New developments of biofluid-based biomarkers for routine diagnosis and disease trajectories in frontotemporal dementia

Frontotemporal dementia (FTD) covers a spectrum of neurodegenerative disorders with different phenotypes, genetic backgrounds, and pathological states. Its clinicopathological diversity challenges the diagnostic process and the execution of clinical trials, calling for specific diagnostic biomarkers of pathologic FTD types. There is also a need for biomarkers that facilitate disease staging, quantification of severity, monitoring in clinics and observational studies, and for evaluation of target engagement and treatment response in clinical trials. This review discusses current FTD biofluid-based biomarker knowledge taking into account the differing applications. The limitations, knowledge gaps, and challenges for the development and implementation of such markers are also examined. Strategies to overcome these hurdles are proposed, including the technologies available, patient cohorts, and collaborative research initiatives. Access to robust and reliable biomarkers that define the exact underlying pathophysiological FTD process will meet the needs for specific diagnosis, disease quantitation, clinical monitoring, and treatment development

Optimizing care for children with difficult-to-treat and severe asthma through specialist paediatric asthma centres:expert practical experience and advice

Severe asthma in children carries an unacceptable treatment burden, yet its rarity means clinical experience in treating it is limited, even among specialists. Practical guidance is needed to support clinical decision-making to optimize treatment for children with this condition. This modified Delphi convened 16 paediatric pulmonologists and allergologists from northern Europe, all experienced in treating children with severe asthma. Informed by interviews with stakeholders involved in the care of children with severe asthma (including paediatricians, nurses and carers), and an analysis of European guidelines, the experts built a consensus focused on the gaps in existing guidance. Explored were considerations for optimizing care for patients needing biologic treatment, and for selecting home or hospital delivery of biologics. This consensus is aimed at clinicians in specialist centres, as well as general paediatricians, paediatric allergologists and paediatric pulmonologists who refer children with the most severe asthma to specialist care. Consensus is based on expert opinion and is intended for use alongside published guidelines. Our discussions revealed three key facets to optimizing care. Firstly, early asthma detection in children presenting with wheezing and/or dyspnoea is vital, with a low threshold for referral from primary to specialist care. Secondly, children who may need biologics should be referred to and managed by specialist paediatric asthma centres; we define principles for the specialist team members, tests, and expertise necessary at such centres, as well as guidance on when homecare biologics delivery is and is not appropriate. Thirdly, shared decision-making is essential at all stages of the patient’s journey: clear, concise treatment plans are vital for patient/carer self-management, and structured processes for transition from paediatric to adult services are valuable. The experts identified the potential for specialist paediatric asthma nurses to play a significant role in facilitating multidisciplinary working. Through this project is agreed a framework of practical advice to optimize the care of children with severe asthma. We encourage clinicians and policymakers to implement this practical advice to enhance patient care.</p

Reducing Asthma Attacks in Children using Exhaled Nitric Oxide as a biomarker to inform treatment strategy:a randomised trial (RAACENO)

Acknowledgements The authors are indebted to the following persons who have helped deliver the RAACENO trial: Mrs J Wood and Mrs V Bell for implementation of protocol; Miss A Fraser for data coordination; colleagues in the Clinical Trials Unit in Aberdeen (Centre for Healthcare Randomised Trials, CHaRT); the Clinical Research Networks in East of England; the Scottish Primary Care Research Network; the local recruiting teams, participants and participant parents and care givers. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Health Technology Assessment Programme, National Institute for Health Research (NIHR), NHS or the Department of Health. Funding {4} The trial is funded by the NIHR Efficacy and Mechanism Evaluation (EME) programme, project number 15-18-14. The funding body had no role in the design of the study, collection of data or the writing of this paper, nor will the funding body have a role in analysis, interpretation of data or in writing future manuscripts. Co-sponsor 1 is the University of Aberdeen, Foresterhill House Annexe, Foresterhill, Aberdeen, AB25 2ZB. Co-sponsor 2 is NHS Grampian, Foresterhill House Annexe, Foresterhill, Aberdeen, AB25 2ZB.Peer reviewedPublisher PD

Catholic Healthcare Organizations and the Articulation of Their Identity

Contains fulltext : 69947.pdf (publisher's version ) (Open Access

LISA pathfinder optical interferometry

The LISA Technology Package (LTP) aboard of LISA pathfinder mission is dedicated to demonstrate and verify key technologies for LISA, in particular drag free control, ultra-precise laser interferometry and gravitational sensor. Two inertial sensor, the optical interferometry in between combined with the dimensional stable Glass ceramic Zerodur structure are setting up the LTP. The validation of drag free operation of the spacecraft is planned by measuring laser interferometrically the relative displacement and tilt between two test masses (and the optical bench) with a noise levels of 10pm/[square root of]Hz and 10 nrad/[square root of]Hz between 3mHz and 30mHz. This performance and additionally overall environmental tests was currently verified on EM level. The OB structure is able to support two inertial sensors ([approximate]17kg each) and to withstand 25 g design loads as well as 0...40°C temperature range. Optical functionality was verified successfully after environmental tests. The engineering model development and manufacturing of the optical bench and interferometry hardware and their verification tests will be presented

