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ObjectiveMelanopsin 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.MethodsWe 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.ResultsWe 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.InterpretationWe 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. ANN NEUROL 2016;79:90–109

The mechanisms of incomplete penetrance in Leber’s hereditary optic neuropathy are elusive. Giordano et al. show that mitochondrial DNA content and mitochondrial mass are both increased in tissues and cells from unaffected mutation carriers relative to affected relatives and control individuals. Upregulation of mitochondrial biogenesis may represent a therapeutic target.

An animal model of Leber hereditary optic neuropathy (LHON) was produced by introducing the human optic atrophy mtDNA ND6 P25L mutation into the mouse. Mice with this mutation exhibited reduction in retinal function by elecroretinogram (ERG), age-related decline in central smaller caliber optic nerve fibers with sparing of larger peripheral fibers, neuronal accumulation of abnormal mitochondria, axonal swelling, and demyelination. Mitochondrial analysis revealed partial complex I and respiration defects and increased reactive oxygen species (ROS) production, whereas synaptosome analysis revealed decreased complex I activity and increased ROS but no diminution of ATP production. Thus, LHON pathophysiology may result from oxidative stress.eber hereditary optic neuropathy (LHON), the first inherited mitochondrial (mt)DNA disease reported (1), is thought to be one of the most prevalent diseases caused by mtDNA missense mutations, having an estimated frequency of 15 in 100,000 (2). Most European LHON mutations occur in the mtDNA oxidative phosphorylation (OXPHOS) complex I (NADH:ubiquinone oxidoreductase or NADH dehydrogenase) genes, the three most common being the ND4 gene mutation at nucleotide G11778A causing an arginine 340 to histidine (R340H) substitution (1), the ND1 G3460A (A52T) mutation (3), and the ND6 T14484C (M64V) mutation (4). Milder LHON mutations are generally homoplasmic (pure mutant). In contrast, more severe mtDNA complex I ND gene mutations can cause basal ganglia degeneration presenting as dystonia or Leigh syndrome when homoplasmic but optic atrophy when heteroplasmic (mixed mutant and normal mtDNAs). Two examples of such mutations are ND6 G14459A (A72V) (5) and ND6 G14600A (P25L) (6).LHON generally presents in the second or third decade of life as acute or subacute onset of central vision loss, first in one eye and then in the other. The percentage of optic atrophy in patients varies markedly among pedigrees. Male patients are two to five times more likely to develop blindness than female patients (2), and maternal relatives who have not progressed to subacute optic atrophy can still show signs of visual impairment (7,8).In LHON, optic atrophy is associated with preferential loss of the central small-caliber optic nerve fibers of the papillomacular bundle, resulting in central scotoma but with sparing of the largercaliber peripheral fibers and retention of peripheral vision. The loss of the optic nerve fibers is attributed to the death of retinal ganglion cells (RGC) as a result of the high energy demand placed on the unmyelinated portion of the optic nerve fibers anterior to the lamina cribosa, an area associated with high mitochondrial density (2).Complex I is the largest and most intricate of the mitochondrial OXPHOS complexes. It is comprised of 45 subunits, 7 (ND1, -2, -3, -4, -4L, -5, and -6) of which are coded by the mtDNA (9). Complex I transfers electrons from NADH to ubiquinone, and the energy released from this redox reaction is coupled to pumping protons across the mitochondrial in...