Roles of interleukin-17 in uveitis

Th17 cells, a CD4+ T-cell subset, produce interleukin (IL)-17, a pro-inflammatory cytokine that has been shown to be involved in several forms of infectious and noninfectious uveitis. Here, we explore the roles of this IL in uveitic disorders as well as in experimental autoimmune uveitis, the possible pathogenic implications of several cytokines associated with IL-17 and analyze the current outcomes and goals for drugs aiming for the IL-17 pathway.info:eu-repo/semantics/publishedVersio

Epigenetic and post-transcriptional regulation of somatostatin receptor subtype 5 (SST5 ) in pituitary and pancreatic neuroendocrine tumors.

Somatostatin receptor subtype 5 (SST5 ) is an emerging biomarker and actionable target in pituitary (PitNETs) and pancreatic (PanNETs) neuroendocrine tumors. Transcriptional and epigenetic regulation of SSTR5 gene expression and mRNA biogenesis is poorly understood. Recently, an overlapping natural antisense transcript, SSTR5-AS1, potentially regulating SSTR5 expression, was identified. We aimed to elucidate whether epigenetic processes contribute to the regulation of SSTR5 expression in PitNETs (somatotropinomas) and PanNETs. We analyzed the SSTR5/SSTR5-AS1 human locus in silico to identify CpG islands. SSTR5 and SSTR5-AS1 expression was assessed by quantitative real-time PCR (qPCR) in 27 somatotropinomas, 11 normal pituitaries (NPs), and 15 PanNETs/paired adjacent (control) samples. We evaluated methylation grade in four CpG islands in the SSTR5/SSTR5-AS1 genes. Results revealed that SSTR5 and SSTR5-AS1 were directly correlated in NP, somatotropinoma and PanNET samples. Interestingly, selected CpG islands were differentially methylated in somatotropinomas compared with NPs. In PanNETs cell lines, SSTR5-AS1 silencing downregulated SSTR5 expression, altered aggressiveness features, and influenced pasireotide response. These results provide evidence that SSTR5 expression in PitNETs and PanNETs can be epigenetically regulated by the SSTR5-AS1 antisense transcript and, indirectly, by DNA methylation, which may thereby impact tumor behavior and treatment response

Verifying for Compliance to Data Constraints in Collaborative Business Processes.

Production processes are nowadays fragmented across different companies and organized in global collaborative networks. This is the result of the first wave of globalization that, among the various factors, was enabled by the diffusion of Internet-based Information and Communication Technologies (ICTs) at the beginning of the years 2000. The recent wave of new technologies possibly leading to the fourth industrial revolution – the so-called Industry 4.0 – is further multiplying opportunities. Accessing global customers opens great opportunities for organizations, including small and medium enterprises (SMEs), but it requires the ability to adapt to different requirements and conditions, volatile demand patterns and fast-changing technologies. Regardless of the industrial sector, the processes used in an organization must be compliant to rules, standards, laws and regulations. Non-compliance subjects enterprises to litigation and financial fines. Thus, compliance verification is a major concern, not only to keep pace with changing regulations but also to address the rising concerns of security, product and service quality and data privacy. The software, in particular process automation, used must be designed accordingly. In relation to process management, we propose a new way to pro-actively check the compliance of current running business processes using Descriptive Logic and Linear Temporal Logic to describe the constraints related to data. Related algorithms are presented to detect the potential violations

NKG2A inhibits TH2 cell effector function in vitro

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Feasibility of a walking virtual reality system for rehabilitation: objective and subjective parameters

