**3. Ageing and vision**

The term 'ageing' refers to the process of morphofunctional changes that organisms experience as time goes by. That process can be analysed from two main perspectives. On the one hand, there is the view that takes into account the physiological changes that happen to any indi‐ vidual, regardless of life experiences. On the other hand, there is the perspective referring to pathological changes, unique in each individual and related to alterations on the organic balance [65]. The eye is not an exception to this process, and indeed the eye is one of the organs most affected by ageing.

#### **3.1. Theories on ageing**

Diagnosis and follow‐up of AD, especially the early‐onset cases, become difficult, due to imprecise neuropsychological testing, sophisticated but expensive neuroimaging techni‐ ques, and invasive sampling of cerebrospinal fluid [31, 32]. OCT is a reliable noninvasive technique, routinely used in ophthalmology to visualise and quantify the layers of the retina. This technique enables quantitative cross‐sectional imaging of the RNFL and macular volume. As a measure of neuronal degeneration, changes in longitudinal OCT measurements of the RNFL can act as a surrogate marker of axonal health. Thus, OCT could become an invalua‐ ble tool for measuring axonal loss, as a biomarker, in different neurological conditions [33, 51–

In a review of a meta‐analysis which investigates the role of OCT in detecting RNFL thinning in AD patients, it was found that the OCT is a well‐suited paraclinical methodology to assess RNFL thickness in both AD and mild cognitive impairment (MCI) disorders [19]. Macular studies in AD using OCT have recently reported that mild AD patients with a high average score (23.3 ± 3.1) on the Mini‐Mental State Examination (MMSE) had significantly reduced macular nerve‐fibre‐layer thickness with or without significant peripapillary involvement [19, 40, 62, 63]. OCT thus offers the clinician a fast, reliable, reproducible, noninvasive method to

A literature search was performed up to April 2016 using the MEDLINE database, PubMed and Google Scholar search services with the following key words and word combinations: dementia, Alzheimer's disease, ageing, vision, eye, physiopathology, visual pathway, visual

After filtering by author criteria, English or Spanish language, and the condition that they all addressed dementia and vision as the main theme, 325 articles were included after a full text review. All the abstracts were then carefully divided into subcategories covering topics including ageing and vision, visual pathway, physiopathology, visual psychophysical test,

This review covers systematic reviews, original articles and letters to the editor. We did not

The term 'ageing' refers to the process of morphofunctional changes that organisms experience as time goes by. That process can be analysed from two main perspectives. On the one hand, there is the view that takes into account the physiological changes that happen to any indi‐ vidual, regardless of life experiences. On the other hand, there is the perspective referring to pathological changes, unique in each individual and related to alterations on the organic

evaluate and monitor several neurological diseases [64].

psychophysical test, optical coherence tomography, glaucoma.

**2. Search strategy and selection criteria**

contact other authors for further articles inclusion.

Alzheimer's and glaucoma.

**3. Ageing and vision**

61] (**Figure 1**).

382 Update on Dementia

Many theories and classifications have been proposed to explain human ageing, although a combination of several of them may explain the process. In 2013, in a review called 'The hallmarks of ageing' [66], the current theories were widely discussed and nine fundamental traits of ageing were described: genomic instability, telomere shortening, epigenetic changes, loss of proteostasis, deregulation of the detection of nutrients, mitochondrial dysfunction, cell ageing, depletion of stem cells, and altered intercellular communication. Additionally, it is clear that there are other environmental and behavioural factors that can contribute to this degradation process, such as, for instance, smoking and regular exposure to UV light.

#### **3.2. The ageing eye**

As the eye ages, some morphological, structural, and functional changes take place in both the eye itself and other extraocular structures. This process is generically referred to as 'eye ageing'.

#### *3.2.1. Structural changes in the ageing eye*

In the orbit and the adjacent tissue, there is a reduction of the adipose tissue with relative preservation of the nasal fat pad [67]. This generates eyeball sinking (enophthalmos).

The eyelids progressively lose their elastic properties, with an increase in palpebral skin laxity [68].

