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Functional MRI (fMRI) and EEG may reveal residual consciousness in patients with disorders of consciousness (DoC), as reflected by a rapidly expanding literature on chronic DoC. However, acute DoC is rarely investigated, although identifying residual consciousness is key to clinical decision-making in the intensive care unit (ICU). Therefore, the objective of the prospective, observational, tertiary centre cohort, diagnostic phase IIb study ‘Consciousness in neurocritical care cohort study using EEG and fMRI’ (CONNECT-ME, NCT02644265) was to assess the accuracy of fMRI and EEG to identify residual consciousness in acute DoC in the ICU. Between April 2016 and November 2020, 87 acute DoC patients with traumatic or non-traumatic brain injury were examined with repeated clinical assessments, fMRI and EEG. Resting-state EEG and EEG with external stimulations were evaluated by visual analysis, spectral band analysis and a Support Vector Machine (SVM) consciousness classifier. In addition, within- and between-network resting-state connectivity for canonical resting-state fMRI networks was assessed. Next, we used EEG and fMRI data at study enrolment in two different machine-learning algorithms (Random Forest and SVM with a linear kernel) to distinguish patients in a minimally conscious state or better (≥MCS) from those in coma or unresponsive wakefulness state (≤UWS) at time of study enrolment and at ICU discharge (or before death). Prediction performances were assessed with area under the curve (AUC). Of 87 DoC patients (mean age, 50.0 ± 18 years, 43% female), 51 (59%) were ≤UWS and 36 (41%) were ≥ MCS at study enrolment. Thirty-one (36%) patients died in the ICU, including 28 who had life-sustaining therapy withdrawn. EEG and fMRI predicted consciousness levels at study enrolment and ICU discharge, with maximum AUCs of 0.79 (95% CI 0.77–0.80) and 0.71 (95% CI 0.77–0.80), respectively. Models based on combined EEG and fMRI features predicted consciousness levels at study enrolment and ICU discharge with maximum AUCs of 0.78 (95% CI 0.71–0.86) and 0.83 (95% CI 0.75–0.89), respectively, with improved positive predictive value and sensitivity. Overall, both machine-learning algorithms (SVM and Random Forest) performed equally well. In conclusion, we suggest that acute DoC prediction models in the ICU be based on a combination of fMRI and EEG features, regardless of the machine-learning algorithm used.

BackgroundIn intensive care unit (ICU) patients with coma and other disorders of consciousness (DoC), outcome prediction is key to decision-making regarding prognostication, neurorehabilitation, and management of family expectations. Current prediction algorithms are largely based on chronic DoC, while multimodal data from acute DoC are scarce. Therefore, CONNECT-ME (Consciousness in neurocritical care cohort study using EEG and fMRI,NCT02644265) investigates ICU-patients with acute DoC due to traumatic and non-traumatic brain injuries, utilizing EEG (resting-state and passive paradigms), fMRI (resting-state) and systematic clinical examinations.MethodsWe previously presented results for a subset of patients (n=87) concerning prediction of consciousness levels at ICU discharge. Now, we report 3- and 12-month outcomes in an extended cohort (n=123). Favourable outcome was defined as modified Rankin Scale ≤3, Cerebral Performance Category ≤2, and Glasgow Outcome Scale-Extended ≥4. EEG-features included visual-grading, automated spectral categorization, and Support Vector Machine (SVM) consciousness classifier. fMRI-features included functional connectivity measures from six resting-state networks. Random-Forest and SVM machine learning were applied to EEG- and fMRI-features to predict outcomes. Here, Random-Forest results are presented as area under the curve (AUC) of receiver operating curves or accuracy. Cox proportional regression with in-hospital death as competing risk was used to assess independent clinical predictors of time to favourable outcome.ResultsBetween April-2016 and July-2021, we enrolled 123 patients (mean age 51 years, 42% women). Of 82 (66%) ICU-survivors, 3- and 12-month outcomes were available for 79 (96%) and 77 (94%), respectively. EEG-features predicted both 3-month (AUC 0.79[0.77-0.82] and 12-month (0.74[0.71-0.77]) outcomes. fMRI-features appeared to predict 3-month outcome (accuracy 0.69-0.78) both alone and when combined with some EEG-features (accuracies 0.73-0.84), but not 12-month outcome (larger sample sizes needed). Independent clinical predictors of time to favourable outcome were younger age (Hazards-Ratio 1.04[95% CI 1.02-1.06]), TBI (1.94[1.04-3.61]), command-following abilities at admission (2.70[1.40-5.23]), initial brain-imaging without severe pathology (2.42[1.12-5.22]), improving consciousness in the ICU (5.76[2.41-15.51]), and favourable visual-graded EEG (2.47[1.46-4.19]).ConclusionFor the first time, our results indicate that EEG- and fMRI-features and readily available clinical data reliably predict short-term outcome of patients with acute DoC, and EEG also predicts 12-month outcome after ICU discharge.

Objective: Head motion is one of the most common sources of artefacts in brain MRI. When imaging young children, general anaesthesia is common, which is a limited resource. We evaluate the performance of markerless prospective motion correction (PMC) and selective reacquisition in a complete clinical protocol for brain MRI, comparing acquisitions with and without instructed intentional head motion.Materials and Methods: Image quality metrics and ratings were analysed for scans with and without PMC - acquired with six 2D- and 3D-encoded sequences in twenty-two healthy adults. The influence of PMC on motion-artefact-related changes in cortical thickness estimates was quantified using a general linear model.Results: For the motion-degraded 3D-encoded MPR and FLAIR sequences, image quality increased with PMC and reacquisition (p0.05, corrected), which is known to be sensitive to motion-related changes in B0. Discussion: Using PMC and selective reacquisition in sequences for standard clinical brain MRI improves diagnostic image quality when there is head motion.

