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The retina is an emerging CNS target for potential noninvasive diagnosis and tracking of Alzheimer's disease (AD). Studies have identified the pathological hallmarks of AD, including amyloid β-protein (Aβ) deposits and abnormal tau protein isoforms, in the retinas of AD patients and animal models. Moreover, structural and functional vascular abnormalities such as reduced blood flow, vascular Aβ deposition, and blood-retinal barrier damage, along with inflammation and neurodegeneration, have been described in retinas of patients with mild cognitive impairment and AD dementia. Histological, biochemical, and clinical studies have demonstrated that the nature and severity of AD pathologies in the retina and brain correspond. Proteomics analysis revealed a similar pattern of dysregulated proteins and biological pathways in the retina and brain of AD patients, with enhanced inflammatory and neurodegenerative processes, impaired oxidative-phosphorylation, and mitochondrial dysfunction. Notably, investigational imaging technologies can now detect AD-specific amyloid deposits, as well as vasculopathy and neurodegeneration in the retina of living AD patients, suggesting alterations at different disease stages and links to brain pathology. Current and exploratory ophthalmic imaging modalities, such as optical coherence tomography (OCT), OCT-angiography, confocal scanning laser ophthalmoscopy, and hyperspectral imaging, may offer promise in the clinical assessment of AD. However, further research is needed to deepen our understanding of AD's impact on the retina and its progression. To advance this field, future studies require replication in larger and diverse cohorts with confirmed AD biomarkers and standardized retinal imaging techniques. This will validate potential retinal biomarkers for AD, aiding in early screening and monitoring., Competing Interests: Declaration of competing interest HH declares no competing financial interests related to the present article. He is an employee of Eisai Inc. The present article has been initiated and prepared as part of his academic position at Sorbonne University, Paris, France, and reflects entirely and exclusively his own opinion. He serves as Senior Associate Editor for the Journal Alzheimer's & Dementia and does not receive any fees or honoraria since May 2019. He is inventor of 11 patents and has received no royalties: AV declares no competing financial interests related to the present article. AV contribution to this work relates to his previous academic position at Sorbonne University, Paris, France. AV was an employee of Eisai Inc. (Nov 2019–June 2021). AV does not receive any fees or honoraria since November 2019. Before November 2019 he had he received lecture honoraria from Roche, MagQu LLC, and Servier. YK and MKH are co-founding members and consultants of NeuroVision Imaging, Inc., 1395 Garden Highway, Suite 250, Sacramento, CA 95833, USA. KLB is chair and SV is CEO, co-founders and shareholders of NeuroVision Imaging, Inc., 1395 Garden Highway, Suite 250, Sacramento, CA 95833, USA. All other authors declare no competing interests related to this article., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: To determine normative values, intra- and inter-session variability for a range of parameters derived from the photopic negative response (PhNR) using a handheld mini-Ganzfeld stimulator in healthy normal adults., Methods: Light-adapted flash full-field electroretinograms (ERGs) were recorded from healthy individuals with no visual complaints, visual acuity equal to or better than 0.0 logMAR (20/20 Snellen), and negative family history for visual diseases. ERGs were recorded from both eyes using a DTL ® type fiber electrode after dilation of the pupils with instillation of 1 drop of tropicamide eye drops (1%). The full-field PhNR stimulus conditions were produced by a LED-based ColorBurst™ (Diagnosys LLC, Lowell, MA, USA) handheld stimulator. Red flashes of 1, 5 and 7 cd.s/m 2 on a blue background of 10 cd/m 2 were presented. A-wave, b-wave and PhNR amplitude (determined by both baseline to trough-BT and peak to trough-PT) and peak times were analyzed. Normal limits were determined as 5% percentile for amplitudes and 95% percentile for latencies. Intra- and inter-session variability were assessed with Wilcoxon signed-rank test, intraclass correlation coefficient (ICC) and the coefficient of variability (COV)., Results: Normative limits for PhNR amplitude (µV) using 1, 5 and 7 cd.s./m2 stimuli were, respectively: 20.81; 18.06 and 19.60 for BT and 69.11; 77.98; 76.51 for PT. Peak times (ms) normative limits for 1, 5 and 7 cd.s/m2 intensities were, respectively, 65.98; 78.20 and 77.96. Overall, intra-session variability assessed by coefficients of variation ranged from 1.35 to 10.28%. Inter-session variability disclosed significant intraclass correlation values for all PhNR parameters only for 1 cd.s/m2 stimuli., Conclusions: The normative values provided by this study are clinically helpful in the diagnosis of inner retinal disorders, especially those affecting retinal ganglion cells such as glaucoma and other optic neuropathies. Further studies, including a larger sample with variable age range would extend the validity of the current results.

