Parkinsonism and Related Disorders 81 (2020) 60–66 Available online 11 October 2020 1353-8020/© 2020 Elsevier Ltd. All rights reserved. Prolonged visual fixation as a surrogate marker of cholinergic deficit in Parkinson’s disease: A 2-year follow-up study Oscar WH. Wong a, * , Anne Chan b , Adrian Wong c , Claire KY. Lau b , Jonas HM. Yeung d , Vincent Mok c , Sandra Chan a a Department of Psychiatry, The Chinese University of Hong Kong, G/F, Multi-centre Building, 9 Chuen on Road, Tai Po Hospital, Tai Po, Hong Kong Special Administrative Region b Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong Special Administrative Region c Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region d Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, Hong Kong Special Administrative Region A R T I C L E INFO Keywords: Parkinson’s disease Eye tracking Cholinergic Biomarker Cognition Dementia ABSTRACT Introduction: The search for biomarkers of cognitive impairment in Parkinson’s disease is driven by the potential clinical applications in disease prognostication. Various eye tracking studies on cognitive functions in Parkin- son’s disease suggest a promising role of eye movement parameters as a biomarker for cognitive decline but the clinical utility has not been validated in longitudinal studies. The present study aims to investigate the longi- tudinal progression of eye fixation duration in a visual search task and its correlation with domain-specific cognitive impairment. Method: This is a 2-year follow-up study on a group of non-demented Parkinson’s disease patients, with baseline eye movement metrics and multi-domain cognitive functions measured, to assess the association between domain-specific cognitive impairment and progression of visual fixation duration. Results: A total of 49 from the original 62 non-demented Parkinson’s disease patients were re-examined at a 2- year follow-up. 15 cases (31%) were classified as having mild cognitive impairment. Visual fixation duration was significantly prolonged after 2 years. Using repeated measures ANOVA, impairment in semantic verbal fluency, visual and verbal recognition memory and orienting function of attention had a significant effect on prolonging visual fixation over time. Conclusion: Correlation between prolonged visual fixation and multiple domains of cognitive impairment related to cholinergic dysfunction in repeated measures over two years provides preliminary evidence for the eye tracking paradigm as a surrogate marker for cholinergic deficit in Parkinson’s disease. The clinical utility in terms of disease prognostication is yet to be confirmed in prospective longitudinal studies with longer follow-up periods. 1. Introduction Parkinson’s disease is a neurodegenerative disorder with progressive disturbances in a wide range of brain functions. Various non-motor manifestations occur as pathologies of Parkinson’s disease go beyond the regions for movement control. Among these manifestations, the importance of cognitive impairment is increasingly being recognized, as the presence of which represents a more aggressive subtype associated with functional impairment and mortality [1]. The onset of cognitive impairment cannot be simply predicted by age and illness duration alone due to the variable time to progression to dementia. Therefore, there has been a search for biomarkers of cognitive impairment in Parkinson’s disease, including the utility of eye tracking. Impairment of eye movement is commonly found in patients with Parkinson’s disease. As control of eye movement involves complex neural circuitries overlapping with cognitive controls, pathologies could affect these functions concurrently. This provides a theoretical premise to use eye movement parameters as biomarkers for cognitive * Corresponding author. E-mail addresses: oscarwhwong@cuhk.edu.hk (O.WH. Wong), cyy912@ha.org.hk (A. Chan), adrianwong@cuhk.edu.hk (A. Wong), yeekaclaire@surgery.cuhk. edu.hk (C.KY. Lau), yeunghmj@ha.org.hk (J.HM. Yeung), vctmok@cuhk.edu.hk (V. Mok), schan@cuhk.edu.hk (S. Chan). Contents lists available at ScienceDirect Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis https://doi.org/10.1016/j.parkreldis.2020.10.019 Received 9 April 2020; Received in revised form 18 September 2020; Accepted 10 October 2020