**2. The ageing brain and retina: intimate connections**

**1. Introduction**

86 Update on Dementia

ly leads to death [2].

Dementiaposesasignificantrisktothoseovertheageof65,affectingupto46.8millionindividuals globally, a number that is expected to increase to approximately 131 million by 2050 [https:// www.alz.co.uk/research/WorldAlzheimerReport2015.pdf]. Currently, no reliable treatments exist, although it has been estimated that slowing disease progression by just 5 years would reduce the number of dementia-related deaths by almost half [https://www.alzheim‐ ers.org.uk].Alzheimer'sdisease (AD)is anage-relatedneurodegenerativedisorderofthebrain, and the most common cause of dementia amongst the elderly [1]. AD is typified by progres‐ sive memory loss and significant cognitive decline amongst other complications that ultimate‐

A major pathological feature of AD is misfolding and aggregation of the naturally occurring amyloid beta (Aβ) family of proteins. A variety of different Aβ peptides are generated by successive proteolytic cleavage of the amyloid precursor protein (APP). These accumulate as large insoluble aggregates in AD brains and are referred to as 'senile plaques'. The amyloid cascade hypothesis proposes that Aβ plays a central role in AD [2]. However, AD and dementia are complex diseases, and the role of Aβ and other disease factors are still incompletely understood. Studies are also hampered by the brain's relative inaccessibility, and clinical diagnosis typically occurs many years after disease onset [3]. Consequently, there is consid‐ erable impetus towards developing non-invasive, reliable and cost-effective diagnostic methods so those at risk may be identified at relatively early stages to maximise the chances of clinical intervention. Most studies into AD and dementia are primarily focused on memory loss and cognitive decline [4, 5]. However, many AD patients are also reported to suffer from a variety of visual complications, which by contrast has received comparatively little attention. The recent discovery that Aβ deposits in the ageing human retina correlate with complex retinopathies such as age-related macular degeneration (AMD) has given support to the

hypothesis that shared pathologies may exist between the brain and senescent retina.

In this chapter, we provide a comprehensive review of the latest findings reporting visual abnormalities in patients with AD and dementia. The methodology for this review is based on searches conducted in the NCBI PubMed (http://www.ncbi.nlm.nih.gov/pubmed) database using keywords 'dementia and retina' (396 articles) and 'AD and retina' (457 articles) in June 2016. These numbers contrast starkly with larger numbers of studies in areas related to memory loss and cognitive decline. For example, use of keywords 'dementia and memory loss' (12,383 articles) or 'AD and cognitive impairment' (19,883 articles) yield many more citations; highlighting the as yet limited interest in systematically reporting visual abnormalities in AD and dementia patients. Additionally, we used keywords such as 'retina and Aβ' (111 articles) and 'retinal pigment epithelium (RPE) and amyloid' (59 citations) to include specific articles related to ophthalmology and dementia, and to describe studies in ex vivo and animal models that provide insights into Aβ-mediated pathogenesis. Centring on these articles, specific information in hyperlinks, as well as insights from our own work, we discuss the role of Aβ in driving retinal degeneration and neurodegeneration, and propose that the eye may provide a powerful model to study Aβ pathology. We suggest that the retina may act as an anatomical

The neuroretina and the central nervous system (CNS) share common origins as both derive from the developing neural ectoderm and maintain a direct and permanent connection via the optic nerve [6]. The neuroretina may therefore be considered an extension of the brain that resides within a discrete compartment—the eye. In addition to this anatomical link, both the retina and tissues of the CNS exhibit similar structural and functional arrangements. These include specialised structural adaptations such as surface infolds, postmitotic neuronal and epithelial cells, immunologically privileged compartmentalisation via a blood-brain/retinal barrier, as well as more importantly, similar patterns of damage with increasing age [7]. It is therefore possible that common disease mechanisms may also be involved in diseases of the ageing eye and brain.

Gathering of visual information first occurs when light enters the eye's anterior pole and is projected to the neuroretina. Here, incident light is converted by specialised photoreceptors in the neuroretina into electrical impulses which are subsequently relayed to second- and thirdorder neurons [8] (**Figure 1**). Axons of retinal ganglion cells (RGCs) then convey these signals to the brain. The synaptic arrangement in the neuroretina comprises of three sequential neuronal layers: photoreceptors, bipolar, and RGCs (referred to as the three neuron links) [9]. Neuronal cell bodies and processes exist in alternate layers giving rise to the laminated structure of the retina where cell bodies typically exist within the inner and outer nuclear layers, whereas processes and synapses of retinal neurons reside within the inner and outer plexiform layers [10]. In addition to these cell types, specialised neurons referred to as amacrine and horizontal cells facilitate the parallel processing of information [9]. Furthermore, a highly specialised monolayer of epithelial cells which originates from the neuroectoderm referred to as the RPE forms the margins of the outer retina and the interface with the outer vasculature (**Figure 1**) [11]. Here, within this strategic position, the RPE performs many critical metabolic and supportive functions for the overlying neuroretina. These include the absorption of stray light, phagocytosis of shed photoreceptor outer segments (POS) as part of the daily visual cycle, maintenance of the blood-retinal barrier (BRB), ion homeostasis as well as playing a role in retinal adhesion [11, 12]. The normal function of the RPE monolayer is therefore critical to maintain healthy vision in old age.

