OBJECTIVE: The objective of this study was to identify clinical predictors of motor complications (dyskinesia and motor fluctuations) of levodopa in a prospectively recruited PD cohort using longitudinal analysis. METHODS: An inception cohort (Oxford Discovery) of 734 patients was followed to a maximum of 10 years from diagnosis using a discrete-time survival analysis. A subset analysis was used to validate an online dyskinesia-risk calculator developed from the results of the Stalevo Reduction in Dyskinesia Evaluation PD trial. RESULTS: A total of 186 cases of dyskinesia and 254 cases of motor fluctuations were observed. Dyskinesia incidence increased with time (risk per 100 participants [95% confidence interval] 13 [11-16] <3.5 years, 16 [13-21] 3.5-5.0 years, 19 [14-26] 5-6.5 years, and 23 [16-33] >6.5 years from diagnosis). Motor complication predictors were grouped as medication predictors, disease predictors and patient predictors. Baseline nonmotor feature severity, low mood, anxiety, and age at symptom onset were associated with motor complications among a number of previously identified predictors. Replication of the Stalevo Reduction in Dyskinesia Evaluation PD calculator was reasonable with the area under the curve for dyskinesia risk score as a predictor of dyskinesia being 0.68 (95% confidence interval, 0.55-0.81). CONCLUSIONS: This study quantifies risk of motor complications, finds consistent predictors, and demonstrates the novel finding that nonmotor features of PD, particularly low mood and anxiety, are significant risk factors for motor complications. Further validation of dyskinesia risk scores are required as well as evidence to determine if the routine use of such scores can be clinically valuable in enhancing patient care and quality of life. \u00a9 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
\n \n\n \n \nIMPORTANCE: Persecutory delusions are common, distressing, and difficult to treat. Testing computational neuroscience models of delusions can identify new therapeutic targets. OBJECTIVE: To determine whether change in delusion severity is associated with a corresponding change in volatility priors and brain activation estimated during a belief updating task. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted from April 9, 2021, to December 5, 2023, within the Vanderbilt University Medical Center Psychiatric Hospital and at a community mental health center in Nashville, Tennessee. Participants were adults (aged between 18 and 65 years) with schizophrenia spectrum or delusional disorder and an active, persistent (\u22653 months) persecutory delusion with strong conviction (>50%). Participants were randomly assigned 1:1 to either cognitive behavioral therapy for psychosis (CBTp)-based intervention or befriending therapy. Intention-to-treat analysis was performed from June 1 to October 31, 2024. INTERVENTION: The CBTp was a manualized intervention targeting persecutory delusions. The befriending therapy involved engaging in conversations and activities focused on neutral topics. Both interventions were provided in person, lasted for 8 weeks, and included standard care. Standard care consisted of medication management and ancillary services. MAIN OUTCOMES AND MEASURES: Primary outcomes were volatility priors (ie, prior expectations of volatility) derived from a 3-option probabilistic reversal learning task; persecutory delusion severity measured by the Psychotic Symptom Rating Scales (PSYRATS delusion subscale; score range: 0-16, with the highest score indicating severe preoccupation, distress, conviction, and functioning impact); and brain activation in the striatum and prefrontal cortex measured by blood oxygenation level-dependent signal change. Associations between volatility priors, clinical improvement, and change in neural activation were examined. RESULTS: Sixty-two participants (median [range] age, 31 [19-63] years; 38 males [61%]) were randomly assigned to the CBTp (n\u2009=\u200932) or befriending therapy (n\u2009=\u200930) arms. A subgroup of 35 participants (57%) completed functional magnetic resonance imaging. Volatility priors decreased following treatment (F1,112\u2009=\u20097.7 [P\u2009=\u2009.006]; Cohen d\u2009=\u20090.52 [95% CI, 0.15-0.90]), as did delusion severity (F1,112\u2009=\u200959.7 [P\u2009
\n \n\n \n \nPsychological literature indicates that actions performed with the assistance of cognition-enhancing biomedical technologies are often deemed to be less praiseworthy than similar actions performed without such assistance. This study examines (i) whether this result extends to the bioenhancement of moral capacities, and (ii) if so, what explains the effect of moral bioenhancement on perceived praiseworthiness. The findings indicate that actions facilitated by morally bioenhanced individuals are considered less deserving of praise than similar actions facilitated by 'traditional' moral enhancement-for example, moral self-education. This diminished praise does not seem to be driven by an aversion to (moral) bioenhancement per se. Instead, it appears to be primarily attributable to a perceived lack of effort exerted by bioenhanced individuals in the course of their moral enhancement. Our findings advance the philosophical discourse on the foundations of praise in the context of moral bioenhancement by elucidating the empirical basis underlying some assumptions commonly employed to argue for or against the permissibility of moral bioenhancement.
