Scientists Eye Ocular Movements for Clues to Brain Pathology

Watching the eyes of a person with ALS might help clinicians assess their brain function, according to a paper in the November 11 PLoS One. Researchers from the University of Ulm, Germany, used gaze-tracking technology to classify two stages of ocular deficit in people with the disease. First, conscious control over the line of sight weakens, suggesting problems with executive function that likely reflect pathology in the cortex. By the second stage, involuntary eye movements become erratic, indicating neurodegeneration in the brainstem. “Eye movement may serve as a window into the brain and its pathological alterations in ALS,” said senior author Elmar Pinkhardt. It could even serve as a biomarker for progression, the authors posit.

ALS causes paralysis, but the nerves controlling the eyes traditionally have been thought to be spared. However, scientists have observed that in people who survive for a long time with the disease, eye control is affected (reviewed in Sharma et al., 2011). Eye movements are affected in other diseases too, including Alzheimer’s (Molitor et al., 2015). Pinkhardt and co-author Albert Ludolph wondered if defects in eye movement might correlate with the spread of pathology across the brain. Specifically, they probed how eye-tracking lined up with a staging scheme for TDP-43 proteinopathy proposed in 2013. In this four-step staging, aggregates are thought to appear first in the motor cortex, brainstem, and spinal cord, and then spread to the prefrontal neocortex, precerebellar nuclei, and midbrain by stage 2. Next they creep into the postcentral neocortex and striatum, and finally affect the temporal lobe by stage 4 (see Nov 2013 conference news). However, those stages are only apparent upon autopsy. Eye-tracking, Pinkhardt and Ludolph reasoned, might give them an opportunity to observe the effects of TDP-43 proteinopathy in living patients.

First author Martin Gorges and colleagues recruited 68 people with ALS (none of them with frontotemporal dementia, which can co-occur with ALS), and 31 healthy controls for eye-tracking tests. Subjects faced a curved screen lined with tiny red and green lights. In diverse tests, the researchers asked participants to look at a newly lit dot, delay looking at the new light, or look away from it. The scientists could also project a smoothly traveling red dot onto the screen for subjects to follow (see image at right). In addition, they asked subjects to look back and forth between two lights as quickly as they could for 30 seconds. A camera tracked the movement of each eye, although, since they tended to move together, the authors averaged their movements as if the subjects were monocular.

The subjects fell into three categories. Thirty people with ALS reacted just like healthy controls. Of the other 38, the authors characterized 25 as oculomotor stage 1, meaning they made more mistakes than controls when asked to delay glancing at a light or look away from it, and reversed gaze fewer times in the 30-second back-and-forth test. These characteristics indicate problems with executive control of eye motion, which is managed by brain regions affected in TDP-43 proteinopathy stage 1.

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