Abstract:
The objective of the present method and apparatus is to provide a portable diagnosis system for a quick and reliable method to examine the conditions of a human eye-lens. The method provides precise and safe technique for the early diagnosis of Alzheimer&#39;s Disease (AD) which is not involved brain surgery or biopsy. The detection of deposited layers of amyloid plaque in the eyes of the patient has been discovered to be a possible diagnosis solution. The disclosed method uses terahertz waves instead of laser for scanning the eye of the AD patient to precisely image the amyloid layer non-evasively in real time and to map the deposited plaque with high resolution which can easily distinguish the abnormality of an AD patient with the comparison of the patient eye-lens test to the available signature of a normal person and the signature of a person with common age-related cataracts.

Description:
FIELD OF THE DISCLOSED METHOD AND APPARATUS 
   This method and apparatus is related to non-invasively detecting early development of Alzheimer by scanning patient eye and, in particular, relates to a method and apparatus for diagnosis and tomography using Terahertz imaging. 
   BACKGROUND OF PRIOR ARTS 
   Alzheimer&#39;s disease (AD) in a medical term is classified as a form of dementia, a group of conditions that gradually destroy brain cells. Alzheimer&#39;s generally appears in older persons, continuing steadily to disorder brain and gradually destroys a person&#39;s memory and ability to make judgments, communicate and carry out daily activities. Scientists now believe that the cause of AD is most likely due to the concentration of Beta-amyloid deposited in some part of the brain. As Alzheimer&#39;s progresses, patients may also experience changes in behavior during their personal lives, such as anger, agitation and sometimes even delusions or hallucinations. 
   There is not a cure and/or successful treatment for Alzheimer&#39;s. All the reported treatment methods do not show a light at the end of the tunnel. The results of the reported treatments are mostly either based on exercise, body treatment, or based on some herbal remedies and dietary supplements. One promising treatment reported by scientists at the University of South Florida promoting the most potent antioxidant EGCG (epigallocatechin-3-gallate), which is found in green tea. Scientists discovered if they treated the Alzheimer&#39;s patients with concentrated EGCG, it will reduce noticeable amount of their Beta-amyloid deposited in brain. 
   During the past few years, several breakthroughs for AD have been reported where all these breakthroughs are only effective on the early stages of Alzheimer&#39;s. Researchers from Rush University Medical Center in Chicago are working in gene transfer using very thin needles; inject the drug into the area of brain that deteriorates very early on Alzheimer&#39;s. This techniques and other similar methods are only promising if Alzheimer&#39;s has been detected at its early development. 
   If the patient is treated at the early stage of disease, the patient can have a relatively good life style even though he/she is not totally cured. Therefore, the diagnosis and early detection of Alzheimer&#39;s is highly desirable and it is in the world&#39;s interest. Many methods and suggestions are reported during the past decade in literatures and patent disclosures for Alzheimer&#39;s detection and diagnosis. Presently, there are no simple methods like blood or urine test that can detect Alzheimer&#39;s. 
   In the following there are several prior art methods presently used for early detection of Alzheimer&#39;s:
         1. Testing the patient&#39;s memory by asking questions and studying the patient&#39;s family history to determine if Alzheimer&#39;s is present. This is not very reliable technique and it mostly is done by a family doctor as initial warning for Alzheimer&#39;s.   2. Brain scanning by such techniques as CT (computed tomography) and MRI (magnetic resonance imaging) could be used for AD diagnosis. The problem of these techniques is that they are only effective at the late stages of Alzheimer&#39;s which the damage is already done.   3. Researchers at New York University Medical Center have reported EEG (electroencephalogram) testing that measures electrical activity in the brain to pinpoint the early signs of Alzheimer&#39;s as warning signal. In this method, the measured brain activity of patient is compared to a standard activity of a patient with no Alzheimer&#39;s disease. This method still is at initial study stage and according to the scientists at Alzheimer&#39;s Association, there is concern that EGG study is too limited and the findings are too preliminary.   4. Researchers in the Netherlands reported that they can predict the early detection of Alzheimer&#39;s by measuring the size of two parts of the brain, the hippocampus, and amygdala. For those patients who have smaller sizes of these two parts against some standard have several time more likely to suffer from the Alzheimer&#39;s decease. The technique is still at study stage and mostly is looking for any type of dementia; they are not focusing on Alzheimer&#39;s. Another drawback of this technique is direct scanning of the brain which is likely harmful to patient.   5. There is a new technique recently reported by several institutes including Hazard Medical School and Brigham and Women&#39;s Hospital in Boston. The technique is detecting early phases of Alzheimer&#39;s disease by measuring the level of Beta-amyloid protein plaques deposited in the lens of the patient&#39;s eye using a non-invasive laser scanning and imaging. This new discovery could revolutionize early detections of Alzheimer&#39;s disease including most of the dementia disorders. All the previous measuring techniques have to use part of the brain for detection which is not advisable. The fact that the plaque (abnormal beta-amyloid protein) which deposits in the brain of Alzheimer&#39;s patient also will deposit simultaneously in the lens of the patient&#39;s eye similar to formation of cataracts, opens a new avenue for early diagnosis and continuous monitoring of Alzheimer&#39;s.       

