Silvia Animali, Alessandro Galgani, Francesco Lombardo, Nicola Martini, Francesco Fornai, Paola Binda, Filippo Sean Giorgi

Pupillometric index of Locus Coeruleus degeneration in Alzheimer disease

BraYn Conference 2021



The cognitive impairment and pathological brain alterations occurring in the Mild Cognitive Impairment (MCI)-dementia continuum of Alzheimer’s disease (AD) are paralleled by a progressive degeneration of the pontine noradrenergic nucleus Locus Coeruleus (LC). Thus, the search of non-invasive indices of LC integrity in humans is a primary interest in the research on AD. Pupillometry stands as a promising option, given that pupil dynamics and LC activity appear to be closely coupled. We performed pupillometry in 30 subjects, for whom an estimate of LC integrity was obtained by post-hoc analysis of neuromelanin-sensitive magnetic resonance imaging (MRI) obtained by 3Tesla scan. At the time of MRI acquisitions, all patients were classified as MCI and had comparable cognitive performance. At the time of pupillometry, 15 patients had developed dementia due to AD (converters) and the remaining 15 had maintained their MCI diagnosis (non-converters). Pupillary responses were recorded in the context of an auditory oddball task, with infrequent target tones eliciting pupil dilation stronger than both infrequent distracters and frequent standard tones. We found that pupillary responses accurately differentiated the two groups of patients, with stronger dilations to target tones in the non-converter than in the converter group. Crucially, the magnitude of pupillary responses was positively correlated with LC integrity measures specifically in the converter group. This suggests that the pupillary oddball response may be a solid, non-invasive proxy of the LC degeneration in AD. It also suggests a strong link between structure and function in the pupil control system, whereby less degenerated LC nuclei support stronger pupillary oddball responses.