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Background and ObjectivesThe severity of white matter hyperintensities (WMH) at presentation with stroke is associated with poststroke dementia and dependency. However, WMH can decrease or increase after stroke; prediction of cognitive decline is imprecise; and there are few data assessing longitudinal interrelationships among changing WMH, cognition, and function after stroke, despite the clinical importance.MethodsWe recruited patients within 3 months of a minor ischemic stroke, defined as NIH Stroke Scale (NIHSS) score 2. Participants repeated MRI at 1 year and cognitive and mRS assessments at 1 and 3 years. We ran longitudinal mixed-effects models assessing change in Addenbrooke’s Cognitive Examination–Revised (ACE-R) and mRS scores. For mRS score, we assessed longitudinal WMH volumes (cube root; percentage intracranial volume [ICV]), adjusting for age, NIHSS score, ACE-R, stroke subtype, and time to assessment. For ACE-R score, we additionally adjusted for ICV, mRS, premorbid IQ, and vascular risk factors. We then used a multivariate model to jointly assess changing cognition/mRS score, adjusted for prognostic variables, using all available data.ResultsWe recruited 264 patients; mean age was 66.9 (SD 11.8) years; 41.7% were female; and median mRS score was 1 (interquartile range 1–2). One year after stroke, normalized WMH volumes were associated more strongly with 1-year ACE-R score (β = −0.259, 95% CI −0.407 to −0.111 more WMH per 1-point ACE-R decrease, p = 0.001) compared to subacute WMH volumes and ACE-R score (β = 0.105, 95% CI −0.265 to 0.054, p = 0.195). Three-year mRS score was associated with 3-year ACE-R score (β = −0.272, 95% CI −0.429 to −0.115, p = 0.001). Combined change in baseline-1-year jointly assessed ACE-R/mRS scores was associated with fluctuating WMH volumes (F = 9.3, p = 0.03).DiscussionAfter stroke, fluctuating WMH mean that 1-year, but not baseline, WMH volumes are associated strongly with contemporaneous cognitive scores. Covarying longitudinal decline in cognition and independence after stroke, central to dementia diagnosis, is associated with increasing WMH volumes.

Contains fulltext : 235277.pdf (Publisher’s version ) (Closed access) BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.

Vast quantities of Magnetic Resonance Images (MRI) are routinely acquired in clinical practice but, to speed up acquisition, these scans are typically of a quality that is sufficient for clinical diagnosis but sub-optimal for large-scale precision medicine, computational diagnostics, and large-scale neuroimaging research. Here, we present a critic-guided framework to upsample low-resolution (often 2D) MRI scans. In addition, we incorporated feature-importance and self-attention methods into our model to improve the interpretability of this work. We evaluate our framework on paired low- and high-resolution brain MRI structural full scans (i.e. T1-, T2-weighted and FLAIR sequences are simultaneously input) obtained in clinical and research settings from scanners manufactured by Siemens, Phillips and GE. We showed that the upsampled MRIs are qualitatively faithful to the ground-truth high-quality scans (PSNR = 35.39; MAE = 3.78E −3; NMSE = 4.32E −10; SSIM = 0.9852; mean normal-appearing grey/white matter ratio intensity differences ranging from 0.0363 to 0.0784 for FLAIR, from 0.0010 to 0.0138 for T1-weighted and from 0.0156 to 0.074 for T2-weighted sequences). The automatic raw segmentations of tissues and lesions using the super-resolved images have fewer false positives and higher accuracy than those obtained from interpolated images in protocols represented with more than three sets in the training sample, making our approach a strong candidate for practical application in clinical research.