   Among the above listed prior arts for early detection of Alzheimer&#39;s, the most promising technique is the last method, Alzheimer&#39;s diagnosis by laser scanning the lens of patient&#39;s eye. Laser imaging of the eye for AD detection has now been accepted among the researchers to be a promising technique. 
   One example is Sianto et al in U.S. Pat. No. 6,162,186 who is claiming that AD Patients&#39; autonomic nervous system is hypersensitive to the neural transmitter mediators (NTM), used as eye drops, with concentration so low that did not affect the pupil&#39;s diameter change and other pupil&#39;s characteristics if applied on a person with no sign of being AD symptom. They use standard CCD camera to measure the change in a diameter and constriction of the pupil in the eye of an AD patient in a short time. For measuring the pupil&#39;s constriction velocity, the test is done under a low light with controlled intensity and duration. The inventors compare this data of an AD patient with some predefined standard data taken from normal persons. 
   Another example is Zhou et al, in U.S. Pat. No. 6,988,995 who is using a diode laser with 780 nm radiation. The laser light is first collimated and then scans in 2 dimensions by a resonance scanner and a galvanometer scanner. The scanned beam is taking data from the eye RNFL (retinal nerve fiber layers) compared with some standard signatures. The inventors claim that their method is using birefringence data of the structural elements of the eye with sufficient accuracy which is required to identify the effects of AD in the RNFL. The drawback of the invention is that there is no experimental data to support the invention. In this patent the laser power is not known and its safety is questionable. Even the inventors are not sure that the method is practical and there is no proof that the RNFL is affected by AD. 
   The present arts have at least three major drawbacks. The first one is high intensity laser scanning which is harmful to the patient&#39;s eyes and sometimes extremely dangerous if it has to penetrate inside the layers of the deposited plague. The second problem of the existing disclosed methods is the requirement of large, heavy, and expensive apparatus which makes testing inconvenient to be done in Doctors&#39; office and the patient has to go to hospital. The third drawback is the lack of a very sensitive and highly efficient testing process which is required for early detection of the AD symptoms. 
   From the above discussions of the prior arts, the only presently known means of positively proving and demonstration of AD case in a person can only be achieved by a brain biopsy or a postmortem examination to determine existing of the plaque (amyloid) in brain tissue. It is overwhelmingly obvious that there has been remained a large demand for an accurate diagnosis for these AD symptoms which do not include brain biopsy, surgery, or even using the harmful high dose MRI and CT. 
   BRIEF SUMMARY OF THE DISCLOSED METHOD AND APPARATUS 
   The primary objective of the present method and apparatus is to provide new systems and technique for the early diagnosis of Alzheimer&#39;s Disease which is not involved brain surgery or biopsy. Based on the above background of the prior arts, it is clear that a precise and accurate measurement of the Alzheimer&#39;s deposited layers of amyloid (plaque) in the eyes of the patient is a possible solution. 
   The disclosed method and apparatus use terahertz waves instead of laser for scanning the eye of the AD patient to precisely image the amyloid layer non-invasively in real time to determine the deposited plaque of amyloid with very high resolution by dividing the amyloid layer thickness to a large number of very thin microlayers. Each microlayer independently is scanned by terahertz waves and all microlayers&#39; images are integrated to generate a well defined signature of the AD patient eyes. The accuracy and high resolution of this method can easily distinguish the abnormality of an AD patient with the signature of a normal person and the signature of a person with common age-related cataracts. 
   Terahertz waves are a segment of electromagnetic waves. Terahertz waves are bounded between millimeters waves (less than 1×10 11  Hz) and photonics waves (greater than 1×10 13  Hz). The electromagnetic frequencies lower than terahertz band are covering mm waves (microwaves), while the electromagnetic frequencies higher than terahertz band are covering near infrared through visible spectrum. 
   Terahertz wave band can be used for time domain and frequency domain imaging. The present applications of terahertz waves are spectroscopy in atmospheric science and in astronomy, imaging for burn diagnostics, tomography, biomedical, medical diagnostics, screening for weapon, explosives, biohazard, imaging of concealed objects, and cancerous tissue detection. 
   Existing water in living tissue limits the penetration depth of terahertz energy to a few millimeters, which is just sufficient for the diagnosis of RNFL which has a thickness of less than 200 microns. Terahertz waves above 0.5 THz can travel in air up to a meter, which is more than sufficient to transmit and receive signals from an eye test. 
   Besides detecting the presence of AD, the present method and apparatus is also valuable to determine how advance is the concentration of Amyloid plaques as well as information regarding whether the progression has stopped or has slowed down. A map showing, the difference between AD plaques and age-related cataracts, can aid in the accurate diagnosis of AD with no ambiguity. This is in contrast to the poor resolution of the prior art using laser techniques. When using terahertz systems such as disclosed herein, the combination of the spatial resolution and the high spectral resolution of a terahertz imaging system can be utilized to detect Alzheimer&#39;s progression with high level of confidence. 
   The present method and apparatus gathers data in three spatial dimensions. Initially, a spot is selected on the outer ring of the lens of the eye which is the location of the AD plaques deposition. The spot travels in depth where a line image is constructed resulting from a rapid optical delay line, so called optical coherence topography (OCT). The depth of the RNFL is binned according to the desired spatial resolution, signal-to-noise ratio, and the characteristic of the rapid optical delay line. Then, the incident beam will be scanned in two directions collecting three dimensional data of a rectangular area alongside of the deposited ring. To improve the reliability of this method several rectangular areas of the outer ring of the patient&#39;s eye are selected for similar experiment. A tomography will then be constructed from the gathered overall data. 
   A better understanding could be achieved with reference to Detailed Description of the disclosed method and apparatus and with reference to the drawings. The description represents a particular case to realize the disclosed method and apparatus and is not intended to define the invention, but merely to provide adequate support for the claims appended hereto. Accordingly, the invention is defined solely by the claims to the invention appended hereto. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
       FIG. 1  is a diagram of the human eye showing its main structures. 
       FIG. 2  is characterization and data in the lens of Human&#39;s eye 
       FIG. 3  is Alzheimer&#39;s signature compared with age related cataracts 
       FIG. 4  is a simplified diagram of the THz scanning the lens of Patient&#39;s eye 
       FIG. 5  is a detailed block diagram of the diagnostic of the present invention. 
       FIG. 6  is detailed of the  FIG. 5  in three locations of A, B, and C. 
       FIG. 7  is a block diagram of the MOEMS rapid scanning optical delay line. 
   

   DETAILED DESCRIPTION 
     FIG. 1  is a diagram of the human eye&#39;s structure which shows the lens  10  dimension relative to other elements of the eye. The lens focuses light rays onto the retina. An iris  11 , the color part of the eye changes the amount of the light requires for optical processing. The eye acts as a perfect high resolution camera. It uses its variable index of reflection to dynamically focus a subject. Cornea  12  is bounded between conjunctiva  13  and aqueous Humor  14 . Retina  15  works as an image processor to convert incoming rays into nerves signals where the brain analyzes the signals and creates the image. 
     FIG. 2  is a close up picture of the eye  20  where the lens  21  is partially exposed by iris  22  acts as a diaphragm and partially exposed the lens in the opening pupil  23 . The lens normal characteristics have shown in  FIG. 2 .  FIG. 3  shows a comparison between Alzheimer&#39;s plaques deposited in the lens of the patient&#39;s eye and the cataracts plaques deposited similarly in the lens of the eye in age related cataracts symptom. The lens of the eye  31  has a dimension of 9 mm in length and 4 mm in thickness. The thickness of the plaques deposited is normally about 200 microns and most likely the plaque is deposited in different locations.  FIG. 3(   a ) shows the lens coloration  31  of an ordinary person. The age related cataracts patient, see  FIG. 3(   b ), where the plaques  32  is deposited in the center of the lens while the Alzheimer&#39;s patient with the Beta amyloid plaques  33  have the same dark coloration, see  FIG. 3(   c ), but is deposited as a ring in the outward portion of the lens. 