Two siblings were diagnosed with adult metachromatic leukodystrophy (MLD) and treated with hematopoietic stem cell transplantation (HSCT). While the older sibling was symptomatic at the time of diagnosis, her younger brother was diagnosed and transplanted at the presymptomatic state. We describe patients' clinical, biochemical, and genetic features, as well as neuropsychological and neurophysiological test results, and brain magnetic resonance imaging from pretransplantation and posttransplantation assessments. Both patients converted to complete donor chimerism and arylsulfatase A levels normalized 3 months posttransplantation. Twelve months posttransplantation, neurological and neuropsychological assessment for both patients showed stabilization, and they remained stable for the 38 months long observation period. To assess the effect of HSCT used as treatment for the rare, adult MLD subtype on survival and stabilization, we performed a systematic literature review and included 7 studies with a total of 26 cases. Of these 26 cases, 6 patients died of HSCT‐related complications and 2 patients had graft rejection. Of the remaining 18 patients, 2 patients improved after HSCT, 13 patients stabilized, and 3 patients progressed, suggesting that HSCT potentially benefits adult MLD patients. Larger studies focusing on this subtype are needed and recommendations on criteria for HSCT in adult MLD need to be evolved.

Purpose: PET with somatostatin receptor ligand [68Ga]Ga-DOTA-D-Phe1-Tyr3-octreotide ([68Ga]Ga-DOTA-TOC) is an established method in radiotherapy planning because of the improved detection and delineation of meningioma tissue. We investigated the diagnostic accuracy of supplementary [68Ga]Ga-DOTA-TOC PET in patients with a 3-month postoperative MRI reporting gross-total resection (GTR). Experimental Design: Thirty-seven patients with a histologically proven meningioma and GTR on postoperative MRI were prospectively referred to [68Ga]Ga-DOTA-TOC PET. Detection and volume measurements of [68Ga]Ga-DOTA-TOC-avid lesions in relation to the primary tumor site were recorded. Residual tumor in suspicious lesions suggested by [68Ga]Ga-DOTA-TOC PET was verified by (i) tumor recurrence/progression on subsequent MRI scans according to the Response Assessment of Neuro-Oncology criteria, (ii) subsequent histology, and (iii) follow-up [68Ga]Ga-DOTA-TOC PET scan. Results: Twenty-three PET scans demonstrated [68Ga]Ga-DOTA-TOC-avid lesions suspicious of residual meningioma, where 18 could be verified by (i) tumor progression on subsequent MRI scans (n = 6), (ii) histologic confirmation (n = 3), and (iii) follow-up [68Ga]Ga-DOTA-TOC PET scans confirming the initial PET findings (n = 9) after an overall median follow-up time of 17 months (range, 9–35 months). In contrast, disease recurrence was seen in only 2 of 14 patients without [68Ga]Ga-DOTA-TOC-avid lesions (P < 0.0001). The sensitivity, specificity, and diagnostic accuracy of [68Ga]Ga-DOTA-TOC PET in detecting meningioma residue was 90% [95% confidence interval (CI), 67–99], 92% (95% CI, 62–100), and 90% (95% CI, 74–98; P < 0.0001), respectively. Conclusions: The majority of patients with GTR on 3-month postoperative MRI may have small unrecognized meningioma residues that can be detected using [68Ga]Ga-DOTA-TOC PET.

We have previously reported that PET with 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) provides a non-invasive assessment of cell proliferation in vivo in meningiomas. The purpose of this prospective study was to evaluate the potential of 18F-FLT PET in predicting subsequent tumour progression in asymptomatic meningiomas. Forty-three adult patients harbouring 46 MRI-presumed (n = 40) and residual meningiomas from previous surgery (n = 6) underwent a 60-min dynamic 18F-FLT PET scan prior to radiological surveillance. Maximum and mean tumour-to-blood ratios (TBRmax, TBRmean) of tracer radioactivity were calculated. Tumour progression was defined according to the latest published trial end-point criteria for bidimensional (2D) and corresponding yet exploratory volumetric measurements from the Response Assessment of Neuro-Oncology (RANO) workgroup. Independent-sample t-test, Pearson correlation coefficient, Cox regression, and receiver operating characteristic (ROC) curve analyses were used whenever appropriate. The median follow-up time after 18F-FLT PET imaging was 18 months (range 5–33.5 months). A high concordance rate (91%) was found with regard to disease progression using 2D-RANO (n = 11) versus volumetric criteria (n = 10). Using 2D-RANO criteria, 18F-FLT uptake was significantly increased in patients with progressive disease, compared to patients with stable disease (TBRmax, 5.5 ± 1.3 versus 3.6 ± 1.1, P