\n \n\n \n \nPurpose: The purpose of this study was to characterize retinal structure in patients with late-stage inherited retinal diseases (IRD) for their suitability for optogenetic gene therapy. Methods: This was a retrospective study using clinical data and spectral-domain optical coherence tomography (SD-OCT) images of patients with late-stage IRD (visual acuity \u2264 1.0), between December 2012 and 2023 from Oxford Eye Hospital, United Kingdom. Depending on the clinical phenotype and history, the patients were divided into three groups: rod-cone dystrophy (group 1), cone-rod/cone dystrophy (group 2), and macular dystrophy (group 3). SD-OCT structural parameters including total subfoveal thickness and, if possible, individual inner layers thickness were analyzed. Results: 36 patients with late-stage IRD (11, 13, and 12 in groups 1, 2, and 3) and 54 eyes (18 per group) with mean age of 55.9 \u00b1 9.8 years and mean visual acuity of 1.72 \u00b1 0.66 were analyzed. Mean subfoveal thickness was reduced to 167.8 \u00b1 54.3, 153.2 \u00b1 65.3, and 138.1 \u00b1 41.7 \u03bcm in groups 1, 2, and 3, respectively, with no significant difference among each group (P = 0.33). Twenty-five of 54 eyes had well-defined inner retinal layers with mean subfoveal thickness of nerve fiber, ganglion cell, inner plexiform, and inner nuclear layers were 12.6 \u00b1 3.9, 17.3 \u00b1 9.9, 18.6 \u00b1 6.7, and 29.4 \u00b1 11.3 \u03bcm, respectively. Conclusions: In our cohort, 46.3% of degenerate retinae had preservation of the inner retina, including nerve fiber, ganglion cell, and inner plexiform layers, and/or thickening of the inner nuclear layer and may benefit from targeted cell-specific optogenetic gene therapy. Patients with indiscernible or disrupted inner layers may be amenable to a noncell-specific approach, to target all surviving neurons. Translational Relevance: SD-OCT structural characterization of different groups of latestage IRD offers insight into vector selection and patient eligibility for optogenetic treatments.
\n \n\n \n \nBackground: Tongue squamous cell carcinoma (TSCC) is an aggressive cancer associated with a poor prognosis and limited treatment options, necessitating new drug targets to improve therapeutic outcomes. Our current work studies protein tyrosine kinases as well-known targets for successful cancer therapies. It focuses on Src family kinases (SFK), which are known to play a critical role in some head and neck tumors. Methods: Western blot analyses of phospho-tyrosine protein patterns in 34 TSCC lines facilitated the investigation of SFK as contributors to these phosphorylations. The SFK inhibitors PP2 and Dasatinib were utilized to determine SFK contributions to cell motility and survival. A high-throughput screen with 1600 FDA-approved drugs was performed with three TSCC lines to discover drugs that act synergistically with Dasatinib against TSCC cell viability. Glucocorticoids emerged as potential candidates and were further investigated in 2D culture and by 3D soft agar colony formation. Dexamethasone was chosen as the major tool for our analyses of synergistic effects of Dasatinib and glucocorticoids on TSCC lines. Effects on the cell cycle were investigated by flow cytometry and expression levels of cell cycle regulators. Senescence was analyzed by senescence-associated \u03b2 galactosidase detection and p27Kip1 protein expression. Autophagy was measured by Acridine Orange staining. Results: A panel of 34 TSCC lines showed a surprisingly homogenous pTyr-protein pattern and a prominent 130 kDa pTyr-protein. Inhibition of SFK activity greatly reduced overall pTyr-protein levels and p130Cas tyrosine phosphorylation. It also impaired TSCC viability in 2D cell culture and 3D soft agar colony formation. A high-throughput drug combination screen with Dasatinib identified glucocorticoids as promising candidates for synergistic activity. Dasatinib and Dexamethasone combination treatment showed strong synergistic effects on Src and p130Cas phosphorylation and led to reduced p130Cas expression. Dexamethasone also suppressed phosphorylation of the MET kinase and its key substrate Gab1. On the cellular level, Dasatinib combination with glucocorticoids led to G1 cell cycle arrest, appeared to increase senescence and enhanced autophagy. This was also reflected by effects on cell cycle regulatory proteins, including CDKs and cyclins. Conclusion: This work is the first to show a strong synergistic activity of Dasatinib in combination with clinically used glucocorticoids in solid tumors. Furthermore, the tyrosine kinase MET and its effector protein Gab1 are newly identified glucocorticoid targets. Given the extensive research on MET as a drug target in various cancers, our findings have the potential to advance future cancer treatments.
