INTRODUCTION:Adverse neurological complications, including postoperative delirium (POD) and stroke, remain one of the major risks after cardiac surgery. A lack of comprehensive knowledge about their causes and neuroprotective strategies has hindered the development of effective interventions to reduce these events. Personalised cerebral autoregulation (CA)-oriented blood pressure monitoring aims to identify blood pressure targets tailored to each individual patient, thereby reducing brain injury. The PRECISION study aims to assess whether perioperative duration and magnitude of mean arterial pressure (MAP) deviation from an individual's CA limits are associated with adverse neurological complications. METHODS AND ANALYSIS:This international, multicentre, prospective cohort study is conducted at two Swiss and one British hospital. Patients aged 65 years or older undergoing elective primary or re-operative coronary artery bypass graft and/or valvular and/or ascending aorta surgery requiring cardiopulmonary bypass are included. Preoperatively, the patient's baseline of physical, cognitive and mental status is established. Intraoperatively, near-infrared spectroscopy (NIRS) and transcranial Doppler (TCD) are recorded in real-time to generate NIRS-derived and TCD-derived CA indices. The primary endpoint is POD, assessed daily on postoperative days 0 to 7 or up to discharge, whichever occurs earlier with the 3D-Confusion Assessment Method (3D-CAM) or CAM-Intensive Care Unit. Secondary endpoints include a composite neurological outcome of POD and overt stroke, postoperative neurocognitive disorders, major morbidity and mortality. Associations between neurologic outcomes, neurobiomarkers and genetic variation will be explored.A total of 500 participants is required to achieve 90% power to find a statistically significant effect of the area under the curve MAP<lower limit of CA (LLA) on the risk of POD at the 5% level. This includes adjustment for potential confounders and for the inability to determine the LLA. ETHICS AND DISSEMINATION:Ethical approval has been obtained from all responsible ethics committees (Swiss lead ethics committee EKNZ 2022-01457 and Health Research Authority and Health and Care Research Wales, UK, REC 23/SW/0076). Results will be disseminated at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER:NCT05595954.

There is increasing evidence for the role of central and peripheral inflammation across neurodegenerative disorders, with animal models and post-mortem studies identifying T-cell infiltration in the brain associated with pathology and neurodegeneration. Peripheral T-cell changes have been measured in Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). This study examines a unique cohort of blood-based T-cell profiles across a range of neurodegenerative dementias including AD, DLB, FTD, corticobasal syndrome (CBS), PSP, and aged-matched healthy controls. Then it also explores their associations with dementia-relevant plasma biomarkers and clinical outcomes. Freshly prepared peripheral blood mononuclear cells (PBMCs) from 174 participants (AD = 20, DLB = 24, FTD = 19, CBS = 18, PSP = 58, controls = 35) were studied using a flow-cytometry panel designed to analyse major T-cell subpopulations, including memory and T-helper subtypes. Neurodegeneration-relevant biomarkers (p-tau217, p-tau231, GFAP, NfL, and A-beta42/40) were measured in plasma samples. T-cell populations were compared between groups and in association with biomarkers, and principal components analysis (PCA) was used to identify T-cell profiles and their association with dementia-relevant biomarkers in diagnostic classification and survival prediction. There was a significant reduction in the fraction of CD3+ cells in patients with DLB compared to other diagnostic groups, and an increase in relative Th1/17-like cell levels in patients with FTD compared to controls. This increase in Th1/17-like cells correlated with NfL and GFAP plasma levels in patients with FTD. PCA identified five components primarily representing CD4+ memory cell population subsets. After sex and age adjustments, component 4 marked by effector memory types including Th2-like, Th-like1 and Th1/17-like cells was a significant predictor of FTD, however was not as accurate as plasma NfL. Higher scores in specific T-cell components (1 and 3) were associated with reduced mortality across all diseases, with component 3 remaining a significant predictor even when controlling for traditional neurodegenerative biomarkers like NfL and p-tau217. This study provides evidence that T-cell dysregulation is not unified in patients with neurodegenerative diseases. We observe different involvement across different dementia types establishing adaptive immunity as a key contributor to disease heterogeneity. However, although plasma biomarkers such as NfL and p-tau217 exhibit superior diagnostic accuracy for clinical classification, peripheral T-cell signature were associated with survival outcomes across diagnostic groups, highlighting their promise for prognostic applications and disease monitoring. The characterisation of T-cell populations across neurodegenerative conditions may inform target development and patient stratification for new interventional trials.

