Introduction
Diabetic retinopathy (DR) is both a microangiopathy and a neurodegenerative disease. However, the connections between both changes are not well known.
Purpose
To characterise the ...longitudinal retinal ganglion cell layer + inner plexiform layer (GCL + IPL) changes and their association with microvascular changes in type‐2 diabetes (T2D) patients with nonproliferative diabetic retinopathy (NPDR).
Methods
This two‐year prospective study (CORDIS, NCT03696810) included 122 T2D individuals with NPDR identified as risk phenotypes B and C, which present a more rapid progression. Phenotype C was identified by decreased VD ≥ 2SD in healthy controls, and phenotype B, identified by subclinical macular oedema with only minimal vascular closure. The GCL + IPL thickness, vessel density, perfusion density and area of intercapillary spaces (AIS) were assessed by optical coherence tomography (OCT) and OCT angiography (OCTA). Linear mixed effects models were employed to evaluate the retinal GCL + IPL progression and its associations.
Results
Regarding GCL + IPL thickness, T2D individuals presented on average 80.1 ± 7.49 μm, statistically significantly lower than the healthy control group, 82.5 ± 5.71 (p = 0.022), with only phenotype C differing significantly from controls (p = 0.006). GCL + IPL thickness steadily decreased during the two‐year period in both risk phenotypes, with an annual decline rate of −0.372 μm/year (p < 0.001). Indeed, phenotype C showed a higher rate of progression (−0.459 μm/year, p < 0.001) when compared to phenotype B (−0.296 μm/year, p = 0.036). Eyes with ETDRS grade 20 showed GCL + IPL thickness values comparable to those of healthy control group (83.3 ± 5.80 and 82.7 ± 5.50 μm, respectively, p = 0.880), whereas there was a progressive decrease in GCL + IPL thickness in ETDRS grades 35 and 43–47 associated with the increase in severity of the retinopathy (−0.276 μm/year, p = 0.004; −0.585 μm/year, p = 0.013, respectively). Furthermore, the study showed statistically significant associations between the progressive thinning of GCL + IPL and the progressive increase in retinal capillary non‐perfusion, with particular relevance for AIS (p < 0.001).
Conclusions
Our findings showed that, in eyes with NPDR and at risk for progression, retinal neurodegeneration occurs at different rates in different risk phenotypes, and it is associated with retinal microvascular non‐perfusion.
Studies carried out during the last few decades have consistently shown that cell surface MHC class I (MHC-I) molecules are endowed with functions unrelated with antigen presentation. These include ...cis–trans-interactions with inhibitory and activating KIR and LILR, and cis-interactions with receptors for hormones, growth factors, cytokines, and neurotransmitters. The mounting body of evidence indicates that these non-immunological MHC-I functions impact clinical and biomedical settings, including autoimmune responses, tumor escape, transplantation, and neuronal development. Notably, most of these functions appear to rely on the presence in hematopoietic and non-hematopoietic cells of heavy chains not associated with β2m and the peptide at the plasma membrane; these are known as open MHC-I conformers. Nowadays, open conformers are viewed as functional cis-trans structures capable of establishing physical associations with themselves, with other surface receptors, and being shed into the extracellular milieu. We review past and recent developments, strengthening the view that open conformers are multifunctional structures capable of fine-tuning cell signaling, growth, differentiation, and cell communication.
MHC class I molecules regulate brain development and plasticity in mice and HLA class I molecules are associated with brain disorders in humans. We investigated the relationship between ...plasma‐derived soluble human HLA class I molecules (sHLA class I), HLA class I serotypes and dementia. A cohort of HLA class I serotyped elderly subjects with no dementia/pre‐dementia (NpD, n = 28), or with dementia (D, n = 28) was studied. Multivariate analysis was used to examine the influence of dementia and HLA class I serotype on sHLA class I levels, and to compare sHLA class I within four groups according to the presence or absence of HLA‐A23/A24 and dementia. HLA‐A23/A24 and dementia, but not age, significantly influenced the level of sHLA class I. Importantly, the concurrent presence of HLA‐A23/A24 and dementia was associated with higher levels of sHLA class I (p < 0.001). This study has shown that the simultaneous presence of HLA‐A23/HLA‐A24 and dementia is associated with high levels of serum sHLA class I molecules. Thus, sHLA class I could be considered a biomarker of neurodegeneration in certain HLA class I carriers.
