Advanced Imaging for Glaucoma Study
Condition: Glaucoma
MeSH terms: Glaucoma
Study type: Observational

Summary: 
      The specific aims of the clinical studies are to:

        1. Predict the development of glaucomatous visual field (VF) abnormality in glaucoma
           suspects and pre-perimetric glaucoma patients based on anatomic abnormalities detected
           by advanced imaging.

        2. Predict the development of glaucomatous VF abnormality in glaucoma suspects and
           pre-perimetric glaucoma patients based on anatomic changes detected between successive
           advanced imaging tests.

        3. Determine the sensitivity and specificity of glaucoma diagnosis based on advanced
           imaging tests.
    

Detailed description: 
      Glaucoma is a leading cause of blindness in the US. Traditional methods of glaucoma diagnosis
      and monitoring lack good sensitivity and specificity. Delays in detecting glaucoma
      progression can lead to inadequate treatment and irreversible visual loss. Our goal is to
      improve glaucoma diagnosis by utilizing new imaging modalities that can reveal changes in the
      retinal layers affected by glaucoma and the associated reduction in retinal blood flow.
      Glaucoma selectively damages the retinal nerve fibers, which originate from cell bodies in
      ganglion cell layer (GCL) and travel to the optic nerve via the nerve fiber layer (NFL). We
      hypothesize that subtle damages in these structures can be detected earlier by optical
      coherence tomography (OCT) and other advanced imaging modalities than with current standard
      methods. OCT is based on infrared light reflectometry. It provides micrometer-scale
      cross-sectional images of retinal structures, which are not possible with other non-invasive
      techniques. More than 7,000 OCT systems are already being used for the diagnosis of glaucoma
      and retinal diseases. Phase I of the Advanced Imaging for Glaucoma (AIG) study demonstrated
      that peripapillary NFL thickness measured with the standard timedomain (TD) OCT technology
      has higher glaucoma diagnostic accuracy than other quantitative diagnostic technologies such
      as scanning laser polarimetry (SLP) and scanning laser tomography (SLT). We also demonstrated
      that more advanced diagnostic software and faster Fourier-domain (FD) OCT systems can achieve
      even better diagnostic accuracy and reproducibility. In the proposed Phase II of the AIG
      study, we will continue the most promising aspects of the research to further improve both
      technology and clinical practice.

      The AIG Partnership investigators at the Oregon Health & Science University (OHSU),
      Massachusetts Institute of Technology (MIT), and University of Pittsburgh (UP) include those
      who invented OCT and pioneered its applications to glaucoma. OHSU, University of Southern
      California (USC), UP and University of Miami (UM) also have major glaucoma referral centers.

      The Partnership combines engineers and clinicians who have the track record and synergy to
      develop novel technologies, evaluate them in a rigorous clinical study, and transfer the
      knowledge to industry and medicine.

      The Specific Aims of this competing renewal proposal are:

        1. Develop image processing and diagnostic analysis for 3-dimensional OCT data. The AIG
           study is currently using 26 kHz (axial scan repetition rate) FD-OCT technology that is
           capable of scanning the macula and the optic nerve head in a fraction of a second. We
           have completed computer algorithms for mapping and analysis of the macular ganglion cell
           complex (mGCC) and the peripapillary NFL, which lead to significant improvement in
           diagnostic accuracy. We propose to continue the work on disc cupping analysis, NFL
           reflectivity analysis, and expert system combination of multiple anatomic parameters to
           further improve diagnostic accuracy. Algorithms to detect progression of glaucoma over
           time are also planned.

        2. Develop ultrafast OCT systems for imaging of the macula and optic nerve head. Although
           current FD-OCT technology at 26 kHz represents a tremendous advance over standard 400 Hz
           TD-OCT (Zeiss Stratus), it still takes ~4 seconds for a full 3-dimensional (3D) raster
           scan of the macula. Our goal is to reduce this time to 0.1-0.2 second so 3D scans will
           be minimally affected by eye movement. This requires an ultrafast speed of 500-1000 kHz.
           We plan to adapt the Fourier-domain modelocked-laser (FDML) swept-source OCT, which has
           already been demonstrated at 249 kHz at MIT. We will further improve its speed to 500
           kHz. The short integration time and phase stability of FDML-OCT is ideal for Doppler
           perfusion measurement (see next aim). For an even faster speed, parallel line-scan
           FD-OCT at 1 MHz will be developed. Line-scan OCT is not suitable for Doppler flow
           measurement due to the relatively long integration time, but is more efficient for
           ultrafast anatomic imaging. It will allow full 8x8 mm macular 3D imaging in 0.2 second.
           We will also continue to develop polarization-sensitive (PS) OCT for NFL birefringence
           measurement, which will also be greatly enhanced by higher speed and greater averaging
           to suppress noise.

        3. Develop Doppler OCT to measure retinal perfusion. One of the significant achievements of
           the AIG project is the demonstration of a reproducible method of measuring total retinal
           blood flow using Doppler FD-OCT. Reduced flow was found in glaucomatous eyes, opening an
           important new approach to measure the severity of glaucoma and assess the risk for
           further progression. An automated algorithm will be developed to improve the robustness
           of Doppler flow measurement. We will also investigate Doppler OCT with the ultrafast
           FDML-OCT system.

        4. Evaluate OCT technologies in a longitudinal clinical study. An extension of the ongoing
           clinical study is proposed. Participants (1000 planned with 700+ already enrolled) in
           normal, glaucoma suspect, and glaucoma groups will be followed. OCT and other imaging
           technologies will be compared for diagnostic accuracy, detection of early progression,
           and prediction of future visual field loss. The impact of intraocular pressure on
           retinal blood flow and how flow affects the risk of glaucoma will also be studied.

      Quantitative imaging technologies such as OCT have improved glaucoma management by reducing
      reliance on insensitive tests such as perimetry and subjective disc grading. The AIG
      Partnership comprises engineers and clinicians who co-invented OCT. We propose to further
      improve its performance with higher speed, more sophisticated software, and novel functional
      measurements. The eventual goal is to save vision by basing glaucoma treatment decisions on
      speedy and reliable imaging tests.
    

Observational model: Other
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        The study will enroll both males and females and include all ethnic and racial groups
        through clinical practices in the centers. The study will enroll subjects in the older
        adult age range commonly affected by glaucoma - 40 years or older. The study will exclude
        people with life-threatening or debilitating illness that would make 5-year participation
        unlikely or cooperation with tests difficult. For similar reasons those older than 79 years
        are excluded. The study also excludes those with any disease that might confound the
        diagnosis of glaucoma. Otherwise people with any health status are eligible for enrollment.
        Three groups of participants are recruited in the AIG study: normal (N), glaucoma suspects
        & preperimetric glaucoma (GSPPG) and perimetric glaucoma (PG).
      
Keywords: Optical Coherence Tomography; Glaucoma; Advanced Imaging