Posters

Background: Regional cerebral blood flow (CBF) abnormalities have been reported in schizophrenia, including increased CBF in subcortical and temporal regions and reductions in frontal, parietal, and occipital cortices. In first-episode psychosis (FEP), striatal CBF has been shown to rise during early treatment with aripiprazole, but it is unclear if this applies to other antipsychotics. Baseline CBF may predict clinical outcomes, with higher frontal CBF linked to greater symptom improvement. However, few studies have examined these associations using MRI-based CBF measures. This study investigated changes in regional CBF during antipsychotic treatment and their relationship to symptom improvement.

Methods: CBF data from two FEP cohorts (STRATA, n=34; OPTIMISE, n=22) were combined. Participants underwent pCASL MRI at baseline and follow-up (weeks 2–6). STRATA participants received various antipsychotics; OPTIMISE participants received amisulpride. CBF was measured in the anterior cingulate cortex (ACC), striatum, hippocampus, and thalamus. Analyses used harmonized data and linear mixed models.

Results & Discussion: Symptoms improved significantly, but no longitudinal CBF changes were detected. Dose correlated with ACC and thalamic CBF, but associations with symptoms were nonsignificant after correction. Baseline CBF did not predict improvement. Variability in prior medication and antipsychotic type may explain the absence of clear effects.

Background: Current biomarker candidates of psychosis risk are informative but lack clinical utility beyond the group level. Mechanistic specificity at the individual-level is required. The 20Hz auditory steady-state response (20HzASSR) elicits both a 20Hz and 40Hz steady-state harmonic response (40HzSSHR), indexing SST+ and PV+ interneurons that stabilise pyramidal output. Disruption of this coordination is central to excitation/inhibition imbalance models of schizophrenia and directly linked to perceptual abnormalities (PAs), a core feature of psychosis and clinical high risk (CHR). Here, 20-40Hz co-modulation was examined to test whether this relationship could be indexed using EEG and whether predict PA outcomes.

Methods: Electroencephalogram (EEG) was recorded from CHR (CHR-S,n=15) with persistent attenuated psychotic symptoms at 1 year follow-up (FU) and healthy controls (HC,n=17) during 20Hz stimulation. 20HzASSR and 40HzSSHR amplitudes (0-750ms) were extracted. Co-modulation was quantified by regression of 40HzSSHR on 20HzASSR, with cluster-based permutation testing and prospective prediction of 1-year outcomes.

Results: 20HzASSR was reduced in CHR-S vs HC (U=185,p=.031,r=-.45); 40HzSSHR (ns). The 20-40 relationship was positive in HC (r=0.54,p=.025) but negative in CHR-S (r=-0.33,n.s.), with significant contrast (z=2.40,p=.016). Dynamic slope analysis identified 325-645ms divergence (p_cluster=.036), HC=0.155 vs CHR-S=-0.120 (t=2.38,p=.027,d=0.87). Baseline slopes predicted FU-PAs (β=-1.41,p=.033,R²=.238). Conclusions: Cross-frequency co-modulation, rather than amplitude alone, differentiates CHR-S from HC and predicts future PAs. This provides preliminary evidence that the 20-40 relationship may serve as an EEG Index of Circuit Instability (E-ICI) at the individual-level. Following validation, the E-ICI may serve as a mechanistically interpretative biomarker with potential for early risk stratification, monitoring, and treatment development.

Background: Mobile apps can support children and young people’s (CYP) mental health, but sustaining engagement, especially among those with higher needs, remains difficult. This study examined engagement with MindCraft, a mental health app using artificial intelligence (AI)-based nudges and both active (self-report) and passive (sensor) tracking. It assessed whether engagement differed by Strengths and Difficulties Questionnaire (SDQ) risk level and intervention group.

Aim(s): • To examine how baseline mental health influences engagement with active and passive tracking and AI nudges. • To compare engagement across three intervention groups over time. - Methods: 130 adolescents (aged 14–18) from London schools completed baseline questionnaires, installed MindCraft, and were randomly assigned to intervention, active control, or control groups. Engagement over three weeks was measured via active tracker use, passive data sharing, AI nudge completion, and total app use days. Data were compared by SDQ risk level and intervention arm.

Results: No significant engagement differences were found by risk group (p > .076) or intervention arm (p > .083). Passive data sharing was moderate, while active engagement varied widely between individuals. The sample was demographically skewed and mostly low risk, limiting generalisability. - Conclusion: Adolescent engagement with mobile interventions appears more influenced by personal, contextual, and behavioural factors than by mental health risk or intervention type. The absence of group differences highlights the need to better understand adolescents’ digital preferences and barriers. Future research should extend monitoring periods, recruit more diverse samples, and adopt participatory design to enhance the relevance and impact of mental health apps.

Background: Personalised dosing of anti-CD20 disease modifying therapies for neurological conditions, including multiple sclerosis (MS), offers benefits but requires frequent and costly CD19 B-cell monitoring, using in-person whole-blood sampling. Remote dried blood spot (DBS) sampling could widen access to personalised dosing.

Aims: To evaluate the acceptability, feasibility, and costs of remote DBS sampling, compared to conventional blood sampling. Methods: 1) Capitainer-B50 (DBS) and venous blood samples were collected from people with MS to compare CD19 estimates. 2) Remote DBS packages were sent to MS patients. Returned samples were analysed for suitability, and questionnaires assessed for satisfaction.

Results: 3.4% of conventional lymphocyte-subset tests were unprocessed due to laboratory errors or delayed arrivals. In clinic, 72% of samples were successfully collected using one device. 11% required multiple devices. 17% were unsuccessful. Of 16 remote samples returned, 12 were sufficient for analysis. 53.8% of respondents preferred remote DBS sampling compared to in-person blood sampling. Of 34 samples collected in clinic, CD19 counts strongly correlated with FACS (R2=0.91), with 100% sensitivity and 81.3% specificity at <10 B-cell/uL. The mean turnaround time from posting remote samples to receiving results was 21.7 days, demonstrating postal feasibility. Costs of DBS sampling to support personalised dosing of ocrelizumab, based on n=50 and decreased annual infusion rate from 2 to 1.5, would result in £7,200 saving per patient.

