WO2020031116A1 - Method of diagnosing and treating alzheimer disease using plasma tau level in conjunt ion with beta-amyloid level as diagnostic index - Google Patents

Method of diagnosing and treating alzheimer disease using plasma tau level in conjunt ion with beta-amyloid level as diagnostic index Download PDF

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WO2020031116A1
WO2020031116A1 PCT/IB2019/056734 IB2019056734W WO2020031116A1 WO 2020031116 A1 WO2020031116 A1 WO 2020031116A1 IB 2019056734 W IB2019056734 W IB 2019056734W WO 2020031116 A1 WO2020031116 A1 WO 2020031116A1
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tau
subject
blood sample
ratio
abi
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PCT/IB2019/056734
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French (fr)
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Inhee Mook-Jung
Dong Young Lee
Sun-Ho Han
Jong-Chan Park
Dahyun YI
Min Soo Byun
Jun Ho Lee
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Seoul National University R&Db Foundation
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Priority to KR1020217007017A priority Critical patent/KR102496845B1/ko
Publication of WO2020031116A1 publication Critical patent/WO2020031116A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4709—Amyloid plaque core protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer

Definitions

  • the present invention is related to a diagnostic method and kit for Alzheimer disease using plasma tau with b-amyloid levels and a method of treating patients diagnosed by the same.
  • AD Alzheimer’s disease
  • Ab b-amyloid
  • NFTs neurofibrillary tangles
  • Tau in particular is known to play a critical role in AD pathogenesis through its association with Ab, and several lines of evidence have suggested tau-dependent Ab toxicity and a feedback loop connecting tau and Ab during the pathogenesis of AD.
  • Tau is encoded by the MAPT (microtubule associated-protein tau) gene and exists in the human brain as six isoforms that differ in their amino-terminal inserts and microtubule-binding- domain repeats. Tau acts through its microtubule-binding-domain repeats to promote tubulin assembly and stabilize microtubule structure and function. Tau contains a number of phosphorylation sites, and its phosphorylation status influences its effects on microtubule assembly. Whether tau is the critical contributor to AD pathogenesis— along the epicenter of AD research— is a question that has been undergoing a recent reassessment because of disappointing results of clinical trials of Ab-targeting therapeutic strategies based on the amyloid hypothesis.
  • MAPT microtubule associated-protein tau
  • PET imaging has been a valuable technique for monitoring brain tau pathology, and a variety of recently developed tau radiotracers for identification of neurofibrillary pathology through PET imaging provide great AD diagnostic and prognostic potential.
  • PET imaging of tau provides a wealth of information and reflects AD pathology fairly well, PET instrumentation is not available in many clinical settings, and PET imaging is associated with high costs and concerns about radiation hazards. Therefore, there is a desperate unmet need for a convenient and accessible method for detecting and monitoring brain tau deposition.
  • the present invention concerns correlation between plasma t-tau, p-tau and Abi -42 levels and AD-associated tau pathology.
  • the diagnostic kit of the present invention can be useful predicting and determining brain tau accumulation level in subjects of interest.
  • One aspect of the invention is a method for determining a level of brain tau accumulation using plasma t-tau, p-tau and Abi -42 levels, comprising obtaining a plasma sample from a subject; measuring plasma total tau, p-tau and plasma Ab under presence of a mixture of protease inhibitors and phosphatase inhibitors; and quantifying ratio of plasma tau/Ab 1-42 wherein the plasma tau/Ab 1-42 ratio is an indicative parameter for the level of brain tau accumulation.
  • Another aspect of the invention is a diagnostic kit for determining a tau positive patient comprising protease inhibitors and phosphatase inhibitors (MPP) and further comprising a blood coagulating inhibitor.
  • MPP phosphatase inhibitors
  • Still another aspect of the invention is a method of detecting a sign or a symptom of Alzheimer disease in a subject, the method comprising: detecting an amount of Abi -42 and t-tau or p-tau in a blood sample of the subject and in a blood sample of a control; quantifying a ratio of t-tau/Ab 1-42 or p-tau/ Abi -42 in the blood sample of the subject and in the blood sample of the control; and comparing the ratio of t-tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the subject and in the blood sample of the control, wherein the higher ratio of t-tau/ Abi -42 or p-tau/ Abi -42 in the blood sample of the subject compared with the ratio of t-tau/Ab 1-42 or p-tau/ Abi -42 in the blood sample of the control indicates a presence of the sign or the symptom of Alzheimer disease in the subject.
  • the sign or the symptom of Alzheimer disease is a tau accumulation in the brain of the subject and/or an Ab deposition in the brain of the subject and/or a neuronal dysfunction in the brain of the subject and/or dysfunctional brain glucose metabolism in the subject and/or a cognitive functional impairment and/or neurodegeneration of the subject.
  • the cognitive functional impairment is measured by an MMSE (Mini-Mental State Examination) score.
  • the amount of Abi -42 and t-tau or p-tau is detected in plasma of the blood sample or in serum of the blood sample.
  • the amount of Abi-42 is detected in a presence of a mixture of protease inhibitors and phosphatase inhibitors.
  • Still another aspect of the invention is a method of diagnosing a tau positive subject, the method comprising: detecting an amount of Abi -42 and t-tau or p-tau in a blood sample of the subject and in a blood sample of a control; quantifying a ratio of t-tau/ Abi -42 or p-tau/ Ab 4 i 2 n the blood sample of the subject and in the blood sample of the control; comparing the ratio of t- tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the subject and in the blood sample of the control; and evaluating a brain tau accumulation level of the subject, wherein the higher ratio of t-tau/Ab 1-42 or p-tau/ Abi -42 in the blood sample of the subject compared with the ratio of t- tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the control indicates a presence of brain tau deposition in the subject.
  • the amount of Abi -42 and t-tau or p-tau is detected in plasma of the blood sample or in serum of the blood sample. In embodiments, the amount of Abi- 42 is detected in a presence of a mixture of protease inhibitors and phosphatase inhibitors.
  • the tau positive subject has Alzheimer disease.
  • Still another aspect of the invention is a method of diagnosing a tau positive subject, the method comprising: genotyping ApoE of the subject; detecting an amount of Abi -42 and t-tau or p-tau in a blood sample of the subject and in a blood sample of a control; quantifying a ratio of t- tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the subject and in the blood sample of the control; and evaluating a brain tau accumulation level of the subject, wherein a presence of a ApoE genotype for risk of AD and the higher amount of t-tau or p-tau or the higher ratio of t- tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the subject compared with the ratio of t-tau/Abi- 42 or p-tau/Ab 1-42 in the blood sample of the control indicates a presence of tau deposition in the brain of the subject.
  • the ApoE genotype for risk of AD is Apo
  • the amount of Abi -42 and t-tau or p-tau is detected in plasma of the blood sample or in serum of the blood sample. In embodiments, the amount of Abi -42 is detected in a presence of a mixture of protease inhibitors and phosphatase inhibitors. In embodiments, the tau positive subject has Alzheimer disease.
  • Still another aspect of the invention is a diagnostic kit for detecting a sign or a symptom of Alzheimer disease in a subject or diagnosing a tau positive subject, comprising a protease inhibitor and a phosphatase inhibitor (MPP).
  • a protease inhibitor and a phosphatase inhibitor (MPP).
  • MPP phosphatase inhibitor
  • Still another aspect of the invention is a method of treating a subject having a sign or a symptom of Alzheimer disease, the method comprising: detecting the sign or the symptom of Alzheimer disease in the subject according to the aforementioned method; and administering a therapeutically effective amount of a medication to the subject in need thereof, thereby alleviating or reducing the sign or the symptom of Alzheimer disease or delaying development of Alzheimer disease.
  • the medication is a pharmacologic treatment, a
  • the pharmacologic treatment is cholinesterase-inhibitors, N-methyl-d-aspartate blockers, anti-amyloid disease modifying therapies, anti-Tau disease-modifying therapies, other mechanisms of action and symptomatic agents, or a combination thereof.
  • Still another aspect of the invention is a method of treating a tau positive subject, the method comprising: evaluating a brain tau accumulation level of the subject according to the aforementioned methods; and administering a therapeutically effective amount of a medication to the subject in need thereof, thereby alleviating or reducing a sign or a symptom of the tau positive subject or delaying development of a sign or a symptom of tau positive subject.
  • the medication is a pharmacologic treatment, a nonpharmacologic treatment, or a combination thereof.
  • the pharmacologic treatment is cholinesterase-inhibitors, N-methyl-d-aspartate blockers, anti-amyloid disease-modifying therapies, anti-Tau disease modifying therapies, other mechanisms of action and symptomatic agents, or a combination thereof.
