Initial Technical and Clinical Validation of Mobile Pupillometry with Virtual Reality: A Digital Biomarker for Screening Cognitive Function and Impairment

Cognitive impairment is a prevalent symptom extending from physiological ageing to disease. It commonly manifests itself in initial memory problems, progressing and co-occurring in more severe conditions such as Mild Cognitive Impairment, Alzheimer's Disease and Major Depressive Disorder. However, current non-invasive screening assessments either lack biological information or are invasive and restricted to specialized centers with complex and cost-intensive set-ups. Here, we conducted an initial validation of mobile pupillometry with Virtual Reality (VR) under experimental conditions as a digital biomarker for cognitive impairment by testing required biomarker-specific properties. For this purpose, we first assessed its construct validity by testing healthy participants (n=43) on an n-back task in VR while pupil size was measured. Mixed effects models revealed that similar to lab-based eye-tracking systems, pupil size increased in a sensible and distinguishable fashion as a function of working memory load. Second, to test the signal's reliability, the same participants were tested on the identical set-up two to three months after their first visit. We observed that the pupil response profile was highly stable over this period. Third, for its clinical validity, we examined patients (n=89) from three different cohorts with varying degrees of cognitive impairment and compared them to healthy control participants (n=81). Mixed-effects models indicated that pupil size was reduced as a function of cognitive impairment levels at higher cognitive load and that this effect was stronger pronounced with increasing age. In conclusion, we provide initial evidence for mobile pupillometry being a sensitive, reliable and clinically valid digital biomarker for cognitive functioning and impairment, which offers desirable properties due to its quick, automatized and location-independent set-up. Keywords: digital biomarker, mobile pupillometry, Virtual Reality, cognition, , Major Depressive Disorder, Mild Cognitive Impairment, Alzheimer's Disease