WO2014151573A1

WO2014151573A1 - Method for detecting amyloid beta plaques and drusen

Info

Publication number: WO2014151573A1
Application number: PCT/US2014/026023
Authority: WO
Inventors: Steven Verdooner; David Biggs; Austin BLANCO
Original assignee: Steven Verdooner; David Biggs; Blanco Austin
Priority date: 2013-03-15
Filing date: 2014-03-13
Publication date: 2014-09-25
Also published as: EP2967327A4; US9566000B2; EP2967327A1; US20140268052A1; JP2016512712A

Abstract

A method for detecting amyloid beta plaques and drusen is disclosed. The method for detecting amyloid beta plaques and drusen may include applying a combination of optical retro mode illumination techniques to acquire a plurality of amyloid beta plaques and drusen images that are too small to be seen with other imaging modalities. The amyloid beta plaques and drusen images may also be detected with a non-transitory computer storage media having instructions stored thereon which, when executed, execute the method for detecting amyloid beta plaques and drusen. The method may track changes in plaque, size, area and density of the amyloid beta plaques and drusen over a predetermined period of time.

Description

METHOD FOR DETECTING AMYLOID BETA PLAQUES AND DRUSEN

This application claims priority to U.S. Provisional Application

61 /800,882 filed on 03/15/2013, the entire disclosure of which is incorporated by reference.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION:

The present invention is a method for detecting. More specifically, the present invention is a method for detecting amyloid beta plaques and drusen.

DESCRIPTION OF THE RELATED ART:

Drusen are early fundus changes characteristic of age-related

maculopathy. Early detection of maculopathy and also Alzheimer's disease with amyloid beta or AB plaques is vitally important to early intervention and treatment. Conventional fundus photography is widely utilized in imaging and detecting drusen. There currently is no method for AB plaque detection except with the utilization of specialized dye and other contrast agents.

Optical coherence tomography or OCT is also an imaging technique that is utilized whereby retinal structures may be viewed in cross-section. Relatively larger drusen are visible in OCT images as elevations of retinal pigment epithelium or RPE. The utilization of infrared imaging is much more comfortable and advantageous in elderly patients with lens opacities, since light is scattered relatively much less in the presence of media opacities. Retro-mode imaging in a

l confocal scanning laser ophthalmoscope or SLO is utilized to image the retina with an infrared laser. It is based on indirect mode imaging of a SLO.

BRIEF SUMMARY OF THE INVENTION

The method for detecting amyloid beta plaques and drusen may include means for imaging a plurality of frames of multiple views of a central portion and a peripheral portion of the patient user's retina, means for aligning and combining the frames utilizing one or more super-resolution techniques, means for monitoring the aligned and combined frames and means for quantifying changes in the monitored, aligned and combined frames.

The method for detecting amyloid beta plaques and drusen may include the steps of utilizing an annual aperture with a central stop that deviates laterally from a confocal light path, blocking directly reflected light from a fundus with only laterally scattered light passing through the annular aperture, thereby imaging the one or more amyloid beta plaques and drusen, identifying the imaged one or more amyloid beta plaques and drusen in a retinal structure and a pathology, applying a combination of optical retro mode illumination techniques to the imaged one or more amyloid beta plaques and drusen and detecting the imaged one or more amyloid beta plaques and drusen that are too small to be seen with other imaging modalities.

A non-transitory computer storage media having instructions stored thereon which, when executed, execute a method for detecting amyloid beta plaques and drusen may include the steps of utilizing an annual aperture with a central stop that deviates laterally from a confocal light path, blocking directly reflected light from a fundus with only laterally scattered light passing through the annular aperture, thereby imaging the one or more amyloid beta plaques and drusen, identifying the imaged one or more amyloid beta plaques and drusen in a retinal structure and a pathology, applying a combination of optical retro mode illumination techniques to the imaged one or more amyloid beta plaques and drusen and detecting the imaged one or more amyloid beta plaques and drusen that are too small to be seen with other imaging modalities.

It is an object of the present invention to provide a method for detecting amyloid beta plaques and drusen that may detect relatively smaller amyloid beta plaques than conventional detection methods.

It is an object of the present invention to provide a method for detecting amyloid beta plaques and drusen that may utilize a combination of optical retro mode illumination techniques utilizing a confocal laser scanning ophthalmoscope and one or more super-resolution image processing techniques to detect one or more plaques at an early stage of pathology.

It is an object of the present invention to provide a method for detecting amyloid beta plaques and drusen that detect pathologies such as dry macular degeneration and Alzheimer's disease.

