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© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com, Several CSF and blood biomarkers for genetic frontotemporal dementia have been proposed, including those reflecting neuroaxonal loss (neurofilament light chain and phosphorylated neurofilament heavy chain), synapse dysfunction [neuronal pentraxin 2 (NPTX2)], astrogliosis (glial fibrillary acidic protein) and complement activation (C1q, C3b). Determining the sequence in which biomarkers become abnormal over the course of disease could facilitate disease staging and help identify mutation carriers with prodromal or early-stage frontotemporal dementia, which is especially important as pharmaceutical trials emerge. We aimed to model the sequence of biomarker abnormalities in presymptomatic and symptomatic genetic frontotemporal dementia using cross-sectional data from the Genetic Frontotemporal dementia Initiative (GENFI), a longitudinal cohort study. Two-hundred and seventy-five presymptomatic and 127 symptomatic carriers of mutations in GRN, C9orf72 or MAPT, as well as 247 non-carriers, were selected from the GENFI cohort based on availability of one or more of the aforementioned biomarkers. Nine presymptomatic carriers developed symptoms within 18 months of sample collection ('converters'). Sequences of biomarker abnormalities were modelled for the entire group using discriminative event-based modelling (DEBM) and for each genetic subgroup using co-initialized DEBM. These models estimate probabilistic biomarker abnormalities in a data-driven way and do not rely on previous diagnostic information or biomarker cut-off points. Using cross-validation, subjects were subsequently assigned a disease stage based on their position along the disease progression timeline. CSF NPTX2 was the first biomarker to become abnormal, followed by blood and CSF neurofilament light chain, blood phosphorylated neurofilament heavy chain, blood glial fibrillary acidic protein and finally CSF C3b and C1q. Biomarker orderings did not differ significantly between genetic subgroups, but more uncertainty was noted in the C9orf72 and MAPT groups than for GRN. Estimated disease stages could distinguish symptomatic from presymptomatic carriers and non-carriers with areas under the curve of 0.84 (95% confidence interval 0.80-0.89) and 0.90 (0.86-0.94) respectively. The areas under the curve to distinguish converters from non-converting presymptomatic carriers was 0.85 (0.75-0.95). Our data-driven model of genetic frontotemporal dementia revealed that NPTX2 and neurofilament light chain are the earliest to change among the selected biomarkers. Further research should investigate their utility as candidate selection tools for pharmaceutical trials. The model's ability to accurately estimate individual disease stages could improve patient stratification and track the efficacy of therapeutic interventions., This study was supported in the Netherlands by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813,733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); V.V. and S.K. have received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 666992 (EuroPOND). E.B. was supported by the Hartstichting (PPP Allowance, 2018B011); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1); J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); I.J.S. is supported by the Alzheimer’s Association; J.B.R. is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to R.S.V.); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 ‘Solve-RD’ from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding and StratNeuro. H.Z. is a Wallenberg Scholar.

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 clinical to preclinical models of pathology, and quantitative assays for experimental medicine. Such biophysical models can also disclose hidden neuronal dynamics generating neurophysiological observations like electro- and magneto-encephalography (MEG). Here, we augment a biophysically informed mesoscale model of human cortical function by inclusion of synaptic density estimates as captured by [11C]UCB-J positron emission tomography, 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 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 MEG 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.

Funder: NIHR Cambridge Clinical Research Facility and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014), There is a pressing need to accelerate therapeutic strategies against the syndromes caused by frontotemporal lobar degeneration, including symptomatic treatments. One approach is for experimental medicine, coupling neurophysiological studies of the mechanisms of disease with pharmacological interventions aimed at restoring neurochemical deficits. Here we consider the role of glutamatergic deficits and their potential as targets for treatment. We performed a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study in 20 people with symptomatic frontotemporal lobar degeneration (10 behavioural variant frontotemporal dementia, 10 progressive supranuclear palsy) and 19 healthy age- and gender-matched controls. Both magnetoencephalography sessions recorded a roving auditory oddball paradigm: on placebo or following 10 mg memantine, an uncompetitive NMDA-receptor antagonist. Ultra-high-field magnetic resonance spectroscopy confirmed lower concentrations of GABA in the right inferior frontal gyrus of people with frontotemporal lobar degeneration. While memantine showed a subtle effect on early-auditory processing in patients, there was no significant main effect of memantine on the magnitude of the mismatch negativity (MMN) response in the right frontotemporal cortex in patients or controls. However, the change in the right auditory cortex MMN response to memantine (vs. placebo) in patients correlated with individuals' prefrontal GABA concentration. There was no moderating effect of glutamate concentration or cortical atrophy. This proof-of-concept study demonstrates the potential for baseline dependency in the pharmacological restoration of neurotransmitter deficits to influence cognitive neurophysiology in neurodegenerative disease. With changes to multiple neurotransmitters in frontotemporal lobar degeneration, we suggest that individuals' balance of excitation and inhibition may determine drug efficacy, with implications for drug selection and patient stratification in future clinical trials., Cambridge Centre for Parkinson-Plus; a Cambridge Trust Vice-Chancellor’s Award and Fitzwilliam College Scholarship; the Association of British Neurologists – Patrick Berthoud Charitable Trust (RG99368); NIHR Cambridge Clinical Research Facility

