Yogesan Kanagasingam

Innovative diagnostic tools for early detection of Alzheimer's disease

Current state‐of‐the‐art diagnostic measures of Alzheimers disease (AD) are invasive (cerebrospinal fluid analysis), expensive (neuroimaging) and time‐consuming (neuropsychological assessment) and thus have limited accessibility as frontline screening and diagnostic tools for AD. Thus, there is an increasing need for additional noninvasive and/or cost‐effective tools, allowing identification of subjects in the preclinical or early clinical stages of AD who could be suitable for further cognitive evaluation and dementia diagnostics. Implementation of such tests may facilitate early and potentially more effective therapeutic and preventative strategies for AD. Before applying them in clinical practice, these tools should be examined in ongoing large clinical trials. This review will summarize and highlight the most promising screening tools including neuropsychometric, clinical, blood, and neurophysiological tests.

Progress on retinal image analysis for age related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of vision loss in those over the age of 50 years in the developed countries. The number is expected to increase by ∼1.5 fold over the next ten years due to an increase in aging population. One of the main measures of AMD severity is the analysis of drusen, pigmentary abnormalities, geographic atrophy (GA) and choroidal neovascularization (CNV) from imaging based on color fundus photograph, optical coherence tomography (OCT) and other imaging modalities. Each of these imaging modalities has strengths and weaknesses for extracting individual AMD pathology and different imaging techniques are used in combination for capturing and/or quantification of different pathologies. Current dry AMD treatments cannot cure or reverse vision loss. However, the Age-Related Eye Disease Study (AREDS) showed that specific anti-oxidant vitamin supplementation reduces the risk of progression from intermediate stages (defined as the presence of either many medium-sized drusen or one or more large drusen) to late AMD which allows for preventative strategies in properly identified patients. Thus identification of people with early stage AMD is important to design and implement preventative strategies for late AMD, and determine their cost-effectiveness. A mass screening facility with teleophthalmology or telemedicine in combination with computer-aided analysis for large rural-based communities may identify more individuals suitable for early stage AMD prevention. In this review, we discuss different imaging modalities that are currently being considered or used for screening AMD. In addition, we look into various automated and semi-automated computer-aided grading systems and related retinal image analysis techniques for drusen, geographic atrophy and choroidal neovascularization detection and/or quantification for measurement of AMD severity using these imaging modalities. We also review the existing telemedicine studies which include diagnosis and management of AMD, and how automated disease grading could benefit telemedicine. As there is no treatment for dry AMD and only early intervention can prevent the late AMD, we emphasize mass screening through a telemedicine platform to enable early detection of AMD. We also provide a comparative study between the imaging modalities and identify potential study areas for further improvement and future research direction in automated AMD grading and screening.

EVALUATION OF ADENO-ASSOCIATED VIRUS-MEDIATED GENE TRANSFER INTO THE RAT RETINA BY CLINICAL FLUORESCENCE PHOTOGRAPHY

The purpose of this study was to evaluate recombinant adeno-associated virus (AAV) as an in vivo gene transfer vector for the retina and to explore the possibility of monitoring the expression of green fluorescent protein (GFP) using a noninvasive method. Rats were injected subretinally with rAAV-gfp or rAAV-lacZ. Strong expression of the reporter gene in a circular area surrounding the injection site was observed in retinal whole mounts and tissue sections. Higher magnification revealed that cells demonstrating high levels of green fluorescence were hexagonal in shape, indicating they were retinal pigment epithelium (RPE) cells. Histological observation of retinal sections demonstrated that recombinant AAV specifically transduced RPE cells. Ten animals were injected with rAAV-gfp for longitudinal studies and the fluorescence was monitored by retinal fluorescence photography. The GFP signal was detected in 100% of the animals as early as 2 weeks postinjection and remained present throughout the experimental period of 4 months. After 2 weeks, a gradual increase in the number of transduced cells occurred before reaching maximal levels of GFP expression at 8 weeks. This was followed by a small decrease over 4 weeks before reaching stable expression at 16 weeks. Our results demonstrated that rAAV efficiently transduces rat RPE cells and that retinal fluorescence photography is suitable for monitoring GFP expression. By using this noninvasive technique, we demonstrated that repetitive measurements of GFP expression in vivo in the rAAV-gfp-transduced retina are possible. This study demonstrated that retinal fluorescence photography is a potent tool for studying AAV-mediated gene delivery in the retina.

