Search results
Found 22668 matches for
The Cheltenham Science Festival was first held in 2002, and has quickly grown to become one of the most significant of its kind in the UK. The 2017 festival ran from 6-11 June and featured three of our scientists.
Neuroimaging-based data-driven subtypes of spatiotemporal atrophy due to Parkinson's disease.
Parkinson's disease is the second most common neurodegenerative disease. Despite this, there are no robust biomarkers to predict progression, and understanding of disease mechanisms is limited. We used the Subtype and Stage Inference algorithm to characterize Parkinson's disease heterogeneity in terms of spatiotemporal subtypes of macroscopic atrophy detectable on T1-weighted MRI-a successful approach used in other neurodegenerative diseases. We trained the model on covariate-adjusted cortical thicknesses and subcortical volumes from the largest known T1-weighted MRI dataset in Parkinson's disease, Enhancing Neuroimaging through Meta-Analysis consortium Parkinson's Disease dataset (n = 1100 cases). We tested the model by analyzing clinical progression over up to 9 years in openly-available data from people with Parkinson's disease from the Parkinson's Progression Markers Initiative (n = 584 cases). Under cross-validation, our analysis supported three spatiotemporal atrophy subtypes, named for the location of the earliest affected regions as: 'Subcortical' (n = 359, 33%), 'Limbic' (n = 237, 22%) and 'Cortical' (n = 187, 17%). A fourth subgroup having sub-threshold/no atrophy was named 'Sub-threshold atrophy' (n = 317, 29%). Statistical differences in clinical scores existed between the no-atrophy subgroup and the atrophy subtypes, but not among the atrophy subtypes. This suggests that the prime T1-weighted MRI delineator of clinical differences in Parkinson's disease is atrophy severity, rather than atrophy location. Future work on unravelling the biological and clinical heterogeneity of Parkinson's disease should leverage more sensitive neuroimaging modalities and multimodal data.
Collaborative care for pregnant women with eye conditions.
The management of ophthalmic conditions in pregnancy presents unique challenges that demand a nuanced approach. Significant knowledge gaps and practice variations persist, likely as a result of the infrequent nature of these issues in pregnancy, as well as the lack of crossover in the specialty training curriculum for both specialties. This commentary explores how multidisciplinary team (MDT) working can address these uncertainties to support shared decision-making and potentially improve outcomes in this vulnerable patient population. We highlight the need to involve ophthalmologists in obstetric MDTs, where appropriate, and the importance of establishing clear communication channels and referral pathways between both specialties and across hospitals in the region. We also share our experience of establishing these pathways locally, the feedback we have received from interdisciplinary educational initiatives to improve knowledge sharing, and possible future directions for this collaborative approach to help fill the evidence gap.
Practical routes to preregistration: a guide to enhanced transparency and rigour in neuropsychological research
Abstract Preregistration is the act of formally documenting a research plan before collecting (or at least before analysing) the data. It allows those reading a final research report to know which aspects of a study were decided before sight of the data, and which were added later. This enables informed evaluation of the severity with which scientific claims have been tested. We, as the British Neuropsychological Society Open Research Group, conducted a survey to explore awareness and adoption of open research practices within our field. Neuropsychology involves the study of relatively rare or hard-to-access participants, creating practical challenges that, according to our survey, are perceived as barriers to preregistration. We survey the available routes to preregistration, and suggest that the barriers are all surmountable in one way or another. However, there is a tension, in that higher levels of bias control require greater restriction over the flexibility of preregistered studies, but such flexibility is often essential for neuropsychological research. Researchers must therefore consider which route provides the right balance of rigour and pragmatic flexibility to render a preregistered project viable for them. By mapping out the issues and potential solutions, and by signposting relevant resources and publication routes, we hope to facilitate well-reasoned decision-making and empower neuropsychologists to enhance the transparency and rigour of their research. Although we focus neuropsychology, our guidance is applicable to any field that studies hard-to-access human samples, or involves arduous or expensive means of data collection.
Improving Outcomes in Survivors of Sepsis-The Transition from Secondary to Primary Care, and the Role of Primary Care: A Narrative Review.