Plasma proteome profiling identifies changes associated to AD but not to FTD

Background Frontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD), characterized mainly by inclusions of Tau (FTLD-Tau) or TAR DNA binding43 (FTLD-TDP) proteins. Plasma biomarkers are strongly needed for specific diagnosis and potential treatment monitoring of FTD. We aimed to identify specific FTD plasma biomarker profiles discriminating FTD from AD and controls, and between FTD pathological subtypes. In addition, we compared plasma results with results in post-mortem frontal cortex of FTD cases to understand the underlying process. Methods Plasma proteins (n = 1303) from pathologically and/or genetically confirmed FTD patients (n = 56; FTLD-Tau n = 16; age = 58.2 +/- 6.2; 44% female, FTLD-TDP n = 40; age = 59.8 +/- 7.9; 45% female), AD patients (n = 57; age = 65.5 +/- 8.0; 39% female), and non-demented controls (n = 148; 61.3 +/- 7.9; 41% female) were measured using an aptamer-based proteomic technology (SomaScan). In addition, exploratory analysis in post-mortem frontal brain cortex of FTD (n = 10; FTLD-Tau n = 5; age = 56.2 +/- 6.9, 60% female, and FTLD-TDP n = 5; age = 64.0 +/- 7.7, 60% female) and non-demented controls (n = 4; age = 61.3 +/- 8.1; 75% female) were also performed. Differentially regulated plasma and tissue proteins were identified by global testing adjusting for demographic variables and multiple testing. Logistic lasso regression was used to identify plasma protein panels discriminating FTD from non-demented controls and AD, or FTLD-Tau from FTLD-TDP. Performance of the discriminatory plasma protein panels was based on predictions obtained from bootstrapping with 1000 resampled analysis. Results Overall plasma protein expression profiles differed between FTD, AD and controls (6 proteins; p = 0.005), but none of the plasma proteins was specifically associated to FTD. The overall tissue protein expression profile differed between FTD and controls (7-proteins; p = 0.003). There was no difference in overall plasma or tissue expression profile between FTD subtypes. Regression analysis revealed a panel of 12-plasma proteins discriminating FTD from AD with high accuracy (AUC: 0.99). No plasma protein panels discriminating FTD from controls or FTD pathological subtypes were identified. Conclusions We identified a promising plasma protein panel as a minimally-invasive tool to aid in the differential diagnosis of FTD from AD, which was primarily associated to AD pathophysiology. The lack of plasma profiles specifically associated to FTD or its pathological subtypes might be explained by FTD heterogeneity, calling for FTD studies using large and well-characterize cohorts

Optical bench development for LISA

For observation of gravitational waves at frequencies between 30 μHz and 1 Hz, the LISA mission will be implemented in a triangular constellation of three identical spacecraft, which are mutually linked by laser interferometry in an active transponder scheme over a 5 million kilometer arm length. On the end point of each laser link, remote and local beam metrology with respect to inertial proof masses inside the spacecraft is realized by the LISA Optical Bench. It implements further- more various ancillary functions such as point-ahead correction, acquisition sensing, transmit beam conditioning, and laser redundancy switching. A comprehensive design of the Optical Bench has been developed, which includes all of the above mentioned functions and at the same time ensures manufacturability on the basis of hydroxide catalysis bonding, an ultrastable integration technology already perfected in the context of LISA's technology demonstrator mission LISA Pathfinder. Essential elements of this design have been validated by dedicated pre-investigations. These include the demonstration of polarizing heterodyne interferometry at the required Picometer and Nanoradian performance levels, the investigation of potential non-reciprocal noise sources in the so-called backlink fiber, as well as the development of a laser redundancy switch breadboard

Design and construction of a telescope simulator for LISA optical bench testing

LISA (Laser Interferometer Space Antenna) is a proposed space-based instrument for astrophysical observations via the measurement of gravitational waves at mHz frequencies. The triangular constellation of the three LISA satellites will allow interferometric measurement of the changes in distance along the arms. On board each LISA satellite there will be two optical benches, one for each testmass, that measure the distance to the local test mass and to the remote optical bench on the distant satellite. For technology development, an Optical Bench Elegant Bread Board (OB EBB) is currently under construction. To verify the performance of the EBB, another optical bench - the so-called telescope simulator bench - will be constructed to simulate the beam coming from the far spacecraft. The optical beam from the telescope simulator will be superimposed with the light on the LISA OB, in order to simulate the link between two LISA satellites. Similarly in reverse, the optical beam from the LISA OB will be picked up and measured on the telescope simulator bench. Furthermore, the telescope simulator houses a test mass simulator. A gold coated mirror which can be manipulated by an actuator simulates the test mass movements. This paper presents the layout and design of the bench for the telescope simulator and test mass simulator