  • Still another aspect of the invention is a method of determining a brain tau accumulation level in a brain region of a subject comprising: detecting an amount of Abi -4 2 and t-tau or p-tau in a blood sample of the subject and in a blood sample of a control; quantifying a ratio of t-tau/Abi- 42 or p-tau/Ab 1-42 in the blood sample of the subject and in the blood sample of the control;
  • Still another aspect of the invention is a method of assessing a progression of a sign or a symptom of Alzheimer disease in a subject comprising: (i) detecting an amount of Abi-42 and t- tau or p-tau in a blood sample of the subject at a first time point; (ii) quantifying a ratio of t- tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the subject at the first time point; (iii) detecting the amount of Abi-42 and t-tau or p-tau in a blood sample of the subject at a second time point; (iv) quantifying the ratio of t-tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the subject at the second time point; and (v) comparing the ratio of t-tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the subject at the first time point and the ratio of t-tau/Ab 1-42 or p-t
  • the step (i) of the method further comprising detecting an amount of Abi-42 and t-tau or p-tau in a blood sample of a control at a first time point; the step (ii) of the method further comprising quantifying a ratio of t-tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the control at the first time point; the step (iii) of the method further comprising detecting the amount of Abi-42 and t- tau or p-tau in a blood sample of the control at a second time point; the step (iv) of the method further comprising quantifying the ratio of t-tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the control at the second time point; and the step (v) of the method further comprising comparing the ratio of t-tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the subject at the first time point and the ratio of t-t
  • the first time point and the second time point are separated by 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, 36 months, 37 months, 38 months, 39 months, 40 months, 41 months, 42 months, 43 months, 44 months, 45 months, 46 months, 47 months, 48 months, 49 months, 50 months, 51 months, 52 months, 53 months, 54 months, 55 months, 56 months, 57 months, 58 months, 59 months, or 60 months.
  • the sign or the symptom of Alzheimer disease is a tau accumulation in the brain of the subject.
  • the sign or the symptom of Alzheimer disease is a tau accumulation in the brain of the subject and/or an Ab deposition in the brain of the subject and/or a neuronal dysfunction in the brain of the subject and/or dysfunctional brain glucose metabolism in the subject and/or a cognitive functional impairment and/or neurodegeneration of the subject.
  • the cognitive functional impairment is measured by an MMSE (Mini-Mental State Examination) score.
  • MMSE Mini-Mental State Examination
  • the amount of Abi -4 2 and t-tau or p-tau is detected in plasma of the blood sample or in serum of the blood sample. In embodiments, the amount of Abi -4 2 is detected in a presence of a mixture of protease inhibitors and phosphatase inhibitors.
  • the method further comprising repeating at multiple time points after the second time points, detecting the amount of Abi -4 2 and t-tau or p-tau in a blood sample of the subject; quantifying the ratio of t-tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the subject; and comparing the ratio of t-tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the subject with the ratio of t-Xsaxl Rf ⁇ L ⁇ or p- t-tau/Ab 1-42 in the blood sample of the subject at the first time point and/or the ratio of t-Xsaxl Rfi-h orp-tau/ Ab 42 in the blood sample of the subject at the second time point.
  • the multiple points are separated by 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, 36 months, 37 months, 38 months, 39 months, 40 months, 41 months, 42 months, 43 months, 44 months, 45 months, 46 months, 47 months, 48 months, 49 months, 50 months, 51 months, 52 months, 53 months, 54 months, 55 months, 56 months, 57 months, 58 months, 59 months, or 60 months.
  • Still another aspect of the invention is a method of treating a subject having a progression of a sign or a symptom of Alzheimer disease comprising detecting the progression of the sign or the symptom of Alzheimer disease in the subject according to the aforementioned methods; and administering a therapeutically effective amount of a medication to the subject in need thereof, thereby preventing or delaying the progression of Alzheimer disease.
  • the medication is a pharmacologic treatment, a nonpharmacologic treatment, or a combination thereof.
  • the pharmacologic treatment is cholinesterase-inhibitors, N-methyl-d- aspartate blockers, anti-amyloid disease-modifying therapies, anti-Tau disease-modifying therapies, other mechanisms of action and symptomatic agents, or a combination thereof.
  • Still another aspect of the invention is a method of determining brain glucose metabolism in a subject comprising: detecting an amount of Abi -4 2 and t-tau or p-tau in a blood sample of the subject and in a blood sample of a control; quantifying a ratio of t-tau/ Abi -4 2 or p-tau/ Ab 42 in the blood sample of the subject and in the blood sample of the control; and comparing the ratio of t-tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the subject and in the blood sample of the control, wherein the higher ratio of t-tau/Ab 1-42 or p-tau/ Ab 42 in the blood sample of the subject compared with the ratio of t-tau/Ab 1-42 or p-tau/ Ab 42 in the blood sample of the control indicates dysfunctional brain glucose metabolism in the subject.
  • the amount of Abi - 4 2 and t-tau or p-tau is detected in plasma of the blood sample or in serum of the blood sample. In embodiments, the amount of Abi -4 2 is detected in a presence of a mixture of protease inhibitors and phosphatase inhibitors. In embodiments, the subject has Alzheimer disease.
  • Still another aspect of the invention is a method of determining a neurodegeneration level in a subject comprising: detecting an amount of Abi -4 2 and t-tau or p-tau in a blood sample of the subject and in a blood sample of a control; quantifying a ratio of t-tau/ Abi -4 2 or p-tau/ Ab 42 in the blood sample of the subject and in the blood sample of the control; and comparing the ratio of t-tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the subject and in the blood sample of the control, wherein the higher ratio of t-tau/Ab 1-42 or t-tau/Ab 1-42 in the blood sample of the subject compared with the ratio oft-tau/Ab 1-42 or p-tau/ Ab 42 in the blood sample of the control indicates the higher neurodegeneration level in the subject.
  • the amount of Abi - 4 2 and t-tau or p-tau is detected in plasma of the blood sample or in serum of the blood sample. In embodiments, the amount of Abi -4 2 is detected in a presence of a mixture of protease inhibitors and phosphatase inhibitors. In embodiments, the subject has Alzheimer disease.
  • Still another aspect of the invention is a method of determining cognitive function in a subject, the method comprising: detecting an amount of Abi -4 2 and t-tau or p-tau in a blood sample of the subject and in a blood sample of a control; quantifying a ratio of t-tau/ Ab ⁇ 42 or p- tau/Ab 1-42 in the blood sample of the subject and in the blood sample of the control; and comparing the ratio of t-tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the subject and in the blood sample of the control, wherein the higher ratio of t-tau/ Ab ⁇ 42 or p-tau/Ab 1-42 in the blood sample of the subject compared with the ratio oft-tau/Ab 1-42 or p-tau/Ab 1-42 in the blood sample of the control indicates cognitive functional impairment in the subject.
  • the amount of Abi -4 2 and t-tau or p-tau is detected in plasma of the blood sample or in serum of the blood sample. In embodiments, the amount of Abi -4 2 is detected in a presence of a mixture of protease inhibitors and phosphatase inhibitors. In embodiments, the subject has Alzheimer disease.
  • FIG. 1 A and FIG. 1B are graphs showing that plasma tau-related biomarkers are significantly correlated with brain tauopathy.
  • FIG. 1 A shows plasma biomarker values according to tau Braak stage.
  • FIG. 1B shows partial correlation plots of plasma biomarker values versus a priori ROIs of AD-signature regions. Braak stage: disease staging in
  • FIG. 2A and FIG. 2B are graphs showing the relationship between plasma tau related biomarkers and cognitive function states.
  • FIG. 3A-FIG. 3D are images showing the correlations between plasma tau-related biomarkers and Tau-PET. Results represents voxel-wise associations between each of the plasma tau biomarkers and regional brain tau burden.
  • FIG. 3 A and FIG. 3B show that higher plasma p-tau and t-tau values were associated with higher brain tau deposition only in the medial temporal regions.
  • 3D show that plasma p-tau/ Ab 42 and t-tau/Ab 1-4 r 2 atios are having positive correlation with tau deposition in diffuse brain regions including the cingulate, lateral temporal, frontal, and parietal cortices as well as the medial temporal regions.
  • brain regions where plasma t-tau/Ab 1-42 ratio correlated with brain tau were very similar to the typical deposition sites of neurofibrillary tangles in AD.
  • FIG. 4A-FIG. 4D are graphs showing the correlations between plasma p-tau (FIG. 4A), plasma t-tau (FIG. 4B), plasma p-tau/Ab 1-42 ratio (FIG. 4C) and t-tau/ Ab ⁇ 42 ratio (FIG. 4D) and neurodegeneration markers such as hippocampal volume, cortical thickness, and FDG-PET ( 18 F- labeled fluoro-2-deoxyglucose ( 18 F-FDG)-positron emission tomography).
  • FDG-PET 18 F- labeled fluoro-2-deoxyglucose ( 18 F-FDG)-positron emission tomography
  • FIG. 5A-FIG. 5E are an illustration and graphs showing performance of plasma biomarkers in discriminating Tau-PET + from Tau-PET- subjects.
  • FIG. 5A shows Tau-PET positivity criteria for ROCs.
  • FIG. 5B shows differences in plasma biomarker levels between Tau-PET- and Tau-PET + subjects.
  • FIG. 5C and FIG. 5D show comparison of ROC analyses among plasma p-tau, t-tau, p-tau/ Ab 42 , and t-tau/amyloid-
  • FIG.5E shows Relative risk (RR) analysis of Tau-PET positivity using plasma biomarker quartiles.
  • Relative risk (RR) of brain Tau-PET positivity fraction of PET + subjects in each quartile
  • FIG. 6A and FIG. 6B are an illustration and graphs showing the relationship between plasma Abi -4 2 and cerebral Ab deposition.