Conclusions: Remote DBS sampling is accepted by patients, feasible, and provides comparable results to venous sampling. Its wider implementation has potential to improve patient convenience and reduce healthcare costs.

INTRODUCTION: Child maltreatment (CM) and adult partner violence correlate with late-onset dementia and mid-life risk factors. Yet, their associations with age at diagnosis and risk of young-onset dementia (YOD) remain unclear.

METHODS: Among 147,938 UK Biobank participants, we identified Alzheimer's-related, vascular, and frontotemporal dementia cases. We examined associations between CM, adult partner violence, age-at-diagnosis, and YOD (diagnosed age 68 years or younger). Weibull accelerated failure time models estimated time from age 18 to diagnosis. Single-mediator and sequential causal mediation models tested CM-YOD direct effects, indirect effects of partner violence and 22 risk factors, and proportions mediated.

RESULTS: Of 915 cases, 128 were YOD. Individuals exposed to CM and partner violence received a dementia diagnosis younger than unexposed participants. CM was associated with YOD (Adjusted OR: 1.51; 95% CI: 1.01, 2.29), with partner violence, socioeconomic deprivation, alcohol excessive consumption, and BMI >30kg/m2, cumulatively mediating 78% of the association. DISCUSSION: Preventing violence and modifying mid-life risk factors may delay dementia.

Introduction: DNA methylation may mediate interactions between genetic and environmental risk factors in Alzheimer’s disease (AD). Previous AD epigenome-wide association studies (EWASs) have largely relied on 450K arrays and have not systematically examined APOE genotype. We conducted EWAS meta-analyses using the EPIC array (≈800K CpGs) to examine associations between DNA methylation, APOE genotype (ε4 risk and ε2 protective variants), and neurofibrillary tangle Braak stage in post-mortem human prefrontal cortex.

Methods: Four post-mortem brain cohorts with matched EPIC array, APOE genotype and Braak stage data were analysed. After quality control, normalisation, and confounder adjustment, EWASs were performed for APOE ε4 carriers vs non-carriers (n=1,308; excluding ε2: n=1,198) and ε2 carriers vs non-carriers (n=1,308; excluding ε4: n=731), followed by fixed- and random-effects meta-analyses. Braak stage analyses compared “controls” (Braak 0–II) with “AD cases” (V–VI) across three cohorts (n=846). Inflation was controlled using Bacon correction and surrogate variables. Differentially methylated positions (DMPs) were prioritised based on Bonferroni significance and differentially methylated regions (DMRs) were identified using comb-p.

Results: Meta-analyses identified 8 Bonferroni-significant DMPs associated with ε4 and 2 with ε2. Signals mapped primarily to the extended APOE locus (including APOC1 and TOMM40). Danalysis identified two ε4-associated regions at the APOE/APOC1 locus and one ε2-associated Dat the CAT promoter. The Braak stage meta-analysis identified 167 Bonferroni-significant DMPs, implicating established AD genes (e.g. SPI1, CSF1R, RIN3) and 121 DMRs. Conclusions: This study provides a comprehensive epigenetic meta-analysis of APOE genotype and Braak stage, revealing both APOE-proximal and broader AD-associated methylation changes.

Stroke is a leading cause of disability, with approximately 30% of ischaemic stroke survivors developing post-stroke pain (PSP). PSP is a chronic neuropathic pain condition, yet research into its underlying molecular and cellular mechanisms remains limited. Calcitonin gene-related peptide (CGRP) has been implicated in nociceptive signalling in neuropathic pain conditions; mitogen-activated protein kinases (MAPKs) in post-ischaemic inflammatory injury; and sustained glial activation in the maintenance of chronic pain states. Matrix metalloproteinase-9 (MMP9) has also been associated with post-stroke neuroinflammation and neuropathic pain. However, the contribution of these pain-related pathways to PSP has yet to be investigated.

This study aimed to characterise neuropathic pain mechanisms in a mouse model of PSP. Male and female C57BL/6 mice underwent permanent ischaemia induced by distal occlusion of the left middle cerebral artery (pMCAO). Dorsal root ganglia, spinal cord, and thalamic tissue were collected 28 days post-injury to assess changes in peripheral and central nociceptive pathways. Immunofluorescence analysis was performed using markers for CGRP, pERK, pP38, Iba1, GFAP, and MMP9. Imaging was conducted using a Leica DMi8 microscope and quantified using FIJI software.

Increased sensitivity in response to no painful mechanical stimulation was observed only contralateral to the site of injury. Similarly, expression of pain-related molecular markers was significantly increased in contralateral dorsal root ganglion, spinal cord, and thalamic tissue following pMCAO.

These findings highlight coordinated peripheral and central molecular changes underlying PSP and provide mechanistic insight into pathways that may represent future therapeutic targets for post-stroke neuropathic pain.

Background: People living with dementia (PLWD) experience frequent emergency admissions, occupying up to 25% of NHS beds at any time. Improved understanding of admission patterns is needed to predict care needs and prevent avoidable admissions, improving care planning and patient outcomes.

Methods: We analysed anonymised electronic health records for n=220,010 individuals (n=31,573 PLWD) in the Discover-NOW/WSIC dataset, comprising data from 3 million individuals across eight boroughs in North West London. Emergency admissions were propensity-matched 1:1 on age, sex, deprivation, and ethnicity between PLWD and controls (CON). We quantified demographic determinants affecting admission risk, the proportion of bed days attributed to different causes of admission, and outcomes of readmission and mortality following discharge.

Results: Across 108,694 admissions in 2017-2024, PLWD experienced 965,691 bed-days (4,024 per 1000 person-years). This was 30% greater than in matched controls over the same number of admissions (745,759 bed-days; 3,108 per 1000 person-years). Infections were the primary cause for the greatest proportion of bed-days in PLWD (37.1%;27.1% CON), followed by injury (15.4% PLWD;15.0% CON). Upon discharge, 6-month mortality was greater in PLWD than matched controls (Overall HR=1.44, 95%CI=[1.39-1.49], p<0.001), and particularly high in deprived individuals (Deprivation quintile (continuous): 0.99[0.98-0.99], p<0.0001; higher quintile=less deprived).

