Reflexive and volitional saccades: biomarkers of Huntington disease severity and progression

Abstract

Background: Huntington disease (HD) is a genetic, neurodegenerative disorder characterized by chorea, behavioral co-morbidities, cognitive deficits, and eye movement abnormalities. We sought to evaluate whether reflexive and voluntary orienting prove useful as biomarkers of disease severity in HD.

Methods: Eleven HD subjects were evaluated with the motor subscale of the Unified Huntington Disease Rating Scale (UHDRS) and the Montreal Cognitive Assessment. Using an infrared eye tracker, we also measured latency and error rates of horizontal and vertical saccades using prosaccade and antisaccade eye movement tasks. We calculated simple and age-controlled correlations between eye movement and clinical parameters.

Results: Prosaccade latency correlated with total chorea score. HD patients with greater clinical severity were significantly slower in the prosaccade task. Antisaccade error rate also correlated with UHDRS motor score and total chorea score. HD patients with greater clinical severity as measured by either measure made significantly more errors in the antisaccade task. All these correlations remained significant even when age was taken into account.

Conclusions: The results of the present age-controlled study show for the first time that both reflexive and voluntary eye motor control in HD patients decrease with increase in disease severity suggesting declines in both motor and cognitive function. Thus, relatively simple eye movement parameters (latency and error rate) obtained from simple tasks (prosaccade and antisaccade) may serve as quantitative biomarkers of sub-cortical and cortical disease severity in HD and could aid in predicting onset, distinguishing subtypes, or evaluating disease progression and novel therapies.

Figure 1

Illustration of the prosaccade and antisaccade tasks. In each task, four square landmarks along with a central fixation point initially are displayed on the computer monitor. After a delay, a bright square target appears within one of the four landmarks. Before each trial block, the subject is instructed to make a saccade to the target (prosaccade task) or make a saccade to the opposite location of the target (antisaccade task). The white arrow illustrates a correct eye movement response. The prosaccade and antisaccade tasks were run in separate 48 trial blocks.

Figure 2

Correlation between reflexive eye movement parameters and clinical scores. A. The simple correlation between latency in the prosaccade task and UHDRS motor score using data from all the subjects. The numbers reported in the bottom right of the left panel (for all other figures as well) represent the Pearson’s correlation coefficient (r) and the p-value (p) associated with the correlation. B. Average prosaccade latency for subjects that had UHDRS motor scores below the first and above the third quartile. The error bars represent ±1 SEM. The number in the bottom right part of right panel represents the p-value obtained from an independent sample t-test comparing the data for subjects below the first and above the third quartile (for all other figures as well). The numbers above each data point indicate the number of subjects (for all other figures as well). C. Simple correlation between latency in prosaccade task and total chorea score using data from all the subjects. D. Average prosaccade latency for subjects that had total chorea score below the first and above the third quartile.

Figure 3

Correlation between voluntary eye movement parameters and clinical scores. A. Simple correlation between latency in antisaccade task and UHDRS motor score using data from all the subjects. B. Average antisaccade latency for subjects that had UHDRS motor score below the first and above the third quartile. C. Simple correlation between latency in antisaccade task and total chorea score using data from all the subjects. D. Average antisaccade latency for subjects that had total chorea score below the first and above the third quartile.