Introduction: The extent of meningioma resection is the most fundamental risk factor for recurrence, and exact knowledge of extent of resection is necessary for prognostication and for planning of adjuvant treatment. Currently used classifications are the EANO-grading and the Simpson grading. The former comprises radiological imaging with contrast-enhanced MRI and differentiation between “gross total removal” and “subtotal removal,” while the latter comprises a five-tiered differentiation of the surgeon’s impression of the extent of resection. The extent of resection of tumors is usually defined via analyses of resection margins but has until now not been implemented for meningiomas. PET/MRI imaging with 68Ga-DOTATOC allows more sensitive and specific imaging than MRI following surgery of meningiomas. Objective: To develop an objective grading system based on microscopic analyses of resection margins and sensitive radiological analyses to improve management of follow-up, adjuvant therapy, and prognostication of meningiomas. Based on the rationale of resection-margin analyses as gold standard and superior imaging performance of 68Ga DOTATOC PET, we propose “Copenhagen Grading” for meningiomas. Results: Copenhagen Grading was described for six pilot patients with examples of positive and negative findings on histopathology and DOTATOC PET scanning. The grading could be traceably implemented and parameters of grading appeared complementary. Copenhagen Grading is prospectively implemented as a clinical standard at Rigshospitalet, Copenhagen. Conclusion: Copenhagen Grading provided a comprehensive, logical, and reproducible definition of the extent of resection. It offers promise to be the most sensitive and specific imaging modality available for meningiomas. Clinical and cost-efficacy remain to be established during prospective implementation.

BackgroundDiagnostic accuracy in previous studies of O-(2-[18F]-fluoroethyl)-L-tyrosine (18F-FET) PET in patients with suspected recurrent glioma may be influenced by prolonged dynamic PET acquisitions, heterogeneous populations, different non–standard-of-care therapies, and PET scans performed at different time points post radiotherapy. We investigated the diagnostic accuracy of a 20-minute 18F-FET PET scan in MRI-suspected recurrent glioblastoma 6 months after standard radiotherapy and its ability to prognosticate overall survival (OS).MethodsIn total, 146 glioblastoma patients with 168 18F-FET PET scans were reviewed retrospectively. Patients with MRI responses to bevacizumab or undergoing re-irradiation or immunotherapy after 18F-FET PET were excluded. Maximum and mean tumor-to-background ratios (TBRmax, TBRmean) and biological tumor volume (BTV) were recorded and verified by histopathology or clinical/radiological follow-up. Thresholds of 18F-FET parameters were determined by receiver operating characteristic (ROC) analysis. Prognostic factors were investigated in Cox proportional hazards models.ResultsSurgery was performed after 104 18F-FET PET scans, while clinical/radiological surveillance was used following 64, identifying 152 glioblastoma recurrences and 16 posttreatment changes. ROC analysis yielded thresholds of 2.0 for TBRmax, 1.8 for TBRmean, and 0.55 cm3 for BTV in differentiating recurrent glioblastoma from posttreatment changes with the best performance of TBRmax (sensitivity 99%, specificity 94%; P < 0.0001) followed by BTV (sensitivity 98%, specificity 94%; P < 0.0001). Using these thresholds, 166 18F-FET PET scans were correctly classified. Increasing BTV was associated with shorter OS (P < 0.0001).ConclusionA 20-minute 18F-FET PET scan is a powerful tool to distinguish posttreatment changes from recurrent glioblastoma 6-month postradiotherapy, and predicts OS.

// Dorte Schou Noroxe 1 , 2 , Olga Ostrup 3 , Christina Westmose Yde 3 , Lise Barlebo Ahlborn 3 , Finn Cilius Nielsen 3 , Signe Regner Michaelsen 1 , Vibeke Andree Larsen 4 , Jane Skjoth-Rasmussen 5 , Jannick Brennum 5 , Petra Hamerlik 6 , Hans Skovgaard Poulsen 1 , 2 and Ulrik Lassen 2 1 Department of Radiation Biology, Rigshospitalet, 2100 Copenhagen, Denmark 2 Department of Oncology, Rigshospitalet, 2100 Copenhagen, Denmark 3 Center for Genomic Medicine, Rigshospitalet, 2100 Copenhagen, Denmark 4 Department of Neuroradiology, Rigshospitalet, 2100 Copenhagen, Denmark 5 Department of Neurosurgery, Rigshospitalet, 2100 Copenhagen, Denmark 6 Danish Cancer Society, 2100 Copenhagen, Denmark Correspondence to: Dorte Schou Noroxe, email: anne.dorte.schou.noeroexe@regionh.dk Keywords: glioblastoma; liquid biopsy; cell-free DNA; fragment length; base-pair Received: March 10, 2019 Accepted: May 29, 2019 Published: July 09, 2019 ABSTRACT Background: Glioblastoma (GB) is an incurable brain cancer with limited treatment options. The aim was to test the feasibility of using cell-free DNA (cfDNA) to support evaluation of treatment response, pseudo-progression and whether progression could be found before clinical and/or radiologic progression. Results: CfDNA fluctuated during treatment with the highest levels before diagnostic surgery and at progression. An increase was seen in 3 out of 4 patients at the time of progression while no increase was seen in 3 out of 4 patients without progression. CfDNA levels could aid in 3 out of 3 questionable cases of pseudo-progression. Methods: Eight newly diagnosed GB patients were included. Blood samples were collected prior to diagnosis, before start and during oncologic treatment until progression. Seven patients received concurrent radiotherapy/Temozolomide with adjuvant Temozolomide with one of the patients included in a clinical trial with either immunotherapy or placebo as add-on. One patient received radiation alone. CfDNA concentration was determined for each blood sample. Conclusions: It was feasible to measure cfDNA concentration. Despite the limited cohort size, there was a good tendency between cfDNA and treatment course and -response, respectively with the highest levels at progression.

