Prosaccade and Antisaccade Behavior in Fragile X‐Associated Tremor/Ataxia Syndrome Progression

Abstract

Background Quantitative measurement of eye movements can reveal subtle progression in neurodegenerative diseases. Objective To determine if quantitative measurements of eye movements may reveal subtle progression of fragile X‐associated tremor and ataxia (FXTAS). Methods Prosaccade (PS) and antisaccade (AS) behavior was analyzed in 25 controls, 57 non‐FXTAS carriers, and 46 carriers with FXTAS. Results Symptomatic individuals with FXTAS had longer AS latencies, increased rates of AS errors, and increased AS dysmetria relative to non‐FXTAS carriers and controls. These deficits, along with PS latency and velocity, were greater in advanced FXTAS stages. Conclusion AS deficits differentiated FXTAS from non‐FXTAS premutation carriers implicating top‐down control and frontostriatal deterioration. However, the absence of group differences between non‐FXTAS carriers and controls in AS and PS markers suggests saccade performance may not be a sensitive enough measure for detecting conversion to FXTAS, but instead more helpful as translational biomarkers of FXTAS progression.

Sensorimotor and inhibitory control in aging FMR1 premutation carriers

“…Prior studies of saccade behavior in asymptomatic premutation carriers have documented mixed findings suggesting both impaired and spared latencies and preserved accuracy ( Shelton et al, 2014 ; Wong et al, 2014 ; Moser et al, 2021 ). Recently, McLennan et al extended these findings by including FXTAS+ premutation carriers in a primarily male sample and showed that saccade accuracy was more variable in FXTAS patients compared to asymptomatic premutation carriers, though this effect did not survive corrections for multiple comparisons ( McLennan et al, 2022 ). Here, we focus on a predominantly female sample and show that saccade latency and accuracy each appear to be unaffected during initial disease stages.…”

“…Antisaccade latency and the proportion of trials in which participants looked toward rather than away from the peripheral target (antisaccade error) were examined. Inhibitory cost was calculated as the difference between VGS latency and antisaccade latency with greater values representing greater inhibitory cost, or lower efficiency in inhibiting unwanted saccades ( Wong et al, 2014 ; McLennan et al, 2022 ).…”

“…The latency of exogenously driven saccades is supported by cerebellar-brainstem circuits involved in movement generation and movement cells in cortical (frontal and parietal eye fields) and subcortical (basal ganglia) circuits supporting action planning and initiation ( Leigh and Zee, 2006 ). Prior studies of visually guided saccades have documented increased trial-to-trial accuracy variability in FXTAS+ ( McLennan et al, 2022 ) and FXTAS- premutation males ( Wong et al, 2014 ). In contrast, studies of female premutation carriers have provided mixed findings.…”

“…Antisaccade paradigms have demonstrated impairments in inhibitory control in premutation carriers. One study of antisaccade behavior demonstrated increased latencies in younger adult asymptomatic male premutation carriers relative to age-matched healthy controls ( Wong et al, 2014 ), but another study did not report latency differences between asymptomatic male and female premutation carriers and controls in their 50s and 60s ( McLennan et al, 2022 ). Additionally, male premutation carriers show both increased antisaccade latencies and elevated error rates associated with increased FXTAS symptom severity ( McLennan et al, 2022 ).…”

“…One study of antisaccade behavior demonstrated increased latencies in younger adult asymptomatic male premutation carriers relative to age-matched healthy controls ( Wong et al, 2014 ), but another study did not report latency differences between asymptomatic male and female premutation carriers and controls in their 50s and 60s ( McLennan et al, 2022 ). Additionally, male premutation carriers show both increased antisaccade latencies and elevated error rates associated with increased FXTAS symptom severity ( McLennan et al, 2022 ). Asymptomatic adult female premutation carriers also appear to show increased rates of antisaccade errors relative to healthy female controls, though no known studies have examined antisaccade behavior in samples of female premutation carriers with symptoms of FXTAS ( Shelton et al, 2014 ; Moser et al, 2021 ), thus limiting our understanding of how FXTAS symptoms may track with oculomotor performance in females.…”