Alignment of Linear Biochemical Pathways Using Protein Structural Classification

Metabolic, signaling and regulatory pathways form the basis of biological processes and are important for the analysis of cellular behavior and evolution. This paper presents an approach of aligning biochemical pathways on the basis of the structure of involved proteins and their classification. The suitable information is retrieved from an integrated database system.
SIGNALIGN is available at: http://agbi.techfak.uni-bielefeld.de/signalign/index.jsp 

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Reliability of Intra-Retinal Layer Thickness Estimates

Purpose Measurement of intra-retinal layer thickness using optical coherence tomography (OCT) has become increasingly prominent in multiple sclerosis (MS) research. Nevertheless, the approaches used for determining the mean layer thicknesses vary greatly. Insufficient data exist on the reliability of different thickness estimates, which is crucial for their application in clinical studies. This study addresses this lack by evaluating the repeatability of different thickness estimates. Methods Studies that used intra-retinal layer segmentation of macular OCT scans in patients with MS were retrieved from PubMed. To investigate the repeatability of previously applied layer estimation approaches, we generated datasets of repeating measurements of 15 healthy subjects and 13 multiple sclerosis patients using two OCT devices (Cirrus HD-OCT and Spectralis SD-OCT). We calculated each thickness estimate in each repeated session and analyzed repeatability using intra-class correlation coefficients and coefficients of repeatability. Results We identified 27 articles, eleven of them used the Spectralis SD-OCT, nine Cirrus HD-OCT, two studies used both devices and two studies applied RTVue-100. Topcon OCT-1000, Stratus OCT and a research device were used in one study each. In the studies that used the Spectralis, ten different thickness estimates were identified, while thickness estimates of the Cirrus OCT were based on two different scan settings. In the simulation dataset, thickness estimates averaging larger areas showed an excellent repeatability for all retinal layers except the outer plexiform layer (OPL). Conclusions Given the good reliability, the thickness estimate of the 6mm-diameter area around the fovea should be favored when OCT is used in clinical research. Assessment of the OPL was weak in general and needs further investigation before OPL thickness can be used as a reliable parameter

Criteria for Blood Vessel Discrimination

Introduction The diagnostic potential of optical coherence tomography (OCT) in neurological diseases is intensively discussed. Besides the sectional view of the retina, modern OCT scanners produce a simultaneous top-view confocal scanning laser ophthalmoscopy (cSLO) image including the option to evaluate retinal vessels. A correct discrimination between arteries and veins (labeling) is vital for detecting vascular differences between healthy subjects and patients. Up to now, criteria for labeling (cSLO) images generated by OCT scanners do not exist. Objective This study reviewed labeling criteria originally developed for color fundus photography (CFP) images. Methods The criteria were modified to reflect the cSLO technique, followed by development of a protocol for labeling blood vessels. These criteria were based on main aspects such as central light reflex, brightness, and vessel thickness, as well as on some additional criteria such as vascular crossing patterns and the context of the vessel tree. Results and Conclusion They demonstrated excellent inter-rater agreement and validity, which seems to indicate that labeling of images might no longer require more than one rater. This algorithm extends the diagnostic possibilities offered by OCT investigations

Investigation of Visual System Involvement in Spinocerebellar Ataxia Type 14

Spinocerebellar ataxia type 14 (SCA-PRKCG, formerly SCA14) is a rare, slowly progressive disorder caused by conventional mutations in protein kinase Cγ (PKCγ). The disease usually manifests with ataxia, but previous reports suggested PRKCG variants in retinal pathology. To systematically investigate for the first time visual function and retinal morphology in patients with SCA-PRKCG. Seventeen patients with PRKCG variants and 17 healthy controls were prospectively recruited, of which 12 genetically confirmed SCA-PRKCG patients and 14 matched controls were analyzed. We enquired a structured history for visual symptoms. Vision-related quality of life was obtained with the National Eye Institute Visual Function Questionnaire (NEI-VFQ) including the Neuro-Ophthalmic Supplement (NOS). Participants underwent testing of visual acuity, contrast sensitivity, visual fields, and retinal morphology with optical coherence tomography (OCT). Measurements of the SCA-PRKCG group were analyzed for their association with clinical parameters (ataxia rating and disease duration). SCA-PRKCG patients rate their vision-related quality of life in NEI-VFQ significantly worse than controls. Furthermore, binocular visual acuity and contrast sensitivity were worse in SCA-PRKCG patients compared with controls. Despite this, none of the OCT measurements differed between groups. NEI-VFQ and NOS composite scores were related to ataxia severity. Additionally, we describe one patient with a genetic variant of uncertain significance in the catalytic domain of PKCγ who, unlike all confirmed SCA-PRKCG, presented with a clinically silent epitheliopathy. SCA-PRKCG patients had reduced binocular vision and vision-related quality of life. Since no structural retinal damage was found, the pathomechanism of these findings remains unclear