The extent of meningioma resection is the most fundamental risk factor for recurrence, and exact knowledge of extent of resection is necessary for prognostication and for planning of adjuvant treatment. Currently used classifications are the EANO-grading and the Simpson grading. The former comprises radiological imaging with contrast-enhanced MRI and differentiation between "gross total removal" and "subtotal removal," while the latter comprises a five-tiered differentiation of the surgeon's impression of the extent of resection. The extent of resection of tumors is usually defined via analyses of resection margins but has until now not been implemented for meningiomas. PET/MRI imaging withTo develop an objective grading system based on microscopic analyses of resection margins and sensitive radiological analyses to improve management of follow-up, adjuvant therapy, and prognostication of meningiomas. Based on the rationale of resection-margin analyses as gold standard and superior imaging performance ofCopenhagen Grading was described for six pilot patients with examples of positive and negative findings on histopathology and DOTATOC PET scanning. The grading could be traceably implemented and parameters of grading appeared complementary. Copenhagen Grading is prospectively implemented as a clinical standard at Rigshospitalet, Copenhagen.Copenhagen Grading provided a comprehensive, logical, and reproducible definition of the extent of resection. It offers promise to be the most sensitive and specific imaging modality available for meningiomas. Clinical and cost-efficacy remain to be established during prospective implementation.

For the radiological assessment of resection of high-grade gliomas, a 72-h diagnostic window is recommended to limit surgically induced contrast enhancements. However, such enhancements may occur earlier than 72 h post-surgery. This systematic review aimed to assess the evidence on the timing of the postsurgical MRI. PubMed, Embase, Web of Science and Cochrane were searched following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only original research articles describing surgically induced contrast enhancements on MRI after resection for high-grade gliomas were included and analysed. The frequency of different contrast enhancement patterns on intraoperative MRI (iMRI) and early postoperative MRI (epMRI) was recorded. The search resulted in 1443 studies after removing duplicates, and a total of 12 studies were chosen for final review. Surgically induced contrast enhancements were reported at all time points after surgery, including on iMRI, but their type and frequency vary. Thin linear contrast enhancements were commonly found to be surgically induced and were less frequently recorded on postoperative days 1 and 2. This suggests that the optimal time to scan may be at or before this time. However, the evidence is limited, and higher-quality studies using larger and consecutively sampled populations are needed.

Predictive biomarkers and prognostic models are required to identify recurrent grade III glioma patients who benefit from existing treatment. In this study of 62 recurrent grade III glioma patients, a range of clinical and paraclinical factors are tested for association with progression-free survival, overall survival, and response to bevacizumab and irinotecan therapy. Significant factors from univariate screening are included in multivariate analysis. Biomarkers previously advanced as predictive or prognostic in the first-line setting did not affect outcome in this patient cohort. Based on the optimized model for overall survival, comprising performance status and p53 expression, a prognostic index is established.

BACKGROUND Positron emission tomography (PET) with 3’-deoxy-3’-[18F]-fluorothymidine (18F-FLT) provides a non-invasive assessment of in vivo tumor proliferation that could be useful for predicting growth potential in meningiomas. We aimed to study static and dynamic 18F-FLT PET metrics prospectively to assess metabolic activity of meningioma, and their associations to potential tumor growth on subsequent MRI scans. METHODS Between April 2017 and December 2018, 44 patients harboring MRI-suspected (n = 37) and histologically-verified residual meningiomas (n = 7) underwent a 60-minute dynamic 18F-FLT PET prior to imaging surveillance. Maximum and mean standardized uptake values (SUVmax, SUVmean) with/without normalisation to blood radioactivity obtained from a 40-60-minute static PET image and a 60-minute venous blood sampling were calculated. Total volume of distribution (VT) was estimated by kinetic modeling using a two-tissue reversible compartmental model with a fractional blood volume and metabolite-corrected image-derived input function. Tumor growth rate was calculated by volumetric analysis of subsequent MRI scans. RESULTS At the time of this writing, a total of 53 follow-up MRI scans from 33 patients were available for review, with a median follow-up time of 11 months (range, 4–22.5 months). Tumor growth/progression was observed in 12 cases with a monthly median growth rate of 0.10 cm3 (range, 0.03–3.41 cm3). All 18F-FLT metrics were significantly higher in patients with radiological progression compared to patients with stable findings with maximum tumor-to-blood-ratio (TBRmax) as the most promising imaging biomarker (4.9 ± 1.4 vs. 3.4 ± 1.0, P = .003; Mann-Whitney) and the strongest predictor for tumor progression (hazard ratio, 3.125; 95% confidence interval, 1.390–7.028; P = .006; univariate binary logistic regression). Age, gender, previous residual remnant(s) and initial tumor volume (median, 3.1 cm3; range, 0.2–55.3 cm3) had no influence. CONCLUSION 18F-FLT PET imaging could be a valuable tool in designing a patient-tailored surveillance strategy for patients with asymptomatic meningiomas.