In the lacrimal gland, there is a proliferation of connective tissue and an atrophy of glandular elements resulting in a decrease in lacrimal tear production [69]. The lacrimal pathology in elderly patients involves different situations ranging from 'dry eye' to profuse lacrimation or epiphora. The result is an alteration in the lacrimal film with its corresponding discomfort and decline in visual acuity (VA).

The conjunctiva undergoes a decrease in density of dendritic cells due to ageing, as well as the degeneration of the subepithelial structures. There is an increase in conjunctival microcysts, indicating that the Goblet cell function is failing, since it has been demonstrated that the Goblet cell population does not decrease in number [70].

The ageing sclera shows hyaline plaques, fat deposits, and loss of aqueous content, hence provoking biomechanical changes due to greater rigidity [71, 72].

Refractively, the ageing cornea suffers a change in keratometry resulting in against‐the‐rule astigmatism. Ageing results in corneal degeneration with a progressive deposit of lipid material that provokes gerontoxon or arcus senilis. Some calcifications appear in the Bowman's membrane periphery while Descemet's membrane thickens. The cornea becomes more rigid and edematous, with a tendency to opacity, causing a sensitivity loss [72, 73]. There is also a reduction in the number of corneal endothelial cells, and hence the development of Fuchs endothelial dystrophy is common. This endothelial loss provokes a dysregulation in corneal homeostasis, which diminishes VA and even leads to blindness [72, 74].

The trabecular meshwork alters its shape due to the ageing process, changing from a wedge‐ shaped structure into a more rhomboidal one [72, 75]. The trabeculae thicken and an ultra‐ structural examination shows a change in the appearance of the extracellular materials [75]. There is a lower number of endothelial trabecular cells as well as of giant vacuoles and intracellular pores in Schelmm's canal [72]. Gonioscopy shows an increase in the trabecular meshwork pigmentation. All of these factors could result in greater resistance to the aqueous outflow, which may favour the onset of glaucoma [76].

The pupil tends to become smaller and the iris is less reactive. There are also more difficulties in terms of pharmacologic dilation of the pupil. Iris pigment is lost with ageing, resulting in iris transillumination in the slit‐lamp examination, especially in the pupillary margin.

The changes in size and tone of the ciliary body, together with the loss of elasticity of the lens capsule and a packing in its fibres, weaken accommodative capacity, causing presbyopia [77].

With age, the lens tends to absorb more blue light (410 nm) due to the accumulation of yellow pigment caused by the oxidation of lens proteins [72]. This is called 'blue blindness' in the cataractogenic processes.

Clinical data from studies on the choroid, using OCT, show an inverse correlation between age and choroid volume [78]. Some histopathological studies have shown a negative correla‐ tion between age and choriocapillaris density [79]. Bruch's membrane is the structure that presents the most changes due to ageing, becoming thicker, with changes in the elastic fibres (calcification among others) and collagen [72]. The major proportion of thickening appears to be due to the deposits of lipids [80] and fibrillar and amorphous material [81]. The basal laminar deposits, material that accumulates between the Bruch's membrane and the retinal pigment epithelium (RPE), are located mainly in the macular area and occasionally appear as drusen [76, 82]. The aforementioned changes in Bruch's membrane lead to the appearance of waste accumulation in the overlying retina. The retinal pigment epithelium, which is vital for the integrity of the rods and cones, shows greater pleomorphism, a lower number of epithelial cells in the posterior pole, a loss of melanin content, an increase in lipofuscin, and a reduction of the cytoplasmic volume [72, 76, 82]. With age, photoreceptor density reduces in the retina [86]. An age‐related loss of rods in the macula occurs with a decline in scotopic sensitivity [72]. In the astroglial plexus of the ganglion‐cell layer and RNFL, the number of astrocytes signifi‐ cantly drops. These cells show stronger GFAP immunoreactivity, more cytoplasmic organelles, glial filaments and lipofuscin deposits [82]. As a result of the ageing process, the retinal‐blood flow diminishes and macular microcirculation diminishes by an estimated 20% [83]. The number of retinal capillaries around the fovea falls and arteriosclerotic changes occur in retinal vessels [72].