[EN] Background: Even though virtual reality (VR) is increasingly used in rehabilitation, the implementation of walking navigation in VR still poses a technological challenge for current motion tracking systems. Different metaphors simulate locomotion without involving real gait kinematics, which can affect presence, orientation, spatial memory and cognition, and even performance. All these factors can dissuade their use in rehabilitation. We hypothesize that a marker-based head tracking solution would allow walking in VR with high sense of presence and without causing sickness. The objectives of this study were to determine the accuracy, the jitter, and the lag of the tracking system and its elicited sickness and presence in comparison of a CAVE system. Methods: The accuracy and the jitter around the working area at three different heights and the lag of the head tracking system were analyzed. In addition, 47 healthy subjects completed a search task that involved navigation in the walking VR system and in the CAVE system. Navigation was enabled by natural locomotion in the walking VR system and through a specific device in the CAVE system. An HMD was used as display in the walking VR system. After interacting with each system, subjects rated their sickness in a seven-point scale and their presence in the Slater-Usoh-Steed Questionnaire and a modified version of the Presence Questionnaire. Results: Better performance was registered at higher heights, where accuracy was less than 0.6 cm and the jitter was about 6 mm. The lag of the system was 120 ms. Participants reported that both systems caused similar low levels of sickness (about 2.4 over 7). However, ratings showed that the walking VR system elicited higher sense of presence than the CAVE system in both the Slater-Usoh-Steed Questionnaire (17.6 +/- 0.3 vs 14.6 +/- 0.6 over 21, respectively) and the modified Presence Questionnaire (107.4 +/- 2.0 vs 93.5 +/- 3.2 over 147, respectively). Conclusions: The marker-based solution provided accurate, robust, and fast head tracking to allow navigation in the VR system by walking without causing relevant sickness and promoting higher sense of presence than CAVE systems, thus enabling natural walking in full-scale environments, which can enhance the ecological validity of VR-based rehabilitation applications.The authors wish to thank the staff of LabHuman for their support in this project, especially José Miguel Martínez and José Roda for their assistance. This study was funded in part by Ministerio de Economia y Competitividad of Spain (Project NeuroVR, TIN2013-44741-R and Project REACT, TIN2014-61975-EXP), by Ministerio de Educacion y Ciencia of Spain (Project Consolider-C, SEJ2006-14301/PSIC), and by Universitat Politecnica de Valencia (Grant PAID-10-14).Borrego, A.; Latorre Grau, J.; Llorens Rodríguez, R.; Alcañiz Raya, ML.; Noé, E. (2016). Feasibility of a walking virtual reality system for rehabilitation: objective and subjective parameters. Journal of NeuroEngineering and Rehabilitation. 13:1-9. https://doi.org/10.1186/s12984-016-0174-1S1913Lee KM. Presence. Explicated Communication Theory. 2004;14(1):27–50.Riva G. Is presence a technology issue? Some insights from cognitive sciences. Virtual Reality. 2009;13(3):159–69.Banos RM, et al. Immersion and emotion: their impact on the sense of presence. Cyberpsychol Behav. 2004;7(6):734–41.Llorens R, et al. Tracking systems for virtual rehabilitation: objective performance vs. subjective experience. A practical scenario. Sensors (Basel). 2015;15(3):6586–606.Navarro MD, et al. Validation of a low-cost virtual reality system for training street-crossing. A comparative study in healthy, neglected and non-neglected stroke individuals. Neuropsychol Rehabil. 2013;23(4):597–618.Parsons TD. Virtual reality for enhanced ecological validity and experimental control in the clinical, affective and social neurosciences. Front Hum Neurosci. 2015;9:660.Cameirao MS, et al. Neurorehabilitation using the virtual reality based Rehabilitation Gaming System: methodology, design, psychometrics, usability and validation. J Neuroeng Rehabil. 2010;7:48.Llorens R, et al. Improvement in balance using a virtual reality-based stepping exercise: a randomized controlled trial involving individuals with chronic stroke. Clin Rehabil. 