Conclusion/Impact: PLWD experience longer emergency admissions and worse outcomes, effects compounded by socioeconomic inequalities. More than half (52%) of emergency bed-days in PLWD are due to potentially preventable infections and injury. Proactive prevention, e.g. digital monitoring and community support, may substantially reduce NHS burden.

Background: Cerebral microbleeds (CMBs) are common in Parkinson’s disease (PD) and Lewy body dementia (LBD). Ultra-high field 7T MRI improves CMB detection compared with 1.5T, but whether it provides meaningful additional sensitivity over 3T MRI, and whether this has clinical relevance, remains unclear. We compared 7T and 3T MRI for CMB detection in PD and LBD and examined associations with clinical measures.

Methods: 72 participants were included: PD without dementia (PD-NC, n=45), LBD (n=8), controls (HC, n=19). All underwent both 3T and 7T MRI. SWI was used for visual detection of CMBs, quantified using the Microbleed Anatomical Rating Scale (MARS). Sensitivity of 3T versus 7T MRI for CMB was compared, and relationship between CMB and cognitive and motor performance assessed.

Results: At 3T, 84 CMBs were detected in 17 participants (4 LBD, 9 PD-NC, 4 HC). At 7T, 109 CMBs were detected in 21 participants (3 LBD, 9 PD-NC, 8 HC), representing a 30% increase. Seven participants (2 PD-NC, 4 HC, 1 LBD) showed CMBs only at 7T. These lesions were either too small to be resolved at 3T or could not be reliably distinguished from background signal. No associations were observed between CMB burden and cognitive or motor performance at either field strength.

Conclusion: 7T MRI showed a slightly higher sensitivity in detecting CMBs compared to 3T in PD and DLB. At neither field-strength, an association was found between CMB quantity and cognitive or motor performance.

Background: Anxiety is frequent in Parkinson’s disease (PD), and may relate to pathological changes in fear and limbic circuits. The hippocampus and amygdala, key structures in these circuits affected in PD, may underlie PD-related anxiety. This study examines the changes in volume in hippocampal subregions and the amygdala in anxious PD patients.

Methods: 45 PD participants and 45 healthy controls were divided into anxious and non-anxious participants (PDA/PDN; HCA/HCN) based on GAD-7 scores. Volumes of automatically segmented hippocampal subregions and the amygdala, measured via 3T MRI as ratio of ROI volume (%00) to TIV, were compared using ANCOVAs (covariates: age, gender, total intracranial volume (TIV)). Correlations with anxiety severity (GAD-7, PAS) were assessed.

Results: The right fimbria was smaller in PDA (0.39%00) compared to both PDN (0.42%00) and HCA (0.41%00). The left fimbria was smaller in PDA (0.40%00) versus HCA (0.49%00). The right HATA was smaller in PDA (0.34%00) versus HCA (0.34%00), but larger when compared to PDN (0.31%00). In PD groups, higher anxiety severity correlated negatively with smaller left fimbria (GAD-7: r=-0.43; PAS: r=-0.35) and left HATA volumes (GAD-7: r=-0.46). No correlations between anxiety and subregion volumes were observed in controls.

Conclusion: To our knowledge, the association between reduced fimbria volume and PD-related anxiety is a novel finding. As the fimbria is a pivotal white matter pathway within the Papez circuit, its disruption may impair emotional regulation, contributing to PD-related anxiety. This supports a disease-specific pathological basis for anxiety in PD, rather than a reactive psychological response to diagnosis.

Introduction: In this work, we combine in-vivo ultra-high resolution 7T quantitative MRI (qMRI) metrics with molecular information from ex-vivo spatially resolved transcriptomics (SRT) data across cortical depths.

Methods: qMRI metrics were extracted from dorsolateral prefrontal cortical (DLPFC) layers in Parkinson’s disease (PD) and controls in-vivo. Glial cell-type counts, and myelin, iron, mineral, and lipid gene ontology (GO) pathway scores were quantified across DLPFC layers from post-mortem SRT data. Significant associations between qMRI and SRT values were examined. Leave-one-out cross validation (LOO-CV) was completed. qMRI metric differences between PD and controls were assessed. PD SRT score projections were generated. Gene set enrichment analysis was run on bulk RNAseq data. Glucosylceramide (GlcCer) was quantified.

Results: There were multiple significant associations between qMRI metrics and SRT-derived cell counts and GO pathways. LOO-CV was able to reliably predict SRT-derived scores from qMRI data. PD had lower MTsat and R1 versus controls in SpD1 of the DLPFC. PD-projected GO pathway scores were significantly lower for “regulation of oligodendrocyte differentiation”, and “glycolipid binding”. Bulk RNA-sequencing dataset showed oligodendrocyte maturation genes were significantly downregulated in PD versus controls. Lipidomic analysis revealed decreases in glycolipid precursor (GlcCer) concentration in PD superficial cortex.

Conclusions: We infer molecular features of neurodegenerative disease in-vivo using qMRI. In PD, we found decreases in myelin- and lipid-sensitive qMRI metrics, and a projected decrease in oligodendrocyte differentiation and glycolipid binding pathway scores, and found corresponding changes in independent post-mortem cohorts. This approach has potential to transform our understanding of neurodegenerative disease in living individuals.

Background: Pituitary adenomas are common intracranial tumours that may compress adjacent neurovascular structures, including the optic apparatus and pituitary stalk. Accurate delineation of the tumour and surrounding anatomy is critical for neuro-oncological surgical planning; however, manual segmentation is time-consuming and subject to inter-observer variability. Although contrast-enhanced MRI is frequently used, contrast administration is not always feasible, and imaging protocols vary substantially across centres.

Methods: Automated segmentation of pituitary adenomas and clinically relevant surrounding structures was evaluated using routinely acquired T1-weighted MRI. Models were trained and tested under pre-contrast, post-contrast, and mixed contrast conditions, using training datasets of 15, 26, and 52 cases. Segmentation accuracy was quantified using Dice similarity coefficients. Cross-contrast experiments were performed to assess robustness to variation in contrast protocols.

