US20190041404A1 - Diagnosing mild cognitive impairment (mci), predicting alzheimer's disease (ad) dementia onset, and screening and monitoring agents for treating mci or preventing dementia onset - Google Patents

Diagnosing mild cognitive impairment (mci), predicting alzheimer's disease (ad) dementia onset, and screening and monitoring agents for treating mci or preventing dementia onset Download PDF

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US20190041404A1
US20190041404A1 US16/077,766 US201716077766A US2019041404A1 US 20190041404 A1 US20190041404 A1 US 20190041404A1 US 201716077766 A US201716077766 A US 201716077766A US 2019041404 A1 US2019041404 A1 US 2019041404A1
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cells
output signal
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Florin V. Chirila
Daniel L. Alkon
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West Virginia University
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    • 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
    • G06F19/12—
    • G06F19/26—
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/60—Complex ways of combining multiple protein biomarkers for diagnosis

Definitions

  • AD Alzheimer's disease
  • a ⁇ beta-amyloid
  • AD is a progressive disorder with a mean duration of around 8-15 years between onset of clinical symptoms and death. AD is believed to represent the seventh most common medical cause of death and affects about 5 million people in the United States.
  • the methods of the present disclosure address these needs by providing for methods of diagnosing MCI, of monitoring the progression of MCI, and of predicting the time to clinical onset of AD dementia.
  • the present disclosure is also directed to methods of screening for a compound useful for treating MCI or for preventing the clinical onset of AD dementia, as well as methods of evaluating or monitoring the therapeutic benefit of an agent for treating MCI or preventing the clinical onset of AD dementia.
  • a method of diagnosing MCI in a subject comprises:
  • step (a) obtaining one or more cells from the subject; (b) determining an output signal of one or more diagnostic biomarkers using the one or more cells from the subject, wherein the diagnostic biomarker is chosen from AD Index Biomarker, Morphometric Imaging Biomarker and PKC Epsilon Biomarker; and (c) comparing the output signal determined in step (b) to output signals of the diagnostic biomarker for age-matched control (AC) cells and for AD cells, wherein MCI is indicated in the subject if the output signal determined in step (b) is less than the lowest output signal for the AD cells but greater than the highest output signal for the AC cells.
  • AC age-matched control
  • a method of monitoring the progression of MCI in a subject comprises:
  • step (a) obtaining one or more cells from the subject; (b) determining an output signal of one or more diagnostic biomarkers using the one or more cells from the subject, wherein the diagnostic biomarker is chosen from AD Index Biomarker, Morphometric Imaging Biomarker and PKC Epsilon Biomarker; (c) comparing the output signal determined in step (b) to output signals of the diagnostic biomarker for AC cells and for AD cells, wherein MCI is indicated in the subject if the output signal determined in step (b) is less than the lowest output signal for the AD cells but greater than the highest output signal for the AC cells; and (d) repeating steps (a) through (c) at one or more subsequent points in time, wherein the subject has progressed toward the clinical onset of AD dementia if the output signals determined in step (b) have increased over time.
