White Paper Issue 16: Seeing ALS

Updated: Apr 7

Could optical coherence tomography be useful in stratifying ALS patients?

Ocular nerves are specialized connections to the central nervous system. The retina is part of the central nervous system and is the only part of the CNS that is visualized non-invasively. The retina is a layer of non-motor neurons that can be damaged in amyotrophic lateral sclerosis, ALS. ALS is a syndrome that lacks effective treatments and biomarkers, retinal changes in disease can be observed in vivo using optical coherence tomography (OCT). It is possible that OCT may provide biomarkers for monitoring treatment of ALS because changes in the retinal layers reflect underlying neurodegenerative processes. Important pathologic mechanisms shared between ocular dysfunction and ALS include oxidative stress, mitochondrial damage and axonal transport disorders.

The first reported in 2014, clinicians identified disease-specific pathologic inclusions in the anterior visual pathway of an fALS patient by histopathology. This patient had mild visual impairment. Histopathology demonstrated ALS-associated perinuclear inclusions in the inner nuclear layer of the retina and CNS. The majority of the retinal inclusions were in the cone bipolar cells and some amacrine and horizontal cells. The inner nuclear layer of the retina consists of the cell bodies of horizontal cells, bipolar cells, amacrine cells, interplexiform neurons, and Muller cells. The processes of the horizontal cells are next to the outer plexiform layer.

Patients with Western Pacific ALS and parkinsonism-dementia complex (ALS/PDC) are clinically indistinguishable from classical ALS. ALS/PDC is an environmental disease due to exposure to plant-derived neurotoxins, along with a specific ALS-specific neuromuscular phenotype they show ophthalmological changes described as linear retinal pigmentary epitheliopathy.

A study showed human retinal spheroids and axon pathology that were similar lesions to hallmark findings in spinal cord motor neurons indicating disrupted axon transport was a shared pathogenesis. In another study, pulmonary function was correlated with macular retinal nerve fiber layer thickness in a cohort of ALS patients that supports the analysis of OCT measurements to assess disease. A pattern of visual loss specific for ALS has not been identified, however ocular involvement in patients and transgenic animals with ALS/dementia has been confirmed.

Changes to the retina observed in late stage disease in SOD1 mouse models include thinning of the neural layers due to loss of retinal neurons. The microglial cells were changed morphologically and the cells were displaced and clustered in the diseased tissues. It is possible that damaged retinal neurons reflect microglial inflammation that are seen in the spinal cord of the diseased SOD1 mice.

ALS is a neurodegenerative disease involving upper and lower motor neurons caused by genetic factors and molecular mechanisms involved with pathologies in altered axonal transport, mitochondrial disorders, oxidative stress, accumulation of misfolded proteins and neuro-inflammation. ALS is defined by pathology that includes ubiquitin-reactive and TDP-43 inclusions. Microglia and reactive astrocytes are proposed as playing a role in progression of ALS.

Optical coherence tomography can show retinopathies in ALS patients such as thinning, axonal degeneration, changes in retinal vessels and microglial cell inclusion bodies.

Sufficient evidence exists that most neuro-degenerative processes in the central nervous system tend to involve the retina. Changes in ALS patients can include color vision deficiency perhaps due to thinning in the outer nuclear layer of the retina that impact photoreceptors. Increase in the inner ring macular thickness of the temporal and lower regions of the eye fundus are suggestive of microglial activation in the neuroinflammatory process. Macula lutea thinning in the lower regions of the inner and outer macular rings and significant thinning of the peripapillary retinal nerve fiber layer in the upper and lower quadrants are seen. Retinal vessels can be thickened indicating microvascular alterations in the brain and spinal cord of ALS model mice and precede the degeneration of motor neurons.

Changes in retinal thickness measured by OCT may be related to different disease stages of ALS patients, or the heterogenous nature of the pathology, and constitute biomarkers for inflammation in disease. It would be important to follow patients to observe retinal changes over time and potentially correlate retinal phenotypes to subgroups of patients. It would also be useful to compare retinopathy with mouse models of ALS.

Rojas and coworkers quantified the signs of microglial activation and the number of retinal ganglion cells (RGCs) in the mSOD1G93A transgenic mouse at 120 days in retinal tissues. The observed changes included an increase in microglia volume, but not number, an increase in the arbor area in the outer plexiform layer inferior sector, cells with retracted processes, areas of cell groupings, and changes in the expression of cytokines. Cytokine changes included an increase in IFNϒ and IL-1β without the presence of IL-10 and arginase-1. There was a decrease in the number of RGCs. They concluded that in this SOD1 mouse model, retinal microglia were activated and expressed a pro-inflammatory phenotype M1 that affected the outer plexiform layer and inner retinal layers that were related to ganglion cell loss in late stage disease.

Platelet-derived growth factor (PDGF) and insulin promote the survival of neuronal cells including RGCs by activation of phosphoinositide 3-kinase (PI 3-kinase)/AKT signaling. The drug Imatinib inhibits PDGF receptors and can induce retinal toxicity in some patients because Imatinib is a PDGF receptor tyrosine kinase inhibitor. The ALS therapy Edavarone was shown to ameliorate reactive oxygen species (ROS) production, RGC death and inner retinal degeneration in an optic nerve injury model. Edavarone also suppressed the activation of the ASK-1 p38 MAPK pathway that induces RCG death. Carvedilol, a nonselective β-adrenoreceptor blocker, has many pleiotropic activities and impacts neuroprotection and neurodegeneration due to its antioxidant effects. Carvedilol also suppresses activation of apoptosis signal regulating kinase-1 and p38 MAPK pathway. Spermidine is a natural polyamine found in cereals, legumes and soy derivatives, and is an endogenous free radical scavenger. It inhibits ROS by suppressing ASK1 p38.

The ALS mouse models that recapitulate retinal stress and disease can be used with OCT to characterize and scale the onset and progression of lesions. The mouse OCT-identified scale could be used to explore similar lesions found in ALS patients and perhaps identify sub-sets of patients. At a minimum, identifying the presence of neuroinflammation in patients is expected. Because there are neuroinflammatory modulating drugs with known pathways that influence retinal health, such as Edavarone and Carvedilol, these agents could be tested in mice and retinal images monitored in patients already taking these therapies. More biomarkers may be uncovered using the non-invasive OCT.

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