In the optic nerve (ON), the number of ON axons reportedly declines [72, 84]. The connective tissue within the fibrovascular pial septae becomes more abundant. As a result, the exchange of nutrients between the capillaries and the nerve fibres is impaired [72]. With ageing, Corpora amylacea may be seen in the ON, appearing as accumulations of intracellular organelles (neurotubules, dense bodies, and mitochondria) in the axons [72].

In the vitreous humour, changes appear in the components of the collagen fibres and hyalur‐ onic acid, causing vitreous floaters [85]. As a result of ageing, the vitreous attachment to the retina weakens, provoking posterior vitreous detachment. This may trigger a contraction at its base, leading to traction on the peripheral retina, which may result in retinal tears [72].

#### *3.2.2. Functional changes in the ageing eye*

endothelial dystrophy is common. This endothelial loss provokes a dysregulation in corneal

The trabecular meshwork alters its shape due to the ageing process, changing from a wedge‐ shaped structure into a more rhomboidal one [72, 75]. The trabeculae thicken and an ultra‐ structural examination shows a change in the appearance of the extracellular materials [75]. There is a lower number of endothelial trabecular cells as well as of giant vacuoles and intracellular pores in Schelmm's canal [72]. Gonioscopy shows an increase in the trabecular meshwork pigmentation. All of these factors could result in greater resistance to the aqueous

The pupil tends to become smaller and the iris is less reactive. There are also more difficulties in terms of pharmacologic dilation of the pupil. Iris pigment is lost with ageing, resulting in

The changes in size and tone of the ciliary body, together with the loss of elasticity of the lens capsule and a packing in its fibres, weaken accommodative capacity, causing presbyopia [77].

With age, the lens tends to absorb more blue light (410 nm) due to the accumulation of yellow pigment caused by the oxidation of lens proteins [72]. This is called 'blue blindness' in the

Clinical data from studies on the choroid, using OCT, show an inverse correlation between age and choroid volume [78]. Some histopathological studies have shown a negative correla‐ tion between age and choriocapillaris density [79]. Bruch's membrane is the structure that presents the most changes due to ageing, becoming thicker, with changes in the elastic fibres (calcification among others) and collagen [72]. The major proportion of thickening appears to be due to the deposits of lipids [80] and fibrillar and amorphous material [81]. The basal laminar deposits, material that accumulates between the Bruch's membrane and the retinal pigment epithelium (RPE), are located mainly in the macular area and occasionally appear as drusen [76, 82]. The aforementioned changes in Bruch's membrane lead to the appearance of waste accumulation in the overlying retina. The retinal pigment epithelium, which is vital for the integrity of the rods and cones, shows greater pleomorphism, a lower number of epithelial cells in the posterior pole, a loss of melanin content, an increase in lipofuscin, and a reduction of the cytoplasmic volume [72, 76, 82]. With age, photoreceptor density reduces in the retina [86]. An age‐related loss of rods in the macula occurs with a decline in scotopic sensitivity [72]. In the astroglial plexus of the ganglion‐cell layer and RNFL, the number of astrocytes signifi‐ cantly drops. These cells show stronger GFAP immunoreactivity, more cytoplasmic organelles, glial filaments and lipofuscin deposits [82]. As a result of the ageing process, the retinal‐blood flow diminishes and macular microcirculation diminishes by an estimated 20% [83]. The number of retinal capillaries around the fovea falls and arteriosclerotic changes occur in retinal

In the optic nerve (ON), the number of ON axons reportedly declines [72, 84]. The connective tissue within the fibrovascular pial septae becomes more abundant. As a result, the exchange of nutrients between the capillaries and the nerve fibres is impaired [72]. With ageing, Corpora

iris transillumination in the slit‐lamp examination, especially in the pupillary margin.

homeostasis, which diminishes VA and even leads to blindness [72, 74].

outflow, which may favour the onset of glaucoma [76].

cataractogenic processes.

384 Update on Dementia

vessels [72].

Normal ageing implies changes in the functionality of the visual system, since there is less light transmission and scattering inside the eye. Also efficiency in phototransduction and photo‐ pigment regeneration declines. The quality of transmission and its synaptic processing in the retina and in the entire visual pathway diminishes [86]. Due to all these changes, vision is affected in different ways. The elderly population experiences significant refractive changes with age. Usually, a change of against‐the‐rule astigmatism takes place as a result of corneal flattening. Moreover, the spherical component becomes more hyperopic due to sclera rigidity, senile myosis and changes in the ageing lens, the latter resulting in a loss of the refractive capacity. The prevalence of oblique astigmatism and anisometropia also increase with age [87].