2015;29(3):261–8.Llorens R, et al. Videogame-based group therapy to improve self-awareness and social skills after traumatic brain injury. J Neuroeng Rehabil. 2015;12:37.Fong KN, et al. Usability of a virtual reality environment simulating an automated teller machine for assessing and training persons with acquired brain injury. J Neuroeng Rehabil. 2010;7:19.Levin MF, Weiss PL, Keshner EA. Emergence of virtual reality as a tool for upper limb rehabilitation: incorporation of motor control and motor learning principles. Phys Ther. 2015;95(3):415–25.Llorens R, et al. Effectiveness, usability, and cost-benefit of a virtual reality-based telerehabilitation program for balance recovery after stroke: a randomized controlled trial. Arch Phys Med Rehabil. 2015;96(3):418–25. e2.Cruz-Neira C, et al. Scientists in wonderland: A report on visualization applications in the CAVE virtual reality environment. In: 1993. Proceedings IEEE 1993 Symposium on Research Frontiers in Virtual Reality. 1993.Juan MC, Perez D. Comparison of the levels of presence and anxiety in an acrophobic environment viewed via HMD or CAVE. Presence. 2009;18(3):232–48.Yang YR, et al. Virtual reality-based training improves community ambulation in individuals with stroke: a randomized controlled trial. Gait Posture. 2008;28(2):201–6.Cho KH, Lee WH. Virtual walking training program using a real-world video recording for patients with chronic stroke: a pilot study. Am J Phys Med Rehabil. 2013;92(5):371–84.Darter BJ, Wilken JM. Gait training with virtual reality-based real-time feedback: improving gait performance following transfemoral amputation. Phys Ther. 2011;91(9):1385–94.Yang S, et al. Improving balance skills in patients who had stroke through virtual reality treadmill training. Am J Phys Med Rehabil. 2011;90(12):969–78.Walker ML, et al. Virtual reality-enhanced partial body weight-supported treadmill training poststroke: feasibility and effectiveness in 6 subjects. Arch Phys Med Rehabil. 2010;91(1):115–22.Riley PO, et al. A kinematic and kinetic comparison of overground and treadmill walking in healthy subjects. Gait Posture. 2007;26(1):17–24.Alton F, et al. A kinematic comparison of overground and treadmill walking. Clin Biomech. 1998;13(6):434–40.Lee SJ, Hidler J. Biomechanics of overground vs. treadmill walking in healthy individuals. J Appl Physiol. 2008;104(3).Slater M. Measuring presence: a response to the witmer and Singer presence questionnaire. Presence. 1999;8(5):560–5.Viau A, et al. Reaching in reality and virtual reality: a comparison of movement kinematics in healthy subjects and in adults with hemiparesis. J Neuroeng Rehabil. 2004;1(1):11.Parsons TD, et al. The potential of function-led virtual environments for ecologically valid measures of executive function in experimental and clinical neuropsychology. Neuropsychol Rehabil. 2015;11:1–31. doi: 10.1080/09602011.2015.1109524 .Aravind G, Lamontagne A. Perceptual and locomotor factors affect obstacle avoidance in persons with visuospatial neglect. J Neuroeng Rehabil. 2014;11:38.Darekar A, Lamontagne A, Fung J. Dynamic clearance measure to evaluate locomotor and perceptuo-motor strategies used for obstacle circumvention in a virtual environment. Hum Mov Sci. 2015;40:359–71.Whittle MW. Chapter 4 - Methods of gait analysis. In: Whittle MW, editor. Gait analysis. Edinburgh: Butterworth-Heinemann; 2007. p. 137–75.Hodgson E, et al. WeaVR: a self-contained and wearable immersive virtual environment simulation system. Behav Res Methods. 2015;47(1):296–307.Akizuki H, et al. Effects of immersion in virtual reality on postural control. Neurosci Lett. 2005;379(1):23–6.Thies SB, et al. Comparison of linear accelerations from three measurement systems during "reach & grasp". Med Eng Phys. 2007;29(9):967–72.Fiala M. Designing highly reliable fiducial markers. IEEE Trans Pattern Anal Mach Intell. 2010;32(7):1317–24.Garrido-Jurado S, et al. Automatic generation and detection of highly reliable fiducial markers under occlusion. Pattern Recognition. 2014;47(6):2280–92.Kim K, et al. Effects of virtual environment platforms on emotional responses. Comput Methods Programs Biomed. 2014;113(3):882–93.Slater M, Steed A. A virtual presence counter. Presence. 