BACKGROUND: The changes of cortical structure in Alzheimer's disease (AD) and frontotemporal dementia (FTD) are usually described in terms of atrophy. However, neurodegenerative diseases may also affect the complexity of cortical shape, such as the fractal dimension of the brain surface. OBJECTIVE: In this study, we aimed at assessing the regional patterns of cortical thickness and fractal dimension changes in a cross-sectional cohort of patients with AD and FTD. METHODS: Thirty-two people with symptomatic AD-pathology (clinically probable AD, n = 18, and amyloid-positive mild cognitive impairment, n = 14), 24 with FTD and 28 healthy controls underwent high-resolution 3T structural brain MRI. Using surface-based morphometry, we created vertex-wise cortical thickness and fractal dimension maps for group comparisons and correlations with cognitive measures in AD and FTD. RESULTS: In addition to the well-established pattern of cortical thinning encompassing temporoparietal regions in AD and frontotemporal areas in FTD, we observed reductions of fractal dimension encompassing cingulate areas and insula for both conditions, but specifically involving orbitofrontal cortex and paracentral gyrus for FTD (FDR p < 0.05). Correlational analyses between fractal dimension and cognition showed that these regions were particularly vulnerable with regards to memory and language impairment, especially in FTD. CONCLUSION: While the present study demonstrates globally similar patterns of fractal dimension changes in AD and FTD, we observed distinct cortical complexity correlates of cognitive domains impairment. Further studies are required to assess cortical complexity measures at earlier disease stages (e.g., in prodromal/asymptomatic carriers of FTD-related gene mutations) and determine whether fractal dimension represents a sensitive imaging marker for prevention and diagnostic strategies.

© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)., A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the disease.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Supplementary Information: Additional file 1 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; Additional file 2 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study; both files are available online at https://doi.org/10.1186/s13024-021-00499-4 Copyright © The Author(s) 2021. Background: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD. This study has received support from the Swedish FTD initiative funded by the Schörling Family Foundation. This work was also funded by KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, grants from Vetenskapsrådet Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Åhlén foundation, Demensfonden, Stohnes foundation, Gamla Tjänarinnor and Stockholm County Council ALF. Furthermore, support was received by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (2019-02248), the Dioraphte Foundation [grant numbers 09-02-00]; the Association for Frontotemporal Dementias Research Grant 2009; The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056-13-018); ZonMw Memorabel (Deltaplan Dementie), (project numbers 733 050 103 and 733 050 813); JPND PreFrontAls consortium (project number 733051042). JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. M.S. was supported by the JPND grant “GENFI-prox” (by DLR/BMBF to M. S, joint with JDR., J.vS., M.O., B.B. and C.G.). Open Access funding provided by Royal Institute of Technology.

Synaptic loss is an early and clinically relevant feature of many neurodegenerative diseases. Here we assess three adults at risk of frontotemporal dementia from C9orf72 mutation, using [11C]UCB‐J PET to quantify synaptic density in comparison with 19 healthy controls and one symptomatic patient with behavioural variant frontotemporal dementia. The three pre‐symptomatic C9orf72 carriers showed reduced synaptic density in the thalamus compared to controls, and there was an additional extensive synaptic loss in frontotemporal regions of the symptomatic patient. [11C]UCB‐J PET may facilitate early, pre‐symptomatic assessment, monitoring of disease progression and evaluation of new preventive treatment strategies for frontotemporal dementia.

Neuroinflammation occurs in frontotemporal dementia, however its timing relative to protein aggregation and neuronal loss is unknown. Using positron emission tomography and magnetic resonance imaging to quantify these processes in a pre‐symptomatic carrier of the 10 + 16 MAPT mutation, we show microglial activation in frontotemporal regions, despite a lack of protein aggregation or atrophy in these areas. The distribution of microglial activation better discriminated the carrier from controls than did protein aggregation at this pre‐symptomatic disease stage. Our findings suggest an early role for microglial activation in frontotemporal dementia. Longitudinal studies are needed to explore the causality of this pathophysiological association.

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.

© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license., Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an increased CTh loss associated with age and estimated proximity to symptoms onset in GRN carriers, even before the disease onset., The authors thank all the volunteers for their participation in this study. SBE is a recipient of the Rio-Hortega post-residency grant from the Instituto de Salud Carlos III, Spain. This study was partially funded by Fundació Marató de TV3, Spain (grant no. 20143810 to RSV). The GENFI study has been supported by the Medical Research Council UK, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, as well as other individual funding to investigators. KM has received funding from an Alzheimer’s Society PhD studentship. JDR acknowledges support from the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit and the University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre, the UK Dementia Research Institute, Alzheimer’s Research UK, the Brain Research Trust and the Wolfson Foundation. JCvS was supported by the Dioraphte Foundation grant 09-02-03-00, the Association for Frontotemporal Dementias Research Grant 2009, The Netherlands Organization for Scientific Research (NWO) grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. CG have received funding from JPND-Prefrontals VR Dnr 529-2014-7504, VR: 2015-02926, and 2018-02754, the Swedish FTD Initiative-Schörling Foundation, Alzheimer Foundation, Brain Foundation and Stockholm County Council ALF. DG has received support from the EU Joint Programme – Neurodegenerative Disease Research (JPND) and the Italian Ministry of Health (PreFrontALS) grant 733051042. JBR is funded by the Wellcome Trust (103838) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. MM has received funding from a Canadian Institutes of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. RV has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. EF has received funding from a CIHR grant #327387. JDR is an MRC Clinician Scientist (MR/M008525/1) and has received funding from the NIHR Rare Diseases Translational Research Collaboration (BRC149/NS/MH), the Bluefield Project and the Association for Frontotemporal Degeneration. MS was supported by a grant 779257 “Solve-RD” from the Horizon 2020 research and innovation programme.