  • FIG. 8A and FIG. 8B are graphs showing that plasma tau-related biomarkers are significantly correlated with brain tauopathy.
  • FIG. 8A shows the plasma biomarker values according to tau Braak stage (P-values by ANOVA followed by Tukey’s multiple comparison test).
  • FIG. 8B shows the partial correlation plots of plasma biomarker values versus a priori regions of interest of Alzheimer’s disease signature regions.
  • FIG. 9A-FIG. 9D are images showing the correlations between plasma tau-related biomarkers and tau-PET. Results are shown using a threshold combining Puncorrected ⁇ 0.005 at the voxel level and PFWE-corrected ⁇ 0.05 at the cluster level; T- values were converted to r values for illustration purposes. Voxel-wise associations were assessed between partial volume error-corrected tau-PET SUVR and plasma p-tau (FIG. 9A) and t-tau (FIG. 9B), and p- tau/amyloid-Pi-42 (FIG. 9C) levels and t-tau/amyloid-b 1-42 . (FIG. 9D) values. Correlation coefficients were positive for all plasma tau biomarkers. All voxel-wise associations were adjusted for age and sex.
  • FIG. 10A-FIG. 10E are an illustration and graphs showing performance of plasma biomarkers in discriminating Tau-PET + from Tau-PET subjects.
  • FIG. 10A shows the Tau-PET positivity criteria for the ROCs.
  • Relative risk of brain Tau-PET positivity was significantly increased in group 2 compared with group 1 (P-values from relative risk analysis) in all plasma biomarkers. See Table 7 for details. * P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001, and **** P ⁇ 0.0001.
  • FIG. 11 is Table 6 showing details of ROC curve analyses (Tau-PET versus Tau-PET + ).
  • FIG. 13A-FIG. 13G are an illustration and graphs showing that baseline plasma t-tau/ amyloid-Pi-42 predicts the longitudinal changes of neurodegeneration.
  • FIG. 13A shows the timeline of the longitudinal study. Tau-PET scans were only performed in the 2nd year cohort.
  • FIG. 13B-FIG. 13E show the baseline plasma t-tau/amyloid-Pi-42 levels correlated with the longitudinal changes of hippocampal volume, cerebral amyloid deposition, and glucose metabolism.
  • FIG. 13F shows the timeline of the longitudinal study using delta (A) plasma t-tau and t-tau/amyloid-Pi-42 levels with 2-year tau-PET results.
  • MCI mild cognitive impairment
  • AD Alzheimer’s disease
  • MMSE z-score mini-mental state examination with the correction for age, sex, and education level
  • CDR clinical dementia rating
  • ApoE Apolipoprotein e4.
  • P-value p-values between baseline and 2nd year; a p, p-values from paired /-test; b p, p-values from unpaired /-test; c p, p-values from chi-square test.
  • FIG. 15 is Table 9 showing demographic data of the participants (related to FIGs. 8A and 9B, and FIGs. 9A-9D, 2nd year samples). Data were presented as mean ⁇ SEM or N (%); a P, significance by chi-squared test; b P, significance by ANOVA with Tukey’s post hoc test; CN, cognitively normal; MCI, mild cognitive impairment; AD, Alzheimer’s disease; MMSE z-score, mini-mental state examination with the correction for age, sex, and education level; CDR, clinical dementia rating; ApoE, Apolipoprotein e4; A beta, Ab, amyloid beta, b-amyloid;
  • FIG. 16 is Table 10 showing the correlation between plasma markers and brain regional tauopathy (related to FIG. 8B). P, significance by partial correlation analyses (correction for age and sex differences).
  • FIG. l7A and FIG. 17B are graphs showing the relationships between plasma tau-related biomarkers and cognitive function.
  • FIG. 17A shows the plasma biomarker levels in relation to subjects’ cognitive function states (by ANOVA followed by Tukey’s multiple comparison test).
  • FIG. 17B shows the correlation between CERAD-K delayed verbal memory and plasma biomarkers. Variables were adjusted with statistical control for the effect of covariates (age, sex) by partial correlation analyses. # P ⁇ 0.10, * P ⁇ 0.05, and ** P ⁇ 0.01.
  • CERAD-K refers to a Korean version of the consortium to establish a Registry for Alzheimer's Disease Assessment Packet.
  • FIG. 18 A-FIG. 18D are graphs showing the correlations between plasma tau-related biomarkers and neurodegeneration markers.
  • FIG. 18A-FIG. 18D show that plasma p-tau, plasma t-tau, p-tau/APi -4 2, and t-tau/Ab 1-42 were significantly correlated with neurodegeneration markers (hippocampal volume, cortical thickness, and FDG-PET). Variables were adjusted with statistical control for the effect of covariates (age, sex). # P ⁇ 0.10, * P ⁇ 0.05, ** P ⁇ 0.01, and *** P ⁇ 0.001 ; partial correlation analyses.
  • FIG. 19A-19C are an illustration and graphs showing the relationship between plasma Abi - 4 2 and brain Ab deposition.
  • FIG. 19A shows criterion for PiB (Pittsburgh compound B) - PET vs PiB-PET + .
  • FIG. 19B shows the plasma Abi -4 2 levels between PiB-PET and PiB-PET + (by unpaired /-test) and the correlation between brain Ab deposition and plasma Abi -4 2 levels. Covariates (age and sex) were adjusted and SUVR values for global Ab deposition (ROI) were natural log transformed to normalize variance (by partial correlation analyses).
  • FIG. 19A shows criterion for PiB (Pittsburgh compound B) - PET vs PiB-PET + .
  • FIG. 19B shows the plasma Abi -4 2 levels between PiB-PET and PiB-PET + (by unpaired /-test) and the correlation between brain Ab deposition and plasma Abi -4 2 levels. Covariates (
  • 19C shows the plasma Abi -4 2 levels between Tau-PET and Tau-PET + (by unpaired /-test) and the correlation between brain tau deposition and plasma Abi -4 2 levels. Covariates (age and sex) were adjusted and SUVR values for AD signature ROI were natural log transformed to normalize variance (by partial correlation analyses). * P ⁇ 0.05, * P ⁇ 0.01, and *** P ⁇ 0.001.
  • PIB PIB
  • Pittsburgh compound B (PiB), a radioactive analog of thioflavin T, which can be used in positron emission tomography scans to image beta-amyloid plaques in neuronal tissue.
  • FIG. 20 is a graph and a table showing the logistic regression followed by ROC curve analysis using plasma Abi -4 2.
  • Plasma Abi -4 2 black dotted line
  • ROC curves except for plasma Abi -4 2 were equal graphs displayed in FIG. 10.
  • FIG. 21 A- FIG. 21D are graphs and a table showing that there are no significant correlations between baseline plasma t-tau/Ab 1-42 and baseline neurodegeneration.
  • FIG. 21 C show the correlation between neurodegeneration markers (FDG-PET, hippocampal volumes) and PiB-PET SUVR both baseline and 2nd year time-points.
  • FIG. 21D shows that conjectured subject distribution range of both baseline samples and 2nd year samples were marked on a hypothetical AD progression-abnormality plot.
  • FIG. 22A-FIG. 22D are pairwise plots showing longitudinal age (X axis) and the neurodegeneration markers (Y axis). Dotted circles (baseline timepoint) and solid circles (follow-up 2nd year timepoint) indicate ranges of the values from ADD patients (red).
  • FIG. 23A-FIG. 23D are graphs and tables showing the comparison of ROC curves with ApoE genotype.
  • FIG. 24 is a graph and a table showing the correlation between plasma t-tau/Ap42 and MMSE score.
  • FIG. 25 is an illustration showing the longitudinal study design for plasma t-tau/Ap42.
  • FIG. 26 is Table 11 showing the correlation between FDG-PET standardized uptake ratio value (SUVR) and plasma t-tau/Ap42.
  • FIG. 27 is Table 12 showing the correlation between PiB-PET standardized uptake ratio value (SUVR) and plasma t-tau/Ap42.
  • FIG. 28 is a graph and a table showing that adding blood t-tau/Ap42 as a variable increases AUC values compared with ApoE alone (0.803 to 0.911).
  • FIG. 29A and 29B are Table 13 and Table 14, respectively, showing that blood t-tau/Ap42 reflects brain glucose metabolism both longitudinally and cross-sectionally.
  • FIG. 30 is Table 15 showing that blood t-tau/Ap42 reflects cognitive functions of patients.
  • FIG. 31 is Table 16 showing that blood t-tau/Ap42 reflects brain Ab deposition (another pathological hallmark of AD).
  • FIG. 32 is an illustration showing the summary of Ab-independent roles for ApoE in the pathogenesis of AD (reproduced from Yu et al., 2014, Annu. Rev. Neurosci. 37:79-100). The isoform-dependent effects of ApoE are indicated. Abbreviations: ApoE, apolipoprotein E; BBB, blood-brain barrier; NFT, neurofibrillary tangle.
  • the invention relates the method for determining a level of brain tau accumulation using plasma t-tau, p-tau and Abi -4 2 levels, comprising obtaining a plasma sample from a subject; measuring plasma total tau, p-tau and plasma Ab under presence of a mixture of protease inhibitors and phosphatase inhibitors; and quantifying ratio of plasma t-tau/Ab 1-4 ; 2 wherein the plasma tau/Ab 1-42 ratio is an indicative parameter for the level of brain tau accumulation.
