Methods for the Diagnosis and Treatment of Neurological and Neurodegenerative Diseases, Disorders and Associated Processes

Abstract

Methods for the diagnosis, prognosis, treatment and determining the efficacy of a therapeutic regimen for neurological and neurodegenerative diseases, disorders, and associated processes include using a detectable label to measure levels of alpha-synuclein.

1 . A method to determine prognosis, diagnosis or efficacy of a therapeutic regimen in a subject comprising contacting a biological sample from a subject with a detectable isotope to detect the level of alpha-synuclein in the sample wherein the level is compared with a reference standard level [to determine the prognosis, diagnosis or efficacy of the therapeutic regimen. 
     
     
         2 . A method to diagnose an alpha-synuclein related disease or disorder comprising:
 (a) administration of a labeled moiety to a subject suspected of having an alpha-synuclein related disease or disorder;   (b) collection of a biological sample from the subject and a corresponding normal sample;   (c) measurement of labeled alpha-synuclein and unlabeled alpha-synuclein from the subject and corresponding normal sample;   (d) determination of the ratio of labeled alpha-synuclein to unlabeled alpha-synuclein from the subject and corresponding normal sample;   (e) determination of alpha-synuclein metabolism from the ratios of step (d); and   (f) comparison of the alpha-synuclein metabolism from the subject to the alpha-synuclein metabolism from the corresponding normal sample;   wherein a change in the alpha-synuclein metabolism of the subject compared to the corresponding normal sample is indicative of positive diagnosis of an alpha-synuclein related disease or disorder;   thereby diagnosing an alpha-synuclein related disease or disorder.   
     
     
         3 . A method to determine the prognosis of an alpha-synuclein related disease or disorder comprising:
 (a) administration of a labeled moiety to a subject suspected of having an alpha-synuclein related disease or disorder;   (b) collection of a biological sample from the subject and a corresponding normal sample;   (c) measurement of labeled alpha-synuclein and unlabeled alpha-synuclein from the subject and corresponding normal sample;   (d) determination of the ratio of labeled alpha-synuclein to unlabeled alpha-synuclein from the subject and corresponding normal sample;   (e) determination of alpha-synuclein metabolism from the ratios of step (d); and   (f) comparison of the alpha-synuclein metabolism from the subject to the alpha-synuclein metabolism from the corresponding normal sample;   wherein a change in the alpha-synuclein metabolism of the subject compared to the corresponding normal sample is indicative of positive prognosis of an alpha-synuclein related disease or disorder;   thereby prognosing an alpha-synuclein related disease or disorder.   
     
     
         4 . A method to determine the efficacy of a therapeutic regimen to treat an alpha-synuclein related disease or disorder comprising:
 (a) administration of a labeled moiety and a therapeutic agent to a subject having an alpha-synuclein related disease or disorder;   (b) collection of a biological sample from the subject and a corresponding normal sample;   (c) measurement of labeled alpha-synuclein and unlabeled alpha-synuclein from the subject and corresponding normal sample;   (d) determination of the ratio of labeled alpha-synuclein to unlabeled alpha-synuclein from the subject and corresponding normal sample;   (e) determination of alpha-synuclein metabolism from the ratios of step (d); and   (f) comparison of the alpha-synuclein metabolism from the subject to the alpha-synuclein metabolism from the corresponding normal sample;   wherein a change in the alpha-synuclein metabolism of the subject compared to the corresponding normal sample is indicative of efficacy of a therapeutic regimen of a therapeutic agent to treat an alpha-synuclein related disease or disorder;   thereby determining the efficacy of a therapeutic regimen to treat an alpha-synuclein related disease or disorder.   
     
     
         5 . An in vivo method to identify a therapeutic agent to treat an alpha-synuclein related disease or disorder comprising:
 (a) administration of a labeled moiety and a therapeutic agent to a subject suspected of having an alpha-synuclein related disease or disorder;   (b) collection of a biological sample from the subject and a corresponding normal sample;   (c) measurement of labeled alpha-synuclein and unlabeled alpha-synuclein from the subject and corresponding normal sample;   (d) determination of the ratio of labeled alpha-synuclein to unlabeled alpha-synuclein from the subject and corresponding normal sample;   (e) determination of alpha-synuclein metabolism from the ratios of step (d); and   (f) comparison of the alpha-synuclein metabolism from the subject to the alpha-synuclein metabolism from the corresponding normal sample;   wherein a change in alpha-synuclein metabolism of the subject compared to the corresponding normal sample is indicative of the identification of a therapeutic agent to treat an alpha-synuclein related disease or disorder;   thereby identifying a therapeutic agent to treat an alpha-synuclein related disease or disorder an alpha-synuclein related disease or disorder.   
     
