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The benefit of combined treatment with intravenous thrombolysis before endovascular thrombectomy in patients with acute ischaemic stroke caused by large vessel occlusion remains unclear. We hypothesised that the clinical outcomes of patients with stroke with large vessel occlusion treated with direct endovascular thrombectomy within 4·5 h would be non-inferior compared with the outcomes of those treated with standard bridging therapy (intravenous thrombolysis before endovascular thrombectomy).DIRECT-SAFE was an international, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Adult patients with stroke and large vessel occlusion in the intracranial internal carotid artery, middle cerebral artery (M1 or M2), or basilar artery, confirmed by non-contrast CT and vascular imaging, and who presented within 4·5 h of stroke onset were recruited from 25 acute-care hospitals in Australia, New Zealand, China, and Vietnam. Eligible patients were randomly assigned (1:1) via a web-based, computer-generated randomisation procedure stratified by site of baseline arterial occlusion and by geographic region to direct endovascular thrombectomy or bridging therapy. Patients assigned to bridging therapy received intravenous thrombolytic (alteplase or tenecteplase) as per standard care at each site; endovascular thrombectomy was also per standard of care, using the Trevo device (Stryker Neurovascular, Fremont, CA, USA) as first-line intervention. Personnel assessing outcomes were masked to group allocation; patients and treating physicians were not. The primary efficacy endpoint was functional independence defined as modified Rankin Scale score 0-2 or return to baseline at 90 days, with a non-inferiority margin of -0·1, analysed by intention to treat (including all randomly assigned and consenting patients) and per protocol. The intention-to-treat population was included in the safety analyses. The trial is registered with ClinicalTrials.gov, NCT03494920, and is closed to new participants.Between June 2, 2018, and July 8, 2021, 295 patients were randomly assigned to direct endovascular thrombectomy (n=148) or bridging therapy (n=147). Functional independence occurred in 80 (55%) of 146 patients in the direct thrombectomy group and 89 (61%) of 147 patients in the bridging therapy group (intention-to-treat risk difference -0·051, two-sided 95% CI -0·160 to 0·059; per-protocol risk difference -0·062, two-sided 95% CI -0·173 to 0·049). Safety outcomes were similar between groups, with symptomatic intracerebral haemorrhage occurring in two (1%) of 146 patients in the direct group and one (1%) of 147 patients in the bridging group (adjusted odds ratio 1·70, 95% CI 0·22-13·04) and death in 22 (15%) of 146 patients in the direct group and 24 (16%) of 147 patients in the bridging group (adjusted odds ratio 0·92, 95% CI 0·46-1·84).We did not show non-inferiority of direct endovascular thrombectomy compared with bridging therapy. The additional information from our study should inform guidelines to recommend bridging therapy as standard treatment.Australian National Health and Medical Research Council and Stryker USA.

Introduction: Magnetic susceptibility is a radiological contrast mechanism that may provide a measure of oxygenation and contribute to an understanding the pathophysiology of stroke. Currently, there are few studies that have explored magnetic susceptibility in ischemic tissue as a marker of tissue injury. Our study assesses day one ischemic tissue post-reperfusion for changes in magnetic susceptibility and evaluates its relationship with radiological markers of ischemic injury - apparent diffusion coefficient (ADC). Methods: In a prospective observational study, thirty-five ischemic stroke patients who underwent endovascular thrombectomy were scanned with MRI (24 – 72 hours after reperfusion) to obtain multi-echo Gradient Echo and DWI images. An experienced neuroradiologist manually delineated ischemic tissue ROIs (region of interest) on DWI images. Contralateral ROIs were obtained using an automated method. The cerebrospinal fluid and regions of haemorrhagic transformation were excluded from the ROIs. A Morphology Enabled Dipole Inversion (MEDI) pipeline was employed to generate Quantitative Susceptibility Mapping (QSM) images, and these were used to quantify magnetic susceptibility. Mean magnetic susceptibility and mean ADC values were measured in these ROIs, and these values were then correlated. Results: Mean magnetic susceptibility of the ischemic ROI was significantly higher than that of the contralateral ROI (0.71±11.72 ppb, -5.59±7.30 ppb; p = 0.003). Mean ADC values of the ROI in the ischemic hemisphere were significantly lower than those in the contralateral hemisphere (0.65±0.09 х 10 -3 mm 2 /s, 0.81±0.05 х 10 -3 mm 2 /s; p = 1.31 х 10 -11 ). No significant correlation between susceptibility and ADC was found (ρ = -0.278, p = 0.106). Conclusion: Magnetic susceptibility in the ischemic tissue is measurable and is elevated when compared to the normal tissue. This may be attributed to the increased oxygen extraction fraction in the ischemic tissue. Further voxel wise analysis and larger longitudinal multi-parametric analysis correlating magnetic susceptibility with other imaging measures of tissue injury over time will help characterise the significance of lesional magnetic susceptibility changes in ischemic tissue.

