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Purpose Surveillance of patients with high-grade glioma (HGG) and identification of disease progression remain a major challenge in neurooncology. This study aimed to develop a support vector machine (SVM) classifier, employing combined longitudinal structural and perfusion MRI studies, to classify between stable disease, pseudoprogression and progressive disease (3-class problem). Methods Study participants were separated into two groups: group I (total cohort: 64 patients) with a single DSC time point and group II (19 patients) with longitudinal DSC time points (2-3). We retrospectively analysed 269 structural MRI and 92 dynamic susceptibility contrast perfusion (DSC) MRI scans. The SVM classifier was trained using all available MRI studies for each group. Classification accuracy was assessed for different feature dataset and time point combinations and compared to radiologists’ classifications. Results SVM classification based on combined perfusion and structural features outperformed radiologists’ classification across all groups. For the identification of progressive disease, use of combined features and longitudinal DSC time points improved classification performance (lowest error rate 1.6%). Optimal performance was observed in group II (multiple time points) with SVM sensitivity/specificity/accuracy of 100/91.67/94.7% (first time point analysis) and 85.71/100/94.7% (longitudinal analysis), compared to 60/78/68% and 70/90/84.2% for the respective radiologist classifications. In group I (single time point), the SVM classifier also outperformed radiologists’ classifications with sensitivity/specificity/accuracy of 86.49/75.00/81.53% (SVM) compared to 75.7/68.9/73.84% (radiologists). Conclusion Our results indicate that utilisation of a machine learning (SVM) classifier based on analysis of longitudinal perfusion time points and combined structural and perfusion features significantly enhances classification outcome (p value= 0.0001).

Background A readily implemented MRI biomarker for glioma genotyping is currently lacking. Purpose To evaluate clinically available MRI parameters for predicting isocitrate dehydrogenase (IDH) status in patients with glioma. Materials and Methods In this retrospective study of patients studied from July 2008 to February 2019, untreated World Health Organization (WHO) grade II/III gliomas were analyzed by three neuroradiologists blinded to tissue results. Apparent diffusion coefficient (ADC) minimum (ADCmin) and mean (ADCmean) regions of interest were defined in tumor and normal appearing white matter (ADCNAWM). A visual rating of anatomic features (T1 weighted, T1 weighted with contrast enhancement, T2 weighted, and fluid-attenuated inversion recovery) was performed. Interobserver comparison (intraclass correlation coefficient and Cohen κ) was followed by nonparametric (Kruskal-Wallis analysis of variance) testing of associations between ADC metrics and glioma genotypes, including Bonferroni correction for multiple testing. Descriptors with sufficient concordance (intraclass correlation coefficient, >0.8; κ > 0.6) underwent univariable analysis. Predictive variables (P < .05) were entered into a multivariable logistic regression and tested in an additional test sample of patients with glioma. Results The study included 290 patients (median age, 40 years; interquartile range, 33-52 years; 169 male patients) with 82 IDH wild-type, 107 IDH mutant/1p19q intact, and 101 IDH mutant/1p19q codeleted gliomas. Two predictive models incorporating ADCmean-to-ADCNAWM ratio, age, and morphologic characteristics, with model A mandating calcification result and model B recording cyst formation, classified tumor type with areas under the receiver operating characteristic curve of 0.94 (95% confidence interval [CI]: 0.91, 0.97) and 0.96 (95% CI: 0.93, 0.98), respectively. In the test sample of 49 gliomas (nine IDH wild type, 21 IDH mutant/1p19q intact, and 19 IDH mutant/1p19q codeleted), the classification accuracy was 40 of 49 gliomas (82%; 95% CI: 71%, 92%) for model A and 42 of 49 gliomas (86%; 95% CI: 76%, 96%) for model B. Conclusion Two algorithms that incorporated apparent diffusion coefficient values, age, and tumor morphologic characteristics predicted isocitrate dehydrogenase status in World Health Organization grade II/III gliomas on the basis of standard clinical MRI sequences alone. © RSNA, 2020 Online supplemental material is available for this article.

Introduction: In the UK, neuroparasitological infections are rare but important diagnoses. Diagnostic delay can result in significant morbidity. The Hospital for Tropical Diseases (HTD) runs a neuroparasitology multidisciplinary team meeting (MDT) consisting of two consultant parasitologists, neurologist and neuroradiologist, both with specialist interests in neuroinfection, and registrars, working closely with the reference parasitology service. Clinical history, imaging and laboratory results are reviewed to recommend a differential diagnosis and management plan. Methods: We reviewed MDT records between 1st October 2015 and 31st August 2020. We collected data on demographics, referring specialties, travel history and exposures, final diagnoses and MDT outcomes. Results: Overall, 162 patients were discussed in 51 MDTs. Referrals were made by 54 different hospitals, 3 outside the UK. The median age was 40 (IQR 29,53) and 45% were female. Parasitic infections accounted for 43%, including neurocysticercosis (75%, 52/69), hydatid (9%, 6/69), neuroschistosomiasis (6%, 4/69) and non-HIV associated cerebral toxoplasmosis (3%, 2/69). Non-parasitological diagnoses included other infection (e.g. HSV, cryptococcus), ADEM and malignancy. The MDT recommended further investigation in 28% (45/162) including imaging, serological tests or brain biopsy. For 8% (13/162) treatment was recommended under the home team, 9% (15/162) were treated as an HTD outpatient, 4% (7/162) were admitted for anti-parasitic treatment at HTD. In 5 patients with neurocysticercosis, unnecessary brain biopsy was avoided. Discussion: The HTD neuroparasitology MDT consults on complex neuroinfections from around the UK. Specialist review helps establish or exclude parasitological diagnoses, leading to appropriate parasitological treatment, saving patients from invasive procedures such as brain biopsy.

Objective: Cerebrovascular diseases are one of the main global causes of death and disability in the adult population. The preferred imaging modality for the diagnostic routine is digital subtraction angiography, an invasive modality. Time-resolved three-dimensional arterial spin labeling magnetic resonance angiography (4D ASL MRA) is an alternative non-invasive modality, which captures morphological and blood flow data of the cerebrovascular system, with high spatial and temporal resolution. This work proposes advanced medical image processing methods that extract the anatomical and hemodynamic information contained in 4D ASL MRA datasets. Methods: A previously published segmentation method, which uses blood flow data to improve its accuracy, is extended to estimate blood flow parameters by fitting a mathematical model to the measured vascular signal. The estimated values are then refined using regression techniques within the cerebrovascular segmentation. The proposed method was evaluated using fifteen 4D ASL MRA phantoms, with ground-truth morphological and hemodynamic data, fifteen 4D ASL MRA datasets acquired from healthy volunteers, and two 4D ASL MRA datasets from patients with a stenosis. Results: The proposed method reached an average Dice similarity coefficient of 0.957 and 0.938 in the phantom and real dataset segmentation evaluations, respectively. The estimated blood flow parameter values are more similar to the ground-truth values after the refinement step, when using phantoms. A qualitative analysis showed that the refined blood flow estimation is more realistic compared to the raw hemodynamic parameters. Conclusion: The proposed method can provide accurate segmentations and blood flow parameter estimations in the cerebrovascular system using 4D ASL MRA datasets. Significance: The information obtained with the proposed method can help clinicians and researchers to study the cerebrovascular system non-invasively.

