Pro-Saccades Predict Cognitive Decline in Parkinson's Disease: ICICLE-PD.

BACKGROUND: Cumulative dementia incidence in Parkinson's disease (PD) is significant, with major personal and socioeconomic impacts on individuals with PD and their carers. Early identification of dementia risk is vital to ensuring optimal intervention. Saccadic deficits often distinguish neurodegenerative disorders and cognitive impairment, but their ability to predict cognitive decline in PD has yet to be determined. The aims of this study were to (1) evaluate baseline (6.4 ± 6.1 months since PD diagnosis) differences in pro-saccadic metrics between those with early PD and healthy age-matched adults; and (2) assess the ability of baseline pro-saccades to predict subsequent cognitive decline over 4.5 years. METHODS: One hundred and forty-one PD and 90 age-matched participants recruited at diagnosis underwent saccadometric assessment of pro-saccades at baseline and had cognition assessed at baseline, 18, 36, and 54 months. Pro-saccadic characteristics included latency, duration, amplitude, peak, and average velocity. Cognitive assessment included executive function, attention, fluctuating attention, and memory. Linear mixed-effects models examined pro-saccadic metrics as predictors of cognitive decline over 54 months. RESULTS: Pro-saccades were significantly impaired at baseline in PD compared with controls. Pro-saccadic characteristics of latency, duration, peak, and average velocity predicted decline in global cognition, executive function, attention, and memory over 54 months in PD. In addition, only reduction in global cognition and attention were predicted by pro-saccadic metrics in age-matched adults, indicating that PD findings were not purely age related. CONCLUSIONS: Saccadic characteristics are impaired in early PD and are predictive of cognitive decline in several domains. Assessment of saccades may provide a useful non-invasive biomarker for long-term PD cognitive decline in early disease. © 2019 International Parkinson and Movement Disorder Society.This work was funded by grants from Parkinson’s UK (J-0802, G-1301, G-1507) and Lockhart Parkinson’s Disease Research Fund. The research was supported by the National Institute for Health Research (NIHR) Newcastle Biomedical Research Unit based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University and a NIHR Biomedical Research Centre award to the University of Cambridge/Addenbrooke’s Hospital

Social perception drives eye-movement related brain activity: evidence from pro- and anti-saccades to faces

Social stimuli such as faces attract and retain attention to a greater extent than other objects. Using fMRI, we investigated how the activity of oculomotor and visual brain regions is modulated when participants look towards or away from visual stimuli belonging to different categories (faces and cars). We identified a region within the superior frontal sulcus showing greater difference between anti- and pro-saccades to faces than to cars, and thereby supporting inhibitory control in a social context. In contrast, ventral occipito-temporal regions and the amygdala, which are associated with face perception, showed higher activity for pro-saccades than anti-saccades for faces, but the reverse for cars, suggesting that contextual, top-down mechanisms modulate the functional specialisation of areas involved in perception. In addition, during saccades in the presence of faces, we found increased functional connectivity between the frontal eye-fields and other cortical and subcortical oculomotor structures, namely the inferior frontal eye field, the posterior parietal cortex and the basal ganglia, possibly reflecting the higher demand put on the oculomotor system to inhibit responses to socially salient stimuli. For the first time, these data highlight neural bases for the different orienting responses towards or away from faces as compared to other objects