  • a method of predicting the time to clinical onset of AD dementia in a subject comprises:
  • a method of predicting the time to clinical onset of AD dementia in a subject comprises:
  • a method of screening for a compound useful for treating MCI or preventing the clinical onset of AD dementia comprises:
  • step (a) obtaining one or more cells from a subject; (b) determining an output signal of one or more diagnostic biomarkers using the one or more cells from the subject, wherein the diagnostic biomarker is chosen from AD Index Biomarker, Morphometric Imaging Biomarker and PKC Epsilon Biomarker; (c) comparing the output signal determined in step (b) to output signals of the diagnostic biomarker for AC cells and for AD cells, wherein MCI is indicated in the subject if the output signal determined in step (b) is less than the lowest output signal for the AD cells but greater than the highest output signal for the AC cells; (d) if MCI is indicated in step (c), determining the output signal of the diagnostic biomarker in step (b) after contacting cells from the subject with a compound for an initial time period and/or for an ongoing time period; and (e) comparing the output signal determined in step (d) to the output signal determined in step (b), wherein the test compound is indicated as useful for the treatment of MCI or the prevention of the clinical onset of AD
  • a method of evaluating or monitoring the therapeutic benefit of an agent for treating MCI or preventing the clinical onset of AD dementia in a subject comprises:
  • step (a) obtaining one or more cells from a subject; (b) determining an output signal of one or more diagnostic biomarkers using the one or more cells from the subject, wherein the diagnostic biomarker is chosen from AD Index Biomarker, Morphometric Imaging Biomarker and PKC Epsilon Biomarker; (c) comparing the output signal determined in step (b) to output signals of the diagnostic biomarker for AC cells and for AD cells, wherein MCI is indicated in the subject if the output signal determined in step (b) is less than the lowest output signal for the AD cells but greater than the highest output signal for the AC cells; (d) if MCI is indicated in step (c), determining the output signal of the diagnostic biomarker in step (b) using one or more cells from the subject after initial, ongoing, and/or cessation of treatment with an agent; and (e) comparing the output signal determined in step (d) to the output signal determined in step (b), wherein the agent is indicated as providing therapeutic benefit for treating MCI or preventing the clinical onset of AD dementia in
  • FIGS. 1A and 1B show a correlation between the loss of synapses and the Mini-Mental State Examination (MMSE) score in MCI patients based on the average of the total number of synapses in the outer molecular layer of the hippocampal dentate gyms and the average MMSE score for three populations: Age-matched controls (AC), MCI patients, and AD patients.
  • FIG. 1A shows the total number of synapses ⁇ 10 10 in the outer molecular layer of the hippocampal dentate gyrus (closed triangles and the left y-scale) and the MMSE score (open triangles and the right y-scale).
  • FIG. 1B uses the same values as in FIG. 1A and scales them between 0 and 100, showing a severity score for total number of synapses and the MMSE score. The curves are the best-fit logistic functions.
  • FIG. 2A shows a linear dependence of the AD Index Biomarker on the MMSE score for AC cells (squares) and AD cells (circles).
  • FIG. 2B shows normalized output signals for AC (squares) and AD (circles) cells as a function of AD duration for the AD cells and age difference for the AC cells.
  • AD duration for the AD cells was the age difference between an AD subject's age at the time of clinical onset of AD and the AD subject's age at the time of collecting one or more cells for generating the output signals of the diagnostic biomarker.
  • Age difference for the AC cells was the difference between an AC subject's age at the time of collecting one or more cells for generating the output signals of the diagnostic biomarker and the age at the time of collecting one or more cells for generating the output signals of the diagnostic biomarker of the oldest AC subject in the AC group.
  • the age difference for the AC group was plotted to the left of the AD onset as negative age differences.
  • FIGS. 3A and 3B show Severity Scores for the Morphometric Imaging Biomarker and the PKC Epsilon Biomarker as a function of AD duration;
  • FIG. 3A plots the output signals of the Morphometric Imaging Biomarker as a function of AD duration (The minimum and maximum values for Ln(A/N) were scaled between 0 and 100) and
  • FIG. 3B plots the output signals of the PKC Epsilon Biomarker as a function of AD duration (The minimum and maximum values for S/I were called between 0 and 100.).
  • Each plot includes a linear fit line.
  • FIG. 4A shows normalized output signals for the Morphometric Imaging Biomarker as a function of AD duration for the AD cells and age difference for the AC cells.
  • FIG. 4B shows normalized output signals for the PKC Epsilon Biomarker as a function of AD duration for the AD cells and age difference for the AC cells. The age difference for the AC group was plotted to the left of the AD onset line in both figures. The error bars are standard errors of the mean. The vertical arrows indicate the gap between the AC and AD groups. Patients with a Severity Score within this gap are MCI patients.
