Biomarkers of mild cognitive impairment and alzheimer's disease

Abstract

A method for quantifying a neurodegenerative disorder in a patient that includes obtaining a fluid sample from the subject; measuring a protein biomarker complex in said fluid sample and correlating the measurement with mild cognitive impairment or Alzheimer's disease status. The biomarkers include those that comprise at least one of a transthyretin protein and/or a prostaglandin-H2 D-isomerase protein, and at least one second, different protein selected from a transthyretin, prostaglandin-H2 D-isomerase, beta-2-microglobulin, cystatin C, superoxide dismutase [Cu—Zn], plasma retinol-binding protein, phosphatidylethanolamine-binding protein, carbonic anhydrase 2, prostaglandin-H2 D-isomerase, and/or serotransferrin protein;

1 . A method for quantifying a neurodegenerative disorder in a patient, comprising:
 (a) obtaining a fluid sample from the subject;   (b) measuring a protein biomarker complex in said fluid sample that comprises:   at least one of a transthyretin protein and/or a prostaglandin-H2 D-isomerase protein, and   at least one second, different protein selected from a transthyretin, prostaglandin-H2 D-isomerase, beta-2-microglobulin, cystatin C, superoxide dismutase [Cu—Zn], plasma retinol-binding protein, phosphatidylethanolamine-binding protein, carbonic anhydrase 2, prostaglandin-H2 D-isomerase, and/or serotransferrin protein; and   (c) correlating the measurement with mild cognitive impairment or Alzheimer's disease status.   
     
     
         2 . The method of  claim 1 , wherein the protein biomarker complex comprises transthyretin and prostaglandin-H2 D-isomerase. 
     
     
         3 . The method of  claim 1 , wherein said measuring step comprises trapping by enzyme linked immunosorbent assay (ELISA) at least one of transthyretin and/or prostaglandin-H2 D-isomerase; and
 probing for a second, different protein selected from the group consisting of at least one of transthyretin, prostaglandin-H2 D-isomerase, beta-2-microglobulin, cystatin C, superoxide dismutase [Cu—Zn], plasma retinol-binding protein, phosphatidylethanolamine-binding protein, carbonic anhydrase 2, prostaglandin-H2 D-isomerase, and/or serotransferrin is identified by probing the trapped protein.   
     
     
         4 . The method of  claim 3 , wherein the measuring step comprises trapping for a transthyretin protein. 
     
     
         5 . The method of  claim 4 , wherein the measuring step further comprises, after trapping for the transthyretin protein, probing for at least one of prostaglandin-H2 D-isomerase, beta-2-microglobulin, cystatin C, superoxide dismutase [Cu—Zn], plasma retinol-binding protein, phosphatidylethanolamine-binding protein, carbonic anhydrase 2, prostaglandin-H2 D-isomerase, and/or serotransferrin. 
     
     
         6 . The method of  claim 4 , wherein the measuring step further comprises, after trapping for a transthyretin protein, probing for a prostaglandin-H2 D-isomerase protein. 
     
     
         7 . The method of  claim 1 , wherein the correlating step comprises comparing an amount of said protein biomarker complex with a reference value in a control sample. 
     
     
         8 . The method of  claim 7 , wherein the control sample is from a normal individual. 
     
     
         9 . The method of  claim 8 , wherein the control sample is from a previous sample taken from a patient. 
     
     
         10 . The method of  claim 9 , further comprising comparing the control sample with the fluid sample of the subject to determine the progression of the mild cognitive impairment or the Alzheimer's disease. 
     
     
         11 . The method of  claim 1 , wherein the fluid sample is cerebrospinal fluid. 
     
     
         12 . The method of  claim 1 , wherein the sample from the subject is collected via a spinal tap. 
     
     
         13 . A method of monitoring the progression of a neurological disorder, comprising:
 comparing a first measured level of a biomarker complex with a reference level of said biomarker complex, the complex comprising at least one of a transthyretin protein and/or a prostaglandin-H2 D-isomerase protein, and at least one second, different protein selected from a transthyretin, prostaglandin-H2 D-isomerase, beta-2-microglobulin, cystatin C, superoxide dismutase [Cu—Zn], plasma retinol-binding protein, phosphatidylethanolamine-binding protein, carbonic anhydrase 2, prostaglandin-H2 D-isomerase, and/or serotransferrin protein; and   after allowing a period of time to pass, comparing a second measured level of the biomarker complex to said reference level and/or to said first measured level of the biomarker complex; and   determining the progression of the disease based on the first and second measured level of said biomarker complex.   
     
     
         14 . The method of  claim 13 , wherein the biomarker complex comprises a transthyretin protein and a prostaglandin-H2 D-isomerase protein. 
     
     
         15 . The method of  claim 13 , wherein the neurological disorder is mild cognitive impairment. 
     
     
         16 . The method of  claim 13 , wherein the neurological disorder is Alzheimer's disease. 
     
     
         17 . The method of  claim 13 , wherein the biomarker is measured by enzyme linked immunosorbent assay (ELISA). 
     
     
         18 . A diagnostic kit for quantifying Alzheimer's disease status, comprising:
 a solid support coated with an antibody to capture at lease one of a protein complex selected from prostaglandin-D-synthase and/or transthyretin; and   a second primary antibody to recognize the second component of the protein complex, the second component selected from a transthyretin, prostaglandin-H2 D-isomerase, beta-2-microglobulin, cystatin C, superoxide dismutase [Cu—Zn], plasma retinol-binding protein, phosphatidylethanolamine-binding protein, carbonic anhydrase 2, prostaglandin-H2 D-isomerase, and/or serotransferrin protein.   
     
     
         19 . The kit of  claim 18 , wherein the solid support is a 96 well polystyrene microtiter plate. 
     
     
         20 . The kit of  claim 18 , wherein the solid support is coated with anti-prostaglandin-D-synthase for protein capture. 
     
     
         21 . The kit of  claim 18 , wherein said second primary antibody is anti-human transthyretin. 
     
     
         22 . The kit of  claim 18 , further comprising TMB color reagent and stopping solution.