Summary Background Oral anticoagulation reduces the rate of systemic embolism for patients with atrial fibrillation by two-thirds, but its benefits for patients with previous intracranial haemorrhage are uncertain. In the Start or STop Anticoagulants Randomised Trial (SoSTART), we aimed to establish whether starting is non-inferior to avoiding oral anticoagulation for survivors of intracranial haemorrhage who have atrial fibrillation. Methods SoSTART was a prospective, randomised, open-label, assessor-masked, parallel-group, pilot phase trial done at 67 hospitals in the UK. We recruited adults (aged ≥18 years) who had survived at least 24 h after symptomatic spontaneous intracranial haemorrhage, had atrial fibrillation, and had a CHA2DS2-VASc score of at least 2. Web-based computerised randomisation incorporating a minimisation algorithm allocated participants (1:1) to start or avoid long-term (≥1 year) full treatment dose open-label oral anticoagulation. The participants assigned to start oral anticoagulation received either a direct oral anticoagulant or vitamin K antagonist, and the group assigned to avoid oral anticoagulation received standard clinical practice (antiplatelet agent or no antithrombotic agent). The primary outcome was recurrent symptomatic spontaneous intracranial haemorrhage, and was adjudicated by an individual masked to treatment allocation. All outcomes were ascertained for at least 1 year after randomisation and assessed in the intention-to-treat population of all randomly assigned participants, using Cox proportional hazards regression adjusted for minimisation covariates. We planned a sample size of 190 participants (one-sided p=0·025, power 90%, allowing for non-adherence) based on a non-inferiority margin of 12% (or adjusted hazard ratio [HR] of 3·2). This trial is registered with ClinicalTrials.gov (NCT03153150) and is complete. Findings Between March 29, 2018, and Feb 27, 2020, consent was obtained at 61 sites for 218 participants, of whom 203 were randomly assigned at a median of 115 days (IQR 49–265) after intracranial haemorrhage onset. 101 were assigned to start and 102 to avoid oral anticoagulation. Participants were followed up for median of 1·2 years (IQR 0·97–1·95; completeness 97·2%). Starting oral anticoagulation was not non-inferior to avoiding oral anticoagulation: eight (8%) of 101 in the start group versus four (4%) of 102 in the avoid group had intracranial haemorrhage recurrences (adjusted HR 2·42 [95% CI 0·72–8·09]; p=0·152). Serious adverse events occurred in 17 (17%) participants in the start group and 15 (15%) in the avoid group. 22 (22%) patients in the start group and 11 (11%) patients in the avoid group died during the study. Interpretation Whether starting oral anticoagulation was non-inferior to avoiding it for people with atrial fibrillation after intracranial haemorrhage was inconclusive, although rates of recurrent intracranial haemorrhage were lower than expected. In view of weak evidence from analyses of three composite secondary outcomes, the possibility that oral anticoagulation might be superior for preventing symptomatic major vascular events should be investigated in adequately powered randomised trials. Funding British Heart Foundation, Medical Research Council, Chest Heart & Stroke Scotland.

Supplemental Digital Content is available in the text., Background and Purpose— Computed tomography (CT) perfusion (CTP) provides potentially valuable information to guide treatment decisions in acute stroke. Assessment of interobserver reliability of CTP has, however, been limited to small, mostly single center studies. We performed a large, internet-based study to assess observer reliability of CTP interpretation in acute stroke. Methods— We selected 24 cases from the IST-3 (Third International Stroke Trial), ATTEST (Alteplase Versus Tenecteplase for Thrombolysis After Ischaemic Stroke), and POSH (Post Stroke Hyperglycaemia) studies to illustrate various perfusion abnormalities. For each case, observers were presented with noncontrast CT, maps of cerebral blood volume, cerebral blood flow, mean transit time, delay time, and thresholded penumbra maps (dichotomized into penumbra and core), together with a short clinical vignette. Observers used a structured questionnaire to record presence of perfusion deficit, its extent compared with ischemic changes on noncontrast CT, and an Alberta Stroke Program Early CT Score for noncontrast CT and CTP. All images were viewed, and responses were collected online. We assessed observer agreement with Krippendorff-α. Intraobserver agreement was assessed by inviting observers who reviewed all scans for a repeat review of 6 scans. Results— Fifty seven observers contributed to the study, with 27 observers reviewing all 24 scans and 17 observers contributing repeat readings. Interobserver agreement was good to excellent for all CTP. Agreement was higher for perfusion maps compared with noncontrast CT and was higher for mean transit time, delay time, and penumbra map (Krippendorff-α =0.77, 0.79, and 0.81, respectively) compared with cerebral blood volume and cerebral blood flow (Krippendorff-α =0.69 and 0.62, respectively). Intraobserver agreement was fair to substantial in the majority of readers (Krippendorff-α ranged from 0.29 to 0.80). Conclusions— There are high levels of interobserver and intraobserver agreement for the interpretation of CTP in acute stroke, particularly of mean transit time, delay time, and penumbra maps.

Purpose: Dynamic contrast-enhanced (DCE) -MRI with Patlak model analysis is increasingly used to quantify low-level blood-brain barrier (BBB) leakage in studies of pathophysiology. We aimed to investigate systematic errors due to physiological, experimental, and modeling factors influencing quantification of the permeability-surface area product PS and blood plasma volume v p, and to propose modifications to reduce the errors so that subtle differences in BBB permeability can be accurately measured. Methods: Simulations were performed to predict the effects of potential sources of systematic error on conventional PS and v p quantification: restricted BBB water exchange, reduced cerebral blood flow, arterial input function (AIF) delay and (Formula presented.) error. The impact of targeted modifications to the acquisition and processing were evaluated, including: assumption of fast versus no BBB water exchange, bolus versus slow injection of contrast agent, exclusion of early data from model fitting and (Formula presented.) correction. The optimal protocol was applied in a cohort of recent mild ischaemic stroke patients. Results: Simulation results demonstrated substantial systematic errors due to the factors investigated (absolute PS error ≤ 4.48 × 10 −4 min −1). However, these were reduced (≤0.56 × 10 −4 min −1) by applying modifications to the acquisition and processing pipeline. Processing modifications also had substantial effects on in-vivo normal-appearing white matter PS estimation (absolute change ≤ 0.45 × 10 −4 min −1). Conclusion: Measuring subtle BBB leakage with DCE-MRI presents unique challenges and is affected by several confounds that should be considered when acquiring or interpreting such data. The evaluated modifications should improve accuracy in studies of neurodegenerative diseases involving subtle BBB breakdown.

