**4. The eye as an extension of the central nervous system**

Given that the eye is an extension of the CNS, evidence is being sought to determine whether the retina is a window to the brain and whether eye research could improve our understanding of CNS disorders [114]. The retina is made up of specialised neuron layers that are intercon‐ nected via synapses. The light that enters the eye is captured by the photoreceptor cells in the outer retina, initiating a cascade of neural signals that finally reach the retinal ganglion cells (RGCs), whose axons form the ON. These axons project to the lateral geniculate nucleus (LGN) in the thalamus and to the superior colliculus (SC) in the midbrain, whose information is then transmitted to more specialised visual processing centres that provide a perception of the world [114, 115].

Most of the RGC axons come together to form the ON. After passing through the lamina cribrosa of the eye the ON is covered by a myelin sheath produced by the oligodendrocytes and surrounded by the three meningeal layers. As in the CNS, ON injury may result in anterograde and retrograde degeneration of the damaged axons, scarring, myelin destruction and creation of a neurotoxic environment involving oxidative stress, deprivation of neurotro‐ phic factors, raised levels of excitotoxic neurotransmitters and abnormal aggregation of proteins and waste products. Such a hostile environment often provokes the death of the initially undamaged neighbouring neurons in a process called secondary degeneration [116– 121].

Axonal regeneration after injury is limited both in the CNS and ON. In fact, most of our knowledge on axonal response to traumatic brain injury stems from studies of the ON [122– 128]. The factors responsible for creating an environment that is non‐permissive for axonal growth are the same by CNS and ON. The first discoveries of CNS axon regeneration in the presence of peripheral nerve grafts were performed in experimental models of ON transection and of spinal‐cord injury [122, 123, 129]. We should underline that there are similar restrictive growth conditions in these two structures of the nervous system.

The eye, and especially the retina as a part of the CNS, must maintain regulated interactions with the immune system. In fact, the retina occupies a special immune site. The eyeball is made up of some unique physical structures and contains a set of surface molecules and cytokines responsible of some specialised immune responses, similar to those observed in the brain and the spinal cord [130, 131]. The eye possesses the blood‐retinal barrier, whose structure, characteristics and mechanisms are similar to those of the blood‐brain barrier. The anterior chamber of the eye contains the aqueous humour, a fluid with anti‐inflammatory and immu‐ noregulatory mediators. This fluid resembles the cerebrospinal fluid circulating around the brain and the spinal cord parenchyma [132, 133]. Besides the similarities with the CNS, the ocular immunoprivilege involves a unique phenomenon called 'anterior chamber associated immune deviation' (ACAID), wherein the antigen‐presenting cells entering the anterior chamber capture the antigen and then migrate to the spleen. There the effector leukocytes become regulatory leukocytes. This process establishes a tightly regulated immune response towards ocular antigens [130]. The combination of the aforementioned mechanisms allows the eye to benefit from the immune defence machinery that would eliminate the risk of tissue damage due to uncontrolled inflammation [114].

#### **4.1. Visual pathway**

The visual information collected by the photoreceptors (rods, sensitive to contrast; and cones, sensitive to colour) goes through the inner plexiform layer of the retina (bipolar, horizontal and amacrine cells) to the RGC layer (midget, parasol and bistratified cells) [134]. The layout of these three different RGC types forms different receptive fields, which help in segregating and coding visual information [135]. Then, the RGC are projected through different pathways (parvocellular (P), magnocellular (M) and koniocellular (K)) to the sub‐cortical region of the LGN and to the V1 cortical area [135–137]. The P‐pathway receives colour and shape infor‐ mation from the midget cells. The K‐pathway receives some blue‐on/yellow‐off opponent colour information from the bistratified cells. Finally, the M‐pathway carries the luminance and motion data from the parasol cells. Thus, the visual information segregated in the V1 region is projected into the V2 region for processing [135, 138, 139]. The information about colour, orientation and spatial frequency continues ventrally through V2 and V4. This route continues to the infero‐temporal cortex, where more‐complex aspects of the visual processing of objects are carried out, such as face perception. Motion and location follow the dorsal pathway through V2 and V3. The V3 dorsal area seems to be specialised in the detection of global motion [140, 141]. The V5 is specialised in local movement [142]. The dorsal pathway continues to the posterior parietal cortex, where the complex aspects of spatial perception, e.g. details within a scene as an integrated perception are processed [141].

