Search results
Found 21168 matches for
The Motor Neuron Disease Association has published a blog post from Martin Turner about 'BioMOx', the Oxford Study for Biomarkers in MND.
Oxford Spine Buddies: an acceptability and feasibility project for peer-to-peer support in a spine sarcoma service
Background: Primary bone and soft tissue sarcoma of the spine are rare and account for less than 0.2% of all neoplasm incidences. Following a patient and public involvement event, the need to explore patient support pathways was identified, which initiated this service evaluation project. Aim: To determine the acceptability and feasibility of a peer-to-peer support project among people using the spine sarcoma service. Methods: Users were paired and introduced via Microsoft Teams. Quantitative and qualitative data both pre- and post-introduction of a buddy were collected. Findings: Service users felt that, although they would have preferred having a buddy at the time of their diagnosis, being allocated a buddy made them feel reassured and better supported. Conclusion: The project was well received and preliminary data are encouraging. Therefore, due to early findings from the first participants, the service is continuing to roll out the buddy programme.
Amplitudes of resting-state functional networks - investigation into their correlates and biophysical properties.
Resting-state fMRI studies have shown that multiple functional networks, which consist of distributed brain regions that share synchronised spontaneous activity, co-exist in the brain. As these resting-state networks (RSNs) have been thought to reflect the brain's intrinsic functional organization, intersubject variability in the networks' spontaneous fluctuations may be associated with individuals' clinical, physiological, cognitive, and genetic traits. Here, we investigated resting-state fMRI data along with extensive clinical, lifestyle, and genetic data collected from 37,842 UK Biobank participants, with the object of elucidating intersubject variability in the fluctuation amplitudes of RSNs. Functional properties of the RSN amplitudes were first examined by analyzing correlations with the well-established between-network functional connectivity. It was found that a network amplitude is highly correlated with the mean strength of the functional connectivity that the network has with the other networks. Intersubject clustering analysis showed the amplitudes are most strongly correlated with age, cardiovascular factors, body composition, blood cell counts, lung function, and sex, with some differences in the correlation strengths between sensory and cognitive RSNs. Genome-wide association studies (GWASs) of RSN amplitudes identified several significant genetic variants reported in previous GWASs for their implications in sleep duration. We provide insight into key factors determining RSN amplitudes and demonstrate that intersubject variability of the amplitudes primarily originates from differences in temporal synchrony between functionally linked brain regions, rather than differences in the magnitude of raw voxelwise BOLD signal changes. This finding additionally revealed intriguing differences between sensory and cognitive RSNs with respect to sex effects on temporal synchrony and provided evidence suggesting that synchronous coactivations of functionally linked brain regions, and magnitudes of BOLD signal changes, may be related to different genetic mechanisms. These results underscore that intersubject variability of the amplitudes in health and disease need to be interpreted largely as a measure of the sum of within-network temporal synchrony and amplitudes of BOLD signals, with a dominant contribution from the former.
The effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease.
We have previously identified a network of higher-order brain regions particularly vulnerable to the ageing process, schizophrenia and Alzheimer's disease. However, it remains unknown what the genetic influences on this fragile brain network are, and whether it can be altered by the most common modifiable risk factors for dementia. Here, in ~40,000 UK Biobank participants, we first show significant genome-wide associations between this brain network and seven genetic clusters implicated in cardiovascular deaths, schizophrenia, Alzheimer's and Parkinson's disease, and with the two antigens of the XG blood group located in the pseudoautosomal region of the sex chromosomes. We further reveal that the most deleterious modifiable risk factors for this vulnerable brain network are diabetes, nitrogen dioxide - a proxy for traffic-related air pollution - and alcohol intake frequency. The extent of these associations was uncovered by examining these modifiable risk factors in a single model to assess the unique contribution of each on the vulnerable brain network, above and beyond the dominating effects of age and sex. These results provide a comprehensive picture of the role played by genetic and modifiable risk factors on these fragile parts of the brain.
Genome sequence analyses identify novel risk loci for multiple system atrophy.
Multiple system atrophy (MSA) is an adult-onset, sporadic synucleinopathy characterized by parkinsonism, cerebellar ataxia, and dysautonomia. The genetic architecture of MSA is poorly understood, and treatments are limited to supportive measures. Here, we performed a comprehensive analysis of whole genome sequence data from 888 European-ancestry MSA cases and 7,128 controls to systematically investigate the genetic underpinnings of this understudied neurodegenerative disease. We identified four significantly associated risk loci using a genome-wide association study approach. Transcriptome-wide association analyses prioritized USP38-DT, KCTD7, and lnc-KCTD7-2 as novel susceptibility genes for MSA within these loci, and single-nucleus RNA sequence analysis found that the associated variants acted as cis-expression quantitative trait loci for multiple genes across neuronal and glial cell types. In conclusion, this study highlights the role of genetic determinants in the pathogenesis of MSA, and the publicly available data from this study represent a valuable resource for investigating synucleinopathies.
The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.
Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.
Feasibility of multiorgan risk prediction with routinely collected diagnostics: a prospective cohort study in the UK Biobank.