Lacunar strokes are a common type of ischemic stroke. They are known to have long-term cognitive deficits, but the influencing factors are still largely unknown. We investigated if the location of the index lacunar stroke or regional WMH and their change at 1 year could predict the cognitive performance at 1 and 3 years post-stroke in lacunar stroke patients. We used lacunar lesion location and WMH-segmented data from 118 patients, mean age 64.9 who had a brain MRI scan soon after presenting with symptoms, of which 88 had a repeated scan 12 months later. Premorbid intelligence (National Adult Reading Test) and current intelligence [Addenbrooke's Cognitive Exam-Revised (ACE-R)] were measured at 1, 12, and 36 months after the stroke. ANCOVA analyses adjusting for baseline cognition/premorbid intelligence, vascular risk factors, age, sex and total baseline WMH volume found that the recent small subcortical infarcts (RSSI) in the internal/external capsule/lentiform nucleus and centrum semiovale did not predict cognitive scores at 12 and 36 months. However, RSSI location moderated voxel-based associations of WMH change from baseline to 1 year with cognitive scores at 1 and 3 years. WMH increase in the external capsule, intersection between the anterior limb of the internal and external capsules, and optical radiation, was associated with worsening of ACE-R scores 1 and 3 years post-stroke after accounting for the location of the index infarct, age and baseline cognition.

Lacunar strokes are a common type of ischemic stroke. They are associated with long-term disability, but the factors affecting the dynamic of the infarcted lesion and the brain imaging features associated with them, reflective of small vessel disease (SVD) severity, are still largely unknown. We investigated whether the distribution, volume and 1-year evolution of white matter hyperintensities (WMH), one of these SVD features, relate to the extent and location of these infarcts, accounting for vascular risk factors. We used imaging and clinical data from all patients [n = 118, mean age 64.9 (SD 11.75) years old] who presented to a regional hospital with a lacunar stroke syndrome within the years 2010 and 2013 and consented to participate in a study of stroke mechanisms. All patients had a brain MRI scan at presentation, and 88 had another scan 12 months after. Acute lesions (i.e., recent small subcortical infarcts, RSSI) were identified in 79 patients and lacunes in 77. Number of lacunes was associated with baseline WMH volume (B = 0.370, SE = 0.0939, P = 0.000174). RSSI volume was not associated with baseline WMH volume (B = 3.250, SE = 2.117, P = 0.129), but predicted WMH volume change (B = 2.944, SE = 0.913, P = 0.00184). RSSI location was associated with the spatial distribution of WMH and the pattern of 1-year WMH evolution. Patients with the RSSI in the centrum semiovale (n = 33) had significantly higher baseline volumes of WMH, recent and old infarcts, than patients with the RSSI located elsewhere [median 33.69, IQR (14.37 50.87) ml, 0.001 ≤ P ≤ 0.044]. But patients with the RSSI in the internal/external capsule/lentiform nucleus experienced higher increase of WMH volume after a year [n = 21, median (IQR) from 18 (11.70 31.54) ml to 27.41 (15.84 40.45) ml]. Voxel-wise analyses of WMH distribution in patients grouped per RSSI location revealed group differences increased in the presence of vascular risk factors, especially hypertension and recent or current smoking habit. In our sample of patients presenting to the clinic with lacunar strokes, lacunar strokes extent influenced WMH volume fate; and RSSI location and WMH spatial distribution and dynamics were intertwined, with differential patterns emerging in the presence of vascular risk factors. These results, if confirmed in wider samples, open potential avenues in stroke rehabilitation to be explored further.

Dynamic contrast-enhanced MRI (DCE-MRI) is increasingly used to quantify and map the spatial distribution of blood-brain barrier (BBB) leakage in neurodegenerative disease, including cerebral small vessel disease and dementia. However, the subtle nature of leakage and resulting small signal changes make quantification challenging. While simplified one-dimensional simulations have probed the impact of noise, scanner drift, and model assumptions, the impact of spatio-temporal effects such as gross motion, k-space sampling and motion artefacts on parametric leakage maps has been overlooked. Moreover, evidence on which to base the design of imaging protocols is lacking due to practical difficulties and the lack of a reference method. To address these problems, we present an open-source computational model of the DCE-MRI acquisition process for generating four dimensional Digital Reference Objects (DROs), using a high-resolution brain atlas and incorporating realistic patient motion, extra-cerebral signals, noise and k-space sampling. Simulations using the DROs demonstrated a dominant influence of spatio-temporal effects on both the visual appearance of parameter maps and on measured tissue leakage rates. The computational model permits greater understanding of the sensitivity and limitations of subtle BBB leakage measurement and provides a non-invasive means of testing and optimising imaging protocols for future studies., Graphical abstract Image, graphical abstract