Objective:\ud It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed.\ud \ud Methods:\ud We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OACprior ) with those without prior oral anticoagulation (OACnaive ). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OACchanged ) with those who continued the same anticoagulation as secondary prevention (OACunchanged ). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine-Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).\ud \ud Results:\ud We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71-84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2-12]). The median CHA2 DS2 -Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) was 5 (IQR = 4-6) and was similar for OACprior (n = 1,195) and OACnaive (n = 4,119, p = 0.103). During 6,128 patient-years of follow-up, 289 patients had AIS (4.7% per year, 95% CI = 4.2-5.3%). OACprior was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2-2.3, p = 0.005). OACchanged (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7-2.1, p = 0.415) compared with OACunchanged (n = 585).\ud \ud Interpretation:\ud Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA2 DS2 -Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group.

Rapidly progressive encephalopathy in an HIV-positive patient presents a major diagnostic and management challenge. CD8+ encephalitis is a severe but treatable form of HIV-related acute encephalopathy, characterised by diffuse perivascular and intraparenchymal CD8+ lymphocytic infiltration. It can occur in patients who are apparently stable on antiretroviral treatment and probably results from viral escape into the central nervous system. Treatment, including high-dose corticosteroids, can give an excellent neurological outcome, even in people with severe encephalopathy and a very poor initial neurological status. We report a woman with CD8+ encephalitis, with a normal CD4 count and undetectable serum viral load, who made a good recovery despite the severity of her presentation.

Background and Purpose— We set out to investigate whether MRI-visible centrum semiovale perivascular spaces (CSO-PVS), a potential biomarker of impaired interstitial fluid drainage in sporadic cerebral amyloid angiopathy, is associated with cortical superficial siderosis (cSS), reflecting recurrent hemorrhage from severe leptomeningeal and superficial cortical vascular amyloid. Methods— Retrospective multicenter cohort study of possible/probable cerebral amyloid angiopathy according to the Boston criteria. PVS were rated in basal ganglia and CSO (CSO-PVS) on axial T2-weighted sequences, using a validated 4-point visual rating scale and were classified as high (score >2) or low degree (score ≤2) for prespecified analyses. Independent risk factors for high CSO-PVS degree were investigated in logistic regression. Results— The final cohort consisted of 138 cerebral amyloid angiopathy patients (mean age, 71.8 years; 95% confidence interval, 70.2–73.4 years; 52.2% men). High CSO-PVS degree was present in 61.2% of cases. The prevalence of any cSS, and disseminated cSS (involving >3 sulci), was higher in patients with high versus low CSO-PVS degree (for any cSS 45.9% versus 13.5%; P P P =0.004) was an independent predictors of high CSO-PVS degree. We found no associations between basal ganglia PVS and cSS. Conclusions— High degree of CSO-PVS is highly prevalent in sporadic cerebral amyloid angiopathy and is related to cSS. Our findings suggest that severe leptomeningeal and cortical vascular amyloid (causing cSS) is related to impaired interstitial fluid drainage from cerebral white matter, although determining the causal direction of this relationship requires prospective studies.

Making robust inferences about the functional neuroanatomy of the brain is critically dependent on experimental techniques that examine the consequences of focal loss of brain function. Unfortunately, the use of the most comprehensive such technique-lesion-function mapping-is complicated by the need for time-consuming and subjective manual delineation of the lesions, greatly limiting the practicability of the approach. Here we exploit a recently-described general measure of statistical anomaly, zeta, to devise a fully-automated, high-dimensional algorithm for identifying the parameters of lesions within a brain image given a reference set of normal brain images. We proceed to evaluate such an algorithm in the context of diffusion-weighted imaging of the commonest type of lesion used in neuroanatomical research: ischaemic damage. Summary performance metrics exceed those previously published for diffusion-weighted imaging and approach the current gold standard-manual segmentation-sufficiently closely for fully-automated lesion-mapping studies to become a possibility. We apply the new method to 435 unselected images of patients with ischaemic stroke to derive a probabilistic map of the pattern of damage in lesions involving the occipital lobe, demonstrating the variation of anatomical resolvability of occipital areas so as to guide future lesion-function studies of the region. © 2012 Elsevier Ltd.

