The longitudinal relation between executive functioning and multilayer network topology in glioma patients.

Many patients with glioma, primary brain tumors, suffer from poorly understood executive functioning deficits before and/or after tumor resection. We aimed to test whether frontoparietal network centrality of multilayer networks, allowing for integration across multiple frequencies, relates to and predicts executive functioning in glioma. Patients with glioma (n = 37) underwent resting-state magnetoencephalography and neuropsychological tests assessing word fluency, inhibition, and set shifting before (T1) and one year after tumor resection (T2). We constructed binary multilayer networks comprising six layers, with each layer representing frequency-specific functional connectivity between source-localized time series of 78 cortical regions. Average frontoparietal network multilayer eigenvector centrality, a measure for network integration, was calculated at both time points. Regression analyses were used to investigate associations with executive functioning. At T1, lower multilayer integration (p = 0.017) and epilepsy (p = 0.006) associated with poorer set shifting (adj. R2 = 0.269). Decreasing multilayer integration (p = 0.022) and not undergoing chemotherapy at T2 (p = 0.004) related to deteriorating set shifting over time (adj. R2 = 0.283). No significant associations were found for word fluency or inhibition, nor did T1 multilayer integration predict changes in executive functioning. As expected, our results establish multilayer integration of the frontoparietal network as a cross-sectional and longitudinal correlate of executive functioning in glioma patients. However, multilayer integration did not predict postoperative changes in executive functioning, which together with the fact that this correlate is also found in health and other diseases, limits its specific clinical relevance in glioma.

Regional healthy brain activity, glioma occurrence and symptomatology.

It is unclear why exactly gliomas show preferential occurrence in certain brain areas. Increased spiking activity around gliomas leads to faster tumour growth in animal models, while higher non-invasively measured brain activity is related to shorter survival in patients. However, it is unknown how regional intrinsic brain activity, as measured in healthy controls, relates to glioma occurrence. We first investigated whether gliomas occur more frequently in regions with intrinsically higher brain activity. Second, we explored whether intrinsic cortical activity at individual patients' tumour locations relates to tumour and patient characteristics. Across three cross-sectional cohorts, 413 patients were included. Individual tumour masks were created. Intrinsic regional brain activity was assessed through resting-state magnetoencephalography acquired in healthy controls and source-localized to 210 cortical brain regions. Brain activity was operationalized as: (i) broadband power; and (ii) offset of the aperiodic component of the power spectrum, which both reflect neuronal spiking of the underlying neuronal population. We additionally assessed (iii) the slope of the aperiodic component of the power spectrum, which is thought to reflect the neuronal excitation/inhibition ratio. First, correlation coefficients were calculated between group-level regional glioma occurrence, as obtained by concatenating tumour masks across patients, and group-averaged regional intrinsic brain activity. Second, intrinsic brain activity at specific tumour locations was calculated by overlaying patients' individual tumour masks with regional intrinsic brain activity of the controls and was associated with tumour and patient characteristics. As proposed, glioma preferentially occurred in brain regions characterized by higher intrinsic brain activity in controls as reflected by higher offset. Second, intrinsic brain activity at patients' individual tumour locations differed according to glioma subtype and performance status: the most malignant isocitrate dehydrogenase-wild-type glioblastoma patients had the lowest excitation/inhibition ratio at their individual tumour locations as compared to isocitrate dehydrogenase-mutant, 1p/19q-codeleted glioma patients, while a lower excitation/inhibition ratio related to poorer Karnofsky Performance Status, particularly in codeleted glioma patients. In conclusion, gliomas more frequently occur in cortical brain regions with intrinsically higher activity levels, suggesting that more active regions are more vulnerable to glioma development. Moreover, indices of healthy, intrinsic excitation/inhibition ratio at patients' individual tumour locations may capture both tumour biology and patients' performance status. These findings contribute to our understanding of the complex and bidirectional relationship between normal brain functioning and glioma growth, which is at the core of the relatively new field of 'cancer neuroscience'.

Understanding Global Brain Network Alterations in Glioma Patients.