Chorea-acanthocytosis (ChAc) is a rare genetic disorder characterised by a hyperkinetic movement disorder, dystonia, cognitive and neuropsychiatric deficits and seizures.We report the case of a 30-year-old patient who presented with a decade of episodic neurological dysfunction and seizures. The condition was initially suspected to be an immunotherapy-responsive seronegative autoimmune encephalitis but progressed to oromandibular dystonia, raising suspicion of a neurodegenerative condition. Neuroimaging showed bilateral caudate atrophy and acanthocytes were seen on blood film microscopy in association with raised creatine kinase. Genetic testing revealed our patient to be compound heterozygous for two pathogenic variants in the VPS13A gene and confirmed the diagnosis of ChAc.This case highlights the importance of considering ChAc in the differential diagnosis of a progressive treatment-refractory seizure disorder in the context of oromandibular dystonia.

Neuroinflammation is known to contribute to worse patient outcomes following severe traumatic brain injury (TBI). Specifically, complement activation as part of the innate immune response has been explored in animal models and post-mortem human tissue. However, it has not been well-characterized in a substantial clinical cohort. We aimed to investigate the complement cascade, specifically focusing on the lectin pathway initiators, in patients with TBI compared with healthy controls. We describe temporal profiles of complement proteins, and investigate their association with outcome, and clinical variables following TBI. Plasma blood samples collected from 64 patients with TBI (on days 1-7, 42, and 365) and 17 healthy controls (single samples) were analyzed for 10 complement proteins using single and multiplexing protein assays. We quantified initiator (MBL, MASP2, ficolin3), effector (C4b, C2, factor D, factor I), and downstream (C5, C5a, C5b9) complement proteins. Clinical variables included injury severity score, Glasgow Coma Scale motor score, pupil reactivity, and Glasgow Outcome Scale Extended at 6 months post-injury. 7 out of 10 measured complement proteins had median concentrations that were significantly different in patients with TBI compared with healthy controls (all p values < 0.05). Ficolin3, an initiator, was particularly lower in TBI versus controls (0.22 vs. 1.84 ng/mL, p < 0.001), and consistently lower over time, showing depressed levels even 1 year post-injury (p < 0.001). Initiators MBL and MASP2, effector C2 and downstream proteins C5, C5a, and factor I demonstrate a steady rise in the first week post-injury, and are consistently elevated compared with control levels. Patients with unfavorable outcome had higher levels of C4b, C5, and factor I, with C5 demonstrating this trend over time (OR: 1.53 [1.52-1.53], p value < 0.001), and showing additional prognostic benefit over and above IMPACT clinical outcome predictors. This study characterized the complement cascade in human TBI with high temporal resolution in initiator, effector, and downstream proteins. Seven out of the 10 measured proteins were significantly different in patients with TBI compared with healthy controls. Notably, C5 has an independent and robust association with outcome in both univariate and linear mixed regression, where a higher C5 concentration was associated with unfavorable outcome 6 months post-injury. Further investigation is required to explore the potential of complement as a therapeutic target in TBI.

Post-traumatic seizure (PTS) is a significant complication of traumatic brain injury (TBI), associated with unfavourable outcomes. However, reported risk factors for PTS are inconsistent, and considerable variation exists in clinical practice regarding seizure prophylaxis. This systematic review and meta-analysis aimed to identify and evaluate the risk factors for early and late PTS in adults. A systematic search was conducted on PubMed, MEDLINE, EMBASE, and the Cochrane Library for studies published from 1975 to November 2024, investigating risk factors for PTS in adults with TBI. The protocol was registered with PROSPERO (CRD42021287959). Two independent reviewers screened studies, extracted data, and assessed the risk of bias using the Critical Appraisal Skills Programme (CASP) tool. A narrative synthesis and random-effects meta-analysis were performed to pool data on PTS incidence and key risk factors. From 13,999 records identified, 11 studies involving 242,803 patients were included. The pooled incidence of PTS was 7.2

Disturbed cerebral autoregulation (represented by a positive pressure reactivity index [PRx]), elevated intracranial pressure (ICP), and decreased cerebral perfusion pressure (CPP) are key treatment targets following severe traumatic brain injury (sTBI). This study investigated neuroinflammation as a potential mechanism underlying these intracranial disturbances. Plasma samples from 11 sTBI patients (from a prior Phase II drug trial) were analyzed for 174 proteins using an antibody-based suspension bead array, with intervention effects accounted for where possible. Dimensionality reduction techniques, including principal component analysis (PCA) and supervised methods, were applied to protein data, informed by physiological variables (ICP, CPP, and PRx). PCA revealed distinct protein clustering patterns related to ICP >20 mmHg and PRx > 0, with PC1 linked to patient ID, time from injury, and intervention, and PC2/PC3 significantly associated with PRx dose (p < 0.001). Markers relating to inflammation of the vascular system comprised 20% of the top 50 proteins influencing PC2, implicating complement inflammation in these processes. Notably, MASP-2 (p = 0.027) and complement factor I (p = 0.039) were significantly associated with PRx dose in a mixed-effects model. These findings suggest that vascular inflammation, particularly complement activation, may contribute to intracranial physiological disturbances in sTBI, highlighting the complement pathway as a potential target for further investigation.

