Neurophysiological and brain structural markers of cognitive frailty differs from Alzheimer’s disease

AbstractWith increasing life span, there is growing importance of understanding the mechanisms of successful cognitive ageing. In contrast, cognitive frailty has been proposed to be a precursor to Alzheimer’s disease. Here we test the hypothesis that cognitively frail adults represent a branch of healthy ageing, distinct from latent dementia. We used electro-magnetoencephalography and magnetic resonance imaging to investigate the structural and neurophysiological features of cognitive frailty in relation to healthy aging, and clinical presentations of mild cognitive impairment and Alzheimer’s disease. Cognitive performance of the cognitively frail group was similar to those with mild cognitive impairment. We used a novel cross-modal oddball task to induce mismatch responses to unexpected stimuli. Both controls and cognitively frail showed stronger mismatch responses and larger temporal grey matter volume, compared to people with mild cognitive impairment and Alzheimer’s disease. Our results suggest that cognitively frail represents a spectrum of normal ageing rather than incipient or undiagnosed Alzheimer’s disease. Lower cognitive reserve, hearing impairment and medical comorbidity might contribute to the aetiology of cognitive impairment.The study was supported by the Medical Research Council [SUAG/004 RG91365, SUAG/046 RG101400; SUAG/051 RG101400], the Wellcome Trust [103838], the Dementias Platform UK [MR/L023784/1 & MR/L023784/2], Alzheimer’s Research UK [ARUK-PG2017B-19], a Holt Fellowship, and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. For the purpose of open access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission

An evaluation of a training tool and study day in chest image interpretation

Background: With the use of expert consensus a digital tool was developed by the research team which proved useful when teaching radiographers how to interpret chest images. The training tool included A) a search strategy training tool and B) an educational tool to communicate the search strategies using eye tracking technology. This training tool has the potential to improve interpretation skills for other healthcare professionals.Methods: To investigate this, 31 healthcare professionals i.e. nurses and physiotherapists, were recruited and participants were randomised to receive access to the training tool (intervention group) or not to have access to the training tool (control group) for a period of 4-6 weeks. Participants were asked to interpret different sets of 20 chest images before and after the intervention period. A study day was then provided to all participants following which participants were again asked to interpret a different set of 20 chest images (n=1860). Each participant was asked to complete a questionnaire on their perceptions of the training provided. Results: Data analysis is in progress. 50% of participants did not have experience in image interpretation prior to the study. The study day and training tool were useful in improving image interpretation skills. Participants perception of the usefulness of the tool to aid image interpretation skills varied among respondents.Conclusion: This training tool has the potential to improve patient diagnosis and reduce healthcare costs

Challenges of Investigating Community Outbreaks of Cyclosporiasis, British Columbia, Canada

Investigations of community outbreaks of cyclosporiasis are challenged by case-patients’ poor recall of exposure resulting from lags in detection and the stealthy nature of food vehicles. We combined multiple techniques, including early consultation with food regulators, traceback of suspected items, and grocery store loyalty card records, to identify a single vehicle for a cyclosporiasis outbreak in British Columbia, Canada, in 2007

GABA-ergic Dynamics in Human Frontotemporal Networks Confirmed by Pharmaco-Magnetoencephalography.

To bridge the gap between preclinical cellular models of disease and in vivo imaging of human cognitive network dynamics, there is a pressing need for informative biophysical models. Here we assess dynamic causal models (DCM) of cortical network responses, as generative models of magnetoencephalographic observations during an auditory oddball roving paradigm in healthy adults. This paradigm induces robust perturbations that permeate frontotemporal networks, including an evoked 'mismatch negativity' response and transiently induced oscillations. Here, we probe GABAergic influences in the networks using double-blind placebo-controlled randomized-crossover administration of the GABA reuptake inhibitor, tiagabine (oral, 10 mg) in healthy older adults. We demonstrate the facility of conductance-based neural mass mean-field models, incorporating local synaptic connectivity, to investigate laminar-specific and GABAergic mechanisms of the auditory response. The neuronal model accurately recapitulated the observed magnetoencephalographic data. Using parametric empirical Bayes for optimal model inversion across both drug sessions, we identify the effect of tiagabine on GABAergic modulation of deep pyramidal and interneuronal cell populations. We found a transition of the main GABAergic drug effects from auditory cortex in standard trials to prefrontal cortex in deviant trials. The successful integration of pharmaco- magnetoencephalography with dynamic causal models of frontotemporal networks provides a potential platform on which to evaluate the effects of disease and pharmacological interventions.SIGNIFICANCE STATEMENT Understanding human brain function and developing new treatments require good models of brain function. We tested a detailed generative model of cortical microcircuits that accurately reproduced human magnetoencephalography, to quantify network dynamics and connectivity in frontotemporal cortex. This approach identified the effect of a test drug (GABA-reuptake inhibitor, tiagabine) on neuronal function (GABA-ergic dynamics), opening the way for psychopharmacological studies in health and disease with the mechanistic precision afforded by generative models of the brain

GABAergic cortical network physiology in frontotemporal lobar degeneration.

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients' GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials

A multi-site, multi-participant magnetoencephalography resting-state dataset to study dementia: The BioFIND dataset

Early detection of Alzheimer's Disease (AD) is vital to reduce the burden of dementia and for developing effective treatments. Neuroimaging can detect early brain changes, such as hippocampal atrophy in Mild Cognitive Impairment (MCI), a prodromal state of AD. However, selecting the most informative imaging features by machine-learning requires many cases. While large publically-available datasets of people with dementia or prodromal disease exist for Magnetic Resonance Imaging (MRI), comparable datasets are missing for Magnetoencephalography (MEG). MEG offers advantages in its millisecond resolution, revealing physiological changes in brain oscillations or connectivity before structural changes are evident with MRI. We introduce a MEG dataset with 324 individuals: patients with MCI and healthy controls. Their brain activity was recorded while resting with eyes closed, using a 306-channel MEG scanner at one of two sites (Madrid or Cambridge), enabling tests of generalization across sites. A T1-weighted MRI is provided to assist source localisation. The MEG and MRI data are formatted according to international BIDS standards and analysed freely on the DPUK platform (https://portal.dementiasplatform.uk/Apply). Here, we describe this dataset in detail, report some example (benchmark) analyses, and consider its limitations and future directions

Seeking Abraham: A Report of Furman University\u27s Task Force on Slavery and Justice

After more than a year of study, the Furman University Task Force on Slavery and Justice presents its findings in this report. The report includes the Task Force’s values and process, a presentation of the history of Furman’s early ties to slavery, a number of short vignettes by individual Task Force members, and a number of recommendations for the university to address. Members of the Task Force represent diverse students and alumni, as well as faculty and staff. The report is the result of commissioning a history, activating student research projects, hosting scholars who consulted with the Task Force, creating oral histories and curating viewpoints, and attending Universities Studying Slavery, a consortium headquartered at the University of Virginia with more than 40 international colleges and universities. The university has made a commitment to serious consideration of the entire report

GABAergic cortical network physiology in frontotemporal lobar degeneration.

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients' GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials