Methods of determining a treatment protocol for and/or a prognosis of a patient's recovery from a brain injury
Inventors
Wilson, David • Zetterberg, John Henrik • Blennow, Kaj • Randall, Jeffrey D.
Assignees
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Publication Number
US-11275092-B2
Publication Date
2022-03-15
Expiration Date
Abstract
The present invention, in some embodiments, generally relates to methods of determining a treatment protocol for and/or a prognosis of a patient's recovery from a brain injury. In some embodiments, the brain injury results from a hypoxic event. In some embodiments, methods are provided for determining a measure of the concentration of tau protein in a patient sample containing or suspected of containing tau protein.
Core Innovation
The disclosed subject matter provides methods to determine a treatment protocol and/or prognosis for recovery after brain injury, including hypoxic events, by using highly sensitive peripheral tau protein measurements in blood, plasma, or serum. The approach centers on producing a bodily fluid sample containing an analytically quantified amount of endogenous tau protein and quantifying tau protein concentration with an analytical protein concentration measurement assay at very low concentration levels.
The disclosure links serial serum tau kinetics after cardiac arrest to neurological outcome, including bimodal release kinetics. Tau time-course parameters derived from serial measurements, including total area under the curve and secondary-peak area under the curve, are described as predictive for good versus poor outcomes based on Cerebral Performance Category scoring.
A key technical aspect is the use of an ultra-sensitive digital immunoassay format to extend analytical performance beyond conventional ELISA for detecting tau protein at extremely low levels. The assay framework includes highly sensitive protein concentration measurement with very low limit of detection and limit of quantification, and digital quantification enabled by femtoliter single-molecule array and digital imaging concepts with spatially resolved locations and statistical evaluation consistent with single-molecule presence versus absence.
Claims Coverage
The independent claim covers a method of producing a bodily fluid sample from a patient suspected of a neurological condition, where the method includes obtaining blood, plasma, or serum, diluting the volume, and quantifying endogenous tau protein using an analytical protein concentration measurement assay under stringent concentration and assay performance limits. The dependent claims refine the assay workflow, spatial segregation for single-molecule statistics, and constraints on detection sensitivity, tau isoform selection, and patient/time context.
Quantified endogenous tau in diluted blood, plasma, or serum
A method of producing a bodily fluid sample of a patient suspected of having a neurological condition containing an analytically quantified amount of endogenous tau protein, comprising obtaining blood or a blood component selected from plasma and serum, diluting the volume of bodily fluid, and quantifying through an analytical protein concentration measurement assay a concentration of tau protein in the volume of bodily fluid to produce the bodily fluid sample containing the analytically quantified amount of endogenous tau protein.
Low tau concentration and assay limit of quantification thresholds
The analytically quantified concentration of endogenous tau protein contained in the bodily fluid sample is less than about 5 pg/ml, and a limit of quantification of the analytical protein concentration measurement assay used for quantifying the concentration of tau protein is less than about 0.2 pg/mL.
Affinity capture objects with interrogation to determine tau concentration
The analytical protein concentration measurement assay suspends tau-protein-affinity capture objects in diluted bodily fluid, immobilizes tau molecules on the capture objects, interrogates associated capture objects, and determines a measure of tau protein molecule concentration based on the interrogation.
Single-molecule spatial segregation for concentration measurement statistics
The analytical protein concentration measurement assay analyzes tau protein by spatially separating tau molecules into multiple locations so that some locations contain single molecules and others contain none, with statistically significant fractions.
Assay sensitivity with limit of detection threshold
A limit of detection for the analytical protein concentration measurement assay is less than about 0.02 pg/mL.
Selected tau isoforms for the quantified endogenous tau
Each quantified tau protein molecule is selected from the group consisting of tau 23, tau 2.4, tau 37, tau 34, tau 39, and tau 40.
Post-brain-injury sample collection timing constraint
The method includes collecting a patient's bodily fluid within 12 hours after a brain injury.
Across the independent method and its refinements, the coverage centers on producing a diluted blood, plasma, or serum sample and quantifying endogenous tau at very low concentrations using an analytical protein concentration measurement assay with stringent concentration and quantification limits. Dependent refinements emphasize an ultra-sensitive digital immunoassay approach using affinity capture objects and interrogation with spatially segregated locations supporting single-molecule statistics, along with constraints on limit of detection, selected tau isoforms, and bodily fluid collection timing after brain injury.
Stated Advantages
The assay extends analytical performance beyond conventional ELISA for detecting tau protein at extremely low levels.
The methods are described as useful to determine a treatment protocol and/or prognosis for recovery after brain injury, including hypoxic events.
Serial tau time-course parameters are described as predictive for good versus poor outcomes based on Cerebral Performance Category scoring.
Documented Applications
Determining a treatment protocol and/or prognosis for recovery after brain injury, including hypoxic events.
Serial serum tau kinetics after cardiac arrest for neurological outcome assessment.
Prediction of good versus poor outcomes based on Cerebral Performance Category scoring.
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