  • the invention provides the diagnostic kit for determining a tau positive patient comprising protease inhibitors and phosphatase inhibitors (MPP) and further comprising a blood coagulating inhibitor.
  • MPP phosphatase inhibitors
  • the invention provides the method for treating or ameliorating the symptoms of a tau positive patient determined or predicted using the method described herein.
  • the invention provides the method for treating or ameliorating the symptoms of a tau positive patient determined or diagnosed or predicted using the diagnostic kit described herein.
  • Alzheimer's Disease refers to a neurodegenerative disorder and encompasses familial and sporadic AD.
  • Symptoms indicative of AD in human subjects typically include, but are not limited to, mild to severe cognitive impairment dementia, progressive impairment of memory (ranging from mild forgetfulness to disorientation and severe memory loss), poor visio-spatial skills, personality changes, poor impulse control, poor judgment, distrust of others, increased stubbornness, restlessness, poor planning ability, poor decision making, and social withdrawal.
  • Hallmark pathologies within brain tissues include extracellular neuritic b-amyloid plaques, neurofibrillary tangles, neurofibrillary degeneration, granulovascular neuronal degeneration, synaptic loss, and extensive neuronal cell death.
  • AD patient refers to an AD patient that is identified as having or likely to have AD based on known AD pathologies or symptoms.
  • AD patient is individuals with abovementioned hallmark pathologies and can be in cognitively normal, mild cognitive impairment, or dementia state.
  • Braak stages I and II are used when neurofibrillary tangle involvement is confined mainly to the transentorhinal region of the brain, stages III and IV when there is also involvement of limbic regions such as the hippocampus, and V and VI when there is extensive neocortical involvement.
  • Braak stages 0-II are determined as Tau-PET negative and Braak stages III -VI are determined as Tau-PET positive.
  • the present invention provides a method of measuring plasma tau and Ab.
  • the contents of US Patent Application 15/570,186 filed April 30, 2018 is incorporated herein by reference.
  • Overnight fasting blood samples are collected in a blood collection tube including a blood coagulation inhibitor such as EDTA such as, for example, but not limited to K2 EDTA tube (BD Vacutainer Systems, Madison, UK). Collected blood samples are stabilized and centrifuged to obtain plasma and serum supernatants, and huffy coat. To obtain samples with high purity, the plasma and serum supernatants are further centrifuged under the same conditions, and the collected pure plasma and serum supernatants are aliquoted and immediately stored at -80°C. The levels of plasma total tau and p-tau (Thr 181) are measured using analytic assays including but not limited to immunoassay and mass spectrometry. A mixture of protease inhibitors and phosphatase inhibitor (MPP) are pretreated to stabilize plasma Ab and plasma Ab levels are quantified using analytic assays including but not limited to immunoassay and mass spectrometry.
  • a blood coagulation inhibitor such as, for example, but not limited to K
  • the present invention provides a diagnostic kit for determining a tau positive patient, wherein the kit comprising a protease inhibitor and a phosphatase inhibitor (MPP).
  • the kit further comprises a blood coagulating inhibitor.
  • the diagnostic kit comprises components and/or compositions for determining a quantitative ratio of t-tau, p-tau and Abi -4 2 in a plasma sample of a subject and/or patient, wherein the components and/or compositions are selected such that they enable the quantitative determination of t-tau, p-tau and Abi-42 for the purposes of determining the quantitative ratio of t- tauM ⁇ i -4 2 or p-tau/ Abi -4 2.
  • the components or compositions of the inventive kit may especially be compositions or components for purification, concentration, separation or the like of the tau and Ab to be examined.
  • Cholinesterase inhibitors such as donepezil (Aricept®), galantamine (Razadyne®) and rivastigmine (Exelon®) delays the loss of mental abilities in patients with mild to moderate Alzheimer' s disease. These drugs work by boosting levels of a cell-to-cell communication by providing a neurotransmitter (acetylcholine) that is depleted in the brain by Alzheimer's disease. Cholinesterase inhibitors can improve neuropsychiatric symptoms, such as agitation or depression, as well.
  • Memantine (Namenda®), an N-methyl D-aspartate antagonist, is used to treat moderate to severe Alzheimer' s Disease. This medication works in another brain cell communication network by regulating glutamate and slows the progression of symptoms with moderate to severe Alzheimer's disease. Memantine can be used in combination with a cholinesterase inhibitor.
  • AD pharmacotherapy first involves identification and elimination of potentially harmful medications and supplements.
  • First line treatment for neuropsychiatric symptoms and problem behaviors is nonpharmacological and involves psychoeducation, trigger identification, and implementation, iterative evaluation, and adjustment of behavioral and environmental interventions.
  • AD Alzheimer's disease
  • symptomatic and disease-modifying treatments in symptomatic AD are directed at diverse therapeutic targets including neurochemicals, amyloid and tau pathological processes, mitochondria, inflammatory pathways, neuroglia, and multimodal lifestyle interventions.
  • the key elements of effective multifactorial management of AD include patient-caregiver dyad-centered evaluation, diagnosis and disclosure, and care planning processes, nonpharmacological management, such as interventions and behavioral approaches and strategies, pharmacological management, and pragmatic modifications to sustain alliance, adherence and well-being of patient-caregiver dyad.
  • AD medications include, for example, cholinesterase-inhibitors (ChEI), such as donepezil, rivastigmine, rivastigmine transdermal patch, galantamine, and galantamine extended-release, and AD dementia voltage-dependent, low affinity, open-channel NMDA (N-methyl-d-aspartate) blockers (NMDA antagonist), such as memantine, AVP-786, AXS-05, and Riluzole.
  • Cholinesterase-inhibitors such as donepezil
  • rivastigmine rivastigmine transdermal patch
  • galantamine and galantamine extended-release
  • AD dementia voltage-dependent, low affinity, open-channel NMDA (N-methyl-d-aspartate) blockers (NMDA antagonist) such as memantine, AVP-786, AXS-05, and Riluzole.
  • DMTs disease-modifying therapies
  • secretase inhibitors gamma-secretase inhibitors
  • gamma-secretase inhibitors for example, Semagacestat, Avagacestat, EVP-0962
  • b-secretase inhibitors for example, BACE inhibitor BI 1181181, RG7129, LY2811376, LY2886721, E2609, AZD3293, CNP520, JNJ- 54861911, AZD3293 (LY3314814), CAD106 & CNP520, Crenezumab, and Verubecestat
  • reduction of Ab-plaque burden via aggregation inhibitors for example, GV-971 (Sodium Oligo- mannurarate)
  • promotion of Ab clearance via active or passive immunotherapy for example, Abclearance AN-1792, Bapineuzumab, AAB-003, GSK933776, Solanezumab, Crenezum
  • Octohydroaminoacridine succinate, RAGE antagonist TTP488 (azeliragon), and positive allosteric modulator of GAB A-A receptors Zolpidem are also contemplated (see, e.g., Atri, Semin Neurol 2019;39:227-240, Graham et al. Annu. Rev. Med. 2017. 68:413-30, Cummings et al., Alzheimer’s & Dementia: Translational Research & Clinical Interventions 2018, 4: 195-214, and Pinheiro and Faustino, Current Alzheimer Research, 2019, 16, 418-452, the contents of which are incorporated herein by reference).
  • the AD treatment also includes nonpharmacologic treatments.
  • cognitive impairment, dementia, and AD are multifactorial and complex conditions with several potentially modifiable risk factors including vascular and lifestyle factors, such as hypertension,
  • inventive concept is meaningful since it is based on the analysis of defined neurochemical biomarkers in a defined sample, these being directly correlated to Alzheimer' s disease.
  • method and use of the invention as described herein can be performed in a much specific, sensitive, simplified and inexpensive manner compare to the methods used in the prior art, such as PET imaging methods or the like. ApoE genotype for risk of Alzheimer disease
  • ApoE has been recognized as the strong late onset (LOAD)- Alzheimer’s disease (AD) risk factor (Yu et al, 2014, Annu Rev Neurosci. 2014;37:79-100).
  • LOAD late onset
  • AD Alzheimer’s disease
  • ApoE4 genotype is the major risk allele (Corder et al, 1993, Science. 26l(5l23):92l-3) and ApoE2 was identified as being protective against AD (Chartier-Harlin et al, 1994, Hum Mol Genet. 3(4): 569-74).
  • Difference of ApoE genotypes contributes to AD pathogenesis through various pathways such as beta-amyloid clearance, mitochondrial dysfunctions, and
  • subject as used herein is intended to include a living organism in which alleviation of symptoms or inhibition of a neurological disorder is sought.
  • Preferred subjects are mammals. Examples of subjects include but are not limited to, humans, monkeys, dogs, cats, mice, rats, cows, horses, pigs, goats and sheep.
  • neurodegenerative disorder or a“neurological disorder” as used herein refers to a disorder which causes morphological and/or functional abnormality of a neural cell or a population of neural cells.
  • the neurodegenerative disorder can result in an impairment or absence of a normal neurological function or presence of an abnormal neurological function in a subject.
  • neurodegenerative disorders can be the result of disease, injury, and/or aging.
