Multimodal investigation of melanopsin retinal ganglion cells in Alzheimer's disease
Chiara La Morgia, Micaela Mitolo, Martina Romagnoli, Michelangelo Stanzani Maserati, Stefania Evangelisti, Maddalena De Matteis, Sabina Capellari, Claudio Bianchini, Claudia Testa, Gilles Vandewalle, Aurelia Santoro, Michele Carbonelli, Pietro D'Agati, Marco Filardi, Pietro Avanzini, Piero Barboni, Corrado Zenesini, Flavia Baccari, Rocco Liguori, Caterina Tonon, Raffaele Lodi, Valério Carelli
Abstract
OBJECTIVE: In Alzheimer's disease (AD), the presence of circadian dysfunction is well-known and may occur early in the disease course. The melanopsin retinal ganglion cell (mRGC) system may play a relevant role in contributing to circadian dysfunction. In this study, we aimed at evaluating, through a multimodal approach, the mRGC system in AD at an early stage of disease. METHODS: We included 29 mild-moderate AD (70.9 ± 11 years) and 26 (70.5 ± 8 years) control subjects. We performed an extensive neurophtalmological evaluation including optical coherence tomography with ganglion cell layer segmentation, actigraphic evaluation of the rest-activity rhythm, chromatic pupillometry analyzed with a new data-fitting approach, and brain functional MRI combined with light stimuli assessing the mRGC system. RESULTS: We demonstrated a significant thinning of the infero-temporal sector of the ganglion cell layer in AD compared to controls. Moreover, we documented by actigraphy the presence of a circadian-impaired AD subgroup. Overall, circadian measurements worsened by age. Chromatic pupillometry evaluation highlighted the presence of a pupil-light response reduction in the rod condition pointing to mRGC dendropathy. Finally, brain fMRI showed a reduced occipital cortex activation with blue light particularly for the sustained responses. INTERPRETATION: Overall, the results of this multimodal innovative approach clearly document a dysfunctional mRGC system at early stages of disease as a relevant contributing factor for circadian impairment in AD providing also support to the use of light therapy in AD.