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The number of patients with sepsis requiring critical care admission is increasing. At the same time, overall mortality from sepsis is declining. With increasing survival to hospital discharge, there are an increasing number of sepsis survivors whose care needs shift from the acute to chronic care settings. Recently, the phrase "post-sepsis syndrome" has emerged to encompass the myriad of complications in patients recovering from sepsis. The aim of this narrative review is to provide a contemporary summary of the available literature on post-sepsis care and highlight areas of ongoing research. There are many incentives for improving the quality of survivorship following sepsis, including individual health-related outcomes (e.g., increased survival, enhanced physical and psychological health) and wider socio-economic benefits (e.g., reduced economic burden on the healthcare systems, reduced physical and psychological burden on carers, ability for individuals (and carers) to return to workforce). Modifiable factors influencing long-term outcomes can be in-hospital or after discharge, when primary care physicians play a pivotal role. Despite national and international guidance being available, this area has been under-recognised historically, despite its profoundly negative impact on both patients and their families or caregivers. Contributing factors likely include the lack of a formally recognised "disease" or pathology, the presence of challenging-to-treat symptoms such as fatigue, weakness and cognitive impairment, and the prevailing assumption that ongoing rehabilitation merely requires time. Our review will focus on the following areas: screening for new cognitive and physical impairments; optimisation of pre-existing comorbidities; transition to primary care; and palliative care. Primary care physicians may have a crucial role to play in improving outcomes in sepsis survivors, and candidate interventions include education on common complications of post-sepsis syndrome.
The prevalence and topography of spinal cord demyelination in multiple sclerosis: a retrospective study
AbstractSpinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and distribution of demyelination, staged by lesion activity, was determined and topographical maps were created to identify patterns of lesion prevalence and distribution using mixed models and permutation-based voxelwise analysis. 460 lesions were observed throughout the spinal cord with 76.5% of cases demonstrating at least 1 lesion. The cervical level was preferentially affected by lesions. 58.3% of lesions were inflammatory with 87.9% of cases harbouring at least 1 inflammatory lesion. Topographically, lesions consistently affected the dorsal and lateral columns with relative sparing of subpial areas in a distribution mirroring the vascular network. The presence of spinal cord lesions and the proportion of active lesions related strongly with clinical disease milestones, including time from onset to wheelchair and onset to death. We demonstrate that spinal cord demyelination is common, highly inflammatory, has a predilection for the cervical level, and relates to clinical disability. The topography of lesions in the dorsal and lateral columns and relative sparing of subpial areas points to a role of the vasculature in lesion pathogenesis, suggesting short-range cell infiltration from the blood and signaling molecules circulating in the perivascular space incite lesion development. These findings challenge the notion that end-stage progressive multiple sclerosis is ‘burnt out’ and an outside-in lesional gradient predominates in the spinal cord. Taken together, this study provides support for long-term targeting of inflammatory demyelination in the spinal cord and nominates vascular dysfunction as a potential target for new therapeutic approaches to limit irreversible disability.
Regional contribution of vascular dysfunction in white matter dementia: clinical and neuropathological insights
The maintenance of adequate blood supply and vascular integrity is fundamental to ensure cerebral function. A wide range of studies report vascular dysfunction in white matter dementias, a group of cerebral disorders characterized by substantial white matter damage in the brain leading to cognitive impairment. Despite recent advances in imaging, the contribution of vascular-specific regional alterations in white matter dementia has been not extensively reviewed. First, we present an overview of the main components of the vascular system involved in the maintenance of brain function, modulation of cerebral blood flow and integrity of the blood–brain barrier in the healthy brain and during aging. Second, we review the regional contribution of cerebral blood flow and blood–brain barrier disturbances in the pathogenesis of three distinct conditions: the archetypal white matter predominant neurocognitive dementia that is vascular dementia, a neuroinflammatory predominant disease (multiple sclerosis) and a neurodegenerative predominant disease (Alzheimer’s). Finally, we then examine the shared landscape of vascular dysfunction in white matter dementia. By emphasizing the involvement of vascular dysfunction in the white matter, we put forward a hypothetical map of vascular dysfunction during disease-specific progression to guide future research aimed to improve diagnostics and facilitate the development of tailored therapies.
Neuroaxonal damage in natalizumab-treated MS patients: The role of JCV antibody titres
Background: While John Cunningham virus (JCV) is known to cause neuronal damage in progressive multifocal leukoencephalopathy (PML) among natalizumab-treated MS patients, its association with axonal loss in non-PML conditions remains unclear. Methods: In a cohort of 128 natalizumab-treated MS patients, serum neurofilament (sNfL) levels and JCV antibody titres were measured. Results: Among 128 patients (mean age = 38.4 years, 71.9% female), 51 (40%) were JCV positive. NfL levels increased by 15.3% for JCV index <0.7 (95% confidence interval [CI] = 0.963–1.381), by 18.6% for index 0.7–1.5 (95% CI = 1.009–1.394) and by 21.1% for index >1.5 (95% CI = 1.040–1.409) compared to JCV negative patients. Conclusion: These findings indicate a potential link between JCV burden and neuroaxonal degeneration in natalizumab-treated MS patients.
