Investigation of adaptive optics imaging biomarkers for detecting pathological changes of the cone mosaic in patients with type 1 diabetes mellitus

Purpose To investigate a set of adaptive optics (AO) imaging biomarkers for the assessment of changes of the cone mosaic spatial arrangement in patients with type 1 diabetes mellitus (DM1). Methods 16 patients with 20/20 visual acuity and a diagnosis of DM1 in the past 8 years to 37 years and 20 age-matched healthy volunteers were recruited in this study. Cone density, cone spacing and Voronoi diagrams were calculated on 160x160 μm images of the cone mosaic acquired with an AO flood illumination retinal camera at 1.5 degrees eccentricity from the fovea along all retinal meridians. From the cone spacing measures and Voronoi diagrams, the linear dispersion index (LDi) and the heterogeneity packing index (HPi) were computed respectively. Logistic regression analysis was conducted to discriminate DM1 patients without diabetic retinopathy from controls using the cone metrics as predictors. Results Of the 16 DM1 patients, eight had no signs of diabetic retinopathy (noDR) and eight had mild nonproliferative diabetic retinopathy (NPDR) on fundoscopy. On average, cone density, LDi and HPi values were significantly different (P<0.05) between noDR or NPDR eyes and controls, with these differences increasing with duration of diabetes. However, each cone metric alone was not sufficiently sensitive to discriminate entirely between membership of noDR cases and controls. The complementary use of all the three cone metrics in the logistic regression model gained 100% accuracy to identify noDR cases with respect to controls. PLOS ONE | DOI:10.1371/journal.pone.0151380 March 10, 2016 1 / 14 OPEN ACCESS Citation: Lombardo M, Parravano M, Serrao S, Ziccardi L, Giannini D, Lombardo G (2016) Investigation of Adaptive Optics Imaging Biomarkers for Detecting Pathological Changes of the Cone Mosaic in Patients with Type 1 Diabetes Mellitus. PLoS ONE 11(3): e0151380. doi:10.1371/journal. pone.0151380 Editor: Knut Stieger, Justus-Liebig-University Giessen, GERMANY Received: December 17, 2015 Accepted: February 27, 2016 Published: March 10, 2016 Copyright: © 2016 Lombardo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: Research for this work was supported by the Italian Ministry of Health (5x1000 funding), by the National Framework Program for Research and Innovation PON (grant n. 01_00110) and by Fondazione Roma. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Vision Engineering Italy srl funder provided support in the form of salaries for author GL, but did not have any Conclusion The present set of AO imaging biomarkers identified reliably abnormalities in the spatial arrangement of the parafoveal cones in DM1 patients, even when no signs of diabetic retinopathy were seen on fundoscopy

Software-enforced Interconnect Arbitration for COTS Multicores

The advent of multicore processors complicates timing analysis owing to the need to account for the interference between cores accessing shared resources, which is not always easy to characterize in a safe and tight way. Solutions have been proposed that take two distinct but complementary directions: on the one hand, complex analysis techniques have been developed to provide safe and tight bounds to contention; on the other hand, sophisticated arbitration policies (hardware or software) have been proposed to limit or control inter-core interference. In this paper we propose a software-based TDMA-like arbitration of accesses to a shared interconnect (e.g. a bus) that prevents inter-core interference. A more flexible arbitration scheme is also proposed to reserve more bandwidth to selected cores while still avoiding contention. A proof-of-concept implementation on an AURIX TC277TU processor shows that our approach can apply to COTS processors, thus not relying on dedicated hardware arbiters, while introducing little overhead

Lost in classification: lower cognitive functioning in apparently cognitive normal newly diagnosed RRMS patients

Cognitive functioning in multiple sclerosis (MS) patients is usually related to the classic, dichotomic classification of impaired vs. unimpaired cognition. However, this approach is far from mirroring the real efficiency of cognitive functioning. Applying a different approach in which cognitive functioning is considered as a continuous variable, we aimed at showing that even newly diagnosed relapsing-remitting MS (RRMS) patients might suffer from reduced cognitive functioning with respect to a matched group of neurologically healthy controls (HCs), even if they were classified as having no cognitive impairment (CI). Fifty newly diagnosed RRMS patients and 36 HCs were tested with an extensive battery of neuropsychological tests. By using Z-scores applied to the whole group of RRMS and HCs together, a measure of cognitive functioning (Z-score index) was calculated. Among the 50 RRMS patients tested, 36 were classified as cognitively normal (CN). Even though classified as CN, RRMS patients performed worse than HCs at a global level (p = 0.004) and, more specifically, in the domains of memory (p = 0.005) and executive functioning (p = 0.006). These results highlight that reduced cognitive functioning can be present early in the disease course, even in patients without an evident CI. The current classification criteria of CI in MS should be considered with caution