Objective To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of rimegepant for treatment of migraine. Data Sources A comprehensive PubMed and Cochrane search (1985 to May 2020) was performed utilizing the keywords rimegepant, Nurtec, orally disintegrating tablet, migraine, migraine headache, migraine disorder, calcitonin gene-related peptide, and calcitonin gene-related peptide antagonist. Additional data were obtained from the references of identified articles, manufacturer’s product labeling and website, ClinicalTrials.gov, and governmental sources. Study Selection and Data Extraction All English-language trials evaluating oral rimegepant were included for this review. Data Synthesis Rimegepant orally disintegrating tablet (ODT) is Food and Drug Administration approved for the treatment of migraine. According to data from 3 phase 3 randomized controlled trials, rimegepant has been shown to significantly improve freedom from pain at 2 hours after the dose and freedom from the most bothersome symptom 2 hours postdose. Additional outcomes improved include freedom from photophobia and phonophobia at 2 hours postdose and pain relief 2 hours after the dose. Adverse effects of rimegepant include nausea, urinary tract infection, and dizziness. Relevance to Patient Care and Clinical Practice Orally disintegrating rimegepant provides a novel mechanism of action for the treatment of acute migraine. When patients experience inadequate relief from other therapies, have contraindications to triptans, or are unable to tolerate the adverse effects of triptans, rimegepant is a promising therapeutic option. Conclusion Rimegepant ODT is an efficacious migraine treatment option with a novel mechanism of action, convenient dosage form, and limited adverse effect profile.

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., Using biophysical modelling of data from controls and FTLD patients, on and off a GABAergic drug, combined with GABA spectroscopy, Adams et al. show that the potential restoration of neurotransmission in neurodegeneration depends on the degree of disruption to baseline physiology.

INTRODUCTIONWe report in vivo patterns of neuroinflammation and abnormal protein aggregation in seven cases of familial frontotemporal dementia with mutations in MAPT, GRN and C9orf72 genes.METHODSUsing 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 to healthy controls.RESULTSFamilial FTD patients 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.DISCUSSIONThis case series suggests a consistent role for neuroinflammation in the pathophysiology of familial FTD, warranting further consideration of immunomodulatory therapies for disease modification and prevention.

Bevan-Jones, Cope et al. report that neuroinflammation co-localizes with protein aggregation in all major types of frontotemporal dementia, both in vivo with positron emission tomography, and at post mortem. In vivo neuroinflammation patterns are disease-specific and can accurately classify patients into groups., 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-β 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.

In the healthy human brain, the processing of language is strongly lateralised, usually to the left hemisphere, while the processing of complex non-linguistic sounds recruits brain regions bilaterally. Here we asked whether the anterior temporal lobes, strongly implicated in semantic processing, are critical to this special treatment of spoken words. Nine patients with semantic dementia (SD) and fourteen age-matched controls underwent magnetoencephalography and structural MRI. Voxel based morphometry demonstrated the stereotypical pattern of SD: severe grey matter loss restricted to the anterior temporal lobes, with the left side more affected. During magnetoencephalography, participants listened to word sets in which identity and meaning were ambiguous until word completion, for example PLAYED versus PLATE. Whereas left-hemispheric responses were similar across groups, patients demonstrated increased right hemisphere activity 174–294 msec after stimulus disambiguation. Source reconstructions confirmed recruitment of right-sided analogues of language regions in SD: atrophy of anterior temporal lobes was associated with increased activity in right temporal pole, middle temporal gyrus, inferior frontal gyrus and supramarginal gyrus. Overall, the results indicate that anterior temporal lobes are necessary for normal and efficient lateralised processing of word identity by the language network.

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers - in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load - a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial. ispartof: NEUROIMAGE-CLINICAL vol:24 ispartof: location:Netherlands status: published

We describe an assessment of the impact on mortality of eight major sources of PM

Prion-like, trans-neuronal spread of tau pathology in humans is controversial. By evaluating tau burden and functional connectivity in living patients, Cope et al. demonstrate relationships consistent with this in Alzheimer's disease but not progressive supranuclear palsy. Tau distribution in the latter is better explained by metabolic demand and trophic support., 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.

