Retinal Nerve Fiber Layer Thickness Changes in Parkinson Disease: A Meta-Analysis

Background

Parkinson disease (PD) is a neurodegenerative process that leads to a selective loss of dopaminergic neurons, mainly in the basal ganglia of the brain. Numerous studies have analyzed the ability of optical coherence tomography (OCT) to detect retinal nerve fiber layer (RNFL) thickness abnormalities and changes in PD, but the results have not always been consistent. Therefore, we carried out a meta-analysis to evaluate the RNFL thickness measured with OCT in PD.

Methods and Findings

Case-control studies were selected through an electronic search of the Cochrane Controlled Trials Register, PUBMED and EMBASE. For the continuous outcomes, we calculated the weighted mean difference (WMD) and 95% confidence interval (CI). The statistical analysis was performed by RevMan 5.0 software. Thirteen case-control studies were included in the present meta-analysis, containing a total of 644 eyes in PD patients and 604 eyes in healthy controls. The results of our study showed that there was a significant reduction in average RNFL thickness in patients with PD compared to healthy controls (WMD = −5.76, 95% CI: −8.99 to −2.53, P = 0.0005). Additionally, differences of RNFL thickness in superior quadrant (WMD = −4.44, 95% CI: −6.93 to −1.94, P = 0.0005), inferior quadrant (WMD = −7.56, 95% CI: −11.33 to −3.78, P<0.0001), nasal quadrant (WMD = −3.12, 95% CI: −5.63 to −0.61, P = 0.01) and temporal quadrant (WMD = −4.63, 95% CI: −7.20 to −2.06, P = 0.0004) were all significant between the two groups.

Conclusion

In view of these results and the noninvasive nature of OCT technology, we surmise that OCT could be a useful tool for evaluating the progression of the Parkinson disease.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01928212","term_id":"NCT01928212"}}NCT01928212     

Changes in Retinal Function and Morphology Are Early Clinical Signs of Disease in Cattle with Bovine Spongiform Encephalopathy

Bovine spongiform encephalopathy (BSE) belongs to a group of fatal, transmissible protein misfolding diseases known as transmissible spongiform encephalopathies (TSEs). All TSEs are caused by accumulation of misfolded prion protein (PrP^Sc) throughout the central nervous system (CNS), which results in neuronal loss and ultimately death. Like other protein misfolding diseases including Parkinson’s disease and Alzheimer’s disease, TSEs are generally not diagnosed until the onset of disease after the appearance of unequivocal clinical signs. As such, identification of the earliest clinical signs of disease may facilitate diagnosis. The retina is the most accessible part of the central nervous system, and retinal pathology in TSE affected animals has been previously reported. Here we describe antemortem changes in retinal function and morphology that are detectable in BSE inoculated animals several months (up to 11 months) prior to the appearance of any other signs of clinical disease. We also demonstrate that differences in the severity of these clinical signs reflect the amount of PrP^Sc accumulation in the retina and the resulting inflammatory response of the tissue. These results are the earliest reported clinical signs associated with TSE infection and provide a basis for understanding the pathology and evaluating therapeutic interventions.     

Fingerprint Changes in Coeliac Disease

Study of the fingerprints of 73 patients with coeliac disease, taken carefully, showed changes varying between moderate epidermal ridge atrophy and actual loss of fingerprint patterns. Of the patients 63 had these abnormalities, compared with 3 out of 485 controls. A high degree of correlation existed between ridge atrophy and changes in the clinical state of patients with coeliac disease.     

Early Retinal Function Deficit without Prominent Morphological Changes in the R6/2 Mouse Model of Huntington’s Disease

Huntington’s disease (HD) is an inherited neurodegenerative disorder that primarily affects the medium-size GABAergic neurons of striatum. The R6/2 mouse line is one of the most widely used animal models of HD. Previously the hallmarks of HD-related pathology have been detected in photoreceptors and interneurons of R6/2 mouse retina. Here we aimed to explore the survival of retinal ganglion cells (RGCs) and functional integrity of distinct retinal cell populations in R6/2 mice. The pattern electroretinography (PERG) signal was lost at the age of 8 weeks in R6/2 mice in contrast to the situation in wild-type (WT) littermates. This defect may be attributable to a major reduction in photopic ERG responses in R6/2 mice which was more evident in b- than a-wave amplitudes. At the age of 4 weeks R6/2 mice had predominantly the soluble form of mutant huntingtin protein (mHtt) in the RGC layer cells, whereas the aggregated form of mHtt was found in the majority of those cells from the 12-week-old R6/2 mice and onwards. Retinal astrocytes did not contain mHtt deposits. The total numbers of RGC layer cells, retinal astrocytes as well as optic nerve axons did not differ between 18-week-old R6/2 mice and their WT controls. Our data indicate that mHtt deposition does not cause RGC degeneration or retinal astrocyte loss in R6/2 mice even at a late stage of HD-related pathology. However, due to functional deficits in the rod- and cone-pathways, the R6/2 mice suffer progressive deficits in visual capabilities starting as early as 4 weeks; at 8 weeks there is severe impairment. This should be taken into account in any behavioral testing conducted in R6/2 mice.     