  • FIG. 5A is similar to FIG. 4A but further illustrates the predictive value of Morphometric Imaging Biomarker applying the linear dependence of the AD group.
  • FIG. 5B is similar to FIG. 4B but further illustrates the predictive value of the PKC Epsilon Biomarker following the linear dependence of the AD group.
  • FIGS. 6A, 6B, and 6C illustrate the predictive value of the Morphometric, PKC Epsilon, and AD Index Biomarkers, respectively, applying a logistic fit function rather than linear.
  • FIG. 7A shows the significant overlap in the Severity Score of the three biomarkers.
  • FIG. 7B shows the significant overlap for the average for the total number of synapses in the outer molecular layer of the hippocampal dentate gyrus and the average MMSE score for the three populations, AC, MCI, and AD.
  • FIGS. 8A, 8B, and 8C shows logistic fit curves for ranked output signals for the Morphometric Imaging, PKC Epsilon, and AD Index Biomarkers, respectively.
  • the MCI patients are located in the gap between the AC and AD groups of patients as indicated by the horizontal arrows and thick lines.
  • FIG. 8D summarizes FIGS. 8A, 8B, and 8C (Morphometric Imaging—red; PKC Epsilon—green; AD Index—blue).
  • protein kinase C activator or “PKC activator” refers to a substance that increases the rate of the reaction catalyzed by PKC.
  • PKC activators can be non-specific or specific activators.
  • a specific activator activates one PKC isoform, e.g., PKC- ⁇ (epsilon), to a greater detectable extent than another PKC isoform.
  • subject or “subjects” used herein is non-limiting. It refers to humans, but can also include other mammals, such as mice, rats, monkeys, and apes.
  • PKC ⁇ Activation Prevents Synaptic Loss, A ⁇ Elevation, and Cognitive Deficits in Alzheimer's Disease Transgenic Mice,” J. Neuroscience, 31(2):630-643 (2011); Khan et al., “PKC ⁇ Deficits in Alzheimer's Disease Brains and Skin Fibroblasts,” Journal of Alzheimer's Disease, 2015;43(2):491-509.
  • the reduction of PKC ⁇ and ⁇ occurs in association with elevation of soluble beta amyloid protein (A ⁇ ), but before the appearance of the amyloid plaques or neuronal loss. Id.
  • Biomarker Severity Score corresponds to output signals of a respective biomarker for Age-matched controls (AC) and AD patients.
  • the output signals can, but need not, be normalized, e.g. scaled between 0 and 100%.
  • the Biomarker Severity Score is represented as a continuous logistic fit function on normalized values (between 0 and 100%) of the output signals for a respective biomarker.
  • the present inventors have discovered that these biomarkers, using the Biomarker Severity Score, can detect the signature of AD before the clinical onset of dementia, such as years before clinical onset, and can be used to diagnose MCI, monitor the progression of MCI, and predict the time to clinical onset of AD dementia.
  • the Biomarker Severity Score the inventors have also discovered methods of screening for a compound useful for treating MCI or for preventing the clinical onset of AD dementia, as well as methods of evaluating or monitoring the therapeutic benefit of an agent for treating MCI or preventing the clinical onset of AD dementia.
  • a method of diagnosing MCI in a subject comprises:
  • step (a) obtaining one or more cells from the subject; (b) determining an output signal of one or more diagnostic biomarkers using the one or more cells from the subject, wherein the diagnostic biomarker is chosen from AD Index Biomarker, Morphometric Imaging Biomarker and PKC Epsilon Biomarker; and (c) comparing the output signal determined in step (b) to output signals of the diagnostic biomarker for AC cells from a group of AC subjects and to output signals of the diagnostic biomarker for AD cells from a group of AD subjects, wherein MCI is indicated in the subject if the output signal determined in step (b) is less than the lowest output signal for the AD cells but greater than the highest output signal for the AC cells.
