Dissociable contributions of frontal and temporal brain regions to basic semantic composition

Semantic composition is the ability to combine single words to form complex meanings and is an essential component for successful communication. Evidence from neuroimaging studies suggests that semantic composition engages a widely distributed left-hemispheric network, including the anterior temporal lobe, the inferior frontal gyrus and the angular gyrus. To date, the functional relevance of these regions remains unclear. Here, we investigate the impact of lesions to key regions in the semantic network on basic semantic composition. We conducted a multivariate lesion-behaviour mapping study in 36 native German speaking participants with chronic lesions to the language network after left-hemispheric stroke. During the experiment, participants performed a plausibility judgement task on auditorily presented adjective-noun phrases that were either meaningful (‘anxious horse’), anomalous (‘anxious salad’) or had the noun replaced by a pseudoword (‘anxious gufel’), as well as a single-word control condition (‘horse’). We observed that reduced accuracy for anomalous phrases is associated with lesions in left anterior inferior frontal gyrus, whereas increased reaction times for anomalous phrases correlates with lesions in anterior-to-mid temporal lobe. These results indicate that anterior inferior frontal gyrus is relevant for accurate semantic decisions, while anterior-to-mid temporal lobe lesions lead to slowing of the decision for anomalous two-word phrases. These differential effects of lesion location support the notion that anterior inferior frontal gyrus affords executive control for decisions on semantic composition while anterior-to-mid temporal lobe lesions slow the semantic processing of the individual constituents of the phrase

MR Imaging of Prostate Cancer: Diffusion Weighted Imaging and (3D) Hydrogen 1 (1H) MR Spectroscopy in Comparison with Histology

Purpose. To evaluate retrospectively the impact of diffusion weighted imaging (DWI) and (3D) hydrogen 1 (1H) MR-spectroscopy (MRS) on the detection of prostatic cancer in comparison to histological examinations. Materials and Methods: 50 patients with suspicion of prostate cancer underwent a MRI examination at a 1.5T scanner. The prostate was divided into sextants. Regions of interest were placed in each sextant to evaluate the apparent diffusion coefficient (ADC)-values. The results of the DWI as well as MRS were compared retrospectively with the findings of the histological examination. Sensitivity and specificity of ADC and metabolic ratio (MET)—both separately and in combination—for identification of tumor tissue was computed for variable discrimination thresholds to evaluate its receiver operator characteristic (ROC). An association between ADC, MET and Gleason score was tested by the non-parametric Spearman ρ-test. Results. The average ADC-value was 1.65 ± 0.32mm2/s × 10−3 in normal tissue and 0.96±0.24 mm2/s × 10−3 in tumor tissue (mean ± 1 SD). MET was 0.418 ± 0.431 in normal tissue and 2.010 ± 1.649 in tumor tissue. The area under the ROC curve was 0.966 (95%-confidence interval 0.941–0.991) and 0.943 (0.918–0.968) for DWI and MRS, respectively. There was a highly significant negative correlation between ADC-value and the Gleason score in the tumor-positive tissue probes (n = 62, ρ = −0.405, P = .001). MRS did not show a significant correlation with the Gleason score (ρ = 0.117, P = .366). By using both the DWI and MRS, the regression model provided sensitivity and specificity for detection of tumor of 91.9% and 98.3%, respectively. Conclusion. The results of our study showed that both DWI and MRS should be considered as an additional and complementary tool to the T2-weighted MRI for detecting prostate cancer

Current management of primary mitochondrial disorders in EU countries: the European Reference Networks survey

Background and purpose: Primary mitochondrial diseases (PMDs) are rare diseases for which diagnosis is challenging, and management and training programs are not well defined in Europe. To capture and assess care needs, five different European Reference Networks have conducted an exploratory survey. Methods: The survey covering multiple topics relating to PMDs was sent to all ERNs healthcare providers (HCPs) in Europe. Results: We have collected answers from 220 members based in 24/27 European member states and seven non-European member states. Even though most of the responders are aware of neurogenetic diseases, difficulties arise in the ability to deliver comprehensive genetic testing. While single gene analysis is widely available in Europe, whole exome and genome sequencing are not easily accessible, with considerable variation between countries and average waiting time for results frequently above 6 months. Only 12.7% of responders were happy with the ICD-10 codes for classifying patients with PMDs discharged from the hospital, and more than 70% of them consider that PMDs deserve specific ICD codes to improve clinical management, including tailored healthcare, and for reimbursement reasons. Finally, 90% of responders declared that there is a need for further education and training in these diseases. Conclusions: This survey provides information on the current difficulties in the care of PMDs in Europe. We believe that the results of this survey are important to help rare disease stakeholders in European countries identify key care and research priorities