Results: For tumour segmentation, Dice scores ranged from approximately 0.67 to 0.73 across contrast conditions at the largest training size, with no statistically significant differences between pre-contrast, post-contrast, and mixed-contrast training when testing conditions were matched. Segmentation of the optic apparatus achieved Dice scores of approximately 0.47–0.57 at higher training volumes. Increasing training dataset size reduced performance variability and improved cross-contrast robustness, with absolute Dice performance gaps decreasing by up to ~75% between the smallest and largest training cohorts. Mixed-contrast training consistently demonstrated improved generalisation across contrast protocols.

Conclusion: Clinically meaningful automated segmentation of pituitary adenomas and adjacent critical structures can be achieved without dependence on contrast-enhanced MRI. Contrast-robust approaches may support wider clinical adoption of automated tools for surgical planning, particularly in heterogeneous imaging environments and resource-limited settings.

Background: Alzheimer’s Disease (AD) is the most common form of dementia and a leading contributor to global mortality. Brain volume changes are used to aid diagnosis as they are both non-invasive and widely used clinically. The rate of brain atrophy on MRI scans can be accurately quantified using Boundary Shift Integrals (BSI). When applied in longitudinal scans, they are preferable to cross-sectional scans due to their ability to provide a more individualised reference, however the need to wait for repeat scans delays prognostication. To address this problem, we explored the possibility of using supervised machine learning models to accurately predict the rate of brain atrophy in patients with AD, using BSI, from baseline T1-weighted MRI scans during first presentation.

Methods: T1-weighted baseline MRI scans from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were used to train the following machine learning models, Random Forest, Ridge Regression and Support Vector Regression, to predict 12-month BSI outcomes. 10-fold cross validation, R2 (Coefficient of Determination) score, was used to compare the accuracy of predicting Ventricular BSI (1555 scans), Whole-brain BSI (1563 scans).

Results: Average cross-validated prediction performance for Ventricular BSI (VBSI) was significantly higher (R2 score of 0.38, 95% CI 0.36-0.41) than that for Whole-brain BSI (0.23, 95% CI 0.21-0.25).

Conclusion: We found that predictions with Ventricular BSIs were more accurate than Whole-brain BSIs, however overall model performance remains insufficient following cross-validation. Future work should consider incorporation of additional clinical, biomarker and genomic data to better capture the complexity of neurodegeneration in AD.

Background: Our previous work demonstrated that electroencephalogram (EEG) slowing predicts accelerated cognitive aging, increased neurodegenerative disease risk, and earlier all-cause mortality in the general population. Building on this, we hypothesised EEG slowing may serve as a neural marker of overall biological aging. Here we investigate whether EEG slowing predicts accelerated biological aging, measured by two second-generation epigenetic clocks (DNAm PhenoAge and GrimAge2), and more rapid development of aging-related health outcomes, including physical frailty and multimorbidity.

Methods: 10,624 adults (ages 36-96) from five population-based cohorts underwent EEG at baseline and were followed over 15-years. Theta-to-alpha ratio (TAR) was calculated using spectral analysis from 3-minutes of resting EEG. Multivariable regression models examined whether higher TAR at baseline predicted accelerated epigenetic aging, incident frailty, and faster accumulation of multiple chronic diseases (multimorbidity).

Results: At baseline, participants with higher TARs were epigenetically older, frailer, more multimorbid, and had poorer self-rated health (all p’s <0.05). Among healthy participants, higher TAR was associated with substantially increased risk of frailty (Incidence rate ratio (IRR) for high TAR vs low TAR = 2.11, p = 0.004) and accelerated accumulation of multimorbidity (IRR for high TAR vs low TAR = 1.51; p = 0.004) over follow-up.

Discussion: EEG slowing predicts accelerated whole-body aging trajectories and may serve as a scalable, non-invasive marker of biological aging in the general population.

Alzheimer's disease (AD) is a neurodegenerative condition distinguished by a deterioration in cognitive function and the loss of memory. The aggregation of amyloid-beta (Aβ) protein is a central pathological feature of this disease. Also, there is increasing recognition of the role of circadian disruptions in AD pathogenesis. The current knowledge about AD focuses on the independent impacts of circadian disturbances and Aβ pathology. However, the simultaneous effects of these elements have not been adequately investigated. Hence, this study examined the synergistic effects of specific Aβ isoforms (Aβ40, Aβ42, and Aβ42arc) and circadian disruption (cyc01 mutation) on Drosophila locomotor behaviour and lifespan. Locomotor activity in both female and male flies was evaluated using climbing assays at four key stages of their life cycle. The data were statistically analysed with repeated measures ANOVA in SPSS. Lifespan was monitored over time using Kaplan-Meier survival plots and log-rank tests in SPSS. Findings demonstrated exacerbated climbing deficits in Aβ-expressing flies with the cyc01 mutation compared to controls at later ages of life. The Aβ42 isoform significantly impaired locomotor function in both males and females. Survival assays showed the cyc01 mutation alone significantly shortened the lifespan, while the combined impacts with Aβ isoforms were varied. Especially, the Aβ42 isoform slightly mitigated the cyc01-induced lifespan reduction, unlike Aβ40 and Aβ42arc. These results indicate a complex relationship between Aβ and circadian disruption fromthe cyc01 mutation in modulating AD-related traits, highlighting the need for further research into mechanisms and potential therapies.