Visual acuity (VA) worsens with age for many reasons, the standard being a vision of 0.8. Regarding the ageing process, this reduction in near VA may be due to presbyopia or phys‐ iological loss of accommodation because of ciliary muscle‐tone loss. Likewise, the changes in the lens can cause alterations in VA: late‐onset myopia can appear, owing to the rigidity in the lens nucleus that is related to the senile cataract; also, early nuclear sclerosis can cause eye glare.

Contrast sensitivity (CS) undergoes small changes starting in childhood up until the age of 65. After that, the decline is more pronounced, especially in medium and high spatial frequencies. This decline in CS is due partially to the opacity in the media of the eye, which decreases depth perception [87, 88].

With age, the normal visual field (VF) is impaired due to a retraction. The blind spot size enlarges. Additionally, the reduction in the number of cones in the fovea causes a general decline in colour vision [76].

Old people experience trouble with light and dark adaptation and they are incapable of tolerating glare [76].

There are also age‐related binocular problems that affect the neuromuscular mechanisms and the structures of the tissues adjacent to the eye. Patients suffer from accommodation‐conver‐ gence problems and thus, they show greater exophoria in near vision. Vertical deviations and poor stereopsis are very frequent with ageing [89].

#### **3.3. Brain ageing**

The nervous system is particularly vulnerable to ageing due to the main cellular elements of this tissue are post‐mitotic cells and thus their regeneration capacity is limited.

Age‐related worsening of cognitive functions occurs both in humans and in animals. This is especially true for the functions related to executive capacities, attention processes, and the learning and storage of new information. Also, the senescent brain is capable of using func‐ tional strategies to compensate for functional and/or structural deficiencies. This brain plasticity observed in senescence can decrease or mask the clinical expression of brain ageing [90].

#### *3.3.1. Structural changes in the brain*

Research conducted a few years ago on anatomical brain changes seems to demonstrate a clear reduction in brain volume due to neuronal death [91]. The greatest part of this volume loss is the reduction of synaptic density [92] and volume of white matter in the frontal lobes [93]. Even so, the most recent studies indicate that age‐related changes do not affect the brain globally. On the contrary, these changes would be highly limited to the dorsolateral prefrontal cortex and, to a lesser extent, to some subdivisions within the medial temporal lobe, such as the subiculum and the dentate gyrus [94]. It is believed that the age‐related drop in cognitive skills is the consequence of a selective alteration in the corticocortical pathways that connect the temporal and frontal association areas to the corticostriatal pathways [93, 94].

Age‐related microscopic changes include regional brain atrophy [93], axonal cortical dystro‐ phy [95], lipofuscin accumulation [96], astrogliosis [91], neurofibrillary degeneration, senile plaques [97, 98] and scattered vascular or dystrophic focal changes in the white matter [99]. Many of these changes cannot be regarded as being specific to ageing. For instance, most cases of cortical atrophy could indicate an underlying degenerative brain [100] or vascular [101] disease. Changes in the periventricular white matter (leukoaraiosis or subcortical leukoence‐ phalopathy) occur in patients with vascular risk factors, reflecting an insufficiency of the deep vessels of the brain secondary to a hypertensive, diabetic or multifactorial degenerative arteriopathy [102]. Perhaps the only brain change attributable to the passage of time is lipofuscin accumulation; this indicates oxidative stress and lipid peroxidation [96], as well as local synaptic loss [93, 94].

The vascular volume in the brain decreases, specifically the surface of the capillaries [103]. The blood‐brain barrier is selective place for the exchange of nutrients between the blood and the brain parenchyma. With ageing, the molecular transport systems operating at this level are reduced. This has some metabolic consequences for the normal functioning of the nervous system [104].

One of the least known aspects in the ageing process is the role of the brain glial cells [105]. The glia is a group of CNS cells whose main function is to maintain the homeostasis of the neural environment (astrocytes), immunosurveillance (microglia) and the formation of myelin (oligodendrocytes).