Management of rare movement disorders in Europe:outcome of surveys of the European Reference Network for Rare Neurological Diseases

Background and purpose The diagnosis of rare movement disorders is difficult and specific management programmes are not well defined. Thus, in order to capture and assess care needs, the European Reference Network for Rare Neurological Diseases has performed an explorative care need survey across all European Union (EU) countries. Methods This is a multicentre, cross‐sectional study. A survey about the management of different rare movement disorders (group 1, dystonia, paroxysmal dyskinesia and neurodegeneration with brain iron accumulation; group 2, ataxias and hereditary spastic paraparesis; group 3, atypical parkinsonism; group 4, choreas) was sent to an expert in each group of disorders from each EU country. Results Some EU countries claimed for an increase of teaching courses. Genetic testing was not readily available in a significant number of countries. Regarding management, patients’ accessibility to tertiary hospitals, to experts and to multidisciplinary teams was unequal between countries and groups of diseases. The availability of therapeutic options, such as botulinum toxin or more invasive treatments like deep brain stimulation, was limited in some countries. Conclusions The management of these conditions in EU countries is unequal. The survey provides evidence that a European care‐focused network that is able to address the unmet rare neurological disease care needs and inequalities is highly warranted

European Reference Networks: challenges and opportunities

European Reference Networks (ERNs) were founded on the principle that many rare disease (RD) issues are pan-European and any single Member State cannot solve them alone. In 2021, ERNs are already in the deployment stage; however, their day-to-day functioning and realization of their potential are still severely hampered by many challenges, including issues in governance and regulation, lack of legal status, insufficient and unsustainable funding, lack of ERN integration into national systems, endangered collaboration with UK RD experts due to Brexit, insufficient exploitation of ERN potential in RD research, underappreciation of highly qualified human resources, problems with the involvement of patient representatives, and still unclear place of ERNs in the overall European RD and digital ecosystem. Bold and innovative solutions that must be taken to solve these challenges inevitably involve pan-European collaboration across several sectors and among multistakeholder RD communities and in many cases crucially rely on the constructive dialogue and coherent, united decisions of national and European authorities that are based on common EU values. Importantly, unresolved challenges may have a strong impact on the further sustainability of ERNs and their ability to realize full potential in addressing huge unmet needs of RD patients and their families.Diabetes mellitus: pathophysiological changes and therap

Preparing n-of-1 antisense oligonucleotide treatments for rare neurological diseases in Europe: genetic, regulatory, and ethical perspectives

Antisense oligonucleotide (ASO) therapies present a promising disease-modifying treatment approach for rare neurological diseases (RNDs). However, the current focus is on "more common" RNDs, leaving a large share of RND patients still without prospect of disease-modifying treatments. In response to this gap, n-of-1 ASO treatment approaches are targeting ultrarare or even private variants. While highly attractive, this emerging, academia-driven field of ultimately individualized precision medicine is in need of systematic guidance and standards, which will allow global scaling of this approach. We provide here genetic, regulatory, and ethical perspectives for preparing n-of-1 ASO treatments and research programs, with a specific focus on the European context. By example of splice modulating ASOs, we outline genetic criteria for variant prioritization, chart the regulatory field of n-of-1 ASO treatment development in Europe, and propose an ethically informed classification for n-of-1 ASO treatment strategies and level of outcome assessments. To accommodate the ethical requirements of both individual patient benefit and knowledge gain, we propose a stronger integration of patient care and clinical research when developing novel n-of-1 ASO treatments: each single trial of therapy should inherently be driven to generate generalizable knowledge, be registered in a ASO treatment registry, and include assessment of generic outcomes, which allow aggregated analysis across n-of-1 trials of therapy.Genetics of disease, diagnosis and treatmen

Solving patients with rare diseases through programmatic reanalysis of genome-phenome data