OBJECTIVES: Despite rising rates of multimorbidity, existing risk assessment tools are mostly limited to a single outcome of interest. This study tests the feasibility of producing multiple disease risk estimates with at least 70% discrimination (area under the receiver operating curve, AUROC) within the time and information constraints of the existing primary care health check framework. DESIGN: Observational prospective cohort study SETTING: UK Biobank. PARTICIPANTS: 228 240 adults from the UK population. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Myocardial infarction, atrial fibrillation, heart failure, stroke, all-cause dementia, chronic kidney disease, fatty liver disease, alcoholic liver disease, liver cirrhosis and liver failure. RESULTS: Using a set of predictors easily gathered at the standard primary care health check (such as the National Health Service Health Check), we demonstrate that it is feasible to simultaneously produce risk estimates for multiple disease outcomes with AUROC of 70% or greater. These predictors can be entered once into a single form and produce risk scores for stroke (AUROC 0.727, 95% CI 0.713 to 0.740), all-cause dementia (0.823, 95% CI 0.810 to 0.836), myocardial infarction (0.785, 95% CI 0.775 to 0.795), atrial fibrillation (0.777, 95% CI 0.768 to 0.785), heart failure (0.828, 95% CI 0.818 to 0.838), chronic kidney disease (0.774, 95% CI 0.765 to 0.783), fatty liver disease (0.766, 95% CI 0.753 to 0.779), alcoholic liver disease (0.864, 95% CI 0.835 to 0.894), liver cirrhosis (0.763, 95% CI 0.734 to 0.793) and liver failure (0.746, 95% CI 0.695 to 0.796). CONCLUSIONS: Easily collected diagnostics can be used to assess 10-year risk across multiple disease outcomes, without the need for specialist computing or invasive biomarkers. Such an approach could increase the utility of existing data and place multiorgan risk information at the fingertips of primary care providers, thus creating opportunities for longer-term multimorbidity prevention. Additional work is needed to validate whether these findings would hold in a larger, more representative cohort outside the UK Biobank.
Development of a national maternity early warning score: centile based score development and Delphi informed escalation pathways
ObjectiveTo derive a new maternity early warning score (MEWS) from prospectively collected data on maternity vital signs and to design clinical response pathways with a Delphi consensus exercise.DesignCentile based score development and Delphi informed escalation pathways.SettingPregnancy Physiology Pattern Prediction (4P) prospective UK cohort study, 1 August 2012 to 28 December 2016.ParticipantsPregnant people from the 4P study, recruited before 20 weeks' gestation at three UK maternity centres (Oxford, Newcastle, and London). 841, 998, and 889 women provided data in the early antenatal, antenatal, and postnatal periods.Main outcome measuresDevelopment of a new national MEWS, assigning numerical weights to measurements in the lower and upper extremes of distributions of individual vital signs from the 4P prospective cohort study. Comparison of escalation rates of the new national MEWS with the Scottish and Irish MEWS systems from 18 to 40 weeks' gestation. Delphi consensus exercise to agree clinical responses to raised scores.ResultsA new national MEWS was developed by assigning numerical weights to measurements in the lower and upper extremes (5%, 1%) of distributions of vital signs, except for oxygen saturation where lower centiles (10%, 2%) were used. For the new national MEWS, in a healthy population, 56% of observation sets resulted in a total score of 0 points, 26% a score of 1 point, 12% a score of 2 points, and 18% a score of ≥2 points (escalation of care is triggered at a total score of ≥2 points). Corresponding values for the Irish MEWS were 37%, 25%, 22%, and 38%, respectively; and for the Scottish MEWS, 50%, 18%, 21%, and 32%, respectively. All three MEWS were similar at the beginning of pregnancy, averaging 0.7-0.9 points. The new national MEWS had a lower mean score for the rest of pregnancy, with the mean score broadly constant (0.6-0.8 points). The new national MEWS had an even distribution of healthy population alerts across the antenatal period. In the postnatal period, heart rate threshold values were adjusted to align with postnatal changes. The centile based score derivation approach meant that each vital sign component in the new national MEWS had a similar alert rate. Suggested clinical responses to different MEWS values were agreed by consensus of an independent expert panel.ConclusionsThe centile based MEWS alerted escalation of care evenly across the antenatal period in a healthy population, while reducing alerts in healthy women compared with other MEWS systems. How well the tool predicted adverse outcomes, however, was not assessed and therefore external validation studies in large datasets are needed. Unlike other MEWS systems, the new national MEWS was developed with prospectively collected data on vital signs and used a systematic, expert informed process to design an associated escalation protocol.
Perspectives on the diagnosis and management of functional cognitive disorder: An international Delphi study.