  • the method may further comprise predicting the time to clinical onset of AD dementia, comprising:
  • each AD duration is the age difference between the AD subject's age at the time of clinical onset of AD and the AD subject's age at the time of collecting one or more cells for generating the output signals of the diagnostic biomarker; (2) fitting a function to the plotted output signals of step (1); and (3) if MCI is indicated in step (c), predicting the time to clinical onset of AD dementia by inputting into the fit function the output signal of the diagnostic biomarker determined in step (b) and determining the time to clinical onset of AD dementia.
  • FIGS. 5A and 5B show an example of predicting the time to clinical onset of AD dementia for a hypothetical MCI subject.
  • the fit function is a linear function.
  • the method may further comprise predicting the time to clinical onset of AD dementia, comprising:
  • each AD duration is the age difference between an AD subject's age at the time of clinical onset of AD and the AD subject's age at the time of collecting one or more cells for generating the output signals of the diagnostic biomarker;
  • a method of monitoring the progression of MCI comprises repeating steps (a) through (c) above at one or more subsequent points in time, wherein the subject has progressed toward the clinical onset of AD dementia if the output signals determined in step (b) above have increased over time.
  • a method of screening for a compound useful for treating MCI or preventing the clinical onset of AD dementia comprises:
  • step (a) obtaining one or more cells from a subject; (b) determining an output signal of one or more diagnostic biomarkers using the one or more cells from the subject, wherein the diagnostic biomarker is chosen from AD Index Biomarker, Morphometric Imaging Biomarker and PKC Epsilon Biomarker; (c) comparing the output signal determined in step (b) to output signals of the diagnostic biomarker for AC cells and for AD cells, wherein MCI is indicated in the subject if the output signal determined in step (b) is less than the lowest output signal for the AD cells but greater than the highest output signal for the AC cells; (d) if MCI is indicated in step (c), determining the output signal of the diagnostic biomarker in step (b) after contacting cells from the subject with a compound for an initial time period and/or for an ongoing time period; and (e) comparing the output signal determined in step (d) to the output signal determined in step (b), wherein the test compound is indicated as useful for the treatment of MCI or the prevention of the clinical onset of AD
  • the present disclosure also includes a method of screening for a compound useful for treating MCI or preventing the clinical onset of AD dementia, comprising:
  • step (a) obtaining one or more cells from a non-AD, non-demented, non-MCI subject; (b) contacting the one or more cells with an A ⁇ peptide; (c) determining an output signal of one or more diagnostic biomarkers using the one or more cells contacted with the A ⁇ peptide, wherein the diagnostic biomarker is chosen from AD Index Biomarker, Morphometric Imaging Biomarker and PKC Epsilon Biomarker; (d) comparing the output signal determined in step (c) to output signals of the diagnostic biomarker for AC cells and for AD cells, wherein MCI is triggered in the subject by step (b) if the output signal determined in step (c) is less than the lowest output signal for the AD cells but greater than the highest output signal for the AC cells; (e) if MCI is indicated in step (d), determining the output signal of the diagnostic biomarker in step (c) after contacting cells from the subject with a compound for an initial time period and/or for an ongoing time period; and (f) comparing the
  • a method of evaluating or monitoring the therapeutic benefit of an agent for treating MCI or preventing the clinical onset of AD dementia in a subject comprises:
  • step (a) obtaining one or more cells from a subject; (b) determining an output signal of one or more diagnostic biomarkers using the one or more cells from the subject, wherein the diagnostic biomarker is chosen from AD Index Biomarker, Morphometric Imaging Biomarker and PKC Epsilon Biomarker; (c) comparing the output signal determined in step (b) to output signals of the diagnostic biomarker for AC cells and for AD cells, wherein MCI is indicated in the subject if the output signal determined in step (b) is less than the lowest output signal for the AD cells but greater than the highest output signal for the AC cells; (d) if MCI is indicated in step (c), determining the output signal of the diagnostic biomarker in step (b) using one or more cells from the subject after initial, ongoing, and/or cessation of treatment with an agent; and (e) comparing the output signal determined in step (d) to the output signal determined in step (b), wherein the agent is indicated as providing therapeutic benefit for treating MCI or preventing the clinical onset of AD dementia in
  • the output signals for AC cells and for AD cells as described herein may be determined at or around the same time as determining the output signal for the subject, or the output signals for AC cells and for AD cells may be determined ahead of time, for example, and maintained in a database for comparison to an output signal determined for a given subject.
