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

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...

PURPOSE. Leber's hereditary optic neuropathy (LHON), a mitochondrial disease, has clinical manifestations that reflect the initial preferential involvement of the papillomacular bundle (PMB). The present study seeks to predict the order of axonal loss in LHON optic nerves using the Nerve Fiber Layer Stress Index (NFL-S I ), which is a novel mathematical model. METHODS.Optic nerves were obtained postmortem from four molecularly characterized LHON patients with varying degrees of neurodegenerative changes and three age-matched controls. Tissues were cut in cross-section and stained with pphenylenediamine to visualize myelin. Light microscopic images were captured in 32 regions of each optic nerve. Control and LHON tissues were evaluated by measuring axonal dimensions to generate an axonal diameter distribution map. LHON tissues were further evaluated by determining regions of total axonal depletion. RESULTS.A size gradient was evident in the control optic nerves, with average axonal diameter increasing progressively from the temporal to nasal borders. LHON optic nerves showed an orderly loss of axons, starting inferotemporally, progressing centrally, and sparing the superonasal region until the end. Values generated from the NFL-S I equation fit a linear regression curve (R 2 ¼ 0.97; P < 0.001).CONCLUSIONS. The quantitative histopathologic data from this study revealed that the PMB is most susceptible in LHON, supporting clinical findings seen early in the course of disease onset. The present study also showed that the subsequent progression of axonal loss within the optic nerve can be predicted precisely with the NFL-S I equation. The results presented provided further insight into the pathophysiology of LHON. (Invest Ophthalmol Vis Sci. 2012;53:7608-7617)

PurposeThe purpose of this study was to evaluate the benefit of analyzing an increased number of anterior segment optical coherence tomography (AS-OCT) images on measurement values of various anterior segment parameters.MethodsSubjects for this cross-sectional study were recruited from the Chinese American Eye Study (CHES), a population-based study in Los Angeles, CA. Thirty-two AS-OCT images were acquired from one eye each of 83 consecutive subjects. Sixteen parameters were analyzed in each image, including angle opening distance (AOD), angle recess area (ARA), trabecular iris space area (TISA), trabecular iris angle (TIA), scleral spur angle (SSAngle), lens vault (LV), pupillary diameter (PD), anterior chamber depth (ACD), anterior chamber width (ACW), iris area (IA), and anterior chamber area (ACA). Data from 1, 2, 4, 8, 16, or 32 OCT images were averaged across subjects to calculate the range and mean of measurement values for each parameter.ResultsAnatomical variations were poorly captured with fewer OCT images for AOD, ARA, TISA, SSAngle, IA, and LV. For these parameters, the range and mean of measurement values obtained from one OCT image deviated from 32-image values by up to 43.9% and 13.3% of the 32-image mean, respectively. These deviations decreased when additional OCT images were analyzed. Deviations from 32-image range and mean values were less pronounced regardless of image number for PD, ACD, ACW, and ACA, measuring up to 3.5% and 5.0%, respectively.ConclusionsA multi-image approach should be the standard in OCT-based studies of AOD, ARA, TISA, TIA, SSAngle, IA, and LV.

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