It is an object of the present invention to provide a method for detecting amyloid beta plaques and drusen that tracks changes in a pathology that includes changes in plaque, size, area and density over time.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be described by way of exemplary embodiments, but not limitations, illustrated in the accompanying drawing in which like references denote similar elements, and in which:

FIG. 1 illustrates a flowchart of a first method for detecting amyloid beta plaques and drusen, in accordance with one embodiment of the present invention.

FIG. 2 illustrates a flowchart of a second method for detecting amyloid beta plaques and drusen, in accordance with one embodiment of the present invention.

FIG. 3 illustrates a flowchart of a method for detecting amyloid beta plaques and drusen by a non-transitory computer storage media having instructions stored thereon which, when executed, execute the method, in accordance with one embodiment of the present invention.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Various aspects of the illustrative embodiments will be described using terms commonly employed by those skilled in the art to convey the substance of their work to others skilled in the art. However, it will be apparent to those skilled in the art that the present invention may be practiced with only some of the described aspects. For purposes of explanation, specific numbers, materials and configurations are set forth in order to provide a thorough understanding of the illustrative embodiments. However, it will be apparent to one skilled in the art that the present invention may be practiced without the specific details. In other instances, well-known features are omitted or simplified in order not to obscure the illustrative embodiments. Various operations will be described as multiple discrete operations, in turn, in a manner that is most helpful in understanding the present invention. However, the order of description should not be construed as to imply that these operations are necessarily order dependent. In particular, these

operations need not be performed in the order of presentation.

The phrase "in one embodiment" is used repeatedly. The phrase generally does not refer to the same embodiment, however, it may. The terms "comprising", "having" and "including" are synonymous, unless the context dictates otherwise.

While the present invention has been related in terms of the foregoing embodiments, those skilled in the art will recognize that the invention is not limited to the embodiments described. The present invention may be

practiced with modification and alteration within the spirit and scope of the appended claims. Thus, the description is to be regarded as illustrative instead of restrictive on the present invention.

FIG. 1 illustrates a flowchart of a first method 1 00 for detecting amyloid beta plaques and drusen, in accordance with one embodiment of the present invention.

The overall first method 100 may include means for imaging a plurality of frames of multiple views of a central portion and a peripheral portion of the patient user's retina 1 10, means for aligning and combining the frames utilizing one or more super-resolution techniques 120, means for monitoring the aligned and combined frames 130 and means for quantifying changes in the monitored, aligned and combined frames 140. The means for imaging 1 10 may utilize an optical coherence tomography or OCT imaging technique that is utilized whereby retinal structures may be viewed in cross-section. The means for aligning and combining 120 may utilize a combination of optical retro mode illumination techniques utilizing a confocal laser scanning ophthalmoscope and one or more super-resolution image processing techniques. The means for monitoring the aligned and combined frames 130 may be performed by a non-transitory storage media that receives the retinal structures viewed in cross-section from the optical coherence tomography imaging technique and confocal laser scanning ophthalmoscope and one or more super-resolution image processing techniques. The non-transitory storage media may be executed by a processor and a memory system. The means for quantifying 140 may also be performed by the non-transitory storage media.

FIG. 2 illustrates a flowchart of a second method 200 for detecting amyloid beta plaques and drusen, in accordance with one embodiment of the present invention.

The second method 200 may include the steps of utilizing an annual aperture with a central stop that deviates laterally from a confocal light path 210, blocking directly reflected light from a fundus with only laterally scattered light passing through the annular aperture, thereby imaging the one or more amyloid beta plaques and drusen 220, identifying the imaged one or more amyloid beta plaques and drusen in a retinal structure and a pathology 230, applying a combination of optical retro mode illumination techniques to the imaged one or more amyloid beta plaques and drusen 240 and detecting the imaged one or more amyloid beta plaques and drusen that are too small to be seen with other imaging modalities 250.

The utilizing step 210 may include utilizing an optical coherence

tomography or OCT imaging technique that is utilized whereby retinal structures may be viewed in cross-section. The blocking step 220 may include utilizing an optical coherence tomography or OCT imaging technique that is utilized whereby retinal structures may be viewed in cross-section. The identifying step 230 may include the pathology that is Alzheimer's disease or the pathology that is dry macular degeneration. The applying step 240 may include the optical retro mode illumination techniques that may include a confocal laser scanning

ophthalmoscope and one or more super-resolution image processing techniques. The one or more super-resolution image processing techniques may be multi- image super-resolution image processing techniques. The detecting step 250 may include tracking changes in the pathology over a predetermined period time. The tracking changes may include plaque, size, area and density over the

predetermined period of time.

