Biomarkers for Neurodegenerative Disease
The present invention provides a method for early detection or diagnosis of a neurodegenerative disease, disorder, or condition in a subject at risk of developing or suspected of having the neurodegenerative disease, disorder, or condition, the method comprising measuring in a blood sample obtained from the subject or a fraction thereof the levels of at least one biomarker selected from CD38 + peripheral blood mononuclear cells (PBMCs), trigonelline, GLUT1 expression in CD4 + T cells, T h 2, T h 2/T h 1 ratio, naïve T cells, adenosine, allose, and HLA-DR T cells, as well as related methods and kits.
1 . A method for early detection or diagnosis of a neurodegenerative disease, disorder, or condition in a subject at risk of developing or suspected of having the neurodegenerative disease, disorder, or condition, the method comprising measuring in a blood sample obtained from the subject or a fraction thereof the levels of at least one biomarker selected from the group consisting of CD38 + peripheral blood mononuclear cells (PBMCs), trigonelline, GLUT1 expression in CD4 + T cells, T h 2, T h 2/T h 1 ratio, naïve T cells, adenosine, allose, and HLA-DR T cells,
wherein an increased level of at least one of CD38 + PBMCs, T h 2, T h 2/T h 1 ratio, naïve T cells, and adenosine, as compared to a respective reference, and/or a decreased level of at least one of trigonelline, GLUT1 expression in CD4 + T cells, allose, and HLA-DR T cells as compared to a respective reference, indicates that the subject is likely developing, or affected by, said neurodegenerative disease, disorder, or condition.
2 . The method of claim 1 , wherein the at least one biomarker comprises CD38 + PBMCs.
3 . The method of claim 2 , wherein the increased level of CD38 + PBMCs compared to the respective reference for CD38 + PBMCs level is increased by at least about 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.
4 . The method of claim 2 , wherein the CD38 + PBMCs are CD38 + CD4 + or CD38 + CD8 + T cells, and their level is calculated by measuring the levels of (1) CD38 + CD4 + cells and (2) total CD4 + cells, and calculating the proportion of (1) out of (2), or measuring the levels of (1) CD38 + CD8 + cells and (2) total CD8 + cells, and calculating the proportion of (1) out of (2), respectively.
5 . The method of claim 4 , wherein the at least one biomarker comprises CD38 + CD4 + T cells and CD38 + CD8 + T cells.
6 . The method of claim 4 , wherein the respective reference for CD38 + CD4 + T cells out of total CD4 + T cells is between about 35% and about 40%, and the respective reference for CD38 + CD8 + T cells out of total CD8 + T cells is between about 15% and about 25%.
7 . The method of claim 1 , wherein the at least one biomarker comprises T h 2 cells and/or T h 2/T h 1 ratio.
8 . The method of claim 7 , wherein the level of the T h 2 cells is measured by measuring the level of CXCR5 − CCR6 − CXCR3 − CD 4+ cells, and/or the T h 2/T h 1 ratio is calculated by measuring the level of (1) CXCR5 − CCR6 − CXCR3 − CD4 + cells (T h 2), and (2) CXCR5 − CCR6 − CXCR3 + CD4 + cells (T h 1), and calculating the proportion of (1) out of (2).
9 . The method of claim 7 , wherein the increased T h 2/T h 1 ratio is increased by at least about 30%, 35%, 40%, 45%, 50%, 60%, or 70% compared to the respective reference for T h 2/T h 1 ratio.
10 . The method of claim 7 , wherein the respective reference for T h 2/T h 1 ratio is at least about 10, 11, 12, 13, or 14.
11 . The method of claim 1 , wherein the at least one biomarker comprises naïve CD4 + T cells level.
12 . The method of claim 11 , wherein the naïve CD4 + T cells level is calculated by measuring the level of (1) CCR7 + CD45RO − CD45RA + (naïve) CD4 + T cells, and (2) total CD4 + T cells, and calculating the proportion of (1) out of (2).