Introduction: Glioma patients show increased global brain network clustering related to poorer cognition and epilepsy. However, it is unclear whether this increase is spatially widespread, localized in the (peri)tumor region only, or decreases with distance from the tumor. Materials and Methods: Weighted global and local brain network clustering was determined in 71 glioma patients and 53 controls by using magnetoencephalography. Tumor clustering was determined by averaging local clustering of regions overlapping with the tumor, and vice versa for non-tumor regions. Euclidean distance was determined from the tumor centroid to the centroids of other regions. Results: Patients showed higher global clustering compared with controls. Clustering of tumor and non-tumor regions did not differ, and local clustering was not associated with distance from the tumor. Post hoc analyses revealed that in the patient group, tumors were located more often in regions with higher clustering in controls, but it seemed that tumors of patients with high global clustering were located more often in regions with lower clustering in controls. Conclusions: Glioma patients show non-local network disturbances. Tumors of patients with high global clustering may have a preferred localization, namely regions with lower clustering in controls, suggesting that tumor localization relates to the extent of network disruption. Impact statement This work uses the innovative framework of network neuroscience to investigate functional connectivity patterns associated with brain tumors. Glioma (primary brain tumor) patients experience cognitive deficits and epileptic seizures, which have been related to brain network alterations. This study shows that glioma patients have a spatially widespread increase in global network clustering, which cannot be attributed to local effects of the tumor. Moreover, tumors occur more often in brain regions with higher network clustering in controls. This study emphasizes the global character of network alterations in glioma patients and suggests that preferred tumor locations are characterized by particular network profiles.

Comparison of videolaryngoscopy alone with video-assisted fibreoptic intubation in a difficult cadaver airway model.

ABSTRACT: No Abstract.

Suitability and realism of the novel Fix for Life cadaver model for videolaryngoscopy and fibreoptic tracheoscopy in airway management training.

BACKGROUND: Videolaryngoscopy is increasingly advocated as the standard intubation technique, while fibreoptic intubation is broadly regarded as the 'gold standard' for difficult airways. Traditionally, the training of these techniques is on patients, though manikins, simulators and cadavers are also used, with their respective limitations. In this study, we investigated whether the novel 'Fix for Life' (F4L) cadaver model is a suitable and realistic model for the teaching of these two intubation techniques to novices in airway management. METHODS: Forty consultant anaesthetists and senior trainees were instructed to perform tracheal intubation with videolaryngoscopy and fibreoptic tracheoscopy in four F4L cadaver models. The primary outcome measure was the verbal rating scores (scale 1-10, higher scores indicate a better rating) for suitability and for realism of the F4L cadavers as training model for these techniques. Secondary outcomes included success rates of the procedures and the time to successful completion of the procedures. RESULTS: The mean verbal rating scores for suitability and realism for videolaryngoscopy was 8.3 (95% CI, 7.9-8.6) and 7.2 (95% CI, 6.7-7.6), respectively. For fibreoptic tracheoscopy, suitability was 8.2 (95% CI, 7.9-8.5) and realism 7.5 (95% CI, 7.1-7.8). In videolaryngoscopy, 100% of the procedures were successful. The mean (SD) time until successful tracheal intubation was 34.8 (30.9) s. For fibreoptic tracheoscopy, the success rate was 96.3%, with a mean time of 89.4 (80.1) s. CONCLUSIONS: We conclude that the F4L cadaver model is a suitable and realistic model to train and teach tracheal intubation with videolaryngoscopy and fibreoptic tracheoscopy to novices in airway management training.

Postoperative oscillatory brain activity as an add-on prognostic marker in diffuse glioma.

