Melanopsin retinal ganglion cell loss in Alzheimer disease

Chiara La Morgia, Fred N. Ross-Cisneros, Yosef Koronyo, Jens Hannibal, Roberto Gallassi, Gaetano Cantalupo, Luisa Sambati, Billy X. Pan, Kevin R. Tozer, Piero Barboni, Federica Provini, Pietro Avanzini, Michele Carbonelli, Annalisa Pelosi, Helena Chui, Rocco Liguori, Agostino Baruzzi, Maya Koronyo-Hamaoui, Alfredo A. Sadun, Valerio Carelli

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Abstract

Objective Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction. Methods We assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild-moderate AD patients, and in a subgroup of 16 we evaluated rest-activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross-sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid β (Aβ) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age-matched controls. Results We demonstrated an age-related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (p = 0.038), more evident in the superior quadrant (p = 0.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (p = 0.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (p = 0.003) across all ages and abnormal mRGC dendritic morphology and size (p = 0.003). In flat-mounted AD retinas, Aβ accumulation was remarkably evident inside and around mRGCs. Interpretation We show variable degrees of rest-activity circadian dysfunction in AD patients. We also demonstrate age-related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with Aβ deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD.

Original languageEnglish
Pages (from-to)90-109
Number of pages20
JournalAnnals of Neurology
Volume79
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

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Retinal Ganglion Cells
Alzheimer Disease
Optic Nerve
Optical Coherence Tomography
Circadian Rhythm
melanopsin
Nerve Fibers
Axons
Retina
Actigraphy
Optic Nerve Diseases
Amyloid
Sleep

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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La Morgia, C., Ross-Cisneros, F. N., Koronyo, Y., Hannibal, J., Gallassi, R., Cantalupo, G., ... Carelli, V. (2016). Melanopsin retinal ganglion cell loss in Alzheimer disease. Annals of Neurology, 79(1), 90-109. https://doi.org/10.1002/ana.24548

Melanopsin retinal ganglion cell loss in Alzheimer disease. / La Morgia, Chiara; Ross-Cisneros, Fred N.; Koronyo, Yosef; Hannibal, Jens; Gallassi, Roberto; Cantalupo, Gaetano; Sambati, Luisa; Pan, Billy X.; Tozer, Kevin R.; Barboni, Piero; Provini, Federica; Avanzini, Pietro; Carbonelli, Michele; Pelosi, Annalisa; Chui, Helena; Liguori, Rocco; Baruzzi, Agostino; Koronyo-Hamaoui, Maya; Sadun, Alfredo A.; Carelli, Valerio.

In: Annals of Neurology, Vol. 79, No. 1, 01.01.2016, p. 90-109.

Research output: Contribution to journalArticle

La Morgia, C, Ross-Cisneros, FN, Koronyo, Y, Hannibal, J, Gallassi, R, Cantalupo, G, Sambati, L, Pan, BX, Tozer, KR, Barboni, P, Provini, F, Avanzini, P, Carbonelli, M, Pelosi, A, Chui, H, Liguori, R, Baruzzi, A, Koronyo-Hamaoui, M, Sadun, AA & Carelli, V 2016, 'Melanopsin retinal ganglion cell loss in Alzheimer disease', Annals of Neurology, vol. 79, no. 1, pp. 90-109. https://doi.org/10.1002/ana.24548
La Morgia C, Ross-Cisneros FN, Koronyo Y, Hannibal J, Gallassi R, Cantalupo G et al. Melanopsin retinal ganglion cell loss in Alzheimer disease. Annals of Neurology. 2016 Jan 1;79(1):90-109. https://doi.org/10.1002/ana.24548
La Morgia, Chiara ; Ross-Cisneros, Fred N. ; Koronyo, Yosef ; Hannibal, Jens ; Gallassi, Roberto ; Cantalupo, Gaetano ; Sambati, Luisa ; Pan, Billy X. ; Tozer, Kevin R. ; Barboni, Piero ; Provini, Federica ; Avanzini, Pietro ; Carbonelli, Michele ; Pelosi, Annalisa ; Chui, Helena ; Liguori, Rocco ; Baruzzi, Agostino ; Koronyo-Hamaoui, Maya ; Sadun, Alfredo A. ; Carelli, Valerio. / Melanopsin retinal ganglion cell loss in Alzheimer disease. In: Annals of Neurology. 2016 ; Vol. 79, No. 1. pp. 90-109.
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AU - Hannibal, Jens

AU - Gallassi, Roberto

AU - Cantalupo, Gaetano

AU - Sambati, Luisa

AU - Pan, Billy X.

AU - Tozer, Kevin R.

AU - Barboni, Piero

AU - Provini, Federica

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AU - Sadun, Alfredo A.

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N2 - Objective Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer disease (AD). We investigated mRGCs in AD, hypothesizing that they contribute to circadian dysfunction. Methods We assessed retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) in 21 mild-moderate AD patients, and in a subgroup of 16 we evaluated rest-activity circadian rhythm by actigraphy. We studied postmortem mRGCs by immunohistochemistry in retinas, and axons in optic nerve cross-sections of 14 neuropathologically confirmed AD patients. We coimmunostained for retinal amyloid β (Aβ) deposition and melanopsin to locate mRGCs. All AD cohorts were compared with age-matched controls. Results We demonstrated an age-related optic neuropathy in AD by OCT, with a significant reduction of RNFL thickness (p = 0.038), more evident in the superior quadrant (p = 0.006). Axonal loss was confirmed in postmortem AD optic nerves. Abnormal circadian function characterized only a subgroup of AD patients. Sleep efficiency was significantly reduced in AD patients (p = 0.001). We also found a significant loss of mRGCs in postmortem AD retinal specimens (p = 0.003) across all ages and abnormal mRGC dendritic morphology and size (p = 0.003). In flat-mounted AD retinas, Aβ accumulation was remarkably evident inside and around mRGCs. Interpretation We show variable degrees of rest-activity circadian dysfunction in AD patients. We also demonstrate age-related loss of optic nerve axons and specifically mRGC loss and pathology in postmortem AD retinal specimens, associated with Aβ deposition. These results all support the concept that mRGC degeneration is a contributor to circadian rhythm dysfunction in AD.

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