**1. Introduction**

The eye is a special sensory organ, as the retina is an extension ofthe brain.Both brain andretina derive from the neural tube and consist of neurons and glial cells. As with the CNS, any insult to the retina and optic nerve cause anterograde and retrograde axon degeneration, myelin destruction, and scar formation. Chronic progressive retinal neurodegeneration is involved in the pathophysiology of ocular diseases [1] such as glaucoma, age‐related macular degenera‐ tion (ARMD) and diabetic retinopathy (DR).

In the brain, neurodegeneration is a key event in disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). PD is a neurodegenerative disease of middle and old age; the origin of defect lies in the basal ganglia and it is characterised by deficiency of dopamine in the mid‐brain area.

AD, the most common cause of dementia, afflicts 67 in 1000 people over the age of 65 and more than 26 million people worldwide, its prevalence and incidence increasing exponentially with age [2, 3]. In 2006, the worldwide prevalence of Alzheimer's was 26.6 million, and by 2050, the prevalence is expected to quadruple [3]. A chronic progressive degenerative neurological disorder affecting cognition and memory [4], AD is characterised by the formation of extrac‐ ellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (made of hyper‐ phosphorylated tau), primarily in the cerebral cortex [5, 6]. Currently, there is no definitive antemortem diagnosis for AD, and therefore new biomarkers for diagnosis are needed. It can be argued that improved methods of screening and early detection are essential to identify patients without cognitive impairment but with a high risk of developing AD. Thus, protocols for early treatment could be established to help slow the disease progression [7]. Over the last few decades, the importance of ophthalmic examination in neurodegenerative diseases of the CNS has reportedly increased. As mentioned above, the retina is an extension of the CNS and thus the impairment of ocular function in patients with CNS degeneration should not be surprising. In fact, both the test exploring visual processing/visual pathways and those examining the retina of such patients display abnormal results. Current in vivo imaging techniques are allowing ophthalmologists to detect and quantify data consistent with the histopathological findings described in the retinas of AD patients years ago [8] and may help to reveal unsuspected retinal and optic‐nerve repercussions of other CNS diseases. Specifically, over the last decades, accurate tools for analysing the eye fundus such as optical coherence tomography (OCT) and laser polarimetry have been developed, opening new ways of examining the retina in vivo. The retinal nerve‐fibre layer (RNFL) is composed of retinal ganglion‐cell axons, which form the optic nerve. Decreased thickness of the RNFL can reflect retinal neuronal ganglion‐cell death and axonal loss in the optic nerve [9, 10], and RNFL reportedly thins with ageing [11, 12]. Notably, some studies have shown that AD patients show greater RNFL thinning than is normal for their age [9, 10, 13–20]. In this context, Hinton et al. [8] were the first to show histopathological evidence of retinal ganglion‐cell loss and optic‐ nerve degeneration in AD patients. These findings were later confirmed in several follow‐up studies [21–24]. Indeed, axonal degeneration of the large M‐cells in AD has been documented [22, 25, 26]. Nevertheless, other histopathological studies [27–33] have failed to confirm these findings, suggesting that methodological differences were responsible for the different results. In addition to the anatomical findings in AD, this disease can exert an impact on most aspects of visual processing, such as visual‐field abnormalities [34–36], colour‐perception deficits [37– 40], pattern electroretinogram changes [26, 41, 42] and reduced contrast sensitivity (CS) [43– 46]. Psychophysical investigations of CS in AD patients have demonstrated results consistent with the neuropathological evidence [47]. However, studies of CS in patients with AD have reported no AD‐related deficits in spatial CS [48, 49], while others have found deficits at all spatial frequencies tested [40, 50].

**1. Introduction**

380 Update on Dementia

the mid‐brain area.

tion (ARMD) and diabetic retinopathy (DR).