BACKGROUND: Current proposed criteria for functional cognitive disorder (FCD) have not been externally validated. We sought to analyse the current perspectives of cognitive specialists in the diagnosis and management of FCD in comparison with neurodegenerative conditions. METHODS: International experts in cognitive disorders were invited to assess seven illustrative clinical vignettes containing history and bedside characteristics alone. Participants assigned a probable diagnosis and selected the appropriate investigation and treatment. Qualitative, quantitative and inter-rater agreement analyses were undertaken. RESULTS: Eighteen diagnostic terminologies were assigned by 45 cognitive experts from 12 countries with a median of 13 years of experience, across the seven scenarios. Accurate discrimination between FCD and neurodegeneration was observed, independently of background and years of experience: 100% of the neurodegenerative vignettes were correctly classified and 75%-88% of the FCD diagnoses were attributed to non-neurodegenerative causes. There was <50% agreement in the terminology used for FCD, in comparison with 87%-92% agreement for neurodegenerative syndromes. Blood tests and neuropsychological evaluation were the leading diagnostic modalities for FCD. Diagnostic communication, psychotherapy and psychiatry referral were the main suggested management strategies in FCD. CONCLUSIONS: Our study demonstrates the feasibility of distinguishing between FCD and neurodegeneration based on relevant patient characteristics and history details. These characteristics need further validation and operationalisation. Heterogeneous labelling and framing pose clinical and research challenges reflecting a lack of agreement in the field. Careful consideration of FCD diagnosis is advised, particularly in the presence of comorbidities. This study informs future research on diagnostic tools and evidence-based interventions.
Excessive left anterior hippocampal and caudate activation in schizophrenia underlie cognitive underperformance in a virtual navigation task.
We used a virtual navigation paradigm in a city environment to assess neuroanatomical correlates of cognitive deficits in schizophrenia spectrum disorders (SSD). We studied a total of N = 36 subjects: 18 with SSD and 18 matched unaffected controls. Participants completed 10 rapid, single-trial navigation tasks within the virtual city while undergoing functional magnetic resonance imaging (fMRI). All trials tested ability to find different targets seen earlier, during the passive viewing of a path around different city blocks. SSD patients had difficulty finding previously-encountered targets, were less likely to find novel shortcuts to targets, and more likely to attempt retracing of the path observed during passive viewing. Based on a priori region-of-interest analyses, SSD participants had hyperactivation of the left hippocampus when passively viewing turns, hyperactivation of the left caudate when finding targets, and hypoactivation of a focal area of the dorsolateral prefrontal cortex when targets were initially shown during passive viewing. We propose that these brain-behaviour relations may bias or reinforce stimulus-response navigation approaches in SSD and underlie impaired performance when allocentric spatial memory is required, such as when forming efficient shortcuts. This pattern may extend to more general cognitive impairments in SSD that could be used to design remediation strategies.
The cortical neurophysiological signature of amyotrophic lateral sclerosis
Abstract The progressive loss of motor function characteristic of amyotrophic lateral sclerosis is associated with widespread cortical pathology extending beyond primary motor regions. Increasing muscle weakness reflects a dynamic, variably compensated brain network disorder. In the quest for biomarkers to accelerate therapeutic assessment, the high temporal resolution of magnetoencephalography is uniquely able to non-invasively capture micro-magnetic fields generated by neuronal activity across the entire cortex simultaneously. This study examined task-free magnetoencephalography to characterise the cortical oscillatory signature of amyotrophic lateral sclerosis for potential as a pharmacodynamic biomarker. Eight-ten minutes of magnetoencephalography in the task-free, eyes-open state was recorded in amyotrophic lateral sclerosis (n=36) and healthy age-matched controls (n=51), followed by a structural MRI scan for co-registration. Extracted magnetoencephalography metrics from the delta, theta, alpha, beta, low-gamma, high-gamma frequency bands included oscillatory power (regional activity), 1/f exponent (complexity) and amplitude envelope correlation (connectivity). Groups were compared using a permutations-based general linear model with correction for multiple comparisons and confounders. To test whether the extracted metrics could predict disease severity, a Random Forest Regression model was trained and evaluated using nested Leave-One-Out Cross-Validation. Amyotrophic lateral sclerosis was characterised by reduced sensorimotor beta band and increased high-gamma band power. Within the premotor cortex, increased disability was associated with a reduced 1/f exponent. Increased disability was more widely associated with increased global connectivity in the delta, theta, and high-gamma bands. Intra-hemispherically, increased disability scores were particularly associated with increases in temporal connectivity and inter-hemispherically with increases in frontal and occipital connectivity. The Random Forest model achieved a coefficient of determination (R2) of 0.24. The combined reduction in cortical sensorimotor beta and rise in gamma power is compatible with the established hypothesis of loss of inhibitory, GABAergic interneuronal circuits in pathogenesis. A lower 1/f exponent potentially reflects a more excitable cortex and a pathology unique to amyotrophic lateral sclerosis when considered with the findings published in other neurodegenerative disorders. Power and complexity changes corroborate with the results from paired-pulse transcranial magnetic stimulation. Increased magnetoencephalography connectivity in worsening disability is thought to represent compensatory responses to a failing motor system. Restoration of cortical beta and gamma band power has significant potential to be tested in an experimental medicine setting. Magnetoencephalography-based measures have potential as sensitive outcome measures of therapeutic benefit in drug trials and may have wider diagnostic value with further study, including as predictive markers in asymptomatic carriers of disease-causing genetic variants.