Patients with non-fluent aphasias display impairments of expressive and receptive grammar. This has been attributed to deficits in processing configurational and hierarchical sequencing relationships. This hypothesis had not been formally tested. It was also controversial whether impairments are specific to language, or reflect domain general deficits in processing structured auditory sequences. Here we used an artificial grammar learning paradigm to compare the abilities of controls to participants with agrammatic aphasia of two different aetiologies: stroke and frontotemporal dementia. Ten patients with non-fluent variant primary progressive aphasia (nfvPPA), 12 with non-fluent aphasia due to stroke, and 11 controls implicitly learned a novel mixed-complexity artificial grammar designed to assess processing of increasingly complex sequencing relationships. We compared response profiles for otherwise identical sequences of speech tokens (nonsense words) and tone sweeps. In all three groups the ability to detect grammatical violations varied with sequence complexity, with performance improving over time and being better for adjacent than non-adjacent relationships. Patients performed less well than controls overall, and this was related more strongly to aphasia severity than to aetiology. All groups improved with practice and performed well at a control task of detecting oddball nonwords. Crucially, group differences did not interact with sequence complexity, demonstrating that aphasic patients were not disproportionately impaired on complex structures. Hierarchical cluster analysis revealed that response patterns were very similar across all three groups, but very different between the nonsense word and tone tasks, despite identical artificial grammar structures. Overall, we demonstrate that agrammatic aphasics of two different aetiologies are not disproportionately impaired on complex sequencing relationships, and that the learning of phonological and non-linguistic sequences occurs independently. The similarity of profiles of discriminatory abilities and rule learning across groups suggests that insights from previous studies of implicit sequence learning in vascular aphasia are likely to prove applicable in nfvPPA., Graphical abstract fx1, Highlights • Patients with Broca's aphasia and nfvPPA show implicit artificial grammar learning. • Both groups displayed global deficits compared to controls but improved with practice. • Neither group was disproportionately impaired on more complex ordering relationships. • Learning did not transfer between otherwise identical speech and tone-based grammars. • Separate linguistic and non-linguistic sequence processing was maintained in aphasia.

The authors gratefully acknowledge the support of the UK Biotechnology and Biological Sciences Research Council (BBSRC) who funded this research. The authors also gratefully acknowledge the support of the Wellcome Trust for the provision of mass spectrometry facilities at St Andrews. We report the initial characterisation of an N-terminal oligopeptide ‘2A-like’ sequence that is able to function both as a signal sequence and as a translational recoding element. Due to this translational recoding activity, two forms of nascent polypeptide are synthesised: (i) when 2A-mediated translational recoding has not occurred: the nascent polypeptide is fused to the 2A-like N-terminal signal sequence and the fusion translation product is targeted to the exocytic pathway, and, (ii) a translation product where 2A-mediated translational recoding has occurred: the 2A-like signal sequence is synthesised as a separate translation product and, therefore, the nascent (downstream) polypeptide lacks the 2A-like signal sequence and is localised to the cytoplasm. This type of dual-functional signal sequence results, therefore, in the partitioning of the translation products between the two sub-cellular sites and represents a newly described form of dual protein targeting. Publisher PDF

A 71-year-old woman presented acutely with seizures; her MRI suggested a low-grade glioma of the right temporal lobe. Over the preceding 18 months, she had developed progressive limb chorea and orofacial dyskinesia. Examination showed a predominantly amnestic cognitive profile. Initial investigations were normal, but later she was found to have antibodies to collapsin response mediator protein 5 (also called CV2). Her symptoms and neuroimaging abnormalities gradually improved without treatment. Four months later, surveillance imaging with (18)F-fluorodeoxyglucose-positron-emission tomography revealed a lesion confirmed by biopsy as a TX, N2, M0 small-cell lung cancer. This case is unusual for the strikingly unilateral neuroimaging abnormalities, which led to an initial misdiagnosis, and the spontaneous symptomatic improvement without treatment. In retrospect, the co-occurrence of paraneoplastic chorea, limbic encephalitis and neuropathy in the presence of an occult lung tumour make this almost a 'full house' of symptoms associated with antibodies to collapsin response mediator protein 5. It underlines the importance in clinical reasoning of avoiding the cognitive errors of premature closure and anchoring.

Previous studies investigating sensitivity to step changes in tempo and prediction of tone onset time have generally utilized isochronous sequences. This study investigates subjects' ability to detect deviations from a gradual change in the tempo of a tone sequence (experiment 1) and their judgment of the perceptually optimal timing of this tone (experiment 2). In experiment 1, inter-onset-intervals within pairs of eight-tone sequences followed a geometric progression to create a gradual tempo change. In one sequence, the final tone was presented either earlier or later than specified by the progression. Subjects performed well at detecting deviations that exaggerated the tempo progression but poorly when it was counteracted. Experiment 2 used similar pairs except that the final tone was always presented earlier in one sequence than the other. Final interval length was adaptively adjusted to subjects' judgments; it was adjudged in best agreement with the progression when its length was roughly half way between the mathematically correct value and the length of the penultimate interval. The data support "multiple-look" and entrainment models of tempo sensitivity and suggest that temporal prediction is based less on the tempo contour of a whole sequence than on the duration of the preceding interval.