BACKGROUND:Remyelination offers a potential neuroprotective strategy in multiple sclerosis (MS). In the Cambridge Centre of Myelin Repair One (CCMR-One) trial, bexarotene, an RXR agonist, promoted remyelination in people with MS, evidenced through a reduction in the latency of the full-field visual evoked potential (VEP). However, it remained uncertain whether bexarotene additionally promoted neuroprotection. METHODS:We conducted a sub-study of the Cambridge-based (n = 31) participants of the CCMR-One trial. Participants were aged 18-50 years, had baseline EDSS 0-6.0 and had been stable on dimethyl fumarate for at least 6 months. Consenting participants contributed serum samples at baseline and month 6, which were analysed for neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total Tau protein (Tau), and C-terminal hydrolase L1 (UCHL1). The change in serum biomarker values and their associations with changes in VEP latency were assessed using linear models adjusted for age, sex, EDSS, disease duration and baseline biomarker levels. RESULTS:27 participants consented to provide blood samples (15 bexarotene, 12 placebo). There were no significant differences in biomarker change between these groups. However, a significant interaction was observed between treatment group and sNfL change (p = 0.001) among those with prolonged baseline VEP latency (≥118 ms). In the bexarotene group, latency improvement was associated with a reduction in sNfL (β = 23.4 ms per log[pg/mL] decrease; 95 % CI 11.1 to 36.2); this relationship was not seen in the placebo group. CONCLUSIONS:Bexarotene-induced remyelination was associated with reduced sNfL in individuals with prior demyelination, suggesting a potential neuroprotective effect.

Abstract Therapeutics for traumatic brains injuries constitute a global unmet medical need. Despite the advances in neurocritical care, which have dramatically improved the survival rate for the ~ 70 million patients annually, few treatments have been developed to counter the long-term neuroinflammatory processes and accompanying cognitive impairments, frequent among patients. This review looks at gene delivery as a potential therapeutic development avenue for traumatic brain injury. We discuss the capacity of gene delivery to function in traumatic brain injury, by producing beneficial biologics within the brain. Gene delivery modalities, promising vectors and key delivery routes are discussed, along with the pathways that biological cargos could target to improve long-term outcomes for patients. Coupling blood-brain barrier crossing with sustained local production, gene delivery has the potential to convert proteins with useful biological properties, but poor pharmacodynamics, into effective therapeutics. Finally, we review the limitations and health economics of traumatic brain injury, and whether future gene delivery approaches will be viable for patients and health care systems.

As the dimensionality, throughput and complexity of cytometry data increases, so does the demand for user-friendly, interactive analysis tools that leverage high-performance machine learning frameworks. Here we introduce FlowAtlas: an interactive web application that enables dimensionality reduction of cytometry data without down-sampling and that is compatible with datasets stained with non-identical panels. FlowAtlas bridges the user-friendly environment of FlowJo and computational tools in Julia developed by the scientific machine learning community, eliminating the need for coding and bioinformatics expertise. New population discovery and detection of rare populations in FlowAtlas is intuitive and rapid. We demonstrate the capabilities of FlowAtlas using a human multi-tissue, multi-donor immune cell dataset, highlighting key immunological findings. FlowAtlas is available at https://github.com/gszep/FlowAtlas.jl.git.

Neurological complications, including encephalopathy and stroke, occur in a significant proportion of COVID-19 cases but viral protein is seldom detected in the brain parenchyma. To model this situation, we developed a novel low-inoculum K18-hACE2 mouse model of SARS-CoV-2 infection during which active viral replication was consistently seen in mouse lungs but not in the brain. We found that several mediators previously associated with encephalopathy in clinical samples were upregulated in the lung, including CCL2, and IL-6. In addition, several inflammatory mediations, including CCL4, IFNγ, IL-17A, were upregulated in the brain, associated with microglial reactivity. Parallel in vitro experiments demonstrated that the filtered supernatant from SARS-CoV-2 virion exposed brain endothelial cells induced activation of uninfected microglia. This model successfully recreates SARS-CoV-2 virus-associated para-infectious brain inflammation which can be used to study the pathophysiology of the neurological complications and the identification of potential immune targets for treatment.

Liver disease is increasingly common, estimated to affect over 25% of the world's population. Failure of the liver to maintain a normal metabolic milieu leads to impaired brain function (hepatic encephalopathy), and conditions that cause liver disease can themselves predispose to neurological disease. As neurologists' involvement with the acute take increases, it is important that we are familiar with the neurological complications of liver disease, their investigation and management, and to know which other neurological diseases occur in this patient population. In this article, we review the causes, presentation and treatment of hepatic encephalopathy, and discuss important differential diagnoses in patients with liver disease who present with neurological disturbance.

