Assessing blood brain barrier dynamics or identifying or measuring selected substances or toxins in a subject by analyzing raman spectrum signals of selected regions in the eye
First Claim
1. An in vivo method for monitoring the blood brain barrier dynamics of a subject, comprising the step of:
- obtaining a Raman spectrum of a selected region in the eye of the subject; and
monitoring the dynamics of the blood brain barrier of the subject based on said obtaining step.
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Accused Products
Abstract
A non-invasive method for analyzing the blood-brain barrier includes obtaining a Raman spectrum of a selected portion of the eye and monitoring the Raman spectrum to ascertain a change to the dynamics of the blood brain barrier.
Also, non-invasive methods for determining the brain or blood level of an analyte of interest, such as glucose, drugs, alcohol, poisons, and the like, comprises: generating an excitation laser beam (e.g., at a wavelength of 600 to 900 nanometers); focusing the excitation laser beam into the anterior chamber of an eye of the subject so that aqueous humor, vitreous humor, or one or more conjunctiva vessels in the eye is illuminated; detecting (preferably confocally detecting) a Raman spectrum from the illuminated portion of the eye; and then determining the blood level or brain level (intracranial or cerebral spinal fluid level) of an analyte of interest for the subject from the Raman spectrum. In certain embodiments, the detecting step may be followed by the step of subtracting a confounding fluorescence spectrum from the Raman spectrum to produce a difference spectrum; and determining the blood level and/or brain level of the analyte of interest for the subject from that difference spectrum, preferably using linear or nonlinear multivariate analysis such as partial least squares analysis. Apparatus for carrying out the foregoing methods are also disclosed.
65 Citations
60 Claims
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1. An in vivo method for monitoring the blood brain barrier dynamics of a subject, comprising the step of:
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obtaining a Raman spectrum of a selected region in the eye of the subject; and
monitoring the dynamics of the blood brain barrier of the subject based on said obtaining step. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)
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15. A method of non-invasively monitoring the blood brain barrier of a subject, comprising the steps of:
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generating an excitation beam at a wavelength of from about 600 to 900 nanometers;
focusing the excitation beam of said generating step into the eye of the subject so that a selected region is illuminated;
detecting a Raman spectrum corresponding to the illuminated region; and
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16. A method according to
claim 16 , wherein said method is carried out during drug trials to assess the impact of the drug on the dynamics of the blood brain barrier of the subject.
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17. A method according to
claim 17 , wherein said method is carried out when the brain of the subject has been exposed to a trauma injury to determine whether there is an alteration of the dynamics of the blood brain barrier.
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18. A method for identifying an alteration in the blood brain barrier of a biological subject, comprising the steps of:
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non-invasively obtaining a first in vivo Raman spectrum of the aqueous humor of the subject;
non-invasively obtaining a second in vivo Raman spectrum of the aqueous humor of the subject; and
comparing the first and second Raman spectrums to detect an alteration in the function of the blood brain barrier.
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19. A method for identifying an alteration or abnormality in the blood brain barrier of a biological subject, comprising the steps of:
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non-invasively obtaining a first in vivo Raman spectrum of the aqueous humor of the subject;
obtaining a reference spectrum of an in vitro sample representing the aqueous humor and comprising at least one selected analyte; and
comparing the in vivo Raman spectrum to the reference spectrum to detect the presence of at least one selected analyte in the aqueous humor thereby identifying an abnormality in the blood brain barrier.
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21. A computer program product for determining the identity of an unknown substance in a subject, the computer program product comprising:
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a computer readable storage medium having computer readable program code embodied in said medium, said computer-readable program code comprising;
computer readable program code for defining at least one signature reference spectrum for at least one selected substance of interest; and
computer readable program code for analyzing an in vivo obtained Raman spectrum of the aqueous humor of the subject; and
computer readable program code for comparing selected characteristics between the reference spectrum and the in vivo spectrum to evaluate whether the in vivo Raman spectrum corresponds to at least one of the at lest one signature reference spectra.
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27. A non-invasive method for determining the alcohol level in a subject, comprising the steps of:
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generating an excitation beam at a wavelength of from 600 to 900 nanometers;
focusing the excitation beam of said generating step into the anterior chamber of an eye of the subject so that aqueous humor in the anterior chamber is illuminated;
detecting a Raman spectrum corresponding to the illuminated aqueous humor;
comparing the Raman spectrum from said detecting step to reference spectrums corresponding to different concentrations of alcohol; and
assessing the blood or brain alcohol level in the subject based on said detecting and comparing steps.
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28. A non-invasive method for identifying an unknown poison in a subject, comprising the steps of:
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generating an excitation beam at a wavelength of from 600 to 900 nanometers;
focusing the excitation beam of said generating step into a selected region in the eye of the subject so that the selected region is illuminated;
detecting a Raman spectrum corresponding to the illuminated selected region;
comparing the Raman spectrum from said detecting step to reference spectrums corresponding to different concentrations of a plurality of different substances; and
identifying the unknown substance in the subject based on said detecting and comparing steps. - View Dependent Claims (22, 23)
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30. A method for non-invasively directly measuring the blood level of a substance of interest in a subject, comprising the steps of:
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obtaining a plurality of reference Raman spectrums of varying concentrations of at least one analyte of interest;
generating an excitation beam at a wavelength of from 600 to 900 nanometers;
focusing the excitation beam of said generating step into at least one conjunctiva vessel in the eye of the subject so that the vessel is illuminated;
detecting a Raman spectrum corresponding to the illuminated vessel;
comparing the Raman spectrum from said detecting step to the reference spectrums; and
determining the blood level of the at least one analyte based on said detecting and comparing steps.
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41. A method according to
claim 41 , wherein said reference spectra for each analyte of interest comprises spectra generated from a Raman spectra training set comprising at least 10 in vitro aqueous humor samples for each analyte of interest with each of the at least 10 samples including different amounts of the analyte therein, and an analyte level corresponding to each of the samples.
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42. An apparatus for the non-invasive determination of a blood level of an analyte of interest in a subject, comprising:
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a light source for generating an excitation beam;
an optical system operatively associated with said laser for directing said excitation beam into the eye of said subject so that a selected region in the eye is sufficiently illuminated to generate a detectable Raman spectrum thereof;
a detector operatively associated with said optical system and configured to detect a Raman spectrum from the selected region in the eye;
a system processor operably associated with said detector and including computer programs with computer program code for comparing the detected Raman spectrum signal to reference spectrums associated with at least one analyte of interest to identify the presence or absence of at least one analyte of interest in the subject;
a housing configured to overlie at least one eye of a subject during use and to house said optical system and said detector therein, so that, in position, the optical system is spaced apart from the eye of the subject; and
a focus adjustment unit including a visual display adapted to display visual indicia thereon, mounted in said housing so that, in operation, the visual indicia on said display is visible to a user to allow a user to look at a visual reference presented thereon to allow the visual indicia to be focused so that the excitation beam can be directed to the appropriate location in the eye of the subject and so that said detector can detect the generated Raman spectrum.
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49. A method according to
claim 49 , wherein said optical system is configured to illuminate at least one blood vessel in the conjunctiva of the eye.
- 60. An apparatus according to claim 66, wherein said housing is configured and sized to be a hand held device.
Specification