PURPOSE: Arterial spin labelling, (ASL) is an MRI perfusion technique that uses endogenous contrast and is currently underused in neuro-oncology MRI protocols in the UK. The purpose of this study was to examine the feasibility, ease of implementation and added value of arterial spin labelling (ASL) perfusion imaging in neuro-oncology protocols. METHODS: Radiographers at a large tertiary MRI centre received in-house training in protocol selection and performing pseudo-continuous ASL (pcASL). During a 10 month period, 104 consecutive patients with gliomas, undergoing diagnostic MRI at 3.0 T, underwent an extended MRI protocol that included pcASL. ASL perfusion weighted images (ASL-PWI) were automatically generated by the scanner and archived together with conventional imaging. A qualitive retrospective survey was performed for feedback on the process. A sub-group of patients with available follow up imaging (n=39) were selected for further analysis (n=39: 20 glioblastoma multiforme, 15 astrocytoma, 4 oligodendroglioma). Two observers examined images and concluded RANO scores in two parts: conventional images alone and conventional imaging with ASL-PWI. Confidence was measured using Likert scales 1–5 (1,very unconfident to 5, very confident) and differences compared. Lastly, all diagnoses were checked against follow up imaging. RESULTS: 90% of radiographers felt either confident or very confident in performing ASL technique. 100% of reviewed PWIs were considered diagnostic quality. A statistically significant increase in average confidence levels was observed for inclusion of ASL (4.44 (SD 0.8)) compared to conventional imaging alone (4.02 (SD 0.65)). CONCLUSION: ASL is a reliable, non-contrast, low cost and well tolerated technique that can be easily implemented. ASL-PWI can be produced at time of scanning which can be utilised to build confidence in assessing response to treatment in low and high grade gliomas.

IgG4-related disease is a recently recognised multi-system disease. Common organ involvement includes the pancreas, biliary tree and salivary glands. Central nervous system involvement has been infrequently reported. In a single-centre cohort of 84 patients, we report cerebral involvement in three (4%) patients. Details of cerebral involvement in these patients are outlined, including pituitary involvement in two patients and a diffuse autoimmune-like encephalopathy in the other.

British history contains several periods of major Cultural change. It remains controversial as to how much these periods coincided with substantial immigration from continental Europe. even for those that Occurred most recently. In this study, we examine genetic data for evidence of male immigration at particular times into Central England and North Wales. To do this, we used 12 biallelic polymorphisms and six microsatellite markers to define high-resolution Y chromosome haplotypes in a sample of 3 13 males from seven towns located along an east-west transect from East Anglia to North Wales. The Central English towns were genetically very similar, whereas the two North Welsh towns differed significantly both from each other and from the Central English towns. When we compared our data with an additional 177 samples collected in Friesland and Norway. We found that the Central English and Frisian samples were statistically indistinguishable. Using novel population genetic models that incorporate both mass migration and continuous gene flow, we conclude that these striking patterns are best explained by a substantial migration of Anglo-Saxon Y chromosomes into Central England (contributing 50%-100% to the gene pool Lit that time) but not into North Wales.

