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Distinct brain atrophy progression subtypes underlie phenoconversion in isolated REM sleep behaviour disorder.
BACKGROUND: Synucleinopathies include a spectrum of disorders varying in features and severity, including idiopathic/isolated REM sleep behaviour disorder (iRBD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Distinct brain atrophy patterns may already be seen in iRBD; however, how brain atrophy begins and progresses remains unclear. METHODS: A multicentric cohort of 1276 participants (451 polysomnography-confirmed iRBD, 142 PD with probable RBD, 87 DLB, and 596 controls) underwent T1-weighted MRI and longitudinal clinical assessments. Brain atrophy was quantified using vertex-based cortical surface reconstruction and volumetric segmentation. The unsupervised machine learning algorithm, Subtype and Stage Inference (SuStaIn), was used to reconstruct spatiotemporal patterns of brain atrophy progression. FINDINGS: SuStaIn identified two distinct subtypes of brain atrophy progression: 1) a "cortical-first" subtype, with atrophy beginning in the frontal lobes and involving the subcortical structures at later stages; and 2) a "subcortical-first" subtype, with atrophy beginning in the limbic areas and involving cortical structures at later stages. Both cortical- and subcortical-first subtypes were associated with a higher rate of increase in MDS-UPDRS-III scores over time, but cognitive decline was subtype-specific, being associated with advancing stages in patients classified as cortical-first but not subcortical-first. Classified patients were more likely to phenoconvert over time compared to stage 0/non-classified patients. Among the 88 patients with iRBD who phenoconverted during follow-up, those classified within the cortical-first subtype had a significantly increased likelihood of developing DLB compared to PD, unlike those classified within the subcortical-first subtype. INTERPRETATION: There are two distinct atrophy progression subtypes in iRBD, with the cortical-first subtype linked to an increased likelihood of developing DLB, while both subtypes were associated with worsening parkinsonian motor features. This underscores the potential utility of subtype identification and staging for monitoring disease progression and patient selection for trials. FUNDING: This study was supported by grants to S.R. from Alzheimer Society Canada (0000000082) and by Parkinson Canada (PPG-2023-0000000122). The work performed in Montreal was supported by the Canadian Institutes of Health Research (CIHR), the Fonds de recherche du Québec - Santé (FRQS), and the W. Garfield Weston Foundation. The work performed in Oxford was funded by Parkinson's UK (J-2101) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The work performed in Prague was funded by the Czech Health Research Council (grant NU21-04-00535) and by The National Institute for Neurological Research (project number LX22NPO5107), financed by the European Union - Next Generation EU. The work performed in Newcastle was funded by the NIHR Newcastle BRC based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The work performed in Paris was funded by grants from the Programme d'investissements d'avenir (ANR-10-IAIHU-06), the Paris Institute of Neurosciences - IHU (IAIHU-06), the Agence Nationale de la Recherche (ANR-11-INBS-0006), Électricité de France (Fondation d'Entreprise EDF), the EU Joint Programme-Neurodegenerative Disease Research (JPND) for the Control-PD Project (Cognitive Propagation in Prodromal Parkinson's disease), the Fondation Thérèse et René Planiol, the Fonds Saint-Michel; by unrestricted support for research on Parkinson's disease from Energipole (M. Mallart) and the Société Française de Médecine Esthétique (M. Legrand); and by a grant from the Institut de France to Isabelle Arnulf (for the ALICE Study). The work performed in Sydney was supported by a Dementia Team Grant from the National Health and Medical Research Council (#1095127). The work performed in Cologne was funded by the Else Kröner-Fresenius-Stiftung (grant number 2019_EKES.02), the Köln Fortune Program, Faculty of Medicine, University of Cologne, and the "Netzwerke 2021 Program (Ministry of Culture and Science of Northrhine Westphalia State). The work performed in Aarhus was supported by funding from the Lundbeck Foundation, Parkinsonforeningen (The Danish Parkinson Association), and the Jascha Foundation.
Dopamine encodes deep network teaching signals for individual learning trajectories.