\n \n\n \n \nThe dorsal raphe nucleus (DRN) is an important source of serotonin in the brain, but fundamental aspects of its function remain elusive. Here, we present a combination of minimally invasive recording and disruption studies to show that DRN brings about changes in motivation states. We use recently developed methods for identifying temporal patterns in behavior to show that monkeys change their motivation depending on the availability of rewards in the environment. Distinctive patterns of DRN activity occur when monkeys transition between a high-motivation state occupied when rewards are abundant, to a low-motivation state engendered by reward scarcity. Disrupting DRN diminishes sensitivity to the reward environment and perturbs transitions in motivational states.
\n \n\n \n \nNavigating social environments is a fundamental challenge for the brain. It has been established that the brain solves this problem, in part, by representing social information in an agent-centric manner; knowledge about others' abilities or attitudes is tagged to individuals such as 'oneself' or the 'other'1-6. This intuitive approach has informed the understanding of key nodes in the social parts of the brain, the dorsomedial prefrontal cortex (dmPFC) and the anterior cingulate cortex (ACC)7-9. However, the patterns or combinations in which individuals might interact with one another is as important as the identities of the individuals. Here, in four studies using functional magnetic resonance imaging, behavioural experiments and a social group decision-making task, we show that the dmPFC and ACC represent the combinatorial possibilities for social interaction afforded by a given situation, and that they do so in a compressed format resembling the basis functions used in spatial, visual and motor domains10-12. The basis functions align with social interaction types, as opposed to individual identities. Our results indicate that there are deep analogies between abstract neural coding schemes in the visual and motor domain and the construction of our sense of social identity.
\n \n\n \n \nDiverse individual energy-budgeting tactics within wild populations provide resilience to natural fluctuations in food availability and expenditure costs. Although substantial heterogeneity in activity-related energy expenditure has been documented, few studies differentiate between responses to the environment and inter-individual differences stemming from life history, allometry, or somatic stores. Using tri-axial accelerometry, complemented by diet analysis, we investigated inter-individual within-season variation in overall dynamic body acceleration (ODBA; activity intensity measure) and \"Activity\" (above an ODBA threshold) in a high-density population of European badgers (Meles meles). Weather (including wind speed) affected ODBA and activity according to predictors of earthworm (food) availability and cooling potential. In spring, maximal ODBA expenditure at intermediate rainfall and temperature values suggested that badgers traded foraging success against thermoregulatory losses, where lower-condition badgers maintained higher spring ODBA irrespective of temperature while badgers in better body condition reduced ODBA at colder temperatures. Conversely, in summer, lower-condition badgers modulated ODBA according to temperature, likely in response to super-abundant food supply. Between 35% (spring, summer) and 57% (autumn) of residual total daily ODBA variance related to inter-individual differences unexplained by seasonal predictors, suggesting within-season tactical activity typologies. We propose that this heterogeneity among individual energy-expenditure profiles may contribute to population resilience under rapid environmental change.