Objectives: (1) To use a loudness model to assess the influence of loudness recruitment on estimates of the loudness of tinnitus obtained by loudness matching; (2) To compare the effect of background noise on the loudness of tinnitus for individuals who are unilaterally deaf after resection of vestibular schwannoma (VS) and those with idiopathic tinnitus. Background: After translabyrinthine resection of VS, patients experience unilateral deafness and tinnitus in the operated ear. Most complain that their tinnitus is more bothersome in noisy environments, unlike those with idiopathic tinnitus. Participants: Unilaterally deaf individuals experiencing tinnitus as a consequence of VS surgery and a comparison group with idiopathic tinnitus. Methods: Participants adjusted the level of a probe tone at the frequency where their hearing was best to match the loudness of their tinnitus in quiet; for VS participants, matches were made using a probe in the unaffected ear. Matches were then obtained in the presence of threshold-equalizing noise. Results: For those with idiopathic tinnitus, the probe loudness level, calculated using a loudness model, was almost invariant with hearing loss at the probe frequency and was usually between 20 and 50 phons. For the VS group, the probe loudness level ranged from 6 to 51 phons. With increasing threshold-equalizing-noise level, the loudness match decreased slightly for the comparison group but increased significantly for the VS group. Conclusion: The tinnitus in quiet had a moderate loudness for both groups. Background noise slightly decreased tinnitus loudness for most participants with idiopathic tinnitus but increased tinnitus loudness for VS participants. We propose 2 possible mechanisms for the effect of noise in the VS group.

We report the case of a 97-year-old woman who had a prolonged hospital admission for the treatment of right-sided heart failure. During her stay she experienced a rapid deterioration, characterised by shortness of breath, cardiovascular compromise and a hot, red, swollen calf. Post-mortem examination demonstrated that this was caused by necrotising fasciitis due to Serratia marcescens as a single pathogen. This is only the second reported case of this condition in the absence of diabetes or immunosuppression, and clinical deterioration was much more rapid. The case underlines the importance of circumspection and regular review in the diagnosis of the elderly patient. It reminds us that these patients should be viewed as functionally immunosuppressed, and that some or all of the haematological markers of infection can be absent even in severe disease.

Thyrotoxic periodic paralysis is rare in Caucasian populations, but affects approximately 2% of East Asians with thyrotoxicosis (13% of males, 0.17% of females). The presentation is characterized by abrupt-onset hypokalemia and profound proximal muscular weakness, and commonly occurs after carbohydrate loading or exercise.To raise awareness of this condition through the description of a typical case of thyrotoxic periodic paralysis; to remind readers that, despite intravascular hypokalemia, total body potassium is normal and that correction must be done with caution; to highlight the differences in treatment compared to familial hypokalemic periodic paralysis.We describe the presentation of a 36-year-old Filipino man with a background history of Graves disease. Over-administration of intravenous potassium was narrowly averted in this case.It may be important to check thyroid function in patients presenting with acute paralysis, especially those of Asian origin. In patients with thyrotoxic periodic paralysis, administration of potassium, with cardiac monitoring and a total dose of50 mmol, limits the dysrhythmia risk. Patients are likely to benefit from the prescription of non-selective beta-blockers until they become euthyroid. In contrast to familial periodic paralysis, regular oral potassium supplementation is ineffective in thyrotoxic periodic paralysis, and acetazolamide precipitates, rather than prevents, attacks.

Individuals with Autism Spectrum Disorder (ASD) perform worse than controls when listening to speech in a temporally modulated noise (Alcantara, Weisblatt, Moore, & Bolton, 2004; Groen et al., 2009). The current study examined whether this is due to poor auditory temporal-envelope processing. Temporal modulation transfer functions were measured in 6 high-functioning children with ASD and 6 control listeners, using sinusoidal amplitude modulation of a broadband noise. Modulation-depth thresholds at low modulation rates were significantly higher for the ASD group than for the Control group, and generally higher at all modulation rates tested. Low-pass filter model estimates of temporal-envelope resolution and temporal-processing efficiency showed significant differences between the groups for modulation-depth threshold values at low modulation rates. Intensity increment-detection thresholds, measured on a subset of individuals in the ASD and Control groups, were not significantly different. The results are consistent with ASD individuals having reduced processing efficiency of temporal modulations. Possible neural mechanisms that might underlie these findings are discussed.

Background: Musical hallucination is the subjective experience of hearing music, or aspects of music, when none is being played, and as such is a disorder of the processing of complex sounds. Objective of Review: To determine the extent to which the otological system is responsible for musical hallucination, and to evaluate approaches to clinical management. Type of Review: A review of all studies and literature reviews pertaining to musical hallucination, supplemented by inclusion of informative case reports. Search Strategy: A systematic search of multiple databases carried out on 22nd March 2009 was complemented by referral to the reference lists of included manuscripts. Results: Although not always troublesome in itself, musical hallucination can be a marker of underlying pathology in the ear or brain, or indicate obsessive-compulsive traits or social isolation, and is likely to be clinically underreported. Associations have been reported with hearing loss, female gender, social isolation and being over 60 years of age, although it is rare even in this group, and these may well not be independent risk factors. Robust comparative analysis of these factors with controls has yet to be undertaken. Underlying causes include neurovascular pathology, psychiatric disorders and opioid medications, however these are absent in the majority of cases. Conclusions: This review supports the proposal that the otological system plays a role in the pathogenesis of musical hallucination. Hearing impairment may act as an initiating factor, and the primary dysfunction is overactivity of auditory association cortex, although an impairment of higher-level inhibition does also seem necessary. Once underlying sinister causes have been excluded, first line treatment should be explanation of the condition and optimisation of hearing. Medications have a role only in selected patient groups.