Stroke poses a significant individual and global health challenge and there is an urgent need for novel rehabilitation tools to support post-stroke motor recovery. Motor cortical theta-gamma (θγ) oscillations can positively modulate motor behaviour, and can be artificially driven with transcranial alternating current stimulation (tACS). However, the underlying neurophysiology of tACS-induced behavioural modulations, and whether they apply to higher-level motor learning, remains poorly understood. Here, using a combined tACS-7T-fMRI approach in right-handed healthy participants (n=30), who performed a sequence-based grip force modulation task in the MRI scanner, I assessed the effects of 75Hz/6Hz θγ peak phase-amplitude coupled tACS on both motor sequence learning and sensorimotor functional connectivity. I found that θγ-tACS has no significant effect on motor sequence learning or sensorimotor network strength. However, I did demonstrate dynamic modulations in sensorimotor network strength related to sequence learning, where learning produced initial reductions in sensorimotor network strength, followed by an significant overall increase in sensorimotor network strength during latter stages. These results demonstrate that resting state fMRI can capture learning-related modulations in sensorimotor functional connectivity. However, to date, we have not demonstrated that driving θγ motor cortical oscillations significantly modulates higher-level motor learning or sensorimotor network strength. Future research should focus on the application of dynamic closed-loop tACS. Furthermore, our study collected MRS data regarding GABAergic changes which accompany motor learning, with research indicating that differential roles for extrasynaptic and synaptic GABA in motor performance, thus future analysis of this data may significantly inform our understanding of the underlying neurophysiology.

Spasticity affects a high proportion of people with multiple sclerosis (pwMS), drives pain and mobility loss, and commonly requires symptomatic prescribing. However, long term comparative effectiveness evidence is limited due to the costly and difficult nature of maintaining a traditional randomised controlled trial (RCT). We used the United Kingdom MS Register (UKMSR), a UK wide longitudinal registry with ~50,000 pwMS and >1 million patient-reported outcome (PRO) measures collected over 14 years, to emulate a pseudo-trial comparing Baclofen and Sativex. We derived a PRO spasticity scale (MSIS-Spasticity) from MSIS-29 items on stiffness and limb spasms, demonstrating good internal consistency and test-retest reliability. In participants reporting spasticity, the index date was first initiation of treatment. Baseline was the closest PRO within 180 days of initiation, with ≥3 follow-up assessments over 3.5 years. Treated participants were propensity matched 1:2 to comparators on baseline PROs, age, sex, disease duration and phenotype. Events were the first minimally clinically important change from baseline (direction-specific), analysed with time-dependent Cox models; linear mixed-effects models assessed longitudinal trajectories. In the emulated trial, Sativex was associated with reduced risk of clinically meaningful spasticity worsening (HR 0.41, 95%CI 0.18-0.92;p=0.032) and, over time, improvement in MSIS-Spasticity(β=-0.11;p<0.001) and MSWS-12 walking (β=-0.77;p=0.003). Baclofen showed no evidence of spasticity benefit and did not improve walking. By capturing routine UKMSR participation with broad eligibility, the pseudo-trial improved generalisability and provides robust comparative effectiveness evidence for clinical practice. Registry based pseudo-trials provide scalable, externally valid evidence for neurological treatments, complementing RCTs by informing and guiding clinical care.

Apathy is a common symptom in neurological conditions, associated with poor prognosis and increased caregiver burden. There are currently no proven treatments. A loss of precision on action outcomes may cause apathy by reducing the expected difference between the state of the world following action versus non-action. We test if this loss of precision is reversible with GABAergic medication in individuals with syndromes associated with frontotemporal degeneration. Twenty healthy controls, twenty people with behavioural variant frontotemporal dementia and twenty people with progressive supranuclear palsy took part in a randomised placebo-controlled double-blind trial using zolpidem, an allosteric GABAA modulator. We use the ‘Goal Prior Assay’ task and dynamic causal modelling of MEG resting-state data to explore the cognitive and neural concomitants of prior precision, and the effect of GABAergic regulation on both prior precision and superficial pyramidal gain. We found strong evidence for a difference in prior precision between patients and controls on placebo (B=20.4, p<0.01), but not in the drug condition (B=0.86, p=0.11). There was strong evidence of a correlation between apathy and prior precision across groups (B>100, p<0.001). Dynamic causal modelling confirmed that reductions in gain on the prefrontal superficial pyramidal neurons were associated with prior precision in the patient group, and partially restored on zolpidem. We suggest that apathy is in part caused by a reduction in prior precision on action outcomes, mediated by reduced synaptic gain of prefrontal superficial pyramidal neurons, which can be partially restored using GABAergic intervention.

Associative binding, which supports the integration of object and spatial information in working memory, is disproportionately vulnerable in Alzheimer’s disease (AD). Although EEG abnormalities are well documented in AD, conventional analyses provide limited insight into the rapid, large‑scale brain activity patterns that support cognition. EEG microstate analysis offers a complementary approach by segmenting the signal into brief, recurring whole‑brain activity patterns. Here, we asked whether these patterns are altered in AD at rest and during working memory binding, and whether task‑related microstates are specifically linked to misbinding. Forty people with AD and thirty age‑matched healthy controls (HC) underwent high‑density, eyes‑closed resting‑state EEG and completed an object-location working memory task with concurrent EEG. Microstate analysis was applied separately to resting and task data. For each microstate, we quantified occurence, duration, coverage, and its global explained variance (GEV). Behaviourally, AD participants showed clear working memory impairment, with a marked increase in misbinding errors relative to HC. Resting‑state analysis revealed four microstates. Compared with HC, AD showed more frequent but shorter episodes and reduced time in one microstate, together with longer duration of another, indicating a reorganisation of cortical activity. During the working memory task, four task‑specific microstates were identified; AD participants showed reduced time in a task‑related microstate. Within the AD group, lower GEV of this microstate was associated with greater misbinding, independent of identification accuracy. These findings link altered large‑scale brain dynamics to a core cognitive deficit in AD and support EEG microstates as a cognition‑anchored biomarker candidate.

Background: Ultra-low-field (ULF) MRI offers accessible and low-cost neuroimaging. Paediatric ULF imaging faces unique challenges including lower SNR, reduced resolution, and motion-related artifacts, which particularly compromise automated tissue and subcortical segmentation. We compared multiple automated structural MRI pipelines to identify those that most closely reproduce high-field results across key developmental stages in the first 3 years of life.