Background and ObjectivesThe relevance of impaired microvascular tissue-level reperfusion despite complete upstream macrovascular angiographic reperfusion (no-reflow) in human stroke remains controversial. We investigated the prevalence and clinical-radiologic features of this phenomenon and its associations with outcomes in 3 international randomized controlled thrombectomy trials with prespecified follow-up perfusion imaging.MethodsIn a pooled analysis of the Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-Arterial (EXTEND-IA; ClinicalTrials.govNCT01492725), Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke (EXTEND-IA TNK; NCT02388061), and Determining the Optimal Dose of Tenecteplase Before Endovascular Therapy for Ischaemic Stroke (EXTEND-IA TNK Part 2; NCT03340493) trials, patients undergoing thrombectomy with final angiographic expanded Treatment in Cerebral Infarction score of 2c to 3 score for anterior circulation large vessel occlusion and 24-hour follow-up CT or MRI perfusion imaging were included. No-reflow was defined as regions of visually demonstrable persistent hypoperfusion on relative cerebral blood volume or flow maps within the infarct and verified quantitatively by >15% asymmetry compared to a mirror homolog in the absence of carotid stenosis or reocclusion.ResultsRegions of no-reflow were identified in 33 of 130 patients (25.3%), encompassed a median of 60.2% (interquartile range 47.8%–70.7%) of the infarct volume, and involved both subcortical (n = 26 of 33, 78.8%) and cortical (n = 10 of 33, 30.3%) regions. Patients with no-reflow had a median 25.2% (interquartile range 16.4%–32.2%, p < 0.00001) relative cerebral blood volume interside reduction and 19.1% (interquartile range 3.9%–28.3%, p = 0.00011) relative cerebral blood flow reduction but similar mean transit time (median −3.3%, interquartile range −11.9% to 24.4%, p = 0.24) within the infarcted region. Baseline characteristics were similar between patients with and those without no-reflow. The presence of no-reflow was associated with hemorrhagic transformation (adjusted odds ratio [aOR] 1.79, 95% confidence interval [CI] 2.32–15.57, p = 0.0002), greater infarct growth (β = 11.00, 95% CI 5.22–16.78, p = 0.00027), reduced NIH Stroke Scale score improvement at 24 hours (β = −4.06, 95% CI 6.78–1.34, p = 0.004) and being dependent or dead at 90 days as assessed by the modified Rankin Scale (aOR 3.72, 95% CI 1.35–10.20, p = 0.011) in multivariable analysis.DiscussionCerebral no-reflow in humans is common, can be detected by its characteristic perfusion imaging profile using readily available sequences in the clinical setting, and is associated with posttreatment complications and being dependent or dead. Further studies evaluating the role of no-reflow in secondary injury after angiographic reperfusion are warranted.Classification of EvidenceThis study provides Class II evidence that cerebral no-reflow on CT/MRI perfusion imaging at 24 hours is associated with posttreatment complications and poor 3-month functional outcome.

Lack of physical activity is a risk factor for dementia, however, the utility of interventional physical activity programs as a protective measure against brain atrophy and cognitive decline is uncertain. Here we present the effect of a randomized controlled trial of a 24-month physical activity intervention on global and regional brain atrophy as characterized by longitudinal voxel-based morphometry with T1-weighted MRI images. The study sample consisted of 98 participants at risk of dementia, with mild cognitive impairment or subjective memory complaints, and having at least one vascular risk factor for dementia, randomized into an exercise group and a control group. Between 0 and 24 months, there was no significant difference detected between groups in the rate of change in global, or regional brain volumes.

Brain iron is central to dopaminergic neurotransmission, a key component in schizophrenia pathology. Iron can also generate oxidative stress, which is one proposed mechanism for gray matter volume reduction in schizophrenia. The role of brain iron in schizophrenia and its potential link to oxidative stress has not been previously examined. In this study, we used 7-Tesla MRI quantitative susceptibility mapping (QSM), magnetic resonance spectroscopy (MRS), and structural T1 imaging in 12 individuals with chronic schizophrenia and 14 healthy age-matched controls. In schizophrenia, there were higher QSM values in bilateral putamen and higher concentrations of phosphocreatine and lactate in caudal anterior cingulate cortex (caCC). Network-based correlation analysis of QSM across corticostriatal pathways as well as the correlation between QSM, MRS, and volume, showed distinct patterns between groups. This study introduces increased iron in the putamen in schizophrenia in addition to network-wide disturbances of iron and metabolic status.

The relationship between reperfusion and edema is unclear, with experimental and clinical data yielding conflicting results. We investigated whether the extent of salvageable and irreversibly-injured tissue at baseline influenced the effect of therapeutic reperfusion on cerebral edema. In a pooled analysis of 415 patients with anterior circulation large vessel occlusion from the Tenecteplase-versus-Alteplase-before-Endovascular-Therapy-for-Ischemic-Stroke (EXTEND-IA TNK) part 1 and 2 trials, associations between core and mismatch volume on pre-treatment CT-Perfusion with cerebral edema at 24-hours, and their interactions with reperfusion were tested. Core volume was associated with increased edema (p

Objective: The volumes of various brain regions can be rapidly quantified using automated magnetic resonance imaging tools. While these appear to be useful at face value, their formal clinical utility is not yet understood, particularly for non-neuroradiologists and in patients presenting with suspected dementia. This study investigated the utility of an automated normative morphometry tool on determinations of brain atrophy by psychiatrists and radiologists in a tertiary hospital. Methods: Consecutive magnetic resonance scans ( n = 110) of patients referred with suspected neurodegenerative disorders were obtained retrospectively and rated by two neuroradiologists, two general radiologists and four psychiatrists over two sessions. First, conventional magnetic resonance sequences were shown. Then, morphometry colour-coded maps, which segmented T1-weighted magnetisation prepared rapid gradient echo images into brain regions and visualised these regions in colour according to their volumetric standard deviation from a normative population, were added to the second reading which occurred ⩾6 weeks later. Presence and laterality of atrophy in frontal, parietal and temporal lobes and hippocampal regions were measured using a digital checklist. The primary outcome of inter-rater agreement on atrophy was measured with Fleiss’ Kappa (κ). We also evaluated the accuracy of the atrophy ratings for differentiating post hoc diagnosis of subjective cognitive impairment, mild cognitive impairment and dementia. Results: Agreement among all raters was fair in frontal lobe and moderate in other regions with conventional method (κ = 0.362–0.555). With morphometry, higher agreement was seen in all regions (κ = 0.551–0.654), reaching significant improvement in the frontal and temporal lobes. No significant improvement was seen within the various disciplines, except in frontal lobes rated by psychiatrists. Accuracy of atrophy ratings on determining post hoc diagnosis was significantly improved for distinguishing subjective cognitive impairment versus dementia. Conclusion: In routine clinical assessment, automated normative morphometry complements the determination of regional atrophy and improves inter-rater agreement regardless of neuroradiology experience.

BACKGROUND AND PURPOSE: Recently, there has been growing interest in the glymphatic system (the functional waste clearance pathway for the central nervous system and its role in flushing solutes (such as amyloid s and tau), metabolic, and other cellular waste products in the brain. Herein, we investigate a recent potential biomarker for glymphatic activity (the diffusion tensor imaging along the perivascular space [DTI-ALPS] parameter) using diffusion MRI imaging in an elderly cohort comprising 10 cognitively normal, 10 mild cognitive impairment (MCI), and 16 Alzheimer's disease (AD). METHODS: All 36 participants imaged on a Siemens 3.0T Tim Trio. Single-SE diffusion weighted Echo-planar imaging scans were acquired as well as T1 magnetization prepared rapid gradient echo, T2 axial, and susceptibility weighted imaging. Three millimeter regions of interest were drawn in the projection and association fibers adjacent to the medullary veins at the level of the lateral ventricle. The DTI-ALPS parameter was calculated in these regions and correlated with cognitive status, Mini-Mental State Examination (MMSE), and ADASCog11 measures. RESULTS: Significant correlations were found between DTI-ALPS and MMSE and ADASCog11 in the right hemisphere adjusting for age, sex, and APoE e4 status. Significant differences were also found in the right DTI-ALPS indices between cognitively normal and AD groups (P < .026) and MCI groups (P < .025) in a univariate general linear model corrected for age, sex, and APoE e4. Significant differences in apparent diffusion coefficient between cognitively normal and AD groups were found in the right projection fibers (P = .028). CONCLUSION: Further work is needed to determine the utility of DTI-ALPS index in larger elderly cohorts and whether it measures glymphatic activity.