  • Non-limiting examples of morphological and functional abnormalities include physical deterioration and/or death of neural cells, abnormal growth patterns of neural cells, abnormalities in the physical connection between neural cells, under- or over production of a substance or substances, e.g, a neurotransmitter, by neural cells, failure of neural cells to produce a substance or substances which it normally produces, production of substances, e.g., neurotransmitters, and/or transmission of electrical impulses in abnormal patterns or at abnormal times.
  • Neurodegeneration can occur in any area of the brain of a subject and is seen with many disorders including, for example, epilepsy, head trauma, stroke, ALS, multiple sclerosis,
  • amyloid protein is meant a protein or peptide that is associated with an AD neuritic senile plaque.
  • the amyloid protein is amyloid precursor protein (APP) or a naturally-occurring proteolytic cleavage product.
  • APP cleavage products include, but are not limited to, Abi -4 o, Ab 2-4 o, Abi -4 2, as well as oxidized or crosslinked Ab.
  • AD is characterized by pathologic accumulation of insoluble protein in vulnerable brain regions and followed neuronal toxicity and dysfunction.
  • the toxic amyloid Ab peptides and tau are generally considered to be major pathogenic participants in AD. These various peptides are generated by cleavage of a larger protein called the b-amyloid precursor protein (APP).
  • Proteins called presenilins may mediate cleavage.
  • Other neuritic plaque-associated proteins include b-amyloid secretase enzymes I and II (BASE I and II) which associate with amyloid proteins.
  • BASE I and II b-amyloid secretase enzymes I and II
  • Some of the resulting Ab peptides are more toxic than others. Elevation of specific Ab peptides in the brain is believed to be causally associated with all known forms of AD. This generally accepted“Ab hypothesis” states that Ab generation, deposition and/or accumulation in the brain is an important final common pathway which underlies the disease process in this devastating neurological disorder.
  • Braak stage refers to a disease staging in Alzheimer's disease. Braak stages I and II are used when neurofibrillary tangle involvement is confined mainly to the transentorhinal region of the brain, stages III and IV when there is also involvement of limbic regions such as the hippocampus, and V and VI when there is extensive neocortical involvement. This should not be confused with the degree of senile plaque involvement, which progresses differently.
  • MMSE Mini-Mental State Examination
  • CDR Clinical Dementia Rating
  • CDR-K Korean version of CDR
  • FDG PET 18 F-labeled fluoro-2-deoxyglucose
  • 18 F-FDG is glucose analog.
  • the uptake of 18 F-FDG by tissues is a marker for the tissue uptake of glucose, which in turn is closely correlated with certain types of tissue metabolism.
  • a PET scanner can form two-dimensional or three-dimensional images of the distribution of 18F-FDG within the body, which indicates brain glucose metabolism.
  • cross sectional study refers to a comparative analysis of samples taken at the same time. For example, as shown in, e.g., FIG. 13 A, first, the blood samples from patients and the normal control group were collected as the baseline, and second, after two years, the blood samples were collected again from the same patients and the same normal group.
  • a cross sectional study as used herein refers to a cross-sectional analysis of comparing the blood samples from patients with those from the normal control group collected at the baseline, or comparing the blood samples from patients with those from the normal control group collected at the 2 nd year.
  • longitudinal study refers to a comparative analysis of samples collected from the same group at different times. For example, it means an analysis of comparing the blood samples from patients collected at the baseline with those collected at the 2 nd year (see, e.g., FIG. 13 A).
  • treatment refers to a decrease in the symptoms associated with the disorder or an amelioration of the recurrence of the symptoms of the disorder, prophylaxis, or reversal of a disease or disorder, or at least one discernible symptom thereof.
  • treatment or“treating” refers to inhibiting or slowing the progression of a disease or disorder, e.g., epilepsy, physically, e.g., stabilization of a discernible symptom, such as seizures.
  • treatment or“treating” refers to delaying the onset of a disease or disorder.
  • prevention or“preventing” refers to delaying the onset of the symptoms of the disorder.
  • control refers to a subject or sample that serves as a reference, usually a known reference, for comparison to a test subject or a test sample.
  • the control or the normal may be two types, a disease control (or disease-associated control) and a normal (non-disease control).
  • a control in particular a disease control (or reference) is a control subject, sample or value taken from a patient who was previously diagnosed with a neurological disease of interest or any population thereof.
  • a disease control is a control subject, sample, image or value taken from a subject who was previously known to have symptoms that are indicative of or associated ( i.e .
  • a normal (non-disease) control refers to a subject, sample, image or value taken from a health subject who is known not to have or suspected of not having a neurological disease.
  • a control or reference can also represent an average value gathered from a population of similar individuals, e.g., neurological and/or psychiatric patients or healthy individuals with a similar medical background, same age, weight, etc.
  • a control or reference sample, value or image can also be obtained from the same individual, e.g, from an earlier-obtained sample, prior to disease, or prior to treatment, especially when a plurality of samples, values or images from the same individual are monitored over a course of time.
  • therapeutic intervention refers to, for example, medicine (e.g. therapeutic compositions) and/or therapy (e.g. chemical and/or surgical procedures) used to reduce or cure disease or pain by the involvement and intercession of therapeutic practice.
  • medicine e.g. therapeutic compositions
  • therapy e.g. chemical and/or surgical procedures
  • Therapeutic intervention can vary in methods, for example, depending on a condition or disease of a patient who is in need of such a therapeutic intervention.
  • a therapeutic intervention can be performed to a subject identified for the treatment.
  • administration which may be administration to cells in vitro, administration to cells in vivo, administration to a subject by a medical professional or by self-administration by the subject and/or to indirect administration, which may be the act of prescribing a composition.
  • an effective amount is administered, which amount can be determined by one of skill in the art. Any method of administration may be used.
  • Compounds e.g., drugs
  • Administration to a subject can be achieved by, for example, oral delivery, parenteral delivery, intravascular injection, direct intracranial delivery, intranasal delivery, and the like.
  • the appropriate dose of the pharmaceutical composition is that amount effective to prevent occurrence of the symptoms of the disorder or to treat some symptoms of the disorder from which the patient suffers.
  • By“effective amount”,“therapeutic amount” or“effective dose” is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of the disorder.
  • the effective dose varies, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered.
  • the effective dose of the composition differs from patient to patient but in general includes amounts starting where desired therapeutic effects occur, but below that amount where significant undesirable side effects are observed.
  • an effective amount of composition is an amount sufficient to pass across the blood-brain barrier of the subject and to interact with relevant sites in the brain of the subject, thus resulting in effective prevention or treatment of the disorder.
  • compositions suitable for use with the present invention include compositions wherein the purified compounds or functional analogs are present in effective amounts, i.e., in amounts effective to achieve the intended purpose, for example, treating, preventing, or reducing a symptom of neurological diseases.
  • effective amounts i.e., in amounts effective to achieve the intended purpose, for example, treating, preventing, or reducing a symptom of neurological diseases.
  • the actual amounts of the compounds effective for a particular application depends upon a variety of factors including, inter alia, the type of disorder being treated, and the age and weight of the subject.
  • Such compositions contain amounts of compound effective to achieve these results. Determination of effective amounts is well within the capabilities of those skilled in the art.
  • the compounds can be administered in any manner that achieves the requisite therapeutic or prophylactic effect.
  • Therapeutically or prophylactically effective doses of the compounds of the invention can be determined from animal or human data for analogous compounds that are known to exhibit similar
  • the applied doses are adjusted based on the relative bioavailability, potency and in vivo half-life of the administered compounds as compared with these other agents. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods that are well-known is well within the capabilities of the ordinarily skilled artisan.
  • the ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and is expressed as the ratio between LD 50 (the amount of compound lethal in 50% of the population) and ED 50 (the amount of compound effective in 50% of the population).
  • Therapeutic index data is obtained from animal studies and used in formulating a range of dosages for use in humans. The dosage of such compounds preferably lies within a range of plasma concentrations that include the ED 50 with little or no toxicity.
  • the dosage varies within this range depending upon the dosage form employed and the route of administration utilized.
  • phrases“pharmaceutically acceptable salt(s)” as used herein includes, but is not limited to, salts of acidic or basic groups that may be present in the natural product compounds, and hydrates thereof. Natural product compounds, and hydrates thereof that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • acids that may be used to prepare pharmaceutically acceptable salts of such basic compounds are those that form salts comprising pharmacologically acceptable anions including, but not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, edetate, camsylate, carbonate, bromide, chloride, iodide, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, muscate, napsylate, nitrate, pantothenate, phosphate/diphosphate,
  • Natural product compounds, and hydrates thereof that include an amino moiety can also form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Natural product compounds, and hydrates thereof that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts.
  • Amyloid-beta A4 protein (Amyloid precursor protein (APP)” as provided herein includes any of Amyloid-beta A4 protein naturally occurring forms, homologs or variants that maintain the protein activity (e.g ., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to the native protein).
  • variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring form.
  • Amyloid-beta A4 protein is the protein as identified by UniProt P05067 or a functional fragment thereof.
  • Amyloid-beta A4 protein includes the sequence of SEQ ID NO: 1.
  • Amyloid- beta protein 42 (Abeta42) corresponds to the fragment of amino acid residues 672-713 of Amyloid-beta A4 protein.
