melanopsin; Rod Opsins; Humans; Retina; Retinal Ganglion Cells; Alzheimer Disease/diagnostic imaging; Neuroscience (all); Neurology (clinical); General Neuroscience
Abstract :
[en] [en] 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.
Research Center/Unit :
CRC - Centre de Recherches du Cyclotron - ULiège
Disciplines :
Neurology
Author, co-author :
La Morgia, Chiara ; IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy ; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy ; IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy
Mitolo, Micaela; IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma Neuroimmagini Funzionali e Molecolari, Bologna, Italy ; Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy
Romagnoli, Martina ; IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy
Stanzani Maserati, Michelangelo; IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy
Evangelisti, Stefania ; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
De Matteis, Maddalena; IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy
Capellari, Sabina; IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy ; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
Bianchini, Claudio; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
Testa, Claudia; IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma Neuroimmagini Funzionali e Molecolari, Bologna, Italy ; Dipartimento di Fisica ed Astronomia, Università di Bologna, Bologna, Italy
Vandewalle, Gilles ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Santoro, Aurelia; Dipartimento di Medicina Specialistica Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy ; Alma Mater Research Institute on Global Challenges and Climate Change (Alma Climate), Università di Bologna, Bologna, Italy
Carbonelli, Michele; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
D'Agati, Pietro; IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy
Filardi, Marco; Dipartimento di Medicina di Base, Neuroscienze e degli Organi di Senso, Università di Bari Aldo Moro, Bari, Italy ; Centro per le Malattie Neurodegenerative e l'Invecchiamento Cerebrale, Università di Bari Aldo Moro- A.O. Pia Fondazione Cardinale G. Panico, Tricase, Italy
Avanzini, Pietro; CNR, Istituto di Neuroscienze, Parma, Italy
Barboni, Piero; IRCCS San Raffaele, Milan, Italy
Zenesini, Corrado; IRCCS Istituto delle Scienze Neurologiche di Bologna, Unità di Epidemiologia e Statistica, Bologna, Italy
Baccari, Flavia; IRCCS Istituto delle Scienze Neurologiche di Bologna, Unità di Epidemiologia e Statistica, Bologna, Italy
Liguori, Rocco ; IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Italy ; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
Tonon, Caterina; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy ; IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma Neuroimmagini Funzionali e Molecolari, Bologna, Italy
Lodi, Raffaele; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy ; IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma Neuroimmagini Funzionali e Molecolari, Bologna, Italy
Carelli, Valerio; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy ; IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy
This work has been supported by the Italian Ministry of Health Young Researcher Project Grant (GR-2013-02358026 to CL). We are deeply grateful to patients and their caregivers for participating to the study. We also thank Prof. Piero Parchi for performing the CSF examination of the AD subjects included, Dr. Lidia Di Vito and Dr. Giulia Amore for their support in the initial evaluation of the patients, Prof. Gaetano Cantalupo and Dr. Jason Park for support in developing and setting the chromatic pupillometry protocol, Dr. Vincenzo Allegri for performing amyloid PET in AD patients, Prof. Claudio Franceschi for his support in the recruitment of centenarians, Dr. Maria Lunardelli and Dr. Maria Macchiarulo for the support in the recruitment of AD patients and Prof. Alfredo Sadun for his advice and fruitful discussions. This work has been also supported by Bibliosan. Open access funding provided by BIBLIOSAN.This work has been supported by the Italian Ministry of Health Young Researcher Project Grant (GR‐2013‐02358026 to CL). We are deeply grateful to patients and their caregivers for participating to the study. We also thank Prof. Piero Parchi for performing the CSF examination of the AD subjects included, Dr. Lidia Di Vito and Dr. Giulia Amore for their support in the initial evaluation of the patients, Prof. Gaetano Cantalupo and Dr. Jason Park for support in developing and setting the chromatic pupillometry protocol, Dr. Vincenzo Allegri for performing amyloid PET in AD patients, Prof. Claudio Franceschi for his support in the recruitment of centenarians, Dr. Maria Lunardelli and Dr. Maria Macchiarulo for the support in the recruitment of AD patients and Prof. Alfredo Sadun for his advice and fruitful discussions. This work has been also supported by Bibliosan. Open access funding provided by BIBLIOSAN.
Hannibal J, Hindersson P, Knudsen SM, Georg B, Fahrenkrug J. The photopigment melanopsin is exclusively present in pituitary adenylate cyclase-activating polypeptide-containing retinal ganglion cells of the retinohypothalamic tract. J Neurosci. 2002;22(1):RC191.
Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science. 2002;295(5557):1070-1073.