2000;9(5):413–34.Witmer BG, Singer MJ. Measuring presence in virtual environments: a presence questionnaire. Presence Teleop Virt. 1998;7(3):225–40.Martín-Gutiérrez J, et al. Design and validation of an augmented book for spatial abilities development in engineering students. Comput Graph. 2010;34(1):77–91.Lopez-Mir F, et al. Design and validation of an augmented reality system for laparoscopic surgery in a real environment. Biomed Res Int. 2013;2013:758491.Abawi DF, Bienwald J, Dorner R. Accuracy in optical tracking with fiducial markers: an accuracy function for ARToolKit. In: Third IEEE and ACM International symposium on mixed and augmented reality, ISMAR 2004. 2004.Malbezin P, Piekarski W, Thomas BH. Measuring ARTootKit accuracy in long distance tracking experiments. In: The first IEEE International workshop augmented reality toolkit. 2002.Paquette C, Paquet N, Fung J. Aging affects coordination of rapid head motions with trunk and pelvis movements during standing and walking. Gait Posture. 2006;24(1):62–9.Graham JE, et al. Walking speed threshold for classifying walking independence in hospitalized older adults. Phys Ther. 2010;90(11):1591–7.Gorea A. A refresher of the original Bloch’s Law paper (bloch, july 1885). i-Perception. 2015;6:4.Moss JD, Muth ER. Characteristics of head-mounted displays and their effects on Simulator sickness. Hum Factors. 2011;53(3):308–19.Draper MH, et al. Effects of image scale and system time delay on Simulator sickness within head-coupled virtual environments. Hum Factors. 2001;43(1):129–46.Fujisaki W. Effects of delayed visual feedback on grooved pegboard test performance. Front Psychol. 2012;3:61.Keshner EA, et al. Augmenting sensory-motor conflict promotes adaptation of postural behaviors in a virtual environment. Conf Proc IEEE Eng Med Biol Soc. 2011;2011:1379–82.Slaboda JC, Keshner EA. Reorientation to vertical modulated by combined support surface tilt and virtual visual flow in healthy elders and adults with stroke. J Neurol. 2012;259(12):2664–72.Tossavainen T. Comparison of CAVE and HMD for visual stimulation in postural control research. Stud Health Technol Inform. 2004;98:385–7.Akiduki H, et al. Visual-vestibular conflict induced by virtual reality in humans. Neurosci Lett. 2003;340(3):197–200.Duh HBL, et al. Effects of field of view on balance in an immersive environment. In: Virtual Reality, 2001. Proceedings. IEEE. 2001.Krijn M, et al. Treatment of acrophobia in virtual reality: the role of immersion and presence. Behav Res Ther. 2004;42(2):229–39.Mania K, Chalmers A. The effects of levels of immersion on memory and presence in virtual environments: a reality centered approach. Cyberpsychol Behav. 2001;4(2):247–64.Gorini A, et al. The role of immersion and narrative in mediated presence: the virtual hospital experience. Cyberpsychol Behav Soc Netw. 2011;14(3):99–105.Fromberger P, et al. Virtual viewing time: the relationship between presence and sexual interest in androphilic and gynephilic Men. PLoS One. 2015;10(5), e0127156.Slater M, et al. Visual realism enhances realistic response in an immersive virtual environment. IEEE Comput Graph Appl. 2009;29(3):76–84.Nir-Hadad SY, et al. A virtual shopping task for the assessment of executive functions: Validity for people with stroke. Neuropsychol Rehabil. 2015;11:1–26. doi: 10.1080/09602011.2015.1109523 .Vasilyeva M, Lourenco SF. Development of spatial cognition. Wiley Interdiscip Rev Cogn Sci. 2012;3(3):349–62.Banakou D, Groten R, Slater M. Illusory ownership of a virtual child body causes overestimation of object sizes and implicit attitude changes. Proc Natl Acad Sci U S A. 2013;110(31):12846–51.Yee N, Bailenson JN, Ducheneaut N. The proteus effect: implications of transformed digital self-representation on online and offline behavior. Commun Res. 2009;36(2):285–312.Baylor AL. Promoting motivation with virtual agents and avatars: role of visual presence and appearance. Philos Trans R Soc Lond B Biol Sci. 2009;364(1535):3559–65.Clemente M, et al. Assessment of the influence of navigation control and screen size on the sense of presence in virtual reality using EEG. Expert Sys App. 2014;41(4, Part 2):1584–92.Clemente M, et al. An fMRI study to analyze neural correlates of presence during virtual reality experiences. 2013. Interacting with Computers

