Histological and OCT studies in AD demonstrated a significant loss of RGCs and consequent axonal depletion in the optic nerve. Hinton and colleagues in 1986 reported the first histological demonstration of optic neuropathy in AD describing loss of RGCs and axons in the optic nerve (13). After this seminal work, other histological studies reported degeneration of the inner retina in AD, more pronounced in the superior and inferior sectors of the optic nerve (14–20).

These histological findings are corroborated by many recent OCT studies pointing to retinal nerve fiber layer (RNFL) thinning in AD, as confirmed by a recent meta-analysis of 11 OCT studies in AD (21). RNFL thinning is more pronounced in the superior sector of the optic nerve (20–23) and is age related (20) (Figure 1). This pattern of RGC loss is consistent with the predominant inferior visual field defect described in AD patients (24). Moreover, a recent OCT study using segmentation analysis in a large series of AD patients showed a significantly reduced macular retinal ganglion cell–inner plexiform layer thickness in AD retinas compared to controls (25).

The pattern of axonal loss in the optic nerve, for example, the prominent superior quadrant involvement, is consistent with the histological findings that magnocellular RGCs are more vulnerable to AD pathology (16), which also resembles the pattern of RGC loss described in glaucoma (26). Recently developed in vivo imaging methods, such as the detection of retinal cells undergoing apoptosis (DARC), are extremely promising in quantifying and visualizing in vivo RGC loss in AD retinas (27).

The presence of the cerebral hallmarks of AD, such as amyloid plaques, in the retina gives strength to the specific vulnerability of the eye, and in particular of the inner retina to AD pathology. Koronyo-Hamaoui and colleagues provided the first demonstration of extra-cerebral Aβ deposits in postmortem human flat-mounted retinas of AD patients and ex vivo in APPSWE/PS1ΔE9 transgenic mice after curcumin administration (28). Subsequent studies confirmed the presence of specific amyloid pathology, including both extracellular plaques and intracellular Aβ deposits, more evident in the superior quadrant, and increased Aβ peptides levels in human AD retinas (20, 29, 30) (Figure 1). Other promising imaging techniques, recently developed for visualizing amyloid deposits in AD retinas, include hyperspectral imaging (31), the use of cross-polarizers (32), and the polarization-sensitive OCT (33). Schön and coauthors also demonstrated the presence of the other hallmark of AD pathology, such as the phosphorylated tau, in human AD retinas (34).

Finally, our group recently demonstrated that a specific subpopulation of RGCs, the mRGCs, are specifically lost in AD and affected by the amyloid pathology. In fact, using melanopsin and Aβ co-staining, our group showed that Aβ deposits are evident within and around these cells affecting also mRGC neuritis (20). Remarkably, the loss of these cells is evident even with a normal RGC count, pointing to a specific AD pathology affecting mRGCs (20). The loss of these cells is particularly relevant for interpreting the occurrence of sleep and circadian disturbances in AD (see next section).

The occurrence of visual problems is a frequent finding in PD patients. These include blink, dry eyes, reduced visual acuity, contrast sensitivity, color vision abnormalities, oculomotor disturbances, and visual hallucinations (35, 36).

In particular, contrast sensitivity abnormalities are related to dopamine depletion at the retina levels (37–39) and can be partially reversed by the administration of l-DOPA therapy in PD patients (40). In fact, dopaminergic amacrine cells in the retina regulate the center-surround organization of RGC receptive fields and their dysfunction leads the retina to be in an inappropriately dark-adapted state (35). Color vision in PD patients is an early sign involving, at difference with the color defects observed with aging, the protan–deutan axis (red–green) (41). Interestingly, color vision abnormalities have good discriminative power in distinguishing PD patients from controls in the early stage of disease and may predict the conversion of idiopathic REM behavior disorder patients to PD (42, 43). However, the Farnsworth–Munsell 100 Hue test, commonly used for testing color abilities in PD, is influenced also by cognitive functions such as executive functions, and this must be taken into account in the interpretation of these results.

Besides the retinal dopaminergic depletion, which explains the occurrence of contrast sensitivity abnormalities in PD, there are multiple evidences pointing to RGC loss in PD (44, 45) (Figure 1). The presence of optic neuropathy has been reported by many OCT studies and, interestingly, the pattern of axonal loss resembles that typically seen in mitochondrial optic neuropathies, affecting the temporal sector of the optic nerve, i.e., the papillomacular bundle (RGC) (44, 46, 47). This pattern of RGC loss, which affects predominantly the parvocellular component, is clearly distinguishable from that described in AD, for which more frequently the magnocellular RGCs are affected (16, 20, 21) and other Parkinsonian syndromes, such as multiple system atrophy (Figure 1) (48).

Moreover, the optic neuropathy in PD is more pronounced in the eye contralateral to the most affected body side (46), suggesting a congruent asymmetry of the neurodegenerative process affecting also the retina. This asymmetry has been also documented for the foveal remodeling demonstrated in PD patients, as a hallmark of retinal pathology in PD (49, 50).