     
         6 . An in vitro method to identify a therapeutic agent to treat an alpha-synuclein related disease or disorder comprising:
 (a) administration of a labeled moiety and a therapeutic agent to cells;   (b) collection of alpha-synuclein from the cells and a corresponding normal sample;   (c) measurement of labeled alpha-synuclein and unlabeled alpha-synuclein from the cells and corresponding normal sample;   (d) determination of the ratio of labeled alpha-synuclein to unlabeled alpha-synuclein from the cells and corresponding normal sample;   (e) determination of alpha-synuclein metabolism from the ratios of step (d); and   (f) comparison of the alpha-synuclein metabolism from the cells to the alpha-synuclein metabolism from the corresponding normal sample;   wherein a change in alpha-synuclein metabolism of the cells compared to the corresponding normal sample is indicative of the identification of a therapeutic agent to treat an alpha-synuclein related disease or disorder;   thereby identifying a therapeutic agent to treat an alpha-synuclein related disease or disorder an alpha-synuclein related disease or disorder.   
     
     
         7 . A method to predict subject response to a therapeutic agent to treat an alpha-synuclein related disease or disorder comprising:
 (a) administration of a labeled moiety and a therapeutic agent to a subject suspected of having an alpha-synuclein related disease or disorder   (b) collection of a biological sample from the subject and a corresponding normal sample;   (c) measurement of labeled alpha-synuclein and unlabeled alpha-synuclein from the subject and corresponding normal sample;   (d) determination of the ratio of labeled alpha-synuclein to unlabeled alpha-synuclein from the subject and corresponding normal sample;   (e) determination of alpha-synuclein metabolism from the ratios of step (d); and   (f) comparison of the alpha-synuclein metabolism from the subject to the alpha-synuclein metabolism from the corresponding normal sample;   wherein a change in the alpha-synuclein metabolism of the subject compared to the corresponding normal sample is indicative of the identification of a therapeutic agent to treat an alpha-synuclein related disease or disorder;   thereby diagnosing an alpha-synuclein related disease or disorder.   
     
     
         8 . The method of  claims 2 - 7 , wherein the labeled moiety is a labeled amino acid or labeled water. 
     
     
         9 . The method of  claim 8 , wherein the amino acid is labeled with a radioisotope or a non-radio-labeled isotope. 
     
     
         10 . The method of  claim 9  wherein the amino acid is labeled with a non-radio labeled isotope. 
     
     
         11 . The method of  claim 10 , wherein the non-radio labeled isotope is selected from the group consisting of:  2 H,  13 C,  15 N,  17  or  18 O and  33, 34 or 36 S. 
     
     
         12 . The method of  claim 8 , wherein the amino acid is selected from the group consisting of leucine, isoleucine and phenylalanine. 
     
     
         13 . The method of  claim 12 , wherein the labeled amino acid is selected from the group consisting of one or more of:  15 N x  labeled leucine, wherein x=1-6;  13 C x  labeled phenylalanine, wherein x=1-9 and  13 C x  labeled isoleucine, wherein x=1-6. 
     
     
         14 . The method of  claims 2 - 7 , wherein the labeled moiety is a labeled water. 
     
     
         15 . The method of  claim 14 , wherein the labeled water is selected from the group consisting of deuterated water or oxygen 18 water. 
     
     
         16 . The method of  claims 2 - 7 , wherein the biological sample is selected from the group consisting of a bodily fluid or a tissue sample. 
     
     
         17 . The method of  claim 16 , wherein the bodily fluid is selected from the group consisting of: blood, plasma, blood serum, cerebral spinal fluid (CSF), urine, saliva, perspiration and tears. 
     
     
         18 . The method of  claim 17 , wherein the bodily fluid is CSF. 
     
     
         19 . The method of  claim 16 , wherein the tissue sample is a CNS sample. 
     
     
         20 . The method of  claim 19 , wherein the CNS sample is selected from the group consisting of: tissue from the CNS system, brain tissue, the forebrain tissue, the interbrain tissue, the midbrain tissue, the hindbrain tissue and the spinal cord tissue. 
     
     
         21 . The method of  claims 4 - 7 , where in the therapeutic agent is selected from the group consisting of small molecule inhibitors of alpha-synuclein, antibodies against alpha-synuclein, alpha-synuclein clearance activators, sirtuin 2 inhibitors, proteomsome inhibitors, small molecule inhibitors of alpha-synuclein polymerization, L-DOPA, cholesterylester transfer protein (CEPT) inhibitors, metalloprotease inhibitors, cholinesterase inhibitors, NMDA receptor antagonists, hormones, neuroprotective agents and cell death inhibitors. 
     
     
         22 . The method of  claim 21 , wherein the therapeutic agent is L-DOPA. 
     
     
         23 . A kit for determine prognosis, diagnosis or efficacy of a therapeutic regimen in a subject having or suspected of having an alpha-synuclein related disease or disorder. 
     
     
         24 . The kit of  claim 23 , wherein the kit comprises one or more labeled moieties and a means for administering the one or more moieties to a subject. 
     
     
         25 . The kit of  claim 23 , further comprising a means for obtaining a biological sample and instructions for determining the ratio of labeled to unlabeled alpha-synuclein.