Methods for the diagnosis of dementia and other neurological disorders

Abstract

The present invention is directed to a method for differentially diagnosing dementia or the risk of dementia in a patient. The method comprises obtaining a sample from the patient; analyzing the sample to obtain quantifying data for one or more than one metabolite marker; comparing the quantifying data for the one or more than one metabolite marker to corresponding data obtained from one or more than one reference sample; and using the comparison to differentially diagnose dementia or the risk of dementia. The method may also assist in assessing dementia or the risk of dementia in a patient. The present invention is also directed to metabolite markers and compounds useful in the present method.

What is claimed: 
     
         1 . A method for diagnosing a patient's Alzheimer's disease health state or change in health state, or for diagnosing Alzheimer's disease, dementia, cognitive impairment, the risk of Alzheimer's disease, the risk of cognitive impairment, or the risk of dementia in a patient, the method comprising the steps of:
 a) analyzing a blood sample from said patient by high resolution mass spectrometry to obtain accurate mass intensity data;   b) comparing the accurate mass intensity data to corresponding data obtained from one or more than one reference sample to identify an increase or decrease in accurate mass intensity; and   c) using said increase or decrease in accurate mass intensity for diagnosing said patient's Alzheimer's disease health state or change in health state, or for diagnosing Alzheimer's disease, dementia, cognitive impairment, the risk of Alzheimer's disease, the risk of cognitive impairment, or the risk of dementia in said patient,   wherein the accurate mass intensity is measured, in Daltons, at or substantially equivalent to a hydrogen and electron adjusted accurate mass, or neutral accurate mass, selected from the group consisting of: 161.1053, 174.1409, 183.0661, 183.0662, 186.1408, 188.1566, 190.0330, 195.8577, 197.8549, 200.1564, 202.0453, 202.1720, 203.1157, 204.1876, 205.8865, 206.0789, 207.0822, 214.1720, 215.9153, 216.1877, 218.0192, 220.0798, 228.1877, 231.8893, 232.2188, 242.2030, 243.0718, 244.0559, 244.2187, 246.1465, 246.1472, 250.0366, 252.2095, 253.8163, 253.8164, 255.8135, 257.8105, 260.2135, 262.0221, 262.0777, 262.2293, 264.2452, 265.8423, 270.2343, 275.8712, 276.2095, 278.2254, 278.2255, 282.2573, 283.2602, 283.9028, 287.2824, 294.1443, 294.2207, 295.2239, 295.2287, 302.2255, 303.1079, 304.2402, 304.2410, 305.2438, 306.2569, 310.2883, 311.7750, 312.2312, 312.2663, 313.1153, 313.2690, 313.7721, 313.7722, 315.7693, 320.2356, 320.2357, 321.8039, 328.2402, 336.2662, 338.2821, 339.2850, 340.2976, 341.8614, 350.2423, 351.8903, 365.3159, 369.7338, 371.3542, 371.7311, 373.7280, 380.3096, 382.1082, 382.1083, 383.3283, 383.3284, 392.2938, 399.8196, 401.8166, 409.0208, 409.8484, 411.3211, 411.3212, 419.8773, 429.3749, 429.6888, 429.6890, 430.3818, 431.3860, 431.9570, 432.1532, 432.3254, 440.3532, 444.2717, 446.3403, 458.2404, 458.2405, 467.8070, 469.8042, 474.3706, 478.2540, 478.3664, 481.3172, 482.3215, 484.3041, 484.3794, 485.6503, 487.6482, 488.3873, 489.6451, 490.3641, 492.3816, 493.3850, 494.4342, 494.4343, 495.3320, 496.3355, 501.3212, 504.3814, 505.3229, 506.2851, 506.3213, 506.3214, 507.3316, 507.7055, 508.3356, 509.3493, 509.3494, 512.3356, 512.4082, 513.4122, 514.6879, 517.3136, 517.3140, 517.3722, 518.3174, 518.4345, 518.4346, 519.3321, 520.3353, 520.3354, 520.4499, 520.4500, 521.3474, 521.3477, 521.4522, 522.3511, 522.4634, 522.4635, 523.3634, 523.3635, 523.4678, 523.4679, 523.4680, 529.3166, 529.3167, 530.3213, 530.3471, 530.3820, 530.3821, 535.7944, 536.4794, 538.4224, 541.3139, 541.3430, 541.3432, 541.3433, 541.3435, 541.4425, 542.3173, 542.3461, 543.3296, 544.3970, 544.3971, 544.4479, 544.4481, 545.3453, 545.6062, 546.3485, 546.3486, 547.6031, 548.4815, 549.4844, 549.4845, 549.6005, 550.4956, 550.4957, 551.4985, 551.4986, 552.5021, 552.5022, 555.3098, 555.3101, 555.3102, 558.4667, 559.4690, 559.4700, 562.4600, 564.5134, 565.3393, 565.3394, 565.3396, 565.4104, 566.3434, 566.4130, 567.3545, 567.3547, 568.3573, 568.3574, 569.3685, 569.3687, 569.3690, 569.4784, 570.3724, 570.3725, 572.4468, 572.4816, 573.4852, 574.4597, 574.4637, 575.2728, 575.4632, 575.4990, 576.4770, 576.5097, 576.5098, 577.5136, 577.5137, 578.1574, 578.5277, 579.5325, 580.5350, 580.5351, 580.5352, 581.3344, 581.3345, 582.2473, 582.6334, 584.2646, 585.2664, 585.2673, 588.4731, 589.3403, 589.3404, 590.3430, 590.3431, 591.3542, 592.3571, 593.4743, 594.4878, 595.4932, 596.4791, 597.4840, 598.4965, 598.5124, 599.4936, 600.5127, 601.5164, 602.5282, 603.5317, 604.5432, 604.5433, 605.5456, 605.5457, 606.4869, 607.4919, 610.3686, 613.3405, 614.4914, 615.3539, 615.4798, 615.4938, 616.4673, 616.5052, 617.5089, 618.4829, 622.2539, 624.5131, 625.5075, 625.5076, 625.5161, 626.5104, 626.5108, 626.5277, 626.5278, 627.5201, 627.5302, 627.5304, 628.5237, 628.5421, 629.5449, 630.4861, 630.5586, 630.5587, 631.4902, 631.5619, 631.6280, 632.5032, 632.5035, 632.5762, 633.5078, 638.2465, 638.5149, 640.2637, 640.5294, 641.2661, 646.4837, 651.5221, 653.5360, 653.5361, 656.2587, 661.6233, 