Antigen-driven human effector-memory CD8+ T cells expressing low levels of the CD8β chain have been previously described. However, little is known on a possible antigen-independent trigger. We have ...examined the impact that IL-15 has on the expression of CD8β on purified human naïve CD8+ T cells after CFSE labeling and culture with IL-15. As expected, IL-15 induced naïve CD8+ T cells to proliferate and differentiate. Remarkably, the process was associated with a cell-cycle dependent down-modulation of CD8β from the cell surface, leading to the generation of CD8αβ low and CD8αβ − (i.e., CD8αα) T cells. In contrast, expression of the CD8α chain remained steady or even increased. Neither IL-2 nor IL-7 reproduced the effect of IL-15. Determination of mRNA levels for CD8α and CD8β isoforms by qPCR revealed that IL-15 promoted a significant decrease in mRNA levels of the CD8β M-4 isoform, while levels of the M-1/M-2 isoforms and of CD8α increased. Noteworthy, CD8+ T cell blasts obtained after culture of CD8+ T cells with IL-15 showed a cell-cycle dependent increase in the level of the tyrosine kinase Lck, when compared to CD8+ T cells at day 0. This study has shown for the first time that IL-15 generates CD8αα + αβ low and CD8αα + αβ − T cells containing high levels of Lck, suggesting that they may be endowed with unique functional features.
There is increasing evidence that in humans the adaptive immunological system can influence cognitive functions of the brain. We have undertaken a comprehensive immunological analysis of lymphocyte ...and monocyte populations as well as of HLA molecules expression in a cohort of elderly volunteers (age range, 64-101) differing in their cognitive status. Hereby, we report on the identification of a novel signature in cognitively impaired elderly characterized by: (1) elevated percentages of CD8+ T effector-memory cells expressing high levels of the CD45RA phosphate receptor (Temra
); (2) high percentages of CD8+ T cells expressing high levels of the CD8β chain (CD8β
); (3) augmented production of IFNγ by
activated CD4+ T cells. Noteworthy, CD3+CD8+ Temra
and CD3+CD8β
cells were associated with impaired cognition. Cytomegalovirus seroprevalence showed that all volunteers studied but one were CMV positive. Finally, we show that some of these phenotypic and functional features are associated with an increased frequency of the HLA-B8 serotype, which belongs to the ancestral haplotype HLA-A1, Cw7, B8, DR3, DQ2, among cognitively impaired volunteers. To our knowledge, this is the first proof in humans linking the amount of cell surface CD45RA and CD8β chain expressed by CD8+ Temra cells, and the amount of IFNγ produced by
activated CD4+ T cells, with impaired cognitive function in the elderly.
To determine the degree of central microvascular closure using optical coherence tomography angiography in eyes of patients with type 2 diabetes with visible lesions only in the central retina or ...only in the periphery.
Cross-sectional study. All 127 eyes underwent ultra-widefield fundus photography 200° examinations with OPTOS California (Optos, Dunfermline, United Kingdom) and Cirrus Angioplex optical coherence tomography angiography 3 × 3 mm acquisitions (ZEISS, Dublin, CA).
Twenty-five eyes showed visible lesions only in the central retina, 57 only in the peripheral retina, and 45 presented visible lesions in entire retina. The group with visible lesions only in the periphery showed definite closure in the superficial capillary plexus in 49% of the eyes, whereas the group with visible lesions only in the central seven-early treatment diabetic retinopathy study fields area showed a definite closure in 64%.