Optical coherence tomography with voxel-based morphometry: a new tool to unveil focal retinal neurodegeneration in multiple sclerosis
AbstractNeurodegeneration is the main contributor to disability accumulation in multiple sclerosis. Previous studies in neuro-ophthalmology have revealed that neurodegeneration in multiple sclerosis also affects the neuro-retina. Optical coherence tomography has been used to measure thinning of retinal layers, which correlates with several other markers for axonal/neuronal loss in multiple sclerosis. However, the existing analytical tools have limitations in terms of sensitivity and do not provide topographical information. In this study, we aim to evaluate whether voxel-based morphometry can increase sensitivity in detecting neuroaxonal degeneration in the retina and offer topographical information. A total of 131 people with multiple sclerosis (41 clinically isolated syndrome, 53 relapsing-remitting and 37 progressive multiple sclerosis) and 50 healthy subjects were included. Only eyes with normal global peripapillary retinal nerve fibre layer thickness and no history of optic neuritis were considered. Voxel-based morphometry and voxel-wise statistical comparisons were performed on the following: (i) patients at different disease stages and 2) patients who experienced the first demyelination attack without subclinical optic neuritis, assessed by visual evoked potentials. Standard parameters failed to discern any differences; however, voxel-based morphometry–optical coherence tomography successfully detected focal macular atrophy of retinal nerve fibre layer and ganglion cell/inner plexiform layer, along with thickening of inner nuclear layer in patients who experienced the first demyelination attack (disease duration = 4.2 months). Notably, the atrophy pattern of the ganglion cell/inner plexiform layer was comparable across disease phenotypes. In contrast, the retinal nerve fibre layer atrophy spread from the optic nerve head to the fovea as the disease evolved towards the progressive phase. Furthermore, for patients who experienced the first neurological episode, the severity of retinal nerve fibre layer atrophy at entry could predict a second attack. Our results demonstrate that voxel-based morphometry–optical coherence tomography exhibits greater sensitivity than standard parameters in detecting focal retinal atrophy, even at clinical presentation, in eyes with no history of optic neuritis and with normal latency of visual evoked potentials. Thinning of the ganglion cell/inner plexiform layer primarily concentrated in nasal perifovea in all disease phenotypes, indicating selective vulnerability of retinal ganglion cells and their perifoveal axons. Conversely, the degree of retinal nerve fibre layer thinning seems to be related to the clinical course of multiple sclerosis. The findings suggest bidirectional neurodegeneration in the visual pathway. Voxel-based morphometry–optical coherence tomography shows potential as a valuable tool for monitoring neurodegeneration on a patient level and evaluating the efficacy of novel neuroprotective treatments.
Anatomy of the superior hypogastric plexus and its relevance to anterior lumbar interbody fusion
OBJECTIVE Retrograde ejaculation (RE) is a known complication of anterior lumbar interbody fusion (ALIF) and results from injury to the superior hypogastric plexus (SHP) during intervertebral disc exposure. Yet, there has been no recommendation for SHP mobilization. Thus, the aim of this study was to describe the anatomy of the SHP and vessels at the L5–S1 level, and to evaluate the possibility of SHP mobilization and its retraction to the side. METHODS Twelve formaldehyde-embalmed cadavers (6 female and 6 male; mean age 65.5 years [range 60–77 years]) were dissected. Distances from the SHP and middle sacral vessels to the midline were measured at the L5–S1 level. The relationship of the great vessel bifurcations and common iliac vessels to the SHP were noted. The extent of lateral retraction of the SHP following mobilization was measured in relation to the midline. Moreover, the positions of the SHP and middle sacral vessels relative to the midline at the L5–S1 level were determined. RESULTS The SHP formed below the aortic bifurcation and was present at the L5–S1 level in all cases. The SHP overlaid the midline with a left-sided shift. There were 4 cases (33.3%) in which lateral retraction was not achievable because the plexus divided into hypogastric nerves at the L5–S1 level or was too wide for safe mobilization. In the remaining cases, retraction on the left side was achievable up to 15.3 mm from the midline, while retraction to the right side was limited to 5.3 mm from the midline. The types of SHP morphological arrangement included single cord (41.7%), plexiform (41.7%), and fiber (16.6%). CONCLUSIONS Based on the more extensive left-sided shift of the SHP at the L5–S1 level and frequent presence of the third left splanchnic lumbar nerve, attempting retraction to the left side is recommended. If it is not feasible, the SHP should be split at the midline, with both components mobilized laterally.