The current study evaluated retinal function using electroretinography (ERG) in cognitively healthy (CH) participants with preclinical Alzheimer's disease (AD), as classified by cerebral spinal fluid (CSF) Aβ 42 /Tau ratio. Individuals with normal retinal morphology ascertained by spectral-domain optical coherence tomography were enrolled. Full-field ERG, pattern PERG, and photopic negative response (PhNR) were performed in 29 adult participants (58 eyes). Amplitude and implicit times of the ERG wave components were analyzed. Preclinical AD participants showed marked retinal ganglion cell dysfunction relative to controls. The PhNR was significantly diminished in preclinical AD relative to controls. PhNR amplitude and N95 implicit time differentiated CH individuals with CSF biomarkers of AD pathology with 87% sensitivity and 82% specificity. These quantitative electrophysiologic findings expand our understanding of early retinal functional changes that precede cognitive decline in AD. Retinal ganglion cell dysfunction, as detected by ERG, may be a clinically useful, non-invasive in vivo biomarker for early disease detection, which is necessary for ultimately pursuing early intervention.

Melanopsin retinal ganglion cells (mRGCs) are the third class of retinal photoreceptors with unique anatomical, electrophysiological, and biological features. There are different mRGC subtypes with differential projections to the brain. These cells contribute to many nonimage-forming functions of the eye, the most relevant being the photoentrainment of circadian rhythms through the projections to the suprachiasmatic nucleus of the hypothalamus. Other relevant biological functions include the regulation of the pupillary light reflex, mood, alertness, and sleep, as well as a possible role in formed vision. The relevance of the mRGC-related pathways in the brain is highlighted by the role that the dysfunction and/or loss of these cells may play in affecting circadian rhythms and sleep in many neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's disease and in aging. Moreover, the occurrence of circadian dysfunction is a known risk factor for dementia. In this chapter, the anatomy, physiology, and functions of these cells as well as their resistance to neurodegeneration in mitochondrial optic neuropathies or their predilection to be lost in other neurodegenerative disorders will be discussed., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To assess preganglionic retinal function using multifocal electroretinogram (mfERG) in patients affected by dominant optic atrophy (DOA) stratified by OPA1 gene mutation., Methods: Multifocal electroretinogram (mfERG) was recorded in 18 DOA patients (DOA group, 35 eyes) and 25 age-matched healthy subjects (control group, 25 eyes). Patients were stratified in two groups based on gene mutation: missense mutation (DOA-M group, 11 eyes) and mutation causing haploinsufficiency (DOA-H group, 24 eyes). The mfERG N1-P1 response amplitude density (RAD) has been evaluated in five annular retinal areas with different eccentricity from the fovea (ring 1: 0-5 degrees, R1; ring 2: 5-10 degrees, R2; ring 3: 10-15 degrees, R3; ring 4: 15-20 degrees, R4; and ring 5: 20-25 degrees, R5) and in eight sectors on the basis of the retinal topography: temporal-superior (TS), temporal-inferior (TI), nasal-superior (NS) and nasal-inferior (NI), temporal (T), superior (S), nasal (N) and inferior (I)., Results: Compared to controls, DOA group revealed a significant reduction in N1-P1 RADs values in R1-R4 rings and in TI, NS and N sectors [analysis of variance (ANOVA), p < 0.01). DOA-M group showed a significant reduction in N1-P1 RADs values in R1-R5 rings and in TI, NS, NI, T, N and I sectors (p < 0.01). Dominant optic atrophy-H (DOA-H) group displayed only a significant (p < 0.01) reduction in N1-P1 RADs values, exclusively in R1 and in the NS sector., Conclusion: Preganglionic retinal impairment occurs in DOA with a clear genotype to retinal dysfunction association. Missense mutations are characterized by a far more severe functional impairment., (© 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