Inhibition of Mesothelin as a Novel Strategy for Targeting Cancer Cells

Mesothelin, a differentiation antigen present in a series of malignancies such as mesothelioma, ovarian, lung and pancreatic cancer, has been studied as a marker for diagnosis and a target for immunotherapy. We, however, were interested in evaluating the effects of direct targeting of Mesothelin on the viability of cancer cells as the first step towards developing a novel therapeutic strategy. We report here that gene specific silencing for Mesothelin by distinct methods (siRNA and microRNA) decreased viability of cancer cells from different origins such as mesothelioma (H2373), ovarian cancer (Skov3 and Ovcar-5) and pancreatic cancer (Miapaca2 and Panc-1). Additionally, the invasiveness of cancer cells was also significantly decreased upon such treatment. We then investigated pro-oncogenic signaling characteristics of cells upon mesothelin-silencing which revealed a significant decrease in phospho-ERK1 and PI3K/AKT activity. The molecular mechanism of reduced invasiveness was connected to the reduced expression of β-Catenin, an important marker of EMT (epithelial-mesenchymal transition). Ero1, a protein involved in clearing unfolded proteins and a member of the ER-Stress (endoplasmic reticulum-stress) pathway was also markedly reduced. Furthermore, Mesothelin silencing caused a significant increase in fraction of cancer cells in S-phase. In next step, treatment of ovarian cancer cells (OVca429) with a lentivirus expressing anti-mesothelin microRNA resulted in significant loss of viability, invasiveness, and morphological alterations. Therefore, we propose the inhibition of Mesothelin as a potential novel strategy for targeting human malignancies

Imaging Single Retrovirus Entry through Alternative Receptor Isoforms and Intermediates of Virus-Endosome Fusion

A large group of viruses rely on low pH to activate their fusion proteins that merge the viral envelope with an endosomal membrane, releasing the viral nucleocapsid. A critical barrier to understanding these events has been the lack of approaches to study virus-cell membrane fusion within acidic endosomes, the natural sites of virus nucleocapsid capsid entry into the cytosol. Here we have investigated these events using the highly tractable subgroup A avian sarcoma and leukosis virus envelope glycoprotein (EnvA)-TVA receptor system. Through labeling EnvA pseudotyped viruses with a pH-sensitive fluorescent marker, we imaged their entry into mildly acidic compartments. We found that cells expressing the transmembrane receptor (TVA950) internalized the virus much faster than those expressing the GPI-anchored receptor isoform (TVA800). Surprisingly, TVA800 did not accelerate virus uptake compared to cells lacking the receptor. Subsequent steps of virus entry were visualized by incorporating a small viral content marker that was released into the cytosol as a result of fusion. EnvA-dependent fusion with TVA800-expressing cells occurred shortly after endocytosis and delivery into acidic endosomes, whereas fusion of viruses internalized through TVA950 was delayed. In the latter case, a relatively stable hemifusion-like intermediate preceded the fusion pore opening. The apparent size and stability of nascent fusion pores depended on the TVA isoforms and their expression levels, with TVA950 supporting more robust pores and a higher efficiency of infection compared to TVA800. These results demonstrate that surface receptor density and the intracellular trafficking pathway used are important determinants of efficient EnvA-mediated membrane fusion, and suggest that early fusion intermediates play a critical role in establishing low pH-dependent virus entry from within acidic endosomes

Identifying Where REDD+ Financially Out Competes Oil Palm in Floodplain Landscapes Using a Fine-Scale Approach