Finally, recent studies reported the presence of α-synuclein deposition in the retina of PD patients and in particular in the inner retina, pointing to a specific PD pathology affecting the eye (51, 52) (Figure 1). Interestingly, the staining of phosphorylated synuclein (p-syn) shown by Beach and colleagues (52) affected a large cell with an extensive dendritic tree, which resembles an mRGC. The possible occurrence of α-synuclein pathology affecting the mRGCs in PD may contribute to the occurrence of circadian dysfunction in PD that remains to be tested.

Sleep and circadian disturbances are a frequent complaint of AD patients, appearing in the majority of cases early in the disease course and including daytime somnolence, increased sleep latency, and frequent night-time awakenings with sleep fragmentation (3). Some of the sleep changes described in AD are the same reported with aging, such as the reduction of slow wave sleep and the difficulty in sleep maintenance (53). Other sleep abnormalities, such as the reduction of REM sleep, are more specifically related to AD (54).

Circadian rhythm abnormalities are reported in AD patients even in the early stage of the disease including a delayed phase of the temperature rhythm (55), sundowning, i.e., the appearance of behavioral agitation in the evening (56), the reduction of melatonin levels during the night (57), and the circadian expression profile of clock genes (57, 58). Moreover, abnormalities of the rest–activity circadian rhythm, including increased intra-daily variability (IV) and reduced inter-daily stability (IS) and relative amplitude of the rest–activity rhythm are described in AD (59, 60), and the presence of circadian dysfunction may predict a poor outcome in terms of cognitive functions (59).

We recently demonstrated the presence of variable degrees of rest–activity circadian dysfunction in mild–moderate AD patients and a specific loss of mRGCs in AD retinas (20). A specific AD pathology affecting these cells may contribute to circadian dysfunction in AD patients. Moreover, these cells have a direct effect on sleep through direct and indirect projections to brain nuclei relevant for sleep regulation such as the LH and the VLPO (61, 62). The role of mRGC loss in contributing to sleep and circadian misalignment in AD is particularly relevant for its potential therapeutic options. In fact, the use of bright light therapy has been proven to be effective in counteracting sleep and circadian dysfunction in AD (63, 64).

Other possible components of the circadian imbalance demonstrated in AD is the presence of SCN neuronal loss and amyloid pathology documented in neuropathological studies of AD postmortem brain (65, 66), which correlates with the degree of rest–activity disruption (67) and can contribute secondarily to the mRGC loss demonstrated in AD retinas.

The strict relationship between cognition, sleep, and circadian rhythms is highlighted also by the demonstration that the presence of circadian dysfunction may predict the onset of dementia (68), as well as that sleep loss may promote the accumulation of amyloid and predispose to AD (53, 69). Many recent studies point to direct and indirect effects of circadian derangement in cognitive disturbances and hence dementia. Counteracting the circadian imbalance may have important clinical implications. A summary of circadian abnormalities in AD is reported in Table 1.

Sleep disturbances are reported in about 80% of PD patients (5). Furthermore, circadian dysfunction has been extensively described in PD patients, in terms of the following: (1)

Abnormal melatonin rhythm, i.e., abnormal phase angle of melatonin rhythm (70, 71) and decreased amplitude (72, 73). However, the phase advance of the melatonin rhythm documented by these studies was evident only in l-DOPA-treated PD patients, suggesting a possible influence of medications on these findings.

Interestingly, at difference with AD, where neuropathological hallmarks of pathology such as amyloid plaques and neurofibrillary tangles are described in the SCN of the hypothalamus, the neurodegenerative changes characteristics of PD, such as synuclein deposition and Lewy bodies, are not reported in the SCN. This suggests that in PD, the circadian imbalance, at least in the early phase, is not primarily due to a master clock pathology (6). This is consistent with the finding that PD patients in the early stage of the disease do not exhibit frank circadian rhythm abnormalities, such as for melatonin and other hormones (6, 83). It is not clear, based on the currently available evidences, if circadian misalignment occurs as an independent hallmark of PD pathology or can be interpreted as a consequence of many other non-motor manifestations of PD, such as sleep, cognitive, and behavioral problems. Moreover, the investigation of circadian dysfunction in PD is hampered by the possible influence of many confounding factors, such as the motor fluctuations intrinsic to the disease and the influence of l-DOPA therapy. However, the presence of circadian imbalance in PD is well supported by circadian abnormalities described in many animal models of PD [for a review, see Ref. (79)].

In this complex scenario, a possible role in the pathogenesis of circadian problems described in PD patients can also involve the eye, and in particular the mRGC system. At this regard, there is documentation of a strict interaction between the mRGCs and the dopaminergic amacrine cells (84), a depletion of dopamine levels, and a specific synuclein deposition, particularly in the inner retina (39, 51, 52). Furthermore, a possible direct link between the eye, through the regulation of the melatonin synthesis, and the motor symptoms of PD has been postulated by Willis (85), as supported by the amelioration of motor symptoms after light exposure in PD patients (86). A summary of the main circadian abnormalities in PD is reported in Table 1.

In this wide scenario, it is possible that many factors, including the influence of mRGCs on modulating circadian rhythms and sleep, may play a role in the pathogenesis of circadian and sleep problems in PD. A more detailed investigation of this system is warranted, especially in de novo PD cases to elucidating the mechanisms behind.