INTRODUCTION Gliosarcoma (GS) is a rare histopathologic variant of glioblastoma (GBM) characterized by a biphasic growth pattern consisting of both glial and sarcomatous components. Reports regarding its relative prognosis compared to conventional GBM are conflicting and although GS is treated as conventional GBM, supporting evidence is lacking. The aim of this study was to characterize demographic trends, clinical outcomes and prognostic variables of GS patients receiving standardized therapy and compare these to conventional GBM. METHODS 680 GBM patients, treated with maximal safe resection followed by Stupp’s regimen (radiotherapy with concomitant and adjuvant temozolomide) at a single institution, were retrospective reevaluated by reviewing histopathological records and tumor tissue for identification of GS patients. Clinicohistopathological characteristics obtained via assessment of medical records and imaging analysis were compared between the GS and GBM cohorts. Kaplan-Meier survival estimates were compared with log-rank testing, while cox-regression modeling tested for prognostic factors in GS patients. RESULTS The cohort revealed 26 primary gliosarcoma (PGS) patients (3.8 %) and 7 secondary gliosarcoma (SGS) patients (1.0 %). Compared to conventional GBM tumors, PGS tumors were significantly more often located in the temporal lobe (53.8 %, p = 0.006) and MGMT-unmethylated (73.9 %, p = 0.009). No significant differences were found between PGS and conventional GBM in progression-free-survival (6.8 and 7.6 months respectively, p = 0.105) and in overall survival (13.4 and 15.7 months respectively, p = 0.201). Also, survival from recurrence was not significant different between PGS, SGS and GBM (5.8, 8.6 and 7.4 months respectively, p = 0.694). MGMT status was the only factor prognostic for PGS survival (p = 0.022). CONCLUSION Despite tumor difference between GS and GBM, the patients present similar survival outcome from standardized treatment. This support continues practice of radiation and temozolomide for GS patients.

Recurrent glioblastoma patients achieving response to bevacizumab combination therapy have clinical improvement and prolonged survival. High gene-expression of angiotensinogen (AGT) is associated with a poor response to bevacizumab combination therapy. Because AGT gene-expression is epigenetically regulated, we investigate if lower AGT promoter methylation in tumor tissue predicts a poor response to bevacizumab combination therapy in recurrent glioblastoma patients. Methods: Patients were assessed for eligibility using our clinical database comprising all recurrent glioblastoma patients consecutively treated with bevacizumab combination therapy at our center. The study included 159 response and biomarker evaluable patients: A training cohort of 77 patients and a validation cohort of 82 patients treated in the period between year 2005–2011 and 2012–2015. DNA methylation of 4 CpG sites in the AGT promoter was measured using pyrosequencing. Using logistic regression analysis, a predictive model for non-response was established. Results: In the training cohort, lower methylation of each of the four CpG sites was significantly associated with non-response (p < 0.05). Lower mean methylation of the AGT promoter was significantly associated with non-response (2-fold decrease: OR &eq; 3.01; 95% CI:1.41–6.44; p &eq; 0.004). A predictive model able to predict bevacizumab non-response in clinical practice was established. This predictor was significantly associated with non-response in the validation cohort (p &eq; 0.037). Conclusion: AGT promoter methylation is lower in tumor tissue from non-responsive recurrent glioblastoma patients treated with bevacizumab combination therapy. A predictive model for non-response was established and successfully validated. This model can be used to identify patients who will not benefit from bevacizumab combination therapy.

Background Huntington’s disease (HD) is an inherited, progressive neurodegenerative disease that has no cure. Striatal atrophy and hypometabolism has been described in HD as far as 15 years before clinical onset and therefore structural and functional imaging biomarkers are the most applied biomarker modalities which call for these to be exact; however, most studies are not considering the partial volume effect and thereby tend to overestimate metabolic reductions, which may bias imaging outcome measures of interventions. Objective Evaluation of partial volume effects in a cohort of premanifest HD gene-expansion carriers (HDGECs). Methods 21 HDGECs and 17 controls had a hybrid 2-[18F]FDG PET/MRI scan performed. Volume measurements and striatal metabolism, both corrected and uncorrected for partial volume effect were correlated to an estimate of disease burden, the CAG age product scaled (CAPS). Results We found significantly reduced striatal metabolism in HDGECs, but not in striatal volume. There was a negative correlation between the CAPS and striatal metabolism, both corrected and uncorrected for the partial volume effect. The partial volume effect was largest in the smallest structures and increased the difference in metabolism between the HDGEC with high and low CAPS scores. Statistical parametric mapping confirmed the results. Conclusions A hybrid 2-[18F]FDG PET/MRI scan provides simultaneous information on structure and metabolism. Using this approach for the first time on HDGECs, we highlight the importance of partial volume effect correction in order not to underestimate the standardized uptake value and thereby the risk of overestimating the metabolic effect on the striatal structures, which potentially could bias studies determining imaging outcome measures of interventions in HDGECs and probably also symptomatic HD.

Purpose Magnetic resonance imaging (MRI) plays a key role in neurooncology, i.e., for diagnosis, treatment evaluation and detection of recurrence. However, standard MRI cannot always separate malignant tissue from other pathologies or treatment-induced changes. Advanced MRI techniques such as diffusion-weighted imaging, perfusion imaging and spectroscopy show promising results in discriminating malignant from benign lesions. Further, supplemental imaging with amino acid positron emission tomography (PET) has been shown to increase accuracy significantly and is used routinely at an increasing number of sites. Several centers are now implementing hybrid PET/MRI systems allowing for multiparametric imaging, combining conventional MRI with advanced MRI and amino acid PET imaging. Neurooncology is an obvious focus area for PET/MR imaging. Methods Based on the literature and our experience from more than 300 PET/MRI examinations of brain tumors with 18F-fluoro-ethyl-tyrosine, the clinical use of PET/MRI in adult and pediatric neurooncology is critically reviewed. Results Although the results are increasingly promising, the added value and range of indications for multiparametric imaging with PET/MRI are yet to be established. Robust solutions to overcome the number of issues when using a PET/MRI scanner are being developed, which is promising for a more routine use in the future. Conclusions In a clinical setting, a PET/MRI scan may increase accuracy in discriminating recurrence from treatment changes, although sequential same-day imaging on separate systems will often constitute a reliable and cost-effective alternative. Pediatric patients who require general anesthesia will benefit the most from simultaneous PET and MR imaging.

