Blood inflammation relates to neuroinflammation and survival in frontotemporal lobar degeneration.

Neuroinflammation is an important pathogenic mechanism in many neurodegenerative diseases, including those caused by frontotemporal lobar degeneration (FTLD). Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, proportionate to symptom severity and rate of progression. However, evidence for corresponding blood markers of inflammation and their relationship with central inflammation and clinical outcome are limited. There is a pressing need for such scalable, accessible and mechanistically relevant blood markers as these will reduce the time, risk, and costs of experimental medicine trials. We therefore assessed inflammatory patterns of serum cytokines from 214 patients with clinical syndromes associated with FTLD as compared to healthy controls, including their correlation with brain regional microglial activation and disease progression. Serum assays used the MesoScale Discovery V-Plex-Human Cytokine 36 plex panel plus five additional cytokine assays. A sub-group of patients underwent 11C-PK11195 TSPO PET imaging, as an index of microglial activation. A Principal Component Analysis (PCA) was used to reduce the dimensionality of cytokine data, excluding cytokines that were undetectable in >50% of participants. Frequentist and Bayesian analyses were performed on the principal components, to compare each patient cohort to controls, and test for associations with central inflammation, neurodegeneration-related plasma markers and survival. The first component identified by the PCA (explaining 21.5% variance) was strongly loaded by pro-inflammatory cytokines, including TNF-α, TNF-R1, M-CSF, IL-17A, IL-12, IP-10 and IL-6. Individual scores of the component showed significant differences between each patient cohort and controls. The degree to which a patient expressed this peripheral inflammatory profile at baseline correlated negatively with survival (higher inflammation, shorter survival), even when correcting for baseline clinical severity. Higher pro-inflammatory profile scores were associated with higher microglial activation in frontal and brainstem regions, as quantified with 11C-PK11195 TSPO PET. A permutation-based Canonical Correlation Analysis confirmed the association between the same cytokine-derived pattern and central inflammation across brain regions in a fully data-based manner. This data-driven approach identified a pro-inflammatory profile across the FTLD clinical spectrum, which is associated with central neuroinflammation and worse clinical outcome. Blood-based markers of inflammation could increase the scalability and access to neuroinflammatory assessment of people with dementia, to facilitate clinical trials and experimental medicine studies.

Very large fluxes of methane measured above Bolivian seasonal wetlands.

Methane (CH4) mole fractions from the large semiseasonal Llanos de Moxos wetlands (∼70,000 km2) in northern Bolivia were measured by aircraft flights and ground sampling during early March 2019 (late wet season). Daily fluxes of CH4 determined from the measurements using box models and inverse modeling were between 168 (± 50) and 456 (± 145) mg CH4⋅m-2⋅d-1 for the areas overflown, very high compared with those of previous Amazon basin studies. If the seasonality of the CH4 emissions is comparable to other parts of the Amazon Basin, the region could contribute as much as 8% of annual Amazonian CH4 emissions.

Synaptic Loss in Frontotemporal Dementia Revealed by [11 C]UCB-J Positron Emission Tomography.

OBJECTIVE: Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [11 C]UCB-J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity. METHODS: Eleven participants with clinically probable bvFTD and 25 age- and sex-matched healthy controls were included. Participants underwent dynamic [11 C]UCB-J PET, structural magnetic resonance imaging, and a neuropsychological battery, including the revised Addenbrooke Cognitive Examination, and INECO frontal screening. General linear models compared [11 C]UCB-J binding potential maps and gray matter volume between groups, and assessed associations between synaptic density and clinical severity in patients. Analyses were also performed using partial volume corrected [11 C]UCB-J binding potential from regions of interest (ROIs). RESULTS: Patients with bvFTD showed severe synaptic loss compared to controls. [11 C]UCB-J binding was reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex, and medial temporal lobe. Synaptic loss in the frontal and cingulate regions correlated significantly with cognitive impairments. Synaptic loss was more severe than atrophy. Results from ROI-based analyses mirrored the voxelwise results. INTERPRETATION: In accordance with preclinical models, and human postmortem evidence, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to severity. [11 C]UCB-J PET could support translational studies and experimental medicine strategies for new disease-modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142-154.