Clinical Value of Longitudinal Serum Neurofilament Light Chain in Prodromal Genetic Frontotemporal Dementia

BACKGROUND AND OBJECTIVES: Elevated serum neurofilament light chain (NfL) is used to identify carriers of genetic frontotemporal dementia (FTD) pathogenic variants approaching prodromal conversion. Yet, the magnitude and timeline of NfL increase are still unclear. Here, we investigated the predictive and early diagnostic value of longitudinal serum NfL for the prodromal conversion in genetic FTD. METHODS: In a longitudinal observational cohort study of genetic FTD pathogenic variant carriers, we examined the diagnostic accuracy and conversion risk associated with cross-sectional and longitudinal NfL. Time periods relative to prodromal conversion (&gt;3, 3-1.5, 1.5-0 years before; 0-1.5 years after) were compared with values of participants who did not convert. Next, we modeled longitudinal NfL and MRI volume trajectories to determine their timeline.RESULTS: We included 21 participants who converted (5 chromosome 9 open-reading frame 72 [C9orf72], 10 progranulin [GRN], 5 microtubule-associated protein tau [MAPT], and 1 TAR DNA-binding protein [TARDBP]) and 61 who did not (20 C9orf72, 30 GRN, and 11 MAPT). Participants who converted had higher NfL levels at all examined periods before prodromal conversion (median values 14.0-18.2 pg/mL; betas = 0.4-0.7, standard error [SE] = 0.1, p &lt; 0.046) than those who did not (6.5 pg/mL) and showed further increase 0-1.5 years after conversion (28.4 pg/mL; beta = 1.0, SE = 0.1, p &lt; 0.001). Annualized longitudinal NfL change was only significantly higher in participants who converted (vs. participants who did not) 0-1.5 years after conversion (beta = 1.2, SE = 0.3, p = 0.001). Diagnostic accuracy of cross-sectional NfL for prodromal conversion (vs. nonconversion) was good-to-excellent at time periods before conversion (area under the curve range: 0.72-0.92), improved 0-1.5 years after conversion (0.94-0.97), and outperformed annualized longitudinal change (0.76-0.84). NfL increase in participants who converted occurred earlier than frontotemporal MRI volume change and differed by genetic group and clinical phenotypes. Higher NfL corresponded to increased conversion risk (hazard ratio: cross-sectional = 6.7 [95% CI 3.3-13.7]; longitudinal = 13.0 [95% CI 4.0-42.8]; p &lt; 0.001), but conversion-free follow-up time varied greatly across participants. DISCUSSION: NfL increase discriminates individuals who convert to prodromal FTD from those who do not, preceding significant frontotemporal MRI volume loss. However, NfL alone is limited in predicting the exact timing of prodromal conversion. NfL levels also vary depending on underlying variant-carrying genes and clinical phenotypes. These findings help to guide participant recruitment for clinical trials targeting prodromal genetic FTD.</p

Theory of Mind and social functioning among neuropsychiatric disorders:A transdiagnostic study

Social dysfunction is commonly present in neuropsychiatric disorders of schizophrenia (SZ) and Alzheimer's disease (AD). Theory of Mind (ToM) deficits have been linked to social dysfunction in disease-specific studies. Nevertheless, it remains unclear how ToM is related to social functioning across these disorders, and which factors contribute to this relationship. We investigated transdiagnostic associations between ToM and social functioning among SZ/AD patients and healthy controls, and explored to what extent these associations relate to information processing speed or facial emotion recognition capacity. A total of 163 participants were included (SZ: n=56, AD: n=50 and age-matched controls: n=57). Social functioning was assessed with the Social Functioning Scale (SFS) and the De Jong-Gierveld Loneliness Scale (LON). ToM was measured with the Hinting Task. Information processing speed was measured by the Digit Symbol Substitution Test (DSST) and facial emotion recognition capacity by the facial emotion recognition task (FERT). Case-control deficits in Hinting Task performance were larger in AD (rrb = -0.57) compared to SZ (rrb = -0.35). Poorer Hinting Task performance was transdiagnostically associated with the SFS (βHinting-Task = 1.20, p<0.01) and LON (βHinting-Task = -0.27, p<0.05). DSST, but not FERT, reduced the association between the SFS and Hinting Task performance, however the association remained significant (βHinting-Task = 0.95, p<0.05). DSST and FERT performances did not change the association between LON and Hinting Task performance. Taken together, ToM deficits are transdiagnostically associated with social dysfunction and this is partly related to reduced information processing speed