Afferent Visual Pathway Affection in Patients with PMP22 Deletion-Related Hereditary Neuropathy with Liability to Pressure Palsies

Background The PMP22 gene encodes a protein integral to peripheral myelin. Its deletion leads to hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 is not expressed in the adult central nervous system, but previous studies suggest a role in CNS myelin development. The objective of this study was to identify potential structural and functional alterations in the afferent visual system in HNPP patients. Methods Twenty HNPP patients and 18 matched healthy controls (HC) were recruited in a cross-sectional study. Participants underwent neurological examination including visual acuity, visual evoked potential (VEP) examination, optical coherence tomography (OCT), and magnetic resonance imaging with calculation of brain atrophy, regarding grey and white matter, and voxel based morphometry (VBM), in addition answered the National Eye Institute’s 39-item Visual Functioning Questionnaire (NEI- VFQ). Thirteen patients and 6 HC were additionally examined with magnetic resonance spectroscopy (MRS). Results All patients had normal visual acuity, but reported reduced peripheral vision in comparison to HC in the NEI-VFQ (p = 0.036). VEP latency was prolonged in patients (P100 = 103.7±5.7 ms) in comparison to healthy subjects (P100 = 99.7±4.2 ms, p = 0.007). In OCT, peripapillary retinal nerve fiber layer thickness RNFL was decreased in the nasal sector (90.0±15.5 vs. 101.8±16.5, p = 0.013), and lower nasal sector RNFL correlated with prolonged VEP latency (Rho = -0.405, p = 0.012). MRS revealed reduced tNAA (731.4±45.4 vs. 814.9±62.1, p = 0.017) and tCr (373.8±22.2 vs. 418.7±31.1, p = 0.002) in the visual cortex in patients vs. HC. Whole brain volume, grey and white matter volume, VBM and metabolites in a MRS sensory cortex control voxel did not differ significantly between patients and HC. Conclusion PMP22 deletion leads to functional, metabolic and macro- structural alterations in the afferent visual system of HNPP patients. Our data suggest a functional relevance of these changes for peripheral vision, which warrants further investigation and confirmation

Spinocerebellar ataxia type 14: refining clinicogenetic diagnosis in a rare adult‐onset disorder

Objectives: Genetic variant classification is a challenge in rare adult-onset disorders as in SCA-PRKCG (prior spinocerebellar ataxia type 14) with mostly private conventional mutations and nonspecific phenotype. We here propose a refined approach for clinicogenetic diagnosis by including protein modeling and provide for confirmed SCA-PRKCG a comprehensive phenotype description from a German multi-center cohort, including standardized 3D MR imaging. Methods: This cross-sectional study prospectively obtained neurological, neuropsychological, and brain imaging data in 33 PRKCG variant carriers. Protein modeling was added as a classification criterion in variants of uncertain significance (VUS). Results: Our sample included 25 cases confirmed as SCA-PRKCG (14 variants, thereof seven novel variants) and eight carriers of variants assigned as VUS (four variants) or benign/likely benign (two variants). Phenotype in SCA-PRKCG included slowly progressive ataxia (onset at 4-50 years), preceded in some by early-onset nonprogressive symptoms. Ataxia was often combined with action myoclonus, dystonia, or mild cognitive-affective disturbance. Inspection of brain MRI revealed nonprogressive cerebellar atrophy. As a novel finding, a previously not described T2 hyperintense dentate nucleus was seen in all SCA-PRKCG cases but in none of the controls. Interpretation: In this largest cohort to date, SCA-PRKCG was characterized as a slowly progressive cerebellar syndrome with some clinical and imaging features suggestive of a developmental disorder. The observed non-ataxia movement disorders and cognitive-affective disturbance may well be attributed to cerebellar pathology. Protein modeling emerged as a valuable diagnostic tool for variant classification and the newly described T2 hyperintense dentate sign could serve as a supportive diagnostic marker of SCA-PRKCG