Methods: Infants (nsubjects = 110) were scanned between the ages of 3 – 36 months with paired high (3T Siemens Skyra) 1x1x1mm isotropic and ultra-low-field (Hyperfine Swoop®) 1.5x1.5x5mm non-isotropic MRI. T2-weighted images were processed with four pipelines: SuperSynth, Minimorph, recon-all-clinical, and bibsnet2–4 Agreement between ULF-derived and 3T measurements was quantified using Lin’s concordance correlation coefficients (CCC) and relative volumetric percentage difference.

Results: Accuracy improved systematically with age across all methods. Global tissues (Total Brain Volume, Gray/White Matter) showed strong cross-scanner agreement (CCC >0.87 across pipelines), while CSF and subcortical regions had the most variation between scanners. SuperSynth showed the highest overall agreement, maintaining robust reliability even in infants <4 months (e.g., CSF CCC=0.89; Gray Matter CCC=0.93). Conclusions: Global tissue volumes can be quantified with high confidence at all ages from 3 months upwards, while subcortical measures require caution, particularly in the youngest infants. The findings highlight that reliable ULF morphometry in very young infants is feasible but contingent on careful pipeline choice, targeted outcome measures, and age-sensitive interpretation, offering a practical roadmap for deploying ULF neuroimaging in both high- and low-resource settings.

Background: The choroid plexus (CP) is involved in cerebrospinal fluid (CSF) production and forms part of the blood-CSF barrier, located in the ventricles of the brain. While CP enlargement is linked to aging, traumatic brain injury (TBI) and blast effects remains understudied in high-risk military cohorts. Given the sensitivity of tissue boundaries to blast exposure, we hypothesised that CP structure would particularly be vulnerable to these injuries.

Methods: We analysed a subset of 535 male UK servicemen from the ADVANCE Study (age M=39.7, SD=5.4). TBI exposure was classified using Mayo criteria (symptomatic (symTBI), mild (mTBI), and moderate-severe (msTBI)). CP volume, mean diffusivity (MD), and lateral ventricle (LV) volume were derived from MRI scans. We investigated associations between CP measures, LV volume, TBI, blast exposure, and age.

Results: Of the 380 participants reporting lifetime TBI (19.6% symTBI, 39.6% mTBI, 11.8% msTBI), 156 were blast-related. TBI exhibited associations with larger CP volume (p=0.028), increasing with injury severity (mTBI: p=0.042; msTBI: p=0.039), though findings did not survive correction. Blast exposure groups did not differ in CP structure. CP volume increased with age (pFDR<0.001), but TBI exposure did not moderate this relationship. CP volume increased with MD (pFDR<0.001) and LV volume (pFDR<0.001). Conclusion: TBI exposure showed nominal associations with CP enlargement, but not blast exposure in this cohort. This may require further stratification regarding the direction of blast or injury mechanism. Positive associations between CP volume and MD and LV volume suggests CP volume could potentially indicate broader changes in CSF-related structures.

Background: Status epilepticus (SE) is a neurological emergency associated with high morbidity and mortality, yet the early molecular changes accompanying sustained seizure activity remain incompletely understood. Heterogeneity between gene expression studies of animal SE models warrants a robust comparison to define the transcriptomic profile of SE across platforms, species, and experimental models.

Methods: We performed a meta-analysis of published gene expression studies of animal SE models encompassing the first 72 hours following SE onset. Twelve studies, comprising 37 transcriptomic datasets, were included, spanning species (mouse, rat) and experimental model (kainic acid, pilocarpine, self-sustaining SE). Pre-defined time windows (0-12, 12-24, 24-72 hours) were used to improve temporal resolution. Datasets were harmonised, mapped to human orthologues and analysed using multilevel linear mixed-effects models.

Results: Across all datasets, 444,693 animal gene entries mapped to human orthologs, yielding 17,215 unique human genes. Global analysis across time windows and SE models identified 118 differentially expressed genes (112 upregulated and 6 downregulated). Temporal analysis demonstrated largely distinct transcriptional profiles across time windows, with 83-87% of DEGs specific to their respective window. Four genes (FOS, TUBB6, TIMP1, HSPB1) were persistently upregulated across the first 24 hours following onset. Model-stratified analysis revealed distinct transcriptomic profiles across SE models. Pathway enrichment analysis identified early enrichment of inflammatory signalling pathways, including interleukin-17 (IL-17) signalling.

Conclusions: We provide a comprehensive molecular overview of early SE and show it be characterised by a highly dynamic, time-dependent transcriptomic response, with a small core of conserved dysregulated genes and prominent activation of pro-inflammatory cascades.

Background: Quantitative Susceptibility Mapping (QSM) measures tissue magnetic susceptibility but cannot characterize sub-voxel distributions. Paramagnetic (iron) and diamagnetic (myelin) sources may coexist within voxels, with opposing contributions potentially masking pathological changes in Parkinson's disease (PD). DECOMPOSE-QSM addresses this by decomposing bulk susceptibility into Paramagnetic (PCS), Diamagnetic (DCS), and Composite (CompS) maps. We examined source-separated susceptibility in PD and controls, identifying regional differences and clinical associations.

Methods: 59 PD patients aged 50-80 (age=66.9±7.0, 20 female) within 10 years of diagnosis and 17 age-matched controls (age=67.7±6.0, 8 female) underwent 3T MRI with multi-echo gradient-echo acquisitions. DECOMPOSE-QSM generated PCS, DCS, and CompS maps. Cortical ROIs used the Schaefer atlas; subcortical ROIs used MRIcloud. ANOVAs assessed group differences and multiple linear regression examined associations with cognition (MoCA) and motor severity (UPDRS-III), controlling for age and sex with Fcorrection.

Results: Substantia nigra showed increased susceptibility in PD versus controls in paramagnetic and composite maps (PCS: p=0.0041; CompS: p=0.0023). Visual cortex demonstrated lower composite susceptibility in PD (pFDR=0.015). Higher MoCA scores correlated with increased composite (pFDR=0.022) and diamagnetic (pFDR=0.0098) susceptibility in temporal pole. Higher UPDRS-III scores correlated with increased composite susceptibility in visual cortex (pFDR=0.038).