Background Leukoaraiosis is associated with impaired cerebral perfusion, but the effect of individual and combined small-vessel disease (SVD) features on white matter perfusion is unclear. Methods We studied patients recruited with perfusion imaging in the Third International Stroke Trial. We rated individual SVD features (leukoaraiosis, lacunes) and brain atrophy on baseline plain computed tomography or magnetic resonance imaging. Separately, we assessed white matter at the level of the lateral ventricles in the cerebral hemisphere contralateral to the stroke for visible areas of hypoperfusion (present or absent) on 4 time-based perfusion imaging parameters. We examined associations between SVD features (individually and summed) and presence of hypoperfusion using logistic regression adjusted for age, sex, baseline National Institutes of Health Stroke Scale, hypertension, and diabetes. Results A total of 115 patients with median (interquartile range) age of 81 (72-86) years, 78 (52%) of which were male, had complete perfusion data. Hypoperfusion was most frequent on mean transit time (MTT; 63 patients, 55%) and least frequent on time to maximum flow (19 patients, 17%). The SVD score showed stronger independent associations with hypoperfusion (e.g., MTT, odds ratio [OR] = 2.80; 95% confidence interval [CI] = 1.56-5.03) than individual SVD markers (e.g., white matter hypoattenuation score, MTT, OR = 1.49, 95% CI = 1.09-2.04). Baseline blood pressure did not differ by presence or absence of hypoperfusion or across strata of SVD score. Presence of white matter hypoperfusion increased with SVD summed score. Conclusions The SVD summed score was associated with hypoperfusion more consistently than individual SVD features, providing validity to the SVD score concept. Increasing SVD burden indicates worse perfusion in the white matter.

Background: Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy.Methods: RESTART was a prospective, randomised, open-label, blinded-endpoint, parallel-group trial at 122 hospitals in the UK that assessed whether starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. For this prespecified subgroup analysis, consultant neuroradiologists masked to treatment allocation reviewed brain CT or MRI scans performed before randomisation to confirm participant eligibility and rate features of the intracerebral haemorrhage and surrounding brain. We followed participants for primary (recurrent symptomatic intracerebral haemorrhage) and secondary (ischaemic stroke) outcomes for up to 5 years (reported elsewhere). For this report, we analysed eligible participants with intracerebral haemorrhage according to their treatment allocation in primary subgroup analyses of cerebral microbleeds on MRI and in exploratory subgroup analyses of other features on CT or MRI. The trial is registered with the ISRCTN registry, number ISRCTN71907627.Findings: Between May 22, 2013, and May 31, 2018, 537 participants were enrolled, of whom 525 (98%) had intracerebral haemorrhage: 507 (97%) were diagnosed on CT (252 assigned to start antiplatelet therapy and 255 assigned to avoid antiplatelet therapy, of whom one withdrew and was not analysed) and 254 (48%) underwent the required brain MRI protocol (122 in the start antiplatelet therapy group and 132 in the avoid antiplatelet therapy group). There were no clinically or statistically significant hazards of antiplatelet therapy on recurrent intracerebral haemorrhage in primary subgroup analyses of cerebral microbleed presence (2 or more) versus absence (0 or 1) (adjusted hazard ratio [HR] 0·30 [95% CI 0·08–1·13] vs 0·77 [0·13–4·61]; pinteraction=0·41), cerebral microbleed number 0–1 versus 2–4 versus 5 or more (HR 0·77 [0·13–4·62] vs 0·32 [0·03–3·66] vs 0·33 [0·07–1·60]; pinteraction=0·75), or cerebral microbleed strictly lobar versus other location (HR 0·52 [0·004–6·79] vs 0·37 [0·09–1·28]; pinteraction=0·85). There was no evidence of heterogeneity in the effects of antiplatelet therapy in any exploratory subgroup analyses (all pinteraction>0·05).Interpretation: Our findings exclude all but a very modest harmful effect of antiplatelet therapy on recurrent intracerebral haemorrhage in the presence of cerebral microbleeds. Further randomised trials are needed to replicate these findings and investigate them with greater precision.Funding: British Heart Foundation.

Contains fulltext : 208975.pdf (Publisher’s version ) (Open Access) BACKGROUND: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. METHODS: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. FINDINGS: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1.34 years [IQR 0.19-2.44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1.35 (95% CI 1.20-1.50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2.45 (1.82-3.29) for intracranial haemorrhage and 1.23 (1.08-1.40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4.55 [95% CI 3.08-6.72] for intracranial haemorrhage vs 1.47 [1.19-1.80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5.52 [3.36-9.05] vs 1.43 [1.07-1.91]; and for >/=20 cerebral microbleeds, aHR 8.61 [4.69-15.81] vs 1.86 [1.23-1.82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48-84] per 1000 patient-years vs 27 intracranial haemorrhages [17-41] per 1000 patient-years; and for >/=20 cerebral microbleeds, 73 ischaemic strokes [46-108] per 1000 patient-years vs 39 intracranial haemorrhages [21-67] per 1000 patient-years). INTERPRETATION: In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. FUNDING: British Heart Foundation and UK Stroke Association.