Aranda ML, Schmidt TM. Diversity of intrinsically photosensitive retinal ganglion cells: circuits and functions. Cell Mol Life Sci. 2021;78(3):889-907.
Oosterman JM, van Someren EJ, Vogels RL, Van Harten B, Scherder EJ. Fragmentation of the rest-activity rhythm correlates with age-related cognitive deficits. J Sleep Res. 2009;18(1):129-135.
Wu YH, Swaab DF. Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer's disease. Sleep Med. 2007;8(6):623-636.
Froy O. Circadian rhythms, aging, and life span in mammals. Physiology (Bethesda). 2011;26(4):225-235.
Li P, Gao L, Gaba A, et al. Circadian disturbances in Alzheimer's disease progression: a prospective observational cohort study of community-based older adults. Lancet Healthy Longev. 2020;1(3):e96-e105.
Ozcan GG, Lim S, Leighton P, Allison WT, Rihel J. Sleep is bi-directionally modified by amyloid beta oligomers. eLife. 2020;9:e53995.
Tranah GJ, Blackwell T, Stone KL, et al. Circadian activity rhythms and risk of incident dementia and mild cognitive impairment in older women. Ann Neurol. 2011;70(5):722-732.
Do MTH. Melanopsin and the intrinsically photosensitive retinal ganglion cells: biophysics to behavior. Neuron. 2019;104(2):205-226.
Johnson BM, Miao M, Sadun AA. Age-related decline of human optic nerve axon populations. Age. 1987;10(1):5-9.
Feuer WJ, Budenz DL, Anderson DR, et al. Topographic differences in the age-related changes in the retinal nerve fiber layer of normal eyes measured by stratus optical coherence tomography. J Glaucoma. 2011;20(3):133-138.
La Morgia C, Ross-Cisneros FN, Sadun AA, et al. Melanopsin retinal ganglion cells are resistant to neurodegeneration in mitochondrial optic neuropathies. Brain. 2010;133(Pt 8):2426-2438.
Hinton DR, Sadun AA, Blanks JC, Miller CA. Optic-nerve degeneration in Alzheimer's disease. N Engl J Med. 1986;315(8):485-487.
Harper DG, Stopa EG, Kuo-Leblanc V, et al. Dorsomedial SCN neuronal subpopulations subserve different functions in human dementia. Brain. 2008;131(Pt 6):1609-1617.
Chan VTT, Sun Z, Tang S, et al. Spectral-domain OCT measurements in Alzheimer's disease: a systematic review and meta-analysis. Ophthalmology. 2019;126(4):497-510.
La Morgia C, Ross-Cisneros FN, Koronyo Y, et al. Melanopsin retinal ganglion cell loss in Alzheimer disease. Ann Neurol. 2016;79(1):90-109.
Koronyo Y, Biggs D, Barron E, et al. Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer's disease. JCI Insight. 2017;2(16):e93621.
La Morgia C, Carelli V, Carbonelli M. Melanopsin retinal ganglion cells and pupil: clinical implications for neuro-ophthalmology. Front Neurol. 2018;9:1047.
La Morgia C, Romagnoli M, Pizza F, et al. Chromatic pupillometry in isolated rapid eye movement sleep behavior disorder. Mov Disord. 2022;37(1):205-210.
Oh AJ, Amore G, Sultan W, et al. Pupillometry evaluation of melanopsin retinal ganglion cell function and sleep-wake activity in pre-symptomatic Alzheimer's disease. PLoS ONE. 2019;14(12):e0226197.
Romagnoli M, Stanzani Maserati M, De Matteis M, et al. Chromatic pupillometry findings in Alzheimer's disease. Front Neurosci. 2020;14:780.
Vandewalle G, Schmidt C, Albouy G, et al. Brain responses to violet, blue, and green monochromatic light exposures in humans: prominent role of blue light and the brainstem. PLoS ONE. 2007;2(11):e1247.
Vandewalle G, Maquet P, Dijk DJ. Light as a modulator of cognitive brain function. Trends Cogn Sci. 2009;13(10):429-438.
Vandewalle G, Archer SN, Wuillaume C, et al. Effects of light on cognitive brain responses depend on circadian phase and sleep homeostasis. J Biol Rhythms. 2011;26(3):249-259.
Vandewalle G, Collignon O, Hull JT, et al. Blue light stimulates cognitive brain activity in visually blind individuals. J Cogn Neurosci. 2013;25(12):2072-2085.
Daneault V, Hebert M, Albouy G, et al. Aging reduces the stimulating effect of blue light on cognitive brain functions. Sleep. 2014;37(1):85-96.