The neurophysiology of tinnitus is poorly understood, and it can have an origin at a number of neural levels, making a psychological approach to treatment attractive. Clinical hypnosis has been demonstrated to be effective in a number of clinical situations, such as irritable bowel syndrome but, in other areas for which it is commonly employed, such as smoking cessation, the evidence is poor. Its use for the management of troublesome tinnitus has been discussed in the literature for more than 30 years, but little formal research has been conducted into efficacy of this treatment or the relative suitability of techniques. Despite this, a success rate of 70% is commonly quoted by hypnosis practitioners in promotional material. This review summarizes the few peer-reviewed studies on this subject and concludes that, though evidence suggests that hypnosis provides a benefit in some subjects, how this benefit compares to more mainstream approaches is not yet clear. This area is currently under-researched, and engagement is encouraged between researchers in audiology and hypnotherapists to undertake large, well-structured controlled trials with standardized measures of outcome.

The effect of level and frequency on the audibility of partials was measured for complex tones with partials uniformly spaced on an equivalent rectangular bandwidth (ERB(N)) number scale. On each trial, subjects heard a sinusoidal "probe" followed by a complex tone. The probe was mistuned downwards or upwards (at random) by 4.5% from the frequency of one randomly selected partial in the complex. The subject indicated whether the probe was higher or lower in frequency than the nearest partial in the complex. The frequencies were roved from trial to trial, keeping frequency ratios fixed. In experiment 1, the level per partial, L, was 40 or 70 dB SPL and the mean frequency of the central partial, f(c), was 1201 Hz. Scores for the highest and lowest partials in the complexes were generally high for all spacings. Scores for the inner partials were close to chance at 0.75-ERB(N) spacing, and improved as the spacing was increased up to 2 ERB(N). For intermediate spacings, performance was better for the lower level used. In experiment 2, L was 70 dB SPL and f(c) was 3544 Hz. Performance worsened markedly for partial frequencies above 3544 Hz, consistent with a role of phase locking.

This laboratory is developing fluorescence polarization (FP) methods as diagnostic tools to assay antibodies in saliva and other oral fluids. FP provides quantitation of molecular interaction, such as antigen-antibody binding, of a single, small-volume sample in real time and without prior separation of components such as blood cells. There is potential for wide-spread use of these homogeneous assays as noninvasive tests, especially as more compact, simplified fluorescence polarimeters become available. FP tests can be designed that are applicable to a wide spectrum of microorganisms and may be used in a clinic or far-forward deployed setting to aid in diagnosis of disease or verification of vaccination. Rapid salivary diagnostics, including FP, have been identified by the Office of Naval Research as requirements for future naval capabilities in basic and applied medical research for warfighter protection in casualty prevention. The applications of FP salivary diagnostics for determination of tuberculosis exposure and of anthrax immunization status are discussed as examples.

Due to their prokaryotic origins, mitochondria are susceptible to a number of antibiotics that target the bacterial ribosome, and this vulnerability is exacerbated by certain mutations of the mitochondrial genome. MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome is characterised by biochemical and structural abnormalities of the muscle mitochondria, in which episodes of lactic acidosis stem from dysfunction of assembled respiratory complex I. Linezolid is an oxazolidinone antibiotic that has been reported to induce lactic acidosis, especially after prolonged administration, through inhibition of the mitochondrially synthesised components of oxidative phosphorylation. We report a patient with longstanding MELAS who suffered a severe lactic acidosis of rapid onset, with associated features of mitochondrial failure, shortly after the commencement of linezolid therapy and in the context of an otherwise improving clinical picture. This case emphasises the importance of circumspection when utilising drugs known to be toxic to the mitochondrion in patients with mitochondrial disease. In particular, given the biochemically plausible interaction, it would seem prudent to avoid the use of linezolid in patients with MELAS whenever possible.

Background: Methamphetamine (MA) use has a strong correlation with risky sexual behaviors, and thus may be triggering the growing HIV epidemic in Myanmar. Although methamphetamine use is a serious public health concern, only a few studies have examined HIV testing among young drug users. This study aimed to examine how predisposing, enabling and need factors affect HIV testing among young MA users. Methods: A cross-sectional study was conducted from January to March 2013 in Muse city in the Northern Shan State of Myanmar. Using a respondent-driven sampling method, 776 MA users aged 18-24 years were recruited. The main outcome of interest was whether participants had ever been tested for HIV. Descriptive statistics and multivariate logistic regression were applied in this study. Results: Approximately 14.7% of young MA users had ever been tested for HIV. Significant positive predictors of HIV testing included predisposing factors such as being a female MA user, having had higher education, and currently living with one’s spouse/sexual partner. Significant enabling factors included being employed and having ever visited NGO clinics or met NGO workers. Significant need factors were having ever been diagnosed with an STI and having ever wanted to receive help to stop drug use. Conclusions: Predisposing, enabling and need factors were significant contributors affecting uptake of HIV testing among young MA users. Integrating HIV testing into STI treatment programs, alongside general expansion of HIV testing services may be effective in increasing HIV testing uptake among young MA users.