Background: High blood pressure is common in acute stroke and is a predictor of poor outcome; however, large trials of lowering blood pressure have given variable results, and the management of high blood pressure in ultra-acute stroke remains unclear. We investigated whether transdermal glyceryl trinitrate (GTN; also known as nitroglycerin), a nitric oxide donor, might improve outcome when administered very early after stroke onset.Methods: We did a multicentre, paramedic-delivered, ambulance-based, prospective, randomised, sham-controlled, blinded-endpoint, phase 3 trial in adults with presumed stroke within 4 h of onset, face-arm-speech-time score of 2 or 3, and systolic blood pressure 120 mm Hg or higher. Participants were randomly assigned (1:1) to receive transdermal GTN (5 mg once daily for 4 days; the GTN group) or a similar sham dressing (the sham group) in UK-based ambulances by paramedics, with treatment continued in hospital. Paramedics were unmasked to treatment, whereas participants were masked. The primary outcome was the 7-level modified Rankin Scale (mRS; a measure of functional outcome) at 90 days, assessed by central telephone follow-up with masking to treatment. Analysis was hierarchical, first in participants with a confirmed stroke or transient ischaemic attack (cohort 1), and then in all participants who were randomly assigned (intention to treat, cohort 2) according to the statistical analysis plan. This trial is registered with ISRCTN, number ISRCTN26986053.Findings: Between Oct 22, 2015, and May 23, 2018, 516 paramedics from eight UK ambulance services recruited 1149 participants (n=568 in the GTN group, n=581 in the sham group). The median time to randomisation was 71 min (IQR 45–116). 597 (52%) patients had ischaemic stroke, 145 (13%) had intracerebral haemorrhage, 109 (9%) had transient ischaemic attack, and 297 (26%) had a non-stroke mimic at the final diagnosis of the index event. In the GTN group, participants' systolic blood pressure was lowered by 5·8 mm Hg compared with the sham group (pvs 3 [2–5]; n=558, in the sham group; 1·04 [0·84–1·29]; p=0·69). We found no difference in secondary outcomes, death (treatment-related deaths: 36 in the GTN group vs 23 in the sham group [p=0·091]), or serious adverse events (188 in the GTN group vs 170 in the sham group [p=0·16]) between treatment groups.Interpretation: Prehospital treatment with transdermal GTN does not seem to improve functional outcome in patients with presumed stroke. It is feasible for UK paramedics to obtain consent and treat patients with stroke in the ultra-acute prehospital setting.Funding: British Heart Foundation.

Background Research involving brain imaging is important for understanding common brain diseases. Study endpoints can include features and measures derived from imaging modalities, providing a benchmark against which other phenotypical data can be assessed. In trials, imaging data provide objective evidence of beneficial and adverse outcomes. Multi-centre studies increase generalisability and statistical power. However, there is a lack of practical guidelines for the set-up and conduct of large neuroimaging studies. Methods We address this deficit by describing aspects of study design and other essential practical considerations that will help researchers avoid common pitfalls and data loss. Results The recommendations are grouped into seven categories: (1) planning, (2) defining the imaging endpoints, developing an imaging manual and managing the workflow, (3) performing a dummy run and testing the analysis methods, (4) acquiring the scans, (5) anonymising and transferring the data, (6) monitoring quality, and (7) using structured data and sharing data. Conclusions Implementing these steps will lead to valuable and usable data and help to avoid imaging data wastage.

Purpose Quantitative assessment of white matter hyperintensities (WMH) on structural Magnetic Resonance Imaging (MRI) is challenging. It is important to harmonise results from different software tools considering not only the volume but also the signal intensity. Here we propose and evaluate a metric of white matter (WM) damage that addresses this need. Methods We obtained WMH and normal-appearing white matter (NAWM) volumes from brain structural MRI from community dwelling older individuals and stroke patients enrolled in three different studies, using two automatic methods followed by manual editing by two to four observers blind to each other. We calculated the average intensity values on brain structural fluid-attenuation inversion recovery (FLAIR) MRI for the NAWM and WMH. The white matter damage metric is calculated as the proportion of WMH in brain tissue weighted by the relative image contrast of the WMH-to-NAWM. The new metric was evaluated using tissue microstructure parameters and visual ratings of small vessel disease burden and WMH: Fazekas score for WMH burden and Prins scale for WMH change. Results The correlation between the WM damage metric and the visual rating scores (Spearman ρ > =0.74, p =0.72, p