INTRODUCTION: Progression-free survival (PFS) in glioma patients varies widely, even when stratifying for known predictors (i.e. age, molecular tumor subtype, presence of epilepsy, tumor grade and Karnofsky performance status). Neuronal activity has been shown to accelerate tumor growth in an animal model, suggesting that brain activity may be valuable as a PFS predictor. We investigated whether postoperative oscillatory brain activity, assessed by resting-state magnetoencephalography is of additional value when predicting PFS in glioma patients. METHODS: We included 27 patients with grade II-IV gliomas. Each patient's oscillatory brain activity was estimated by calculating broadband power (0.5-48 Hz) in 56 epochs of 3.27 s and averaged over 78 cortical regions of the Automated Anatomical Labeling atlas. Cox proportional hazard analysis was performed to test the predictive value of broadband power towards PFS, adjusting for known predictors by backward elimination. RESULTS: Higher broadband power predicted shorter PFS after adjusting for known prognostic factors (n = 27; HR 2.56 (95% confidence interval (CI) 1.15-5.70); p = 0.022). Post-hoc univariate analysis showed that higher broadband power also predicted shorter overall survival (OS; n = 38; HR 1.88 (95% CI 1.00-3.54); p = 0.038). CONCLUSIONS: Our findings suggest that postoperative broadband power is of additional value in predicting PFS beyond already known predictors.

Understanding cognitive functioning in glioma patients: The relevance of IDH-mutation status and functional connectivity.

INTRODUCTION: Cognitive deficits occur frequently in diffuse glioma patients, but are limitedly understood. An important marker for survival in these patients is isocitrate dehydrogenase (IDH) mutation (IDH-mut). Patients with IDH-mut glioma have a better prognosis but more often suffer from epilepsy than patients with IDH-wildtype (IDH-wt) glioma, who are generally older and more often have cognitive deficits. We investigated whether global brain functional connectivity differs between patients with IDH-mut and IDH-wt glioma, and whether this measure reflects variations in cognitive functioning in these subpopulations beyond the associated differences in age and presence of epilepsy. METHODS: We recorded magnetoencephalography and tested cognitive functioning in 54 diffuse glioma patients (31 IDH-mut, 23 IDH-wt). Global functional connectivity between 78 atlas regions spanning the entire cortex was calculated in two frequency bands (theta and alpha). Group differences in global functional connectivity were tested, as was their association with cognitive functioning, controlling for age, education, and presence of epilepsy. RESULTS: Patients with IDH-wt glioma had lower functional connectivity in the alpha band than patients with IDH-mut glioma (p = 0.040, corrected for age and presence of epilepsy). Lower alpha band functional connectivity was associated with poorer cognitive performance (p < 0.034), corrected for age, education, and presence of epilepsy. CONCLUSION: Global functional connectivity is lower in patients with IDH-wt diffuse glioma compared to patients with IDH-mut diffuse glioma. Moreover, having lower functional alpha connectivity relates to poorer cognitive performance in patients with diffuse glioma, regardless of age, education, and presence of epilepsy.

Oscillatory brain activity associates with neuroligin-3 expression and predicts progression free survival in patients with diffuse glioma.

INTRODUCTION: Diffuse gliomas have local and global effects on neurophysiological brain functioning, which are often seen as 'passive' consequences of the tumor. However, seminal preclinical work has shown a prominent role for neuronal activity in glioma growth: mediated by neuroligin-3 (NLGN3), increased neuronal activity causes faster glioma growth. It is unclear whether the same holds true in patients. Here, we investigate whether lower levels of oscillatory brain activity relate to lower NLGN3 expression and predict longer progression free survival (PFS) in diffuse glioma patients. METHODS: Twenty-four newly diagnosed patients with diffuse glioma underwent magnetoencephalography and subsequent tumor resection. Oscillatory brain activity was approximated by calculating broadband power (0.5-48 Hz) of the magnetoencephalography. NLGN3 expression in glioma tissue was semi-quantitatively assessed by immunohistochemistry. Peritumor and global oscillatory brain activity was then compared between different levels of NLGN3 expression with Kruskal-Wallis tests. Cox proportional hazards analyses were performed to estimate the predictive value of oscillatory brain activity for PFS. RESULTS: Patients with low expression of NLGN3 had lower levels of global oscillatory brain activity than patients with higher NLGN3 expression (P < 0.001). Moreover, lower peritumor (hazard ratio 2.17, P = 0.008) and global oscillatory brain activity (hazard ratio 2.10, P = 0.008) predicted longer PFS. CONCLUSIONS: Lower levels of peritumor and global oscillatory brain activity are related to lower NLGN3 expression and longer PFS, corroborating preclinical research. This study highlights the important interplay between macroscopically measured brain activity and glioma progression, and may lead to new therapeutic interventions in diffuse glioma patients.

