Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in dementia and eventual death. It is the leading cause of dementia and the number of cases are projected to rise in the next few decades. Pathological hallmarks of AD include the presence of hyperphosphorylated tau and amyloid protein deposition. Currently, these pathological biomarkers are detected either through cerebrospinal fluid analysis, brain imaging or post-mortem. Though effective, these methods are not widely available due to issues such as the difficulty in acquiring samples, lack of infrastructure or high cost. Given that the eye possesses clear optics and shares many neural and vascular similarities to the brain, it offers a direct window to cerebral pathology. These unique characteristics lend itself to being a relatively inexpensive biomarker for AD which carries the potential for wide implementation. The development of ocular biomarkers can have far implications in the discovery of treatments which can improve the quality of lives of patients. In this review, we consider the current evidence for ocular biomarkers in AD and explore potential future avenues of research in this area.
Local blood flow control within the central nervous system (CNS) is critical to proper function and is dependent on coordination between neurons, glia, and blood vessels. Macroglia, such as astrocytes and Müller cells, contribute to this neurovascular unit within the brain and retina, respectively. This study explored the role of microglia, the innate immune cell of the CNS, in retinal vasoregulation, and highlights changes during early diabetes. Structurally, microglia were found to contact retinal capillaries and neuronal synapses. In the brain and retinal explants, the addition of fractalkine, the sole ligand for monocyte receptor Cx3cr1, resulted in capillary constriction at regions of microglial contact. This vascular regulation was dependent on microglial Cx3cr1 involvement, since genetic and pharmacological inhibition of Cx3cr1 abolished fractalkine-induced constriction. Analysis of the microglial transcriptome identified several vasoactive genes, including angiotensinogen, a constituent of the renin-angiotensin system (RAS). Subsequent functional analysis showed that RAS blockade via candesartan abolished microglial-induced capillary constriction. Microglial regulation was explored in a rat streptozotocin (STZ) model of diabetic retinopathy. Retinal blood flow was reduced after 4 wk due to reduced capillary diameter and this was coincident with increased microglial association. Functional assessment showed loss of microglial–capillary response in STZ-treated animals and transcriptome analysis showed evidence of RAS pathway dysregulation in microglia. While candesartan treatment reversed capillary constriction in STZ-treated animals, blood flow remained decreased likely due to dilation of larger vessels. This work shows microglia actively participate in the neurovascular unit, with aberrant microglial–vascular function possibly contributing to the early vascular compromise during diabetic retinopathy.
Glaucoma is a leading cause of blindness. It is a multifactorial condition, the risk factors for which are increasingly well defined from large-scale epidemiological studies. One risk factor that remains controversial is the presence of diabetes. It has been proposed that diabetic eyes are at greater risk of injury from external stressors, such as elevated intraocular pressure. Alternatively, diabetes may cause ganglion cell loss, which becomes additive to a glaucomatous ganglion cell injury. Several clinical trials have considered whether a link exists between diabetes and glaucoma. In this review, we outline these studies and consider the causes for their lack of concordant findings. We also review the biochemical and cellular similarities between the two conditions. Moreover, we review the available literature that attempts to answer the question of whether the presence of diabetes increases the risk of developing glaucoma. At present, laboratory studies provide robust evidence for an association between diabetes and glaucoma. Key words: diabetes, dyslipidaemia, ganglion cells, glaucoma, hyperglycaemia, intraocular pressure, retina Diabetes is a leading health priority, as it can cause severe systemic complications, such as retinopathy, neuropathy and nephropathy. This metabolic disorder results from either altered secretion of insulin by the pancreas (type 1 diabetes) or insulin resistance at a cellular level (type 2 diabetes). These changes produce widespread abnormalities in glucose uptake, resulting in hyperglycaemia, as well as abnormal metabolism and formation of lipids (Figure 1), which impact on neurons, blood vessels and glial cells. Indeed, this journal carries an excellent review on glial dysfunction in diabetic eyes.1 Many clinicians will be aware of diabetic retinopathy and its classification, as laid out by the National Health and Medical Research Council Guidelines for the Management of Diabetic Retinopathy. 2 The purpose of this review is not to dwell on the specifics of diabetic retinopathy but to consider whether diabetes predisposes the eye to other disorders, in particular glaucoma.Diabetes has been estimated by the World Health Organization to affect more than 180 million people worldwide. Despite increasing awareness and advances in management of this disease, it is anticipated that the number of sufferers of diabetes will rise to over 360 million by 2030.3 Diabetic eye disease is a leading cause of blindness [4][5][6] in those of working age (aged from 30 to 69 years).7 The Wisconsin Epidemiologic Study of Diabetic Retinopathy reports that both the duration of the disease and its type (1 or 2) affect the chance of expressing retinopathy. 8,9 The prevalence of retinopathy after five years (17 to 29 per cent) increases after 15 years to 78 to 100 per cent.Diabetes is known to increase the risk of other health complications, 10 in particular, cardiovascular problems 11-13 and cerebral ischaemia. 14,15 Of particular interest to eye-care practitioners is the question of whether we should adj...