Objective The posterior cingulate cortex (PCC)/precuneus is a key hub of the default mode network, whose function is known to be altered in epilepsy. Glutamate and γ-aminobutyric acid (GABA) are the main excitatory and inhibitory neurotransmitters in the central nervous system, respectively. Glutathione (GSH) is the most important free radical scavenging compound in the brain. Quantification of these molecules by magnetic resonance spectroscopy (MRS) up to 4 T is limited by overlapping resonances from other molecules. In this study, we used ultra-high-field (7 T) MRS to quantify their concentrations in patients with different epilepsy syndromes. Methods Nineteen patients with temporal lobe epilepsy (TLE) and 16 with idiopathic generalized epilepsy (IGE) underwent magnetic resonance imaging scans using a 7-T research scanner. Single-voxel (8 cm3 ) MRS, located in the PCC/precuneus, was acquired via stimulated echo acquisition mode. Their results were compared to 10 healthy volunteers. Results Mean concentrations of glutamate, GABA, and the glutamate/GABA ratio did not differ between the IGE, TLE, and healthy volunteer groups. The mean ± SD concentration of GSH was 1.9 ± 0.3 mmol·L-1 in healthy controls, 2.0 ± 0.2 mmol·L-1 in patients with TLE, and 2.2 ± 0.4 mmol·L-1 in patients with IGE. One-way analysis of variance with post hoc Tukey-Kramer test revealed a significant difference in the concentration of GSH between patients with IGE and controls (P = .03). Short-term seizure freedom in patients with epilepsy was predicted by an elevated concentration of glutamate in the PCC/precuneus (P = .01). In patients with TLE, the concentration of GABA declined with age (P = .03). Significance Patients with IGE have higher concentrations of GSH in the PCC/precuneus than healthy controls. There is no difference in the concentrations of glutamate and GABA, or their ratio, in the PCC/precuneus between patients with IGE, patients with TLE, and healthy controls. Measuring the concentration of glutamate in the PCC/precuneus may assist with predicting drug response.

Gadolinium-based contrast agents for clinical magnetic resonance imaging are overall safe. However, the discovery of nephrogenic systemic fibrosis in patients with severe renal impairment and gadolinium deposition in patients receiving contrast have generated developments in contrast-free imaging of the vasculature, that is, noncontrast magnetic resonance angiography. This article presents an update on noncontrast magnetic resonance angiography techniques, with comparison to other imaging alternatives. Potential benefits and challenges to implementation, and evidence to date for various clinical applications are discussed.

White matter hyperintensities (WMHs) are a risk factor for cognitive decline. Physical activity (PA) is associated with lower WMH. Whether long-term exposure to PA programs has beneficial effects on WMH progression in older adults with memory complaints and comorbid conditions has had limited exploration. This study explored whether a 24-month moderate-intensity PA intervention can delay the progression of WMH and hippocampus loss in older adults at risk for cognitive decline. Data acquired on magnetic resonance imaging were used to measure the progression of WMH and hippocampus loss. The results of this study showed no effect of intervention on either the primary outcome measure "WMH" or the secondary outcome measure "hippocampal volume." In addition, neither beta amyloid status nor the adherence to the intervention had any effect on the outcome. In this cohort of subjective memory complaints and mild cognitive impairment participants with vascular risk factors, there was no effect of long-term moderate-intensity PA on WMH or hippocampal loss.

Background: There is a paucity of information on the role of microvascular and inflammatory biomarkers in cognitive dysfunction. Objective: This study sought to evaluate the relationships between established and a number of peripheral biomarkers on cognitive patterns in 108 older adults with memory complaints. Methods: Participants in the AIBL Active study aged 60 years and older with at least one vascular risk factor and memory complaints completed a neuropsychological test battery and provided cross-sectional health data. Linear regression models adjusted for covariates examined associations between cognitive performance and a panel of vascular risk factors (Framingham cardiovascular scores, hs-CRP, homocysteine, fasting glucose, LDL-cholesterol) and peripheral biomarkers (TNF-α, BDNF, VCAM-1, ICAM-1, PAI-1, CD40L). Results: Higher fasting glucose and homocysteine levels were independent factors associated with poorer performance in Trail Making Test (TMT) B (adjusted β= 0.40±0.10 and 0.43±0.09, respectively). Increasing homocysteine levels were weakly associated with poorer global cognition and delayed recall (adjusted β= 0.23±0.10 and -0.20±0.10 respectively). Increasing Framingham cardiovascular scores were related to poorer performance in TMT B (β = 0.42±0.19). There was early evidence of associations between increasing plasma TNF-α and poorer TMT B (adjusted β = 0.21±0.10) and between increasing BDNF and better global cognition (β= -0.20±0.09). Conclusion: This study provides evidence to support the associations between vascular risk factors (Framingham scores, fasting glucose, and homocysteine) and poorer cognitive functions. Additionally, we measured several peripheral biomarkers to further investigate their associations with cognition. The relationship between TNF-α, BDNF, and cognitive performance in various domains may offer new insights into potential mechanisms in vascular cognitive impairment.