Central capillary closure is already present in the initial stages of diabetic retinopathy even when lesions are only visible in the peripheral retina. Capillary closure in the superficial capillary plexus is three times more frequent than in the deep capillary plexus, demonstrating earlier closure of the superficial capillary plexus. Eyes with visible lesions only in the periphery show a milder form of retinopathy.
Purpose To characterize the occurrence of diabetic macular edema and the presence of abnormal retinal fluid accumulation in nonproliferative diabetic retinopathy (NPDR). Methods In this two-year ...prospective study, a total of 122 eyes with diabetes type 2 underwent optical coherence tomography (OCT) and OCT-Angiography in association with OCT-Fluid imaging, a novel algorithm of OCT analysis allowing quantification of abnormal accumulation of fluid in the retina through low optical reflectivity ratios (LOR). Early Treatment Diabetic Retinopathy Study (ETDRS) grading for diabetic retinopathy (DR) severity assessment was performed using 7-field color fundus photography. Best corrected visual acuity was also recorded. Results During the 2-year follow-up, 23 eyes (19%) developed central-involved diabetic macular edema (CI-DME) and 2 eyes (2%) developed clinically significant macular edema (CSME). In the two-year period of the study, eyes that developed CI-DME showed a progressive increase in central retinal thickness (CRT) ( β = 7.7 ± 2.1 µm/year, p < 0.001) and in LOR values ( β = 0.009 ± 0.004 ratio/year, p = 0.027). The increase in CRT and abnormal retinal fluid, represented by increased LOR ratios, are associated with increased retinal perfusion in the deep capillary plexus (DCP) (skeletonized vessel density, p = 0.039). In contrast, the eyes with CSME showed decreased retinal perfusion and abnormal fluid located in the outer layers of the retina. Conclusions CI-DME and CSME appear to represent different entities. Eyes with CI-DME show increases in abnormal retinal fluid associated with increased retinal vascular perfusion in the DCP. Eyes with CSME are apparently associated with decreased retinal vascular perfusion in the DCP and abnormal fluid in the outer retina.
Introduction: The aim of the study was to identify retinal microvascular changes using optical coherence tomography angiography (OCTA) in type 2 diabetes (T2D) patients with preclinical retinopathy ...identified by ultra-widefield fundus photography (UWF-FP). Methods: This is a cross-sectional observational study. All patients underwent UWF-FP 200° examinations with OPTOS California (Optos, Dunfermline, UK) and Cirrus AngioPlex ® spectral-domain (SD)-OCTA 3 × 3 mm acquisitions (ZEISS, Dublin, CA, USA). The absence of visible lesions was identified using UWF-FP. Results: One hundred and ninety three eyes of individuals with T2D with no visible lesions in the fundus and identified in a screening setting were included in the study. Skeletonized vessel density (SVD), perfusion density (PD), and areas of capillary nonperfusion (CNP) values on SD-OCTA were significantly decreased when compared with healthy population (p < 0.001). SVD and CNP values of the superficial capillary plexus (SCP) were more frequently decreased (35% and 45%, respectively) than SVD values of the deep capillary plexus (DCP) (9% and 15%, respectively), demonstrating that diabetic microvascular changes occur earlier in the SCP than in the DCP. The ischemic phenotype, identified by a definite decrease in SVD or CNP in the SCP may, therefore, be identified in the preclinical stage of diabetic retinal disease. Conclusions: Retinal capillary nonperfusion detected by OCTA metrics of SVD and CNP can be identified in the central retina in eyes with T2D before development of visible lesions in the retina. Our findings confirm the relevance of OCTA to identify macular microvascular changes in the initial stages of diabetic retinopathy, allowing the identification of its ischemic phenotype very early in the disease process.