662.5175, 663.4870, 663.5216, 664.5322, 664.5323, 665.5010, 665.5354, 666.5455, 666.5456, 667.5474, 667.5475, 670.5689, 670.5690, 671.5722, 671.5723, 671.5726, 675.6357, 675.6377, 678.5477, 680.5623, 684.5489, 684.5491, 685.2600, 685.2601, 685.5538, 686.4877, 686.4880, 691.1957, 691.5960, 694.6161, 699.5198, 699.5199, 699.5200, 699.5203, 700.5520, 701.5359, 702.5677, 703.5516, 703.5709, 705.6093, 709.2594, 709.2595, 711.2577, 715.5167, 715.5169, 717.5308, 719.5465, 719.6231, 719.6233, 720.6258, 720.6438, 721.6390, 722.4789, 722.5334, 722.5335, 722.6424, 723.5194, 723.5195, 723.5197, 723.5203, 724.5256, 724.5257, 724.5258, 724.5493, 725.5359, 725.5385, 725.5527, 726.5459, 726.5461, 726.5462, 727.5516, 727.5567, 727.5568, 727.5569, 728.5626, 728.5627, 728.5629, 729.5672, 730.6493, 731.4914, 731.4916, 731.4917, 731.5463, 731.5464, 731.5829, 731.6530, 732.4937, 732.4938, 732.4939, 732.4940, 733.6426, 738.5445, 738.5448, 739.5141, 739.5142, 739.5143, 739.5164, 741.5305, 741.5307, 741.5319, 742.2972, 743.5464, 743.5466, 743.5467, 743.5468, 743.5469, 743.5470, 743.5471, 744.4954, 744.4956, 744.5500, 744.5535, 744.5536, 745.5621, 745.5656, 745.5658, 746.5119, 746.5570, 746.5714, 746.5717, 746.5719, 746.6210, 747.5201, 747.5203, 747.5244, 747.5245, 747.5778, 748.5286, 748.5287, 748.5721, 748.5735, 749.5359, 749.5365, 749.5367, 749.5406, 749.5407, 749.5408, 749.5760, 749.5761, 749.5777, 750.5402, 750.5403, 750.5438, 750.5440, 751.5516, 751.5529, 751.5553, 751.5555, 751.5556, 752.5564, 752.5581, 752.5583, 753.5672, 753.5672, 755.4860, 755.4861, 755.5467, 755.5468, 757.4989, 757.4991, 757.4993, 757.5014, 757.5016, 757.5625, 757.5626, 758.5092, 758.5094, 758.5655, 758.5656, 759.5162, 759.5163, 759.5164, 759.5165, 759.5779, 760.5215, 760.5216, 760.5217, 760.5811, 761.5843, 761.5846, 763.5157, 765.5313, 765.5334, 765.5335, 767.5469, 767.5470, 767.5494, 767.5495, 768.5503, 768.5504, 768.5538, 768.5539, 769.5654, 769.5655, 769.5656, 771.5813, 771.5814, 771.5815, 772.5278, 772.5280, 772.5860, 772.5862, 772.5863, 773.5347, 773.5368, 773.5370, 774.0313, 774.0316, 775.5516, 775.5527, 775.5528, 775.5530, 775.5533, 775.5535, 777.4426, 777.5287, 777.5288, 777.5530, 777.5531, 777.5672, 779.4393, 779.5441, 779.5442, 779.5444, 779.5829, 780.5474, 780.5475, 781.4354, 781.5607, 781.5616, 781.5617, 781.5620, 781.5985, 782.5084, 782.5085, 782.5086, 782.5647, 782.5649, 782.5650, 782.5653, 783.4315, 783.5147, 783.5148, 783.5671, 783.5672, 783.5778, 784.5235, 784.5237, 784.5239, 784.5810, 784.5811, 785.4288, 785.5933, 786.5415, 786.5416, 786.5967, 787.5464, 787.5465, 787.5728, 787.5729, 789.5892, 789.5893, 793.5386, 793.5387, 793.5679, 793.5681, 794.5421, 794.5422, 795.5181, 795.5182, 795.5183, 795.5550, 795.5551, 795.5837, 795.5838, 795.5839, 796.5290, 796.5292, 796.5874, 796.5876, 798.6742, 801.5550, 802.7056, 803.5445, 803.5677, 803.5678, 803.5680, 803.5681, 804.5475, 804.5476, 804.5713, 804.5718, 804.7227, 804.7230, 805.5604, 805.5605, 805.5831, 805.5832, 805.5839, 806.5637, 806.5638, 806.5639, 806.5873, 807.5757, 807.5758, 807.5768, 807.5899, 807.5900, 808.5792, 808.5803, 809.5936, 809.5937, 810.5399, 810.5400, 810.5401, 810.5969, 810.5971, 811.5732, 811.6096, 812.5761, 812.5762, 813.5885, 814.5917, 814.5919, 817.5375, 817.5376, 817.5377, 817.5378, 817.5838, 817.5840, 819.5551, 819.5552, 819.5553, 819.5641, 819.5642, 820.5677, 820.5679, 820.5680, 821.5711, 821.5712, 821.5713, 824.6892, 825.5544, 825.6926, 825.6927, 826.5581, 826.7048, 826.7069, 826.7070, 827.5448, 827.5699, 827.5700, 827.5701, 827.7083, 827.7086, 828.5736, 828.5737, 828.5742, 828.5743, 828.7202, 828.7207, 829.5604, 829.5856, 829.5859, 829.7239, 829.7242, 829.7244, 829.7246, 830.5894, 830.7352, 830.7355, 830.7362, 830.7363, 831.5759, 831.5760, 831.5995, 831.5997, 831.5998, 831.6000, 831.6001, 831.7387, 831.7408, 832.5791, 832.5792, 832.6024, 832.6026, 832.6027, 832.6036, 832.6037, 832.7492, 832.7495, 832.7521, 832.7522, 832.7523, 833.5931, 833.5932, 833.7551, 833.7558, 833.7570, 833.7571, 835.6998, 835.7001, 835.7006, 836.7076, 837.5027, 837.5881, 837.7180, 838.7226, 838.7232, 839.6031, 840.6063, 842.7387, 847.5316, 847.5953, 847.5954, 851.5698, 852.5738, 852.7250, 853.5854, 853.5855, 853.5862, 853.7296, 854.5902, 855.6015, 855.6016, 855.6023, 855.6025, 855.7417, 856.6061, 856.6063, 856.6720, 856.7481, 857.6186, 857.7531, 858.6211, 858.6212, 858.6860, 858.6861, 858.7632, 858.7663, 859.7694, 859.7695, 859.7696, 859.7706, 860.7752, 860.7753, 860.7756, 861.7801, 861.7806, 863.6876, 863.7336, 864.7380, 864.7596, 865.7486, 865.7487, 866.7532, 866.7533, 867.7579, 867.7581, 870.7307, 871.5527, 871.5528, 871.5529, 871.5934, 871.5935, 874.7645, 878.7400, 879.5999, 879.7454, 880.6035, 880.7516, 880.7566, 881.7558, 881.7616, 882.7660, 882.7723, 883.7705, 883.7765, 884.7801, 884.7877, 885.7854, 885.7922, 886.5582, 886.5584, 886.7916, 886.7917, 886.8012, 887.7352, 887.7999, 887.8001, 887.8005, 888.7394, 889.7492, 890.7535, 894.7810, 908.7832, 909.7882, 910.7968, 911.8032, 913.7513, 914.7583, 915.5191, 915.5192, 915.7681, 916.7743, 921.8142, 921.8145, 921.8153, 928.7505, 931.7695, 942.7879, 1018.9420, 1019.3838, 1019.3840, 1085.3294, 1098.9739, 1098.9740, 1225.0920, 1226.0968, 1226.0970, 1227.1070, 1228.1110, 1228.1111 and combinations thereof.   
     
