Retinal Disorders in Humans and Experimental ALS Models

*Pilar Rojas, Ana I. Ramírez, Rosa de Hoz, Manuel Cadena, Elena Salobrar-García, Inés López-Cuenca, José A. Fernández-Albarral, Lidia Sanchez-Puebla, José Antonio Matamoros, Juan J. Salazar and José M. Ramírez*

### **Abstract**

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease that severely impairs the patient's mobility, as it mainly affects the upper and lower motor neurons in the spinal cord. In addition, alterations have also been demonstrated in different parts of the central nervous system (CNS), such as the brain and brainstem. The retina is a projection to the brain and is considered as a "window" to the CNS. Moreover, it is possible to use the retina as a biomarker in several neurodegenerative diseases, even in the absence of major visual impairment. Classically, it was thought that the eyes were not affected in ALS, with respect to extraocular muscles, whereas the remainder of the muscles of the body were distressed. Nevertheless, retinal changes have recently been found in this pathology and could help in diagnosis, follow-up, and even monitoring therapies in this disease.

**Keywords:** amyotrophic lateral sclerosis, ALS, retina, animal models, SOD1, microglia, protein aggregates, axon pathology, neurodegeneration, neuroinflammation

### **1. Introduction**

Amyotrophic lateral sclerosis (ALS) is the most common progressive motor neuron disease, accounting for 80–90% of all motor neuron diseases cases [1]. Worldwide, the incidence per 100,000 people ranges from 0.3 to 2.5 cases per year [2–5]. Only 10% of the cases are familial [6], ranging from 2 to 15% depending on the population [7], whereas 90% of the cases are sporadic or seemingly sporadic. Overall, both the incidence [8] and the prevalence [9] of ALS vary according to location and race. ALS is more common in men than in women, with a ratio of 1.5:1 [5].

This neurodegenerative disease is rapidly progressive with a typical combination of symptoms of both upper motor neurons (UMNs) and lower motor neurons (LMNs) in different degrees, causing muscle fiber atrophy, which seriously affects the patient's mobility and quality of life [2, 4, 10]. ALS comprises overactive reflexes, as well as muscle weakness and stiffness, and it also involves the swallowing, speech, and respiratory muscles [10–12]. In fact, patients usually die within 2–3 years from

diagnosis, frequently due to respiratory failure [5, 13]. The disease usually has a spinal onset, beginning in the extremities and spreading to the rest of the body; however, one in every four patients has a bulbar onset, which has a worse prognosis [4]. ALS is a heterogeneous disease with asymmetrical onset and spreading of UMN and LMN dysfunction, which makes its classification very complex [14]. In addition, no single specific test exists for ALS diagnosis; it is a diagnosis of exclusion based on the initial symptoms, the progression of the disease, and tests to eliminate overlapping conditions.

Although ALS has been considered an exclusively motor disease, over the last few years, several studies have focused on assessing the possible participation of nonmotor areas of the central nervous system (CNS) in this illness. Actually, neuroimaging tests have shown an overall reduction in brain volume, with a loss of focal gray matter and regional white-matter alterations [15–20]. The alteration of these areas leads to cognitive and behavioral changes [16, 18]. During the course of the disease, it has been found that 50% of ALS patients have some degree of cognitive impairment, mainly featuring executive dysfunction and mild memory loss [15, 21].

Classically, it was thought that the eyes were not affected in this disease, with respect to the eye motor muscles, whereas the remaining muscles of the body were affected [22]. However, some studies have found abnormal ocular movements in these patients [23–28]. Nevertheless, this classical concept did not refer to the retina or the optic nerve. Actually, these patients have demonstrated not only abnormal evoked potentials [29–33] but also astrogliosis in nonmotor areas, specifically in the occipital area [34]. Even a significant interocular difference of the P100 in ALS patients was demonstrated in a study of visual evoked potentials [33], similar to the existing asymmetry in the CNS of these patients [14]. Some researchers have also analyzed changes in the visual pathway (a nonmotor neuron area) using optical coherence tomography (OCT) in ALS patients [35–44], finding different changes in the retina and optic nerve, some with contradictory results, stressing the importance of classifying patients by both stage and type of ALS, given the high heterogeneity of the disease.

The retina is considered as an open window to the CNS, and it is possible to use it as a biomarker in multiple neurodegenerative diseases, whether or not there is visual impairment. In recent years, many studies have emphasized the importance of the retina in the diagnosis and monitoring of neurodegenerative diseases, with various pieces of evidence highlighting its value as a biomarker [45–57]. However, what was not so evident was the possible involvement of the retina in neuromuscular diseases, which are chronic progressive neurological diseases, such ALS, that predominantly affect the spinal cord, whereby the neurological involvement is far from the visual pathway.

The purpose of this review is to analyze the retinal changes that have been described in different animal models in this disease, to compare them with each other and to correlate them with the changes described in humans to highlight the possible role of the retina as a biomarker in this disease.