Neurophysiological consequences of synapse loss in progressive supranuclear palsy.

Synaptic loss occurs early in many neurodegenerative diseases and contributes to cognitive impairment even in the absence of gross atrophy. Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. We advocate that biophysical models of neurophysiology offer both a bridge from preclinical to clinical models of pathology and quantitative assays for experimental medicine. Such biophysical models can also disclose hidden neuronal dynamics generating neurophysiological observations such as EEG and magnetoencephalography. Here, we augment a biophysically informed mesoscale model of human cortical function by inclusion of synaptic density estimates as captured by 11C-UCB-J PET, and provide insights into how regional synapse loss affects neurophysiology. We use the primary tauopathy of progressive supranuclear palsy (Richardson's syndrome) as an exemplar condition, with high clinicopathological correlations. Progressive supranuclear palsy causes a marked change in cortical neurophysiology in the presence of mild cortical atrophy and is associated with a decline in cognitive functions associated with the frontal lobe. Using parametric empirical Bayesian inversion of a conductance-based canonical microcircuit model of magnetoencephalography data, we show that the inclusion of regional synaptic density-as a subject-specific prior on laminar-specific neuronal populations-markedly increases model evidence. Specifically, model comparison suggests that a reduction in synaptic density in inferior frontal cortex affects superficial and granular layer glutamatergic excitation. This predicted individual differences in behaviour, demonstrating the link between synaptic loss, neurophysiology and cognitive deficits. The method we demonstrate is not restricted to progressive supranuclear palsy or the effects of synaptic loss: such pathology-enriched dynamic causal models can be used to assess the mechanisms of other neurological disorders, with diverse non-invasive measures of pathology, and is suitable to test the effects of experimental pharmacology.

Microglial activation in the frontal cortex predicts cognitive decline in frontotemporal dementia.

Frontotemporal dementia is clinically and neuropathologically heterogeneous, but neuroinflammation, atrophy and cognitive impairment occur in all of its principal syndromes. Across the clinical spectrum of frontotemporal dementia, we assess the predictive value of in vivo neuroimaging measures of microglial activation and grey-matter volume on the rate of future cognitive decline. We hypothesized that inflammation is detrimental to cognitive performance, in addition to the effect of atrophy. Thirty patients with a clinical diagnosis of frontotemporal dementia underwent a baseline multimodal imaging assessment, including [11C]PK11195 PET to index microglial activation and structural MRI to quantify grey-matter volume. Ten people had behavioural variant frontotemporal dementia, 10 had the semantic variant of primary progressive aphasia and 10 had the non-fluent agrammatic variant of primary progressive aphasia. Cognition was assessed at baseline and longitudinally with the revised Addenbrooke's Cognitive Examination, at an average of 7-month intervals (for an average of ∼2 years, up to ∼5 years). Regional [11C]PK11195 binding potential and grey-matter volume were determined, and these were averaged within four hypothesis-driven regions of interest: bilateral frontal and temporal lobes. Linear mixed-effect models were applied to the longitudinal cognitive test scores, with [11C]PK11195 binding potentials and grey-matter volumes as predictors of cognitive performance, with age, education and baseline cognitive performance as covariates. Faster cognitive decline was associated with reduced baseline grey-matter volume and increased microglial activation in frontal regions, bilaterally. In frontal regions, microglial activation and grey-matter volume were negatively correlated, but provided independent information, with inflammation the stronger predictor of the rate of cognitive decline. When clinical diagnosis was included as a factor in the models, a significant predictive effect was found for [11C]PK11195 BPND in the left frontal lobe (-0.70, P = 0.01), but not for grey-matter volumes (P > 0.05), suggesting that inflammation severity in this region relates to cognitive decline regardless of clinical variant. The main results were validated by two-step prediction frequentist and Bayesian estimation of correlations, showing significant associations between the estimated rate of cognitive change (slope) and baseline microglial activation in the frontal lobe. These findings support preclinical models in which neuroinflammation (by microglial activation) accelerates the neurodegenerative disease trajectory. We highlight the potential for immunomodulatory treatment strategies in frontotemporal dementia, in which measures of microglial activation may also improve stratification for clinical trials.

