Cognitive correlates of antisaccade behaviour across multiple neurodegenerative diseases
Authors: Riek Heidi C , Brien Donald C , Coe Brian C , Huang Jeff , Perkins Julia E , Yep Rachel , McLaughlin Paula M , Orange Joseph B , Peltsch Alicia J , Roberts Angela C , Binns Malcolm A , Lou Wendy , Abrahao Agessandro , Arnott Stephen R , Beaton Derek , Black Sandra E , Dowlatshahi Dar , Finger Elizabeth , Fischer Corinne E , Frank Andrew R , Grimes David A , Kumar Sanjeev , Lang Anthony E , Lawrence-Dewar Jane M , Mandzia Jennifer L , Marras Connie , Masellis Mario , Pasternak Stephen H , Pollock Bruce G , Rajji Tarek K , Sahlas Demetrios J , Saposnik Gustavo , Seitz Dallas P , Shoesmith Christen , Steeves Thomas D L , Strother Stephen C , Sunderland Kelly M , Swartz Richard H , Tan Brian , Tang-Wai David F , Tartaglia Maria Carmela , Turnbull John , Zinman Lorne , Munoz Douglas P ,   the ONDRI Investigators, Adamo Sabrina , Bartha Rob , Berezuk Courtney , Black Alanna , Borrie Michael , Bronskill Susan , Bulman Dennis , Casaubon Leanne , Cornish Ben , Defrawy Sherif , Dilliott Allison , Dixon Roger A , Farhan Sali , Faria Frederico , Fraser Julia , Freedman Morris , Ghani Mahdi , Greenberg Barry , Haddad Hassan , Hassan Ayman , Hatch Wendy , Hegele Rob , Holmes Melissa , Hudson Chris , Jog Mandar , Kleinstiver Peter , Kwan Donna , Leontieva Elena , Levine Brian , Mandelcorn Efrem , Margolin Ed , McIlroy Bill , Montero-Odasso Manuel , Munoz David , Nanayakkara Nuwan , Ozzoude Miracle , Ramirez Joel , Rashkovan Natalie , Robinson John , Rogaeva Ekaterina , Adamson Yanina Sarquis , Scott Christopher , Strong Michael , Sujanthan Sujeevini , Symons Sean , Theyers Athena , Troyer Angela , Van Ooteghem Karen , Woulfe John , Zamyadi Mojdeh 
Published: March 2023

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.