Neurodegenerative diseases are a heterogeneous group of clinical entities, often presenting with overlapping clinical pictures and characterized by progressive loss of neuronal populations in different brain regions including the visual system. The most relevant neurodegenerative entities in terms of prevalence and impact worldwide are Alzheimer's disease (AD) and Parkinson's disease (PD). Their socioeconomic relevance is currently high and is expected to grow up in the future. AD is an invariably fatal senile dementia with no cure and with a limited ability for early unequivocal diagnosis in primary care settings (1). AD is clinically represented by severe cognitive decline, sociobehavioral manifestations, and various visual dysfunctions (2, 3). Its neuropathology begins with the accumulation and propagation of misfolded amyloid β-protein (Aβ) assembly, followed by the hyperphosphorylation of (p)tau proteins, forming neurofibrillary tangles (NFTs) (4). These processes are associated with a cascade of secondary pathologic events, including inflammatory responses, vascular-associated abnormalities, oxidative stress, and mitochondrial dysregulation, leading to massive synaptic and neuronal loss (5–7). Importantly, growing evidence indicates that AD progressively spreads across the brain involving all visual system from the retina to primary and associative visual cortex (8, 9). PD is the second most common neurodegenerative disease, characterized by motor dysfunctions, such as tremor, rigidity, and bradykinesia, in addition to cognitive deficits, mood variability, and dementia (10, 11). Similar to AD patients, PD patients also complain of visual disturbances such as diplopia and hallucinations (12–14). The pathological hallmark of the diseases is the progressive accumulation of α-synuclein, a neurotransmitter involved in physical movement and reward-seeking behavior, and the depletion of cerebral dopamine. In recent years, various attempts of identifying surrogate clinical markers have been made with the aim of determining specific indicators of disease that may orientate early diagnosis and treatment or may have a prognostic value or improve the quality of life. The visual system from the peripheral sensory organs to the central integration system may be an early target of neurodegeneration in PD and dementia spectrum disorders. In both AD and PD, the progressive damage of visual function affects overall cognitive and motor abilities, is a risk factor for developing hallucinations, and can have a significant influence on general quality of life. Despite a broad variety of ocular disorders and visual problems being reported in patients with PD and AD, their systematic assessment has remained largely out of focus both in research and clinical practice.

With the aim to increase awareness for ocular and visual disorders, easily assessable in an outpatient setting, we collected the main neurophthalmologic and orthoptic parameters, including optical coherence tomography (OCT), in six patients with a diagnosis of PD, six patients with a diagnosis of AD, and eight control subjects. Moreover, in order to evaluate high-order visual function, we also assessed the ability to recognize changes in facial expressions. All patients were in the early stage of the disease and responded well to the treatment. Although ophthalmological examination in these patients frequently shows abnormalities, differences between PD and AD have never been evaluated previously. Our study further supports the idea that visual disturbances are common in PD and AD patients. Moreover, we found a significant damage of ganglion cells (GCs), retinal nerve fibers layer (RNFL), and a defect in facial emotion recognition, with peculiarities depending upon the disease. Ocular misalignment and vergence insufficiency or visual discomfort could be correctly evaluated in these patients and possibly corrected by means of lens, orthoptic exercises, and visual rehabilitation. This practical approach improves motor autonomy, that is, the ability of the subject to move autonomously in the surrounding environment to perform common daily activities.

Almost 80% of visual impairments worldwide are treatable or preventable; thus, timely recognition is pivotal in the general population (15). An intact vision is crucial in AD to preserve as long as possible visual-dependent cognitive functions, and in PD patients for compensating, through visual guidance, the loss of motor automaticity and postural instability. In this study, we confirm that ocular and visual problems commonly occur in patients with AD and PD, compared to healthy subjects of the same age who come to a neurophthalmologic outpatient service. Similar pathological involvement of the visual system is present in both diseases but also in aging. Nevertheless, in our study, differences emerged between the groups. Large population studies have demonstrated a greater prevalence of age-related visual problems among elderly people with mild cognitive impairment/dementia and PD (16, 17) compared to normal individuals (18, 19).

Ocular and visual changes, in terms of incidence, prognosis, and clinical relevance, have been extensively investigated in each disease; nevertheless, there are very few reports comparing them in a practical outpatient setting. The results of our study demonstrate that visual acuity, color vision, and confrontation visual field were in the normal range in all patients; rather, they complained more subtle difficulties, regarding the quality of their vision such as inconstant double or blurred vision and visual discomfort when reading, asthenopia, photophobia, and glare, which were not reported by our control group. We also found a higher prevalence of latent eye deviations (heterophorias, exo/eso-phorias) with larger angle of deviation in PD than AD. All PD patients showed exophorias greater in near viewing, which was associated to CI, remote NPC, and inconstant diplopia. Unlike PD, AD patients had small exo- or eso-phorias and less affected convergence amplitude. It has been reported that more than 20% of PD patients experience intermittent diplopia, which is mostly associated to oculomotor abnormalities and less frequently, due to impaired vision or visual hallucinations (13). The most prevalent oculomotor abnormalities causing misalignment in PD are those related to fusional disorders, including convergence insufficiency, decompensating exophoria, and reduced fusional range. This general impairment of vergence eye movements results from basal ganglia dysfunctions and improve with dopaminergic replacement therapy (20). On the other hand, daily fluctuations in dopamine levels may, in turn, produce inconstant convergence insufficiency. The prevention of dopamine fluctuations associated to orthoptic exercise and prisms may alleviate visual problems in these patients (20, 21). In our experience, photophobia, glare, and dry eye may be alleviated using lenses with specific filters, artificial drops, and cataracts surgery.