Using Adeno-associated Virus as a Tool to Study Retinal Barriers in Disease

Müller cells are the principal glial cells of the retina. Their end-feet form the limits of the retina at the outer and inner limiting membranes (ILM), and in conjunction with astrocytes, pericytes and endothelial cells they establish the blood-retinal barrier (BRB). BRB limits material transport between the bloodstream and the retina while the ILM acts as a basement membrane that defines histologically the border between the retina and the vitreous cavity. Labeling Müller cells is particularly relevant to study the physical state of the retinal barriers, as these cells are an integral part of the BRB and ILM. Both BRB and ILM are frequently altered in retinal disease and are responsible for disease symptoms.There are several well-established methods to study the integrity of the BRB, such as the Evans blue assay or fluorescein angiography. However these methods do not provide information on the extent of BRB permeability to larger molecules, in nanometer range. Furthermore, they do not provide information on the state of other retinal barriers such as the ILM. To study BRB permeability alongside retinal ILM, we used an AAV based method that provides information on permeability of BRB to larger molecules while indicating the state of the ILM and extracellular matrix proteins in disease states. Two AAV variants are useful for such study: AAV5 and ShH10. AAV5 has a natural tropism for photoreceptors but it cannot get across to the outer retina when administered into the vitreous when the ILM is intact (i.e., in wild-type retinas). ShH10 has a strong tropism towards glial cells and will selectively label Müller glia in both healthy and diseased retinas. ShH10 provides more efficient gene delivery in retinas where ILM is compromised. These viral tools coupled with immunohistochemistry and blood-DNA analysis shed light onto the state of retinal barriers in disease.     

Retinal Changes Precede Visual Dysfunction in the Complement Factor H Knockout Mouse

We previously reported that aged mice lacking complement factor H (CFH) exhibit visual defects and structural changes in the retina. However, it is not known whether this phenotype is age-related or is the consequence of disturbed development. To address this question we investigated the effect of Cfh gene deletion on the retinal phenotype of young and mid-age mice. Cfh ^−/− mouse eyes exhibited thickening of the retina and reduced nuclear density, but relatively normal scotopic and photopic electroretinograms. At 12 months there was evidence of subtle astroglial activation in the Cfh ^−/− eyes, and significant elevation of the complement regulator, decay-accelerating factor (DAF) in Müller cells. In the retinal pigment epithelium (RPE) of young control and Cfh ^−/− animals mitochondria and melanosomes were oriented basally and apically respectively, whereas the apical positioning of melanosomes was significantly perturbed in the mid-age Cfh ^−/− RPE. We conclude that deletion of Cfh in the mouse leads to defects in the retina that precede any marked loss of visual function, but which become progressively more marked as the animals age. These observations are consistent with a lifelong role for CFH in retinal homeostasis.     

“Super p53” Mice Display Retinal Astroglial Changes

Tumour-suppressor genes, such as the p53 gene, produce proteins that inhibit cell division under adverse conditions, as in the case of DNA damage, radiation, hypoxia, or oxidative stress (OS). The p53 gene can arrest proliferation and trigger death by apoptosis subsequent to several factors. In astrocytes, p53 promotes cell-cycle arrest and is involved in oxidative stress-mediated astrocyte cell death. Increasingly, astrocytic p53 is proving fundamental in orchestrating neurodegenerative disease pathogenesis. In terms of ocular disease, p53 may play a role in hypoxia due to ischaemia and may be involved in the retinal response to oxidative stress (OS). We studied the influence of the p53 gene in the structural and quantitative characteristics of astrocytes in the retina. Adult mice of the C57BL/6 strain (12 months old) were distributed into two groups: 1) mice with two extra copies of p53 (“super p53”; n = 6) and 2) wild-type p53 age-matched control, as the control group (WT; n = 6). Retinas from each group were immunohistochemically processed to locate the glial fibrillary acidic protein (GFAP). GFAP+ astrocytes were manually counted and the mean area occupied for one astrocyte was quantified. Retinal-astrocyte distribution followed established patterns; however, morphological changes were seen through the retinas in relation to p53 availability. The mean GFAP+ area occupied by one astrocyte in “super p53” eyes was significantly higher (p<0.05; Student’s t-test) than in the WT. In addition, astroglial density was significantly higher in the “super p53” retinas than in the WT ones, both in the whole-retina (p<0,01 Student’s t-test) and in the intermediate and peripheral concentric areas of the retina (p<0.05 Student’s t-test). This fact might improve the resistance of the retinal cells against OS and its downstream signalling pathways.     