White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyperintensities origins. We classified white matter into white matter hyperintensities and normal-appearing white matter and measured fractional anisotropy, mean diffusivity, water content (T1-relaxation time) and blood–brain barrier leakage (signal enhancement slope from dynamic contrast-enhanced magnetic resonance imaging). We studied the effects of age, white matter hyperintensities burden (Fazekas score) and vascular risk factors on each biomarker, in normal-appearing white matter and white matter hyperintensities, and performed receiver-operator characteristic curve analysis. Amongst 204 patients (34.3–90.9 years), all biomarkers differed between normal-appearing white matter and white matter hyperintensities (P P P P = 0.02 signal enhancement slope), but only signal enhancement slope increased with hypertension (P = 0.028). Fractional anisotropy showed complex age-white matter hyperintensities-tissue interactions; enhancement slope showed white matter hyperintensities-tissue interactions. Mean diffusivity distinguished white matter hyperintensities from normal-appearing white matter best at all ages. Blood–brain barrier leakage increases with hypertension and white matter hyperintensities burden at all ages in normal-appearing white matter and white matter hyperintensities, whereas water mobility and content increase as tissue damage accrues, suggesting that blood–brain barrier leakage mediates small vessel disease-related brain damage.

White matter hyperintensities (WMH) seen on FLAIR images are established as a key indicator of Vascular Dementia (VD) and other pathologies.We propose a novel modality transformation technique to generate a subject-specific pathology-free synthetic FLAIR image from a T1 -weighted image. WMH are then accurately segmented by comparing this synthesized FLAIR image to the actually acquired FLAIR image. We term this method Pseudo-Healthy Image Synthesis (PHI-Syn). The method is evaluated on data from 42 stroke patients where we compare its performance to two commonly used methods from the Lesion Segmentation Toolbox. We show that the proposed method achieves superior performance for a number of metrics. Finally, we show that the features extracted from the WMH segmentations can be used to predict a Fazekas lesion score that supports the identification of VD in a dataset of 468 dementia patients. In this application the automatically calculated features perform comparably to clinically derived Fazekas scores.

We aimed to determine associations between multiple vascular risk factors (VRF) at ∼73 years and progression of white matter hyperintensities (WMH) from ∼73 years to ∼76 years. We calculated correlations and generalized estimating equation models of a comprehensive range of VRF at 73 years and change in WMH volume from 73 years to 76 years. Higher systolic (rho = 0.126, p = 0.009) and diastolic (rho = 0.120, p = 0.013) blood pressure at 73 years were significant predictors for greater WMH volume at 76 years in a simple correlation model. However, neither measured blood pressure nor self-reported hypertension at 73 years was significant predictors of WMH volume change in a fully adjusted model which accounted for initial WMH volume at 73 years. Lower high-density lipoprotein cholesterol (beta = −0.15 % intracranial, −1.80 mL; p < 0.05) and current smoking (beta = 0.43 % intracranial, 5.49 mL; p, Graphical abstract

Background White matter hyperintensities (WMHs) are commonly seen on in brain imaging and are associated with stroke and cognitive decline. Therefore, they may provide a relevant intermediate outcome in clinical trials. WMH can be measured as a volume or visually on the Fazekas scale. We investigated predictors of WMH progression and design of efficient studies using WMH volume and Fazekas score as an intermediate outcome. Methods We prospectively recruited 264 patients with mild ischaemic stroke and measured WMH volume, Fazekas score, age and cardiovascular risk factors at baseline and 1 year. We modelled predictors of WMH burden at 1 year and used the results in sample size calculations for hypothetical randomised controlled trials with different analysis plans and lengths of follow-up. Results Follow-up WMH volume was predicted by baseline WMH: a 0.73-ml (95% CI 0.65–0.80, p

Background: Volume measures of normal brain tissue and white matter hyperintensities (WMH) between two time points gives limited information about the complex dynamics of tissue change. We evaluated two quantitative parameters that characterise the microstructure of normal-appearing white matter (NAWM), deep grey matter (DGM) and WMH on brain images obtained at presentation with minor stroke and at 1 year to investigate the microstructural changes. Methods: From 182 brain MRI datasets of patients with minor stroke obtained at baseline and 1 year, we extracted the WMH, DGM and NAWM, and separated WMH into less-intense and intense WMH, using validated semi-automatic methods and validated criteria. We registered the binary structural masks to diffusion space and performed a voxel-wise subtraction of the combined masks at both time points. Then we measured fractional anisotropy (FA) and mean diffusivity (MD)(valuex10 -9 m 2 /s) in each tissue mask at baseline and 1 year. Results: WMH volume median increase was 1.4ml (IQR 6.98) mainly due to changes in less-intense WMH: 0.94ml (7.13). WMH that were visible at both time points, ie damage that remained after a year, had the lowest FA= 0.21(0.06) and highest MD=1.05(0.12) at baseline, and were mainly intense WMH at baseline (FA=0.12(0.03), MD=1.55(0.27)). WMH seen only at follow-up, ie that were NAWM at baseline, had the highest FA=0.30(0.06) and lowest MD=0.85 (0.06) at baseline. WMH that were observed only at baseline had intermediate FA=0.26(0.08) and MD=0.90(0.10). NAWM FA=0.26(0.03), MD=0.78(0.04) and DGM FA=0.23(0.03), MD=0.79(0.06) did not change between time points. Conclusions: WMH at baseline can partially evolve to normal-appearing tissues, remain or precede tissue loss. Differentiation between severe and subtle damage and spatial analysis are necessary to characterise the dynamic of WMH evolution.