13 . The method of claim 11 , wherein the increased level of naïve CD4 + T cells compared to the respective reference is increased by at least about 30%, 35%, 40%, 45, or 50%.
14 . The method of claim 1 , wherein the at least one biomarker comprises GLUT1 expression in CD4 + T cells.
15 - 17 . (canceled)
18 . The method of claim 14 , wherein the at least one biomarker comprises CD38+ PBMCs and GLUT1 expression in CD4 + T cells.
19 . The method of claim 7 , wherein the at least one biomarker comprises CD38 + PBMCs and T h 2/T h 1 ratio.
20 . (canceled)
21 . The method of claim 18 , wherein increased levels of CD38+ PBMCs compared to a respective reference and decreased levels of GLUT1 expression in CD4 + T cells as compared to a respective reference indicate that the subject is likely developing, or affected by, said neurodegenerative disease, disorder, or condition.
22 . (canceled)
23 . The method of claim 1 , wherein said neurodegenerative disease, disorder, or condition is selected from the group consisting of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, primary progressive multiple sclerosis; secondary progressive multiple sclerosis, attention deficit disorder (ADD), corticobasal degeneration, Creutzfeldt-Jakob disease (CJD), Rett syndrome, a retinal degeneration disorder selected from the group consisting of age-related macular degeneration and retinitis pigmentosa; anterior ischemic optic neuropathy; glaucoma; uveitis; depression; trauma-associated stress or post-traumatic stress disorder, frontotemporal dementia (FTD), Lewy body dementias, mild cognitive impairments, posterior cortical atrophy, primary progressive aphasia and progressive supranuclear palsy.
24 - 26 . (canceled)
27 . A method of assessing efficacy of a treatment by an immune checkpoint modulator in a subject diagnosed with a neurodegenerative disease, disorder, or condition, said method comprising:
obtaining a first blood sample from the subject;
administering the immune checkpoint modulator to the subject;
obtaining a second blood sample from the subject;
measuring in the first blood sample or a fraction thereof and in the second blood sample or fraction thereof the levels of at least one biomarker selected from the group consisting of CD38 + peripheral blood mononuclear cells (PBMCs), trigonelline, GLUT1 expression in CD4 + T cells, T h 2, T h 2/T h 1 ratio, naïve T cells, adenosine, allose, and HLA-DR T cells, and
comparing the level of the at least one biomarker in the first blood sample with the level of the biomarker in the second blood sample;
wherein a decreased level of at least one of CD38 + PBMCs, T h 2, T h 2/T h 1 ratio, naïve T cells, and adenosine, and/or an increased level of at least one of trigonelline, GLUT1 expression in CD4 + T cells, allose, and HLA-DR T cells in the second blood sample compared to the first blood sample indicates that the treatment by an immune checkpoint modulator is likely effective.
28 . A method for treating or preventing a neurodegenerative disease, disorder, or condition in a subject, said method comprising measuring in a blood sample or fraction thereof the levels of at least one biomarker selected from the group consisting of CD38 + peripheral blood mononuclear cells (PBMCs), trigonelline, GLUT1 expression in CD4 + T cells, T h 2, T h 2/T h 1 ratio, naïve T cells, adenosine, allose, and HLA-DR T cells,
wherein an increased level of at least one of CD38 + PBMCs, T h 2, T h 2/T h 1 ratio, naïve T cells, and adenosine, as compared to a respective reference, and/or a decreased level of at least one of trigonelline, GLUT1 expression in CD4 + T cells, allose, and HLA-DR T cells as compared to a respective reference, indicates that the subjects is likely developing, or is affected by, the neurodegenerative disease, disorder, or condition, and
the method further comprising administering an immune checkpoint modulator to the subject which is likely developing, or is affected by, the neurodegenerative disease, disorder, or condition, thereby treating the subject.
29 . (canceled)