Striatal dopamine plays fundamental roles in fine-tuning learned decisions. However, when learning from naive to expert, individuals often exhibit diverse learning trajectories, defying understanding of its underlying dopaminergic mechanisms. Here, we longitudinally measure and manipulate dorsal striatal dopamine signals in mice learning a decision task from naive to expert. Mice learning trajectories transitioned through sequences of strategies, showing substantial individual diversity. Remarkably, the transitions were systematic; each mouse's early strategy determined its strategy weeks later. Dopamine signals reflected strategies each animal transitioned through, encoding a subset of stimulus-choice associations. Optogenetic manipulations selectively updated these associations, leading to learning effects distinct from that of reward. A deep neural network using heterogeneous teaching signals, each updating a subset of network association weights, captured our results. Analyzing the model's fixed points explained learning diversity and systematicity. Altogether, this work provides insights into the biological and mathematical principles underlying individual long-term learning trajectories.
Ethyl Pinacol Boronates as Advantageous Precursors for Copper-Mediated Radiofluorination.
(Hetero)aryl pinacol boronic esters are routinely used for 18F-labeling and have accelerated numerous diagnostic and drug discovery programs. An analysis of the current state-of-play, however, highlights a pending challenge. Reports have indicated that some pinacol boronic esters are unstable and difficult to purify, hindering broader adoption in the clinic. Herein, we demonstrate that more stable boronic esters derived from 3,4-diethylhexane-3,4-diol (Epin) are highly suitable for copper-mediated radiolabeling. Impact is illustrated with the automated synthesis of [18F]FMZ.
Mycorrhizal symbioses and tree diversity in global forest communities.
Unraveling the mechanisms underlying the maintenance of species diversity is a central pursuit in ecology. It has been hypothesized that ectomycorrhizal (EcM) in contrast to arbuscular mycorrhizal fungi can reduce tree species diversity in local communities, which remains to be tested at the global scale. To address this gap, we analyzed global forest inventory data and revealed that the relationship between tree species richness and EcM tree proportion varied along environmental gradients. Specifically, the relationship is more negative at low latitudes and in moist conditions but is unimodal at high latitudes and in arid conditions. The negative association of EcM tree proportion on species diversity at low latitudes and in humid conditions is likely due to more negative plant-soil microbial interactions in these regions. These findings extend our knowledge on the mechanisms shaping global patterns in plant species diversity from a belowground view.
Modeling social cohesion with coupled oscillators: Synchrony and fragmentation
Maintaining cohesion is a fundamental challenge in group-living species, where individuals must balance their own activity schedules with the demands of social interactions. In this paper, we model group dynamics using a network of semi-coupled oscillators to investigate how differences in activity schedules impact social cohesion and fragmentation. By introducing parameters for social “stickiness” (interaction strength) and activity synchronization, we simulate group behavior across varying conditions. Our findings reveal that, mathematically, cohesive groups can fragment when individual schedules diverge beyond critical thresholds, and that increasing social stickiness mitigates this effect. We explore these dynamics in the context of group size, subgroup formation, and coupling parameters, drawing parallels to network cohesion and fragmentation in human and artificial social systems. These results highlight the role of synchronization in maintaining stable social structures and suggest future avenues for empirical validation and application in broader social network contexts.
Handheld Spatially Offset Raman Spectroscopy for Rapid Non-invasive Detection of Ethylene Glycol and Diethylene Glycol in Medicinal Syrups
We investigate the potential of Spatially Offset Raman Spectroscopy (SORS) as a rapid, non-invasive screening tool deployable in the field to detect diethylene glycol (DEG) and ethylene glycol (EG) in medicinal syrups within closed containers. Measurements were performed on neat propylene glycol (PG) and glycerol, key components of many medicinal syrups, as well as marketed medicinal syrup formulations spiked with DEG and EG at various concentration levels to assess the technique’s limit of detection in real-life samples. SORS was able to detect these down to ~0.5% concentration level in neat PG for both DEG and EG compounds and ~1% concentration level for DEG and EG in neat glycerol. The DEG and EG detection thresholds for the marketed formulations measured through original bottles was ~1%, for Benylin (active ingredient: Glycerol) and Piriteze (active ingredient: Cetirizine Hydrochloride). For Calpol (active ingredient: Paracetamol) the detection limit was higher, ~2% for EG and ~5% for DEG. Although not reaching the International Pharmacopeial 0.1% detection threshold currently required for purity checks for human consumption, the method can still be used to detect products where DEG or EG has been wrongly used instead of PG or glycerol or if present in large quantities. The technique could also be used for raw material identification testing to ensure no mislabelling has occurred in pre-production stages and as a screening device in distribution chains to detect major deviations from permitted content in non-diffusely scattering, clear formulations, to help prevent serious adverse outcomes, such as acute renal failure and deaths.