BackgroundBrain scans are essential to exclude haemorrhage in patients with suspected acute ischaemic stroke before treatment with alteplase. However, patients with early ischaemic signs could be at increased risk of haemorrhage after alteplase treatment, and little information is available about whether pre-existing structural signs, which are common in older patients, affect response to alteplase. We aimed to investigate the association between imaging signs on brain CT and outcomes after alteplase.MethodsIST-3 was a multicentre, randomised controlled trial of intravenous alteplase (0·9 mg/kg) versus control within 6 h of acute ischaemic stroke. The primary outcome was independence at 6 months (defined as an Oxford Handicap Scale [OHS] score of 0–2). 3035 patients were enrolled to IST-3 and underwent prerandomisation brain CT. Experts who were unaware of the random allocation assessed scans for early signs of ischaemia (tissue hypoattenuation, infarct extent, swelling, and hyperattenuated artery) and pre-existing signs (old infarct, leukoaraiosis, and atrophy). In this prespecified analysis, we assessed interactions between these imaging signs, symptomatic intracranial haemorrhage (a secondary outcome in IST-3) and independence at 6 months, and alteplase, adjusting for age, National Institutes of Health Stroke Scale (NIHSS) score, and time to randomisation. This trial is registered at ISRCTN.com, number ISRCTN25765518.Findings3017 patients were assessed in this analysis, of whom 1507 were allocated alteplase and 1510 were assigned control. A reduction in independence was predicted by tissue hypoattenuation (odds ratio 0·66, 95% CI 0·55–0·81), large lesion (0·51, 0·38–0·68), swelling (0·59, 0·46–0·75), hyperattenuated artery (0·59, 0·47–0·75), atrophy (0·74, 0·59–0·94), and leukoaraiosis (0·72, 0·59–0·87). Symptomatic intracranial haemorrhage was predicted by old infarct (odds ratio 1·72, 95% CI 1·18–2·51), tissue hypoattenuation (1·54, 1·04–2·27), and hyperattenuated artery (1·54, 1·03–2·29). Some combinations of signs increased the absolute risk of symptomatic intracranial haemorrhage (eg, both old infarct and hyperattenuated artery, excess with alteplase 13·8%, 95% CI 6·9–20·7; both signs absent, excess 3·2%, 1·4–5·1). However, no imaging findings—individually or combined—modified the effect of alteplase on independence or symptomatic intracranial haemorrhage.InterpretationSome early ischaemic and pre-existing signs were associated with reduced independence at 6 months and increased symptomatic intracranial haemorrhage. Although no interaction was noted between brain imaging signs and effects of alteplase on these outcomes, some combinations of signs increased some absolute risks. Pre-existing signs should be considered, in addition to early ischaemic signs, during the assessment of patients with acute ischaemic stroke.FundingUK Medical Research Council, Health Foundation UK, Stroke Association UK, Chest Heart Stroke Scotland, Scottish Funding Council SINAPSE Collaboration, and multiple governmental and philanthropic national funders.

BackgroundIntravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) improves outcome after an ischaemic stroke but increases the risk of intracranial haemorrhage. Restricting rt-PA to patients with salvageable tissue, or arterial occlusion, might reduce risk, increase benefit and enable treatment at late time windows.ObjectivesTo determine if computed tomography (CT) or magnetic resonance (MR) perfusion or angiography (CTP/CTA; MRP/MRA) imaging provide important information to guide the use of rt-PA up to 6 hours after a stroke.DesignProspective, multicentre, randomised, open, blinded, end-point trial of rt-PA.SettingForty-eight centres (eight countries) performed CTP/CTA; 37 centres (11 countries) performed MRP/MRA.ParticipantsPatients aged over 18 years in whom brain scanning excluded intracranial haemorrhage, with known time of stroke onset and no clear indication for or contraindication to rt-PA, in whom treatment can start within 6 hours of a stroke.Interventionsrt-PA (0.9 mg/kg, maximum dose 90 mg) intravenously (10% bolus, the rest infused over 1 hour) compared with best medical care.Main outcome measuresPrimary – alive and independent (Oxford Handicap Score 0–2) at 6 months; secondary – symptomatic and fatal intracranial haemorrhage, early and late death. All imaging assessed centrally, blind to other data. Perfusion lesion sizes [cerebral blood volume (CBV); cerebral blood flow; mean transit time (MTT); time to maximum flow], angiographic occlusion, associations with plain scan findings, clinical baseline and outcomes, and the interaction with rt-PA were assessed with dichotomous and ordinal analyses.ResultsBaseline characteristics of patients in the Third International Stroke Trial (IST-3) with perfusion and angiography imaging did not differ from those without (95% did not meet the prevailing licence criteria for rt-PA): 151 patients had perfusion imaging and 423 had angiography (141 and 307 obtained at randomisation respectively). Most randomisation imaging was with CT (n = 125/141, 89% perfusion;n = 277/307, 90% angiography) with little MR (n = 16/141, 11% perfusion;n = 39/307, 10% angiography). The median patient age was 81 (interquartile range 71–86) years; perfusion imaging or angiography imaging was performed at median of 3.9 hours after stroke. Perfusion lesion size differed significantly between parameters (MTT lesions largest, CBV lesions smallest;p n = 253) showed arterial stenosis/occlusion in 42% (95% confidence interval 34% to 47%). Abnormal plain CT and plain CT + CTA were equally associated with worse baseline stroke severity, imaging and functional outcomes. rt-PA accelerated dissolution of arterial thrombus and reduced thrombus extension, but rt-PA effects did not differ between patients with angiographic occlusion compared with those without.ConclusionLarger perfusion lesions and arterial occlusion are associated with severe stroke and worse outcomes. However, patients with perfusion lesions, mismatch or angiographic occlusion had similar benefit and no worse hazard from rt-PA compared with those without. Visual assessment is an effective classification method. Perfusion or angiography imaging may improve diagnostic confidence in acute stroke but this does not improve prediction of prognosis or identify patients who respond differently to rt-PA. Although this trial is larger than others, the conclusion regarding perfusion imaging is limited by the sample size.Trial registrationCurrent Controlled Trials ISRCTN25765518.FundingThis project was funded by the NIHR Efficacy and Mechanism Evaluation programme and the Medical Research Council, and will be published in full inEfficacy and Mechanism Evaluation; Vol. 1, No. 1. See the NIHR Journals Library website for further project information.