Drawing from name in semantic dementia reveals graded object knowledge representations in anterior temporal lobe.

Semantic dementia (SD) is characterized by progressive impairment in conceptual knowledge due to anterior temporal lobe (ATL) neurodegeneration. Extended neuropsychological assessments can quantitatively demonstrate the semantic impairment, but this graded loss of knowledge can also be readily observed in the qualitative observation of patients' recall of single concepts. Here, we present the results of a simple task of object drawing-from-name, by patients with SD (N = 19), who have isolated atrophy of the ATL bilaterally. Both cross-sectionally and longitudinally, patient drawings demonstrated a pattern of degradation in which rare and distinctive features (such as the hump on a camel) were lost earliest in disease course, and there was an increase in the intrusion of prototypical features (such as the typical small ears of most mammals on an elephant) with more advanced disease. Crucially, patient drawings showed a continuum of conceptual knowledge loss rather than a binary 'present' or 'absent' state. Overall, we demonstrate that qualitative evaluation of line drawings of animals and objects provides fascinating insights into the transmodal semantic deficit in SD. Our results are consistent with a distributed-plus-hub model of semantic memory. The graded nature of the deficit in semantic performance observed in our subset of longitudinally observed patients suggests that the temporal lobe binds feature-based semantic attributes in its central convergence zone.

Causal Evidence for the Multiple Demand Network in Change Detection: Auditory Mismatch Magnetoencephalography across Focal Neurodegenerative Diseases.

The multiple demand (MD) system is a network of fronto-parietal brain regions active during the organization and control of diverse cognitive operations. It has been argued that this activation may be a nonspecific signal of task difficulty. However, here we provide convergent evidence for a causal role for the MD network in the "simple task" of automatic auditory change detection, through the impairment of top-down control mechanisms. We employ independent structure-function mapping, dynamic causal modeling (DCM), and frequency-resolved functional connectivity analyses of MRI and magnetoencephalography (MEG) from 75 mixed-sex human patients across four neurodegenerative syndromes [behavioral variant fronto-temporal dementia (bvFTD), nonfluent variant primary progressive aphasia (nfvPPA), posterior cortical atrophy (PCA), and Alzheimer's disease mild cognitive impairment with positive amyloid imaging (ADMCI)] and 48 age-matched controls. We show that atrophy of any MD node is sufficient to impair auditory neurophysiological response to change in frequency, location, intensity, continuity, or duration. There was no similar association with atrophy of the cingulo-opercular, salience or language networks, or with global atrophy. MD regions displayed increased functional but decreased effective connectivity as a function of neurodegeneration, suggesting partially effective compensation. Overall, we show that damage to any of the nodes of the MD network is sufficient to impair top-down control of sensation, providing a common mechanism for impaired change detection across dementia syndromes.SIGNIFICANCE STATEMENT Previous evidence for fronto-parietal networks controlling perception is largely associative and may be confounded by task difficulty. Here, we use a preattentive measure of automatic auditory change detection [mismatch negativity (MMN) magnetoencephalography (MEG)] to show that neurodegeneration in any frontal or parietal multiple demand (MD) node impairs primary auditory cortex (A1) neurophysiological response to change through top-down mechanisms. This explains why the impaired ability to respond to change is a core feature across dementias, and other conditions driven by brain network dysfunction, such as schizophrenia. It validates theoretical frameworks in which neurodegenerating networks upregulate connectivity as partially effective compensation. The significance extends beyond network science and dementia, in its construct validation of dynamic causal modeling (DCM), and human confirmation of frequency-resolved analyses of animal neurodegeneration models.

Stimulus-Induced Relief of Intentionally Incorporated Frustration Drives Refolding of a Water-Soluble Biomimetic Foldamer.