Studies on eye movements in Parkinson's disease

Heterogeneity in Parkinson’s Disease (PD) phenotype and genotype is probably the main reason why, despite the abundance of biomarkers, we still lack a robust method for diagnosis and prognosis, besides clinical evaluation. Subjective changes in vision and objective measures in eye movements have been extensively studied, but the results are mainly used to better understand the pathophysiology of PD and are not integrated into the clinical praxis. The aim of this doctoral project was to examine if eye movements could serve as useful biomarkers for PD diagnosis and prognosis, and investigate their association with motor function, cognition, and medication effect. In addition, we aimed to examine cognition in a group of patients with a rare metabolic disorder and prominent eye-movement difficulties, the Norrbottnian Gaucher Disease 3 (GD3). Saccades, reading, and sustained fixation were examined in PD patients and healthy controls (HC) in the first three studies. Recruitment took place at Karolinska University Hospital Huddinge for the first two studies, and for the third study at Academic Specialist Center in Stockholm. Three different eye trackers were used, a head-mounted and two screen based, and the assessments were performed in a clinical setting. In the first two studies patients were examined in ON and OFF medication status, in order to evaluate the role of levodopa. In study 1, we examined saccadic parameters in 20 HC and 40 PD patients; study 2 involved reading assessments for 13 HC and 19 PD patients; in study 3 we examined sustained fixation in 43 HC and 50 PD patients. Recruitment for study 4 took place at Sunderby Regional Hospital, in Luleå, and we examined 10 patients with the Norrbottnian type of GD3. Cognitive evaluation was done with the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). PD participants had worse saccadic performance, a slower reading speed, and deficient fixation control. Saccadic gain was associated with motor performance, while latency was related to cognition. Levodopa had no effect on saccadic gain, it worsened latency for the horizontal visually guided saccades and ameliorated the latency of antisaccades, but not the error rate or reading performance. We assumed that reading difficulties were attributed to cognitive, rather than oculomotor deficits. Fixation was more easily interrupted in PD compared to HC, and PD participants’ pupils did not dilate to the same extent as HC, in response to the cognitive effort put during sustained fixation. In study 4 we found that patients with the Norrbottnian type of GD3 have an overall worse cognitive performance compared to that of healthy population, scoring worse in memory and attention tests, present however with preserved language and visuospatial skills. The eye-tracking studies led to the conclusion that this method could be integrated into the clinical praxis as part of the clinical evaluation. It is easy to perform and provides reliable results that enable the understanding of motor, cognitive, and behavioral changes in PD. In order to do so, we would need a common protocol of assessment, so that the results would be comparable between different populations. The last study identified RBANS as a useful and easy-to-use tool for the cognitive examination of Norrbottnian GD3 patients

The functional oculomotor network and saccadic cognitive control in healthy elders.

Decline in executive function is the most common age-associated cognitive deficit and may be a risk factor for neurodegenerative disease. The antisaccade (AS) task involves inhibition of a prepotent visuomotor response and is a well-validated executive function test in aging and neurodegeneration. We investigated the functional connectivity of the cortical oculomotor network during successful AS performance in healthy elders. Elevated BOLD activity in the right lateral frontal eye field (rlatFEF), a region linked to volume loss in individuals with impaired AS performance, was associated with worse AS performance and weaker network efficiency. In contrast, hub integrity of the right dorsolateral prefrontal cortex (rDLPFC) and anterior cingulate cortex (rACC) was associated with better AS performance. These data suggest that while several right lateral frontal regions are central nodes in the oculomotor network, the rlatFEF demonstrates early neural aberrations and the rDLPFC and rACC continue to support inhibitory cognitive control in healthy elders. We conclude that alterations in AS task functional connectivity, quantified as hub and network efficiency, may be clinically-relevant biomarkers of cognitive decline in executive functioning

The functional oculomotor network and saccadic cognitive control in healthy elders.

Decline in executive function is the most common age-associated cognitive deficit and may be a risk factor for neurodegenerative disease. The antisaccade (AS) task involves inhibition of a prepotent visuomotor response and is a well-validated executive function test in aging and neurodegeneration. We investigated the functional connectivity of the cortical oculomotor network during successful AS performance in healthy elders. Elevated BOLD activity in the right lateral frontal eye field (rlatFEF), a region linked to volume loss in individuals with impaired AS performance, was associated with worse AS performance and weaker network efficiency. In contrast, hub integrity of the right dorsolateral prefrontal cortex (rDLPFC) and anterior cingulate cortex (rACC) was associated with better AS performance. These data suggest that while several right lateral frontal regions are central nodes in the oculomotor network, the rlatFEF demonstrates early neural aberrations and the rDLPFC and rACC continue to support inhibitory cognitive control in healthy elders. We conclude that alterations in AS task functional connectivity, quantified as hub and network efficiency, may be clinically-relevant biomarkers of cognitive decline in executive functioning

The functional oculomotor network and saccadic cognitive control in healthy elders

Decline in executive function is the most common age-associated cognitive deficit and may be a risk factor for neurodegenerative disease. The antisaccade (AS) task involves inhibition of a prepotent visuomotor response and is a well-validated executive function test in aging and neurodegeneration. We investigated the functional connectivity of the cortical oculomotor network during successful AS performance in healthy elders. Elevated BOLD activity in the right lateral frontal eye field (rlatFEF), a region linked to volume loss in individuals with impaired AS performance, was associated with worse AS performance and weaker network efficiency. In contrast, hub integrity of the right dorsolateral prefrontal cortex (rDLPFC) and anterior cingulate cortex (rACC) was associated with better AS performance. These data suggest that while several right lateral frontal regions are central nodes in the oculomotor network, the rlatFEF demonstrates early neural aberrations and the rDLPFC and rACC continue to support inhibitory cognitive control in healthy elders. We conclude that alterations in AS task functional connectivity, quantified as hub and network efficiency, may be clinically-relevant biomarkers of cognitive decline in executive functioning