Background Glioblastoma patients show a great variability in progression free survival (PFS) and overall survival (OS). To gain additional pretherapeutic information, we explored the potential of O-(2-18F-fluoroethyl)-L-tyrosine (FET) PET as an independent prognostic biomarker. Methods We retrospectively analyzed 146 consecutively treated, newly diagnosed glioblastoma patients. All patients were treated with temozolomide and radiation therapy (RT). CT/MR and FET PET scans were obtained postoperatively for RT planning. We used Cox proportional hazards models with OS and PFS as endpoints, to test the prognostic value of FET PET biological tumor volume (BTV). Results Median follow-up time was 14 months, and median OS and PFS were 16.5 and 6.5 months, respectively. In the multivariate analysis, increasing BTV (HR = 1.17, P

Background Huntington’s disease (HD) is an autosomal dominantly inherited neurodegenerative disorder, caused by an expansion of a trinucleotide (CAG) repeat in the huntingtin gene. There is no cure and only sparse symptomatic treatment. Structural brain imaging is the most applied and well documented technique to demonstrate longitudinal structural changes in premanifest and manifest HD gene-expansion carriers. Changes in the striatum are registered as far as 15 years before symptom onset with MRI. PET studies have found hypometabolism in the Caudate nucleus, Putamen and the temporal and frontal cortex years before clinical diagnosis along with hypermetabolism in Thalamus prior to symptom onset. Aims By a hybrid brain PET-MRI using FDG, we wished to simultaneously characterize the structural and metabolic brain changes in premanifest HD gene-expansion carriers and address the question whether changes in the metabolism precede the structural changes. Methods We recruited 21 premanifest HD gene-expansion carriers and 17 controls from the Neurogenetics Clinic, Danish Dementia Research Centre, Rigshospitalet, Denmark. We included individuals with CAG repeat ≥39 and a Unified HD Rating scale total motor score ≤5. Results We found a significantly lower (p=0.028) striatal metabolism in the HD gene expansion carrier group compared to gene-negative controls, while there was no significant striatal volume difference. We found a significant correlation between both striatal metabolism and CAP score and striatal volume and CAP score. The higher the CAP score, the lower the metabolism and striatal volume. We also found a significant positive association between striatal metabolism and MRI volume. Conclusions Our results suggest that striatal hypometabolism precedes atrophy; however longitudinal studies on larger cohorts using hybrid FDG-PET/MRI are needed to precisely assess the changes and evolution in time.

Recurrence in glioblastoma patients often occur close to the original tumour and indicates that the current treatment is inadequate for local tumour control. In this study, we explored the feasibility of using multi-modality imaging at the time of radiotherapy planning. Specifically, we aimed to identify parameters from pre-treatment PET and MRI with potential to predict tumour recurrence. Sixteen patients were prospectively recruited and treated according to established guidelines. Multi-parametric imaging with 18F-FET PET/CT and 18F-FDG PET/MR including diffusion and dynamic contrast enhanced perfusion MRI were performed before radiotherapy. Correlations between imaging parameters were calculated. Imaging was related to the voxel-wise outcome at the time of tumour recurrence. Within the radiotherapy target, median differences of imaging parameters in recurring and non-recurring voxels were calculated for contrast-enhancing lesion (CEL), non-enhancing lesion (NEL), and normal appearing grey and white matter. Logistic regression models were created to predict the patient-specific probability of recurrence. The most important parameters were identified using standardized model coefficients. Significant median differences between recurring and non-recurring voxels were observed for FDG, FET, fractional anisotropy, mean diffusivity, mean transit time, extra-vascular, extra-cellular blood volume and permeability derived from scans prior to chemo-radiotherapy. Tissue-specific patterns of voxel-wise correlations were observed. The most pronounced correlations were observed for 18F-FDG- and 18F-FET-uptake in CEL and NEL. Voxel-wise modelling of recurrence probability resulted in area under the receiver operating characteristic curve of 0.77 from scans prior to therapy. Overall, FET proved to be the most important parameter for recurrence prediction. Multi-parametric imaging before radiotherapy is feasible and significant differences in imaging parameters between recurring and non-recurring voxels were observed. Combining parameters in a logistic regression model enabled patient-specific maps of recurrence probability, where 18F-FET proved to be most important. This strategy could enable risk-adapted radiotherapy planning.

A 60-year-old man with no medical history was admitted to the Department of Neurology with drooping of his right upper eyelid and an ipsilateral contracted pupil, combined with pain, weakness, and numbness in his upper right limb.

Duplications and deletions of Xq26-27 including SOX3 (Xq27.1) have been associated with X-linked mental retardation and isolated growth hormone deficiency (OMIM 300123) or X-linked panhypopituitarism (OMIM 312000). Yet, pathogenic point mutations seem to be extremely rare. We report a family with three affected males with several clinical features including mild intellectual disability, microphthalmia, coloboma, hypopituitarism, facial dysmorphology and dental anomalies, including microcephaly, retrognathia and a solitary median maxillary central incisor amongst other features. Using Whole Exome Sequencing a missense variant in SOX3, NM_005634.2:c.449C>A; p.(Ser150Tyr) was identified. Segregation analysis in the family demonstrated that the variant was inherited through healthy females with its origin in the maternal grandmother showing germline mosaicism. Thus, we report one of the first cases of a pathogenic variant in SOX3 and germline mosaicism of this variant.