     
         2 . The method of  claim 1 , wherein the accurate mass intensity data is obtained using a Fourier transform ion cyclotron resonance, time of flight, orbitrap, quadrupole or triple quadrupole mass spectrometer. 
     
     
         3 . The method of  claim 1 , wherein the blood sample is a blood serum sample. 
     
     
         4 . The method of  claim 1 , wherein the accurate mass intensities represent ionized metabolites. 
     
     
         5 . The method of  claim 1 , wherein a liquid/liquid extraction is performed on the blood sample whereby non-polar metabolites are dissolved in an organic solvent and polar metabolites are dissolved in an aqueous solvent. 
     
     
         6 . The method of  claim 5 , wherein the accurate mass intensities are obtained from the ionization of the extracted samples using an ionization method selected from the group consisting of: positive electrospray ionization, negative electrospray ionization, positive atmospheric pressure chemical ionization, negative atmospheric pressure chemical ionization, and combinations thereof. 
     
     
         7 . The method of  claim 1 , wherein the accurate mass intensity data is obtained using a Fourier transform ion cyclotron resonance mass spectrometer. 
     
     
         8 . The method of  claim 1 , wherein said one or more than one reference sample is:
 a) one or more than one reference sample obtained from a non-demented control individual;   b) one or more than one reference sample obtained from a demented subject;   c) one or more than one reference sample obtained from a subject pathologically diagnosed as having Alzheimer's Disease;   d) one or more than one reference sample obtained from a subject clinically diagnosed as having Alzheimer's Disease;   e) one or more than one reference sample obtained from a patient with cognitive impairment as measured by Alzheimer's Disease Assessment Scale-cognitive subset (ADAS-cog);   f) one or more than one reference sample obtained from a patient with cognitive impairment as measured by Folstein's Mini-Mental State Exam (MMSE); or   g) any combination of a) to f) above.   
     
     
         9 . The method of  claim 1 , wherein the method is for diagnosing:
 (a) the presence of or risk of Alzheimer's disease (AD);   (b) the presence of or risk of AD pathology;   (c) the presence of or risk of dementia;   (d) the presence of or risk of cognitive impairment; or   (e) a combination of (a) to (d) above.   
     
     
         10 . The method of  claim 1 , further comprising
 analyzing a blood sample from said patient by mass spectrometry to obtain accurate mass intensity data for one or more than one internal control metabolite; and   calculating a ratio for each of the accurate mass intensities obtained in step (a) to the accurate mass intensities obtained for the one or more than one internal control metabolite;   wherein the comparing step (b) comprises comparing each ratio to one or more corresponding ratios obtained for one or more than one reference sample.   
     
     
         11 . The method of  claim 1 , wherein a decrease in accurate mass intensity is identified in the comparing step (b). 
     
     
         12 . The method of  claim 1 , wherein the hydrogen and electron adjusted accurate mass, or neutral accurate mass, is selected from the group consisting of: 699.5198, 723.5195, 723.5197, 751.5555, 541.3432, 569.3687, 803.568, 886.5582, 565.3394, 569.369, 801.555, 857.6186, 207.0822, 275.8712, 371.7311, 373.728, 432.1532, 485.5603, 487.6482, 562.46, 622.2539, 640.2637, 730.6493, 742.2972, 701.53591, 699.52026, 723.52026, 747.52026, 729.56721, 727.55156, 779.58286, 775.55156, and combinations thereof. 
     