It has been demonstrated that, in the ageing brain of experimental animals as well as humans, there is a proliferation of astrocytes which is called reactive gliosis. Its purpose is to mitigate the effects of the physiological age‐related neuronal degeneration [106].

#### *3.3.2. Cognitive functional changes*

Age‐related worsening of cognitive functions occurs both in humans and in animals. This is especially true for the functions related to executive capacities, attention processes, and the learning and storage of new information. Also, the senescent brain is capable of using func‐ tional strategies to compensate for functional and/or structural deficiencies. This brain plasticity observed in senescence can decrease or mask the clinical expression of brain ageing

Research conducted a few years ago on anatomical brain changes seems to demonstrate a clear reduction in brain volume due to neuronal death [91]. The greatest part of this volume loss is the reduction of synaptic density [92] and volume of white matter in the frontal lobes [93]. Even so, the most recent studies indicate that age‐related changes do not affect the brain globally. On the contrary, these changes would be highly limited to the dorsolateral prefrontal cortex and, to a lesser extent, to some subdivisions within the medial temporal lobe, such as the subiculum and the dentate gyrus [94]. It is believed that the age‐related drop in cognitive skills is the consequence of a selective alteration in the corticocortical pathways that connect

Age‐related microscopic changes include regional brain atrophy [93], axonal cortical dystro‐ phy [95], lipofuscin accumulation [96], astrogliosis [91], neurofibrillary degeneration, senile plaques [97, 98] and scattered vascular or dystrophic focal changes in the white matter [99]. Many of these changes cannot be regarded as being specific to ageing. For instance, most cases of cortical atrophy could indicate an underlying degenerative brain [100] or vascular [101] disease. Changes in the periventricular white matter (leukoaraiosis or subcortical leukoence‐ phalopathy) occur in patients with vascular risk factors, reflecting an insufficiency of the deep vessels of the brain secondary to a hypertensive, diabetic or multifactorial degenerative arteriopathy [102]. Perhaps the only brain change attributable to the passage of time is lipofuscin accumulation; this indicates oxidative stress and lipid peroxidation [96], as well as

The vascular volume in the brain decreases, specifically the surface of the capillaries [103]. The blood‐brain barrier is selective place for the exchange of nutrients between the blood and the brain parenchyma. With ageing, the molecular transport systems operating at this level are reduced. This has some metabolic consequences for the normal functioning of the nervous

One of the least known aspects in the ageing process is the role of the brain glial cells [105]. The glia is a group of CNS cells whose main function is to maintain the homeostasis of the neural environment (astrocytes), immunosurveillance (microglia) and the formation of myelin

It has been demonstrated that, in the ageing brain of experimental animals as well as humans, there is a proliferation of astrocytes which is called reactive gliosis. Its purpose is to mitigate

the effects of the physiological age‐related neuronal degeneration [106].

the temporal and frontal association areas to the corticostriatal pathways [93, 94].

[90].

386 Update on Dementia

*3.3.1. Structural changes in the brain*

local synaptic loss [93, 94].

system [104].

(oligodendrocytes).

Age‐related neuromorphological changes trigger cognitive alterations. Cognition is the set of brain activities that enable humans to be aware of themselves, of the others, and of the environment [107]. One of the most important features of cognitive ageing is memory loss. Learning and memory have their neurobiological origin in the hippocampus. The hippocam‐ pus is composed of a series of cell populations that establish certain very precise and well‐ organised synaptic pathways. The information received is processed and sent to the brain cortex for storage and for use in the long‐term memory [108, 109]. Learning processes are based on neuroplasticity, whose neurophysiological basis is long‐term potentiation. This is achieved by a proliferation of AMPA glutamate receptors as well as an increase in dendritic spine density in hippocampal postsynaptic neurons [110]. During the ageing process, a reduction may occur in the neural capacity to synthesise neurotransmitters involved in synapses [111]. The most common neurotransmitters are glutamate, GABA, acetylcholine and dopamine. Changes in the homeostatic levels of these neurotransmitters cause different pathologies that are accen‐ tuated during ageing [112]. For instance, the lowering of acetylcholine levels is one of the most striking features of AD [113].