  • Amyloid-beta protein 42 includes the sequence of SEQ ID NO: 2.
  • Amyloid-beta protein 40 (Abeta40) corresponds to the fragment of amino acid residues 672-711 of Amyloid-beta A4 protein.
  • Amyloid-beta protein 42 includes the sequence of SEQ ID NO: 3.
  • Tau protein as provided herein includes any of Tau protein naturally occurring forms, homologs or variants that maintain the protein activity (e.g ., within at least 50%, 80%, 90%, 95%, 96%, 97%, 98%, 99% or 100% activity compared to the native protein).
  • variants or homologs have at least 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid sequence identity across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid portion) compared to a naturally occurring form.
  • Tau protein is the protein as identified by UniProt P 10636 or a functional fragment thereof.
  • Tau protein includes the sequence of SEQ ID NO: 4.
  • A“Apolipoprotein E (ApoE) gene” as referred to herein includes any of the recombinant or naturally-occurring forms of the gene encoding Apolipoprotein E (ApoE), homologs or variants thereof that maintain ApoE protein activity (e.g., within at least 50%, 60%, 70%, 80%, 90%,
  • variants have at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% amino acid or nucleic acid sequence identity across the whole sequence or a portion of the sequence (e.g., a 50, 100, 150 or 200 continuous amino acid or nucleic acid portion) compared to a naturally occurring ApoE polypeptide or ApoE nucleotide.
  • APOE gene alleles
  • ApoE2, E3 and E4 or ApoE epsilon4 or ApoE e4
  • the ApoE gene is substantially identical to the nucleic acid identified by the NCBI reference number Gene ID: 348 (ApoE4) or a variant having substantial identity thereto.
  • Apolipoprotein e4 Apolipoprotein e4.
  • Plasma Ab levels were determined by xMAP technology (Bioplex 200 System; Bio-Rad, Hercules, CA, USA) using an INNO-BIA plasma Ab forms kit (Fujirebio Diagnostics, Ghent, Belgium) and a modified, stable quantification method employing MPP (mixture of protease inhibitors and phosphatase inhibitors).
  • ROC receiver operating curve
  • Alzheimer’s disease is abnormal deposition of tau proteins in the brain.
  • plasma tau has been proposed as a potential biomarker for Alzheimer’s disease, a direct link to brain deposition of tau is limited.
  • the amount of in vivo tau deposition in the brain by PET imaging was estimated, and plasma levels of total tau (t-tau), phosphorylated tau (p-tau, T181) and amyloid-Pi-42 was measured.
  • Significant correlations of plasma p-tau, t-tau, p-tau/amyloid-bi -42, and t-tau/amyloid-Pi-42 with brain tau deposition in cross-sectional and longitudinal manners were found.
  • t-tau/amyloid-Pi-42 in plasma was highly predictive of brain tau deposition, exhibiting 80% sensitivity and 91% specificity.
  • the brain regions where plasma t-tau/amyloid-Pi-42 correlated with brain tau were similar to the typical deposition sites of neurofibrillary tangles in Alzheimer’s disease.
  • the longitudinal changes in cerebral amyloid deposition, brain glucose metabolism, and hippocampal volume change were also highly associated with plasma t- tau/amyloid-Pi-42.
  • Alzheimer’s disease is the most common neurodegenerative disease in the elderly population. Cerebral accumulation of the amyloid-b peptide and neurofibrillary tangles (NFTs) of tau are the main pathological hallmarks of Alzheimer’s disease, and are closely related to the neurodegenerative mechanism through interacting with binding partners that lead to the toxicity and disruption of neurons and synapses during its pathogenesis (Ballatore et al, 2007, Nat. Rev. Neurosci., 8: 663-72; Han et al., 2016, Prog. Neurobiol., 137: 17-38).
  • NFTs neurofibrillary tangles
  • Tau in particular is known to play a critical role in Alzheimer’s disease pathogenesis through its association with amyloid-b, and several lines of evidence have suggested tau-dependent amyloid-b toxicity and a feedback loop connecting tau and amyloid- b during the pathogenesis of Alzheimer’s disease (Rapoport et al, 2002, Proc. Natl. Acad. Sci. USA, 99: 6364-9).
  • Tau is encoded by the MAPT (microtubule associated protein tau) gene and exists in the human brain as six isoforms that differ in their amino terminal inserts and microtubule binding domain repeats (Goedert et al., 1989, EMBO I, 8: 393-9). Tau acts through its microtubule binding domain repeats that promote tubulin assembly and stabilize microtubule structure as well as function (Weingarten et al., 1975, Proc. Natl. Acad. Sci. USA, 72: 1858-62). Tau contains a number of phosphorylation sites, and its phosphorylation status influences its effects on microtubule assembly (Lindwall and Cole, 1984, J. Biol. Chem., 259: 5301-5).
  • MAPT microtubule associated protein tau
  • PET imaging is a valuable technique for monitoring brain tau pathology, and a variety of recently developed tau radiotracers for identification of neurofibrillary pathology through PET imaging provide great Alzheimer’s disease diagnostic and prognostic potential (Saint- Aubert et al., 2017, Mol. Neurodegener., 12: 19).
  • PET imaging of tau offers a wealth of information and reflects Alzheimer’s disease pathology fairly well, PET instrumentation is unavailable in many clinical settings and PET imaging is associated with high costs and concerns of radiation hazards.
  • the aim of the current study therefore, was threefold.
  • Subjects seventy-six subjects (52 cognitively normal, nine MCI, 15 Alzheimer’s disease dementia) participated in this study. Details of inclusion and exclusion criteria are described previously (Byun et al., 2017, Psychiatry Invest., 14: 851-63). Briefly, all cognitively normal individuals had Clinical Dementia Rating (CDR) global score of 0 and no diagnosis of MCI or dementia. MCI individuals had CDR of 0.5 and met the inclusion criteria based on core clinical criteria for diagnosis of MCI according to the recommendations of the NIA-AA guidelines (Albert et al., 2011, Alzheimers Dement., 7: 270-9).
  • CDR Clinical Dementia Rating
  • Clinical and neuropsychological assessments all participants were administered standardized clinical assessments by trained board-certified psychiatrists based on the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE) clinical assessment protocol which incorporated the CERAD-K clinical assessment (Lee et al., 2002, J. Gerontol. B Psychol. Sci. Soc. Sci., 57: 47-53). All subjects were also given a comprehensive neuropsychological assessment battery, administered by a clinical
  • Neuroimaging data participants underwent PET magnetic resonance scanning sessions to obtain multimodal imaging including l8F-fluorodeoxyglucose (FDG)-PET, MRI using 3.0 T Biograph mMR (PET-MR) scanner (Siemens). They also underwent simultaneous 3D 11C- Pittsburgh compound B (PiB)-PET and 3D Tl -weighted MRI using the 3.0 T PET-MR scanner, and 18FAV-1451 PET scans (Siemens) according to the manufacturer’s approved guidelines.
  • FDG fluorodeoxyglucose
  • PET-MR 3.0 T Biograph mMR
  • FDG-PET acquisition and processing the participants fasted for at least 6 h and rested in a waiting room for 40 min prior to the scans after intravenous administration of 0.1 mCi/kg of 18F-FDG radioligands.
  • the PET data collected in list mode (5 min X four frames) were processed for routine corrections such as uniformity, ultrashort echo time (UTE)-based attenuation, and decay corrections. After inspecting the data for any significant head movements, they were reconstructed into a 20-min summed image using iterative methods (six iterations with 21 subsets).
  • AAL automated anatomical labelling
  • SETVR standard uptake value ratio
  • 18F-AV-1451 PET scans were performed for 10 min on a Biograph True point 40 PET/CT scanner (Siemens) as dynamic scans using LIST-mode 80 min after an injection of 370 MBq of 18F-AV-1451.
  • Low-dose CT scans for attenuation correction were performed in the same patient position immediately prior to the PET scans.
  • Iterative (OSEM3D+PSF) True X algorithm was used for PET data reconstruction with 24 subsets, six iterations with 3 mm Gaussian filter. Average interval between blood samples and 18F-AV-1451 PET imaging was 135 days (range 7-277 days).
  • 18F-AV- 1451 PET SETVR images were created based on the mean uptake over 80 to 100 min post injection, normalized by the mean inferior cerebellar grey matter uptake.
  • the SETVR images were coregistered and resliced into structural MRIs.
  • the Geometric Transfer Matrix approach was used for partial volume correction based on FreeSurfer-derived regions of interest from the Tl taken at the follow-up visit, including corrections for extracerebral tissue as described previously (Baker et al., 2017, Data Brief, 15: 648-57; Jack et al., 2017, Alzheimers Dement., 13: 205-16).
  • Voxelwise analyses used SETVR images (with partial volume correction) that were transformed into MNI- 152 space.
  • the data were extracted from native space, according to the method published by Baker et al. (2017, Data Brief, 15: 648-57). 18F-
  • AV-1451 PET uptake was quantified by grouping together regions of interest that corresponded to the pathological stages of tau protein tangle deposition in Alzheimer’s disease described by Braak and Braak (1995, Neurobiol. Aging, 16: 271-8; discussion 8-4). The regions grouped in each Braak stage region of interest have been published previously (Baker et al., 2017, Data Brief, 15: 648-57; Maass et al., 2017, Neuroimage, 157: 448-63).