     
         13 . A method for diagnosing a patient's Alzheimer's disease health state or change in health state, or for diagnosing Alzheimer's disease, dementia, cognitive impairment, the risk of Alzheimer's disease, the risk of cognitive impairment, or the risk of dementia in a patient, the method comprising the steps of:
 a) analyzing a blood sample from said patient to obtain quantifying data for one or more than one metabolite marker;   b) comparing the quantifying data for said one or more than one metabolite marker to corresponding data obtained for one or more than one reference sample to identify an increase or decrease in the level of said one or more than one metabolite marker in said blood sample; and   c) using said increase or decrease in the level of said one or more than one metabolite marker in said blood sample for diagnosing said patient's Alzheimer's disease health state or change in health state, or for diagnosing Alzheimer's disease, dementia, cognitive impairment, the risk of Alzheimer's disease, the risk of cognitive impairment, or the risk of dementia in said patient,   wherein the one or more than one metabolite marker comprises one or more molecule selected from the group consisting of: phosphatidylethanolamine (PtdEt), plasmenylethanolamine, plasmanylethanolamine, and combinations thereof, wherein the PtdEt is selected from the group consisting of PtdEt 16:0/18:0, PtdEt 16:0/18:1, PtdEt 18:0/18:0, PtdEt 18:0/18:1, and combinations thereof.   
     
     
         14 . The method of  claim 13 , wherein the-plasmanylethanolamine is selected from the group consisting of: plasmanyl 16:0/18:1, plasmanyl 16:0/18:2, plasmanyl 16:0/20:4, plasmanyl 16:0/22:4, plasmanyl 16:0/22:6, plasmanyl 18:0/18:1, plasmanyl 18:0/18:2, plasmanyl 18:0/20:4, plasmanyl 18:0/22:4, plasmanyl 18:0/22:6, and combinations thereof, and the plasmenylethanolamine is selected from the group consisting of: plasmenyl 16:0/18:1, plasmenyl 16:0/18:2, plasmenyl 16:0/20:4, plasmenyl 16:0/22:4, plasmenyl 16:0/22:6, plasmenyl 18:0/18:1, plasmenyl 18:0/18:2, plasmenyl 18:0/20:4, plasmenyl 18:0/22:4, plasmenyl 18:0/22:6, and combinations thereof. 
     
     
         15 . The method of  claim 13 , wherein the quantifying data is obtained using a Fourier transform ion cyclotron resonance, time of flight, orbitrap, quadrupole or triple quadrupole mass spectrometer. 
     
     
         16 . The method of  claim 15 , wherein the mass spectrometer is equipped with a chromatographic system. 
     
     
         17 . The method of  claim 13 , wherein the blood sample is a blood serum sample. 
     
     
         18 . The method of  claim 13 , wherein a liquid/liquid extraction is performed on the blood sample whereby non-polar metabolites are dissolved in an organic solvent and polar metabolites are dissolved in an aqueous solvent. 
     
     
         19 . The method of  claim 18 , wherein the extracted samples are analyzed by positive or negative electrospray ionization or positive or negative atmospheric pressure chemical ionization. 
     
     
         20 . The method of  claim 18 , wherein the extracted samples are analyzed by MS/MS transition. 
     
     
         21 . The method of  claim 18 , wherein the extracted samples are analyzed by extracted ion current (EIC) chromatography and MS/MS transition. 
     
     
         22 . The method of  claim 13 , wherein said one or more than one reference sample is
 a) one or more than one reference sample obtained from a non-demented control individual;   b) one or more than one reference sample obtained from a demented subject;   c) one or more than one reference sample obtained from a subject pathologically diagnosed as having Alzheimer's Disease;   d) one or more than one reference sample obtained from a subject clinically diagnosed as having Alzheimer's Disease;   e) one or more than one reference sample obtained from a patient with cognitive impairment as measured by Alzheimer's Disease Assessment Scale-cognitive subset (ADAS-cog);   f) one or more than one reference sample obtained from a patient with cognitive impairment as measured by Folstein's Mini-Mental State Exam (MMSE); or   g) any combination of a) to f) above.   
     
     
         23 . The method of  claim 13 , further comprising:
 analyzing a blood sample from said patient to obtain quantifying data for one or more than one internal control metabolite; and   obtaining a ratio for each of the levels of said one or more than one metabolite marker to the level obtained for the one or more than one internal control metabolite;   wherein the comparing step (b) comprises comparing each ratio to one or more corresponding ratios obtained for the one or more than one reference sample.   
     
     
         24 . The method of  claim 13 , wherein a decrease in the level of said one or more than one metabolite marker in said blood sample is identified in the comparing step (b). 
     
     
         25 . The method of  claim 14 , wherein the extracted samples are analyzed by MS/MS transitions, and
 the MS/MS transitions for the phosphatidylethanolamines are 718.0/255.0, 716.0/255.0, 746.0/283.0 and 744.0/283.0, respectively;   the MS/MS transitions for the plasmanylethanolamines are 702.0/281.0, 700.0/279.0, 724.0/303.0, 752.0/331.0, 748.0/327.0, 730.0/281.0, 728.0/279.0, 752.0/303.0, 780.0/331.0 and 776.0/327.0, respectively; and   the MS/MS transitions for the plasmenylethanolamines are 700.0/281.0, 698.0/279.0, 722.0/303.0, 750.0/331.0, 746.0/327.0, 728.0/281.0, 726.0/279.0, 750.6/303.2, 778.0/331.0 and 774.0/327.0, respectively.   
     
