Metabolic biomarkers for memory loss
The present invention relates to methods of determining if a subject has an increased risk of suffering from memory impairment. The methods comprise analyzing at least one plasma sample from the subject to determine a value of the subject's metabolite profile and comparing the value of the subject's metabolite profile with the value of a normal metabolite profile. A change in the value of the subject's metabolite profile, over normal values is indicative that the subject has an increased risk of suffering from memory impairment compared to a normal individual.
1. A method of treating a subject who has an increased risk of memory impairment, the method comprising
(a) monitoring whether the subject has an increased risk of memory impairment, wherein the monitoring comprises, at 2 or more time points:
(i) analyzing a set of metabolites from at least one sample from the subject to determine the subject's concentrations of the metabolites in the set of metabolites, and
(ii) comparing the subject's concentrations of the metabolites in the set of metabolites to normal concentrations of the metabolites,
wherein the subject is determined to have an increased risk of memory impairment when the subject's concentrations of the metabolites are altered compared to the normal concentrations of the metabolites, and
(b) administering a treatment for memory impairment when it is determined that the subject has an increased risk of memory impairment;
wherein the set of metabolites comprises phosphatidylcholine acyl-alkyl C36:4 (PC ae C36:4), decadienyl-L-carnitine (C10:2), phosphatidylcholine diacyl C38:3 (PC aa C38:3), phosphatidylcholine diacyl C34:4 (PC aa C34:4), hydroxyoctadecenoyl-L-carnitine (C18:1-OH), phosphatidylcholine acyl-alkyl C34:0 (PC ae C34:0), hydroxyvaleryl-L2 of 5 carnitine/methylmalonyl-L-carnitine (C5-OH/C3-DC-M), phosphatidylcholine diacyl C40:5 (PC aa C40:5), phosphatidylcholine diacyl C32:0 (PC aa C32:0), and dodecenoyl-L-carnitine (C12:1); and
wherein the subject's concentrations of the metabolites are altered compared to the normal concentrations of the metabolites if, for at least 8 of the metabolites in the set of metabolites, the subject's concentration of the metabolite is lower as compared to the normal concentration of the metabolite.
2. The method of claim 1 , wherein the set of metabolites further comprises one or more metabolites selected from the group consisting of proprionyl-L-carnitine (C3), lysophosphatidylcholine acyl C18:2 (lysoPC a C18:2), phosphatidylcholine diacyl C36:6 (PC aa C36:6), phosphatidylcholine diacyl C38:0 (PC aa C38:0), phosphatidylcholine diacyl C38:6 (PC aa C38:6), phosphatidylcholine diacyl C40:1 (PC aa C40:1), phosphatidylcholine acyl-alkyl C40:6 (PC ae C40:6), hexadecadienyl-L-carnitine (C16:2), Asparagine (Asn), Asymmetric dimethylarginine (ADMA), valeryl-L-carnitine (C5), decenoyl-L-carnitine (C10:1), nonayl-L-carnitine (C9), and phosphatidylcholine acyl-alkyl C42:1 (PC ae C42:1).
3. The method of claim 1 , wherein the subject's concentrations of the metabolites are altered compared to the normal concentrations of the metabolites if, for at least 9 of the metabolites in the set of metabolites, the subject's concentration of the metabolite is lower as compared to the normal concentration of the metabolite.
4. The method of claim 1 , wherein the monitoring is at three or more time points over a period of two or more years.
5. The method of claim 1 , wherein the sample is a blood sample.
6. The method of claim 1 , wherein the normal concentration of the metabolites comprise the subject's concentrations of metabolites prior to the onset of memory impairment.
7. The method of claim 1 , wherein the normal concentration of the metabolites comprise concentration of metabolites generated from a population of individuals that do not display memory impairment.