Background and Purpose— Mobile stroke units (MSUs) are increasingly used worldwide to provide prehospital triage and treatment. The benefits of MSUs in giving earlier thrombolysis have been well established, but the impacts of MSUs on endovascular thrombectomy (EVT) and effect on disability avoidance are largely unknown. We aimed to determine the clinical impact and disability reduction for reperfusion therapies in the first operational year of the Melbourne MSU. Methods— Treatment time metrics for MSU patients receiving reperfusion therapy were compared with control patients presenting to metropolitan Melbourne stroke units via standard ambulance within MSU operating hours. The primary outcome was median time difference in first ambulance dispatch to treatment modeled using quantile regression analysis. Time savings were subsequently converted to disability-adjusted life years avoided using published estimates. Results— In the first 365-day operation of the Melbourne MSU, prehospital thrombolysis was administered to 100 patients (mean age, 73.8 years; 62% men). The median time savings per MSU patient, compared with the control cohort, was 26 minutes ( P P P P =0.001) for EVT hospital arrival to arterial puncture for MSU patients. Estimated median disability-adjusted life years saved through earlier provision of reperfusion therapies were 20.9 for thrombolysis and 24.6 for EVT. Conclusions— The Melbourne MSU substantially reduced time to reperfusion therapies, with the greatest estimated disability avoidance driven by the more powerful impact of earlier EVT. These findings highlight the benefits of prehospital notification and direct triage to EVT centers with facilitated workflow on arrival by the MSU.

One outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualize on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide. The Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonized a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance. Our pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. On a restricted ‘gold-standard’ subcohort of seizure-free patients with FCD type IIB who had T1 and fluid-attenuated inversion recovery MRI data, the MELD FCD surface-based algorithm had a sensitivity of 85%. Across the entire withheld test cohort the sensitivity was 59% and specificity was 54%. After including a border zone around lesions, to account for uncertainty around the borders of manually delineated lesion masks, the sensitivity was 67%. This multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions in individuals with epilepsy.

Funder: National Institute for Health Research (NIHR) GOSH BRC, OBJECTIVE: Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome. METHODS: The MELD (Multi-centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging-based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom. RESULTS: FCDs were nonuniformly distributed, concentrating in the superior frontal sulcus, frontal pole, and temporal pole. Epilepsy onset was typically before the age of 10 years. Earlier epilepsy onset was associated with lesions in primary sensory areas, whereas later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor, and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%. SIGNIFICANCE: FCD location is an important determinant of its size, the age at epilepsy onset, and the likelihood of seizure freedom postsurgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counseling in epilepsy.

Background In vivo measurement of hippocampal volume with magnetic resonance imaging (MRI) has become an important element in neuroimaging research. However, hippocampal volumetric findings and their relationship with cardiovascular risk factors and memory performance are still controversial and inconsistent for non-demented adults. Purpose To compare total and regional hippocampal volumes from manual tracing and automated Freesurfer segmentation methods and their relationship with mid-life clinical data and late-life verbal episodic memory performance in older women. Material and Methods This study used structural MRI datasets from 161 women who were scanned in 2012 and underwent neuropsychological assessments. Of these participants, 135 women had completed baseline measures of cardiovascular risk factors in 1992. Results Our results showed a significant correlation between manual tracing and automated Freesurfer output segmentations of total (r = 0.71), anterior (r = 0.65), and posterior (r = 0.38) hippocampal volumes. Mid-life Framingham Cardiovascular Risk Profile score is not associated with late-life hippocampal volumes, adjusted for intracranial volume, age, education, and apolipoprotein E gene ε4 status. Anterior hippocampal volume segmented either with manual tracing or automated Freesurfer software is sensitive to changes in mid-life high-density lipoprotein (HDL) cholesterol level, while posterior hippocampal volume is linked with verbal episodic memory performance in elderly women. Conclusion These findings support the use of Freesurfer automated segmentation measures for large datasets as being highly correlated with the manual tracing method. In addition, our results suggest intervention strategies that target mid-life HDL cholesterol level in women.

IntroductionOne outstanding challenge for machine learning in diagnostic biomedical imaging is algorithm interpretability. A key application is the identification of subtle epileptogenic focal cortical dysplasias (FCDs) from structural MRI. FCDs are difficult to visualise on structural MRI but are often amenable to surgical resection. We aimed to develop an open-source, interpretable, surface-based machine-learning algorithm to automatically identify FCDs on heterogeneous structural MRI data from epilepsy surgery centres worldwide.MethodsThe Multi-centre Epilepsy Lesion Detection (MELD) Project collated and harmonised a retrospective MRI cohort of 1015 participants, 618 patients with focal FCD-related epilepsy and 397 controls, from 22 epilepsy centres worldwide. We created a neural network for FCD detection based on 33 surface-based features. The network was trained and cross-validated on 50% of the total cohort and tested on the remaining 50% as well as on 2 independent test sites. Multidimensional feature analysis and integrated gradient saliencies were used to interrogate network performance.ResultsOur pipeline outputs individual patient reports, which identify the location of predicted lesions, alongside their imaging features and relative saliency to the classifier. Overall, after including a border-zone around lesions, the developed MELD FCD surface-based algorithm had a sensitivity of 67% and a specificity of 54% on the withheld test cohort, and a sensitivity of 85% on a restricted subcohort of seizure free patients with FCD type IIB who had T1 and FLAIR MRI data.ConclusionsThis multicentre, multinational study with open access protocols and code has developed a robust and interpretable machine-learning algorithm for automated detection of focal cortical dysplasias, giving physicians greater confidence in the identification of subtle MRI lesions.HighlightsThis large, multi-centre, multi-scanner neuroimaging cohort captures the heterogeneity of histopathological subtypes and imaging features of patients with FCD.We developed a robust and interpretable surface-based algorithm which detects FCDs with a sensitivity of 67% and a specificity of 54%.The algorithm generates individual patient reports that “open the AI black-box” highlighting predicted lesion locations, alongside the imaging features and their relative saliency to the classifier.

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem co-expression patterns of epilepsy risk genes. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1,328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-genetic signatures could guide diagnosis, and ultimately, tailor therapeutic approaches to specific epilepsy syndromes.

