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Cognitive dysfunction in Alzheimer’s disease (AD) is caused by disturbances in neuronal circuits of the brain underpinned by synapse loss, neuronal dysfunction and neuronal death. Amyloid beta and tau protein cause these pathological changes and enhance neuroinflammation, which in turn modifies disease progression and severity. Vagal nerve stimulation (VNS), via activation of the locus coeruleus (LC), results in the release of catecholamines in the hippocampus and neocortex, which can enhance synaptic plasticity and reduce inflammatory signalling. VNS has shown promise to enhance cognitive ability in animal models. Research in rodents has shown that VNS can have positive effects on basal synaptic plasticity and synaptic function, tune inflammatory signalling, and limit the accumulation of amyloid plaques. Research in humans with invasive and non invasive VNS devices has shown promise for the modulation of cognition. However, the direct stimulation of the vagus nerve afforded with the invasive procedure carries surgical risks. In contrast, non-invasive VNS has the potential to be a broadly available therapy to manage cognitive symptoms in early AD, however the magnitude and specificity of its effects remains to be elucidated. Ongoing clinical trials with healthy individuals and patients with early AD will provide valuable information to clarify the potential benefits of non-invasive VNS in cognition and AD. Whether invasive or non invasive VNS can produce a significant improvement on memory function and whether its effects can modify the progression of AD will require further investigation.

•Brain clocks trained on UK Biobank generalise well to NACC and ADNI datasets.•Achieved <1 year MAE in age prediction, detecting effectively Multiple Sclerosis and Dementia cases (AUROC > 0.90).•Penalised linear models with Zhang correction excelled in age/disease prediction.•Resampling underrepresented ages reduced prediction errors across all age bins. In this study, we present a comprehensive pipeline to train and compare a broad spectrum of machine learning and deep learning brain clocks, integrating diverse preprocessing strategies and correction terms. Our analysis also includes established methodologies which have shown success in prior UK Biobank-related studies. For our analysis we used T1-weighted MRI scans and processed de novo all images via FastSurfer, transforming them into a conformed space for deep learning and extracting image-derived phenotypes for our machine learning approaches. We rigorously evaluated these approaches both as robust age predictors for healthy individuals and as potential biomarkers for various neurodegenerative conditions, leveraging data from the UK Biobank, ADNI, and NACC datasets. To this end we designed a statistical framework to assess age prediction performance, the robustness of the prediction across cohort variability (database, machine type and ethnicity) and its potential as a biomarker for neurodegenerative conditions. Results demonstrate that highly accurate brain age models, typically utilising penalised linear machine learning models adjusted with Zhang's methodology, with mean absolute errors under 1 year in external validation, can be achieved while maintaining consistent prediction performance across different age brackets and subgroups (e.g., ethnicity and MRI machine/manufacturer). Additionally, these models show strong potential as biomarkers for neurodegenerative conditions, such as dementia, where brain age prediction achieved an AUROC of up to 0.90 in distinguishing healthy individuals from those with dementia.

Gliomas are highly malignant brain tumours characterised by extensive areas of poor perfusion which subsequently leads to hypoxia and reduced survival. Therapies that address the hypoxic microenvironment are likely to significantly improve patient outcomes. Verteporfin, a benzoporphyrin-like drug, has been suggested to target the Yes-associated protein (YAP). Increased YAP expression and transcriptional activity has been proposed in other tumour types to promote malignant cell survival and thus YAP-inhibitor, verteporfin, may be predicted to impact glioma cell growth and viability. Due to the extensive hypoxic nature of gliomas, we investigated the effect of hypoxia on YAP expression and found that YAP transcription is increased under these conditions. Treatment of both primary and immortalised glioblastoma cell lines with verteporfin resulted in a significant decrease in viability but strikingly only under hypoxic conditions (1% O 2 ). We discovered that cell death occurs through a YAP-independent mechanism, predominately involving binding of free iron and likely through redox cycling, contributes to production of reactive oxygen species. This results in disruption of normal cellular processes and death in cells already under oxidative stress – such as those in hypoxia. We suggest that through repurposing verteporfin, it represents a novel means of treating highly therapy-resistant, hypoxic cells in glioma.

Background Grade IV glioblastomas exist in two forms, primary ( de novo ) glioblastomas (pGBM) that arise without precursor lesions, and the less common secondary glioblastomas (sGBM) which develop from earlier lower grade lesions. Genetic heterogeneity between pGBM and sGBM has been documented as have differences in the methylation of individual genes. A hypermethylator phenotype in grade IV GBMs is now well documented however there has been little comparison between global methylation profiles of pGBM and sGBM samples or of methylation profiles between paired early and late sGBM samples. Methods We performed genome-wide methylation profiling of 20 matched pairs of early and late gliomas using the Infinium HumanMethylation450 BeadChips to assess methylation at >485,000 cytosine positions within the human genome. Results Clustering of our data demonstrated a frequent hypermethylator phenotype that associated with IDH1 mutation in sGBM tumors. In 80% of cases, the hypermethylator status was retained in both the early and late tumor of the same patient, indicating limited alterations to genome-wide methylation during progression and that the CIMP phenotype is an early event. Analysis of hypermethylated loci identified 218 genes frequently methylated across grade II, III and IV tumors indicating a possible role in sGBM tumorigenesis. Comparison of our sGBM data with TCGA pGBM data indicate that IDH1 mutated GBM samples have very similar hypermethylator phenotypes, however the methylation profiles of the majority of samples with WT IDH1 that do not demonstrate a hypermethylator phenotype cluster separately from sGBM samples, indicating underlying differences in methylation profiles. We also identified 180 genes that were methylated only in sGBM. Further analysis of these genes may lead to a better understanding of the pathology of sGBM vs pGBM. Conclusion This is the first study to have documented genome-wide methylation changes within paired early/late astrocytic gliomas on such a large CpG probe set, revealing a number of genes that maybe relevant to secondary gliomagenesis.