The effect of D-cycloserine on brain connectivity over a course of pulmonary rehabilitation - A randomised control trial with neuroimaging endpoints.
Combining traditional therapies such as pulmonary rehabilitation with brain-targeted drugs may offer new therapeutic opportunities for the treatment of chronic breathlessness. Recently, we asked whether D-cycloserine, a partial NMDA-receptor agonist which may enhance behavioural therapies, modifies the relationship between breathlessness related brain activity and breathlessness anxiety over pulmonary rehabilitation. However, whether any changes are supported by alterations to underlying brain structure remains unknown. Here we examine the effect of D-cycloserine over a course of pulmonary rehabilitation on the connectivity between key brain regions associated with the processing of breathlessness anxiety. 72 participants with mild-to-moderate COPD took part in a longitudinal study in parallel to their pulmonary rehabilitation course. Diffusion tensor brain imaging and clinical measures of respiratory function were collected at three time points (before, during and after pulmonary rehabilitation). Participants were assigned to 250mg of D-cycloserine or placebo, which they were administered with on four occasions in a randomised, double-blind procedure. Following the first four sessions of pulmonary rehabilitation (visit 2), during which D-cycloserine was administered, improvements in breathlessness anxiety were linked with increased insula-hippocampal structural connectivity in the D-cycloserine group when compared to the placebo group. No differences were found between the two groups following the completion of the full pulmonary rehabilitation course 4-6 weeks later (visit 3). The action of D-cycloserine on brain connectivity appears to be restricted to within a short time-window of its administration. This temporary boost of the brain connectivity of two key regions associated with the evaluation of how unpleasant an experience is may support the re-evaluation of breathlessness cues, illustrated improvements in breathlessness anxiety. Trial registration ClinicalTrials.gov (NCT01985750).
Platforms for studying cell-cell recognition by immune cells.
Immune cells interact directly with other cells and make decisions by integrating information from many different receptor-ligand interactions at these cell-cell interfaces. Since they encounter a huge variety of normal and abnormal cells, they experience many different combinations and concentrations of ligands. Understanding immune responses therefore requires platforms that enable ligands to be easily manipulated. We review and compare the available platforms, focusing on T-cell recognition. Although genetically modified antigen-presenting cells (APCs) offer the most physiological system, manipulating their ligands is difficult and slow. In contrast, solid surfaces or supported lipid bilayers allow easy manipulation of ligands but lack the biophysical properties of cells, such as softness, a glycocalyx, and/or ligand mobility. A recently developed CombiCell system enables easy manipulation of ligands while conserving key biophysical properties. By comparing the advantages and limitations of each platform, we provide a framework to choose the most suitable system to study signal integration in both basic and translational contexts.
Differential beta and gamma activity modulation during unimanual and bimanual motor learning.