     
         26 . A method for evaluating the efficacy of a therapy for treating Alzheimer's disease, dementia, or cognitive impairment in a patient, comprising the steps of:
 a) analyzing a blood sample from said patient by high resolution mass spectrometry to obtain accurate mass intensity data;   b) comparing the accurate mass intensity data to corresponding data obtained from one or more than one reference sample to identify an increase or decrease in accurate mass intensity; and   c) using said increase or decrease in accurate mass intensity to determine whether the therapy is improving the biochemical state of the patient,   wherein the accurate mass intensity is measured, in Daltons, at or substantially equivalent to a hydrogen and electron adjusted accurate mass, or neutral accurate mass, selected from the group consisting of: 161.1053, 174.1409, 183.0661, 183.0662, 186.1408, 188.1566, 190.0330, 195.8577, 197.8549, 200.1564, 202.0453, 202.1720, 203.1157, 204.1876, 205.8865, 206.0789, 207.0822, 214.1720, 215.9153, 216.1877, 218.0192, 220.0798, 228.1877, 231.8893, 232.2188, 242.2030, 243.0718, 244.0559, 244.2187, 246.1465, 246.1472, 250.0366, 252.2095, 253.8163, 253.8164, 255.8135, 257.8105, 260.2135, 262.0221, 262.0777, 262.2293, 264.2452, 265.8423, 270.2343, 275.8712, 276.2095, 278.2254, 278.2255, 282.2573, 283.2602, 283.9028, 287.2824, 294.1443, 294.2207, 295.2239, 295.2287, 302.2255, 303.1079, 304.2402, 304.2410, 305.2438, 306.2569, 310.2883, 311.7750, 312.2312, 312.2663, 313.1153, 313.2690, 313.7721, 313.7722, 315.7693, 320.2356, 320.2357, 321.8039, 328.2402, 336.2662, 338.2821, 339.2850, 340.2976, 341.8614, 350.2423, 351.8903, 365.3159, 369.7338, 371.3542, 371.7311, 373.7280, 380.3096, 382.1082, 382.1083, 383.3283, 383.3284, 392.2938, 399.8196, 401.8166, 409.0208, 409.8484, 411.3211, 411.3212, 419.8773, 429.3749, 429.6888, 429.6890, 430.3818, 431.3860, 431.9570, 432.1532, 432.3254, 440.3532, 444.2717, 446.3403, 458.2404, 458.2405, 467.8070, 469.8042, 474.3706, 478.2540, 478.3664, 481.3172, 482.3215, 484.3041, 484.3794, 485.6503, 487.6482, 488.3873, 489.6451, 490.3641, 492.3816, 493.3850, 494.4342, 494.4343, 495.3320, 496.3355, 501.3212, 504.3814, 505.3229, 506.2851, 506.3213, 506.3214, 507.3316, 507.7055, 508.3356, 509.3493, 509.3494, 512.3356, 512.4082, 513.4122, 514.6879, 517.3136, 517.3140, 517.3722, 518.3174, 518.4345, 518.4346, 519.3321, 520.3353, 520.3354, 520.4499, 520.4500, 521.3474, 521.3477, 521.4522, 522.3511, 522.4634, 522.4635, 523.3634, 523.3635, 523.4678, 523.4679, 523.4680, 529.3166, 529.3167, 530.3213, 530.3471, 530.3820, 530.3821, 535.7944, 536.4794, 538.4224, 541.3139, 541.3430, 541.3432, 541.3433, 541.3435, 541.4425, 542.3173, 542.3461, 543.3296, 544.3970, 544.3971, 544.4479, 544.4481, 545.3453, 545.6062, 546.3485, 546.3486, 547.6031, 548.4815, 549.4844, 549.4845, 549.6005, 550.4956, 550.4957, 551.4985, 551.4986, 552.5021, 552.5022, 555.3098, 555.3101, 555.3102, 558.4667, 559.4690, 559.4700, 562.4600, 564.5134, 565.3393, 565.3394, 565.3396, 565.4104, 566.3434, 566.4130, 567.3545, 567.3547, 568.3573, 568.3574, 569.3685, 569.3687, 569.3690, 569.4784, 570.3724, 570.3725, 572.4468, 572.4816, 573.4852, 574.4597, 574.4637, 575.2728, 575.4632, 575.4990, 576.4770, 576.5097, 576.5098, 577.5136, 577.5137, 578.1574, 578.5277, 579.5325, 580.5350, 580.5351, 580.5352, 581.3344, 581.3345, 582.2473, 582.6334, 584.2646, 585.2664, 585.2673, 588.4731, 589.3403, 589.3404, 590.3430, 590.3431, 591.3542, 592.3571, 593.4743, 594.4878, 595.4932, 596.4791, 597.4840, 598.4965, 598.5124, 599.4936, 600.5127, 601.5164, 602.5282, 603.5317, 604.5432, 604.5433, 605.5456, 605.5457, 606.4869, 607.4919, 610.3686, 613.3405, 614.4914, 615.3539, 615.4798, 615.4938, 616.4673, 616.5052, 617.5089, 618.4829, 622.2539, 624.5131, 625.5075, 625.5076, 625.5161, 626.5104, 626.5108, 626.5277, 626.5278, 627.5201, 627.5302, 627.5304, 628.5237, 628.5421, 629.5449, 630.4861, 630.5586, 630.5587, 631.4902, 631.5619, 631.6280, 632.5032, 632.5035, 632.5762, 633.5078, 638.2465, 638.5149, 640.2637, 640.5294, 641.2661, 646.4837, 651.5221, 653.5360, 653.5361, 656.2587, 661.6233, 662.5175, 663.4870, 663.5216, 664.5322, 664.5323, 665.5010, 665.5354, 666.5455, 666.5456, 667.5474, 667.5475, 670.5689, 670.5690, 671.5722, 671.5723, 671.5726, 675.6357, 675.6377, 678.5477, 680.5623, 684.5489, 684.5491, 685.2600, 685.2601, 685.5538, 686.4877, 686.4880, 691.1957, 691.5960, 694.6161, 699.5198, 699.5199, 699.5200, 699.5203, 700.5520, 701.5359, 702.5677, 703.5516, 703.5709, 705.6093, 709.2594, 709.2595, 711.2577, 715.5167, 715.5169, 717.5308, 719.5465, 719.6231, 719.6233, 720.6258, 720.6438, 721.6390, 722.4789, 722.5334, 722.5335, 722.6424, 723.5194, 