Retinal Spheroids and Axon Pathology Identified in Amyotrophic Lateral Sclerosis

Abstract

To determine whether patients with amyotrophic lateral sclerosis (ALS) show retinal axon pathology. METHODS. Postmortem eyes from 10 patients with ALS were sectioned and compared with 10 age-matched controls. Retinal sections were evaluated with periodic acid Schiff and phosphorylated (P-NF) and nonphosphorylated (NP-NF) forms of neurofilament with SMI 31 and 32 antibodies. Spheroids identified in the retinal nerve fiber layer were counted and their overall density was calculated in central, peripheral, and peripapillary regions. P-NF intensity was quantified. Morphometric features of ALS cases were compared with age-matched controls using the exact Wilcoxon matched-pairs signed-rank test. RESULTS. Distinct periodic acid Schiff-positive round profiles were identified in the retinal nerve fiber layer of patients with ALS and were most commonly observed in the peripapillary and peripheral retina. The density of periodic acid Schiff-positive spheroids was significantly greater in patients with ALS compared with controls (P = 0.027), with increased density in the peripapillary region (P = 0.047). Spheroids positive for P-NF and NP-NF were detected. P-NF-positive spheroid density was significantly increased in patients with ALS (P = 0.004), while the density of NP-NF spheroids did not differ significantly between ALS and control groups (P > 0.05). P-NF immunoreactivity in the retinal nerve fiber layer was significantly greater in patients with ALS than in controls (P = 0.002). CONCLUSIONS. Retinal spheroids and axon pathology discovered in patients with ALS, similar to hallmark findings in spinal cord motor neurons, point to disrupted axon transport as a shared pathogenesis. Retinal manifestations detected in ALS suggest a novel biomarker detectable by noninvasive retinal imaging to help to diagnose and monitor ALS disease.

Sensory Involvement in Amyotrophic Lateral Sclerosis

“…Interestingly, one study also showed an increased thickness in certain areas of the retina [ 180 ], suggesting alterations in axonal transport, protein aggregation, and neuroinflammation as possible explanations. Supporting this finding, in post-mortem studies, a significantly greater number of PAS-positive spheroids has been found in RNFL, especially in the peripapillary region [ 198 ]. The increased presence of phosphorylated neurofilaments in these spheroids could be explained by a special vulnerability of the long axons to axonal transport deficits.…”

Retinal Disorders in Humans and Experimental ALS Models

“…In addition, in most of the ALS patients, the NP-NF signal was increased in the RNFL and IPL. Nevertheless, there was no significant correlation of these retinal spheroids and axon pathology with the clinical characteristics of the ALS patients (age at death, gender, disease duration, mode of disease onset, revised ALS functional rating scale, and rate of disease progression) [115].…”

“…There is only one study that focused on this important pathological mechanism in the retina [115]. This study analyzed retinal sections of postmortem eyes from ALS patients with periodic acid Schiff (PAS) and phosphorylated (P-NF) and nonphosphorylated (NP-NF) forms of neurofilament (NF), compared with age-matched controls.…”

“…Consequently, patients with ALS show not only hallmark findings in spinal cord motor neurons pointing to disrupted axon transport [116][117][118][119][120][121] but also retinal spheroids and axon pathology as a shared pathogenesis [115]. Transgenic mice with dysfunctional microtubule-associated motor proteins also display such findings [122][123][124].…”

Research hotspots and trends for axon regeneration (2000–2021): a bibliometric study and systematic review

“…Axons connect the nervous system with the rest of the body to ensure its proper function and the interaction with the outside world. However, any insult to the nervous system such as trauma, ischemia, neurodegeneration, and demyelination [ 2 ] leads to permanent impairment of motor, sensory, cognitive, and automatic nerve functions [ 3 – 5 ]. Thus, understanding mechanisms involved in nervous system repair is crucial not only for the neuroscience field but also for public health.…”