Background Patient-reported outcomes and cross-sectional evidence show an association between COVID-19 and persistent cognitive problems. The causal basis, longevity and domain specificity fi city of this association is unclear due to population variability in baseline cognitive abilities, vulnerabilities, virus variants, vaccination status and treatment. Methods Thirty-four young, healthy, seronegative volunteers were inoculated with Wildtype SARS-CoV-2 under prospectively controlled conditions. Volunteers completed daily physiological measurements and computerised cognitive tasks during quarantine and follow-up at 30, 90, 180, 270, and 360 days. Linear modelling examined differences between ' infected ' and ' inoculated but uninfected' ' individuals. The main cognitive endpoint was the baseline corrected global cognitive composite score across the battery of tasks administered to the volunteers. Exploratory cognitive endpoints included baseline corrected scores from individual tasks. The study was registered on ClinicalTrials.gov with the identifier fi er NCT04865237 and took place between March 2021 and July 2022. Findings Eighteen volunteers developed infection by qPCR criteria of sustained viral load, one without symptoms and the remainder with mild illness. Infected volunteers showed statistically lower baseline-corrected global composite cognitive scores than uninfected volunteers, both acutely and during follow up (mean difference over all time points = - 0.8631, 95% CI = - 1.3613, - 0.3766) with significant fi cant main effect of group in repeated measures ANOVA (F (1,34) = 7.58, p = 0.009). Sensitivity analysis replicated this cross-group difference after controlling for community upper respiratory tract infection, task-learning, remdesivir treatment, baseline reference and model structure. Memory and executive function tasks showed the largest between-group differences. No volunteers reported persistent subjective cognitive symptoms. Interpretation These results support larger cross sectional fi ndings indicating that mild Wildtype SARS-CoV-2 infection can be followed by small changes in cognition and memory that persist for at least a year. The mechanistic basis and clinical implications of these small changes remain unclear.

Background The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Methods Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. Findings Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Interpretation Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. Funding CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

Neuroinflammation is a significant and modifiable cause of secondary injury after traumatic brain injury (TBI), driven by both central and peripheral immune responses. A substantial proportion of outcome after TBI is genetically mediated, with an estimated heritability effect of around 26%, but because of the comparatively small datasets currently available, the individual drivers of this genetic effect have not been well delineated. A hypothesis-driven approach to analyzing genome-wide association study (GWAS) datasets reduces the burden of multiplicity testing and allows variants with a high prior biological probability of effect to be identified where sample size is insufficient to withstand data-driven approaches. Adaptive immune responses show substantial genetically mediated heterogeneity and are well established as a genetic source of risk for numerous disease states; importantly, HLA class II has been specifically identified as a locus of interest in the largest TBI GWAS study to date, highlighting the importance of genetic variance in adaptive immune responses after TBI. In this review article we identify and discuss adaptive immune system genes that are known to confer strong risk effects for human disease, with the dual intentions of drawing attention to this area of immunobiology, which, despite its importance to the field, remains under-investigated in TBI and presenting high-yield testable hypotheses for application to TBI GWAS datasets.

The spectrum, pathophysiology, and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the one-year cognitive, serum biomarker, and neuroimaging findings from a prospective, national longitudinal study of cognition in 351 COVID-19 patients who had required hospitalisation, compared to 2,927 normative matched controls. Cognitive deficits were global and associated with elevated brain injury markers and reduced anterior cingulate cortex volume one year after admission. The severity of the initial infective insult, post-acute psychiatric symptoms, and a history of encephalopathy were associated with greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Treatment with corticosteroids during the acute phase appeared protective against cognitive deficits. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 is immune-mediated, and should guide the development of therapeutic strategies.

The spectrum, pathophysiology and recovery trajectory of persistent post-COVID-19 cognitive deficits are unknown, limiting our ability to develop prevention and treatment strategies. We report the 1-year cognitive, serum biomarker and neuroimaging findings from a prospective, national study of cognition in 351 COVID-19 patients who required hospitalization, compared with 2,927 normative matched controls. Cognitive deficits were global, associated with elevated brain injury markers and reduced anterior cingulate cortex volume 1 year after COVID-19. Severity of the initial infective insult, postacute psychiatric symptoms and a history of encephalopathy were associated with the greatest deficits. There was strong concordance between subjective and objective cognitive deficits. Longitudinal follow-up in 106 patients demonstrated a trend toward recovery. Together, these findings support the hypothesis that brain injury in moderate to severe COVID-19 may be immune-mediated, and should guide the development of therapeutic strategies. A national prospective study of patients requiring hospitalization for COVID-19 demonstrates global cognitive deficits at 1 year, associated with elevated brain injury markers and reduced gray matter volume.