In 1993, Rift Valley fever (RVF) virus reappeared in Egypt. We determined the prevalence and feeding patterns of mosquitoes in 5 villages where the virus was active. Of 10 species recovered, Aedes caspius (Pallas), Culex pipiens L., Cx. antennatus (Becker), and Cx. perexiguus Theobald constituted 99% of > 35,000 mosquitoes captured in dry ice-baited CDC light traps. Ae. caspius was most prevalent, except at Nag' El Hagar where it was replaced by Cx. perexiguus. Cx. pipiens ranked 2nd, except at Nag' El Ghuneimiya, where it was replaced by Cx. antennatus. Most blood meals analyzed by an enzyme-linked immunosorbent assay reacted to > or = 1 antiserum. Cx. pipiens was mainly anthropophagic, and therefore may have been the main vector of RVF virus among humans. Ae. caspius feeds were chiefly from humans, bovines, and equines. Cx. antennatus and Cx. perexiguus fed generally on bovines. Mixed blood meals from humans and RVF virus susceptible animals were identified in the predominant mosquitoes. Prevalence and host selection, as well as predicted probability for a blood meal being interrupted, indicated that Ae. caspius may have served as a bridge vector between humans and bovines in 4 of the villages. Cx. perexiguus may have played this role at Nag' El Hagar. Because potential vectors are abundant, susceptible domestic animals are associated closely with humans, and surveillance of imported livestock is not systematic, we conclude that RVF virus sporadically will recur in Egypt.

534 www.thelancet.com Vol 381 February 16, 2013 existed and for how long. The number of admissions for these procedures was extracted from the Hospital Episode Statistics (HES) dataset from April, 2005, to March, 2011. Admission rates were calculated for each procedure by week of admission for rationing and non-rationing PCTs on the basis of whether the PCT was rationing for that procedure at the time of admission. Responses were received from 119 PCTs (79%). No policy existed in 17 PCTs for any of the fi ve index procedures. The HES data show that between April, 2005, and March, 2011, there has been a signifi cant diff erence between the numbers of index procedures being carried out per 100 000 population for PCTs with a policy restricting funding compared with those without. A signifi cant diff erence between the two groups is shown in each of the fi ve procedures in each year, apart from 2009–10 for cataract surgery. The total number of procedures for which PCTs have restrictions diff ered substantially (range 11–127). This variation of funding for surgical procedures based on location is akin to the “post-code lottery” previously regarded as inequitable. The data support the assertion that PCT funding restrictions are associated with a decreased number of operations. Restriction of funding for “low clinical value treatments” might be necessary to deliver effi ciency savings, but there is poor consensus as to which treatments are of low clinical value, leading to the challenging situation of regional variation described. Policies also run the risk of making referrals less straightforward and therefore less likely, owing to the increased administration that they necessitate. Policies that restrict funding for elective surgery have had a signifi cant eff ect, and this has led to an inequitable geographic variation in access to some surgery. The wider consequences of these policies have yet to manifest in available evidence, but key vulnerable and aff ected populations—sex workers, people who use drugs, sexual and gender minorities, and people living with HIV/AIDS— should be empowered to know their rights and advocate on behalf of themselves and their peers.

From October 1991 to February 1992, an outbreak of acute fever (in which thick blood films were negative for malaria) spread rapidly in the city of Djibouti, Djibouti Republic, affecting all age groups and both nationals and foreigners. The estimated number of cases was 12,000. The clinical features were consistent with a non-haemorrhagic dengue-like illness. Serum samples from 91 patients were analysed serologically for flavivirus infection (dengue 1-4, West Nile, yellow fever, Zika, Banzi, and Uganda-S), and virus isolation was attempted. Twelve strains of dengue 2 virus were isolated. Dengue infection was confirmed by a 4-fold or greater rise in immunoglobulin (Ig) G antibody in paired serum specimens, the presence of IgM antibody, or isolation of the virus. Overall, 46 of the suspected cases (51%) were confirmed virologically or had serological evidence of a recent flavivirus infection. Statistical analysis showed that the presence of a rash was the best predictor of flavivirus seropositivity. In November 1992, Aedes aegypti was widespread and abundant in several districts of Djibouti city. A serological study of serum samples collected from Djiboutian military personnel 5 months before the epidemic showed that only 15/177 (8.5%) had flavivirus antibodies. These findings, together with a negative serosurvey for dengue serotypes 1-4 and yellow fever virus performed in 1987, support the conclusion that dengue 2 virus has only recently been introduced to Djibouti.

Beginning in August 1990, approximately 800,000 coalition troops were deployed to the Persian Gulf during Operations Desert Shield and Desert Storm. There was substantial concern about arthropod-borne diseases, particularly sand fly fever and cutaneous leishmaniasis, because of high morbidity rates in the Persian Gulf during World War II (WWII). In sharp contrast to WWII, there was no report of sand fly fever among coalition forces and only 31 cases of leishmaniasis among 697,000 U.S. troops. To further evaluate the risk of arthropod-borne diseases, an entomologic survey was conducted in 12 areas of Kuwait and Saudi Arabia. A total of 1,556 arthropods was collected during four survey periods in 1992. The suspected vectors of cutaneous Leishmania major infection, sand fly fever, West Nile fever, Rift Valley fever, and Crimean-Congo hemorrhagic fever were identified; however, there was no evidence of arboviruses or Leishmania among collected specimens nor from 51 trapped rodents. There are several possible reasons for the low risk of arthropod-borne infectious diseases among Desert Shield/Storm troops in an area where suspected vectors frequently were found: the use of insecticides and repellents, and the deployment of most ground troops to the open desert during the cooler, winter period-conditions least favorable for the transmission of arthropod-borne diseases.