  • the AC cells as described herein should be age-matched non-AD, non-MCI cells, i.e., should be obtained from an age-matched non-AD, non-MCI population.
  • the AC cells are age-matched non-AD, non-demented, non-MCI cells, i.e., should be obtained from an age-matched non-AD, non-demented, non-MCI population.
  • the methods described herein are performed using a subject who displays no phenotypic symptoms of AD, such as a subject who displays no phenotypic symptoms of AD, but has one or more risk factors for developing AD.
  • the output signals of the diagnostic biomarker for AC cells and AD cells that are compared to the output signal of the subject can be average output signals.
  • output signals, as well as the age differences and AD durations as described herein may be averaged within five-year age intervals resulting in an average output signal and average age difference for each five-year age interval. It will be apparent to those of ordinary skill in the art that other intervals may be applied.
  • the cells used to determine the output signals of the biomarkers described herein may be peripheral cells (i.e., cells obtained from non-CNS tissue), including, but not limited to fibroblast cells or blood cells.
  • the cells are skin fibroblast cells.
  • the cells are blood lymphocyte cells.
  • the “AD Index Biomarker” refers to an assay that measures the change in ratio of a phosphorylated first MAP kinase protein and a phosphorylated second MAP kinase protein when the cells are treated with an agent that is a protein kinase C (PKC) activator.
  • PKC protein kinase C
  • determining an output signal of the AD Index Biomarker comprises (i) contacting one or more cells from a subject with an agent that is a PKC activator; (ii) measuring the ratio of a phosphorylated first MAP kinase protein to a phosphorylated second MAP kinase protein, wherein the phosphorylated first and second MAP kinase proteins are obtained from the cells after the contacting in step (i); (iii) measuring the ratio of phosphorylated first MAP kinase protein to phosphorylated second MAP kinase protein in one or more cells from the subject that have not been contacted with the agent that is a PKC activator used in step (i); and (iv) subtracting the ratio obtained in step (iii) from the ratio obtained in step (ii).
  • the phosphorylated MAP kinase proteins may be sequence variants of each other and belong to the same family of proteins.
  • the phosphorylated first MAP kinase protein is phosphorylated Erk1 and the phosphorylated second MAP kinase protein is phosphorylated Erk2.
  • the AD Index assay is not limited to the use of any particular PKC activator.
  • the PKC activator is chosen from bradykinin, bryostatin, bryologs, neristatin, 8-[2-(2-pentyl-cyclopropylmethyl)cyclopropyl]-octanoic acid (DCPLA), and esters of DCPLA.
  • the bryostatin may be chosen from bryostatin-1, bryostatin-2, bryostatin-3, bryostatin-4, bryostatin-5, bryostatin-6, bryostatin-7, bryostatin-8, bryostatin-9, bryostatin-10, bryostatin-11, bryostatin-12, bryostatin-13, bryostatin-14, bryostatin-15, bryostatin-16, bryostatin-17, or bryostatin-18.
  • suitable PKC activators are disclosed in U.S. Patent Publication No. 2014/0315990, which is incorporated herein by reference.
  • the AD Index assay may be performed as described in those publications.
  • the PKC activator is bradykinin and the first and second MAP kinase proteins are Erk1 and Erk2, respectively.
  • determining an output signal of the Morphometric Imaging Biomarker comprises (i) culturing one or more cells from a subject for a time period sufficient to achieve cell aggregation; (ii) determining the average area of cell aggregates (A) and dividing the average area by the number of aggregates (N) to obtain the average area per number of aggregates (A/N); and (iii) calculating the natural logarithm of (A/N).