Visual-attentional load unveils slowed processing speed in multiple sclerosis patients: a pilot study with a tablet-based videogame

Slowing in information processing speed (IPS) is the key cognitive deficit in multiple sclerosis (MS). Testing IPS in different cognitive load conditions by using computerized tools might reveal initial IPS slowness underestimated by classic paper-and-pencil tests. To investigate the extent to which IPS can be affected by increased task demands, we developed three tasks based on the manipulation of the visual-attentional load, delivered with a home-made, tablet-based videogame. Fifty-one patients with MS (pwMS), classified as having no cognitive impairment in classic paper-and-pencil tests, and 20 healthy controls (HC) underwent the videogame tasks; reaction times (RTs) and accuracy were recorded. A significant reduced performance of pwMS as compared with HC was found on the videogame tasks, with pwMS being on average slower and less accurate than HC. Furthermore, pwMS showed a significantly more pronounced decrement in accuracy as a function of the visual-attentional load, suggesting a higher susceptibility to increased task demands. Significant correlations among the Symbol Digit Modalities Test (SDMT) and the videogame mean RTs and accuracy were found, providing evidence for the concurrent validity of the videogame as a valid tool to test IPS in pwMS. The high potential that might derive from the adoption of computerized assessment tools in clinical practice should be taken into consideration and investigated further

Randomized Caches Can Be Pretty Useful to Hard Real-Time Systems

Cache randomization per se, and its viability for probabilistic timing analysis (PTA) of critical real-time systems, are receiving increasingly close attention from the scientific community and the industrial practitioners. In fact, the very notion of introducing randomness and probabilities in time-critical systems has caused strenuous debates owing to the apparent clash that this idea has with the strictly deterministic view traditionally held for those systems. A paper recently appeared in LITES (Reineke, J. (2014). Randomized Caches Considered Harmful in Hard Real-Time Systems. LITES, 1(1), 03:1-03:13.) provides a critical analysis of the weaknesses and risks entailed in using randomized caches in hard real-time systems. In order to provide the interested reader with a fuller, balanced appreciation of the subject matter, a critical analysis of the benefits brought about by that innovation should be provided also. This short paper addresses that need by revisiting the array of issues addressed in the cited work, in the light of the latest advances to the relevant state of the art. Accordingly, we show that the potential benefits of randomized caches do offset their limitations, causing them to be - when used in conjunction with PTA - a serious competitor to conventional designs

Ocrelizumab reduces cortical and deep grey matter loss compared to the S1P-receptor modulator in multiple sclerosis

Introduction: Ocrelizumab (OCR) and Fingolimod (FGL) are two high-efficacy treatments in multiple sclerosis which, besides their strong anti-inflammatory activity, may limit neurodegeneration. Aim: To compare the effect of OCR and FGL on clinical and MRI endpoints. Methods: 95 relapsing-remitting patients (57 OCR, 38 FGL) clinically followed for 36&nbsp;months underwent a 3-Tesla MRI at baseline and after 24&nbsp;months. The annualized relapse rate, EDSS, new cortical/white matter lesions and regional cortical and deep grey matter volume loss were evaluated. Results: OCR reduced the relapse rate from 0.48 to 0.04, FGL from 0.32 to 0.05 (both p &lt; 0.001). Compared to FGL, OCR-group experienced fewer new white matter lesions (12% vs 32%, p = 0.005), no differences in new cortical lesions, lower deep grey matter volume loss (- 0.12% vs - 0.66%; p = 0.002, Cohen's d = 0.54), lower global cortical thickness change (- 0.45% vs - 0.70%; p = 0.036; d = 0.42) and reduced cortical thinning/volume loss in several regions of interests, including those of parietal gyrus (d-range = 0.65-0.71), frontal gyrus (d-range = 0.47-0.60), cingulate (d-range = 0.41-0.72), insula (d = 0.36), cerebellum (cortex d = 0.72, white matter d = 0.44), putamen (d = 0.35) and thalamus (d = 0.31). The effect on some regional thickness changes was confirmed in patients without focal lesions. Conclusions: When compared with FGL, patients receiving OCR showed greater suppression of focal MRI lesions accumulation and lower cortical and deep grey matter volume loss

Haploinsufficiency as a Foreground Pathomechanism of Poirer-Bienvenu Syndrome and Novel Insights Underlying the Phenotypic Continuum of CSNK2B-Associated Disorders