#### **4.2. Ocular manifestations of CNS disorders**

As mentioned above, the eye is an extension of the brain, and therefore it seems reasonable to look for some ocular manifestations of brain pathologies. In fact, in patients with CNS pathologies such as EP, multiple sclerosis (MS), amyotrophic lateral sclerosis, and AD, ophthalmological changes have been observed. Notably, many of these changes are not exclusive to a certain disease, highlighting the relationship between the retina and the brain. Likewise, in many of these CNS disorders the ocular symptoms precede the cerebral symp‐ toms. Therefore, eye examinations could help in the early diagnosis of these CNS diseases.

#### *4.2.1. Stroke*

presence of peripheral nerve grafts were performed in experimental models of ON transection and of spinal‐cord injury [122, 123, 129]. We should underline that there are similar restrictive

The eye, and especially the retina as a part of the CNS, must maintain regulated interactions with the immune system. In fact, the retina occupies a special immune site. The eyeball is made up of some unique physical structures and contains a set of surface molecules and cytokines responsible of some specialised immune responses, similar to those observed in the brain and the spinal cord [130, 131]. The eye possesses the blood‐retinal barrier, whose structure, characteristics and mechanisms are similar to those of the blood‐brain barrier. The anterior chamber of the eye contains the aqueous humour, a fluid with anti‐inflammatory and immu‐ noregulatory mediators. This fluid resembles the cerebrospinal fluid circulating around the brain and the spinal cord parenchyma [132, 133]. Besides the similarities with the CNS, the ocular immunoprivilege involves a unique phenomenon called 'anterior chamber associated immune deviation' (ACAID), wherein the antigen‐presenting cells entering the anterior chamber capture the antigen and then migrate to the spleen. There the effector leukocytes become regulatory leukocytes. This process establishes a tightly regulated immune response towards ocular antigens [130]. The combination of the aforementioned mechanisms allows the eye to benefit from the immune defence machinery that would eliminate the risk of tissue

The visual information collected by the photoreceptors (rods, sensitive to contrast; and cones, sensitive to colour) goes through the inner plexiform layer of the retina (bipolar, horizontal and amacrine cells) to the RGC layer (midget, parasol and bistratified cells) [134]. The layout of these three different RGC types forms different receptive fields, which help in segregating and coding visual information [135]. Then, the RGC are projected through different pathways (parvocellular (P), magnocellular (M) and koniocellular (K)) to the sub‐cortical region of the LGN and to the V1 cortical area [135–137]. The P‐pathway receives colour and shape infor‐ mation from the midget cells. The K‐pathway receives some blue‐on/yellow‐off opponent colour information from the bistratified cells. Finally, the M‐pathway carries the luminance and motion data from the parasol cells. Thus, the visual information segregated in the V1 region is projected into the V2 region for processing [135, 138, 139]. The information about colour, orientation and spatial frequency continues ventrally through V2 and V4. This route continues to the infero‐temporal cortex, where more‐complex aspects of the visual processing of objects are carried out, such as face perception. Motion and location follow the dorsal pathway through V2 and V3. The V3 dorsal area seems to be specialised in the detection of global motion [140, 141]. The V5 is specialised in local movement [142]. The dorsal pathway continues to the posterior parietal cortex, where the complex aspects of spatial perception, e.g.

details within a scene as an integrated perception are processed [141].

growth conditions in these two structures of the nervous system.

damage due to uncontrolled inflammation [114].