Retinal angiogenesis is tightly regulated to meet oxygenation and nutritional requirements. In diseases such as proliferative diabetic retinopathy and neovascular age-related macular degeneration, uncontrolled angiogenesis can lead to blindness. Our goal is to better understand the molecular processes controlling retinal angiogenesis and discover novel drugs that inhibit retinal neovascularization. Phenotype-based chemical screens were performed using the ChemBridge Diverset
The objective of this study was to determine differences in 2 distinct resistance training protocols and if true variability can be detected after accounting for random error. Individuals (n = 151) were randomly assigned to 1 of 3 groups: (i) a traditional exercise group performing 4 sets to failure; (ii) a group performing a 1-repetition maximum (1RM) test; and (iii) a time-matched nonexercise control group. Both exercise groups performed 18 sessions of elbow flexion exercise over 6 weeks. While both training groups increased 1RM strength similarly (∼2.4 kg), true variability was only present in the traditional exercise group (true variability = 1.80 kg). Only the 1RM group increased untrained arm 1RM strength (1.5 kg), while only the traditional group increased ultrasound measured muscle thickness (∼0.23 cm). Despite these mean increases, no true variability was present for untrained arm strength or muscle hypertrophy in either training group. In conclusion, these findings demonstrate the importance of taking into consideration the magnitude of random error when classifying differential responders, as many studies may be classifying high and low responders as those who have the greatest amount of random error present. Additionally, our mean results demonstrate that strength is largely driven by task specificity, and the crossover effect of strength may be load dependent. Novelty Many studies examining differential responders to exercise do not account for random error. True variability was present in 1RM strength gains, but the variability in muscle hypertrophy and isokinetic strength changes could not be distinguished from random error. The crossover effect of strength may differ based on the protocol employed.
To consider whether a circumlimbal suture can be used to chronically elevate intraocular pressure (IOP) in mice and to assess its effect on retinal structure, function and gene expression of stretch sensitive channels. Anesthetized adult C57BL6/J mice had a circumlimbal suture (10/0) applied around the equator of one eye. In treated eyes (n = 23) the suture was left in place for 12 weeks whilst in sham control eyes the suture was removed at day two (n = 17). Contralateral eyes served as untreated controls. IOP was measured after surgery and once a week thereafter. After 12 weeks, electroretinography (ERG) was performed to assess photoreceptor, bipolar cell and retinal ganglion cell (RGC) function. Retinal structure was evaluated using optical coherence tomography. Retinae were processed for counts of ganglion cell density or for quantitative RT-PCR to quantify purinergic (P2x7, Adora3, Entpd1) or stretch sensitive channel (Panx1, Trpv4) gene expression. Immediately after suture application, IOP spiked to 33 ± 3 mmHg. After 1 day, IOP had recovered to 27 ± 3 mmHg. Between weeks 2 and 12, IOP remained elevated above baseline (control 14 ± 1 mmHg, ocular hypertensive 19 ± 1 mmHg). Suture removal at day 2 (Sham) restored IOP to baseline levels, where it remained through to week 12. ERG analysis showed that 12 weeks of IOP elevation reduced photoreceptor (−15 ± 4%), bipolar cell (−15 ± 4%) and ganglion cell responses (−19 ± 6%) compared to sham controls and respective contralateral eyes (untreated). The retinal nerve fiber layer was thinned in the presence of normal total retinal thickness. Ganglion cell density was reduced across all quadrants (superior −12 ± 5%; temporal, −7% ± 2%; inferior −9 ± 4%; nasal −8 ± 5%). Quantitative RT-PCR revealed a significant increase in Entpd1 gene expression (+11 ± 4%), whilst other genes were not significantly altered (P2x7, Adora3, Trpv4, Panx1). Our results show that circumlimbal ligation produces mild chronic ocular hypertension and retinal dysfunction in mice. Consistent with a sustained change to purinergic signaling we found an up-regulation of Entpd1.
Blood flow restriction exercise involves using a pneumatic cuff or elastic band to restrict arterial inflow into the muscle and block venous return out of the muscle during the exercise bout. The resultant ischemia in conjunction with low-load exercise has shown to be beneficial with increasing muscle size and strength. However, a limitation of using blood flow restriction (BFR) is the accompanying discomfort associated with this type of exercise. Factors that may influence discomfort are applied pressure, width of the cuff, cuff material, sex, and training to failure. The goal of this review was to evaluate the existing literature and elucidate how these factors can be manipulated to reduce discomfort during exercise as well as provide possible directions for future research. Thirty-eight different studies were located investigating BFR and discomfort. It was found that BFR training causes more discomfort than exercise without BFR. However, chronic use of BFR may increase tolerability, but discomfort may still be elevated over traditional non-blood flow restricted exercise. Discomfort can be attenuated by the application of lower applied pressures and stopping short of task failure. Finally, in the upper body, wider cuffs seem to increase ratings of discomfort compared with more narrow cuffs. In conclusion, applying the proper-sized cuff and making the applied pressure relative to both the individual and the cuff applied may attenuate discomfort. Reducing discomfort during exercise may help increase adherence to exercise and rehabilitation programs.
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