Listeria monocytogenes is associated with rhombencephalitis. However, the exact mechanisms of brainstem invasion remains poorly understood. Here, we demonstrate clinical and radiological data suggesting that Listeria may invade the brainstem via the trigeminal nerve. Three females (41, 64 and 70 years) with culture proven L. monocytogenes bacteremia and rhombencephalitis were investigated in the period of 2014-16. T2-weighted and contrast-enhanced T1-weighted MRI revealed a cerebellopontine abscess in all three patients, including the involvement of the trigeminal nerve root. In two patients, MRI also revealed selective contrast enhancement of the sensory trigeminal tract in the pons and medulla oblongata. Prior to any other neurological symptoms, two patients complained of hypoesthesia and a tingling sensation in the ipsilateral half of the face, consistent with sensory trigeminal nerve dysfunction on that side. In addition, we identified another 120 cases of Listeria rhombencephalitis following a systematic review. Cranial nerves VII, V, IX, and X, respectively, medulla oblongata, cerebellum and pons, were the most frequently involved brain structures. The present clinical and radiological findings corroborate earlier data from animal experiments, indicating that L. monocytogenes may be capable of retrograde intra-axonal migration along the cranial nerves. We suggest that in a subset of patients with rhombencephalitis L. monocytogenes enters the cerebellopontine angle through the trigeminal nerve, invading the brainstem via the sensory trigeminal nuclei.

Assessment of the default mode network (DMN) using resting-state functional magnetic resonance imaging (fMRI) may improve assessment of the level of consciousness in chronic brain injury, and therefore, fMRI may also have prognostic value in acute brain injury. However, fMRI is much more challenging in critically ill patients because of cardiovascular vulnerability, intravenous sedation, and artificial ventilation. Using resting-state fMRI, we investigated the DMN in a convenience sample of patients with acute brain injury admitted to the intensive care unit. The DMN was classified dichotomously into “normal” and “grossly abnormal.” Clinical outcome was assessed at 3 months. Seven patients with acute brain injury (4 females; median age 37 years [range 14–71 years]; 1 traumatic brain injury [TBI]; 6 non-TBI) were investigated by fMRI a median of 15 days after injury (range 5–25 days). Neurological presentation included 2 coma, 1 vegetative state/unresponsive wakefulness syndrome (VS/UWS), 3 minimal conscious state (MCS) minus, and 1 MCS plus. Clinical outcomes at 3 months included 1 death, 1 VS/UWS, 1 MCS plus, and 4 conscious states (CS; 1 modified Rankin Scale 0; 2 mRS 4; 1 mRS 5). Normal DMNs were seen in 4 out of 7 patients (1 MCS plus, 3 CS at follow-up). It is feasible to assess the DMN by resting-state fMRI in patients with acute brain injury already in the very early period of intensive care unit admission. Although preliminary data, all patients with a preserved DMN regained consciousness levels at follow-up compatible with MCS+ or better.

Migraine sufferers with aura often report photosensitivity and visual discomfort outside of attacks and many consider bright or flickering light an attack-precipitating factor. The nature of this visual hypersensitivity and its relation to the underlying pathophysiology of the migraine aura is unknown. Using fMRI measurements during visual stimulation we examined the visual cortical responsiveness of patients with migraine with aura. We applied a within-patient design by assessing functional interhemispheric differences in patients consistently experiencing visual aura in the same visual hemifield. We recruited 20 patients with frequent side-fixed visual aura attacks (≥90% of auras occurring in the same visual hemifield) and 20 age and sex matched healthy controls and compared the fMRI blood oxygenation level dependent (BOLD) responses to visual stimulation between symptomatic and asymptomatic hemispheres during the interictal phase and between migraine patients and controls. BOLD responses were selectively increased in the symptomatic hemispheres. This was found in the inferior parietal lobule (P = 0.002), the inferior frontal gyrus (P = 0.003), and the superior parietal lobule (P = 0.017). The affected cortical areas comprise a visually driven functional network involved in oculomotor control, guidance of movement, motion perception, visual attention, and visual spatial memory. The patients also had significantly increased response in the same cortical areas when compared to controls (P < 0.05). We discovered a lateralized alteration of a visually driven functional network in patients with side-fixed aura. These findings suggest a hyperexcitability of the visual system in the interictal phase of migraine with visual aura.

To investigate if perfusion measured with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to differentiate radiation necrosis from tumor recurrence in patients with high-grade glioma. The study was approved by the institutional review board and informed consent was obtained from all subjects. 19 patients were recruited following surgery and radiation therapy for glioma. Patients had contrast enhancing lesions, which during the standard MRI examination could not be exclusively determined as recurrence or radiation necrosis. DCE-MRI was used to measure cerebral blood volume (CBV), blood–brain barrier (BBB) permeability and cerebral blood flow (CBF). Subjects also underwent FDG-PET and lesions were classified as either metabolically active or inactive. Follow-up clinical MRI and lesion histology in case of additional tissue resection was used to determine whether lesions were regressing or progressing. Fourteen enhancing lesions could be classified as progressing (11) or regressing (three). An empirical threshold of 2.0 ml/100 g for CBV allowed detection of regressing lesions with a sensitivity of 100 % and specificity of 100 %. FDG-PET and DCE-MRI agreed in classification of tumor status in 13 out of the 16 cases where an FDG-PET classification was obtained. In two of the remaining three patients, MRI follow-up and histology was available and both indicated that the DCE-MRI answer was correct. CBV measurements using DCE-MRI may predict the status of contrast enhancing lesions and give results very similar to FDG-PET with regards to differentiation between tumor recurrence and radiation necrosis.