Thinking about the nerve impulse: A critical analysis of the electricity-centered conception of nerve excitability.

Nerve impulse generation and propagation are often thought of as solely electrical events. The prevalence of this view is the result of long and intense study of nerve impulses in electrophysiology culminating in the introduction of the Hodgkin-Huxley model of the action potential in the 1950s. To this day, this model forms the physiological foundation for a broad area of neuroscientific research. However, the Hodgkin-Huxley model cannot account for non-electrical phenomena that accompany nerve impulse propagation, for which there is nevertheless ample evidence. This raises the question whether the Hodgkin-Huxley model is a complete model of the nerve impulse. Several alternative models have been proposed that do take into account non-electrical aspects of the nerve impulse and emphasize their importance in gaining a more complete understanding of the nature of the nerve impulse. In our opinion, these models deserve more attention in neuroscientific research, since, together with the Hodgkin-Huxley model, they will help in addressing and solving a number of questions in basic and applied neuroscience which thus far have remained outside our grasp. Here we provide a historico-scientific overview of the developments that have led to the current conception of the action potential as an electrical phenomenon, discuss some major objections against this conception, and suggest a number of scientific factors which have likely contributed to the enduring success of the Hodgkin-Huxley model and should be taken into consideration whilst contemplating the formulation of a more extensive and complete conception of the nerve impulse.

9.4T and 17.6T MRI of Retinoblastoma: Ex Vivo evaluation of microstructural anatomy and disease extent compared with histopathology.

BACKGROUND: Retinoblastoma is the most common intraocular tumor in childhood with a good prognosis in terms of mortality, but detailed information about tumor morphology and disease extent in retinoblastoma is important for treatment decision making. PURPOSE: To demonstrate ultrahigh-field MRI tumor morphology and tumor extent in retinoblastoma correlating with in and ex vivo images with histopathology. STUDY TYPE: Prospective case series. POPULATION: Six retinoblastoma patients (median age 5.5 months, range 2-14) were prospectively included in this study. Median time between diagnosis and enucleation was 8 days (range 7-19). FIELD STRENGTH/SEQUENCE: In vivo pre-enucleation at 1.5T MRI with a circular surface coil. Ex vivo imaging (FLASH T1 -weighted and RARE T2 -weighted) was performed at field strengths of 9.4T and 17.6T. ASSESSMENT: After ex vivo imaging, the eyes were histopathologically analyzed and morphologically matched with MRI findings by three authors (two with respectively 14 and 4 years of experience in ocular MRI and one with 16 years of experience in ophthalmopathology). RESULTS: Small submillimeter morphological aspects of intraocular retinoblastoma were successfully depicted with higher-resolution MRI and matched with histopathology images. With ex vivo MRI a small subretinal tumor seed (300 µm) adjacent to the choroid was morphologically matched with histopathology. Also, a characteristic geographical pattern of vital tumor tissue (400 µm) surrounding a central vessel interspersed with necrotic areas correlated with histopathology images. Tumor invasion into the optic nerve showed a higher signal intensity on T1 -weighted higher-resolution MRI. DATA CONCLUSION: Higher-resolution MRI allows for small morphological aspects of intraocular retinoblastoma and extraocular disease extent not visible on currently used clinical in vivo MRI to be depicted. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1487-1497.

Connectomic profile and clinical phenotype in newly diagnosed glioma patients.