BACKGROUND: The vascular endothelial growth factor receptor (VEGFR) 2 tyrosine kinase inhibitor cediranib failed to improve outcome in recurrent glioblastoma in a randomized phase III trial (Batchelor et al.). One resistance mechanism for cediranib is through up-regulation of epidermal growth factor receptor (EGFR). This study was designed to test if the efficacy of cediranib is improved with the addition of gefitinib (an EGFR inhibitor). METHODS: We planned to 1:1 randomize 112 subjects with recurrent/progressive glioblastoma to cediranib + gefitinib (C + G) or cediranib + placebo (C + P) (NCT01310855), with PFS as the primary endpoint. Secondary end-points: OS, radiographic response rate, PFS rate at 6 months, 12 months survival rate, steroid use, time to deterioration of neurological status, safety and tolerability. Recruitment was discontinued early following AstraZeneca's suspension of the cediranib programme. RESULTS: 38 subjects were randomized, the interim results on 34 subjects (17 in each arm) are currently available. 24 male and 10 female. Mean age 54 (range 30-71). KPS ≤80 (35%), >80 (65%). The base-line characteristics for subjects in the 2 arms of the study were well balanced. Median PFS (95% CI) C + G 4.0 mo (2.7, *n/c), C + P 4.1 mo (2.0, 7.3); 6 month PFS C + G 40%, C + P 26%; 12 month PFS n/c; C + G vs C + P HR = 0.49, 95% CI (0.22, 1.11, p = 0.15). OS (mo): Median C + G 7.7 (95% CI 3.8, n/c), C + P 5.5 (95% CI 2.5, 7.3); 12 month n/c; C + G vs C + P HR = 0.359, 95% CI (0.12, 1.1; p = 0.076). No safety concerns. CONCLUSIONS: These interim results demonstrate no difference in PFS, however there was a trend (p = 0.08) for improved OS with the combination. The final results of the study for all 38 subjects will be available. *n/c not calculable due to limited data at time of analysis

Background MRI-visible perivascular spaces (PVS) are potential neuroimaging markers of cerebral small vessel disease, but their functional significance and mechanisms remain uncertain. We investigated the association between PVS and cognitive impairment, and other MRI markers of small vessel disease, in a patient cohort of ischaemic stroke/transient ischaemic attack (TIA) referrals. Methods Data were collected from a prospective observational database. Standardised detailed neuropsychological testing was performed. A validated visual rating scale on T-2-weighted MRI was used to categorise PVS severity; validated scales were used to assess white matter hyperintensities (WMH), cerebral microbleeds (CMB) and lacunes. Results We included 246 patients (45.1% female, mean age 62 years). No significant association between PVS severity grade in any brain region and impairment in any cognitive domain was identified. In multivariable analysis, WMH and hypertension (but not age) were independently associated with basal ganglia PVS severity (OR: 1.27; p< 0.0001 and OR: 4.89; p= 0.013, respectively). Increasing PVS severity in the basal ganglia was associated with lacunar stroke subtype (p< 0.0001). Age and hypertension (but not WMH or lacunar stroke subtype) were independently associated with centrum semiovale PVS severity (OR: 1.19; p= 0.013 and OR: 3.71; p= 0.007, respectively). Conclusions PVS do not have an independent association with cognitive impairment in patients with ischaemic stroke or TIA. The associations with clinical-radiological factors are consistent with the hypothesis that PVS reflect cerebral small vessel disease; the different associations for basal ganglia and centrum semiovale PVS might indicate different underlying small vessel arteriopathies according to PVS anatomical distribution, but this requires further study.

Armenia has been little-studied genetically, even though it is situated in an important area with respect to theories of ancient Middle Eastern population expansion and the spread of Indo-European languages. We screened 734 Armenian males for 11 biallelic and 6 microsatellite Y chromosome markers, segregated them according to paternal grandparental region of birth within or close to Armenia, and compared them with data from other population samples. We found significant regional stratification, on a level greater than that found in some comparisons between different ethno-national identities. A diasporan Armenian sub-sample (collected in London) was not sufficient to describe this stratified haplotype distribution adequately, warning against the use of such samples as surrogates for the non-diasporan population in future studies. The haplotype distribution and pattern of genetic distances suggest a high degree of genetic isolation in the mountainous southern and eastern regions, while in the northern, central and western regions there has been greater admixture with populations from neighbouring Middle Eastern countries. Georgia, to the north of Armenia, also appears genetically more distinct, suggesting that in the past Trans-Caucasia may have acted as a genetic barrier. A Bayesian full-likelihood analysis of the Armenian sample yields a mean estimate for the start of population growth of 4.8 thousand years ago (95% credible interval: 2.0-11.1), consistent with the onset of Neolithic farming. The more isolated southern and eastern regions have high frequencies of a microsatellite defined cluster within haplogroup 1 that is centred on a modal haplotype one step removed from the Atlantic Modal Haplotype, the centre of a cluster found at high frequencies in England, Friesland and Atlantic populations, and which may represent a remnant paternal signal of a Paleolithic migration event.