   The  FIG. 4  is a simplified diagram of the AD detection by scanning the lens of the patient&#39;s eye using the Terahertz wave imaging. A beam of the femtosecond pulsed laser  40  enters the Terahertz transmitter  41  electronically controlled by the line  43 . The output of the transmitter  42  is using high efficient quasi optics lenses to focus the THz beam on the mirror surface of a MOEMS scanner  50 . The scanned THz waves  46  are programmed to scan the surface of the lens  45 . The reflection  47  from the lens of the patient eye is collected by the mirror  48  and is focused by quasi optics lens  49  onto a detector shown in detailed block diagram of the invention in  FIG. 5 . The detector preferably has the same structure and principles as discussed for the transmitter system  41 . The received signal at the detector has an inherently high signal to noise ratio. The detection process works based on convolution of two electromagnetic waves coming in opposite direction and mixed (see the detail in  FIG. 5 ). As THz beam is penetrated inside the lens of the eye about at least 2 mm, more than 10 layers can be image and processed. Since the thickness of the AD plaques is only about 200 microns, the first 10 layers, give the signature of the Alzheimer&#39;s disease. 
   As shown in  FIG. 5 , a fiber carrier laser light  60 , in accordance with the present method and apparatus is generated by a femtosecond pulsed laser  101  shown in  FIG. 6  with wavelength typically between 800 nanometers to 1.5 μm. The laser light is gated by time domain pulses, the durations of which are preferably measured in femtoseconds. The frequency spectrum of a femtosecond pulse is rather wide, covering from 300 GHz to 10 THz (10,000 GHz). The output beam of the pulsed laser  101  is coupled to the fiber carrier laser light  60  shown in  FIG. 5 , thus transferring the femtosecond pulses to a handheld diagnostic probe (HDP) sketched in  FIG. 5 . All components contained in HDP are shown in  FIG. 5 . All components required for HDP operation that lie outside the HDP are shown in  FIG. 6 . The laser light  61  inside the HDP will split into a pump light  65  and a reference (probe) light  64  by a beam splitter  62 . 
   The pump light  65  will enter a micro-opto-electro-mechanical systems (MOEMS) rapid scanning optical delay line (RSOD)  566 . The detail description of the MOEMS RSOD  566  is provided in Motamedi, et al, U.S. Pat. No. 6,839,172 entitled “Enhanced sampling rate in time domain imaging using MOEMS scanning optical delay line” and its components are shown in  FIG. 7 . As shown in  FIG. 7 , pump beam  65  will reflect by mirror  62  to a special design blazed grating  119 . Beam  65  will split in zero and +1 diffraction order beams  120 . The beams  120  focuses through a lens  121  on a MOEMS scanner mirror  122 . MOEMS scanner  750  has potential to have large-size mirrors (more than 10 mm 2 ) and a surface flatness on the order of optical wavelength, as described in an article entitled “MOEM Scan Engine for Barcode Reading and Factory Automation” by M. E. Motamedi, et al published in SPIE Proceeding of Miniaturized Systems with Micro-optics and Micromechanics III, Vol., 3276, p. p. 66-80, 1998. The reflection beam  125  from scanner mirror  122  is setup to pass through the same lens  121  and refocuses again to beams  126  arriving at a new location on grating  119 , combining to a single beam. A bouncing mirror is mounted in proper location which returns the light beam  127  back through lens  121  and scanner mirror  122  and redirects the beam back from the path beam  65  and mirror  62  to the direction of beam  61  where was originated. As the scanner mirror  122  relocates to a new location, the return beams  126  will move on the surface of the grating  119  from location  129  to another grating location generating time delays of tens of picoseconds. The power required for operating the MOEMS RSOD is fed through the HDP connector  668  from control and display system  690  shown in  FIG. 6 . 