The arrangement of the mammalian retina is such that light must first traverse the entire length of the retina before reaching the photoreceptors. Two distinct types of photoreceptors exist which may be categorised according to histological morphology and which are each special‐ ised for a specific function. Rod photoreceptors constitute 95% of all photoreceptors, express the photopigment rhodopsin and are responsible for scotopic (low light) visual processes [13]. Cone photoreceptors on the other hand encompass a highly invaginated membrane to provide an optimal surface area for phototransduction and are responsible for photopic (normal/high light) visual processes, the perception of colour and visual acuity. Colour vision is achieved through expression of the photopigment opsin, which, depending on the structure of the molecule, confers sensitivity to varying wavelengths of light [9]. Cone photoreceptors typically concentrate within the fovea—an area corresponding to 1.5 mm in diameter at the centre of the human retina where light from the central visual field is focused and which is responsible for high visual acuity and detailed image perception [14]. Within this area, the retina is devoid of the inner retinal layers and retinal vasculature, which ensures minimal interference to focused light when creating a clear foveal image [9]. The region peripheral to the fovea is termed the macula which has a high proportion of cones that extends to a radius of 5.5 mm in diameter [14].

**Figure 1.** Synaptic arrangement of the neuroretina and associated layers. Diagram illustrating the inverted arrange‐ ment of the human neuroretina with light-sensitive photoreceptors forming intimate associations with the underlying retinal pigment epithelium (RPE).

The axons of the RGCs converge at the centre of the retina where they exit the eye through the optic disc and maintain a permanent connection with the brain via the optic nerves (**Figure 2**) [15]. The optic nerve (also referred to as the second cranial nerve) enters the cranial cavity via light) visual processes, the perception of colour and visual acuity. Colour vision is achieved through expression of the photopigment opsin, which, depending on the structure of the molecule, confers sensitivity to varying wavelengths of light [9]. Cone photoreceptors typically concentrate within the fovea—an area corresponding to 1.5 mm in diameter at the centre of the human retina where light from the central visual field is focused and which is responsible for high visual acuity and detailed image perception [14]. Within this area, the retina is devoid of the inner retinal layers and retinal vasculature, which ensures minimal interference to focused light when creating a clear foveal image [9]. The region peripheral to the fovea is termed the macula which has a high proportion of cones that extends to a radius of 5.5 mm in

**Figure 1.** Synaptic arrangement of the neuroretina and associated layers. Diagram illustrating the inverted arrange‐ ment of the human neuroretina with light-sensitive photoreceptors forming intimate associations with the underlying

The axons of the RGCs converge at the centre of the retina where they exit the eye through the optic disc and maintain a permanent connection with the brain via the optic nerves (**Figure 2**) [15]. The optic nerve (also referred to as the second cranial nerve) enters the cranial cavity via

diameter [14].

88 Update on Dementia

retinal pigment epithelium (RPE).

the optic canal where it runs parallel to the middle cranial fossa in close proximity to the pituitary gland. Anterior to the stalk of the pituitary gland, an anatomical crossroad exists known as the optic chiasm, where optic nerves unite and axons from RGCs that reside within the nasal side of both left and right retinas connect with the opposing hemisphere of the brain (**Figure 2**). Conversely, temporal RGC axons project to its corresponding cerebral hemisphere. Soon after exiting the optic chiasm, the RGC axons converge to form the optic tract which predominantly synapses with the lateral geniculate nucleus (LGN), a relay centre for the visual pathway that resides within the thalamus. The internal structure of the LGN comprises several layers which function as maps of visual space and which segregate information according to axonal origin. As the LGN receives information from the right and left visual fields, visual input from the opposing hemisphere is kept separate from that of the corresponding eye. This information is then passed to the visual cortex within the posterior brain for processing via optic radiations formed by the axons of the LGN neurons (**Figure 2**). Here, segregation of visual information is maintained according to the location in the retina from which information was perceived. For example, information derived from the fovea occupies a significant area of the posterior visual cortex, whereas progressively more anterior regions of the visual cortex represent visual perceptions from the periphery of the retina. Several other regions of the brain are innervated from the visual cortex including the occipital, parietal and temporal lobes. These areas are linked with visuoperceptual and visuospatial aspects of vision, as well as visual acuity and the recognition of familiar objects [16, 17].

**Figure 2.** Synaptic terminals of the optic nerve and visual pathway in the brain.

RGC axons within the optic tracts also connect with several diencephalic and midbrain structures. These include the superior colliculi (SC), also termed the optic tectum which is situated on the roof of the midbrain and is involved in controlling eye movement; the supra‐ chiasmatic nucleus (SCN) which is a small, wing-shaped structure within the hypothalamus located directly above the optic chiasm that is involved in circadian rhythm; and nuclei within the midbrain that are implicated in controlling pupil diameter (**Figure 2**). Of note, several of these aforementioned visual centres have been associated with AD pathology. For instance, the SC has been shown to progressively accumulate both Alzheimer-associated senile plaques as well as neurofibrillary tangles (NFT). AD-linked changes have also been reported in the SCN including a reduction in the size, cell number and accumulation of NFTs, which may collectively contribute to the wide range of visual complications reported in these patients [15, 17].