Frustrated, or nonoptimal, interactions have been proposed to be essential to a protein's ability to display responsive behavior such as allostery, conformational signaling, and signal transduction. However, the intentional incorporation of frustrated noncovalent interactions has not been explored as a design element in the field of dynamic foldamers. Here, we report the design, synthesis, characterization, and molecular dynamics simulations of the first dynamic water-soluble foldamer that, in response to a stimulus, exploits relief of frustration in its noncovalent network to structurally rearrange from a pleated to an intercalated columnar structure. Thus, relief of frustration provides the energetic driving force for structural rearrangement. This work represents a previously unexplored design element for the development of stimulus-responsive systems that has potential application to materials chemistry, synthetic biology, and molecular machines.

Design, Heterologous Expression, and Application of an Immobilized Protein Kinase.

Protein kinase A (PKA) is a biologically important enzyme for cell regulation, often referred to as the "central kinase". An immobilized PKA that retains substrate specificity and activity would be a useful tool for laboratory scientists, enabling targeted phosphorylation without interference from downstream kinase contamination or kinase autophosphorylation in sensitive assays. Moreover, it might also provide the benefits of robustness and reusability that are often associated with immobilized enzyme preparations. In this work, we describe the creation of a recombinant PKA fusion protein that incorporates the HaloTag covalent immobilization system. We demonstrate that protein fusion design, including affinity tag placement, is critical for optimal heterologous expression in Escherichia coli. Furthermore, we demonstrate various applications of our immobilized PKA, including the phosphorylation of recombinant PKA substrates, such as vasodilator-stimulated phosphoprotein, and endogenous PKA substrates in a cell lysate. This immobilized PKA also possesses robust activity and reusability over multiple trials. This work holds promise as a generalizable strategy for the production and application of immobilized protein kinases.

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.

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.

Advances in neuroimaging to support translational medicine in dementia.

Advances in neuroimaging are ideally placed to facilitate the translation from progress made in cellular genetics and molecular biology of neurodegeneration into improved diagnosis, prevention and treatment of dementia. New positron emission tomography (PET) ligands allow one to quantify neuropathology, inflammation and metabolism in vivo safely and reliably, to examine mechanisms of human disease and support clinical trials. Developments in MRI-based imaging and neurophysiology provide complementary quantitative assays of brain function and connectivity, for the direct testing of hypotheses of human pathophysiology. Advances in MRI are also improving the quantitative imaging of vascular risk and comorbidities. In combination with large datasets, open data and artificial intelligence analysis methods, new informatics-based approaches are set to enable accurate single-subject inferences for diagnosis, prediction and treatment that have the potential to deliver precision medicine for dementia. Here, we show, through the use of critically appraised worked examples, how neuroimaging can bridge the gaps between molecular biology, neural circuits and the dynamics of the core systems that underpin complex behaviours. We look beyond traditional structural imaging used routinely in clinical care, to include ultrahigh field MRI (7T MRI), magnetoencephalography and PET with novel ligands. We illustrate their potential as safe, robust and sufficiently scalable to be viable for experimental medicine studies and clinical trials. They are especially informative when combined in multimodal studies, with model-based analyses to test precisely defined hypotheses.

In vivo PET imaging of neuroinflammation in familial frontotemporal dementia.

INTRODUCTION: We report in vivo patterns of neuroinflammation and abnormal protein aggregation in seven cases of familial frontotemporal dementia (FTD) with mutations in MAPT, GRN and C9orf72 genes. METHODS: Using positron emission tomography (PET), we explored the association of the distribution of activated microglia, as measured by the radioligand [11C]PK11195, and the regional distribution of tau or TDP-43 pathology, indexed using the radioligand [18F]AV-1451. The familial FTD PET data were compared with healthy controls. RESULTS: Patients with familial FTD across all mutation groups showed increased [11C]PK11195 binding predominantly in frontotemporal regions, with additional regions showing abnormalities in individuals. Patients with MAPT mutations had a consistent distribution of [18F]AV-1451 binding across the brain, with heterogeneous distributions among carriers of GRN and C9orf72 mutations. DISCUSSION: This case series suggests that neuroinflammation is part of the pathophysiology of familial FTD, warranting further consideration of immunomodulatory therapies for disease modification and prevention.

Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum.

The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the localization of tau and TDP-43 pathology, and to the heterogeneity of clinical disease. We used PET in vivo with (i) 11C-PK-11195, a marker of activated microglia and a proxy index of neuroinflammation; and (ii) 18F-AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and TDP-43-related disease, and which is used as a surrogate marker of non-amyloid-ß protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant, 11 with the semantic variant and 10 with the non-fluent variant), 28 of whom underwent both 18F-AV-1451 and 11C-PK-11195 PET, and matched control subjects (14 for 18F-AV-1451 and 15 for 11C-PK-11195). We used a univariate region of interest analysis, a paired correlation analysis of the regional relationship between binding distributions of the two ligands, a principal component analysis of the spatial distributions of binding, and a multivariate analysis of the distribution of binding that explicitly controls for individual differences in ligand affinity for TDP-43 and different tau isoforms. We found significant group-wise differences in 11C-PK-11195 binding between each patient group and controls in frontotemporal regions, in both a regions-of-interest analysis and in the comparison of principal spatial components of binding. 18F-AV-1451 binding was increased in semantic variant primary progressive aphasia compared to controls in the temporal regions, and both semantic variant primary progressive aphasia and behavioural variant frontotemporal dementia differed from controls in the expression of principal spatial components of binding, across temporal and frontotemporal cortex, respectively. There was a strong positive correlation between 11C-PK-11195 and 18F-AV-1451 uptake in all disease groups, across widespread cortical regions. We confirmed this association with post-mortem quantification in 12 brains, demonstrating strong associations between the regional densities of microglia and neuropathology in FTLD-TDP (A), FTLD-TDP (C), and FTLD-Pick's. This was driven by amoeboid (activated) microglia, with no change in the density of ramified (sessile) microglia. The multivariate distribution of 11C-PK-11195 binding related better to clinical heterogeneity than did 18F-AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate classification of participants. These in vivo findings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia.

Exploring UK medical school differences: the MedDifs study of selection, teaching, student and F1 perceptions, postgraduate outcomes and fitness to practise.

BACKGROUND: Medical schools differ, particularly in their teaching, but it is unclear whether such differences matter, although influential claims are often made. The Medical School Differences (MedDifs) study brings together a wide range of measures of UK medical schools, including postgraduate performance, fitness to practise issues, specialty choice, preparedness, satisfaction, teaching styles, entry criteria and institutional factors. METHOD: Aggregated data were collected for 50 measures across 29 UK medical schools. Data include institutional history (e.g. rate of production of hospital and GP specialists in the past), curricular influences (e.g. PBL schools, spend per student, staff-student ratio), selection measures (e.g. entry grades), teaching and assessment (e.g. traditional vs PBL, specialty teaching, self-regulated learning), student satisfaction, Foundation selection scores, Foundation satisfaction, postgraduate examination performance and fitness to practise (postgraduate progression, GMC sanctions). Six specialties (General Practice, Psychiatry, Anaesthetics, Obstetrics and Gynaecology, Internal Medicine, Surgery) were examined in more detail. RESULTS: Medical school differences are stable across time (median alpha = 0.835). The 50 measures were highly correlated, 395 (32.2%) of 1225 correlations being significant with p < 0.05, and 201 (16.4%) reached a Tukey-adjusted criterion of p < 0.0025. Problem-based learning (PBL) schools differ on many measures, including lower performance on postgraduate assessments. While these are in part explained by lower entry grades, a surprising finding is that schools such as PBL schools which reported greater student satisfaction with feedback also showed lower performance at postgraduate examinations. More medical school teaching of psychiatry, surgery and anaesthetics did not result in more specialist trainees. Schools that taught more general practice did have more graduates entering GP training, but those graduates performed less well in MRCGP examinations, the negative correlation resulting from numbers of GP trainees and exam outcomes being affected both by non-traditional teaching and by greater historical production of GPs. Postgraduate exam outcomes were also higher in schools with more self-regulated learning, but lower in larger medical schools. A path model for 29 measures found a complex causal nexus, most measures causing or being caused by other measures. Postgraduate exam performance was influenced by earlier attainment, at entry to Foundation and entry to medical school (the so-called academic backbone), and by self-regulated learning. Foundation measures of satisfaction, including preparedness, had no subsequent influence on outcomes. Fitness to practise issues were more frequent in schools producing more male graduates and more GPs. CONCLUSIONS: Medical schools differ in large numbers of ways that are causally interconnected. Differences between schools in postgraduate examination performance, training problems and GMC sanctions have important implications for the quality of patient care and patient safety.