Reanalysis of inconclusive exome/genome sequencing data increases the diagnosis yield of patients with rare diseases. However, the cost and efforts required for reanalysis prevent its routine implementation in research and clinical environments. The Solve-RD project aims to reveal the molecular causes underlying undiagnosed rare diseases. One of the goals is to implement innovative approaches to reanalyse the exomes and genomes from thousands of well-studied undiagnosed cases. The raw genomic data is submitted to Solve-RD through the RD-Connect Genome-Phenome Analysis Platform (GPAP) together with standardised phenotypic and pedigree data. We have developed a programmatic workflow to reanalyse genome-phenome data. It uses the RD-Connect GPAP’s Application Programming Interface (API) and relies on the big-data technologies upon which the system is built. We have applied the workflow to prioritise rare known pathogenic variants from 4411 undiagnosed cases. The queries returned an average of 1.45 variants per case, which first were evaluated in bulk by a panel of disease experts and afterwards specifically by the submitter of each case. A total of 120 index cases (21.2% of prioritised cases, 2.7% of all exome/genome-negative samples) have already been solved, with others being under investigation. The implementation of solutions as the one described here provide the technical framework to enable periodic case-level data re-evaluation in clinical settings, as recommended by the American College of Medical Genetics

A guide to writing systematic reviews of rare disease treatments to generate FAIR-compliant datasets: Building a Treatabolome

Background: Rare diseases are individually rare but globally affect around 6% of the population, and in over 70% of cases are genetically determined. Their rarity translates into a delayed diagnosis, with 25% of patients waiting 5 to 30 years for one. It is essential to raise awareness of patients and clinicians of existing gene and variant-specific therapeutics at the time of diagnosis to avoid that treatment delays add up to the diagnostic odyssey of rare diseases' patients and their families. Aims: This paper aims to provide guidance and give detailed instructions on how to write homogeneous systematic reviews of rare diseases' treatments in a manner that allows the capture of the results in a computer-accessible form. The published results need to comply with the FAIR guiding principles for scientific data management and stewardship to facilitate the extraction of datasets that are easily transposable into machine-actionable information. The ultimate purpose is the creation of a database of rare disease treatments ("Treatabolome") at gene and variant levels as part of the H2020 research project Solve-RD. Results: Each systematic review follows a written protocol to address one or more rare diseases in which the authors are experts. The bibliographic search strategy requires detailed documentation to allow its replication. Data capture forms should be built to facilitate the filling of a data capture spreadsheet and to record the application of the inclusion and exclusion criteria to each search result. A PRISMA flowchart is required to provide an overview of the processes of search and selection of papers. A separate table condenses the data collected during the Systematic Review, appraised according to their level of evidence. Conclusions: This paper provides a template that includes the instructions for writing FAIR-compliant systematic reviews of rare diseases' treatments that enables the assembly of a Treatabolome database that complement existing diagnostic and management support tools with treatment awareness data

Dystonia management: what to expect from the future? The perspectives of patients and clinicians within DystoniaNet Europe

Improved care for people with dystonia presents a number of challenges. Major gaps in knowledge exist with regard to how to optimize the diagnostic process, how to leverage discoveries in pathophysiology into biomarkers, and how to develop an evidence base for current and novel treatments. These challenges are made greater by the realization of the wide spectrum of symptoms and difficulties faced by people with dystonia, which go well-beyond motor symptoms. A network of clinicians, scientists, and patients could provide resources to facilitate information exchange at different levels, share mutual experiences, and support each other's innovative projects. In the past, collaborative initiatives have been launched, including the American Dystonia Coalition, the European Cooperation in Science and Technology (COST-which however only existed for a limited time), and the Dutch DystonieNet project. The European Reference Network on Rare Neurological Diseases includes dystonia among other rare conditions affecting the central nervous system in a dedicated stream. Currently, we aim to broaden the scope of these initiatives to a comprehensive European level by further expanding the DystoniaNet network, in close collaboration with the ERN-RND. In line with the ERN-RND, the mission of DystoniaNet Europe is to improve care and quality of life for people with dystonia by, among other endeavors, facilitating access to specialized care, overcoming the disparity in education of medical professionals, and serving as a solid platform to foster international clinical and research collaborations. In this review, both professionals within the dystonia field and patients and caregivers representing Dystonia Europe highlight important unsolved issues and promising new strategies and the role that a European network can play in activating them.Neurological Motor Disorder