  • the one or more cells may be cultured in a cell media for growth, such as, for example, a protein mixture.
  • the protein mixture is a gelatinous protein mixture.
  • a non-limiting exemplary gelatinous protein mixture is MatrigelTM.
  • MatrigelTM is the trade name for a gelatinous protein mixture secreted by the Engelbreth-Holm-Swarm (EHS) mouse sarcoma cells and marketed by BD Biosciences. This mixture resembles the complex extracellular environment found in many tissues and is used by cell biologists as a substrate for cell culture.
  • determining an output signal of the PKC Epsilon Biomarker comprises (i) determining the PKC ⁇ level in one or more cells from a subject; (ii) contacting the one or more cells with an A ⁇ peptide; (iii) determining the PKC epsilon level in the one or more cells in step (ii) after the contacting step; and (iv) calculating the output signal as the ratio of the slope (S) and intercept (I), (S/I), of the change in PKC ⁇ level as a function of A ⁇ peptide concentration.
  • U.S. Patent Publication No. 2014/0038186 discloses A ⁇ peptides, contacting cells with an A ⁇ peptide, and determining PKC ⁇ levels and is incorporated herein by reference.
  • Biomarker Severity Score was investigated using the AD Index Biomarker, Morphometric Imaging Biomarker, and PKC Epsilon Biomarker.
  • the normalized output signals of the biomarkers were shown as a function of the age difference.
  • the age difference was between the age of harvesting for the skin biopsy and the clinical onset of the disease, which was a measure of the disease duration.
  • the current age was subtracted from the oldest age in the AC group and was plotted to the left of the AD onset (dotted vertical line in FIGS. 4A and 4B ).
  • the output signals for the PKC ⁇ and Morphometric Imaging Biomarkers, as well as the age differences as described herein, were averaged within five-year age intervals resulting in an average output signal and average age difference for each five-year age interval. For the AD Index Biomarker, this average was not necessary because of the abundance of patient data.
  • the output signals for the AC cells were plotted on the left of the disease onset (dotted vertical line in FIGS. 4A and 4B ).
  • the Severity Scores also significantly separated the outputs for AC and AD cells, leaving a gap (greater than 40%) in which Biomarker Severity Scores of MCI patients would fall, indicating that each of the biomarkers can detect the signature of AD several years before dementia onset, providing a predictive risk of progression to AD dementia. See, e.g., FIGS. 4A and 4B .
  • the output signals for the AD Index Biomarker were determined as the change in ratio of phosphorylated ERK 1 and ERK 2 when skin fibroblast cells were treated with bradykinin (BK+), and were quantified by the difference, (pERK 1 /pERK 2 ) BK+ -(pERK 1 /pERK 2 ) BK ⁇ as described in Khan et al., “An internally controlled peripheral biomarker for Alzheimer's disease: Erk1 and Erk2 responses to the inflammatory signal bradykinin,” Proc Natl Acad Sci 29;103(35), 13203-7 (2006), and Khan et al., “Early diagnostic accuracy and pathophysiologic relevance of an autopsy-confirmed Alzheimer's disease peripheral biomarker,” Neurobiol Aging, 31(6), 889-900 (2010), the methods of which are incorporated herein by reference. See also FIGS. 2A and 2B .
  • the output signals for the Morphometric Imaging Biomarker were determined by culturing the cells on a thick (1.8 mm) substrate of Matrigel for 48 hours and using image analysis software to determine (A/N), as described in Chirila et al., “Spatiotemporal Complexity of Fibroblast Networks Screens for Alzheimer's Disease,” J Alzheimer's Disease 33, 165-176 (2013) and Chirila et al., “Fibroblast aggregation rate converges with validated peripheral biomarkers for Alzheimer's disease,” J Alzheimer's Disease 42, 1279-94 (2014), the methods of which are incorporated herein by reference. See also FIG. 3A .