Conclusions: Source-separated susceptibility mapping reveals cortical and subcortical differences between PD and controls. Increased substantia nigra composite and paramagnetic susceptibility replicated prior findings in a larger, more clinically diverse cohort. Reduced composite susceptibility was observed in visual cortex. Cortical susceptibility measures associated with cognition (MoCA) and motor severity (UPDRS-III), highlighting the clinical relevance of investigating paramagnetic and diamagnetic components separately.

Background: Military personnel are at increased risk of traumatic brain injury (TBI). The ArmeD SerVices TrAuma RehabilitatioN OutComE (ADVANCE) TBI study investigates long-term cognitive and functional outcomes in service-personnel who served in Afghanistan (2003-2014).

Methods: TBI was classified using the Mayo criteria: Symptomatic (symTBI), Mild (mTBI) and Moderate-severe (msTBI), by timing (lifecourse exposure and battlefield injury (~13.7 years post-injury)). Association of TBI across cognitive domains (e.g., executive function, memory, and attention), health-related quality of life (HRQoL ) from EQ-VAS and employment status was assessed.

Results: Of 1019 servicemen, 68% had a history of lifecourse TBI (18.6% symTBI, 36.7% mTBI, 13.0% msTBI). 35.1% were military related and 50.6% civilian. Among the 514 servicemen exposed to major combat trauma, 60% sustained battlefield TBI (15.8% symTBI, 28.1% mTBI, 15.8% msTBI). Battlefield TBI was associated with poorer attention (β=−8.04, p=0.001), delayed memory (β=-3.96, p=0.013), ‘Stroop’ inhibition (β=-4.20, p=0.029), ‘Stroop’ inhibition/switch (β=-5.36, p=0.002) and reaction times (simple: β=31.8ms, p<0.001 and choice: β=32.17ms, p<0.001) compared to uninjured servicemen, with similar associations observed for lifecourse TBI (all p<0.05). Relative to individual full-scale IQ estimates, individuals with msTBI showed a two-fold increased risk of performing outside their expected range across multiple cognitive domains. EQ-VAS was significantly lower in battlefield injury groups relative to uninjured, with the greatest effect in the msTBI group (β=-5.34, p=0.02). Battlefield msTBI was also at greatest risk of unemployment (RR=10.8, p<0.001).

Conclusions: TBI was associated with long-term, multi-domain cognitive impairment, with increased severity linked to greater cognitive dysfunction, reduced HRQoL, and increased unemployment risk.

Background: KCNA6 encodes the voltage-gated potassium channel Kv1.6, a subunit involved in regulating neuronal excitability and action potential repolarization. Previous clinical case reports have demonstrated that KCNA6 mutations affecting potassium channel function correlate with a range of early infantile epileptic and neurodevelopmental disorder phenotypes. This report aims to document the condition of a novel mutation Kv1.6 p.Leu448Val in another patient exhibiting similar clinical features. Patient’s asymptomatic father did not carry the variant while mother’s DNA was not available.

Methods: Target mutant mRNA was obtained through site-directed mutagenesis, introduced into Xenopus laevis oocytes for expression, and its electrophysiological functional characteristics were assessed using the two-electrode voltage clamp technique. Wild-type and mutant RNA were also co-injected in 1:1 ratio. Results： This patient presented with febrile seizures before the age of one, accompanied by phenotypic features including global developmental delay, absent speech, and autism. The p.Leu448Val mutation is located within the S6 α-helical region, overlapping with previously reported mutations at the channel gate. Functional characterisation conducted in Xenopus oocytes revealed that the mutation disrupts the normal closure mechanism, resulting in increased potassium currents. These gain-of-function effects persisted when p.Leu448Val was co-injected with wild-type subunits.

Discussion: The clinical presentation of this individual and the electrophysiological features of the p.Leu448Val channel were consistent with the previously reported cases of KCNA6-associated epilepsy, confirming the pathogenicity of this variant. This case expands the clinical and genetic spectrum, and further establishes the causative role, of KCNA6 gain -of -function variants in developmental and epileptic encephalopathies .

Background: Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative disorder in adults aged over 65 years. The diagnostic accuracy for DLB is low due to disease heterogeneity and overlap with other dementias. This requires diagnostic tools that are non-invasive, accessible, and cost-effective. We develop ML-based classifiers to differentiate DLB from healthy controls (HC) and Alzheimer’s disease (AD) using features extracted from structural MRI in a large, multi-centre dataset.

Methods: We included T1-weighted MRI scans of 201 DLB, 120 AD and 244 age- and sex-matched HC from the European DLB consortium (E-DLB), National Alzheimer’s Coordinating Center (NACC), Neuroimaging of Inflammation in Memory and Related Other Disorders (NIMROD), Multimodal Imaging in Lewy Body Disorders (MILOS) and AMyloid imaging for Phenotyping LEwy body dementia (AMPLE) cohorts. Structural MRI features, extracted using Freesurfer and fractalbrain toolkit, were corrected for age and sex, rescaled, and split into 80:20 training and test datasets. To differentiate DLB from HC and AD, we employed Logistic regression (LR), Random Forest (RF) and Support Vector Machine (SVM) with Lasso regularization for feature selection. Results: For DLB vs HC classifiers, we achieved the highest accuracy of 83% using RF, followed by 82% with LR, and 79% with SVM. For DLB vs AD classifiers, we achieved the highest accuracy of 77% using LR, followed by 75% using RF, and 74% with SVM.

Conclusion: ML-based models using T1 MRI features show reasonable performance in diagnosing DLB. Incorporating multimodal MRI features and deep learning may improve these classifiers for clinical implementation.

Background: Low resting heart-rate (HR) is associated with increased cerebral pulsatility (PI), which is associated with cerebral small vessel disease (cSVD). The OXVASC study showed that cSVD severity, vascular cognitive impairment (VCI), and recurrent stroke were strongly associated with PI reflecting excess energy transmitted through stiffened great vessels. We investigated whether population-level HR->vascular dementia (VaD) associations support this haemodynamic hypothesis.

