Cognitive correlates of antisaccade behaviour across multiple neurodegenerative diseases.

Oculomotor tasks generate a potential wealth of behavioural biomarkers for neurodegenerative diseases. Overlap between oculomotor and disease-impaired circuitry reveals the location and severity of disease processes via saccade parameters measured from eye movement tasks such as prosaccade and antisaccade. Existing studies typically examine few saccade parameters in single diseases, using multiple separate neuropsychological test scores to relate oculomotor behaviour to cognition; however, this approach produces inconsistent, ungeneralizable results and fails to consider the cognitive heterogeneity of these diseases. Comprehensive cognitive assessment and direct inter-disease comparison are crucial to accurately reveal potential saccade biomarkers. We remediate these issues by characterizing 12 behavioural parameters, selected to robustly describe saccade behaviour, derived from an interleaved prosaccade and antisaccade task in a large cross-sectional data set comprising five disease cohorts (Alzheimer's disease/mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease, and cerebrovascular disease; n = 391, age 40-87) and healthy controls ( n = 149, age 42-87). These participants additionally completed an extensive neuropsychological test battery. We further subdivided each cohort by diagnostic subgroup (for Alzheimer's disease/mild cognitive impairment and frontotemporal dementia) or degree of cognitive impairment based on neuropsychological testing (all other cohorts). We sought to understand links between oculomotor parameters, their relationships to robust cognitive measures, and their alterations in disease. We performed a factor analysis evaluating interrelationships among the 12 oculomotor parameters and examined correlations of the four resultant factors to five neuropsychology-based cognitive domain scores. We then compared behaviour between the abovementioned disease subgroups and controls at the individual parameter level. We theorized that each underlying factor measured the integrity of a distinct task-relevant brain process. Notably, Factor 3 (voluntary saccade generation) and Factor 1 (task disengagements) significantly correlated with attention/working memory and executive function scores. Factor 3 also correlated with memory and visuospatial function scores. Factor 2 (pre-emptive global inhibition) correlated only with attention/working memory scores, and Factor 4 (saccade metrics) correlated with no cognitive domain scores. Impairment on several mostly antisaccade-related individual parameters scaled with cognitive impairment across disease cohorts, while few subgroups differed from controls on prosaccade parameters. The interleaved prosaccade and antisaccade task detects cognitive impairment, and subsets of parameters likely index disparate underlying processes related to different cognitive domains. This suggests that the task represents a sensitive paradigm that can simultaneously evaluate a variety of clinically relevant cognitive constructs in neurodegenerative and cerebrovascular diseases and could be developed into a screening tool applicable to multiple diagnoses.
Competing Interests: S.R.A. has consulted for Indoc Research Canada. C.E.F. receives commercial grant support from Vielight Inc. and Hoffman La Roche. S.K. has received research support from Brain and Behavior Foundation, National Institute on Ageing, BrightFocus Foundation, Brain Canada, Canadian Institute of Health Research, Canadian Consortium on Neurodegeneration in Aging, Centre for Ageing and Brain Health Innovation, Centre for Addiction and Mental Health; an Academic Scholars Award from the Department of Psychiatry, University of Toronto; and has received equipment support from Soterix Medical. S.H.P. has received research funding from Zywie Bio LLC. B.G.P. receives research support from the Peter & Shelagh Godsoe Endowed Chair in Late-Life Mental Health, CAMH Foundation, and Discovery Fund, National Institute of Aging, Brain Canada, the Canadian Institutes of Health Research, the Alzheimer’s Drug Discovery Foundation, the Ontario Brain Institute, the Centre for Aging and Brain Health Innovation, the Bright Focus Foundation, the Alzheimer’s Society of Canada, the W. Garfield Weston Foundation, the Weston Brain Institute, the Canadian Consortium on Neurodegeneration in Aging and Genome Canada; receives honoraria from the American Geriatrics Society for book authorship; and is listed on United States Provisional Patent Nos. 6/490,680 and 17/396030 and Canadian Provisional Patent No. 3054093 for a cell-based assay and kits for assessing serum anticholinergic activity. T.K.R. has received research support from Brain Canada, Brain and Behavior Research Foundation, BrightFocus Foundation, Canada Foundation for Innovation, Canada Research Chair, Canadian Institutes of Health Research, Centre for Aging and Brain Health Innovation, National Institutes of Health, Ontario Ministry of Health and Long-Term Care, Ontario Ministry of Research and Innovation, and the Weston Brain Institute; received for an investigator-initiated study in-kind equipment support from Newronika; in-kind research online accounts from Scientific Brain Training Pro; participated in 2021 in one advisory board meeting for Biogen Canada Inc; and is listed on United States Provisional Patent No. 17/396030 that describes cell-based assays and kits for assessing serum cholinergic receptor activity. D.P.S. receives research funding from CIHR, Alzheimer’s Association, University of Calgary, and Hotchkiss Brain Institute. M.C.T. receives grant support from NIH and CIHR and is a clinical trial investigator for Biogen, Janssen, Anavex, Green Valley and Roche. All other authors report no competing interests.
(© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)