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The vast increase in Alzheimer disease (AD) worldwide has grave implications for individuals, family support systems and the health-care systems that will attempt to cope with the disease. Early markers of the disease are essential for efficient selection of clinical trial participants for drug development and for timely treatment once an intervention becomes available. There is avid interest in noninvasive, inexpensive markers that have the potential to identify prodromal AD. This Review considers sensory impairments that have the potential to serve as early indicators of AD, with a focus on olfaction, hearing and vision. Current evidence regarding the potential markers of AD in each modality is examined, with a particular emphasis on olfaction and current findings that olfactory function is associated with prodromal AD. Research suggests that olfactory impairment is associated with other markers that signal the emergence of prodromal AD. Auditory impairment is associated with dementia in epidemiological studies and visual system deficits have been reported in AD; however, the emergence of these deficits in prodromal AD is unclear. Further research is necessary to address the relative sensitivity and specificity of olfactory, auditory and visual measures for the detection of prodromal AD.

NMDA excitotoxicity, as a part of glutamate excitotoxicity, has been proposed to contribute significantly to many retinal diseases. Therefore, understanding mechanisms of NMDA excitotoxicity will provide further insight into the mechanisms of many retinal diseases. To study mechanisms of NMDA excitotoxicity in vivo, we used an animal model in which NMDA (20 mM, 2 µL) was injected into the vitreous of mice. We also used high-throughput expression profiling, various animals with reduced expression of target genes, and animals treated with the oral iron chelator deferiprone. We found that the expression of many genes involved in inflammation, programmed cell death, free radical production, oxidative stress, and iron and calcium signaling was significantly increased 24 h after NMDA treatment. Meanwhile, decreased activity of the pro-inflammatory TNF signaling cascade and decreased levels of ferrous iron (Fe 2+ , required for free radical production) led to significant neuroprotection in NMDA-treated retinas. Since increased TNF signaling activity and high Fe 2+ levels trigger regulated necrosis, which, in turn, lead to inflammation, we proposed an important role in NMDA excitotoxicity of a positive feedback loop in which regulated necrosis promotes inflammation, which subsequently triggers regulated necrosis.

Fishes often have cone photoreceptors organized in lattice-like mosaic formations. In flatfishes, these lattices undergo dramatic changes during metamorphosis whereby a honeycomb mosaic of single cones in the larva is replaced by a square mosaic of single and double cones in the adult. The spatio-temporal dynamics of this transition are not well understood. Here, we describe the photoreceptors and mosaic formations that occur during the larva to juvenile transition of Atlantic halibut from the beginning of eye migration to its completion. To gauge the possibility of colour vision, visual pigments in juveniles were measured by microspectrophotometry and the opsin repertoire explored using bioinformatics. At the start of eye migration, the larva had a heterogeneous retina with honeycomb mosaic in the dorsonasal and ventrotemporal quadrants and a square mosaic in the ventronasal and dorsotemporal quadrants. By the end of metamorphosis, the square mosaic was present throughout the retina except in a centrodorsotemporal area where single, double and triple cones occurred randomly. Six cone visual pigments were found with maximum absorbance (λ max , in nm) in the short [S(431) and S(457)], middle [M(500), M(514) and M(527)], and long [L(550)] wavelengths, and a rod visual pigment with λ max at 491 nm. These pigments only partially matched the opsin repertoire detected by query of the Atlantic halibut genome. We conclude that the Atlantic halibut undergoes a complex re-organization of photoreceptors at metamorphosis resulting in a multi-mosaic retina adapted for a demersal life style.

To assess the distribution of axial length as surrogate for myopia and its determinants in an old population, we performed the Ural Very Old Study as a population-based cohort study. Out of 1882 eligible individuals aged 85 + years, the Ural Very Old Study performed in an urban and rural region in Bashkortostan/Russia included 1526 (81.1%) individuals undergoing ophthalmological and medical examinations with sonographic axial length measurement. Biometric data were available for 717 (47.0%) individuals with a mean age of 88.0 ± 2.6 years (range 85–98 years; 25%). Mean axial length was 23.1 ± 1.1 mm (range 19.37–28.89 mm). Prevalences of moderate myopia (axial length 24.5–< 26.5 mm) and high myopia (axial length ≥ 26.5 mm) were 47/717 (6.6%; 95% CI 4.7, 8.4) and 10/717 (1.4%; 95% CI 0.5, 2.3), respectively. In multivariable analysis, longer axial length was associated (coefficient of determination r 2 0.25) with taller body height (standardized regression coefficient beta:0.16;non-standardized regression coefficient B: 0.02; 95% confidence interval (CI) 0.01, 0.03; P  < 0.001), higher level of education (beta: 0.12; B: 0.07; 95% CI 0.02, 0.11; P  = 0.002), and lower corneal refractive power (beta: − 0.35; B: − 0.23; 95% CI − 0.28, − 0.18; P  < 0.001). Higher prevalence of moderate myopia, however not of high myopia, was associated with higher educational level (OR 1.39; 95% CI 1.09, 1.68; P  = 0.007) and lower corneal refractive power (OR 0.77; 95% CI 0.63, 0.94; P  = 0.01). In this old study population, prevalence of moderate axial myopia (6.6% versus 9.7%) was lower than, and prevalence of high axial myopia (1.4% versus 1.4%) was similar as, in a corresponding study on a younger population from the same Russian region. Both myopia prevalence rates were higher than in rural Central India (1.5% and 0.4%, respectively). As in other, younger, populations, axial length and moderate myopia prevalence increased with higher educational level, while high myopia prevalence was independent of the educational level.