Severe brain damage is often followed by serious complications. Quantitative measurements, such as regional volume and surface area under various conditions, are essential for understanding functional changes in the brain and assessing prognosis. The affected brain tissue is variable, hence traditional imaging methods are not always applicable and automatic methods may not be able to match the individual observer. Stereological techniques are alternative tools in the quantitative description of biological structures, and have been increasingly applied to the human brain. In the present study, we applied stereological techniques to representative CT and MRI brain scans from five patients to describe how stereological methods, when applied to scans of trauma patients, can provide a useful supplement to the estimation of structural brain changes in head injuries. The reliability of the estimates was tested by obtaining repeated intra- and interobserver estimates of selected subdivisions of the brain in patients with acute head injury, as well as in an MR phantom. The estimates of different subdivisions showed a coefficient of variation (CV) below 12% in the patients and below 7% for phantom estimation. The validity of phantom estimates was tested by the average deviation from the true geometric values, and was below 10%. The stereological methods were compared with more traditional region-based methods performed on medical imaging, which showed a CV below 7% and bias below 14%. It is concluded that the stereological estimates may be useful tools in head injury quantification.

Background Predictive markers and prognostic models are required in order to individualize treatment of recurrent glioblastoma (GBM) patients. Here, we sought to identify clinical factors able to predict response and survival in recurrent GBM patients treated with bevacizumab (BEV) and irinotecan. Material and methods A total of 219 recurrent GBM patients treated with BEV plus irinotecan according to a previously published treatment protocol were included in the initial population. Prognostic models were generated by means of multivariate logistic and Cox regression analysis. Results In multivariate analysis, corticosteroid use had a negative predictive impact on response at first evaluation (OR 0.45; 95% CI 0.22-0.93; p = 0.03) and at best response (OR 0.51; 95% CI 0.26-1.02; p = 0.056). Three significant (p

Both [18F]-fluoroethyltyrosine (FET) PET and blood volume (BV) MRI supplement routine T1-weighted contrast-enhanced MRI in gliomas, but whether the two modalities provide identical or complementary information is unresolved. The aims of the study were to investigate the feasibility of simultaneous structural MRI, BV MRI and FET PET of gliomas using an integrated PET/MRI scanner and to assess the spatial and quantitative agreement in tumour imaging between BV MRI and FET PET. A total of 32 glioma patients underwent a 20-min static simultaneous PET/MRI acquisition on a Siemens mMR system 20 min after injection of 200 MBq FET. The MRI protocol included standard structural MRI and dynamic susceptibility contrast (DSC) imaging for BV measurements. Maximal relative tumour FET uptake (TBRmax) and BV (rBVmax), and Dice coefficients were calculated to assess the quantitative and spatial congruence in the tumour volumes determined by FET PET, BV MRI and contrast-enhanced MRI. FET volume and TBRmax were higher in BV-positive than in BV-negative scans, and both VOLBV and rBVmax were higher in FET-positive than in FET-negative scans. TBRmax and rBVmax were positively correlated (R 2 = 0.59, p

Here we compare translocator protein (TSPO) imaging using 6-chloro-2-(4′-123I-iodophenyl)-3-(N,N-diethyl)-imidazo[1,2-a]pyridine-3-acetamide SPECT (123I-CLINDE) and amino acid transport imaging using O-(2-18F-fluoroethyl)-l-tyrosine PET (18F-FET) and investigate whether 123I-CLINDE is superior to 18F-FET in predicting progression of glioblastoma multiforme (GBM) at follow-up. Methods: Three patients with World Health Organization grade IV GBM were scanned with 123I-CLINDE SPECT, 18F-FET PET, and gadolinium-enhanced MR imaging. Molecular imaging data were compared with follow-up gadolinium-enhanced MR images or contrast-enhanced CT scans. Results: The percentage overlap between volumes of interest (VOIs) of increased 18F-FET uptake and 123I-CLINDE binding was variable (12%–42%). The percentage overlap of MR imaging baseline VOIs was greater for 18F-FET (79%–93%) than 123I-CLINDE (15%–30%). In contrast, VOIs of increased contrast enhancement at follow-up compared with baseline overlapped to a greater extent with baseline 123I-CLINDE VOIs than 18F-FET VOIs (21% vs. 8% and 72% vs. 55%). Conclusion: Our preliminary results suggest that TSPO brain imaging in GBM may be a useful tool for predicting tumor progression at follow-up and may be less susceptible to changes in blood–brain barrier permeability than 18F-FET. Larger studies are warranted to test the clinical potential of TSPO imaging in GBM, including presurgical planning and radiotherapy.

A 17-year-old female with migraine with aura complained of fatigue and was diagnosed with anemia. Three years later, changes in her headache pattern prompted hospital referral. Brain MRI showed a bi-lobed extra-axial intracerebral tumor encroaching both parieto-occipital regions. The resection specimen yielded a rare diagnosis of primary intracranial angiomatoid fibrous histiocytoma (AFH). Tumor removal resulted in cessation of her migraine and anemia. AFH may cause systemic symptoms – in this case fatigue and anemia – long before focal neurological symptoms are present. This is the first report of an intracranial AFH presenting as migraine with visual aura and anemia.

A 74-year-old man presented with sensory deficits and lower limb weakness four years after a renal transplant. MRI showed an intramedullary mass at the T5 level. Following surgical excision the diagnosis post-transplant lymphoproliferative disorder (PTLD) was made. Although the frequency of PTLD is low in kidney transplant recipients (≤ 1%), it is an important differential diagnosis in a patient with new-onset neurological deficits following solid-organ transplantation.