Methods: UK-Biobank is a large, community-based, longitudinal cohort recruiting >500,000 UK participants since 2007, with face-to-face assessment and healthcare data-linkage. Associations between baseline HR and VaD were determined by incidence rate and Cox proportional hazards regression with adjustment for age, sex, metabolic and cardiovascular risk factors. Secondary analyses examined HR×diastolic blood pressure (DBP) interactions.

Results: In 467,444 participants (mean age 56.5 years, 54% female) without baseline dementia during 6.2 million person-years(Pyrs) (median 13.6 years), 2,080 VaD events occurred. VaD was increased at both low (<60bpm: HR 1.16, 95%CI 1.03-1.31) and high HR (>90bpm: HR 1.93, 95%CI 1.63-2.28). After adjustment, high HR retained significant VaD risk (HR 1.37, 95%CI 1.09-1.74, p=0.008). However, VaD risk was attenuated in low HR (HR 1.12, 95%CI 0.96-1.31, p=0.149). VaD incidence was highest when high HR was combined with low DBP (113.8 per 100,000Pyrs), consistent with PI mediated injury.

Conclusions: Resting heart rate shows a J-shaped association with vascular dementia, independent of cardiovascular risk factors. The HR×DBP interaction supports a haemodynamic mechanism involving cerebral pulsatility. These findings suggest HR may be a modifiable target for vascular dementia prevention.

Background: Hypofractionated radiotherapy (HFRT) reduces treatment burden in glioblastoma (GBM), but whether MGMT promoter methylation and IDH status should guide hypofractionated strategy selection is unclear. We mapped molecular reporting and patient-centred endpoints in prospective HFRT trials.

Methods: Scoping review of PubMed and Cochrane Library (1997-March 2025) for prospective trials of hypofractionated stereotactic/dose-painted RT in newly diagnosed GBM. Data were charted for fractionation, biomarkers, survival, toxicity, and QoL/cognition.

Results: Four trial-level sources met criteria (three completed early-phase studies; one phase II protocol), all post-surgery with temozolomide-based therapy. Omuro et al. tested dose-painted HFSRT (6×6 Gy to enhancement; 6×4 Gy to FLAIR) plus temozolomide/bevacizumab (n=40): 1-year OS 93% and median OS 19.0 months. Azoulay et al. delivered CyberKnife 40 Gy/5 with temozolomide (n=30): median OS 14.8 months; MGMT-methylated OS 19.9 vs 11.3 months (p=0.031) and no grade ≥3 late adverse radiation effects. Pollom et al. reported dose-escalated 25–40 Gy/5 with temozolomide (n=30): median OS 14.2 months, 12-month progression incidence 64%, and HRQoL stable across most domains with communication decline mainly after progression. HSCK-010 (planned n=50) evaluates IMRT 20 Gy/10 + HSRT 30 Gy/5 with prospective QoL (EORTC QLQ-C30), cognition (MMSE), CTCAE v5.0 toxicity, and advanced imaging-supported response assessment.

Conclusion: Evidence for biomarker-informed HFRT in GBM is sparse and heterogeneous; molecular subgroup reporting beyond MGMT and linkage of toxicity/QoL/cognition to biomarker status remain inconsistent. Standardised MGMT/IDH stratification and harmonised endpoint/BED reporting, with prespecified biomarker-stratified toxicity and QoL analyses, are priorities.

Introduction: Axon outgrowth and regeneration are key determinants of sensory function and are frequently impaired in inherited neuropathies. However, many assays for iPSC-derived sensory neurons (iPSC-SNs) are inconsistent and inadequate. It is therefore essential to develop improved axon outgrowth and regeneration assays to study dysfunction in inherited neuropathies, including LOF mutations in NMNAT2 and LOF mutations in SETDB2 in a congenital insensitivity to pain (CIP) pedigree. Aim 1: Optimize microfluidic in-vitro neurite outgrowth and regeneration assays in human iPSC-SNs. Aim 2: Apply these assays to iPSC-SNs with loss of NMNAT2 or derived from SETDB2 LOF patients.

Methods: For assay assessment and optimization, human iPSCs and immortalized human DRG cells are differentiated into SNs, matured as radial aggregates or in microfluidic devices, and axotomized using vacuum or laser ablation. Optimized assays are then applied to NMNAT2 LOF and SETDB2 LOF iPSC-SNs. Results: Aim 1: Optimized assays include a microfluidic radial outgrowth and two-chamber vacuum ablation assay visualized with tdTomato AAV9 transfection. These methods facilitate time-lapse imaging, reduce debris, and limit samples required. Aim 2: NMNAT2 LOF SNs display significantly reduced baseline neurite outgrowth (p=0.015) and may exhibit reduced regeneration. SETDB2 LOF SNs display significantly reduced baseline neurite outgrowth (p=0.002) and regeneration (p<0.001) independent of initial outgrowth or cell survival.

Conclusion: This study has optimized neurite outgrowth and regeneration assays for iPSC-SNs and applied these assays to demonstrate impaired neurite outgrowth and regeneration in NMNAT2 LOF and SETDB2 LOF iPSC-SNs.

The World Health Organization reports that approximately 332 million people in the world have depression and that this common mental disorder can significantly impair people’s social relationships, work performance, and other aspects of life. In 2021, an estimated 727,000 people lost their lives to suicide, so reasonably there is strong motivation to discover viable treatments for depression. A variety of different treatments aimed at decreasing depression in participants have been developed including psychopharmacology and brain stimulation techniques such as transcranial magnetic stimulation. Yet important questions about this line of research remain. For example, how effective is transcranial magnetic stimulation at reducing major depression? The purpose of the present meta-analytic research is to address this question by systematically reviewing all relevant studies that compared the influence of transcranial magnetic stimulation versus sham stimulation on major depression as measured by the Montgomery-Asberg Depression Rating Scale. Following PRISMA guidelines and using a random effects model, this meta-analysis found a small yet significant effect for transcranial magnetic stimulation versus sham stimulation on decreasing major depression in participants (k = 8, SMD = -0.241, p = 0.009). Here we highlight the results of this meta-analytic research on transcranial magnetic stimulation and major depression, comment on its practical value, and identify limitations and prospects for future research.