Ocular biomarkers for early detection of Alzheimer's Disease

Alzheimers disease (AD) is the most common form of dementia and is clinically characterized by a progressive decline in memory, learning, and executive functions, and neuropathologically characterized by the presence of cerebral amyloid deposits. Despite a century of research, there is still no cure or conclusive premortem diagnosis for the disease. A number of symptom-modifying drugs for AD have been developed, but their efficacy is minimal and short-lived. AD cognitive symptoms arise only after significant, irreversible neural deterioration has occurred; hence there is an urgent need to detect AD early, before the onset of cognitive symptoms. An accurate, early diagnostic test for AD would enable current and future treatments to be more effective, as well as contribute to the development of new treatments. While most AD related pathology occurs in the brain, the disease has also been reported to affect the eye, which is more accessible for imaging than the brain. AD-related proteins exist in the normal human eye and may produce ocular pathology in AD. There is some homology between the retinal and cerebral vasculatures and the retina also contains nerve cells and fibers that form a sensory extension of the brain. The eye is the only place in the body where vasculature or neural tissue is available for non-invasive optical imaging. This article presents a review of current literature on ocular morphology in AD and discusses the potential for an ocular-based screening test for AD.

Working toward a portable tele-ophthalmic system for use in maximum security prisons: a pilot study

The medical care of prisoners is a difficult and often costly process. Basic medical needs are serviced by prison medical officers. However, specialized care often means transport to specialist centers with the attendant cost and safety. We examined portable ophthalmic equipment in a prison environment to screen 11 prisoners who were scheduled for specialist ophthalmic assessment. Medical and ophthalmic histories were documented, visual acuity was tested, digital images were taken of the external eye and retina, and intraocular pressures taken. The data were sent via modem to a specialist ophthalmologist, and the reports were dictated via e-mail at the end of each session. Of the 11 patients who were scheduled to travel for ophthalmic assessment, only 2 were still required to travel to a specialist ophthalmic center. This pilot study showed that there were considerable cost savings to be made by this screening process with the attendant increase in community safety. The prototype equipment requires refinement by further experimentation, but showed the potential as an adjunct to current examination and assessment techniques when applied to a prison population.

Comparison of optic disc image assessment methods when examining serial photographs for glaucomatous progression

AIM To assess serial, simultaneous stereo optic disc images by four methods for glaucomatous progression. METHODS Using varying techniques, two ophthalmologists assessed serial optic disc images of 52 eyes from 27 patients with a mean duration between images of 18 months. The neuroretinal rim width was qualitatively assessed by four assessment methods and compared with quantitative rim measurements made using PC based software. RESULTS The highest sensitivity of 83% was achieved using computerised stereo chronoscopy. CONCLUSION Stereo chronoscopy improved the detection of subtle optic disc changes when compared with simpler assessment techniques.