Peripapillary Retinal Nerve Fiber Layer Changes in Preclinical Diabetic Retinopathy: A Meta-Analysis

BackgroundDiabetic retinopathy is a microvascular neurodegenerative disorder in diabetic patients. Peripapillary retinal nerve fiber layer changes have been described in patients with preclinical diabetic retinopathy, but study results have been inconsistent.ObjectiveTo assess changes in peripapillary retinal nerve fiber layer thickness in diabetic patients with preclinical diabetic retinopathy.MethodsA literature search was conducted through PubMed, EMBASE, Web of Science and Cochrane Library. Case-control studies on RNFL thickness in preclinical diabetic retinopathy patients and healthy controls were retrieved. A meta-analysis of weighted mean difference and a sensitivity analysis were performed using RevMan 5.2 software.ResultsThirteen case-control studies containing 668 diabetic patients and 556 healthy controls were selected. Peripapillary RNFL thickness was significantly reduced in patients with preclinical diabetic retinopathy compared to healthy controls in studies applying Optical Coherence Tomography (-2.88μm, 95%CI: -4.44 to -1.32, P = 0.0003) and in studies applying Scanning Laser Polarimeter (-4.21μm, 95%CI: -6.45 to -1.97, P = 0.0002). Reduction of RNFL thickness was significant in the superior quadrant (-3.79μm, 95%CI: -7.08 to -0.50, P = 0.02), the inferior quadrant (-2.99μm, 95%CI: -5.44 to -0.54, P = 0.02) and the nasal quadrant (-2.88μm, 95%CI: -4.93 to -0.82, P = 0.006), but was not significant in the temporal quadrant (-1.22μm, 95%CI: -3.21 to 0.76, P = 0.23), in diabetic patients.ConclusionPeripapillary RNFL thickness was significantly decreased in preclinical diabetic retinopathy patients compared to healthy control. Neurodegenerative changes due to preclinical diabetic retinopathy need more attention.     

兔先天性青光眼网络膜血管改变

目的　研究青光眼对视网膜脉络膜血液循环的影响。方法　选24月龄、体重3.5～4kg的先天性青光眼大耳白兔5只(7只眼),选10只同龄大耳白兔作为对照组。另选10只2月龄、体重2kg大耳白兔前房内灌注生理盐水制成急性高眼压模型。对三组兔进行眼底照像、闪光视诱发电位(FVEP)检查,观察视网膜脉络膜血管形态和FVEP的变化。对人工急性高眼压组还进行了闪光视网膜电流图(FERG)检查。结果　先天性青光眼组与同龄对照组相比视网膜脉络膜末梢血管网明显减少;人工急性高眼压组眼压升高后首先使视网膜脉络膜末梢血管网灌流不足,随着眼压的继续升高脉络膜大血管变细,末梢血管网灌流不足加重,眼压极度升高时脉络膜大血管血流中断。同龄正常对照组的FVEP的主波P100潜伏期是(83±9)ms,先天性青光眼组则为(112±14)ms,差异有非常显著意义(P＜0.01);人工急性高眼压组高眼压前为(69±5)ms,眼压60～80mm　Hg时延长为(81±7)ms,眼压在100～130mmHg时FVEP波形低平,近似直线;眼压恢复正常后2hFVEP的P100潜伏期为(82±8)ms。人工急性高眼压前后FERG变化显著。结论　青光眼可以影响视网膜脉络膜血液循环;可使FVEP、FERG发生变化。     

Changes of Vision-Related Quality of Life in Retinal Detachment Patients after Cataract Surgery

