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Bispebjerg Hospital - a part of Copenhagen University Hospital
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Melanopsin retinal ganglion cell loss in Alzheimer's disease

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  • 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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OBJECTIVE: Melanopsin retinal ganglion cells (mRGCs) are photoreceptors driving circadian photoentrainment, and circadian dysfunction characterizes Alzheimer's disease (AD). We investigated mRGCs in AD, hypothesizing their contribution 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 co-immunostained 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. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalAnnals of Neurology
ISSN0364-5134
DOIs
Publication statusPublished - 27 Oct 2015

ID: 45980899