**4.1. Visual pathway**

388 Update on Dementia

Prospective studies have shown that retinal microvascular abnormalities (formation of arteriovenous crossings, bleeding, and arteriolar narrowing) could predict the risk of cerebral ischemic changes and stroke [143–145]. In addition, the presence of a retinopathy with arteriovenous crossings has been linked to an increased risk of stroke, especially when these retinal abnormalities were associated with lesions in the cerebral white matter, a feature which is usually indicative of stroke [143, 145, 146]. Beyond these prospective studies, other research on the eyes in some animal models have shown that stroke is associated with functional impairment of the retina, including thinning of the retinal layers, reactive gliosis, increased expression of genes associated with cell damage, restricted oxygen supply, DNA fragmenta‐ tion and ON neurodegeneration [147].

Ocular manifestations are to be expected in stroke, because the small vessels of the retina and the brain have similar embryological origins, anatomical characteristics and physiological properties [148, 149]. Some dysfunctions in the blood‐brain and the blood‐retinal barriers are suspected of playing a central role in the development of brain and retinal microangiopathy, respectively [131, 150, 151].

#### *4.2.2. Multiple sclerosis (MS)*

Visual impairment in MS is a major cause of disability. Visual loss is a symptom that occurs in up to 50% of patients with MS, resulting in some degree of visual impairment throughout the course of the disease for most cases [152–154].

It is not surprising that MS is related to eye disease, since the myelin components, which are essential in both the brain and the visual pathway, are the major autoimmune targets in MS. Visual defects are usually the result of axonal demyelination along the visual pathway [155]. It has been found that some internal areas of the retina, which are not associated with myelin, are also affected in MS. This suggests that the autoimmune response is also directed against other antigens in the eye [156].

Retrobulbar optic neuritis is an inflammatory optic neuropathy associated with demyelination and degeneration of the RGC. Diagnosed in 75% of patients with MS, this is often the first symptom of the disease [154, 155, 157]. It is important to highlight that visual deficits in MS also occur in patients without an optic neuritis diagnosis. Several studies have shown that, although the VA is not affected [158–160], there is a decrease in CS [158–160] and the RNFL thickness in MS patients in comparison with healthy individuals [160, 161]. RNFL thickening occurs in both the peripapillary [60, 160, 162, 163] and the macular area [54, 60]. Furthermore, RNFL thinning in MS patients directly correlates with the progression of neurological impairment and disease duration [160].

#### *4.2.3. Parkinson's disease (PD)*

PD is a chronic neurodegenerative disorder that is associated mainly with motor dysfunction, although it can also involve some non‐motor symptoms, including visual deficits. These deficiencies may manifest as decreased CS [59, 163], impaired colour vision (the tritan axis is altered first) [57], and abnormal electrophysiological responses [57, 164]. The retinas of PD patients show photoreceptor and RGC dysfunction, morphological deterioration of the perifoveal dopaminergic plexus [165], and thinning of the RNFL [52, 53, 164, 166, 167]. According to the hypothesis that the disease results from a dopamine imbalance, it seems that visual deficits in PD could also be caused by dopamine depletion. In fact, some of the visual deficits experienced by PD patients can be improved by levodopa treatment [168].

#### *4.2.4. Alzheimer's disease (AD)*

The first abnormalities in the visual system for AD, observed in the 1970s, were regarded strictly as a dysfunction at the cortical level. Subsequent studies over the past 25 years have revealed that all parts of the visual system, including the ON and the retina, may be affected in AD. Some aspects of this involvement are still not well understood and are still the subject of recent research. Anatomical changes along the visual pathways and their corresponding functional changes have been detected and analysed by psychophysical procedures. AD can affect different aspects of the visual processing in line with the impact of the disease in the dorsal and ventral regions of the brain. Patients with dorsal‐region damage suffer alterations in functions such as discrimination and angular‐motion perception [169–172]. Those with damage in the ventral region show difficulty in discriminating faces, colours, and shapes [37, 173, 174].
