Shaun Frost

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.

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.

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.

Pupil Response Biomarkers for Early Detection and Monitoring of Alzheimer's Disease

INTRODUCTION A screening process that could provide early and accurate diagnosis or prognosis for Alzheimers disease (AD) would enable earlier intervention, and enable current and future treatments to be more effective. Ocular pathology and changes to vision and ocular function are being investigated for early detection and monitoring of AD. OBJECTIVE To explore the relationship between pupil flash response (PFR) parameters, AD and brain amyloid plaque burden. METHODS Nineteen AD and seventy healthy control (HC) participants were recruited from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing. The potential correlations between PFR parameters and 1) AD and 2) brain amyloid plaque burden in the HC group (as a pre-clinical feature of AD), were investigated in this study. RESULTS Our results demonstrate statistically significant relationships between PFR parameters, neocortical plaque burden and AD. A logistical model combining PFR parameters provided AD-classification performance with sensitivity 84.1%, specificity 78.3% and area under the curve 89.6%. Furthermore, some of the AD specific PFR parameters were also associated with neocortical plaque burden in pre-clinical AD. CONCLUSIONS These PFR changes show potential as an adjunct for noninvasive, cost-effective screening for pre-clinical AD.

Retinal image registration and comparison for clinical decision support.

Background For eye diseases, such as glaucoma and age-related macular degeneration (ARMD), involved in long-term degeneration procedure, longitudinal comparison of retinal images is a common step for reliable diagnosis of these kinds of diseases.

Pupil response biomarkers distinguish Amyloid precursor protein mutation carriers from non-carriers

CONTEXT Alzheimers disease (AD) is usually only diagnosed many years after pathology begins. Earlier detection would allow emerging interventions to have a greater chance to preserve healthy brain function. A rare form of Alzheimers disease, caused by autosomal-dominant mutations, affects carriers with 100% certainty and at a younger age specific to their mutation. Studying families with these mutations allows a unique investigation of the temporal sequence of biomarker changes in Alzheimers disease. OBJECTIVE To determine whether the pupil flash response (PFR), previously reported to be altered in sporadic Alzheimers disease, is different in pre-symptomatic mutation carriers. DESIGN Researchers blinded to participant mutation status collected pupil response data from cognitively normal participants in the Dominantly Inherited Alzheimers Network (DIAN) Study during 2010-2011. SETTING The pupil response was examined at the McCusker Alzheimers Research Foundation in Perth, Western Australia. PARTICIPANTS Participants were from a single family harboring an Amyloid-Beta Precursor Protein genetic mutation (APPGlu693Gln). Six carriers and six non-carriers were available for pupil testing (age 43.0±8.3 years old, 2 males and 10 females, 4 with hypertension). MAIN OUTCOME MEASURE Pupil response parameter comparison between mutation carriers and non-carriers. RESULTS 75% recovery time was longer in mutation carriers (p<0.0003, ROC AUC 1.000, Sensitivity 100%, Specificity 100%) and percentage recovery 3.5 seconds after stimulus was less in mutation carriers (p<0.006, ROC AUC 1.000, Sensitivity 100%, Specificity 100%). CONCLUSIONS PFR changes occur pre-symptomatically in autosomal dominant AD mutation carriers, supporting further investigation of PFR for early detection of AD.

Ocular biomarkers for neurodegenerative and systemic disease

The eye is a readily accessible window to the brain and the retina has been proven to reveal presymptomatic evidence of brain disorders and systemic diseases, including Alzheimer disease, stroke and diabetes. Here we describe three approaches we are taking to examine the utility of retinal imaging for age-onset diseases. Alzheimer disease develops slowly, with “plaques” of amyloidbuilding up in the brain 15–20 years before memory symptoms and clinical diagnosis. With United States biotech company NeuroVision Imaging, we have been investigating whether similar plaques deposit in the retina. Researchers in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (aibl.csiro. au) are running a trial that involves highlighting amyloid plaques in the retina using oral dosing of curcumin, a natural ingredient which gives the spice turmeric its fl uorescent yellow colour. The study builds on previous work that found changes to vision and to the retinal blood vessels in Alzheimer disease.1 We believe that retinal imaging may hold a key to early screening for disease and to monitoring interventions aimed at preclinical disease before irreversible brain damage occurs. Vascular risk factors appear years before stroke and may also infl uence the likelihood of recurrent stroke. Another CSIRO study is embedding retinal vascular photography in a hospital stroke ward setting. The aims are to investigate the feasibility and utility of ward-based retinal photography as a tool to screen for retinal signs of disease, which may improve diagnosis of the aetiology of acute ischaemic and haemorrhagic stroke. The study may also facilitate appropriate preventive treatments, and improve the prediction of risk of recurrent stroke and other major vascular events. CSIRO is also a partner in the Remote-I telemedicine project, which supports remote reporting, through a web-based, fully automated disease grading and clinical decision support system for eye diseases, such as diabetic retinopathy and age-related macular degeneration. It is now widely used in Australia and in China.

Alzheimer’s disease: A journey from amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies—Gains from AIBL and DIAN Cohort Studies

Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-β peptide (also known as Aβ or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aβ peptide in Alzheimer’s disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ɛ4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aβ.

Modulation of Retinal Arteriolar Central Reflection by APOE genotype

OBJECTIVE This study investigated the retinal arteriolar central reflex (CR, the central reflection observed in photographs of retinal vessels), which may provide information about micro-vascular health in the retina and also the brain, due to the homology between these vascular networks. The study also describes a novel computer based semi-automated technique that accurately quantifies retinal arteriolar CR and vessel width, and calculates the CR to vessel width ratio (CRR) from digital retinal photographs. METHODS Digital retinal photographs were collected from participants in the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL), including 25 participants diagnosed with Alzheimers disease (AD) (age 72.4 ± 7.5 yrs, 12 male, 13 female) and 123 elderly participants without dementia (cognitively normals: CN) (age 71.6 ± 5.6 yrs, 55 male, 68 female). Using a sub-cohort of 144 (22 AD, 122 CN) with the novel CRR measures, we identified significantly higher CRR levels in AD participants (mean CRR 0.253 (SD 0.04)) as compared with CNs (mean CRR 0.231 (SD 0.04), p = 0.025). Adjustment for APOE ε4 allele status however, reduced the significance (p = 0.081). CRR was significantly higher in APOE ε4 allele carriers (mean CRR 0.254 (SD 0.03) as compared with non-carriers (mean CRR 0.224 (SD 0.05), p < 0.0001). RESULTS These data indicate that CRR is strongly linked to APOE ε4 status and exhibits a weaker, independent trend with AD diagnosis. The retina may be useful as a novel model for non-invasive monitoring of the effects of APOE ε4 on the central nervous system, particularly in cerebrovascular disease.

Retinal image enhancement and registration for the evaluation of longitudinal changes

Retinal images are long-accepted clinical diagnostic method for ocular diseases. Of late, automated assessment of retinal images has proven to be a useful adjunct in clinical decision support systems. In this paper, we propose a retinal image registration method, which combine retinal image enhancement and non-rigid image registration methods, for longitudinal retinal image alignment. A further illumination correction and gray value matching methods are applied for the longitudinal image comparison and subtraction. The solution can enhance the assessment of longitudinal changes of retinal images and image subtraction in a clinical application system. The performance of the proposed solution has been tested on longitudinal retinal images. Preliminary results have demonstrated the accuracy and robustness of the solutions and their potential application in a clinical environment.