  • Weighted mean SETVR in native space was calculated to form three composite regions of interest that roughly correspond to anatomical definitions of Alzheimer’s disease Braak stages 0, stage I/II, stage III/IV, and stage V/VT Participants were then categorized into Alzheimer’s disease Braak stages according to thresholds that were based on Braak region of interest-specific tracer uptake (Maass et al, 2017, Neuroimage, 157: 448-63).
  • a priori region of interest of ‘Alzheimer’s disease signature’ regions of tau accumulation was also included in these analyses, which is a size-weighted average of partial volume corrected uptake in entorhinal, amygdala, parahippocampal, fusiform, inferior temporal and middle temporal regions of interest, based on previous report (Jack et al., 2017, Alzheimers Dement., 13: 205-16).
  • PiB-PET acquisition and processing participants underwent simultaneous 3D HC-PiB- PET and 3D Tl -weighted MRI using the 3.0 T PET-MR scanner. After intravenous administration of 555 MBq of HC-PiB (range, 450-610 MBq), a 30-min emission scan was obtained 40 min after injection.
  • the PiB-PET data collected in list mode were processed for routine corrections such as uniformity, UTE-based attenuation, and decay corrections, and were reconstructed into a 256 X 256 image matrix using iterative methods (six iterations with 21 subsets).
  • inverse transformation parameter was obtained from SPM12 D ARTEL segmentation procedure using individual Tl that was taken at the same day as the PiB- PET and MNI template. Obtained inverse transformation parameters were applied to AAL atlas to acquire AAL atlas in native space for each participant, which were then used to extract PiB retention levels.
  • retention in cerebellum was separately extracted using a spatially unbiased atlas template of the cerebellum and brainstem (SUIT) (Diedrichsen et al., 2011, Neuroimage, 54: 1786-94); retention in cerebellar grey matter was used for intensity normalization.
  • PiB retention index as SUVR for each region of interest was calculated by dividing regional mean value by the individual mean cerebellar uptake values.
  • the AAL algorithm Rolls et al., 2015, Neuroimage, 122: 1-5) and a region combining method (Reiman et al, 2009, Proc. Natl. Acad. Sci. USA, 106: 6820-5) were applied to set the regions of interest to characterize PiB retention level in frontal, lateral parietal, posterior cingulate- precuneus, and lateral temporal regions.
  • Each participant was classified as amyloid-P-positive if the SUVR value was 41.4 in at least one of the four regions of interest or as amyloid-b- negative if the SUVR values of all four regions of interest was 41.4 (Villeneuve et al, 2015, Brain, 138 (Pt 7): 2020-33).
  • global weighted region of interest was calculated to represent in vivo global PiB retention level of the four abovementioned regional regions of interest.
  • Longitudinal imaging data processing the same processing methods were applied to the follow-up imaging data (i.e. MRI, FDG-PET, and PiB-PET) as the baseline.
  • Plasma t-tau and p-tau were measured using the Simoa Human tau immunoassay (Total Tau 2.0 or Phospho-Tau Thr 181 immunoassay) kits on the Simoa HD-l Analyzer (Quanterix) at Seoulin Bioscience.
  • Plasma p-tau was quantified in only 51/76 individuals and plasma t-tau in 75/76 individuals.
  • the results associated with plasma t-tau t-tau or t-tau/amyloid-b 1-42 ) remained essentially similar when restricted to the 50 individuals having all the measurements including plasma amyloid-b 1-42 .
  • Plasma amyloid-b 1-42 levels were determined by xMAP technology (Bio-Plex ® 200 System; Bio-Rad) using an INNO-BIA plasma amyloid-b forms kit (Fujirebio Diagnostics) and a modified, stable quantification method using MPP (mixture of protease inhibitors and phosphatase inhibitors), as described previously (Park et al., 2017, Alzheimers Res. Ther. 9: 20).
  • the measurement of plasma Ab 4 2 as described herein was performed by treating with the mixture of protease inhibitors and phosphatase inhibitors (MPP), which allows stabilization of plasma Ab, followed by measuring (see, e.g., Park et al, 2017. Alz. Res. Ther., 9:20, doi: 10.1186/S13195-017-0248-8 and Korean patent KR 10-1786859, the contents of which are incorporated herein by reference.
  • MPP mixture of protease inhibitors and phosphatase inhibitors
  • ROC receiver operating curve
  • relative risk analyses were also performed (restricted to the 50 individuals having all the measurements). Specifically, plasma biomarkers (p-tau, t-tau, p-tau/amyloid-b 1-42 , and t-tau/amyloid-b 1-42 ) and covariates (age and sex) were appropriately integrated and the predicted probabilities from each regression model were generated. Each was then used as an independent variable for the ROC models to predict tau PET positivity (Tau-PET + , Braak stage III to VI subjects; Tau-PET , Braak stage 0 to II subjects) or for the relative risk analyses.
  • Tau-PET + versus Tau-PET was set to be between Braak stages 0-II and III- VI based on previous reports that showed significant early tau aggregation associated with Alzheimer’s disease dementia in the stage III (Mattsson et al, 2017, EMBO Mol. Med., 9: 1212-23), which is the first stage where the Alzheimer’s disease-related tau pathology extends into the hippocampal formation (Rub et al, 2017, 1. Alzheimers Dis., 57: 683-96).
  • participant were categorized into two groups: (i) subjects were sorted in ascending order of their levels of each predicted probabilities using plasma tau-related biomarkers; (ii) plasma marker low group (Subjects 1-25) was named‘group 1’ and high group (Subjects 26-50) was named‘group 2’). All experimental procedures and statistical analyses were carried out in a blind manner.
  • Table 8 includes the data of longitudinal changes. Furthermore, subjects were classified into four groups according to brain tau Braak staging (25 Braak stage 0, 28 stage I— II,
  • FIG. 8A The levels of all four plasma tau-related biomarkers (p-tau, t-tau, p-tau/amyloid-b 1-42 , and t-tau/amyloid-b 1-42 ) significantly increased as brain tauopathy progressed (Braak stages 0 to VI) (FIG. 8A).
  • FIG. 8B To evaluate the link between plasma tau-related biomarkers and brain tau burden in an Alzheimer’s disease signature region of interest, partial correlation analyses were conducted after correcting for covariates (age and sex) (FIG. 8B). All markers showed highly significant correlations with tau burden in the Alzheimer’s disease signature region of interest in the brain (FIG. 8B).
  • FIG. 16, Table 10 shows all possible correlations between markers and tau burden in each individual brain region.
  • FIGS. 9A-9D represent voxel- wise associations between each of the plasma tau biomarkers and regional brain tau burden. While higher plasma p-tau and t-tau values were associated with higher brain tau deposition only in the medial temporal regions (FIG. 9A and FIG. 9B), plasma p-tau/amyloid-b 1-42 and t-tau/amyloid-b 1-42 ratios showed positive correlations with tau deposition in diffuse brain regions including the cingulate, lateral temporal, frontal, and parietal cortices as well as the medial temporal regions (FIG. 9C and FIG. 9D). In particular, the brain regions where plasma t-tau/amyloid-b 1-42 ratio correlated with brain tau were very similar to the typical deposition sites of neurofibrillary tangles in Alzheimer’s disease (FIG. 9D).
  • FIG. 10A and FIG. 10B ROC and relative risk analyses
  • subjects were divided into two groups: Tau-PET and Tau-PET + (FIG. 10A).
  • Tau-PET Tau-PET +
  • FIG. 8A the levels of plasma tau-related biomarkers were significantly higher in Tau-PET + subjects compared with Tau-PET subjects.
  • the t-tau/amyloid-b 1-42 levels showed a relatively clear dichotomy between Tau-PET and Tau-PET + subjects (FIG. 10B).
  • Four logistic regression models were generated using plasma tau-related biomarkers, corrected for covariates (age and sex), and predicted probabilities were used as the independent values for the ROC models. All four ROC models - p-tau, t-tau, p-tau/amyloid-b 1-42 , and t-tau/amyloid-b 1-42 - showed significantly high performance for discriminating Tau-PET and Tau-PET + subjects (FIG. 10C, FIG. 10D and Table 6).
  • the relative risk values increased in the following order, p-tau, p-tau/amyloid-b 1-42 , t-tau, t-tau/amyloid-b 1-42 ; and, this pattern was in accordance with the AFiC values from the ROC curve analysis (p-tau ⁇ p-tau/amyloid-b 1-42 ⁇ t-tau ⁇ t-tau/amyloid-b 1-42 ) as shown in FIG. 10C and FIG. 10D. Furthermore, an additional analysis (c 2 test) were carried out in order to check for the group composition differences (group 1 versus group 2) (Table 7).
  • the level of plasma t-tau/amyloid-b 1-42 predicts the neuropathological changes in the brain over 2 years
  • Plasma t-tau/amyloid-Pi-42 did not reflect the neuropathologies in the brain at baseline time point
  • Plasma amyloid-Pi- 42 also correlates with brain tau accumulation
  • Plasma amyloid-b 1-42 has been implicated as one of the biomarkers for Alzheimer’s disease diagnosis, there are many concerns about instability of amyloid-b in the blood. Hence, an improved quantification method for plasma amyloid-b 1-42 was used in this study ( i.e . treatment of mixture of protease inhibitors and phosphatase inhibitors, MPP) (Park el al., 2017, Alzheimers Res. Ther. 9: 20). Plasma amyloid-b 1-42 also correlates with not only cerebral amyloid-b deposition (FIG. 19B, P ⁇ 0.001) but also brain tau accumulation (FIG. 19C, P ⁇ 0.01).