BackgroundImplantable brain–computer interfaces (BCIs), functioning as motor neuroprostheses, have the potential to restore voluntary motor impulses to control digital devices and improve functional independence in patients with severe paralysis due to brain, spinal cord, peripheral nerve or muscle dysfunction. However, reports to date have had limited clinical translation.MethodsTwo participants with amyotrophic lateral sclerosis (ALS) underwent implant in a single-arm, open-label, prospective, early feasibility study. Using a minimally invasive neurointervention procedure, a novel endovascular Stentrode BCI was implanted in the superior sagittal sinus adjacent to primary motor cortex. The participants undertook machine-learning-assisted training to use wirelessly transmitted electrocorticography signal associated with attempted movements to control multiple mouse-click actions, including zoom and left-click. Used in combination with an eye-tracker for cursor navigation, participants achieved Windows 10 operating system control to conduct instrumental activities of daily living (IADL) tasks.ResultsUnsupervised home use commenced from day 86 onwards for participant 1, and day 71 for participant 2. Participant 1 achieved a typing task average click selection accuracy of 92.63% (100.00%, 87.50%–100.00%) (trial mean (median, Q1–Q3)) at a rate of 13.81 (13.44, 10.96–16.09) correct characters per minute (CCPM) with predictive text disabled. Participant 2 achieved an average click selection accuracy of 93.18% (100.00%, 88.19%–100.00%) at 20.10 (17.73, 12.27–26.50) CCPM. Completion of IADL tasks including text messaging, online shopping and managing finances independently was demonstrated in both participants.ConclusionWe describe the first-in-human experience of a minimally invasive, fully implanted, wireless, ambulatory motor neuroprosthesis using an endovascular stent-electrode array to transmit electrocorticography signals from the motor cortex for multiple command control of digital devices in two participants with flaccid upper limb paralysis.

Purpose Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. Method A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). Results Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. Discussion This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

Background and hypothesis Intravenous thrombolysis with tenecteplase is more effective than alteplase in achieving substantial reperfusion at initial angiographic assessment and improves functional outcome. However, the optimal dose of tenecteplase remains uncertain. We hypothesized that 0.40 mg/kg tenecteplase is superior to 0.25 mg/kg tenecteplase in achieving reperfusion at initial angiogram, when administered within 4.5 h of ischemic stroke onset, in patients planned to undergo endovascular therapy. Study design EXTEND-IA TNK part 2 is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) study. Eligibility requires a diagnosis of ischemic stroke within 4.5 h of stroke onset, pre-stroke modified Rankin Scale (mRS)≤3 (no upper age limit), absence of contraindications to intravenous thrombolysis, and large vessel occlusion (internal carotid, basilar, or middle cerebral artery) on multimodal CT. Patients are randomized to IV tenecteplase at either 0.40 mg/kg (max 40 mg) or 0.25 mg/kg (max 25 mg) prior to thrombectomy. Study outcomes The primary outcome measure is reperfusion on the initial catheter angiogram, assessed as modified Treatment In Cerebral Infarction (mTICI) 2b/3, or the absence of retrievable intracranial thrombus. Secondary outcomes include mRS at day 90 and early neurological improvement (reduction in National Institutes of Health Stroke Scale (NIHSS) by ≥8 points or reaching 0–1) at day 3. Safety outcomes are death and symptomatic intracerebral hemorrhage. Trial registration: ClinicalTrials.gov NCT03340493

Background and purpose Quantitative susceptibility mapping (QSM) of the brain has become highly reproducible and has applications in an expanding array of diseases. To translate QSM from bench to bedside, it is important to automate its reconstruction immediately after data acquisition. In this work, a server system that automatically reconstructs QSM and exchange images with the scanner using the DICOM standard is demonstrated using a multi-site, multi-vendor reproducibility study and a large, single-site, multi-scanner image quality review study in a clinical environment. Methods A single healthy subject was scanned with a 3D multi-echo gradient echo sequence at nine sites around the world using scanners from three manufacturers. A high-resolution (HiRes, .5 × .5 × 1 mm3 reconstructed) and standard-resolution (StdRes, .5 × .5 × 3 mm3 ) protocol was performed. ROI analysis of various white matter and gray matter regions was performed to investigate reproducibility across sites. At one institution, a retrospective multi-scanner image quality review was carried out of all clinical QSM images acquired consecutively in 1 month. Results Reconstruction times using a GPU were 29 ± 22 seconds (StdRes) and 55 ± 39 seconds (HiRes). ROI standard deviation across sites was below 24 ppb (StdRes) and 17 ppb (HiRes). Correlations between ROI averages across sites were on average .92 (StdRes) and .96 (HiRes). Image quality review of 873 consecutive patients revealed diagnostic or excellent image quality in 96% of patients. Conclusion Online QSM reconstruction for a variety of sites and scanner platforms with low cross-site ROI standard deviation is demonstrated. Image quality review revealed diagnostic or excellent image quality in 96% of 873 patients.

Background: Previous studies have demonstrated that physical activity (PA) interventions can improve physical and cognitive outcomes in older adults, but most have been relatively short in duration (

Background and importance Obsessive-compulsive disorder (OCD) is a disabling psychiatric disorder, mainly treated with psychotherapy and pharmacotherapy. Surgical intervention may be appropriate for patients with treatment-refractory OCD. Deep brain stimulation (DBS) is an alternative for previously common ablative surgical procedures. Tractography has been proposed as a method for individualizing DBS treatment and may have the potential to improve efficacy. Clinical presentation We present a patient with treatment-refractory OCD previously treated with bilateral leucotomies, who underwent DBS surgery with targeting informed by tractography. Preoperative tractography to identify suitable DBS targets was undertaken. Structural images were also utilized for standard stereotactic surgical planning. The anteromedial globus pallidus internus (amGPi) was chosen as the target bilaterally after consideration of white matter projections to frontal cortical regions and neurosurgical approach. Bilateral amGPi DBS surgery was undertaken without adverse events. At 16-mo follow-up, there was a 48.5% reduction in OCD symptom severity as measured by the Yale-Brown Obsessive Compulsive Scale. Conclusion The amGPi can be a successful DBS target for OCD. This is the first known case to report on DBS surgery postleucotomies for OCD and highlights the utility of tractography for surgical planning in OCD.

There is hope that the continuing efforts of researchers will yield a disease-modifying drug for Alzheimer’s disease. Such a drug is likely to be capable of halting, or significantly slowing, the underlying pathological processes driving cognitive decline; however, it is unlikely to be capable of restoring brain function already lost through the pathological process. A therapy capable of halting Alzheimer’s disease, while not providing restoration of function, may prompt serious ethical questions. For example, is there a stage in the disease process when it becomes too late for therapeutic intervention to commence? And who bears the responsibility of making such a decision? Conversations regarding the ethics of treating neurodegenerative conditions with non-restorative drugs have been largely absent within both clinical and research communities. Such discussions are urgently required to ensure that patients’ rights and well-being are protected when such therapeutic options become available.