FIG. 3 illustrates a flowchart of a method 300 for detecting amyloid beta plaques and drusen by a non-transitory computer storage media having instructions stored thereon which, when executed, execute the method 300, in accordance with one embodiment of the present invention.

The non-transitory computer storage media may include the steps of utilizing an annual aperture with a central stop that deviates laterally from a confocal light path 310, blocking directly reflected light from a fundus with only laterally scattered light passing through the annular aperture, thereby imaging the one or more amyloid beta plaques and drusen 320, identifying the imaged one or more amyloid beta plaques and drusen in a retinal structure and a pathology 330, applying a combination of optical retro mode illumination techniques to the imaged one or more amyloid beta plaques and drusen 340 and detecting the imaged one or more amyloid beta plaques and drusen that are too small to be seen with other imaging modalities 350.

The utilizing step 310 may include utilizing an optical coherence

tomography or OCT imaging technique that is utilized whereby retinal structures may be viewed in cross-section. The blocking step 320 may include utilizing an optical coherence tomography or OCT imaging technique that is utilized whereby retinal structures may be viewed in cross-section. The identifying step 330 may include the pathology that is Alzheimer's disease or the pathology that is dry macular degeneration. The applying step 340 may include the optical retro mode illumination techniques that may include a confocal laser scanning

ophthalmoscope and one or more super-resolution image processing techniques. The one or more super-resolution image processing techniques may be multi- image super-resolution image processing techniques. The detecting step 350 may include tracking changes in the pathology over a predetermined period time. The tracking changes may include plaque, size, area and density over the

predetermined period of time.

The method for detecting amyloid beta plaques and drusen may utilize an annular aperture with a central stop that deviates laterally from a confocal light path. Directly reflected light emitted towards a fundus may be blocked by a central stop with only scattered light passing through the annular aperture. Laterally scattered light may be sampled more than light in a direct mode. Retinal structures and pathology may be detected with the only laterally scattered light. Drusen and AB plaques may be imaged with this technique due to increase in scatter. While the method may be helpful in detection of large plaques, the combination of the method with super-resolution and other image processing and analysis techniques may yield a method that may detect relatively much smaller plaques at relatively earlier stages of pathology and may also be tracked over time. Amyloid beta plaque and drusen may be identified in a retinal structure however identification of the deposits at relatively earlier stages of disease and of a relatively small size is impossible with existing retinal imaging technology. This problem may be solved through a combination of optical retro mode illumination techniques utilizing a confocal laser scanning ophthalmoscope in combination with super-resolution image processing techniques that detect relatively very small plaques that are too small to be seen with other imaging modalities. Utilizing retro mode imaging alone does yield some imaging of drusen, AB plaques and other deposits that are relatively small in size but do not reliably image relatively small to very small plaques. Multi-image super-resolution techniques may record a series of images and then combine a data set from the series of images to produce images of relatively greatly improved resolution and image quality thereby resolving the relatively smallest plaques at the relatively earliest stages of disease. Furthermore, tracking changes in plaque, size, area and density over a predetermined period of time is likely an indicator of advancing disease and rate of advancing disease. These aspects have never been previously studied. Multiple images may be acquired utilizing each of the retro-mode

illumination techniques. These images may be transferred to a software or non- transitory storage media to co-registers each of the images. The non-transitory storage media may process the images to increase contrast where intensity shifts occur. The non-transitory storage media may increase a signal by subtracting noise. The subtracted noise may be accomplished by referencing numerous modal images and producing a result where the noise or artifact error from each type of retro mode is removed leaving only the combined signal structures from each retro mode image. The resulting super resolution image may be relatively highly improved over each individual retro mode image and by reducing the signal and building the noise in the individual retro mode image, higher detection sensitivity may be achieved in the final image. A high bit depth final image of approximately eight bits or more may be produced which may be analyzed utilizing conventional methods.

In another embodiment fluorescent emission images may be combined with retro-mode images to produce a co-located detection matrix.

In another embodiment, standard confocal infrared or IR images may be combined with retro-mode images to produce a higher sensitivity traditional confocal image or to produce a hyper-contrast combination image.

In another embodiment, an annual aperture utilized in the retromode may be replaced with a slit, grid, holographic interference image or coded aperture to further increase detection of traditionally sub-resolvable spots.