\n \n\n \n \nBackground: \u03b1-synuclein seed amplification assay (SAA) positivity has been proposed as a diagnostic biomarker for Parkinson's disease. However, studies of the prognostic value of this biomarker have been limited to small, single-centre studies over short follow-up periods. We aimed to assess the diagnostic and prognostic value of quantitative CSF \u03b1-synuclein SAA kinetic measures in Parkinson's disease. Methods: In this longitudinal cohort study, we collected and analysed data from participants with Parkinson's disease, progressive supranuclear palsy, and healthy controls enrolled in three cohorts: the UK parkinsonism cohort, the Parkinson's Progression Markers Initiative (PPMI) international observational study, and the T\u00fcbingen Parkinson's disease cohort. Baseline CSF \u03b1-synuclein SAA data and longitudinal clinical data were collected between Jan 1, 2005, and Nov 1, 2023. The following seeding kinetic measures were calculated from the \u03b1-synuclein SAA curve for each SAA-positive sample: time to threshold (TTT) for a positive SAA result; maximum Thioflavin T fluorescence during the reaction time (MaxThT); and area under the fluorescence curve during the reaction time (AUC). We compared seeding kinetic measures between sporadic Parkinson's disease and progressive supranuclear palsy, and between sporadic Parkinson's disease and monogenic Parkinson's disease. We used time-to-event analyses to assess the ability of \u03b1-synuclein SAA kinetic measures to predict an unfavourable outcome in Parkinson's disease, adjusting for sex, age, and disease duration at SAA testing. Findings: We analysed data from 1631 participants: newly generated data from the UK parkinsonism cohort (Parkinson's disease, n=66; progressive supranuclear palsy, n=52; controls, n=9) and previously generated data from the PPMI (Parkinson's disease, n=1036; controls, n=239) and T\u00fcbingen (Parkinson's disease, n=229) cohorts. In the UK parkinsonism cohort, \u03b1-synuclein SAA was positive in 63 (96%) of 66 Parkinson's disease samples and eight (15%) of 52 progressive supranuclear palsy samples, with six (75%) of eight positive progressive supranuclear palsy samples having distinct low and slow seeding kinetics (low MaxThT and high TTT) as a marker of Lewy body co-pathology. TTT was faster in GBA1-associated Parkinson's disease compared with sporadic Parkinson's disease in both the PPMI (p=0\u00b704) and T\u00fcbingen (p=0\u00b701) cohorts. In the PPMI cohort, after excluding individuals who had an unfavourable outcome at the time of baseline SAA testing, an unfavourable outcome was observed in 593 (73%) of 810 participants with \u03b1-synuclein SAA-positive Parkinson's disease during a median follow-up period of 4\u00b75 years (IQR 2\u20139). TTT at baseline predicted only cognitive decline (Montreal Cognitive Assessment score \u226421) as a component of an unfavourable outcome in Parkinson's disease in both the PPMI (n=824, hazard ratio [HR] 2\u00b736 [95% CI 1\u00b760\u20133\u00b746], p=0\u00b7001) and T\u00fcbingen (n=135, 2\u00b717 [1\u00b707\u20134\u00b741], p=0\u00b703) cohorts. TTT also predicted cognitive decline in a subgroup of participants with Parkinson's disease in the PPMI cohort who were Alzheimer's disease biomarker negative (n=355, HR 1\u00b780 [95% CI 1\u00b703\u20133\u00b718], p=0\u00b704). Interpretation: Assessing \u03b1-synuclein SAA kinetic measures might aid in the diagnostic differentiation of Parkinson's disease from progressive supranuclear palsy with Lewy body co-pathology. Furthermore, faster seeding kinetics are found in GBA1-Parkinson's disease and predict cognitive decline in Parkinson's disease independently of Alzheimer's disease co-pathology. Funding: Medical Research Council, PSP Association. Copyright: \u00a9 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
\n \n\n \n \nThe ability of cerebrovasculature to respond to meet tissue demands is vital for normal brain function and health. Cerebrovascular reactivity (CVR), a measure of the responsiveness of cerebrovasculature to vasoactive stimuli, is a valuable tool for evaluating cerebrovascular health. While CVR is commonly assessed using transcranial Doppler ultrasound (TCD), which measures blood velocity, or MRI-based techniques such as blood oxygenation level-dependent (BOLD) imaging, which reflect changes in blood oxygenation, direct comparisons between these modalities remain limited, particularly with stimuli that induce a large dynamic range. Because both methods capture hypercapnia-induced vascular changes, we hypothesised that their CVR metrics may be correlated. This study evaluates inter-modality correlations of CVR using TCD and BOLD-fMRI extracted from the MCA territory (parietal lobe) during a ramped hypercapnic protocol and different modelling strategies. Linear correlations across broad PETCO2 ranges validated the utility of linear CVR modelling in capturing repeatable metrics using TCD and MRI. A four-parameter sigmoid model revealed significant inter-modality variability in span and bound parameters, improved by fixing these parameters and focusing on slope and inflection point, which enhanced the correlations between modalities. These results support the reliability of linear CVR modelling within narrow vasoactive response ranges in healthy subjects and propose a simplified two-parameter sigmoid model as an effective framework for characterising non-linear CVR dynamics. This work adds to the sparse literature on inter-modality CVR comparisons and indicates which CVR metrics are comparable between TCD and BOLD-fMRI, emphasising CVR as a useful tool for assessing cerebrovascular health in research and clinical contexts.