The belly spot and tail (Bst(+/-)) mouse phenotype is caused by mutations of the ribosomal protein L24 (Rpl24). Among various phenotypes in Bst(+/-) mice, the most interesting are its retinal abnormalities, consisting of delayed closure of choroid fissures, decreased ganglion cells and subretinal vascularization. We further characterized the Bst(+/-) mouse and investigated the underlying molecular mechanisms to assess the feasibility of using this strain as a model for stem cell therapy of retinal degenerative diseases due to retinal ganglion cell (RGC) loss. We found that, although RGCs are significantly reduced in retinal ganglion cell layer in Bst(+/-) mouse, melanopsin(+) RGCs, also called ipRGCs, appear to be unchanged. Pupillary light reflex was completely absent in Bst(+/-) mice but they had a normal circadian rhythm. In order to examine the pathological abnormalities in Bst(+/-) mice, we performed electron microscopy in RGC and found that mitochondria morphology was deformed, having irregular borders and lacking cristae. The complex activities of the mitochondrial electron transport chain were significantly decreased. Finally, for subretinal vascularization, we also found that angiogenesis is delayed in Bst(+/-) associated with delayed hyaloid regression. Characterization of Bst(+/-) retina suggests that the Bst(+/-) mouse strain could be a useful murine model. It might be used to explore further the pathogenesis and strategy of treatment of retinal degenerative diseases by employing stem cell technology., (© 2015. Published by The Company of Biologists Ltd.)

Purpose: To investigate the thickness of the retinal layers and to assess the prevalence of macular microcysts (MM) in the inner nuclear layer (INL) of patients with mitochondrial optic neuropathies (MON)., Methods: All patients with molecularly confirmed MON, i.e. Leber's Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), referred between 2010 and 2012 were enrolled. Eight patients with MM were compared with two control groups: MON patients without MM matched by age, peripapillary retinal nerve fiber layer (RNFL) thickness, and visual acuity, as well as age-matched controls. Retinal segmentation was performed using specific Optical coherence tomography (OCT) software (Carl Zeiss Meditec). Macular segmentation thickness values of the three groups were compared by one-way analysis of variance with Bonferroni post hoc corrections., Results: MM were identified in 5/90 (5.6%) patients with LHON and 3/58 (5.2%) with DOA. The INL was thicker in patients with MON compared to controls regardless of the presence of MM [133.1±7μm vs 122.3±9μm in MM patients (p<0.01) and 128.5±8μm vs. 122.3±9μm in no-MM patients (p<0.05)], however the outer nuclear layer (ONL) was thicker in patients with MM (101.4±1mμ) compared to patients without MM [77.5±8mμ (p<0.001)] and controls [78.4±7mμ (p<0.001)]. ONL thickness did not significantly differ between patients without MM and controls., Conclusion: The prevalence of MM in MON is low (5-6%), but associated with ONL thickening. We speculate that in MON patients with MM, vitreo-retinal traction contributes to the thickening of ONL as well as to the production of cystic spaces.

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.

Purpose: To characterize optic nerve and retinal changes in a patient with end-stage retinitis pigmentosa (RP) with an implanted active epiretinal array., Methods: A 74-year-old man with end-stage X-linked RP underwent implantation of an epiretinal array over the macula in the right eye and subsequent stimulation until his death at 5 years and 3 months after implantation. The optic nerves from this study patient, as well as those from two age-matched normal patients and two age-matched RP patients, were morphometrically analyzed against two different sets of criteria and compared. The retina underlying the array in the study patient was also morphometrically analyzed and compared with corresponding regions of the retina in the age-matched RP patients., Results: Optic nerve total axon counts were significantly lower in the study patient and RP patients than in normal patients. However, there was no significant difference when comparing total axon counts from the optic nerve corresponding to the patient's implanted right eye versus the optic nerves from the RP patients (P = 0.59 and P = 0.61 using the two different criteria). Degenerated axon data quantified damage and did not show increased damage in the optic nerve quadrant that retinotopically corresponded to the site of epiretinal array implantation and stimulation. Except for the tack site, there was no significant difference when comparing the retina underlying the array and the corresponding perimacular regions of two RP patients., Conclusions: Long-term implantation and electrical stimulation with an epiretinal array did not result in damage that could be appreciated in a morphometric analysis of the optic nerve and retina.