Evangelisti S, La Morgia C, Testa C, et al. Brain functional MRI responses to blue light stimulation in Leber's hereditary optic neuropathy. Biochem Pharmacol. 2021;191:114488.
Perneczky R, Wagenpfeil S, Komossa K, Grimmer T, Diehl J, Kurz A. Mapping scores onto stages: mini-mental state examination and clinical dementia rating. Am J Geriatr Psychiatry. 2006;14(2):139-144.
Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 2014;13(6):614-629.
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry. 1961;4:561-571.
Spielberger CDVP, Barker LR, Donham GW, Westberry LG. The factor structure of the state-trait anxiety inventory. In: Sarason IG, Spielberger CD, eds. Stress and Anxiety. Vol 7. Hemisphere Publishing; 1980:95-109.
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189-198.
Gallassi R, Lenzi P, Stracciari A, et al. Neuropsychological assessment of mental deterioration: purpose of a brief battery and a probabilistic definition of “normality” and “non-normality”. Acta Psychiatr Scand. 1986;74(1):62-67.
Gallassi R, Oppi F, Poda R, et al. Are subjective cognitive complaints a risk factor for dementia? Neurol Sci. 2010;31(3):327-336.
van Someren EJ, Hagebeuk EE, Lijzenga C, et al. Circadian rest-activity rhythm disturbances in Alzheimer's disease. Biol Psychiatry. 1996;40(4):259-270.
Goncalves BS, Adamowicz T, Louzada FM, Moreno CR, Araujo JF. A fresh look at the use of nonparametric analysis in actimetry. Sleep Med Rev. 2015;20:84-91.
Wang J, Xian H, Licis A, et al. Measuring the impact of apnea and obesity on circadian activity patterns using functional linear modeling of actigraphy data. J Circadian Rhythms. 2011;9(1):11.
Drummond SP, Bischoff-Grethe A, Dinges DF, Ayalon L, Mednick SC, Meloy MJ. The neural basis of the psychomotor vigilance task. Sleep. 2005;28(9):1059-1068.
Armstrong RA. Statistical guidelines for the analysis of data obtained from one or both eyes. Ophthalmic Physiol Opt. 2013;33(1):7-14.
Ying GS, Maguire MG, Glynn R, Rosner B. Tutorial on biostatistics: linear regression analysis of continuous correlated eye data. Ophthalmic Epidemiol. 2017;24(2):130-140.
Rosner B, Glynn RJ, Lee ML. Extension of the rank sum test for clustered data: two-group comparisons with group membership defined at the subunit level. Biometrics. 2006;62(4):1251-1259.
Eickhoff SB, Paus T, Caspers S, et al. Assignment of functional activations to probabilistic cytoarchitectonic areas revisited. Neuroimage. 2007;36(3):511-521.
Hatfield CF, Herbert J, van Someren EJ, Hodges JR, Hastings MH. Disrupted daily activity/rest cycles in relation to daily cortisol rhythms of home-dwelling patients with early Alzheimer's dementia. Brain. 2004;127(Pt 5):1061-1074.
La Morgia C, Di Vito L, Carelli V, Carbonelli M. Patterns of retinal ganglion cell damage in neurodegenerative disorders: parvocellular vs magnocellular degeneration in optical coherence tomography studies. Front Neurol. 2017;8:710.
Sanchez D, Castilla-Marti M, Rodriguez-Gomez O, et al. Usefulness of peripapillary nerve fiber layer thickness assessed by optical coherence tomography as a biomarker for Alzheimer's disease. Sci Rep. 2018;8(1):16345.
den Haan J, Verbraak FD, Visser PJ, Bouwman FH. Retinal thickness in Alzheimer's disease: a systematic review and meta-analysis. Alzheimers Dement (Amst). 2017;6:162-170.
Hooghiemstra AM, Eggermont LH, Scheltens P, van der Flier WM, Scherder EJ. The rest-activity rhythm and physical activity in early-onset dementia. Alzheimer Dis Assoc Disord. 2015;29(1):45-49.
Shen J, Tower J. Effects of light on aging and longevity. Ageing Res Rev. 2019;53:100913.
Esquiva G, Lax P, Perez-Santonja JJ, Garcia-Fernandez JM, Cuenca N. Loss of melanopsin-expressing ganglion cell subtypes and dendritic degeneration in the aging human retina. Front Aging Neurosci. 2017;9:79.
Mitolo M, Tonon C, La Morgia C, Testa C, Carelli V, Lodi R. Effects of light treatment on sleep, cognition, mood, and behavior in Alzheimer's disease: a systematic review. Dement Geriatr Cogn Disord. 2018;46(5–6):371-384.