OBJECTIVE: We investigated the relationship between the interictal metabolic patterns, the extent of resection of 18 F-fluorodeoxyglucose positron emission tomography (18 FDG-PET) hypometabolism, and seizure outcomes in patients with unilateral drug-resistant mesial temporal lobe epilepsy (MTLE) following anterior temporal lobe (TL) resection. METHODS: Eighty-two patients with hippocampal sclerosis or normal magnetic resonance imaging (MRI) findings, concordant 18 FDG-PET hypometabolism, and at least 2 years of postoperative follow-up were included in this 2-center study. The hypometabolic regions in each patient were identified with reference to 20 healthy controls (p < 0.005). The resected TL volume and the volume of resected TL PET hypometabolism (TLH) were calculated from the pre- and postoperative MRI scans coregistered with interictal 18 FDG-PET. RESULTS: Striking differences in metabolic patterns were observed depending on the lateralization of the epileptogenic TL. The extent of the ipsilateral TLH was significantly greater in left MTLE patients (p < 0.001), whereas right MTLE patients had significantly higher rates of contralateral (CTL) TLH (p = 0.016). In right MTLE patients, CTL hypometabolism was the strongest predictor of an unfavorable seizure outcome, associated with a 5-fold increase in the likelihood of seizure recurrence (odds ratio [OR] = 4.90, 95% confidence interval [CI] = 1.07-22.39, p = 0.04). In left MTLE patients, greater extent of resection of ipsilateral TLH was associated with lower rates of seizure recurrence (p = 0.004) in univariate analysis; however, its predictive value did not reach statistical significance (OR = 0.96, 95% CI = 0.90-1.02, p = 0.19). INTERPRETATION: The difference in metabolic patterns depending on the lateralization of MTLE may represent distinct epileptic networks in patients with right versus left MTLE, and can guide preoperative counseling and surgical planning. Ann Neurol 2019; 1-10 ANN NEUROL 2019;85:241-250.

[EN] Accurate quantification of white matter hyperintensities (WMH) from Magnetic Resonance Imaging (MRI) is a valuable tool for the analysis of normal brain ageing or neurodegeneration. Reliable automatic extraction of WMH lesions is challenging due to their heterogeneous spatial occurrence, their small size and their diffuse nature. In this paper, we present an automatic method to segment these lesions based on an ensemble of overcomplete patch-based neural networks. The proposed method successfully provides accurate and regular segmentations due to its overcomplete nature while minimizing the segmentation error by using a boosted ensemble of neural networks. The proposed method compared favourably to state of the art techniques using two different neurodegenerative datasets. (C) 2018 Elsevier Ltd. All rights reserved., This research has been done thanks to the Australian distinguished visiting professor grant from the CSIRO (Commonwealth Scientific and Industrial Research Organisation) and the Spanish "Programa de apoyo a la investigacion y desarrollo (PAID-00-15)" of the Universidad Politecnica de Valencia. This research was partially supported by the Spanish grant TIN2013-43457-R from the Ministerio de Economia y competitividad. This study has been carried out also with support from the French State, managed by the French National Research Ageny in the frame of the Investments for the future Program IdEx Bordeaux (ANR-10-IDEX-03-02, HL-MRI Project), Cluster of excellence CPU and TRAIL (HR-DTI ANR-10-LABX-57) and the CNRS multidisciplinary project Defi imag'In. Some of the data used in this work was collected by the AIBL study group. Funding for the AIBL study is provided by the CSIRO Flagship Collaboration Fund and the Science and Industry Endowment Fund (SIEF) in partnership with Edith Cowan University (ECU), Mental Health Research Institute (MHRI), Alzheimer's Australia (AA), National Ageing Research Institute (NARI), Austin Health, Macquarie University, CogState Ltd, Hollywood Private Hospital, and Sir Charles Gairdner Hospital.

Temporal lobe epilepsy (TLE), a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter pathology in TLE relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multi-site ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 TLE patients and 1,418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in TLE, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity, and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of TLE-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of TLE and may inform future discovery and validation of complementary MRI biomarkers in TLE.

Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome.The Multi-centre Epilepsy Lesion Detection (MELD) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centres worldwide. MRI-based maps of individual FCDs with accompanying demographic, clinical and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom.FCDs were non-uniformly distributed, concentrating in the superior frontal sulcus, frontal pole and temporal pole. Epilepsy onset was typically before age 10. Earlier epilepsy onset was associated with lesions in primary sensory areas while later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%.FCD location is an important determinant of its size, the age of epilepsy onset and the likelihood of seizure freedom post-surgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counselling in neurology.

Background: methodological challenges limit the use of brain atrophy and lesion burden measures in the followup of multiple sclerosis (MS) patients on clinical routine datasets. Objective: to determine the feasibility of T2-FLAIR-only measures of lateral ventricular volume (LVV) and salient central lesion volume (SCLV), as markers of disability progression (DP) in MS. Methods: a total of 3,228 MS patients from 9 MSBase centers in 5 countries were enrolled. Of those, 2,875 (218 with clinically isolated syndrome, 2,231 with relapsing-remitting and 426 with progressive disease subtype) fulfilled inclusion and exclusion criteria. Patients were scanned on either 1.5 T or 3 T MRI scanners, and 5,750 brain scans were collected at index and on average after 42.3 months at post-index. Demographic and clinical data were collected from the MSBase registry. LVV and SCLV were measured on clinical routine T2-FLAIR images. Results: longitudinal LVV and SCLV analyses were successful in 96% of the scans. 57% of patients had scanner related changes over the follow-up. After correcting for age, sex, disease duration, disability, disease-modifying therapy and LVV at index, and follow-up time, MS patients with DP (n = 671) had significantly greater absolute LVV change compared to stable (n = 1,501) or disability improved (DI, n = 248) MS patients (2.0 mL vs. 1.4 mL vs. 1.1 mL, respectively, ANCOVA p < 0.001, post-hoc pair-wise DP vs. Stable p = 0.003; and DP vs. DI, p = 0.002). Similar ANCOVA model was also significant for SCLV (p = 0.03). Conclusions: LVV-based atrophy and SCLV-based lesion outcomes are feasible on clinically acquired T2-FLAIR scans in a multicenter fashion and are associated with DP over mid-term., Novartis; Genzyme-Sanofi; Biogen; Merck; Genentech; Abbvie; Bayer AG; Celgene/ BMS; Mallinckrodt Pharmaceuticals, Inc.; WebMD Global; Teva; BioCSL; Almirall; Roche; Generica; Deva; Nerve Research Foundation; Multiple Sclerosis Research Australia; Keystone Heart; Bristol Myers Squibb; EMD Serono; V-WAVE Medical; Mapi Pharma; Protembis

Brain atrophy in human epilepsy syndromes is explainable by network architecture and strongest in hub regions., Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies.