Interactions between the immune and nervous systems are of central importance in neuropathic pain, a common and debilitating form of chronic pain caused by a lesion or disease affecting the somatosensory system. Our understanding of neuroimmune interactions in pain research has advanced considerably. Initially considered as passive bystanders, then as culprits in the pathogenesis of neuropathic pain, immune responses in the nervous system are now established to underpin not only the initiation and progression of pain but also its resolution. Indeed, immune cells and their mediators are well-established promoters of neuroinflammation at each level of the neural pain pathway that contributes to pain hypersensitivity. However, emerging evidence indicates that specific subtypes of immune cells (including antinociceptive macrophages, pain-resolving microglia and T regulatory cells) as well as immunoresolvent molecules and modulators of the gut microbiota–immune system axis can reduce the pain experience and contribute to the resolution of neuropathic pain. This Review provides an overview of the immune mechanisms responsible for the resolution of neuropathic pain, including those involved in innate, adaptive and meningeal immunity as well as interactions with the gut microbiome. Specialized pro-resolving mediators and therapeutic approaches that target these neuroimmune mechanisms are also discussed.Chronic neuropathic pain is a leading cause of disability that remains therapeutically challenging. Here, Fiore et al. review the immune mechanisms that contribute to the resolution of chronic neuropathic pain. Contributions of the gut microbiome and specialized pro-resolving mediators are also discussed, along with potential therapeutic strategies.

Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly in the developed world. While treatment is effective for the neovascular or “wet” form of AMD, no therapy is successful for the non-neovascular or “dry” form. Here we discuss the current knowledge on dry AMD pathobiology and propose future research directions that would expedite the development of new treatments. In our view, these should emphasize system biology approaches that integrate omic, pharmacological, and clinical data into mathematical models that can predict disease onset and progression, identify biomarkers, establish disease causing mechanisms, and monitor response to therapy. No effective therapies exist for dry age-related macular degeneration. In this perspective, the authors propose that research should emphasize system biology approaches that integrate various ‘omics’ data into mathematical models to establish pathogenic mechanisms on which to design novel treatments, and identify biomarkers that predict disease progression and therapeutic response.

In severe cases, the deformation stretches and thins the inner parts of the eye, which increases the risk of retinal detachment, cataracts, glaucoma and even blindness. Because the eye grows throughout childhood, myopia generally develops in school-age children and adolescents.

Mental imagery can be advantageous, unnecessary and even clinically disruptive. With methodological constraints now overcome, research has shown that visual imagery involves a network of brain areas from the frontal cortex to sensory areas, overlapping with the default mode network, and can function much like a weak version of afferent perception. Imagery vividness and strength range from completely absent (aphantasia) to photo-like (hyperphantasia). Both the anatomy and function of the primary visual cortex are related to visual imagery. The use of imagery as a tool has been linked to many compound cognitive processes and imagery plays both symptomatic and mechanistic roles in neurological and mental disorders and treatments.

In this Perspective, Murray Sherman discusses connectivity in the thalamocortical system, including the evidence that cortical areas are connected in parallel by direct and transthalamic pathways. Because thalamus receives inputs that form collaterals with subcortical motor regions, the author suggests that it may relay efference copy information. Several challenges to current views of thalamocortical processing are offered here. Glutamatergic pathways in thalamus and cortex are divided into two distinct classes: driver and modulator. We suggest that driver inputs are the main conduits of information and that modulator inputs modify how driver inputs are processed. Different driver sources reveal two types of thalamic relays: first order relays receive subcortical driver input (for example, retinal input to the lateral geniculate nucleus), whereas higher order relays (for example, pulvinar) receive driver input from layer 5 of cortex and participate in cortico-thalamo-cortical (or transthalamic) circuits. These transthalamic circuits represent an unappreciated aspect of cortical functioning, which I discuss here. Direct corticocortical connections are often paralleled by transthalamic ones. Furthermore, driver inputs to thalamus, both first and higher order, typically arrive via branching axons, and the transthalamic branch often innervates subcortical motor centers, leading to the suggestion that these inputs to thalamus serve as efference copies.