  • Plasma t-tau, p-tau, and amyloid ⁇ i-42 levels were quantified in cognitively normal, MCI, and Alzheimer’s disease dementia individuals who underwent 11C- PiB-PET and 18F-AV-1451 tau PET imaging.
  • Plasma t-tau and p-tau were strongly and positively associated with the degree of brain tau deposition observed on tau-PET, whereas plasma amyloid ⁇ i-42 was negatively correlated with brain tau accumulation.
  • the composite biomarker of plasma tau and amyloid ⁇ i-42 represented more significant correlations with tau-PET and Alzheimer’s disease-associated tau pathology compared to a single biomarker of plasma tau.
  • Plasma t-tau/ amyloid ⁇ i-42 showed the strongest association with brain tau accumulation, exhibiting an increased AUC and relative risk.
  • the brain regions where plasma t-tau/amyloid ⁇ i-42 ratio correlated strongly with brain tau were very similar to the typical deposition sites of neurofibrillary tangles in Alzheimer’s disease.
  • plasma t-tau/amyloid-Pi- 4 2 was highly associated with the longitudinal changes of amyloid-b accumulation in the brain, cerebral glucose metabolism, and hippocampal volume over 2 years.
  • plasma t-tau/amyloid-b 1-42 level is a potential biomarker for predicting Alzheimer’s disease-associated tau pathology in the brain.
  • This study is the first to report the relationship among plasma tau level, plasma amyloid-b level and brain tau accumulation on in vivo PET images.
  • longitudinal examinations of plasma tau levels and plasma amyloid-b levels have not been done, especially in relation to various Alzheimer’s disease-associated
  • the baseline plasma t- tau/amyloid ⁇ i-42 might not be able to fully reflect neurodegenerative changes shown on FDG- PET or hippocampal volumes yet.
  • neurodegeneration has not progressed very far yet (compared to the accumulation of brain amyloid or tau) at baseline time point than that of 2- year time point:
  • FIG. 21B showed a trend toward significance; and (iii) while Alzheimer’s disease patients (categorized at the time of the 2-year time point) showed broad range of the degree of neurodegeneration at the baseline time point (FIG. 22A-FIG. 22C, dotted circle), they showed a cluster distribution of neurodegeneration at the 2-year time point (FIG. 22A-FIG. 22C, solid circle).
  • PiB-PET SUVR did not show the similar pattern, possibly due to saturation of brain amyloid deposition (FIG. 22D).
  • FIG. 21D Based on the 2-year longitudinal imaging data shown herein combined with blood composite biomarker, conjectured subject distribution range of both baseline samples and 2-year samples were marked on a hypothetical Alzheimer’s disease progression abnormality plot (FIG. 21D).
  • Plasma t-tau levels were found to be increased in Alzheimer’s disease dementia, but not in MCI, compared to controls (Zetterberg et al., 2013, Alzheimers Res. Ther, 5: 9; Mattsson et al., 2016, Neurology, 87: 1827-35), whereas other study found elevated plasma tau levels in both MCI and early Alzheimer’s disease (Chiu et al, 2014, Hum. Brain Mapp., 35: 3132-42). In contrast, significant decrease of plasma tau levels in Alzheimer’s disease has also been reported (Sparks et al, 2012, Am. J.
  • Plasma tau levels are associated with neurodegeneration and cognitive functions in Alzheimer’s disease, such that higher plasma tau levels were associated with memory decline, abnormal cortical thickness and anatomical volume of various brain regions (Chiu et al, 2014, Hum. Brain Mapp., 35: 3132-42; Mattsson et al, 2016, Neurology,
  • Plasma amyloid-b is also associated with hippocampal and cortical tau pathology and influences neurodegeneration (Johnson et al, 2016, Ann. Neurol., 79: 110-9; Wang et al., 2016, JAMA Neurol., 73: 1070-7). It was recently shown that plasma amyloid-b 1-42 is strongly associated with brain amyloid-b accumulation in
  • Alzheimer’s disease (Park et al, 2017, Alzheimers Res. Ther., 9: 20); utilization of plasma tau level and plasma amyloid-b 1-42 level together, therefore, may be synergistic in predicting brain tau accumulation.
  • both plasma tau and plasma amyloid-b level could be dual indicators for Alzheimer’s disease-related tau pathology (Mielke et al, 2018, Alzheimers Dement., 14: 989-97).
  • the tau/amyloid-b 1-42 ratio was used because it has been commonly used as a CSF biomarker for dementia and Alzheimer’s disease (Gomez-Tortosa et al, 2003, Arch. Neurol., 60: 1218-22; Fagan et al, 2007, Arch. Neurol., 64: 343-9; Pan et al, 2015, J. Alzheimers Dis., 45: 709-19; Ritchie et al, 2017, Cochrane Database Syst. Rev., 3: CD010803).
  • plasma amyloid ⁇ i-42 level yielded highly significant correlations with not only cerebral amyloid ⁇ i-42 deposition but also brain tau accumulation (FIG. 19A-FIG. 19C).
  • the plasma t-tau/amyloid-bi- 42 ratio in particular, showed higher correlation with Alzheimer’s disease-associated brain tau pathology, various Alzheimer’s disease-associated neurodegeneration markers including hippocampal volume, cortical thickness, cerebral glucose metabolism and episodic memory impairment, compared to p-tau/amyloid-b 1-42 (FIG. 8A-FIG. 8B, FIG. 9A-FIG. 9D, FIG. 10A- FIG. 10E, FIG. 17A, FIG. 17B, FIG 18A-FIG.
  • t-tau/amyloid-b 1-42 showed the best performance in discriminating Tau-PET and Tau-PET + subjects among four markers of p-tau, t-tau, p-tau/amyloid-bl-42 and t- tau/amyloid-b 1-42 (FIG. 10B-FIG. 10E, Table 6, and Table 7). Longitudinal follow-up study for period of 2 years supported these significant correlations of plasma t-tau/amyloid-b 1-42 ratio with the changes of Alzheimer’s disease-associated neurodegeneration markers (FIG. 13).
  • CSF tau has been proven to be associated with altered microstructure of brain on diffusion tensor imaging such that CSF t-tau and t-tau/amyloid-b 1-42 showed a widespread association with alteration in brain microstructure whereas p-tau and p-tau/amyloid-b 1-42 was only related to specific recognition performance and failed to show a widespread relationship (Bendlin et al, 2012, PLoS One, 7: e37720). Another study demonstrated that CSF t-tau had regional correlation with impairment of glucose metabolism whereas CSF p-tau showed no significant regional correlations (Haense et al, 2008, Eur. J. Neurol., 15: 1155-62).
  • amyloid-b 1-42 plaques and tau aggregates show up at different times in different regions of the brain (Iaccarino et al., 2018, Neuroimage Clin., 17: 452-64), evidence from animal model shows that two pathologies interact such that presence of amyloid-b 1-42 enhances tau aggregation (Bennett et al, 2017, Am.
  • tau aggregates in dystrophic neurites surrounding amyloid-b plaques a specific type of tau aggregates (i.e.‘tau aggregates in dystrophic neurites surrounding amyloid-b plaques’), which appear to fuel the formation and spreading of other tau conglomerates, including neurofibrillary tangles (He et al, 2018, Nat. Med., 24: 29-38).
  • a methodological limitation is regarding the measurement of plasma tau since the level of tau in plasma is very low picogram per millilitre range and the sensitivity of tau measuring tools is limited so far.
  • possible experimental variability was minimized for quantification of tau and amyloid-p.
  • CSF t-tau, p-tau and amyloid-P levels were typically studied using either ELISA or xMAP technology in multicentre population and the experimental variations were corrected by reanalysis and conversion of xMAP technology values to ELISA values (Mattsson et al., 2012, Neurology, 78: 468-76).
  • one method for each biomarker, xMAP technology for plasma amyloid-b 1-42 level and Simoa for the plasma tau quantification was unified.
  • Simoa human tau immunoassay was used for plasma t-tau and p-tau levels because several studies using Alzheimer’s Disease Neuroimaging Initiative (ADNI) and BioFINDER data applied Simoa to measure plasma levels of t-tau or p-tau (Mattsson et al, 2016, Neurology, 87: 1827-35; Deters et al., 2017, J. Alzheimers Dis., 58: 1245-54; Zhou et al., 2017, Neurosci. Lett., 650: 60-4). Quantification of plasma tau by the Simoa technique has recently been studied and was shown to be reliable to measure plasma t-tau and p-tau level (Deters et al., 2017, J.
  • quantification of p-tau is limited by the sensitivity of Simoa technique and it is only possible to measure p-tau (T181) and no other forms of p-tau. Quantification of diverse forms of p-tau levels in plasma would give better understanding of their association with brain tau pathology and their roles as biomarker in Alzheimer’s disease.

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