\n \n\n \n \nIntrathecal synthesis of central nervous system (CNS)-reactive autoantibodies is observed across patients with autoimmune encephalitis (AE), who show multiple residual neurobehavioral deficits and relapses despite immunotherapies. We leveraged two common forms of AE, mediated by leucine-rich glioma inactivated-1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies, as human models to comprehensively reconstruct and profile cerebrospinal fluid (CSF) B cell receptor (BCR) characteristics. We hypothesized that the resultant observations would both inform the observed therapeutic gap and determine the contribution of intrathecal maturation to pathogenic B cell lineages. From the CSF of three patients, 381 cognate-paired IgG BCRs were isolated by cell sorting and scRNA-seq, and 166 expressed as monoclonal antibodies (mAbs). Sixty-two percent of mAbs from singleton BCRs reacted with either LGI1 or CASPR2 and, strikingly, this rose to 100% of cells in clonal groups with \u22654 members. These autoantigen-reactivities were more concentrated within antibody-secreting cells (ASCs) versus B cells (P < 0.0001), and both these cell types were more differentiated than LGI1- and CASPR2-unreactive counterparts. Despite greater differentiation, autoantigen-reactive cells had acquired few mutations intrathecally and showed minimal variation in autoantigen affinities within clonal expansions. Also, limited CSF T cell receptor clonality was observed. In contrast, a comparison of germline-encoded BCRs versus the founder intrathecal clone revealed marked gains in both affinity and mutational distances (P = 0.004 and P < 0.0001, respectively). Taken together, in patients with LGI1 and CASPR2 antibody encephalitis, our results identify CSF as a compartment with a remarkably high frequency of clonally expanded autoantigen-reactive ASCs whose BCR maturity appears dominantly acquired outside the CNS.
\n \n\n \n \nChildhood adversity and adulthood adversity affect cognition later in life. However, the mechanism through which adversity exerts these effects on cognition remains under-researched. We aimed to investigate if the effect of adversity on cognition was mediated by distress or neuroticism. The UK Biobank is a large, population-based, cohort study designed to investigate risk factors of cognitive health. Here, data were analysed using a cross-sectional design. Structural equation models were fitted to the data with childhood adversity or adulthood adversity as independent variables, distress and neuroticism as mediators and executive function and processing speed as latent dependent variables that were derived from the cognitive scores in the UK Biobank. Complete data were available for 64,051 participants in the childhood adversity model and 63,360 participants in the adulthood adversity model. Childhood adversity did not show a direct effect on processing speed. The effect of childhood adversity on executive function was partially mediated by distress and neuroticism. The effects of adulthood adversity on executive function and processing speed were both partially mediated by distress and neuroticism. In conclusion, distress and neuroticism mediated the deleterious effect of childhood and adulthood adversity on cognition and may provide a mechanism underlying the deleterious consequences of adversity.
\n \n\n \n \nData discovery, the ability to find datasets relevant to an analysis, increases scientific opportunity, improves rigour and accelerates activity. Rapid growth in the depth, breadth, quantity and availability of data provides unprecedented opportunities and challenges for data discovery. A potential tool for increasing the efficiency of data discovery, particularly across multiple datasets is data harmonisation.A set of 124 variables, identified as being of broad interest to neurodegeneration, were harmonised using the C-Surv data model. Harmonisation strategies used were simple calibration, algorithmic transformation and standardisation to the Z-distribution. Widely used data conventions, optimised for inclusiveness rather than aetiological precision, were used as harmonisation rules. The harmonisation scheme was applied to data from four diverse population cohorts.Of the 120 variables that were found in the datasets, correspondence between the harmonised data schema and cohort-specific data models was complete or close for 111 (93%). For the remainder, harmonisation was possible with a marginal a loss of granularity.Although harmonisation is not an exact science, sufficient comparability across datasets was achieved to enable data discovery with relatively little loss of informativeness. This provides a basis for further work extending harmonisation to a larger variable list, applying the harmonisation to further datasets, and incentivising the development of data discovery tools.
\n \n\n \n \nNeurodegenerative diseases of the brain pose a major and increasing global health challenge, with only limited progress made in developing effective therapies over the last decade. Interdisciplinary research is improving understanding of these diseases and this article reviews such approaches, with particular emphasis on tools and techniques drawn from physics, chemistry, artificial intelligence and psychology.
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