Gliomas are primary brain tumors, originating from the glial cells in the brain. In contrast to the more traditional view of glioma as a localized disease, it is becoming clear that global brain functioning is impacted, even with respect to functional communication between brain regions remote from the tumor itself. However, a thorough investigation of glioma-related functional connectomic profiles is lacking. Therefore, we constructed functional brain networks using functional MR scans of 71 glioma patients and 19 matched healthy controls using the automated anatomical labelling (AAL) atlas and interregional Pearson correlation coefficients. The frequency distributions across connectivity values were calculated to depict overall connectomic profiles and quantitative features of these distributions (full-width half maximum (FWHM), peak position, peak height) were calculated. Next, we investigated the spatial distribution of the connectomic profile. We defined hub locations based on the literature and determined connectivity (1) between hubs, (2) between hubs and non-hubs, and (3) between non-hubs. Results show that patients had broader and flatter connectivity distributions compared to controls. Spatially, glioma patients particularly showed increased connectivity between non-hubs and hubs. Furthermore, connectivity distributions and hub-non-hub connectivity differed within the patient group according to tumor grade, while relating to Karnofsky performance status and progression-free survival. In conclusion, newly diagnosed glioma patients have globally altered functional connectomic profiles, which mainly affect hub connectivity and relate to clinical phenotypes. These findings underscore the promise of using connectomics as a future biomarker in this patient population.

Dynamic hub load predicts cognitive decline after resective neurosurgery.

Resective neurosurgery carries the risk of postoperative cognitive deterioration. The concept of 'hub (over)load', caused by (over)use of the most important brain regions, has been theoretically postulated in relation to symptomatology and neurological disease course, but lacks experimental confirmation. We investigated functional hub load and postsurgical cognitive deterioration in patients undergoing lesion resection. Patients (n = 28) underwent resting-state magnetoencephalography and neuropsychological assessments preoperatively and 1-year after lesion resection. We calculated stationary hub load score (SHub) indicating to what extent brain regions linked different subsystems; high SHub indicates larger processing pressure on hub regions. Dynamic hub load score (DHub) assessed its variability over time; low values, particularly in combination with high SHub values, indicate increased load, because of consistently high usage of hub regions. Hypothetically, increased SHub and decreased DHub relate to hub overload and thus poorer/deteriorating cognition. Between time points, deteriorating verbal memory performance correlated with decreasing upper alpha DHub. Moreover, preoperatively low DHub values accurately predicted declining verbal memory performance. In summary, dynamic hub load relates to cognitive functioning in patients undergoing lesion resection: postoperative cognitive decline can be tracked and even predicted using dynamic hub load, suggesting it may be used as a prognostic marker for tailored treatment planning.

Brain iron accumulation in aging and neurodegenerative disorders.

Over the decades, various studies have established an association between accumulation of iron and both aging and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Excess levels of iron can lead to increased oxidative stress through Fenton chemistry, and depletion of iron can similarly have deleterious effects. In addition, metal ions are known to be involved in both Alzheimer's disease and Parkinson's disease protein aggregation. Metal ion chelators have been extensively investigated in preclinical models, and may prove to be appropriate for modulating brain iron levels in age-related neurodegenerative disorders. Investigating age-related iron deposition is vital, and can possibly aid in determining at-risk groups and diagnosing neurodegenerative diseases at an early stage. Novel imaging methods have enabled researchers to examine iron deposition in vivo, and offer a noninvasive method of monitoring the progression of accumulation, and possible therapeutic effects of chelating compounds.

Association between pathological and MRI findings in multiple sclerosis.

The identification of pathological processes that could be targeted by therapeutic interventions is a major goal of research into multiple sclerosis (MS). Pathological assessment is the gold standard for such identification, but has intrinsic limitations owing to the limited availability of autopsy and biopsy tissue. MRI has gained a leading role in the assessment of MS because it allows doctors to obtain an ante mortem picture of the degree of CNS involvement. A number of correlative pathological and MRI studies have helped to define in vivo the pathological substrates of MS in focal lesions and normal-appearing white matter, not only in the brain, but also in the spinal cord. These studies have resulted in the identification of aspects of pathophysiology that were previously neglected, including grey matter involvement and vascular pathology. Despite these important achievements, numerous open questions still need to be addressed to resolve controversies about how the pathology of MS results in fixed neurological disability.