Movement-related dynamics in the beta and gamma bands have been studied in relation to motor execution and learning during unimanual movements, but their roles in complex bimanual tasks remain largely unexplored. This study aimed to investigate how beta and gamma activity differs between unimanual and bimanual movements, and how these neural signatures evolve during the learning process. Our motor task incorporated varying levels of bimanual interaction: unimanual, bimanual-equal, and bimanual-unequal. Magnetoencephalography data were recorded in healthy participants (N = 43, 27 females) during task performance, and beta and gamma activity was quantified. As expected, increasing task complexity from unimanual to bimanual-equal, and then to bimanual-unequal movements resulted in slower and less accurate performance. Across all conditions, significant beta event-related desynchronization (ERD) and gamma event-related synchronization (ERS) were observed during movement, as well as beta ERS after movement. Bimanual movements exhibited greater beta ERD, beta ERS, and gamma ERS compared to unimanual movements. With practice, participants demonstrated faster and more accurate movements, accompanied by enhanced beta ERS responses. Furthermore, learning-related reductions in errors correlated with increases in beta ERS. These findings suggest the distinct behavioural and neural demands of unimanual versus bimanual movements and highlight the important role of beta activity in motor performance and learning.Significance statement Bimanual movements, which dominate daily motor behaviours, require finely tuned coordination between the two hands yet remain poorly understood at the neurophysiological level. Using magnetoencephalography, we tested neural responses to a novel movement task incorporating varying levels of bimanual interaction. We demonstrate that greater task complexity elicits enhanced movement-related brain activity in the beta and gamma frequency bands. Motor learning is associated with an increase in beta movement-related synchronization that correlates with improved movement accuracy. This study provides novel insights into how beta and gamma brain activity adapt to increasing movement complexity and motor learning.
AICAR confers prophylactic cardioprotection in doxorubicin-induced heart failure in rats.
Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to heart failure (HF). Impaired mitochondrial function is thought to be key factor driving progression into HF. We have previously shown in a rat model of DOX-HF that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and energy metabolism, including fatty acid oxidation. We hypothesised that AMPK activation could restore mitochondrial function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. Consequently, we set out to assess whether 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this chronic intravenous rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, independent of mitochondrial number, and in the absence of observable AMPK-activation. In addition, we found that AICAR prevented loss of myocardial mass. RNAseq analysis showed that this may be driven by normalisation of pathways associated with ribosome function and protein synthesis, which are impaired in DOX-treated rat hearts. AICAR furthermore prevented dyslipidemia and excessive body-weight loss in DOX-treated rats, which may contribute to preservation of myocardial mass. Though it is unclear whether AICAR exerted its cardioprotective effect through cardiac or extra-cardiac AMPK-activation or via an AMPK-independent effect, these results show promise for the use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac function and mass.
Targeting glucose metabolism with dichloroacetate (DCA) reduces zika virus replication in brain cortical progenitors at different stages of maturation.
The underlying threat of new Zika virus (ZIKV) outbreaks remains, as no vaccines or therapies have yet been developed. In vitro research has shown that glycolysis is a key factor to enable sustained ZIKV replication in neuroprogenitors. However, neither in vivo nor clinical investigation of glycolytic modulators as potential therapeutics for ZIKV-related fetal abnormalities has been conducted. Accordingly, we tested the therapeutic potential of metabolic modulators in relevant in vitro systems comprising two pools of neuroprogenitors (NPCs), which resemble early and late stages of pregnancy. Effective doses of metabolic modulators [3.0 μM] dimethyl fumarate (DMF), [3.2 mM] dichloroacetate (DCA), and [6.3 μM] VER-246608 were determined for these cells by their effect on lactate release, pyruvate dehydrogenase (PDH) activity and cell survival. The drugs were used in a 24h pre-treatment and kept throughout ZIKV infection of NPCs. Drug effects and ZIKV replication were assessed at 24- and 56-h post-infection. In early NPCs treated with DMF, DCA and VER-246608, there was a significant reduction in the extracellular release of ZIKV potentially by PDH-mediated increased mitochondrial oxidation of glucose. Out of the three drugs, only DCA was observed to reduce viral replication in late NPCs treated with DCA. Altogether, our findings suggest that reduction of anaerobic glycolysis could be of therapeutic potential against ZIKV-related fetal abnormalities and that clinical translation should consider the use of specific glycolytic modulators over different trimesters.
Neurodegenerative Disease and Association Football (NDAF): Systematic Review and Meta-Analysis.