Temporal Retinal Nerve Fiber Loss in Patients with Spinocerebellar Ataxia Type 1

BACKGROUND: Autosomal dominant spinocerebellar ataxia type 1 is an adult onset progressive disorder with well characterized neurodegeneration in the cerebellum and brainstem. Beyond brain atrophy, few data exist concerning retinal and optic nerve involvement. OBJECTIVE: To evaluate retinal changes in SCA1 patients compared to age and gender matched healthy controls. METHODOLOGY/PRINCIPAL FINDINGS: Nine patients with SCA1 were prospectively recruited from the ataxia clinic and were compared to nine age and gender matched healthy controls. Both cohorts received assessment of visually evoked potentials and eye examination by optical coherence tomography to determine retinal nerve fiber layer thickness and total macular volume. While no differences were found in visually evoked potentials, SCA1 patients showed a significant reduction of mean retinal nerve fiber layer thickness (RNFLT) compared to healthy controls (84±13 µm vs. 97±8 µm, p = 0.004). Temporal areas showed the most prominent RNFLT reduction with high statistical significances (temporal-inferior: p<0.001, temporal: p<0.001, temporal-superior: p = 0.005) whereas RNFLT in nasal areas was in the range of the control group. From six SCA1 patients an additional macular scan was obtained. The comparison to the corresponding healthy control showed a slight but not significant reduction in TMV (8.22±0.68 mm(3) vs. 8.61±0.41 mm(3), p = 0.15). CONCLUSION: In SCA1 patients, we found evidence for degeneration of retinal nerve fibers. The temporal focus of the observed retinal nerve fiber layer reduction suggests an involvement of the papillo-macular bundle which resembles pathology found in toxic or mitochondrial optic nerve disease such as Leber's hereditary optic neuropathy (LHON) or dominant optic atrophy (DOA)

Optic Nerve Head Quantification in Idiopathic Intracranial Hypertension by Spectral Domain OCT

Objective: To evaluate 3D spectral domain optical coherence tomography (SDOCT) volume scans as a tool for quantification of optic nerve head (ONH) volume as a potential marker for treatment effectiveness and disease progression in idiopathic intracranial hypertension (IIH). Design and Patients: Cross-sectional pilot trial comparing 19 IIH patients and controls matched for gender, age and body mass index. Each participant underwent SDOCT. A custom segmentation algorithm was developed to quantify ONH volume (ONHV) and height (ONHH) in 3D volume scans. Results:Whereas peripapillary retinal nerve fiber layer thickness did not show differences between controls and IIH patients, the newly developed 3D parameters ONHV and ONHH were able to discriminate between controls, treated and untreated patients. Both ONHV and ONHH measures were related to levels of intracranial pressure (ICP). Conclusion: Our findings suggest 3D ONH measures as assessed by SDOCT as potential diagnostic and progression markers in IIH and other disorders with increased ICP. SDOCT may promise a fast and easy diagnostic alternative to repeated lumba

Characterization of retinal alterations in patients with multiple sclerosis by means of optical coherence tomography

