Melanopsin retinal ganglion cells and circadian dysfunction in Alzheimers disease

Purpose To evaluate optic nerve and in particular melanopsin retinal ganglion cells (mRGCs) in relation to rest-activity rhythm in Alzheimer disease (AD). Methods Retinal nerve fiber layer (RNFL) thickness measurements by optical coherence tomography were performed in 21 AD and 74 age-matched controls. Actigraphic monitoring was performed in 16 AD patients and 10 age-matched controls. Non-parametric methods were applied to assess interdaily stability (IS), intradaily variability (IV) and relative amplitude (RA) of rest-activity rhythm. We also performed immunohistochemical analysis of mRGCs and axonal count on optic nerve cross-sections in 14 neuropathologically confirmed AD and 13 control post-mortem retinas. Results OCT evaluation showed reduced average (p=0.03) and superior (p=0.005) RNFL thickness in AD patients. Actigraphic monitoring demonstrated an increased IV (p=0.04) and reduced RA (p=0.04) in AD. Furthermore, AD patients were significantly less active during the day (p=0.03). Considering the patients with at least one circadian parameter outside the 2SD from the mean of controls, we found a significant correlation between IV, average (p=0.035), superior (p=0.045) and inferior (p=0.017) RNFL thickness. Melanopsin RGCs density was significantly reduced, independently from age, in AD retinas (p=0.003) and AD optic nerves showed variable degree of age-related axonal loss. Conclusion We demonstrated a subclinical optic nerve involvement in AD patients, both by OCT and histopathology. We also documented rest-activity circadian dysfunction in AD patients. Post-mortem investigation revealed loss of mRGCs and RGCs with a different pattern in AD. The reduction of mRGCs may contribute to circadian rhythm dysfunction in AD.