There is increasing concern that head injuries in Association Football (or soccer) may lead to adverse health outcomes. The aim of this study was to determine whether head impacts or injuries are associated with an increased risk of neurodegenerative disease. We performed a systematic search using PubMed, Embase, and Ovid (up to April 2025). Studies included investigated neurodegenerative diseases in football in comparison to control athletic and general populations. Data were extracted according to PRISMA guidelines. Studies with an odds ratio (OR) were included in the meta-analysis. A total of ten studies were included in this review, of which nine were suitable for meta-analysis from eight cohorts. The risk for developing any neurodegeneration was 1.69 OR (95%CI 1.11 to 2.59; p = 0.01); for Dementia, it was 2.16 OR (95%CI 1.60 to 2.93; p < 0.01; for Motor Neurone Disease (MND), it was 1.39 OR (95%CI 0.67 to 2.53; p = 0.21); for Parkinson's Disease (PD), it was 1.14 OR (95%CI 0.55 to 2.89; p = 0.79). Heterogeneity was reduced following the removal of two studies and the revised risk scores for any neurodegenerative disease; Dementia increased, with that for MND reaching significance, 1.81 OR (95%CI 1.22 to 2.30; p = 0.01), but there remained no association with PD. Evidence suggests that professional football significantly increases the odds of neurodegenerative disease.
Teaching humanities in UK medical schools: towards community-building and coherence
Medical humanities teaching in UK medical schools has lacked cohesion, having developed opportunistically in different locations. Cohesion is necessary to develop an identifiable community of practice, but within that community there can be multiple readings of what ‘medical humanities’ are and how they may develop. This article details discussions held by medical humanities scholars teaching in UK medical schools at a workshop in January 2025 at the University of Oxford covering five key areas: the role of humanities scholars in medical schools, patients as partners in medical education, core curriculum teaching, intercalated teaching, and assessment. Our discussion highlights opportunities and challenges facing humanities teaching in UK medical schools today and calls for the creation of a community of medical humanities scholars working in UK medical education embracing diversity of opinion and practices. The article is specifically written as a synopsis of a brainstorming symposium.
User requirements for quantitative radiological reports in multiple sclerosis
Objectives: Quantitative radiological reports (QReports) can enhance clinical management of multiple sclerosis (MS) by including quantitative data from MRI scans. However, the lack of consensus on the specific information to include, on and clinicians’ preferences, hinders the adoption of these imaging analysis tools. This study aims to facilitate the clinical implementation of QReports by determining clinicians’ requirements regarding their use in MS management. Materials and methods: A four-phase Delphi panel approach was employed, involving neurologists and (neuro)radiologists across Europe. Initial interviews with experts helped develop a questionnaire addressing various QReport aspects. This questionnaire underwent refinement based on feedback and was distributed through the MAGNIMS network. A second questionnaire, incorporating additional questions, was circulated following a plenary discussion at the MAGNIMS workshop in Milan in November 2023. Responses from both questionnaire iterations were collected and analyzed, with adjustments made based on participant feedback. Results: The study achieved a 49.6% response rate, involving 78 respondents. Key preferences and barriers to QReport adoption were identified, highlighting the importance of integration into clinical workflows, cost-effectiveness, educational support for interpretation, and validation standards. Strong consensus emerged on including detailed lesion information and specific brain and spinal cord volume measurements. Concerns regarding report generation time, data protection, and reliability were also raised. Conclusion: While QReports show potential for improving MS management, incorporation of the key metrics and addressing the identified barriers related to cost, validation, integration, and clinician education is crucial for practical implementation. These recommendations for developers to refine QReports could enhance their utility and adoption in clinical practice. Key Points: Question A lack of consensus on essential features for quantitative magnetic resonance imaging reports limits their integration into multiple sclerosis management. Findings This study identified key preferences, including detailed lesion information, specific brain and spinal cord measurements, and rigorous validation for effective quantitative reports. Clinical relevance This study identified essential features and barriers for implementing quantitative radiological reports in multiple sclerosis management, aiming to enhance clinical workflows, improve disease monitoring, and ultimately provide better, data-driven care for patients through tailored imaging solutions.