8. A method of treating a subject who has an increased risk of memory impairment, the method comprising
(a) monitoring whether the subject has an increased risk of memory impairment, wherein the monitoring comprises, at 2 or more time points:
(i) analyzing a set of metabolites from at least one sample from the subject to determine the subject's concentrations of the metabolites in the set of metabolites, and
(ii) comparing the subject's concentrations of the metabolites in the set of metabolites to normal concentrations of the metabolites,
wherein the subject is determined to have an increased risk of memory impairment when the subject's concentrations of the metabolites are altered compared to the normal concentrations of the metabolites, and
(b) administering a treatment for memory impairment when it is determined that the subject has an increased risk of memory impairment;
wherein the set of metabolites comprises phosphatidylcholine acyl-alkyl C36:4 (PC ae C36:4), decadienyl-L-carnitine (C10:2), phosphatidylcholine diacyl C38:3 (PC aa C38:3), phosphatidylcholine diacyl C34:4 (PC aa C34:4), hydroxyoctadecenoyl-L-carnitine (C18:1-OH), phosphatidylcholine acyl-alkyl C34:0 (PC ae C34:0), hydroxyvaleryl-L2 of 5 carnitine/methylmalonyl-L-carnitine (C5-OH/C3-DC-M), phosphatidylcholine diacyl C40:5 (PC aa C40:5), phosphatidylcholine diacyl C32:0 (PC aa C32:0), and dodecenoyl-L-carnitine (C12:1);
wherein the normal concentrations of the metabolites comprise the subject's concentrations of the metabolites prior to the onset of memory impairment; and
wherein the subject's concentrations of the metabolites are altered compared to the normal concentrations of the metabolites if, for at least 8 of the metabolites in the set of metabolites, the ratio of the subject's concentration of the metabolite to the normal concentration of the metabolite is less than one.
9. The method of claim 8 , wherein the set of metabolites further comprises one or more metabolites selected from the group consisting of proprionyl-L-carnitine (C3), lysophosphatidylcholine acyl C18:2 (lysoPC a C18:2), phosphatidylcholine diacyl C36:6 (PC aa C36:6), phosphatidylcholine diacyl C38:0 (PC aa C38:0), phosphatidylcholine diacyl C38:6 (PC aa C38:6), phosphatidylcholine diacyl C40:1 (PC aa C40:1), phosphatidylcholine acyl-alkyl C40:6 (PC ae C40:6), hexadecadienyl-L-carnitine (C16:2), Asparagine (Asn), Asymmetric dimethylarginine (ADMA), valeryl-L-carnitine (C5), decenoyl-L-carnitine (C10:1), nonayl-L-carnitine (C9), and phosphatidylcholine acyl-alkyl C42:1 (PC ae C42:1).
10. The method of claim 8 , wherein the subject's concentrations of the metabolites are altered compared to the normal concentrations of the metabolites if, for at least 9 of the metabolites in the set of metabolites, the ratio of the subject's concentration of the metabolite to the normal concentration of the metabolite is less than one.
11. The method of claim 8 , wherein the monitoring is at three or more time points over a period of two or more years.
12. The method of claim 8 , wherein the sample is a blood sample.
13. A method of measuring levels of metabolites of a set of metabolites in a subject at two or more time points, the method comprising:
(a) obtaining a sample from the subject at each of the time points, and
(b) determining individual levels of the metabolites;
wherein the set of metabolites comprises phosphatidylcholine acyl-alkyl C36:4 (PC ae C36:4), decadienyl-L-carnitine (C10:2), phosphatidylcholine diacyl C38:3 (PC aa C38:3), phosphatidylcholine diacyl C34:4 (PC aa C34:4), hydroxyoctadecenoyl-L-carnitine (C18:1-OH), phosphatidylcholine acyl-alkyl C34:0 (PC ae C34:0), hydroxyvaleryl-L-carnitine/methylmalonyl-L-carnitine (C5-OH/C3-DC-M), phosphatidylcholine diacyl C40:5 (PC aa C40:5), phosphatidylcholine diacyl C32:0 (PC aa C32:0), and dodecenoyl-L-carnitine (C12:1).
14. The method of claim 13 , wherein the set of metabolites further comprises one or more metabolites selected from the group consisting of proprionyl-L-carnitine (C3), lysophosphatidylcholine acyl C18:2 (lysoPC a C18:2), phosphatidylcholine diacyl C36:6 (PC aa C36:6), phosphatidylcholine diacyl C38:0 (PC aa C38:0), phosphatidylcholine diacyl C38:6 (PC aa C38:6), phosphatidylcholine diacyl C40:1 (PC aa C40:1), phosphatidylcholine acyl-alkyl C40:6 (PC ae C40:6), hexadecadienyl-L-carnitine (C16:2), Asparagine (Asn), Asymmetric dimethylarginine (ADMA), valeryl-L-carnitine (C5), decenoyl-L-carnitine (C10:1), nonayl-L-carnitine (C9), and phosphatidylcholine acyl-alkyl C42:1 (PC ae C42:1).
15. The method of claim 13 , comprising obtaining the sample from the subject at three or more time points over a period of two or more years.
16. The method of claim 13 , wherein the sample is a blood sample.