The Analysis of Teaching of Medical Schools (AToMS) survey: an analysis of 47,258 timetabled teaching events in 25 UK medical schools relating to timing, duration, teaching formats, teaching content, and problem-based learning.

BACKGROUND: What subjects UK medical schools teach, what ways they teach subjects, and how much they teach those subjects is unclear. Whether teaching differences matter is a separate, important question. This study provides a detailed picture of timetabled undergraduate teaching activity at 25 UK medical schools, particularly in relation to problem-based learning (PBL). METHOD: The Analysis of Teaching of Medical Schools (AToMS) survey used detailed timetables provided by 25 schools with standard 5-year courses. Timetabled teaching events were coded in terms of course year, duration, teaching format, and teaching content. Ten schools used PBL. Teaching times from timetables were validated against two other studies that had assessed GP teaching and lecture, seminar, and tutorial times. RESULTS: A total of 47,258 timetabled teaching events in the academic year 2014/2015 were analysed, including SSCs (student-selected components) and elective studies. A typical UK medical student receives 3960 timetabled hours of teaching during their 5-year course. There was a clear difference between the initial 2 years which mostly contained basic medical science content and the later 3 years which mostly consisted of clinical teaching, although some clinical teaching occurs in the first 2 years. Medical schools differed in duration, format, and content of teaching. Two main factors underlay most of the variation between schools, Traditional vs PBL teaching and Structured vs Unstructured teaching. A curriculum map comparing medical schools was constructed using those factors. PBL schools differed on a number of measures, having more PBL teaching time, fewer lectures, more GP teaching, less surgery, less formal teaching of basic science, and more sessions with unspecified content. DISCUSSION: UK medical schools differ in both format and content of teaching. PBL and non-PBL schools clearly differ, albeit with substantial variation within groups, and overlap in the middle. The important question of whether differences in teaching matter in terms of outcomes is analysed in a companion study (MedDifs) which examines how teaching differences relate to university infrastructure, entry requirements, student perceptions, and outcomes in Foundation Programme and postgraduate training.

Neurophysiological signatures of Alzheimer's disease and frontotemporal lobar degeneration: pathology versus phenotype.