723.5195, 723.5197, 723.5203, 724.5256, 724.5257, 724.5258, 724.5493, 725.5359, 725.5385, 725.5527, 726.5459, 726.5461, 726.5462, 727.5516, 727.5567, 727.5568, 727.5569, 728.5626, 728.5627, 728.5629, 729.5672, 730.6493, 731.4914, 731.4916, 731.4917, 731.5463, 731.5464, 731.5829, 731.6530, 732.4937, 732.4938, 732.4939, 732.4940, 733.6426, 738.5445, 738.5448, 739.5141, 739.5142, 739.5143, 739.5164, 741.5305, 741.5307, 741.5319, 742.2972, 743.5464, 743.5466, 743.5467, 743.5468, 743.5469, 743.5470, 743.5471, 744.4954, 744.4956, 744.5500, 744.5535, 744.5536, 745.5621, 745.5656, 745.5658, 746.5119, 746.5570, 746.5714, 746.5717, 746.5719, 746.6210, 747.5201, 747.5203, 747.5244, 747.5245, 747.5778, 748.5286, 748.5287, 748.5721, 748.5735, 749.5359, 749.5365, 749.5367, 749.5406, 749.5407, 749.5408, 749.5760, 749.5761, 749.5777, 750.5402, 750.5403, 750.5438, 750.5440, 751.5516, 751.5529, 751.5553, 751.5555, 751.5556, 752.5564, 752.5581, 752.5583, 753.5672, 753.5672, 755.4860, 755.4861, 755.5467, 755.5468, 757.4989, 757.4991, 757.4993, 757.5014, 757.5016, 757.5625, 757.5626, 758.5092, 758.5094, 758.5655, 758.5656, 759.5162, 759.5163, 759.5164, 759.5165, 759.5779, 760.5215, 760.5216, 760.5217, 760.5811, 761.5843, 761.5846, 763.5157, 765.5313, 765.5334, 765.5335, 767.5469, 767.5470, 767.5494, 767.5495, 768.5503, 768.5504, 768.5538, 768.5539, 769.5654, 769.5655, 769.5656, 771.5813, 771.5814, 771.5815, 772.5278, 772.5280, 772.5860, 772.5862, 772.5863, 773.5347, 773.5368, 773.5370, 774.0313, 774.0316, 775.5516, 775.5527, 775.5528, 775.5530, 775.5533, 775.5535, 777.4426, 777.5287, 777.5288, 777.5530, 777.5531, 777.5672, 779.4393, 779.5441, 779.5442, 779.5444, 779.5829, 780.5474, 780.5475, 781.4354, 781.5607, 781.5616, 781.5617, 781.5620, 781.5985, 782.5084, 782.5085, 782.5086, 782.5647, 782.5649, 782.5650, 782.5653, 783.4315, 783.5147, 783.5148, 783.5671, 783.5672, 783.5778, 784.5235, 784.5237, 784.5239, 784.5810, 784.5811, 785.4288, 785.5933, 786.5415, 786.5416, 786.5967, 787.5464, 787.5465, 787.5728, 787.5729, 789.5892, 789.5893, 791.5386, 793.5387, 791.5679, 793.5681, 794.5421, 794.5422, 795.5181, 795.5182, 795.5183, 795.5550, 795.5551, 795.5837, 795.5838, 795.5839, 796.5290, 796.5292, 796.5874, 796.5876, 798.6742, 801.5550, 802.7056, 803.5445, 803.5677, 803.5678, 803.5680, 803.5681, 804.5475, 804.5476, 804.5713, 804.5718, 804.7227, 804.7230, 805.5604, 805.5605, 805.5831, 805.5832, 805.5839, 806.5637, 806.5638, 806.5639, 806.5873, 807.5757, 807.5758, 807.5768, 807.5899, 807.5900, 808.5792, 808.5803, 809.5936, 809.5937, 810.5399, 810.5400, 810.5401, 810.5969, 810.5971, 811.5732, 811.6096, 812.5761, 812.5762, 813.5885, 814.5917, 814.5919, 817.5375, 817.5376, 817.5377, 817.5378, 817.5838, 817.5840, 819.5551, 819.5552, 819.5553, 819.5641, 819.5642, 820.5677, 820.5679, 820.5680, 821.5711, 821.5712, 821.5713, 824.6892, 825.5544, 825.6926, 825.6927, 826.5581, 826.7048, 826.7069, 826.7070, 827.5448, 827.5699, 827.5700, 827.5701, 827.7083, 827.7086, 828.5736, 828.5737, 828.5742, 828.5743, 828.7202, 828.7207, 829.5604, 829.5856, 829.5859, 829.7239, 829.7242, 829.7244, 829.7246, 830.5894, 830.7352, 830.7355, 830.7362, 830.7363, 831.5759, 831.5760, 831.5995, 831.5997, 831.5998, 831.6000, 831.6001, 831.7387, 831.7408, 832.5791, 832.5792, 832.6024, 832.6026, 832.6027, 832.6036, 832.6037, 832.7492, 832.7495, 832.7521, 832.7522, 832.7523, 833.5931, 833.5932, 833.7551, 833.7558, 833.7570, 833.7571, 835.6998, 835.7001, 835.7006, 836.7076, 837.5027, 837.5881, 837.7180, 838.7226, 838.7232, 839.6031, 840.6063, 842.7387, 847.5316, 847.5953, 847.5954, 851.5698, 852.5738, 852.7250, 853.5854, 853.5855, 853.5862, 853.7296, 854.5902, 855.6015, 855.6016, 855.6023, 855.6025, 855.7417, 856.6061, 856.6063, 856.6720, 856.7481, 857.6186, 857.7531, 858.6211, 858.6212, 858.6860, 858.6861, 858.7632, 858.7663, 859.7694, 859.7695, 859.7696, 859.7706, 860.7752, 860.7753, 860.7756, 861.7801, 861.7806, 863.6876, 863.7336, 864.7380, 864.7596, 865.7486, 865.7487, 866.7532, 866.7533, 867.7579, 867.7581, 870.7307, 871.5527, 871.5528, 871.5529, 871.5934, 871.5935, 874.7645, 878.7400, 879.5999, 879.7454, 880.6035, 880.7516, 880.7566, 881.7558, 881.7616, 882.7660, 882.7723, 883.7705, 883.7765, 884.7801, 884.7877, 885.7854, 885.7922, 886.5582, 886.5584, 886.7916, 886.7917, 886.8012, 887.7352, 887.7999, 887.8001, 887.8005, 888.7394, 889.7492, 890.7535, 894.7810, 908.7832, 909.7882, 910.7968, 911.8032, 913.7513, 914.7583, 915.5191, 915.5192, 915.7681, 916.7743, 921.8142, 921.8145, 921.8153, 928.3505, 931.7695, 942.7879, 1018.9420, 1019.3838, 1019.3840, 1085.3294, 1098.9739, 1098.9740, 1225.0920, 1226.0968, 1226.0970, 1227.1070, 1228.1110, 1228.1111 and combinations thereof.   
     