Purpose: To evaluate early changes in the central retinal response in human immunodeficiency virus (HIV)-positive patients without infectious retinitis using multifocal electroretinography (mfERG)., Design: Case control study., Methods: We evaluated three cohorts: HIV-negative controls and two groups of HIV-positive patients separated according to their nadir CD4 counts (>or= 100 cells/mm(3) and < 100 cells/mm(3) for a minimum of six months). mfERG first-order kernels (FOKs) and second-order kernels (SOKs) were analyzed separately by areas of rings, quadrants, and individual hexagons for each cohort., Results: Of 103 hexagon locations of FOK results, there were no significant differences in amplitudes of P1 and N1 across the groups (.05 < P < .50), although there was a trend for an overall reduction in the amplitudes. Similarly, latency N1 did not differ (.28 < P < .95). There were significantly delayed latencies of P1 between cohorts across 103 hexagons in both kernels. SOK results also showed significant delay in latencies of P1 and a trend of reduced P1 amplitudes across studied locations among cohorts (.24 < P < .08)., Conclusions: The results demonstrate widespread delay in latency in HIV-positive patients, especially in those with prolonged low (below 100 cells/mm(3)) CD4 nadir counts. These findings suggest early diffuse dysfunction of the inner retina results from severe HIV disease even in the HAART era.

We previously demonstrated that endogenous interleukin-6 (IL-6) is upregulated and may be neuroprotective after retinal ischemia. The purpose of this study is to investigate the role of nuclear factor kappa-B (NF-kappaB) in regulating IL-6 expression after ischemia. NF-kappaB p65 mRNA levels were significantly elevated between 2 and 12 h after the insult. A high number of NF-kappaB p65 positive cells were detected in the inner retina at 12 h after ischemia. Activated nuclear NF-kappaB p65 and IL-6 were colocalized in cells, which were also marked by a microglial/phagocytic cell marker (ED1) in the inner retina. Carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG-132, a proteasome inhibitor, which inhibits IkappaB degradation and hence prevents the activation and translocation of NF-kappaB into the nucleus) abolished the increase in NF-kappaB p65 mRNA levels after the insult, while there was no effect by helenalin (an inhibitor which inhibits NF-kappaB activity by alkylation of the p65 subunit, thereby blocking its binding to the target DNA). However, MG-132 and/or helenalin significantly diminished the increase in IL-6 mRNA levels after the insult. Small interfering RNAs (siRNAs, inhibit target gene expression through the sequence-specific destruction of the target messenger RNA) against NF-kappaB p65 significantly reduced the increase in NF-kappaB p65 mRNA levels as well as IL-6 mRNA levels after ischemia. The number of retinal ganglion cells (RGCs) was also significantly decreased using the inhibitors of NF-kappaB compared with those of the controls after ischemia. These findings support the hypothesis that upregulation of endogenous retinal IL-6 in retinal I/R injury in microglial/phagocytic cells is controlled predominantly by NF-kappaB p65.

Ethambutol is an efficacious antituberculosis agent. However, its use has been limited by the occurrence of ocular toxicity. To investigate characteristics and possible mechanisms of ethambutol ocular toxicity, we used primary rat retinal cultures as a model. Primary rat retinal cultures were obtained from newborn Sprague-Dawley rats and used for experiments after maturation (DIV > or = 10). Cytopathologic changes were examined under light and electron microscopes. Thy-1 (a membrane glycoprotein expressed by retinal ganglion neurons)-containing neurons and gamma-aminobutyric acid (GABA)-ergic neurons were identified immunocytochemically. Exposure of retinal cultures for 24-48 h to ethambutol induced cytoplasmic vacuolar changes and neuronal loss. Vacuolar changes were partially reversible with the termination of ethambutol exposure. Of neurons, Thy-1(+) ganglion neurons were more vulnerable than GABA(+) neurons. Glutamate antagonists, an antioxidant (trolox), or cycloheximide, did not attenuate either vacuolar changes or neuronal loss. A cell-permeant zinc chelator N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN) markedly attenuated vacuolar degeneration and neuronal loss, while the addition of zinc augmented both. In rat retinal cultures, ethambutol induces reversible vacuolar degeneration as well as irreversible neuronal loss, more preferentially of Thy-1(+) ganglion neurons. Contrary to the current theories, ethambutol-induced retinal cytotoxicity in the present study is mediated not by excitotoxicity or zinc deficiency but by a mechanism requiring intracellular zinc. In addition, features of the ethambutol-induced cell death were not consistent with those of apoptosis., (Copyright 2000 Academic Press.)