Objective: We investigated whether severe, MRI-visible perivascular spaces (PVS) in the cerebral hemisphere white matter (centrum semiovale) are more common in patients with pathologyproven cerebral amyloid angiopathy (CAA) than in those with pathology-proven non-CAA-related intracerebral hemorrhage (ICH). Methods: Using a validated 4-point scale on axial T2-weighted MRI, we compared PVS in patients with pathology-proven CAA to PVS in those with spontaneous ICH but no histopathologic evidence of CAA. In a preliminary analysis restricted to patients with T2*-weighted gradient-recalled echo MRI, we also investigated whether including severe centrum semiovale PVS increases the sensitivity of existing diagnostic criteria for probable CAA. Results: Fourteen patients with CAA and 10 patients with non-CAA-related ICH were included. Eight of the patients with CAA were admitted for symptomatic, spontaneous lobar ICH, 1 because of ischemic stroke, 1 with transient focal neurologic episodes, and 4 due to cognitive decline. Severe (>20) centrum semiovale PVS were more frequent in patients with CAA compared to controls (12/14 [85.7%; 95% confidence interval (CI): 57.2%-98.2%] vs 0/10 [1-sided 95% CI: 0%-30.8%], p < 0.0005); this was robust to adjustment for age. The original Boston criteria for probable CAA showed a sensitivity of 76.9% (95% CI: 46.2%-95%), which increased to 92.3% (95% CI: 64%-99.8%), without loss of specificity, after including severe centrum semiovale PVS. Conclusions: Severe centrum semiovale PVS on MRI may be a promising new neuroimaging marker for the in vivo diagnosis of CAA. However, our findings are preliminary and require confirmation and external validation in larger cohorts of pathology-proven CAA. © 2013 American Academy of Neurology.

To investigate whether cortical superficial siderosis (cSS) on MRI, especially if disseminated (involving more than 3 sulci), increases the risk of future symptomatic lobar intracerebral hemorrhage (ICH) in cerebral amyloid angiopathy (CAA).European multicenter cohort study of 118 patients with CAA (104 with baseline symptomatic lobar ICH) diagnosed according to the Boston criteria. We obtained baseline clinical, MRI, and follow-up data on symptomatic lobar ICH. Using Kaplan-Meier and Cox regression analyses, we investigated cSS and ICH risk, adjusting for known confounders.During a median follow-up time of 24 months (interquartile range 9-44 months), 23 of 118 patients (19.5%, 95% confidence interval [CI]: 12.8%-27.8%) experienced symptomatic lobar ICH. Any cSS and disseminated cSS were predictors of time until first or recurrent ICH (log-rank test: p = 0.0045 and p = 0.0009, respectively). ICH risk at 4 years was 25% (95% CI: 7.6%-28.3%) for patients without siderosis; 28.9% (95% CI: 7.7%-76.7%) for patients with focal siderosis; and 74% (95% CI: 44.1%-95.7%) for patients with disseminated cSS (log-rank test: p = 0.0031). In Cox regression models, any cSS and disseminated cSS were both independently associated with increased lobar ICH risk, after adjusting for ≥ 2 microbleeds and age (hazard ratio: 2.53; 95% CI: 1.05-6.15; p = 0.040 and hazard ratio: 3.16; 95% CI: 1.35-7.43; p = 0.008, respectively). These results remained consistent in sensitivity analyses including only patients with symptomatic lobar ICH at baseline.Our findings indicate that cSS, particularly if disseminated, is associated with an increased risk of symptomatic lobar ICH in CAA. cSS may help stratify future bleeding risk in CAA, with implications for prognosis and treatment.