   The return scanning delayed beam is output through beam light  66  from the RSOD line to a quasi-optics chopper  67 . The input power and the returned chopping signals are coupled from the quasi optics chopper  67  to the control and display system  690  through connector  69 . The chopped beam output  540  exits from the quasi optics chopper system  67  and enters a terahertz transmitter system  541 . The transmitter system  541  is a preferably a solid state, semi-insulated GaAs, electromagnetic emitter coupled by metal-film strip lines about 10 μm wide and spaced 100 μm apart. For the purpose of this description, the transmission lines are considered to be part of the transmitter system  541 . As the number of the lines increases, the emitter bandwidth decreases. If the transmitter is excited by a train of femtosecond pulses emitted from the beam quasi optics chopper  67 , the strip lines in the transmitter system  541  act as an antenna and radiate waves in the terahertz spectrum. If only two strips are used, the system  541  radiates in a spectrum ranging from 100 GHz to sometimes 10 THz. In the presently disclosed method and apparatus, the particular range of terahertz frequencies will be selected in accordance with what is demanded by type of diagnostic or other application. The transmitter system  541  requires a DC voltage for biasing, which is provided through the connector  92  from the system  690  shown in  FIG. 6 . 
   The terahertz waves  72  emitted from the transmitter system  541  are focused through a quasi optics lens  77  and a mirror surface of a MOEMS scanner  78  to the eye sample  645  shown in  FIG. 6 . The eye sample  645 , which is outside the probe, is diagnosed by a projection beam  646  (shown in both  FIG. 5  and  FIG. 6 ) and its reflection beam  647 . The focusing spot and its propagation through the eye lens  10  of  FIG. 1  and its detailed description  21  in  FIG. 2 , taking into consideration the diffusion and dispersion phenomenon are controlled by quasi optics lens  77  shown in  FIG. 5 . To cover a large area of eye lens  21  in  FIG. 2 , the patient&#39;s eye lens should stays stationary, and the beam should be scanned inside the probe by a MOEM scanner  50 . This option is shown in  FIG. 4 . 
   The reflection  547  from patient&#39;s eye in  FIG. 5  is collected by the mirror  548  and is focused by quasi optics lens  549  onto a detector  84 . The detector  84  preferably has the same structure and principles as discussed for the transmitter system  541 . The received signal at the detector  87  has an inherently high signal to noise ratio, but it suffers significantly from misalignment and large bandwidth requirements. The detection process works based on convolution of two electromagnetic waves coming in opposite direction and mixed. Since the mixed waves are identical in characteristic when split at beam splitter  62 , the detector acts as a convolver where the difference signal has the frequency of scanner  50  shown in  FIG. 4  with diagnosis information of the eye lens under test. 
   The probe beam  64 , which is split from beam splitter  62 , enters in optical arrangement  87  via mirrors  85  and  86 . A controlled terahertz reference beam  88  exits from the optical arrangement  87  and enters the detector  84  at the exact time as the reflected terahertz signal  547  carrying information regarding the patient&#39;s eye test. The mixing of these two terahertz waves within the detector  84  will detect the eye testing information. The detected output has high input impedance. The output preferably goes through several improvement stages, including a matching impedance amplifier  90 . Using a MOEMS high speed scanning delay line allows the layer information of the eye under test to be collected. In addition, a representative tomography of the Amyloid layer volume is constructed. The test information of the detector  84  is transferred in real time to the display and control system  690  shown in  FIG. 6 . The detector  84  is coupled to the display and control system  690  through the connector  91 . The diagnosis results can then be displayed in a handheld display system. Alternatively, the diagnosis results could be transmitted to a medical center by means such as wireless communications. 
   The tissue image is comprised of a plurality of horizontal bands, each band being adjacent to another, with equal bandwidths and comprised of a plurality of pixels where each pixel being adjacent to another. The images with a calibrated reference are stored in a handheld memory, indicating regions of coincidence and region of non-coincidence, and combining the images at different layers to obtain the tomography of the eye Amyloid layer. 
   It should be understood by those skilled in the art that modifications from the disclosed method and apparatus may be made without departing from the spirit of the invention claimed in the appended claims provided herein. Furthermore, the invention is defined only by the appended claims. Accordingly, it will be understood that the above description is provided only to enable one of ordinary skill in the art to make and use the invention. However, departures from the disclosed method and apparatus that fall within the scope of the claims should be considered to be within the scope of the claimed invention.