To identify progression of nonproliferative diabetic retinopathy (NPDR) in patients with type 2 diabetes by combining optical coherence tomography angiography (OCTA) metrics and color fundus ...photography (CFP) images.
This study was a post hoc analysis of a prospective longitudinal cohort study (CORDIS, NCT03696810) with 2-year duration. This study enrolled 122 eyes. Ophthalmological examinations included OCTA and CFP. OCTA metrics included skeletonized vessel density (SVD) and perfusion density (PD) at the superficial capillary plexus (SCP) and deep capillary plexus (DCP). Microaneurysm turnover analysis and Early Treatment Diabetic Retinopathy Study (ETDRS) grading for diabetic retinopathy (DR) severity assessment were performed on 7-field CFP.
Eyes graded as ETDRS level 20 showed significant capillary nonperfusion predominantly in the inner ring area in the SCP (P < 0.001), whereas eyes graded as ETDRS level 35 and ETDRS levels 43 and 47 showed significant capillary nonperfusion in both the SCP and DCP in both inner and outer rings (P < 0.001). When evaluating rates of progression in capillary nonperfusion for the 2-year period of follow-up, changes were found predominantly in the DCP for SVD and PD and were better identified in the outer ring area. Microaneurysm turnover contributes to the characterization of NPDR progression by discriminating ETDRS level 35 from ETDRS levels 43 and 47 (P < 0.001), which could not be achieved using only OCTA metrics.
Patterns of progression of NPDR can be identified combining OCTA examinations of the superficial and deep retinal capillary plexi of central retina and determination of microaneurysm turnover from fundus photographs.
Our study reports results from a registered clinical trial that advances understanding of disease progression in NPDR.
Introduction
Characterization of 2-year progression of different risk phenotypes in eyes with mild and moderate nonproliferative diabetic retinopathy (NPDR) in type 2 diabetes (T2D).
Methods
A 2-year ...prospective longitudinal cohort study (CORDIS, NCT03696810) was conducted. Ophthalmological examinations were performed including best corrected visual acuity, color fundus photography and optical coherence tomography (OCT and OCTA). OCT metrics, central retinal thickness and ganglion cell layer + inner plexiform layer (GCL + IPL) thickness were analyzed. OCTA metrics, vessel density (VD), perfusion density (PD) and area of intercapillary spaces (AIS) were obtained from superficial and deep capillary plexus (SCP, DCP). Only phenotype C identified by decreased VD ≥ 2 SD of healthy controls and phenotype B identified by subclinical macular edema with decreased VD < 2 SD of healthy controls were included.
Results
One hundred twenty-two eyes from T2D individuals were included in study; 65 eyes (53%) were classified as phenotype B and 57 eyes (47%) as phenotype C. For phenotype B, progression was associated with thinning of the GCL + IPL (ETDRS 35, 1 year
p
= 0.013, 2 year
p
< 0.001; ETDRS 43–47, 2 year
p
= 0.003) and vessel closure involving mainly the DCP for both ETDRS grades (ETDRS 35, 1 year
p
= 0.025, 2 year
p
= 0.034; ETDRS 43–47, 1 year
p
= 0.011). For phenotype C there was also progressive thinning of the GCL + IPL (ETDRS 35, in both years
p
≤ 0.001; ETDRS 43–47, 1 year
p
= 0.002, 2 year
p
= 0.001), with vessel closure involving mainly SCP (ETDRS 35, 1 year
p
= 0.012, 2 year
p
= 0.023 in full-retina), which appeared to stabilize at maximal values in ETDRS grade 43–47 at the end of 2 years. ETDRS severity changes at the end of the 2-year period showed that worsening was associated with phenotype C with changes involving predominantly the SCP (VD,
p
= 0.005; PD,
p
= 0.008; AIS,
p
= 0.005).
Conclusions
Association between ETDRS classification of NPDR severity and identification of different risk phenotypes offers new perspective to predict disease progression in T2D individuals with NPDR.
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