Contrary to PD, reading difficulties reported by AD patients are less likely related to convergence insufficiency and fusional disorder but may indicate an early cortical disturbance of visual perception or sensory motor integration. Early pathological changes in visual integration areas may produce subtle deficit of visual spatial attention or ambiguity in distinguishing letters, object shapes, or orientation. Overall, these symptoms are distinctive features of the posterior variant of dementia, but, even if less prominent, may also be present in the more common variants of AD (17, 22). Rehabilitation of visual attention and other cortical visual functions using eye tracking and orthoptic exercises have been suggested to reduce the impact of these symptoms on patient's autonomy (17).

In this study, we also demonstrate a reduction of the RNFL and GCL in both patient's groups with respect to normal controls with further differences distinguishing the two diseases. In particular, we found a global decrease of the RNFL thickness in both patients compared to controls. Analogously to what was reported in the literature, the RNFL thinning is typically localized in the superior and inferior quadrants without significant differences among groups (see Figure 1) (23, 24).

A more sensitive parameter in differentiating the three groups was the GCL thickness. According to previous OCT studies (25–27), we demonstrated a GC loss in the superior quadrants of AD patients with respect to both PD and controls; however, due to the small sample, the difference did not reach the level of significance. Figure 2 shows a different trend of the curves representing GCL thickness across retinal quadrants. Several post-mortem studies and animal models have revealed the AD-specific hallmarks in the retina. Aβ plaques and hyperphosphorylated (p)tau were particularly abundant in the inner retinal layers, especially in the GCL (28) and co-localized around and within degenerating retinal GCs (29). Furthermore, multiple recent studies into region-specific retinal degeneration in AD patients showed that the most significant damage of the inner retinal layer and RNFL are localized in far and midperiphery of the superior quadrant (30, 31). Analogously, studies examining the retina of PD patients by OCT have revealed a significant thinning of macular volume (32–34) and a decrease of GCL and RNFL thickness mostly in inferior and temporal quadrants (23, 24, 35, 36) compared to healthy subjects.

In both diseases, OCT parameters have been correlated with clinical scores of disease progression supporting the important role of OCT in monitoring both PD and AD evolution (37).

Finally, all patients demonstrated a difficulty in the recognition of facial expression changes, particularly for negative emotions. In particular, AD patients showed a significant higher number of errors in identifying the correct emotion and a longer latency than PD, and both did worse than the controls. Recognition of emotional expressions is considered an important prerequisite for interpersonal functioning and quality of life. Emotion perception has been shown to rely on a ventral affective system, including the hippocampus, amygdala, insula, ventral striatum, and ventral regions of the anterior cingulate gyrus and prefrontal cortex (38). Regions in the ventral system, including the amygdala, are susceptible to atrophy in PD and AD at any stage. Both groups experienced difficulty with negative emotions recognition (see Figure 3) compared with controls. In a quantitative MRI study, a direct correlation has been found between temporal volume and low score in negative facial expression recognition. However, while previous reports agree with the observation that negative emotions are poorly recognized in AD and PD, conflicting results have been obtained when searching for a specific emotion (39, 40). Most studies on facial expression recognition have been made using a static image presentation, which is a less naturalistic and less-sensitive approach. In this study, we proposed an emotion-intensity-based approach using an interactive software that is more sensitive to identify subtle impairment in detecting specific facial expression changes. Moreover, most studies suggest that deficits in emotion perception occur in the context of unimpaired face perception (41); however, we found a significant longer latency in the identification of expression changes, suggesting almost in part, a slow facial perception or processing load in both pathological conditions, particularly AD.

A limitation of the study is the small sample; however, even if further studies will be necessary to confirm the differences between groups, it is evident that visual deficits are common, occur early, and impact the quality of life in both diseases. Early identification of visual changes is useful for developing interventions that are specifically targeted at these core visual problems in AD and PD patients. Among intervention, orthoptic rehabilitation may help to minimize ocular symptoms, contributing to improve every activities of day living. A home and outpatient exercise program, based on NPC and vergences training, pencil push-ups, prisms, and 3D stereograms exercises, is an effective treatment in convergence insufficiency. Prismatic lenses can be a satisfactory solution in case of subjective diplopia. In conclusion, clinicians should be encouraged to consider orthoptic rehabilitation, a therapy with minimal risk, in patients with neurodegenerative disease whose quality of life is affected by binocular dysfunction.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethical Committee Azienda Ospedaliera Universitaria Senese, EVAlab protocol CEL no. 48/2010. The patients/participants provided their written informed consent to participate in this study.

We would like to thank IC who, in life, has contributed with the realization of the morphing videos with human facial expressions, leveraging an implementation of Active Appearance Models (AAMs, originally by Stefano Melacci). She was among the first to understand their possible applications in medical and rehabilitative fields.

AR, AB, and EF conceived of the study. IC lead the software project of the morphing faces. AB and EF collected the data under the supervision of GT, MD, AC, ID, CB, and AR. AB, EF, and DZ analyzed the data. The paper was drafted by AB, EF, DZ, SM, and AR. All authors provided detailed comments.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.