Background The Melbourne Mobile Stroke Unit (MSU) is the first Australian service to provide prehospital acute stroke treatment, including thrombolysis and facilitated triage for endovascular thrombectomy. Aims To estimate the cost-effectiveness of the MSU during the first full year of operation compared with standard ambulance and hospital stroke care pathways (standard care). Methods The costs and benefits of the Melbourne MSU were estimated using an economic simulation model. Operational costs and service utilization data were obtained from the MSU financial and patient tracking reports. The health benefits were estimated as disability-adjusted life years (DALYs) avoided using local data on reperfusion therapy and estimates from the published literature on their effectiveness. Costs were presented in Australian dollars. The robustness of results was assessed using multivariable (model inputs varied simultaneously: 10,000 Monte Carlo iterations) and various one-way sensitivity analyses. Results In 2018, the MSU was dispatched to 1244 patients during 200 days of operation. Overall, 167 patients were diagnosed with acute ischemic stroke, and 58 received thrombolysis, endovascular thrombectomy, or both. We estimated 27.94 DALYs avoided with earlier access to endovascular thrombectomy (95% confidence interval (CI) 15.30 to 35.93) and 16.90 DALYs avoided with improvements in access to thrombolysis (95% CI 9.05 to 24.68). The MSU was estimated to cost an additional $30,982 per DALY avoided (95% CI $21,142 to $47,517) compared to standard care. Conclusions There is evidence that the introduction of MSU is cost-effective when compared with standard care due to earlier provision of reperfusion therapies.

SUMMARYEpilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1,021 adults with epilepsy compared to 1,564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy co-localized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Indices of progressive atrophy further revealed a strong influence of connectome architecture on disease progression in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients, and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided novel insights into the macroscale features that shape the pathophysiology of common epilepsies.

Importance Intravenous thrombolysis with tenecteplase improves reperfusion prior to endovascular thrombectomy for ischemic stroke compared with alteplase. Objective To determine whether 0.40 mg/kg of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion ischemic stroke. Design, setting, and participants Randomized clinical trial at 27 hospitals in Australia and 1 in New Zealand using open-label treatment and blinded assessment of radiological and clinical outcomes. Patients were enrolled from December 2017 to July 2019 with follow-up until October 2019. Adult patients (N = 300) with ischemic stroke due to occlusion of the intracranial internal carotid, \basilar, or middle cerebral artery were included less than 4.5 hours after symptom onset using standard intravenous thrombolysis eligibility criteria. Interventions Open-label tenecteplase at 0.40 mg/kg (maximum, 40 mg; n = 150) or 0.25 mg/kg (maximum, 25 mg; n = 150) given as a bolus before endovascular thrombectomy. Main outcomes and measures The primary outcome was reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists. Prespecified secondary outcomes were level of disability at day 90 (modified Rankin Scale [mRS] score; range, 0-6); mRS score of 0 to 1 (freedom from disability) or no change from baseline at 90 days; mRS score of 0 to 2 (functional independence) or no change from baseline at 90 days; substantial neurological improvement at 3 days; symptomatic intracranial hemorrhage within 36 hours; and all-cause death. Results All 300 patients who were randomized (mean age, 72.7 years; 141 [47%] women) completed the trial. The number of participants with greater than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group (unadjusted risk difference, 0.0% [95% CI, -8.9% to -8.9%]; adjusted risk ratio, 1.03 [95% CI, 0.66-1.61]; P = .89). Among the 6 secondary outcomes, there were no significant differences in any of the 4 functional outcomes between the 0.40 mg/kg and 0.25 mg/kg groups nor in all-cause deaths (26 [17%] vs 22 [15%]; unadjusted risk difference, 2.7% [95% CI, -5.6% to 11.0%]) or symptomatic intracranial hemorrhage (7 [4.7%] vs 2 [1.3%]; unadjusted risk difference, 3.3% [95% CI, -0.5% to 7.2%]). Conclusions and relevance Among patients with large vessel occlusion ischemic stroke, a dose of 0.40 mg/kg, compared with 0.25 mg/kg, of tenecteplase did not significantly improve cerebral reperfusion prior to endovascular thrombectomy. The findings suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned. Trial registration ClinicalTrials.gov Identifier: NCT03340493.

Iron has been found to play an important role in neurodegeneration. Quantitative susceptibility mapping (QSM) is a relatively new – and the most accurate - MRI technique available for assessment of iron deposition in the brain. There is a rapidly growing number of studies using QSM to investigate brain iron distribution in neurodegenerative diseases including but not limited to Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Huntington disease and Wilson’s disease. These studies have shown increased iron deposition in the brain regions that are associated with the pathology of the disease. Additionally, QSM is found to be accurate in differential diagnosis of neurodegenerative diseases where clinical presentations are indistinguishable. Structural changes evidenced by QSM are reported to precede the onset of clinical manifestation of neurodegenerative diseases suggesting its benefit in early diagnosis. To our knowledge, no systematic review of QSM findings in neurodegenerative diseases has been published before. A systematic synthesis and conclusion of the existing evidence can improve our understanding of the pathophysiology of neurodegeneration, describe the clinical and research utility of QSM, and point out the direction for future studies in neuropsychiatric disorders.This document is a systematic review protocol developed in accordance with Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) guideline. This protocol is prepared as a guide for conducting a systematic review of studies investigating brain iron and microstructural changes in neurodegenerative diseases using quantitative susceptibility mapping (QSM). This protocol has also been submitted to Prospective Register of Systematic Reviews (PROSPERO) for registration. By publishing this protocol, we aim to enhance clarity and transparency of our systematic review and minimise the risk of bias in the process of its development.

