Melanopsin retinal ganglion cell loss in Alzheimer disease.
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.


CONCLUSIONS
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.
IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Neurology Unit, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Chiara
C
La Morgia
Doheny Eye Institute, Los Angeles, CA.
Fred N
FN
Ross-Cisneros
Department of Neurosurgery and Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
Yosef
Y
Koronyo
Department of Clinical Biochemistry, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
Jens
J
Hannibal
IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Neurology Unit, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Roberto
R
Gallassi
Child Neuropsychiatry, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy.
Gaetano
G
Cantalupo
IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Neurology Unit, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Luisa
L
Sambati
Keck School of Medicine, University of Southern California, Los Angeles, CA.
Billy X
BX
Pan
Keck School of Medicine, University of Southern California, Los Angeles, CA.
Kevin R
KR
Tozer
Studio Oculistico d'Azeglio, Bologna, Italy.
Piero
P
Barboni
IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Neurology Unit, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Federica
F
Provini
Department of Neurosciences, University of Parma, Parma, Italy.
Pietro
P
Avanzini
IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.
Michele
M
Carbonelli
Department of Neurosciences, University of Parma, Parma, Italy.
Annalisa
A
Pelosi
Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA.
Helena
H
Chui
IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Neurology Unit, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Rocco
R
Liguori
IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Neurology Unit, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Agostino
A
Baruzzi
Department of Neurosurgery and Maxine Dunitz Neurosurgical Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.|Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA.
Maya
M
Koronyo-Hamaoui
Doheny Eye Institute, Los Angeles, CA.|Department of Ophthalmology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA.
Alfredo A
AA
Sadun
IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Bologna, Italy.|Neurology Unit, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Valerio
V
Carelli
D056044:Actigraphy; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001369:Axons / Q000473:pathology*; D021081:Chronobiology Disorders / Q000209:etiology / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009900:Optic Nerve / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology; D017299:Rod Opsins / Q000378:metabolism; D041623:Tomography, Optical Coherence; D000099210:Melanopsin
D016229:Amyloid beta-Peptides; D017299:Rod Opsins; D000099210:Melanopsin