The disruption of brain networks is characteristic of neurodegenerative dementias. However, it is controversial whether changes in connectivity reflect only the functional anatomy of disease, with selective vulnerability of brain networks, or the specific neurophysiological consequences of different neuropathologies within brain networks. We proposed that the oscillatory dynamics of cortical circuits reflect the tuning of local neural interactions, such that different pathologies are selective in their impact on the frequency spectrum of oscillations, whereas clinical syndromes reflect the anatomical distribution of pathology and physiological change. To test this hypothesis, we used magnetoencephalography from five patient groups, representing dissociated pathological subtypes and distributions across frontal, parietal and temporal lobes: amnestic Alzheimer's disease, posterior cortical atrophy, and three syndromes associated with frontotemporal lobar degeneration. We measured effective connectivity with graph theory-based measures of local efficiency, using partial directed coherence between sensors. As expected, each disease caused large-scale changes of neurophysiological brain networks, with reductions in local efficiency compared to controls. Critically however, the frequency range of altered connectivity was consistent across clinical syndromes that shared a likely underlying pathology, whilst the localization of changes differed between clinical syndromes. Multivariate pattern analysis of the frequency-specific topographies of local efficiency separated the disorders from each other and from controls (accuracy 62% to 100%, according to the groups' differences in likely pathology and clinical syndrome). The data indicate that magnetoencephalography has the potential to reveal specific changes in neurophysiology resulting from neurodegenerative disease. Our findings confirm that while clinical syndromes have characteristic anatomical patterns of abnormal connectivity that may be identified with other methods like structural brain imaging, the different mechanisms of neurodegeneration also cause characteristic spectral signatures of physiological coupling that are not accessible with structural imaging nor confounded by the neurovascular signalling of functional MRI. We suggest that these spectral characteristics of altered connectivity are the result of differential disruption of neuronal microstructure and synaptic physiology by Alzheimer's disease versus frontotemporal lobar degeneration.

Tau burden and the functional connectome in Alzheimer's disease and progressive supranuclear palsy.

Alzheimer's disease and progressive supranuclear palsy (PSP) represent neurodegenerative tauopathies with predominantly cortical versus subcortical disease burden. In Alzheimer's disease, neuropathology and atrophy preferentially affect 'hub' brain regions that are densely connected. It was unclear whether hubs are differentially affected by neurodegeneration because they are more likely to receive pathological proteins that propagate trans-neuronally, in a prion-like manner, or whether they are selectively vulnerable due to a lack of local trophic factors, higher metabolic demands, or differential gene expression. We assessed the relationship between tau burden and brain functional connectivity, by combining in vivo PET imaging using the ligand AV-1451, and graph theoretic measures of resting state functional MRI in 17 patients with Alzheimer's disease, 17 patients with PSP, and 12 controls. Strongly connected nodes displayed more tau pathology in Alzheimer's disease, independently of intrinsic connectivity network, validating the predictions of theories of trans-neuronal spread but not supporting a role for metabolic demands or deficient trophic support in tau accumulation. This was not a compensatory phenomenon, as the functional consequence of increasing tau burden in Alzheimer's disease was a progressive weakening of the connectivity of these same nodes, reducing weighted degree and local efficiency and resulting in weaker 'small-world' properties. Conversely, in PSP, unlike in Alzheimer's disease, those nodes that accrued pathological tau were those that displayed graph metric properties associated with increased metabolic demand and a lack of trophic support rather than strong functional connectivity. Together, these findings go some way towards explaining why Alzheimer's disease affects large scale connectivity networks throughout cortex while neuropathology in PSP is concentrated in a small number of subcortical structures. Further, we demonstrate that in PSP increasing tau burden in midbrain and deep nuclei was associated with strengthened cortico-cortical functional connectivity. Disrupted cortico-subcortical and cortico-brainstem interactions meant that information transfer took less direct paths, passing through a larger number of cortical nodes, reducing closeness centrality and eigenvector centrality in PSP, while increasing weighted degree, clustering, betweenness centrality and local efficiency. Our results have wide-ranging implications, from the validation of models of tau trafficking in humans to understanding the relationship between regional tau burden and brain functional reorganization.

[18F]AV-1451 binding in vivo mirrors the expected distribution of TDP-43 pathology in the semantic variant of primary progressive aphasia.