Eighteen patients with objective evidence of menorrhagia (more than 80 ml menstrual blood loss) were treated with danazol for twelve weeks. Danazol significantly reduced the menstrual blood loss from 231 +/- 39 ml (mean +/- SEM) to 135 +/- 33 ml in the first treatment month and the mean loss thereafter was only 21 ml and 3 ml for the second and third months respectively. A rapid increase in haemoglobin level and a reduction in the number of days of bleeding were also observed on danazol treatment. No important effect on the coagulation profile was observed during the period of study. Three months after stopping danazol, menstrual blood loss (103 +/- 27 ml) was still significantly less than the pre-treatment loss.

In women with menorrhagia of unknown cause, the efficacy of the drug danazol in reducing heavy menstrual blood loss was investigated making objective measurements of menstrual blood loss. Drug regimens tested were daily administration of 200 or 100 mg danazol for 12 weeks and daily danazol given in the luteal phase or during menstruation. The results suggest that 200 mg danazol daily is the most acceptable regimen clinically since it significantly reduced menstrual blood loss and was associated with a relatively low incidence of side effects. In 16 women on this dose menstrual blood loss was suppressed from a mean pre-treatment loss of 183 +/- 25 ml to 38 +/- 11 ml (p < 0.01) in the second, and 26 +/- 9 ml (p < 0.01) in the third treatment months. The majority of women had regular episodes of bleeding with no alteration in cycle length and a reduction in the number of days of bleeding. Although 100 mg daily suppressed menstrual blood loss, particularly by the third month of treatment, it increased the number of episodes of bleeding in some women which they found unacceptable. Both 200 mg and 100 mg relieved dysmenorrhoea in the majority of women presenting with the symptoms. Danazol taken daily in the early follicular or luteal phase of the menstrual cycle did not significantly alter menstrual blood loss. There was no effect of placebo therapy on measured menstrual blood loss in a single blind trial in eight women with menorrhagia.

The most commonly used medical therapies for the treatment of menorrhagia have been progestogens alone or combined with an oestrogen, and antifibrinolytic drugs. Most recently, prostaglandin synthetase inhibitors have been shown to reduce menstrual blood loss in some women. This paper reviews the use of danazol in the treatment of women complaining of regular but heavy menstrual blood loss and in whom objective measurements of blood loss were made. 18 patients with menorrhagia (more than 80ml menstrual blood loss) were treated with danazol 400mg daily for 12 weeks. Danazol significantly reduced the menstrual blood loss from 231 ± 39ml (mean ± SEM) to 135 ± 33 ml in the first treatment month, and the mean loss thereafter was only 21ml and 3ml for the second and third months respectively. A rapid increase in haemoglobin level, and a reduction in the number of days of bleeding were also observed on danazol treatment. No important effect on the coagulation profile was observed during the period of study. 3 months after stopping danazol, menstrual blood loss (103 ± 27 ml) was still significantly less than the pretreatment loss. Because of side effects of weight gain and muscle cramps in some patients, a smaller dose of danazol, 200mg daily, has since been evaluated. This dose effectively reduced menstrual loss to acceptable amounts, with continuing regular menstrual periods in most women, and greatly reduced the incidence of side effects of the drug.

In 1987 the U.K. Medical Research Council established a Directed Programme of AIDS Research, the primary objective of which is the development of vaccines and therapeutic approaches against HIV infection and AIDS. The Programme's activities have been rapidly built up and by mid-1989 comprised some 130 individual research projects. The Programme provides the framework for a cohesive approach to AIDS research, comprising a clearly defined scientific development plan, the central provision of resources including laboratory reagents and specialized laboratory facilities and special arrangements for interaction with industry and for international collaboration and training. This article describes the organization, scientific strategies and progress of the Programme.

Preliminary results are presented on the effect of 400, 200 and 100 mg of daily danazol on measured menstrual blood loss, in women with menorrhagia. Both 400 and 200 mg daily effectively suppressed menstrual blood loss, 400 mg reducing menstrual blood loss from a pretreatment mean of 456 +/- 48 ml to 45 +/- 26 ml and 6 +/- 5 ml during the second and third months of treatment. Menstrual blood loss on 100 mg danazol was only minimally reduced. After two to three months on danazol, the pituitary showed ability to respond to gonadotrophin releasing hormone and to oestradiol benzoate. A lack of effect of danazol on most coagulation and fibrinolytic factors was demonstrated.

Summary In 13 ovulatory women with objective evidence of menorrhagia (menstrual blood loss greater than 80 ml), danazol 400 mg given daily for 12 weeks suppressed ovulation as shown by absence of gonadotrophin peaks, low serum progesterone levels and flat basal body temperature recordings. Serum concentrations of luteinising hormone and follicle stimulating hormone were within the range found during the normal menstrual cycle but oestradiol concentrations tended to fall, reaching levels less than 100 pmol/1 in some patients. Danazol treatment had no effect on levels of androstenedione or dehydroepiandrosterone and its sulphate. The presence or absence of cyclical bleeding on treatment, and the measured blood loss was unrelated to circulating oestradiol levels.