     
         27 . The method of  claim 26 , wherein the accurate mass intensity data is obtained using a Fourier transform ion cyclotron resonance, time of flight, orbitrap, quadrupole or triple quadrupole mass spectrometer. 
     
     
         28 . The method of  claim 26 , wherein the blood sample is a blood serum sample. 
     
     
         29 . The method of  claim 26 , wherein the accurate mass intensities represent ionized metabolites. 
     
     
         30 . The method of  claim 26 , wherein a liquid/liquid extraction is performed on the blood sample whereby non-polar metabolites are dissolved in an organic solvent and polar metabolites are dissolved in an aqueous solvent. 
     
     
         31 . The method of  claim 30 , wherein the accurate mass intensities are obtained from the ionization of the extracted samples using an ionization method selected from the group consisting of: positive electrospray ionization, negative electrospray ionization, positive atmospheric pressure chemical ionization, negative atmospheric pressure chemical ionization, and combinations thereof. 
     
     
         32 . The method of  claim 26 , wherein the accurate mass intensity data is obtained using a Fourier transform ion cyclotron resonance mass spectrometer. 
     
     
         33 . The method of  claim 26 , wherein said one or more than one reference sample is:
 a) one or more than one reference sample obtained from a non-demented control individual;   b) one or more than one reference sample obtained from a demented subject;   c) one or more than one reference sample obtained from a subject pathologically diagnosed as having Alzheimer's Disease;   d) one or more than one reference sample obtained from a subject clinically diagnosed as having Alzheimer's Disease;   e) one or more than one reference sample obtained from a patient with cognitive impairment as measured by Alzheimer's Disease Assessment Scale-cognitive subset (ADAS-cog);   f) one or more than one reference sample obtained from a patient with cognitive impairment as measured by Folstein's Mini-Mental State Exam (MMSE); or   g) any combination of a) to above.   
     
     
         34 . The method of  claim 26 , wherein the method is for evaluating the efficacy of a therapy for treating:
 (a) Alzheimer's disease (AD);   (b) AD pathology;   (c) dementia;   (d) cognitive impairment; or   (e) a combination of (a) to (d) above.   
     
     
         35 . The method of  claim 26 , further comprising
 analyzing a blood sample from said patient by mass spectrometry to obtain accurate mass intensity data for one or more than one internal control metabolite; and   calculating a ratio for each of the accurate mass intensities obtained in step (a) to the accurate mass intensities obtained for the one or more than one internal control metabolite;   wherein the comparing step (b) comprises comparing each ratio to one or more corresponding ratios obtained for one or more than one reference sample.   
     
     
         36 . The method of  claim 26 , wherein an increase in accurate mass intensity is identified in the comparing step (b). 
     
     
         37 . The method of  claim 26 , wherein the hydrogen and electron adjusted accurate mass, or neutral accurate mass, is selected from the group consisting of: 699.5198, 723.5195, 723.5197, 751.5555, 541.3432, 569.3687, 803.568, 886.5582, 565.3394, 569.369, 801.555, 857.6186, 207.0822, 275.8712, 371.7311, 373.728, 432.1532, 485.5603, 487.6482, 562.46, 622.2539, 640.2637, 730.6493, 742.2972, 701.53591, 699.52026, 723.52026, 747.52026, 729.56721, 727.55156, 779.58286, 775.55156, and combinations thereof. 
     
     
         38 . A method for evaluating the efficacy of a therapy for treating Alzheimer's disease, dementia, or cognitive impairment in a patient, comprising the steps of:
 a) analyzing a blood sample from said patient to obtain quantifying data for one or more than one metabolite marker;   b) comparing the quantifying data for said one or more than one metabolite marker to corresponding data obtained for one or more than one reference sample to identify an increase or decrease in the level of said one or more than one metabolite marker in said blood sample; and   c) using said increase or decrease in the level of said one or more than one metabolite marker in said blood sample to determine whether the therapy is improving the biochemical state of the patient,   wherein the one or more than one metabolite marker comprises one or more molecule selected from the group consisting of: phosphatidylethanolamine (PtdEt), plasmenylethanolamine, plasmanylethanolamine, and combinations thereof, wherein the PtdEt is selected from the group consisting of: PtdEt 16:0/18:0, PtdEt 16:0/18:1, PtdEt 18:0/18:0, PtdEt 18:0/18:1, and combinations thereof.   
     