  • the output signals for the PKC Epsilon Biomarker were determined by measuring the change in PKC ⁇ when the cells were treated with spherical aggregates of ⁇ -amyloid Amylospheroids (ASPD), and were quantified by the ratio of the slope (S) and Intercept (I), S/I, as described in Khan et al., “PKC ⁇ Deficits in Alzheimer's Disease Brains and Skin Fibroblasts,” Journal of Alzheimer's Disease, 2015;43(2):491-509, the methods of which are incorporated herein by reference. See also FIG. 3B .
  • both the Morphometric Imaging Biomarker ( FIG. 4A ) and the PKC Epsilon Biomarker ( FIG. 4B ) showed slight changes with the age difference for the AC group as well as a significant gap of >40% between the AC and AD outputs.
  • the Morphometric Imaging Biomarker showed a slight increase with the age difference, while the PKC Epsilon a slight decrease for the AC group (AC fit lines in FIGS. 4A and 4B ).
  • the Severity Scores for both biomarkers for the AC group was below 15% and was almost flat for the age differences studied. A saturation toward the lower limit as the age difference became more negative was also expected for the AC group. Therefore, the linear approximation was only a first approximation and a potentially improved approximation was a sigmoidal/logistic function which saturated for the lower limit.
  • FIGS. 6A-6C A potentially improved approximation for the location of the MCI patients group was assumed to follow the logistic function ( FIGS. 6A-6C ).
  • the intersection of the logistic functions with the ⁇ 15% Severity Score gave an estimate of the time in advance of the clinical onset for which the biomarkers can detect an MCI patient (horizontal arrows in FIGS. 6A-6C ).
  • the Morphometric Imaging Biomarker detected MCI patients ⁇ 4 years before the clinical onset ( FIG. 6A )
  • the PKC Epsilon Biomarker detected MCI patients ⁇ 5 years before clinical onset ( FIG. 6B ).
  • the Cut-Off line which was determined as the intersection of the logistic fit curve with the AD onset vertical line was the same for both of those biomarkers, i.e. ⁇ 45%.
  • the location of the MCI patients were in the gap between AC and AD patients and likely followed a logistic type curve.
  • the AC group should be at some distance to the left of the AD onset vertical line.
  • the AD group should show an upper limit and therefore a saturation of the signal.
  • FIG. 7A The remarkable overlap of the biomarkers in their normalized form of the Severity Score is represented by the logistic fit functions in FIG. 7A .
  • the inflection points determined as the intersection between the AD onset line and the logistic curves were practically the same for the Morphometric Imaging and PKC Epsilon Biomarkers.
  • FIG. 7B also shows the significant overlap for the average for the total number of synapses in the outer molecular layer of the hippocampal dentate gyms and the average MMSE score for the three populations, AC, MCI, and AD.
  • FIGS. 7A and 7B indicate that the three biomarkers track synaptic loss.
  • the output signals of the three biomarkers were not noise free. Noise can arise from the measurement methods, instruments, or human manipulation. Ranking the output signals of the biomarkers for the AC and AD groups alleviated noise and produced similar results as the “age difference” approach, as shown in FIGS. 8A-8D . The ranking of the output signal for the three biomarkers showed the same gap between the AD and AC groups for the MCI patients and the logistic dependence was more evident in this representation ( FIGS. 8A-8D ).

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US11415574B2 (en) 2017-03-31 2022-08-16 NeuroDiagnostics LLC Lymphocyte-based morphometric test for alzheimer's disease

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US11415574B2 (en) 2017-03-31 2022-08-16 NeuroDiagnostics LLC Lymphocyte-based morphometric test for alzheimer's disease
US20210090746A1 (en) * 2019-09-24 2021-03-25 International Business Machines Corporation Machine learning for amyloid and tau pathology prediction
US11621087B2 (en) * 2019-09-24 2023-04-04 International Business Machines Corporation Machine learning for amyloid and tau pathology prediction

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