In another embodiment, multiple focal planes may be acquired and combined, to produce a three-dimensional render of the detected spots. In another embodiment the aperture position may be stepped in the optical path, to alter its interaction with the reflected or emitted light from a subject.

In another embodiment the method may be utilized for a variety of imaging procedures including color fundus imaging, fluorescein angiography, I ndocyanine Green or ICG angiography, red-free, infrared or IR retro-illumination, hyper spectral and multi-spectral imaging, and devices that are utilized in combination with OCT.

The method for detecting amyloid beta plaques and drusen will be utilized for the detection and advancement of dry macular degeneration and

Alzheimer's disease. The method includes imaging a plurality of frames of multiple views of a central portion and a peripheral portion of a patient user's retina, aligning and combining the frames utilizing one or more super-resolution techniques, monitoring the aligned and combined frames and quantifying changes in the monitored, aligned and combined frames. The changes in the aligned and combined frames may be tracked over a predetermined period of time such as a day, a week, a month, a year or other suitable predetermined period of time.

Claims

1 . A method for detecting one or more amyloid beta plaques and drusen in a patient user's retina, comprising:

means for imaging a plurality of frames of multiple views of a central portion and a peripheral portion of the patient user's retina;

means for aligning and combining the frames utilizing one or more super-resolution techniques;

means for monitoring the aligned and combined frames; and means for quantifying changes in the monitored, aligned and combined frames.

2. The method according to claim 1 , wherein the means for imaging utilizes an optical coherence tomography imaging technique.

3. The method according to claim 1 , wherein the means for aligning and combining utilizes a combination of one or more optical retro mode illumination techniques and one or more super-resolution image processing techniques.

4. The method according to claim 3, wherein the combination of one or more optical retro mode illumination techniques and one or more super-resolution image processing techniques utilizes a confocal laser scanning ophthalmoscope.

5. The method according to claim 1 , wherein the means for monitoring and the means for quantifying is performed by a non-transitory storage media, a processor and a memory system.

6. The method according to claim 1 , wherein the method detects Alzheimer's disease and dry macular degeneration.

7. A method for detecting one or more amyloid beta plaques and drusen, comprising the steps of:

utilizing an annular aperture with a central stop that deviates laterally from a confocal light path;

blocking directly reflected light from a fundus with only laterally scattered light passing through the annular aperture, thereby imaging the one or more amyloid beta plaques and drusen;

identifying the imaged one or more amyloid beta plaques and drusen in a retinal structure and pathology;

applying a combination of optical retro mode illumination techniques to the imaged one or more amyloid beta plaques and drusen; and

detecting the imaged one or more amyloid beta plaques and drusen that are too small to be seen with other imaging modalities.

8. The method according to claim 7, wherein the pathology is Alzheimer's disease.

9. The method according to claim 7, wherein the pathology is dry macular degeneration.

10. The method according to claim 7, wherein the optical retro mode

illumination techniques includes a confocal laser scanning ophthalmoscope and one or more super-resolution image processing techniques.

1 1 . The method according to claim 10, wherein the one or more super- resolution image processing techniques are multi-image super-resolution image processing techniques.

12. The method according to claim 7, wherein the method tracks changes in the pathology over a predetermined period time.

13. The method according to claim 12, wherein changes include tracking changes in plaque, size, area and density over the predetermined period of time.

14. A non-transitory computer storage media having instructions stored thereon which, when executed, execute a method comprising the steps of:

utilizing an annual aperture with a central stop that deviates laterally from a confocal light path;

applying a combination of optical retro mode illumination techniques to the imaged one or more amyloid beta plaques and drusen; and detecting the imaged one or more amyloid beta plaques and drusen that are too small to be seen with other imaging modalities.

15. The non-transitory computer storage media according to claim 14, wherein the pathology is Alzheimer's disease.

16. The non-transitory computer storage media according to claim 14, wherein the pathology is dry macular degeneration.

17. The non-transitory computer storage media according to claim 14, wherein the optical retro mode illumination techniques include a confocal laser scanning ophthalmoscope and one or more super-resolution image processing techniques.

18. The non-transitory computer storage media according to claim 17, wherein the one or more super-resolution image processing techniques are multi-image super-resolution image processing techniques.

19. The non-transitory computer storage media according to claim 14, wherein the method tracks changes in the pathology over a predetermined period time.

20. The non-transitory computer storage media according to claim 19, wherein changes include tracking changes in plaque, size, area and density over the predetermined period of time.