Alzheimer’s disease and the early signs of age-related macular degeneration

This study investigated signs of age related macular degeneration (AMD) in Alzheimers disease (AD). These age-related diseases primarily affect different parts of the central nervous system but are substantially similar in terms of abnormal extracellular deposits, metabolic and oxidative stress, neuroinflammation and microvascular abnormalities. While AMD is a retinal disease, AD is reported to affect not only the brain but also the retina, with Aβ deposits, neurodegeneration and vascular changes. Large population based studies have provided conflicting results regarding the comorbidity of AD and AMD. This study investigated signs of AMD in a small but well characterized cohort from the Australian Imaging Biomarkers and Lifestyle study of aging (AIBL). The cohort consisted of 22 AD patients (age 70.2 ± 9.0 yrs, 13 male, 9 female) and 101 cognitively normal (CN) participants (age 71.3 ± 6.0 yrs, 40 male, 61 female). In comparison with the CN group, the AD group had a greater proportion of participants with early AMD (p < 0.0001, odds ratio 18.67, 95% CI 4.42 - 78.80). A logistic model for early AMD found a significant association with AD diagnosis (p < 0.0001), after adjusting for confounders (age, smoking, hypertension, high and low density lipoproteins, cataract surgery and APOE ε4 carrier status). The results of this study are consistent with an increased risk of AMD in AD. While the pathophysiology of these diseases are unclear, understanding the shared features between them may provide further knowledge about their pathogenesis and could lead to accelerated development of therapies for both diseases.

Light and portable novel device for diabetic retinopathy screening

Background:  To validate the use of an economical portable multipurpose ophthalmic imaging device, EyeScan (Ophthalmic Imaging System, Sacramento, CA, USA), for diabetic retinopathy screening.

A proof-of-concept evaluation of a cloud-based store-and-forward telemedicine app for screening for oral diseases

Objective It is widely considered that telemedicine can make positive contributions to dental practice. This study aimed to evaluate a cloud-based telemedicine application for screening for oral diseases. Methods A telemedicine system, based on a store-and-forward method, was developed to work as a platform for data storage. An Android application was developed to facilitate entering demographic details and capturing oral photos. As a proof-of-concept, six volunteers were enrolled in a trial to obtain oral images using smartphone cameras. Following an onsite oral examination, images of participants’ teeth were obtained by a trained dental assistant. Oral images were directly uploaded from the smartphone to a cloud-based server via broadband network. The assessments of oral images by offsite dentists were compared with those carried out via face-to-face oral examinations. Results A complete set of 30 oral images was obtained from all six participants. Out of 192 teeth reviewed, the proportion of ungradable teeth was 8%. Sensitivity and specificity of teledental screening were 57% and 100% respectively. The inter-grader agreement estimated for two examination modalities and between two teledental graders was 70% and 62% respectively. Findings indicate that the proposed system for screening of oral diseases can be implemented to provide a valid and reliable alternative to traditional oral screening. Conclusion This study provided evidence that a robust system for store-and-forward screening for dental problems can be developed, and leads to the need for further testing of its robustness to confirm the accuracy and reliability of the teledentistry system.

Diagnostic accuracy of teledentistry in the detection of dental caries: a systematic review

OBJECTIVE This study sought to systematically review the literature for research evidence for the diagnostic accuracy of teledentistry in the detection of dental caries. METHODS Two reviewers searched PubMed, EMBASE, and Scopus databases through January 2016 for comparative studies that examined the diagnostic accuracy of teledentistry for detecting caries compared with nontelemedicine alternatives. Retrieved studies were screened for inclusion criteria and were evaluated for methodological quality using the quality assessment of diagnostic accuracy studies (QUADAS-2) checklist. RESULTS Of 287 citations identified, 10 met the preset inclusion criteria. Sensitivity and specificity were the most common measures of diagnostic accuracy used in 10 studies. Despite very limited published evidence on the diagnostic accuracy of teledentistry, the reviewed teledentistry studies showed comparable diagnostic performance compared with nontelemedicine alternatives. The average methodological quality of the selected articles is low, since none of the selected studies satisfied all 4 QUADAS-2 domains. Only 6 articles were scored as having a low risk of bias in 3 of 4 of QUADAS-2 domains. All the selected studies had low concerns regarding applicability. The main shortcoming was that in most of the selected studies, the methodology, in particular patient selection and index tests, was insufficiently described. CONCLUSIONS Teledentistry has an acceptable diagnostic performance in the detection of dental caries. However, due to the heterogeneity of the reviewed studies, the generalization of results may be difficult. Further well-designed research to investigate the effectiveness of the teledentistry approach to caries detection is needed to determine the capability of this technology in epidemiologic oral surveys.