Rhegmatenous retinal detachment (RRD) is one of the most serious complications after phacoemulsification combined with intraocular lens implantation surgery. It has been reported that vision-related quality of life (VRQoL), as well as visual acuity rapidly decreased when RRD developed. However, little is known of the VRQoL in those RRD patients after anatomical retinal re-attachment, especially whether or not the VRQoL is higher than that before cataract surgery. In this prospective case series study, we use the Chinese-version low vision quality of life questionnaire (CLVQOL) to assess the changes of VRQoL in age-related cataract patients who suffered from RRD after phacoemulsification with intraocular lens (phaco-IOL) implantation. All participants were asked to complete questionnaires in face- to-face interviews one day before and two weeks after cataract surgery, as well as one day before and three months after RRD surgery. A total of 10,127 consecutive age-related cataract patients were followed up to one year after phaco-IOL implantation; among these patients, 17 were diagnosed as RRD. The total CLVQOL scores and subscale scores except “Mobility” decreased significantly when RRD developed. After retinal surgery, only the score of “General vision and lighting” in the CLVQOL questionnaires improved when compared to the scores two weeks after cataract surgery, although the best corrected visual acuity of all patients significantly raised up. However, the mean CLVQOL scores and subscale scores were still considerably higher than the level prior to cataract surgery. Our study suggests that cataract patients at high risk of postoperative RRD should not deny the opportunity to undergo phaco-IOL implantation, even though potential VRQoL impairment induced by RRD exists.     

Changes in Chromatin Structure Associated with Alzheimer's Disease

Abstract— The enzyme micrococcal nuclease was used to examine the accessibility of chromatin extracted from brains of 13 patients with senile and presenile dementia of the Alzheimer type. Compared with chromatin extracted from brains of 8 patients without neurological signs or brain pathology and brains of 7 patients with nonAlzheimer dementia, Alzheimer chromatin was less accessible to this enzyme-. Reduced accessibility was reflected by a reduced yield of mononucleosomes in comparison with dinucleosomes and larger oligomers. Both neuronal and glial chromatin were found to be similarly affected. The reduced yield of mononucleosomes from Alzheimer chromatin is not due to their increased breakdown, but is probably related to protein associated with the internucleosomal linker region that retards nuclease action. Dinucleosomes isolated from control and Alzheimer nuclease digests were examined for their protein complement. Three perchloric acid-soluble proteins situated in the histone HI region of sodium dodecyl sulfate (SDS) gels were present in elevated levels in Alzheimer dinucleosomes. These results represent the first example of altered chromosomal proteins associated with a diseased state of the brain.     

microRNA在常见致死性心脏病中的改变

微小RNA(micro RNA,mi RNA)是一类真核生物内源性非编码单链的小RNA分子,长度大约为19-23个核苷酸,拥有高度的保守性,不编码蛋白质,也是近年来研究最热门的一个新领域,通过与靶m RNA特异性结合来调节基因表达,且表达都具有组织特异性。最近,许多研究表明mi RNA在心血管系统疾病和肿瘤疾病方面的相关研究都取得了突破性的进展,mi RNA在肿瘤疾病中是通过调节癌基因及抑癌基因而调控肿瘤的生物学过程,在心血管系统疾病中与心肌肥厚及心肌再生等过程有密切的关系,包括冠状动脉疾病、心肌肥大、心肌梗死、心律失常、高血压和心力衰竭等疾病,且在心脏病学中扮演着及其重要的角色。Mi RNA的表达量增加或者减少对心血管疾病都有影响,该文对新近有关的mi RNA在心血管系统疾病中的研究进展、诊断、治疗以及预后予以综述。     

Lactate Transport and Receptor Actions in Retina: Potential Roles in Retinal Function and Disease

In retina, like in brain, lactate equilibrates across cell membranes via monocarboxylate transporters and in the extracellular space by diffusion, forming a basis for the action of lactate as a transmitter of metabolic signals. In the present paper, we argue that the lactate receptor GPR81, also known as HCAR1, may contribute importantly to the control of retinal cell functions in health and disease. GPR81, a G-protein coupled receptor, is known to downregulate cAMP both in adipose and nervous tissue. The receptor also acts through other down-stream mechanisms to control functions, such as excitability, metabolism and inflammation. Recent publications predict effects of the lactate receptor on neurodegeneration. Neurodegenerative diseases in retina, where the retinal ganglion cells die, notably glaucoma and diabetic retinopathy, may be linked to disturbed lactate homeostasis. Pilot studies reveal high GPR81 mRNA in retina and indicate GPR81 localization in Müller cells and retinal ganglion cells. Moreover, monocarboxylate transporters are expressed in retinal cells. We envision that lactate receptors and transporters could be useful future targets of novel therapeutic strategies to protect neurons and prevent or counteract glaucoma as well as other retinal diseases.