     
         39 . The method of  claim 38 , wherein the plasmanylethanolamine is selected from the group consisting of: plasmanyl 16:0/18:1, plasmanyl 16:0/18:2, plasmanyl 16:0/20:4, plasmanyl 16:0/22:4, plasmanyl 16:0/22:6, plasmanyl 18:0/18:1, plasmanyl 18:0/18:2, plasmanyl 18:0/20:4, plasmanyl 18:0/22:4, plasmanyl 18:0/22:6, and combinations thereof; and, the plasmenylethanolamine is selected from the group consisting of: plasmenyl 16:0/18:1, plasmenyl 16:0/18:2, plasmenyl 16:0/20:4, plasmenyl 16:0/22:4, plasmenyl 16:0/22:6, plasmenyl 18:0/18:1, plasmenyl 18:0/18:2, plasmenyl 18:0/20:4, plasmenyl 18:0/22:4, plasmenyl 18:0/22:6, and combinations thereof. 
     
     
         40 . The method of  claim 38 , wherein the quantifying data is obtained using a Fourier transform ion cyclotron resonance, time of flight, orbitrap, quadrupole or triple quadrupole mass spectrometer. 
     
     
         41 . The method of  claim 40 , wherein the mass spectrometer is equipped with a chromatographic system. 
     
     
         42 . The method of  claim 38 , wherein the blood sample is a blood serum sample. 
     
     
         43 . The method of  claim 38 , wherein a liquid/liquid extraction is performed on the blood sample whereby non-polar metabolites are dissolved in an organic solvent and polar metabolites are dissolved in an aqueous solvent. 
     
     
         44 . The method of  claim 43 , wherein the extracted samples are analyzed by positive or negative electrospray ionization or positive or negative atmospheric pressure chemical ionization. 
     
     
         45 . The method of  claim 43 , wherein the extracted samples are analyzed by MS/MS transition. 
     
     
         46 . The method of  claim 43 , wherein the extracted samples are analyzed by extracted ion current (EIC) chromatography and MS/MS transition. 
     
     
         47 . The method of  claim 38 , wherein said one or more than one reference sample is
 a) one or more than one reference sample obtained from a non-demented control individual;   b) one or more than one reference sample obtained from a demented subject;   c) one or more than one reference sample obtained from a subject pathologically diagnosed as having Alzheimer's Disease;   d) one or more than one reference sample obtained from a subject clinically diagnosed as having Alzheimer's Disease;   e) one or more than one reference sample obtained from a patient with cognitive impairment as measured by Alzheimer's Disease Assessment Scale-cognitive subset (ADAS-cog);   f) one or more than one reference sample obtained from a patient with cognitive impairment as measured by Folstein's Mini-Mental State Exam (MMSE); or   g) any combination of a) to f) above.   
     
     
         48 . The method according to  claim 38 , further comprising:
 analyzing a blood sample from said patient to obtain quantifying data for one or more than one internal control metabolite; and   obtaining a ratio for each of the levels of said one or more than one metabolite marker to the level obtained for the one or more than one internal control metabolite;   wherein the comparing step (b) comprises comparing each ratio to one or more corresponding ratios obtained for the one or more than one reference sample.   
     
     
         49 . The method of  claim 38 , wherein an increase in the level of said one or more than one metabolite marker in said blood sample is identified in the comparing step (b). 
     
     
         50 . The method of  claim 39 , wherein the extracted samples are analyzed by MS/MS transition, and
 the MS/MS transitions for the phosphatidylethanolamines are 718.0/255.0, 716.0/255.0, 746.0/283.0 and 744.0/283.0, respectively;   the MS/MS transitions for the plasmanylethanolamines are 702.0/281.0, 700.0/279.0, 724.0/303.0, 752.0/331.0, 748.0/327.0, 730.0/281.0, 728.0/279.0, 752.0/303.0, 780.0/331.0 and 776.0/327.0, respectively; and   the MS/MS transitions for the plasmenylethanolamines are 700.0/281.0, 698.0/279.0, 722.0/303.0, 750.0/331.0, 746.0/327.0, 728.0/281.0, 726.0/279.0, 750.6/303.2, 778.0/331.0 and 774.0/327.0, respectively.   
     
     
         51 . The method of  claim 26 , wherein at least one of the one or more than one reference sample defined in step (b) is a pre-therapy baseline blood sample obtained from the patient. 
     
     
         52 . The method of  claim 1 , wherein substantially equivalent refers to ±5 ppm of the hydrogen and electron adjusted accurate mass, or neutral accurate mass. 
     
     
         53 . The method of  claim 1 , wherein substantially equivalent refers to ±1 ppm of the hydrogen and electron adjusted accurate mass, or neutral accurate mass. 
     
     
         54 . The method of  claim 26 , wherein substantially equivalent refers to ±5 ppm of the hydrogen and electron adjusted accurate mass, or neutral accurate mass. 
     
     
         55 . The method of  claim 26 , wherein substantially equivalent refers ±1 ppm of the hydrogen and electron adjusted accurate mass, or neutral accurate mass. 
     
     
         56 . The method of  claim 23 , wherein the one or more than one internal control metabolite is a phosphatidylethanolamine (PtdEt). 
     
     
         57 . The method of  claim 56 , wherein the phosphatidylethanolamine is selected from the group consisting of PtdEt 16:0/18:0, PtdEt 16:0/18:1, PtdEt 18:0/18:0, PtdEt 18:0/18:1, and combinations thereof. 
     
     
         58 . The method of  claim 48 , wherein the one or more than one internal control metabolite is a phosphatidylethanolamine (PtdEt). 
     
     
         59 . The method of  claim 58 , wherein the phosphatidylethanolamine is selected from the group consisting of PtdEt 16:0/18:0, PtdEt 16:0/18:1, PtdEt 18:0/18:0, PtdEt 18:0/18:1, and combinations thereof.