Multimodal gradients unify local and global cortical organization.
Functional specialization of brain areas and subregions, as well as their integration into large-scale networks, are key principles in neuroscience. Consolidating both local and global perspectives on cortical organization, however, remains challenging. Here, we present an approach to integrate inter- and intra-areal similarities of microstructure, structural connectivity, and functional interactions. Using high-field in-vivo 7 tesla (7 T) Magnetic Resonance Imaging (MRI) data and a probabilistic post-mortem atlas of cortical cytoarchitecture, we derive multimodal gradients that capture cortex-wide organization. Inter-areal similarities follow a canonical sensory-fugal gradient, linking cortical integration with functional diversity across tasks. However, intra-areal heterogeneity does not follow this pattern, with greater variability in association cortices. Findings are replicated in an independent 7 T dataset and a 100-subject 3 tesla (3 T) cohort. These results highlight a robust coupling between local arealization and global cortical motifs, advancing our understanding of how specialization and integration shape human brain function.
Approval of retinal gene therapies in the US and Europe based on visual acuity and microperimetry
Introduction: Gene therapy is an emerging technology for the treatment of inherited retinal diseases. Whilst the development of delivery vectors and genotyping is progressing at speed, outcome measures used for regulatory approval are slow to change and hinder progress at clinical trial stage. Traditional measures of visual function such as best corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) may only be useful across a very short window and in late stages of disease. They are unsuitable measures for early- to mid- stage disease where foveal function, and so letter reading, is primarily unaffected. In such cases, microperimetry is an accurate and repeatable measure of retinal function of the whole of the macular region. Areas covered: This article provides evidence-based guidance on criteria for microperimetry outcome measures, drawing on experience from long-term clinical trials in RPGR-related retinitis pigmentosa. Expert opinion: Microperimetry provides a sensitive and repeatable measure of retinal function, with mean sensitivity across the macula or central 16-point region offering a more reliable metric than single-point requirements recommended by the FDA. A 2.5 dB gain in mean sensitivity is equivalent to a 13-letter increase in low-luminance ETDRS representing a clinically significant change and aligning closely with regulatory standards.
Treatment Selection and Prioritization for the EJS ACT-PD MAMS Trial Platform.
BACKGROUND: There are currently no disease-modifying therapies (DMTs) registered for Parkinson's disease (PD). The Edmond J. Safra Accelerating Clinical Trials in Parkinson Disease (EJS ACT-PD) initiative will expedite clinical assessment of putative DMTs through a multi-arm multistage (MAMS) trial, testing several treatments against a common placebo arm and replacing unsuccessful therapies early. OBJECTIVE: The objective of this study was to describe the treatment selection process for the EJS ACT-PD clinical trial platform. METHODS: A Treatment Selection Working Group (TSWG) identified compounds using complementary strategies, such as literature search, related initiatives (Cure Parkinson's International Linked Clinical Trials [iLCT] initiative), and expert suggestions. Compounds were classified into five mechanistic subgroups (mitochondrial, lysosomal, protein, inflammation, "other"). "Go/No-Go" criteria and a scoring system covering preclinical, pharmacological, and clinical evidence were devised. Experts scored the candidates for quantitative rankings. Dossiers adapted from iLCT documents were produced for the top-ranked compounds and in turn prioritized by the TSWG. Practical and logistical considerations from the Steering Committee (SC) guided the final decision. Patient and Public Involvement and Engagement representatives provided feedback throughout the process. RESULTS: A total of 293 interventions were identified, 52 of which passed the "Go/No-Go" criteria and were scored. Dossiers of the 14 top-ranked compounds were submitted to the SC. Telmisartan, terazosin, and ursodeoxycholic acid were selected as the initial interventions. CONCLUSIONS: Drug selection in DMT PD MAMS trials requires consideration of scientific and practical issues. We present a robust system that can inform similar initiatives. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.