B-cell depletion attenuates white and gray matter pathology in marmoset experimental autoimmune encephalomyelitis.

This study investigated the effect of CD20-positive B-cell depletion on central nervous system (CNS) white and gray matter pathology in experimental autoimmune encephalomyelitis in common marmosets, a relevant preclinical model of multiple sclerosis. Experimental autoimmune encephalomyelitis was induced in 14 marmosets by immunization with recombinant human myelin oligodendrocyte glycoprotein in complete Freund adjuvant. At 21 days after immunization, B-cell depletion was achieved by weekly intravenous injections of HuMab 7D8, a human-anti-human CD20 antibody that cross-reacts with marmoset CD20. In vivo magnetic resonance imaging showed widespread brain white matter demyelination in control marmosets that was absent in CD20 antibody-treated marmosets. High-contrast postmortem magnetic resonance imaging showed white matter lesions in 4of the 7 antibody-treated marmosets, but these were significantly smaller than those in controls. The same technique revealed gray matter lesions in 5 control marmosets, but none in antibody-treated marmosets. Histologic analysis confirmed that inflammation, demyelination, and axonal damage were substantially reduced in brain, spinal cord, and optic nerves of CD20 antibody-treated marmosets. In conclusion, CD20-postive B-cell depletion by HuMab 7D8 profoundly reduced the development of both white and gray matter lesions in the marmoset CNS. These data underline the central role of B cells in CNS inflammatory-demyelinating disease.

Meningeal inflammation is not associated with cortical demyelination in chronic multiple sclerosis.

Cortical demyelination can be extensive in chronic multiple sclerosis (MS) patients. Cortical lesions are not associated with lymphocyte infiltration, blood-brain barrier disruption, or complement deposition; therefore, their pathogenesis is unclear. We analyzed the extent and cellular composition of leptomeningeal inflammatory infiltrates and their relationship with cortical demyelinated lesions in brain autopsy samples from 28 chronic MS patients; samples from 6 nonneurological disease control patients were also studied. Immunohistochemistry was used to detect meningeal T cells, B cells, macrophages, mature and immature dendritic cells, T-helper cells, (activated) cytotoxic T cells, and plasma cells. Quantitative analysis revealed significant meningeal inflammation in chronic MS patients; T cells were the predominant inflammatory cells. Morphometric analysis was performed on coronal hemisphere sections of the MS cases to assess subpial demyelination; no correlation between the extent of subpial demyelination and extent of meningeal inflammation was identified. Moreover, no differences were observed in the degree or cellular composition of meningeal infiltrates in areas directly adjacent to subpial lesions compared with areas adjacent to normal-appearing gray matter in the MS cases. In addition, no follicle-like structures were found in the MS samples. Our data suggest that the occurrence of cortical lesions is not related to the presence of meningeal inflammation in a large number of chronic MS patients.

Use of ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced MRI to demonstrate diffuse inflammation in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) patients: an exploratory study.

PURPOSE: To explore ultrasmall superparamagnetic particles of iron oxide (USPIO) as a marker for diffuse inflammation in multiple sclerosis (MS) normal-appearing white matter (NAWM), using quantitative MRI. Disease activity in the NAWM of MS patients partly explains why MRI lesion burden correlates only moderately with disability. USPIO have been shown to visualize the cellular component of inflammation in focal MS lesions. In this study, we aimed to explore USPIO as a marker for the more diffuse inflammation in MS NAWM, using quantitative MRI. MATERIALS AND METHODS: In this prospective MRI study, 16 MS patients (eight relapsing-remitting MS [RRMS] and eight primary-progressive MS [PPMS] cases) and five healthy control (HC) subjects were included. Using a flip-angle (FA) array, B1-corrected T1 maps were generated before and 24 hours after USPIO (SHU555C) injection. White-matter (WM) T1 histogram and region-of-interest (ROI) characteristics were compared between both time points using Wilcoxon signed-rank test. RESULTS: Both NAWM ROI and histogram analyses showed T1 shortening after USPIO injection in MS patients (P < 0.01), but not in HCs (P = 0.68). CONCLUSION: This exploratory study suggests that USPIO-enhanced MRI may be a new potential marker for subtle inflammatory activity in MS NAWM. Further studies should focus on relating diffuse inflammation to clinical disease activity and treatment efficacy.