We measured the production of reactive oxygen species (ROS) using luminol-horseradish peroxidase-induced chemiluminescence in mechanically dispersed cell suspensions from bovine corpus luteum (CL). Since other cell types besides luteal cells were present in crude cell suspensions from CL, cell preparations were purified by centrifugation on Percoll. Only cell suspensions that gave no significant response when stimulated with formyl-methionyl-leucyl-phenylalanine, a potent stimulator of ROS production by phagocytes, were used routinely. Basal ROS production by purified bovine luteal cell preparations was low but could be stimulated rapidly and in a dose-dependent manner by nanomolar concentrations of the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA), though only in cells purified by fractionation on Percoll. Luteal ROS responses to PMA were quenched by returning bovine erythrocytes to purified luteal cells, or by exogenous catalase or superoxide dismutase. The magnitude of the response to PMA varied markedly from one luteal cell preparation to another but appeared to be unrelated to the stage of the luteal phase of the CL from which the cells were prepared. The luteal ROS response to PMA was blocked by staurosporine, an inhibitor of PKC. Although the inactive phorbol ester (4 alpha-phorbol didecanoate; 4 alpha PDD) alone had little or no effect on luteal ROS production, 4 alpha PDD significantly potentiated the effects of submaximal concentrations of PMA in a dose-dependent manner. ROS production could also be stimulated by the Ca2+ ionophore A23187. This response was rapidly abolished by treatment with EDTA or EGTA. A23187 also augmented the response to submaximal PMA levels: however, pretreatment with 4 alpha PDD did not significantly enhance the ROS response to A23187. In conclusion, we have shown that isolated bovine luteal cell suspensions are capable of generating a marked acute ROS response triggered by activation of PKC and/or elevation of cytosolic calcium.

Antiphospholipid syndrome (APS) is an autoimmune disease. Less than 1% of patients with APS present with life-threatening catastrophic APS (CAPS). We report here a case of CAPS in a young girl with cardiac, gastrointestinal and renal involvement. Although the management was complicated, the outcome was better than expected. We suggest that CAPS be included in the differential diagnosis of acute renal failure in children with multi-organ involvement and prolonged phospholipid-dependent coagulation time and promptly treated with immunomodulating agents and anticoagulants.

Chronic renal patients and patients with end stage renal disease are a distinctive patient group with a serious, chronic and irreversible health condition, which is mainly treated at home. As such they are unique candidates for support via telehealth services. This paper introduces a novel monitoring system for hemodialysis patients. The leading aims of this system are the development of innovative biomedical signals management system and the implementation of integrated model medical signal projection and processing tools. The system is expected to contribute to the increase of the demand in the medical services field as well as to reduce the patient transfer abroad for recovery.

INTERLIFE is a revolutionary product that can radically change the way healthcare services are offered by introducing new means for quality health care management by the healthcare providers, and by improving the patients', health providers' and citizens' quality of life. INTERLIFE is a technological and medical knowledge management and processing infrastructure able to support an early discharge and a continuous home monitoring service thus leading to reduction hospitalisation rates and to the increased efficacy of healthcare service delivery of patients suffering from chronic diseases such as CHF, COPD and Diabetes as well as a special category of acute health care related patients. Six test sites are participating in the validation trials, more specifically EAP Sardenya and MUTUAM in Spain, Hippokrateion Hospital and AHEPA Hospital in Greece, RAMIT in Belgium and University of Regensburg Medical Centre in Germany.