Hintergrund: Die Netzhaut ist entwicklungsbiologisch Teil des zentralen Nervensystems und stellt daher ein vielversprechendes Zielgewebe für entzündliche und neurodegenerative Prozesse bei Patienten mit Multipler Sklerose (MS) dar. Mit der optischen Kohärenztomographie (OCT) ist es möglich, die retinale Anatomie schnell und nicht-invasiv zu untersuchen. Bisherige OCT Studien konnten einen axonalen und neuronalen Schaden in der Retina bei MS Patienten mit und ohne vorherige Sehnervenentzündung (ON) zeigen. Allerdings sind die Unterschiede zwischen den MS-Subtypen und der zeitliche Verlauf der retinalen Veränderungen bisher nur unzureichend erforscht und die Ergebnisse zum Teil widersprüchlich. Bei einem Teil der MS Patienten wurden zudem makuläre Mikrozysten in der inneren Körnerschicht (INL) festgestellt und eine Verdickung der INL konnte mit der Krankheitsprogression assoziiert werden. Für das Auftreten von Mikrozysten und der Korrelationen zwischen INL Dicke und Krankheitsprogression existieren unterschiedliche Erklärungsmodelle (z. B. Glaskörpertraktion), die bisher allerdings nur unzureichend auf Validität untersucht wurden. Zielsetzung: Ziel dieser Arbeit war eine bessere Charakterisierung retinaler Veränderungen bei Patienten mit MS mittels hochauflösender spectral-domain OCT (SD-OCT). Methodik: In den vier hier präsentierten Studien wurden Patienten mit MS, klinisch isoliertem Syndrom (CIS), Neuromyelitis optica (NMO) und Chronic relapsing inflammatory optic neuropathy (CRION) mit SD-OCT untersucht. Für den Vergleich der Kohorten untereinander und zu gesunden Kontrollen wurden durchschnittliche retinale Schichtdicken und räumliche Dickenkarten verwendet. Ergebnisse: In einer großen Multicenterstudie konnten wir zeigen, dass retinale Schädigung bei Patienten mit progressiven Verlaufsformen stärker ausgeprägt ist als bei Patienten mit schubförmiger MS. Entgegen früheren Arbeiten zeigten die Ergebnisse der intra-retinalen Segmentierung bereits bei CIS Patienten ohne vorherige ON eine Reduzierung der Ganglienzellschichtdicke. Eine retrospektive Analyse ergab, dass Mikrozysten mit hoher Sensitivität und guter Spezifität auf Fundusbildern detektiert werden können. Mikrozysten sind allerdings nicht spezifisch für MS, sondern stehen im Zusammenhang mit vorherigen ON Ereignissen und finden sich vermehrt auch bei anderen Erkrankungen wie NMO und CRION. Auch ohne sichtbare Mikrozysten führt eine ON zu Verdickung der INL. In einem Fall kam es zu dynamischen Veränderungen der Mikrozysten, die aber nicht mit einer Zugwirkung der Glaskörpermembran an der Retina (Glaskörpertraktion) erklärt werden konnte. Diskussion: Die OCT etabliert sich immer mehr als Marker von Neurodegeneration in der MS. Mit neuer hochauflösender SD-OCT Technik und retinaler Schichtsegmentierung wird die Sensitivität weiter gesteigert und klinische Studien mit OCT als primärer und sekundärer Endpunkt- Parameter laufen bereits oder stehen unmittelbar bevor. Zudem liefert die OCT in der MS Forschung neue Einblicke in den Pathomechanismus der Erkrankung.Background: During biological development, the retina originates from central nervous system tissue and therefore offers an interesting opportunity to monitor inflammatory and neurodegenerative processes in the context of multiple sclerosis (MS). Optical coherence tomography (OCT) is a fast and non- invasive technique to investigate the retinal architecture. While previous studies could show axonal and neuronal damage in the retina of patients with and without a history of optic neuritis (ON), only scarce and in part conflicting data exist on different MS subtypes and the temporal course of retinal alterations. Macular microcysts located in the inner nuclear layer (INL) were described in a subset of MS patients and an association between INL thickening and disease progression was found. Various theories exist explaining the appearance of macular microcysts and the correlation between INL thickening and disease progression (i. e. vitreous traction), but only insufficient tests for validity of these theories were performed. Objective: To better characterize retinal alterations in patients with MS using high- resolution spectral-domain OCT (SD-OCT). Methods: In the four studies presented here, patients with MS, clinically isolated syndrome (CIS), neuromyelitis optica (NMO) and chronic relapsing inflammatory optic neuropathy (CRION) were investigated with SD-OCT. Mean retinal layer thicknesses and spatial thickness maps were applied to compare the different cohorts with each other and to healthy controls. Results: In a large multicentre study, we could show that patients with progressive MS subtypes exhibit more severe retinal neurodegeneration than relapsing-remitting MS patients. In contrast to previous works, intra-retinal layer segmentation was able to detect ganglion cell layer reduction in CIS patients even in the absence of previous ON events. A retrospective analysis showed that macular microcysts could be identified with high sensitivity and good specificity using fundus images. However, microcysts are not specific for MS but were strongly associated with a previous ON and also occurred in other diseases like NMO and CRION. Even without visible microcysts, the INL thickness increased after an ON. One case presented with dynamic changes of microcysts, which could not be explained by vitreous traction. Discussion: OCT is gradually being established as a marker for neurodegeneration in MS. New high-resolution SD-OCT technique and retinal layer segmentation further increase the sensitivity, and clinical studies using OCT derived primary and secondary outcome parameters are on-going or about to commence. Furthermore, OCT continues to be an interesting tool in MS research and is providing new insights in the pathomechanisms of MS