Reducing Emissions from Deforestation and forest Degradation (REDD+) aims to avoid forest conversion to alternative land-uses through financial incentives. Oil-palm has high opportunity costs, which according to current literature questions the financial competitiveness of REDD+ in tropical lowlands. To understand this more, we undertook regional finescale and coarse-scale analyses (through carbon mapping and economic modelling) to assess the financial viability of REDD+ in safeguarding unprotected forest (30,173 ha) in the Lower Kinabatangan floodplain in Malaysian Borneo. Results estimate 4.7 million metric tons of carbon (MgC) in unprotected forest, with 64% allocated for oil-palm cultivations. Through fine-scale mapping and carbon accounting, we demonstrated that REDD+ can outcompete oil-palm in regions with low suitability, with low carbon prices and low carbon stock. In areas with medium oil-palm suitability, REDD+ could outcompete oil palm in areas with: very high carbon and lower carbon price; medium carbon price and average carbon stock; or, low carbon stock and high carbon price. Areas with high oil palm suitability, REDD + could only outcompete with higher carbon price and higher carbon stock. In the coarse-scale model, oil-palm outcompeted REDD+ in all cases. For the fine-scale models at the landscape level, low carbon offset prices (US $3 MgCO2e) would enable REDD+ to outcompete oil-palm in 55$27 million to secure these areas for 25 years. Higher carbon offset price (US $30 MgCO2e) would increase the competitiveness of REDD+ within the landscape but would still only capture between 69$380–416 million in carbon financing. REDD+ has been identified as a strategy to mitigate climate change by many countries (including Malaysia). Although REDD+ in certain scenarios cannot outcompete oil palm, this research contributes to the global REDD+ debate by: highlighting REDD+ competitiveness in tropical floodplain landscapes; and, providing a robust approach for identifying and targeting limited REDD+ funds

A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia

Supplementary material: Supplementary material is available at Brain online: https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/brain/145/5/10.1093_brain_awab382/1/awab382_supplementary_data.zip?Expires=1665139578&Signature=C7VStQxldRqnpcchAWh4igaKwveciF~gaQCbInqMnI1YkIFV0euPXlI-0ZlRZ26hbRum6myjm88d3KzOM-wqVG~H7JO9TTUXoyi-n3hRRd1a4Vw0Hay9ykagca92gMqWij5ax4WzsEGlv~dKGSKKivH02pflzQyDAwF6xjjObYRYe29grdOZQ5h8orT6XNAdK5YFqpiX7L6mpVaNs7AOgNDdxtwshaa4kq1xxCgojTgAaIR3WFTFDpHkJ6wnhncxuteykTzq5~w1RCoDIfKQSA9C42i~iWryOeOvjv-P6j-R0tSkDGzFKcI3kUo3lUT9GiPG-vDwAO5EsLkUikJLOw__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA.GENFI consortium members Full details are available in the Supplementary material. Sónia Afonso, Maria Rosario Almeida, Sarah Anderl-Straub, Christin Andersson, Anna Antonell, Silvana Archetti, Andrea Arighi, Mircea Balasa, Myriam Barandiaran, Nuria Bargalló, Robart Bartha, Benjamin Bender, Alberto Benussi, Luisa Benussi, Valentina Bessi, Giuliano Binetti, Sandra Black, Martina Bocchetta, Sergi Borrego-Ecija, Jose Bras, Rose Bruffaerts, Marta Cañada, Valentina Cantoni, Paola Caroppo, David Cash, Miguel Castelo-Branco, Rhian Convery, Thomas Cope, Giuseppe Di Fede, Alina Díez, Diana Duro, Chiara Fenoglio, Camilla Ferrari, Catarina B. Ferreira, Nick Fox, Morris Freedman, Giorgio Fumagalli, Alazne Gabilondo, Roberto Gasparotti, Serge Gauthier, Stefano Gazzina, Giorgio Giaccone, Ana Gorostidi, Caroline Greaves, Rita Guerreiro, Tobias Hoegen, Begoña Indakoetxea, Vesna Jelic, Hans-Otto Karnath, Ron Keren, Tobias Langheinrich, Maria João Leitão, Albert Lladó, Gemma Lombardi, Sandra Loosli, Carolina Maruta, Simon Mead, Gabriel Miltenberger, Rick van Minkelen, Sara Mitchell, Katrina Moore, Benedetta Nacmias, Jennifer Nicholas, Linn Öijerstedt, Jaume Olives, Sebastien Ourselin, Alessandro Padovani, Georgia Peakman, Michela Pievani, Yolande Pijnenburg, Cristina Polito, Enrico Premi, Sara Prioni, Catharina Prix, Rosa Rademakers, Veronica Redaelli, Tim Rittman, Ekaterina Rogaeva, Pedro Rosa-Neto, Giacomina Rossi, Martin Rosser, Beatriz Santiago, Elio Scarpini, Sonja Schönecker, Elisa Semler, Rachelle Shafei, Christen Shoesmith, Miguel Tábuas-Pereira, Mikel Tainta, Ricardo Taipa, David Tang-Wai, David L Thomas, Paul Thompson, Hakan Thonberg, Carolyn Timberlake, Pietro Tiraboschi, Emily Todd, Philip Van Damme, Mathieu Vandenbulcke, Michele Veldsman, Ana Verdelho, Jorge Villanua, Jason Warren, Ione Woollacott, Elisabeth Wlasich, Miren Zulaica.Copyright © The Author(s) 2021. Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions.Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte founda tion (grant number 1402 1300), the European Joint Programme— Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and in novation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundacio´ Marato´ de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Scho¨rling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tja¨narinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar

Comparison of clinical rating scales in genetic frontotemporal dementia within the GENFI cohort

BACKGROUND: Therapeutic trials are now underway in genetic forms of frontotemporal dementia (FTD) but clinical outcome measures are limited. The two most commonly used measures, the Clinical Dementia Rating (CDR)+National Alzheimer’s Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) and the FTD Rating Scale (FRS), have yet to be compared in detail in the genetic forms of FTD. METHODS: The CDR+NACC FTLD and FRS were assessed cross-sectionally in 725 consecutively recruited participants from the Genetic FTD Initiative: 457 mutation carriers (77 microtubule-associated protein tau (MAPT), 187 GRN, 193 C9orf72) and 268 family members without mutations (non-carrier control group). 231 mutation carriers (51 MAPT, 92 GRN, 88 C9orf72) and 145 non-carriers had available longitudinal data at a follow-up time point. RESULTS: Cross-sectionally, the mean FRS score was lower in all genetic groups compared with controls: GRN mutation carriers mean 83.4 (SD 27.0), MAPT mutation carriers 78.2 (28.8), C9orf72 mutation carriers 71.0 (34.0), controls 96.2 (7.7), p<0.001 for all comparisons, while the mean CDR+NACC FTLD Sum of Boxes was significantly higher in all genetic groups: GRN mutation carriers mean 2.6 (5.2), MAPT mutation carriers 3.2 (5.6), C9orf72 mutation carriers 4.2 (6.2), controls 0.2 (0.6), p<0.001 for all comparisons. Mean FRS score decreased and CDR+NACC FTLD Sum of Boxes increased with increasing disease severity within each individual genetic group. FRS and CDR+NACC FTLD Sum of Boxes scores were strongly negatively correlated across all mutation carriers (r_{s} =−0.77, p<0.001) and within each genetic group (r_{s} =−0.67 to −0.81, p<0.001 in each group). Nonetheless, discrepancies in disease staging were seen between the scales, and with each scale and clinician-judged symptomatic status. Longitudinally, annualised change in both FRS and CDR+NACC FTLD Sum of Boxes scores initially increased with disease severity level before decreasing in those with the most severe disease: controls −0.1 (6.0) for FRS, −0.1 (0.4) for CDR+NACC FTLD Sum of Boxes, asymptomatic mutation carriers −0.5 (8.2), 0.2 (0.9), prodromal disease −2.3 (9.9), 0.6 (2.7), mild disease −10.2 (18.6), 3.0 (4.1), moderate disease −9.6 (16.6), 4.4 (4.0), severe disease −2.7 (8.3), 1.7 (3.3). Sample sizes were calculated for a trial of prodromal mutation carriers: over 180 participants per arm would be needed to detect a moderate sized effect (30%) for both outcome measures, with sample sizes lower for the FRS. CONCLUSIONS: Both the FRS and CDR+NACC FTLD measure disease severity in genetic FTD mutation carriers throughout the timeline of their disease, although the FRS may be preferable as an outcome measure. However, neither address a number of key symptoms in the FTD spectrum, for example, motor and neuropsychiatric deficits, which future scales will need to incorporate