Multimodal investigation of melanopsin retinal ganglion cells in Alzheimer's disease

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 AE 11 years) and 26 (70.5 AE 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.

Chromatic pupillometry for evaluating melanopsin retinal ganglion cell function in Alzheimer’s disease and other neurodegenerative disorders: a review

“…We summarize our recently published chromatic pupillometry metrics ( La Morgia et al, 2023 ) as indirect and direct measures of mRGC contribution to the PLR ( Table 1 and Figure 3 ). Generally speaking, the PLR entity and its dynamics could be measured by two approaches.…”

“…Moreover, there are several metrics to quantify mRGC intrinsic sustained response, starting from real data as well as based on exponential best-fitting ( Adhikari et al, 2015 ). Based on our previous publications ( Romagnoli et al, 2020 ; La Morgia et al, 2023 ), the parameters for assessing mRGC sustained response produced by 1 s (s) bright blue light-flash could be the so-called PIPR, early area under curve (AUC) and redilation velocity ( Figures 3D , E ). PIPR parameter was defined as the difference between the normalized baseline and the median normalized PLR measured over a 5 to 7 s time interval from the light-stimulus offset.…”

“…mRGC investigation in humans, in particular at early disease stage ( Hannibal et al, 2004 ; La Morgia et al, 2010 ; Esquiva et al, 2017 ; Hannibal et al, 2017 ; Ortuno-Lizaran et al, 2018 ; Esquiva and Hannibal, 2019 ; La Morgia et al, 2023 ), remains challenging due to objective difficulties of in-vivo mRGC system exploration and high variability in terms of technical protocols. A few studies that utilized chromatic pupillometry have been carried out on both AD and pre-symptomatic patients in recent years ( Table 2 ).…”

“…In order to perform a multimodal investigation of the mRGC system, those patients were further evaluated with OCT, actigraphy recording of the sleep–wake cycle, and brain functional MRI (fMRI) with visual and cognitive stimulation, and compared to controls ( La Morgia et al, 2023 ). The fMRI visual stimulation consisted of periods of illumination with blue or red light (50 s) alternated with darkness (20 to 30 s).…”

“…In particular, the PIPR magnitude measured after 1.7 s (s) from offset of the light stimulus is considered a specific measure of mRGC function ( Adhikari et al, 2015 , 2016 ). In this context, chromatic pupillometry has been used to evaluate this cellular system in several clinical settings, including blinding disorders such as hereditary optic neuropathies ( Kawasaki et al, 2010 ; Moura et al, 2013 ; Kawasaki et al, 2014 ; Munch et al, 2015 ; Nissen et al, 2015 ; Ba-Ali and Lund-Andersen, 2017 ; Loo et al, 2017 ), glaucoma ( Kankipati et al, 2011 ; Rukmini et al, 2015 ; Kelbsch et al, 2016 ; Najjar et al, 2018 , 2023 ) and neurodegenerative disorders such as Parkinson’s disease (PD) ( Joyce et al, 2018 ; Feigl et al, 2020 ; Tabashum et al, 2021 ; Gaynes et al, 2022 ), idiopathic/isolated rapid eye movement sleep behavior disorder (iRBD) ( La Morgia et al, 2022 ; Steiner et al, 2022 ), and Alzheimer’s disease (AD) ( Oh et al, 2019 ; Romagnoli et al, 2020 ; La Morgia et al, 2023 ).…”