Objective: To evaluate the degree of variability in microstructural injury within and adjacent to regions identified as infarcted tissue using Diffusion Tensor Imaging (DTI). Methods: Perfusion CT was performed in 18 patients within 12 hours of ischemic stroke onset followed by Fluid-attenuated Inversion recovery (FLAIR) and DTI one month after stroke. Four regions of interest (ROIs) corresponding to the severity of hypoperfusion on CT perfusion within and beyond the radiological infarct lesion defined on FLAIR were segmented. Fractional anisotropy (FA) and mean diffusivity (MD) were quantified for each ROI and compared to a mirror homologue in the contralateral hemisphere. Ipsilateral to contralateral FA and MD ratios were compared across ROIs. Results: Lower FA and higher MD values were observed within both the infarct lesion and the peri-infarct tissue compared with their homologous contralateral brain regions (all comparisons p≤0.01). No difference was observed in FA and MD between remote non-hypoperfused tissue and its contralateral homologous region (FA p=0.42, MD p≥0.99). The magnitude of asymmetry (ipsilateral/contralateral ratios) of FA and MD was greater with increasing severity of hypoperfusion in a dose-response pattern. Asymmetry greatest in the area of infarction with severe hypoperfusion, followed by infarction with moderate hypoperfusion, the peri-infarct hypoperfused tissue and lastly the remote non-hypoperfused normal tissue (median on clustered quantile regression p≤0.01). Conclusion: A gradient of microstructural injury corresponding to the severity of ischemic insult is present within and beyond conventionally-defined infarct boundaries. The traditional dichotomized notion of infarcted versus non-infarcted tissue widely adopted in clinical research and in practice warrants re-examination.

Introduction: Intravenous alteplase reduces disability after ischemic stroke in patients 4.5-9h after onset and with wake-up onset stroke who have favorable perfusion imaging. We examined the benefit of reperfusion in reducing disability, including by onset to randomization time strata in the EXTEND and EPITHET randomized trials. Methods: Patients were randomized to alteplase or placebo after perfusion mismatch imaging. Reperfusion was defined as >90% reduction in Tmax>6s lesion volume at 24h. Ordinal logistic regression adjusted for baseline age and NIHSS was used to analyze functional improvement in day 90 modified Rankin scale overall, including a reperfusion*time to randomization interaction term, and in the 4.5-6h, 6-9h and wake-up time strata. Symptomatic hemorrhage was defined as large parenchymal hematoma with ≥4 point NIHSS increase (SITS). Results: Reperfusion was assessable in 270/294 (92%) patients, 68/133 (51%) alteplase and 38/137 (28%) placebo reperfused (p Conclusions: Strong benefits of reperfusion in all time strata without differential risk in symptomatic hemorrhage support the durable treatment effect of alteplase in perfusion mismatch-selected patients throughout the 4.5-9h and wake-up stroke time window.

Background: Mobile stroke units (MSUs) are ambulances with brain scanning capability and specialised staff. In Australia, the first MSU was launched in Melbourne, November 2017. The Melbourne MSU has two paramedics, a radiographer, a stroke neurologist and a stroke nurse specialist (5 days per week/ 8am-6pm). The MSU is co-dispatched with a standard ambulance to a patient with suspected stroke within metropolitan Melbourne (20km radius). In cases where the standard ambulance assessed the patient first and stroke is eliminated, the MSU is contacted to ‘stand-down’. The cost-effectiveness of this type of ‘pre-hospital’ service remains unclear. Methods: The potential cost-effectiveness of the Melbourne MSU was estimated for 2018 following the pilot period (Nov-Dec 2017). A simulation model was developed for 2018 with a) program costs: operational/finance reports, self-report program leads/senior operational staff; b) clinical processes: MSU medical records/historical data; and c) health effects of treatment taken from the literature for reperfusion therapies to patients with ischaemic stroke (i.e. benefits: additional patients treated/faster treatment). Primary outcome: incremental cost per disability adjusted life year (DALY) avoided. The comparison was to standard pre-hospital and emergency department historical ‘usual’ care. Probabilistic, multivariable uncertainty analyses with Monte Carlo (10,000) simulations and sensitivity analyses were conducted. Results: In 2018, the Melbourne MSU was dispatched for 1244 suspected strokes (200 operational days). Overall, 46.9 DALYs were potentially avoided (95% uncertainty interval 33.02, 82.15 DALYs). The net cost of operating the MSU was ~$US 980,000, and the incremental cost/DALY avoided was $US 20,681 compared to standard care (95% uncertainty interval $US 14,167, $US 32,214). Conclusion: The Melbourne MSU is a cost-effective model for stroke care based on a standard willingness-to-pay cost-effectiveness threshold (

Background: Severity-based selection tools for large vessel occlusion (LVO) are limited by lack of validation in unselected prehospital stroke patients and concerns regarding delayed thrombolysis (tPA) and comprehensive stroke center (CSC) burdening. We examined these issues in a real-world validation of the two exam step (severe arm motor + speech or neglect) ACT-FAST LVO triage algorithm. Methods: The ACT-FAST statewide validation involved 15 metro and 17 rural hospitals in Victoria, Australia from Nov 2017-July 2019 with training of paramedics using an 8 min video. Prehospital paramedic assessments were correlated with hospital imaging to determine presence of LVO. Data were then examined for diagnostic accuracy, time saving for direct bypass to CSC using a validated Google maps model, rates and magnitude of delayed tPA in false-positive non-LVO infarcts, and extra CSC workload. Results: In 517 completed assessments, 58% involving non-EVT centers and including 114 (22%) LVO, ACT-FAST sensitivity was 81% (92/114) and specificity was 81% (325/403; 89% if ICH are not regarded as false-positive) for LVO. Figure compares to other LVO scales. Bypass to CSC was modelled to save median 71 min for analysis of 29 thrombectomy patients requiring inter-hospital transfer. Of 27 non-LVO infarcts with false positive ACT-FAST, only 4 (15%) received tPA at a non-CSC center, and bypass would have only added median 10 mins in these cases. The increase in CSC presentation using ACT-FAST triage was estimated to be 2-3.3 patients/week using estimated 7,200 suspected stroke cases/year across entire metro Victoria. Conclusion: In comprehensive real-world validation, the simple ACT-FAST algorithm detected LVO or ICH in almost 80% of positive assessments with highly favorable comparison to other scales. Prehospital bypass to CSC substantially reduces thrombectomy delay, and appears to strongly outweigh negatives of bypassing false positive cases on tPA delay and CSC overburdening.