Title: Enabling Research Award: Retinal Evaluation in Alzheimer's Disease and Mild Cognitive Impairment
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: There is evidence that non-invasive measurement of retinal blood vessels offer insight into certain systemic diseases, highlighting the eye as a unique window to view microvascular health elsewhere in the body. Clinicians and scientists may therefore be afforded mechanistic insight into diseases with a microvascular component. The retina and cerebral small blood vessels share similar embryological origin, anatomical features and physiological properties (e.g. nonanastomotic end arteries, blood-brain and blood-retina barriers) (Wong, 2001; Patton, 2005). Cerebral small vessel disease has long been implicated in the development of AD and vascular risk factors especially those affecting the cerebral microcirculation (e.g. hypertension, diabetes) have been shown to play an important role in the pathogenesis of AD (Kalaria, 2012; Gorelick, 2011). The neural retina is also an extension of the central nervouse system, sharing similar properties with cerebral neurons and therefore provide a non-invasive method for the investigation of cognitive function and dementia (Ikram, 2012; London, 2012). Altered microvascular networks (narrower retinal venules and sparser and more tortuous retinal vessels) have been demonstrated in a group of AD patients compared to controls and the hypothesis is these changes in retinal microvasculature reflect similar pathophysiological processes in cerebral microvasculature in the brains of patients with AD(Cheung, 2014). Relationships between retinal vascular parameters, neocortical brain amyloid plaque burden and AD have also been demonstrated (Frost, 2013). Furthermore evidence of retinal vascular change was demonstrated in a small group of healthy individuals with high neocortical amyloid plaque burden (deemed at high risk of AD). As a result of these studies a research question has arisen: does retinal vascular change occur early in the disease process? Retinal vascular change can be measured by standard field film photographs or by mydriatic ultrawide field imaging (Optos plc. Scotland UK). An advantage of the latter imaging is more peripheral lesions can be identified (Silva, 2013). In addition amyloid has been located with retinal drusen deposits (yellow lipid deposits under the retina) (Isas, 2010) raising the possibility that drusen may be used as a surrogate marker for AD. Pilot studies have shown a significant quantity of drusen in peripheral retina of patients with AD (https://reviewofopthamology.com/content/d/technology_update/i/1628/c/29944/) which contrasts with the more central location of drusen associated with age-related macular degeneration. To our knowledge no group has evaluated the added utility of ultra wide field imaging in AD or MCI. A further question therefore is: what is the best imaging modality for detecting retinal vascular change and drusen in AD or MCI? Decreased thickness of the retinal nerve fibre layer (RNFL) can reflect retinal neuronal ganglion cell death and axonal loss of the optic nerve. Changes in thickness of the RNFL have also been demonstrated in small groups of AD patients compared to controls (Parisi, 2001; Iseti, 2006; Lu, 2010; Kesler, 2011) using optical coherence tomography (OCT). This is a non-invasive imaging technology offering resolution at the cellular level and facilitates quantitative assessment of optic nerve axons. The technology has improved dramatically over the years and more recent spectral-domain OCT (SD-OCT) enables more detailed assessment and measurement of the retinal ganglion cell layer through improved spatial resolution. Such advances improve the sensitivity to discriminate changes in ganglion cell layer thickness and RNFL thinning which occurs during cognitive decline. AD is often preceded by mild cognitive impairment (MCI); this is defined as a transitional state between normal ageing and dementia; it is a syndrome defined by clinical, cognitive and functional criteria in which the patient has a cognitive decline adjusted for age and educational level which does not interfere with ability to function independently (Petersen, 1999). Patients with MCI are at increased risk of conversion to AD (10-15% per year) and are a target population for evaluating pathophysiological change early in the AD continuum. To date we are not aware of any study that has examined retinal vascular parameter change in a MCI population although there have been calls for such to be carried out. Only one study has assessed RNFL thickness using OCT in a small group (n=24) of amnestic MCI participants; a significant decrease in RNFL thickness was seen in MCI and AD patients compared to controls and in addition no statistical difference was found between the results in MCI patients and mild AD patients suggesting that RNFL may be involved early during the course of the disease (Paquet, 2007). This highlights the need for further investigation and prospective studies. Regarding prognosis of MCI there is no single test that can predict who will convert to dementia versus who will not. Greatest utility has been found most recently in neuropsychological testing especially in the domains of episodic memory and executive function (Gomar, 2014). There is added value in CSF analysis for AB32/tau ratio and FDG-PEC CT Brain scanning but these measures are expensive and invasive (CSF analysis). This feasibility study aims to ascertain if there is a detectable difference in retinal vasculature and retinal nerve fibre thickness between MCI, AD patients and controls. This will lead to further work assessing the utility of these measures as biomarkers against standard neuropsychological tests, CSF analysis and FDG-PET CT brain scanning.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: NEUROLOGICAL;MENTAL HEALTH