A1 Nov. 1, 2007 particular, BMAA. Methods of the invention are suitable for 0015 Table 3 shows levels of free and protein-associated detecting cyanobacteria producing
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