Driving is an integral part of adult life and losing a driving licence is potentially a major problem. Many neurological conditions may impact on driving, either by increasing the risk of a sudden disabling event or by affecting cognition, vision, reaction speed, motor coordination, peripheral sensation or visuospatial processing. In the UK, the Drivers Medical Group of the Driver and Vehicle Licensing Agency (DVLA) decides whether an individual’s medical condition meets the appropriate standards for driving. The licensing decision rests with the DVLA and is not at the clinician’s discretion. However, clinicians must inform patients of their legal obligations towards the DVLA and how their neurological symptoms may restrict their driving. We discuss risk assessment, how chronic disabling neurological disease may impact on driving and the general principles of applying medical standards for fitness to drive. We also highlight how legal driving eligibility varies around the world. Finally, we discuss the practical applications relating to a specific case.

Glioblastomas are impossible to completely resect and almost always recur at the borders of the resection margin. There is no established chemotherapy regimen available to patients who recur, while systemic treatment is hampered by the blood–brain barrier. Here, we report on the first evaluation in humans of the intraparenchymal injection of irinotecan into the resection cavity after surgical resection of recurrent glioblastoma patients. The cytotoxicity of irinotecan was compared to SN-38 in primary cells from recurrent glioblastoma patients. Irinotecan was injected at multiple (~30) sites of the resection cavity wall at a depth of 3 to 5 mm. SN-38 was more cytotoxic than irinotecan at concentrations below 1 µM due to enzyme kinetics. The intraparenchymal administration of irinotecan was safe, with good wound healing and an absence of swelling, inflammation, or pseudo-abscess formation. The median survival post irinotecan administration was 32.6 weeks. The median overall survival was 30.5 months, with a two-year survival rate of 56%. This study demonstrates that local delivery of irinotecan into the brain parenchyma offers a safe route of administration over systemic delivery in the treatment of recurrent glioblastoma.

The aim of this study was to investigate possible delays in referral time for Glioblastoma multiforme (GBM) patients diagnosed at two similar neurosurgical centres (in Birmingham, UK and Strasbourg, France) and their impact on survival. Differences in the referral patterns for GBM patients within these healthcare systems may affect subsequent management and are potential targets to optimise the care of patients with GBM. Medical case notes of 105 GBM patients in Birmingham and 81 in Strasbourg, admitted during October 2006 and April 2008, were reviewed. Data regarding demographic details, route of admission, presenting symptoms, date of initial presentation to a medical professional and dates of the first CT or MRI scan, first neurosurgical intervention, histological diagnosis and mortality was recorded. The median time taken from initial presentation to first neurosurgical intervention was lower in Birmingham compared to Strasbourg (13 vs. 21 days, respectively; p = 0.026). Similarly, the time taken from initial presentation to histological diagnosis was lower in Birmingham (15 vs. 24 days, respectively; p = 0.011). However, survival was poorer in Birmingham than Strasbourg ( p = 0.001) and age (HR = 1.029; 95%CI 1.010–1.048; p = 0.003) and time from initial presentation to neurosurgical intervention (HR = 0.993; 95%CI 0.988–0.998; p = 0.011) were predictors of mortality in these groups. Patients in Birmingham are diagnosed with GBM more rapidly than those in Strasbourg but they have poorer survival. Differences in disease severity may partially account for the observed results and further large scale work is required to support this study.

ObjectivesHeadaches and facial pain have been identified as the most prevalent form of pain among patients with glioblastoma multiforme, the most common malignant primary brain tumour. Despite this, minimal research has been undertaken investigating the direct and indirect impact these headaches have on their quality of life. Therefore, in this study, we aimed at gaining a personal insight into the importance and impact that these headaches have on the quality of life of patients with glioblastoma multiforme.DesignExploratory study using face-to-face semistructured interviews. Interviews were audio-recorded, transcribed verbatim and then qualitatively analysed using thematic analysis.SettingParticipants recruited from a tertiary referral hospital in Birmingham, UK.ParticipantsPurposive sampling of 14 registered outpatients recently diagnosed with glioblastoma multiforme.Results3 themes were identified: (1) an underlying attitude of determination and positivity; (2) impact of headache unpredictability on social interaction; (3) headaches found to act as a springboard onto thoughts regarding their disease and future.ConclusionsWhile the quality of life of patients with glioblastoma multiforme is clearly multifactorial, headaches do indeed play a part for some. However, it is not the direct pain of the headache as one might expect that impacts on the quality of life of these patients, but the indirect effect of headaches through limiting patients' social lives and by serving as a painful psychological reminder of having a life-threatening illness. In clinical practice, using headache diaries for these patients may help provide a more comprehensive assessment and further aid management plans. Alongside acting as an important reminder of the potential secondary implications of this disease, suggestions for future research include quantitatively investigating whether headaches can act as a prognostic indicator for quality of life within this patient demographic and determining whether these conclusions also hold true for a wider spectrum of patients with brain tumour.