Optic nerves from ten patients with Alzheimer's disease were histologically examined and compared with those from age-matched controls. Specific and nonspecific measures of degeneration were noted in eight of ten Alzheimer's disease optic nerves; no degeneration was noted in any of the controls. Results of histologic examination of the retinas of one eye of three Alzheimer's disease patients also showed degeneration of retinal ganglion cells and their axons in the nerve fiber layer. Morphometric analysis suggested that in many cases of Alzheimer's disease, the optic nerve showed predominant loss of the largest class of retinal ganglion cells (M-cells) that contribute large caliber fibers to the optic nerve. The M-cell system is known to mediate specific visual functions, and selective involvement of the M-cell population leads to clinically measurable neuro-ophthalmic and psychophysical impairments in many Alzheimer's disease patients.

Funduscopic examination of two young adults complaining of blurred vision revealed small symmetrical macular lesions suggestive of solar retinopathy. Although both patients had recently looked at the sun for less than one minute, it is common to look at the sun for longer periods (ie, sunsets) without incurring visual symptoms of retinal lesions. Our biophysical analysis revealed the important parameters of solar retinopathy and the minimum exposure to the sun that would produce such lesions. Under ideal optical conditions, solar retinopathy can occur following extremely short observations of the sun.

Transneuronal degeneration of retinal ganglion cells was directly demonstrated in a patient who had unilateral removal of the striate cortex forty years prior to necropsy. For comparison, another case is presented showing anterograde transneuronal atrophy forty years after enucleation of one eye.

It has been proposed that, in animals, a retinohypothalamic pathway exists which mediates the synchronization of the diurnal light-dark cycle with the central neural components regulating endogenous rhythms. There have been numerous anatomic, physiologic and behavioral investigations to substantiate this proposed connection in experimental animals. Morphologic investigation of a retinohypothalamic tract in man has awaited the development of a technique capable of axonal tracing in the human brain. The paraphenylenediamine method was applied to 7 post-mortem human brains. Degenerated axons were found in the suprachiasmatic nuclei of the hypothalamus in each of the 4 patients who had incurred prior optic nerve damage. The retinosuprachiasmatic pathway may be the anatomical substrate for the integration of retinal light information with endogenous rhythms in man.

Alzheimer's disease is a dementing disorder of unknown cause in which there is degeneration of neuronal subpopulations in the central nervous system. In postmortem studies, we found widespread axonal degeneration in the optic nerves of 8 of 10 patients with Alzheimer's disease. The retinas of four of the patients were also examined histologically, and three had a reduction in the number of ganglion cells and in the thickness of the nerve-fiber layer. There was no retinal neurofibrillary degeneration or amyloid angiopathy, which are typically seen in the brains of patients with Alzheimer's disease. The changes we observed in the patients with Alzheimer's disease were clearly distinguishable from the findings in 10 age-matched controls and represent a sensory-system degeneration that occurs in Alzheimer's disease. Study of the retina in patients with this disease may be helpful diagnostically, and isolation of the affected ganglion cells may facilitate molecular analysis of the disorder.

This study documents the light-microscopic and ultrastructural characteristics of ganglion cell degeneration in the retinas of patients with Alzheimer's disease (AD). The results show degeneration in the retinal ganglion cells (RGCs) characterized by a vacuolated, 'frothy' appearance of the cytoplasm. The degeneration is unique in AD because of the absence of neurofibrillary tangles within the RGCs, or of neuritic plaques or amyloid angiopathy in the retinas or optic nerves of any of the cases examined. These results suggest that neuronal degeneration in the ganglion cell layer (GCL) should be added to the constellation of neuropathologic changes found in patients with Alzheimer's disease.

A retinofugal projection to the suprachiasmatic nucleus of the hypothalamus has been described in man by means of a newly developed staining technique (PPD) for tracing degenerated fibers in the human brain. We applied the PPD method to the chiasmal/hypothalamic area of human autopsy brains from patients who had incurred prior optic nerve damage. We followed degenerated fibers from the optic nerve through the optic chiasm and the optic tract. At the optic chiasm/tract junction, some fibers were seen to diverge and to form an optic fascicle which traversed the lateral preoptic-anterior hypothalamic area towards the third ventricle. These degenerated fibers terminated in the paraventricular nucleus of the hypothalamus. We suggest that there are at least two retinohypothalamic pathways in man. Some of the neuroendocrine imbalances in blind persons may be attributed to the disruption of the retinal input to the paraventricular and suprachiasmatic nuclei of the hypothalamus. These retinohypothalamic pathways may be the anatomical substrates for light/dark entrainment of human neuroendocrine and autonomic regulatory processes.