Clinicopathological and immunohistochemical findings in an autopsy case of tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder caused by mutations in either the TSC1 or TSC2 genes and characterized by developmental brain abnormalities. In the present study we discuss the neuropathological findings of a 32-year-old patient with a germ-line mutation in the TSC2 gene. Post mortem MRI combined with histology and immunocytochemical analysis was applied to demonstrate widespread anatomical abnormalities of gray and white matter structure. TSC brain lesions were analyzed for loss of heterozygosity (LOH) on chromosome 16p13. The neuropathological supratentorial abnormalities were represented by multiple subependymal nodules (SENs) and cortical tubers. In addition to cerebral cortical lesions, cerebellar lesions and hippocampal sclerosis were also observed. LOH was not found in the cortical tubers and SENs of this patient. Immunocytochemical analysis of the TSC brain lesions confirmed the cell-specific activation of the mTOR pathway in cortical tubers, SENs and cerebellum, as well as differential cellular localization of hamartin and tuberin, the TSC1 and TSC2 gene products. Examination of the pathological brain regions revealed activated microglial cells and disruption of blood-brain barrier permeability. Predominant intralesional cell-specific distribution was also detected for the multidrug transporter protein P-gp, possibly explaining the mechanisms underlying the pharmacoresistance to antiepileptic drugs. Autopsy findings confirm the complexity of the brain abnormalities encountered in TSC patients and proved useful in clarifying certain aspects of the pathogenesis, epileptogenesis and pharmacoresistance of TSC lesions.

Pluriformity of inflammation in multiple sclerosis shown by ultra-small iron oxide particle enhancement.

Gadolinium-DTPA (Gd-DTPA) is routinely used as a marker for inflammation in MRI to visualize breakdown of the blood-brain barrier (BBB) in multiple sclerosis. Recent data suggest that ultra-small superparamagnetic particles of iron oxide (USPIO) can be used to visualize cellular infiltration, another aspect of inflammation. This project aimed to compare the novel USPIO particle SHU555C to the longitudinal pattern of Gd-DTPA enhancement in multiple sclerosis. Nineteen relapsing-remitting patients were screened monthly using Gd-enhanced MRI. In case of new enhancing lesions, USPIO were injected and 24 h later, MRI was performed and blood was collected to confirm USPIO loading of circulating monocytes. Lesion development was monitored by 3 monthly Gd-DTPA-enhanced scans and a final scan 7-11 months after injection. USPIO-enhancement was observed as hyperintensity on T1-weighted images, whereas no signal changes were observed on T2-weighted-gradient-echo images. In 14 patients with disease activity, 188 USPIO-positive lesions were seen, 144 of which were Gd-negative. By contrast, there were a total of 59 Gd-positive lesions, 15 of which were USPIO negative. Three patterns of USPIO-enhancement were seen: (i) focal enhancement; (ii) ring-like enhancement and (iii) return to isointensity of a previously hypointense lesion. The latter pattern was most frequently observed for lesions that turned out to be transiently hypointense on follow-up scans, and ring-enhancing lesions were less likely to evolve into black holes at follow-up than lesions without ring-like USPIO-enhancement; we speculate this to be associated with repair. In 4% of the USPIO-positive/Gd negative lesions, USPIO-enhancement preceded Gd-enhancement by 1 month. USPIO-enhancement remained visible for up to 3 months in 1.5% of all USPIO-positive lesions. In 29% of the lesions enhancing with both contrast agents, USPIO-enhancement persisted whereas Gd-enhancement had already resolved. In conclusion, the new nano-particle SHU555C provides complementary information to Gd-enhanced MRI, probably related to monocyte infiltration. The use of USPIO-enhanced MRI is likely to lead to more insight in the pluriformity of inflammation in multiple sclerosis.