The eye is a special sensory organ, as the retina is an extension ofthe brain.Both brain andretina derive from the neural tube and consist of neurons and glial cells. As with the CNS, any insult to the retina and optic nerve cause anterograde and retrograde axon degeneration, myelin destruction, and scar formation. Chronic progressive retinal neurodegeneration is involved in the pathophysiology of ocular diseases [1] such as glaucoma, age‐related macular degenera‐

In the brain, neurodegeneration is a key event in disorders such as Parkinson's disease (PD) and Alzheimer's disease (AD). PD is a neurodegenerative disease of middle and old age; the origin of defect lies in the basal ganglia and it is characterised by deficiency of dopamine in

AD, the most common cause of dementia, afflicts 67 in 1000 people over the age of 65 and more than 26 million people worldwide, its prevalence and incidence increasing exponentially with age [2, 3]. In 2006, the worldwide prevalence of Alzheimer's was 26.6 million, and by 2050, the prevalence is expected to quadruple [3]. A chronic progressive degenerative neurological disorder affecting cognition and memory [4], AD is characterised by the formation of extrac‐ ellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (made of hyper‐ phosphorylated tau), primarily in the cerebral cortex [5, 6]. Currently, there is no definitive antemortem diagnosis for AD, and therefore new biomarkers for diagnosis are needed. It can be argued that improved methods of screening and early detection are essential to identify patients without cognitive impairment but with a high risk of developing AD. Thus, protocols for early treatment could be established to help slow the disease progression [7]. Over the last few decades, the importance of ophthalmic examination in neurodegenerative diseases of the CNS has reportedly increased. As mentioned above, the retina is an extension of the CNS and thus the impairment of ocular function in patients with CNS degeneration should not be surprising. In fact, both the test exploring visual processing/visual pathways and those examining the retina of such patients display abnormal results. Current in vivo imaging techniques are allowing ophthalmologists to detect and quantify data consistent with the histopathological findings described in the retinas of AD patients years ago [8] and may help to reveal unsuspected retinal and optic‐nerve repercussions of other CNS diseases. Specifically, over the last decades, accurate tools for analysing the eye fundus such as optical coherence tomography (OCT) and laser polarimetry have been developed, opening new ways of examining the retina in vivo. The retinal nerve‐fibre layer (RNFL) is composed of retinal ganglion‐cell axons, which form the optic nerve. Decreased thickness of the RNFL can reflect retinal neuronal ganglion‐cell death and axonal loss in the optic nerve [9, 10], and RNFL reportedly thins with ageing [11, 12]. Notably, some studies have shown that AD patients show greater RNFL thinning than is normal for their age [9, 10, 13–20]. In this context, Hinton et al. [8] were the first to show histopathological evidence of retinal ganglion‐cell loss and optic‐ nerve degeneration in AD patients. These findings were later confirmed in several follow‐up studies [21–24]. Indeed, axonal degeneration of the large M‐cells in AD has been documented [22, 25, 26]. Nevertheless, other histopathological studies [27–33] have failed to confirm these

**Figure 1.** Retinal nerve fibre layer (RNFL) thickness analysis. Optical coherence tomography (OCT) study. (**A**) Peripa‐ pillary OCT. Upper left: peripapillary retinography with a green circle marking the retinal tissue considered for analy‐ sis. Upper right: diagram of the peripapillary quadrants analysed: temporal quadrant (316–45), superior quadrant (46– 135), nasal quadrant (136–225), inferior quadrant (226–315). Bottom: retinal b‐scan and diagram of thickness normality. (**B**) Macular OCT. Upper left: central retinography with a green square marking the retinal tissue considered for analy‐ sis. Upper right: diagram showing the concentric rings and quadrants considered for analysis of the macular RNFL thickness and measurements automatically provided by the analyser. Bottom: retinal b‐scan of the macula. ETDRS: Early Treatment Diabetic Retinopathy Study (from Figure 1 of [19] with permission).

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– 61] (**Figure 1**).

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 evaluate and monitor several neurological diseases [64].