CSNK2B encodes for the regulatory subunit of the casein kinase II, a serine/threonine kinase that is highly expressed in the brain and implicated in development, neuritogenesis, synaptic transmission and plasticity. De novo variants in this gene have been identified as the cause of the Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) characterized by seizures and variably impaired intellectual development. More than sixty mutations have been described so far. However, data clarifying their functional impact and the possible pathomechanism are still scarce. Recently, a subset of CSNK2B missense variants affecting the Asp32 in the KEN box-like domain were proposed as the cause of a new intellectual disability-craniodigital syndrome (IDCS). In this study, we combined predictive functional and structural analysis and in vitro experiments to investigate the effect of two CSNK2B mutations, p.Leu39Arg and p.Met132LeufsTer110, identified by WES in two children with POBINDS. Our data prove that loss of the CK2beta protein, due to the instability of mutant CSNK2B mRNA and protein, resulting in a reduced amount of CK2 complex and affecting its kinase activity, may underlie the POBINDS phenotype. In addition, the deep reverse phenotyping of the patient carrying p.Leu39Arg, with an analysis of the available literature for individuals with either POBINDS or IDCS and a mutation in the KEN box-like motif, might suggest the existence of a continuous spectrum of CSNK2B-associated phenotypes rather than a sharp distinction between them

Bilateral Symmetry of Visual Function Loss in Cone-Rod Dystrophies.

PURPOSE: To investigate bilateral symmetry of visual impairment in cone-rod dystrophy (CRD) patients and understand the feasibility of clinical trial designs treating one eye and using the untreated eye as an internal control. METHODS: This was a retrospective study of visual function loss measures in 436 CRD patients followed at the Ophthalmology Department of the Catholic University in Rome. Clinical measures considered were best-corrected visual acuity, focal macular cone electroretinogram (fERG), and Ganzfeld cone-mediated and rod-mediated electroretinograms. Interocular agreement in each of these clinical indexes was assessed by t- and Wilcoxon tests for paired samples, structural (Deming) regression analysis, and intraclass correlation. Baseline and follow-up measures were analyzed. A separate analysis was performed on the subset of 61 CRD patients carrying likely disease-causing mutations in the ABCA4 gene. RESULTS: Statistical tests show a very high degree of bilateral symmetry in the extent and progression of visual impairment in the fellow eyes of CRD patients. CONCLUSIONS: These data contribute to a better understanding of CRDs and support the feasibility of clinical trial designs involving unilateral eye treatment with the use of fellow eye as internal control

CSF parvalbumin levels reflect interneuron loss linked with cortical pathology in multiple sclerosis

Introduction and methods: In order to verify whether parvalbumin (PVALB), a protein specifically expressed by GABAergic interneurons, could be a MS-specific marker of grey matter neurodegeneration, we performed neuropathology/molecular analysis of PVALB expression in motor cortex of 40 post-mortem progressive MS cases, with/without meningeal inflammation, and 10 control cases, in combination with cerebrospinal fluid (CSF) assessment. Analysis of CSF PVALB and neurofilaments (Nf-L) levels combined with physical/cognitive/3TMRI assessment was performed in 110 na\uefve MS patients and in 32 controls at time of diagnosis. Results: PVALB gene expression was downregulated in MS (fold change = 3.7 \ub1 1.2, P &lt; 0.001 compared to controls) reflecting the significant reduction of PVALB+ cell density in cortical lesions, to a greater extent in MS patients with high meningeal inflammation (51.8, P &lt; 0.001). Likewise, post-mortem CSF-PVALB levels were higher in MS compared to controls (fold change = 196 \ub1 36, P &lt; 0.001) and correlated with decreased PVALB+ cell density (r = -0.64, P &lt; 0.001) and increased MHC-II+ microglia density (r = 0.74, P &lt; 0.01), as well as with early age of onset (r = -0.69, P &lt; 0.05), shorter time to wheelchair (r = -0.49, P &lt; 0.05) and early age of death (r = -0.65, P &lt; 0.01). Increased CSF-PVALB levels were detected in MS patients at diagnosis compared to controls (P = 0.002). Significant correlation was found between CSF-PVALB levels and cortical lesion number on MRI (R = 0.28, P = 0.006) and global cortical thickness (R = -0.46, P &lt; 0.001), better than Nf-L levels. CSF-PVALB levels increased in MS patients with severe cognitive impairment (mean \ub1 SEM:25.2 \ub1 7.5 ng/mL) compared to both cognitively normal (10.9 \ub1 2.4, P = 0.049) and mild cognitive impaired (10.1 \ub1 2.9, P = 0.024) patients. Conclusions: CSF-PVALB levels reflect loss of cortical interneurons in MS patients with more severe disease course and might represent an early, new MS-specific biomarker of cortical neurodegeneration, atrophy, and cognitive decline