INTRODUCTION: Semantic dementia, including the semantic variant of primary progressive aphasia (svPPA), is strongly associated with TAR-DNA binding protein 43 (TDP-43) type C pathology. It provides a useful model in which to test the specificity of in vivo binding of the putative tau ligand [18F]AV-1451, which is elevated in frontotemporal lobar degeneration tauopathies. METHODS AND RESULTS: Seven patients (five with svPPA and two with 'right' semantic dementia) and 12 healthy controls underwent positron emission tomography brain imaging with [18F]AV-1451. Two independent preprocessing methods were used. For both methods, all patients had clearly elevated binding potential (BPND (non-displaceable binding potential)) in temporal lobes, lateralising according to their clinical syndrome and evident in raw images. Region of interest analyses confirmed that BPND was significantly increased in temporal regions, insula and fusiform gyrus, consistent with those areas known to be most affected in semantic dementia. Hierarchical cluster analysis, based on the distribution of [18F]AV-1451 binding potential, separated semantic dementia from controls with 86% sensitivity and 100% specificity. CONCLUSIONS: [18F]AV-1451 binds in vivo regions that are likely to contain TDP-43 and not significant tau pathology. While this suggests a non-tau target for [18F]AV-1451, the pathological regions in semantic dementia do not normally contain significant levels of recently proposed 'off target' binding sites for [18F]AV-1451, such as neuronal monoamine oxidase or neuromelanin. Postmortem and longitudinal data will be useful to assess the utility of [18F]AV-1451 to differentiate and track different types of frontotemporal lobar degeneration.

18F-AV-1451 positron emission tomography in Alzheimer's disease and progressive supranuclear palsy.

The ability to assess the distribution and extent of tau pathology in Alzheimer's disease and progressive supranuclear palsy in vivo would help to develop biomarkers for these tauopathies and clinical trials of disease-modifying therapies. New radioligands for positron emission tomography have generated considerable interest, and controversy, in their potential as tau biomarkers. We assessed the radiotracer 18F-AV-1451 with positron emission tomography imaging to compare the distribution and intensity of tau pathology in 15 patients with Alzheimer's pathology (including amyloid-positive mild cognitive impairment), 19 patients with progressive supranuclear palsy, and 13 age- and sex-matched controls. Regional analysis of variance and a support vector machine were used to compare and discriminate the clinical groups, respectively. We also examined the 18F-AV-1451 autoradiographic binding in post-mortem tissue from patients with Alzheimer's disease, progressive supranuclear palsy, and a control case to assess the 18F-AV-1451 binding specificity to Alzheimer's and non-Alzheimer's tau pathology. There was increased 18F-AV-1451 binding in multiple regions in living patients with Alzheimer's disease and progressive supranuclear palsy relative to controls [main effect of group, F(2,41) = 17.5, P < 0.0001; region of interest × group interaction, F(2,68) = 7.5, P < 0.00001]. More specifically, 18F-AV-1451 binding was significantly increased in patients with Alzheimer's disease, relative to patients with progressive supranuclear palsy and with control subjects, in the hippocampus and in occipital, parietal, temporal, and frontal cortices (t's > 2.2, P's < 0.04). Conversely, in patients with progressive supranuclear palsy, relative to patients with Alzheimer's disease, 18F-AV-1451 binding was elevated in the midbrain (t = 2.1, P < 0.04); while patients with progressive supranuclear palsy showed, relative to controls, increased 18F-AV-1451 uptake in the putamen, pallidum, thalamus, midbrain, and in the dentate nucleus of the cerebellum (t's > 2.7, P's < 0.02). The support vector machine assigned patients' diagnoses with 94% accuracy. The post-mortem autoradiographic data showed that 18F-AV-1451 strongly bound to Alzheimer-related tau pathology, but less specifically in progressive supranuclear palsy. 18F-AV-1451 binding to the basal ganglia was strong in all groups in vivo. Postmortem histochemical staining showed absence of neuromelanin-containing cells in the basal ganglia, indicating that off-target binding to neuromelanin is an insufficient explanation of 18F-AV-1451 positron emission tomography data in vivo, at least in the basal ganglia. Overall, we confirm the potential of 18F-AV-1451 as a heuristic biomarker, but caution is indicated in the neuropathological interpretation of its binding. Off-target binding may contribute to disease profiles of 18F-AV-1451 positron emission tomography, especially in primary tauopathies such as progressive supranuclear palsy. We suggest that 18F-AV-1451 positron emission tomography is a useful biomarker to assess tau pathology in Alzheimer's disease and to distinguish it from other tauopathies with distinct clinical and pathological characteristics such as progressive supranuclear palsy.