Sex Differences in White Matter Microstructure in the Human Brain Predominantly Reflect Differences in Sex Hormone Exposure.

Sex differences have been described regarding several aspects of human brain morphology; however, the exact biological mechanisms underlying these differences remain unclear in humans. Women with the complete androgen insensitivity syndrome (CAIS), who lack androgen action in the presence of a 46,XY karyotype, offer the unique opportunity to study isolated effects of sex hormones and sex chromosomes on human neural sexual differentiation. In the present study, we used diffusion tensor imaging to investigate white matter (WM) microstructure in 46,XY women with CAIS (n = 20), 46,XY comparison men (n = 30), and 46,XX comparison women (n = 30). Widespread sex differences in fractional anisotropy (FA), with higher FA in comparison men than in comparison women, were observed. Women with CAIS showed female-typical FA throughout extended WM regions, predominantly due to female-typical radial diffusivity. These findings indicate a predominant role of sex hormones in the sexual differentiation of WM microstructure, although sex chromosome genes and/or masculinizing androgen effects not mediated by the androgen receptor might also play a role.

Perivascular spaces in MS patients at 7 Tesla MRI: a marker of neurodegeneration?

BACKGROUND: Virchow-Robin spaces (VRS) are associated with vascular and neurodegenerative disease. In multiple sclerosis (MS), VRS have been associated with neuroinflammation. Ultra-high field imaging may be used to gain insight in these contradictory findings. OBJECTIVE: The objective of this paper is to analyze VRS in MS patients using high-resolution 7 Tesla (T) MRI. Additionally, we investigated whether the widening of VRS is related to inflammatory or neurodegenerative aspects of MS. METHODS: Thirty-four MS patients and 11 healthy controls were examined at 7T. Number and size of VRS were measured on three-dimensional (3D) T1-weighted images, and 3D fluid-attenuated inversion recovery (FLAIR) images were used for MS lesion detection. Brain atrophy was quantified by computing supratentorial brain volume fraction (sBVF). VRS counts were correlated with clinical variables, lesion count and sBVF. RESULTS: MS patients displayed more VRS (median 11) than healthy controls (median four), p = 0.001. VRS size did not differ between both groups. VRS count in MS patients was associated with sBVF (rho = -0.40, p = 0.02), but not with lesion count (p = 0.22). CONCLUSIONS: The 7T MRI reveals increased numbers of VRS in MS. The finding that VRS are associated with supratentorial brain atrophy, but not with lesion count, suggests that VRS might rather serve as a neurodegenerative than an inflammatory marker in MS.

Multimodal MRI study on the relation between WM integrity and connected GM atrophy and its effect on disability in early multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is characterized by pathology in white matter (WM) and atrophy of grey matter (GM), but it remains unclear how these processes are related, or how they influence clinical progression. OBJECTIVE: To study the spatial and temporal relationship between GM atrophy and damage in connected WM in relapsing-remitting (RR) MS in relation to clinical progression. METHODS: Healthy control (HC) and early RRMS subjects visited our center twice with a 1-year interval for MRI and clinical examinations, including the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores. RRMS subjects were categorized as MSFC decliners or non-decliners based on ΔMSFC over time. Ten deep (D)GM and 62 cortical (C) GM structures were segmented and probabilistic tractography was performed to identify the connected WM. WM integrity was determined per tract with, amongst others, fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI), and myelin water fraction (MWF). Linear mixed models (LMMs) were used to investigate GM and WM differences between HC and RRMS, and between MSFC decliners and non-decliners. LMM was also used to test associations between baseline WM z-scores and changes in connected GM z-scores, and between baseline GM z-scores and changes in connected WM z-scores, in HC/RRMS subjects and in MSFC decliners/non-decliners. RESULTS: We included 13 HCs and 31 RRMS subjects with an average disease duration of 3.5 years and a median EDSS of 3.0. Fifteen RRMS subjects showed declining MSFC scores over time, and they showed higher atrophy rates and greater WM integrity loss compared to non-decliners. Lower baseline WM integrity was associated with increased CGM atrophy over time in RRMS, but not in HC subjects. This effect was only seen in MSFC decliners, especially when an extended WM z-score was used, which included FA, MD, NDI and MWF. Baseline GM measures were not significantly related to WM integrity changes over time in any of the groups. DISCUSSION: Lower baseline WM integrity was related to more cortical atrophy in RRMS subjects that showed clinical progression over a 1-year follow-up, while baseline GM did not affect WM integrity changes over time. WM damage, therefore, seems to drive atrophy more than conversely.

Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: a randomised controlled trial.

AIM/HYPOTHESIS: To assess whether low-dose glucocorticoid treatment induces adverse metabolic effects, as is evident for high glucocorticoid doses. METHODS: In a randomised placebo-controlled double-blind (participants and the investigators who performed the studies and assessed the outcomes were blinded) dose-response intervention study, 32 healthy men (age 22 ± 3 years; BMI 22.4 ± 1.7 kg/m(2)) were allocated to prednisolone 7.5 mg once daily (n = 12), prednisolone 30 mg once daily (n = 12), or placebo (n = 8) for 2 weeks using block randomisation. Main outcome measures were glucose, lipid and protein metabolism, measured by stable isotopes, before and at 2 weeks of treatment, in the fasted state and during a two-step hyperinsulinaemic clamp conducted in the Clinical Research Unit of the Academic Medical Centre, Amsterdam, the Netherlands RESULTS: Prednisolone, compared with placebo, dose dependently and significantly increased fasting plasma glucose levels, whereas only prednisolone 30 mg increased fasting insulin levels (29 ± 15 pmol/l). Prednisolone 7.5 mg and prednisolone 30 mg decreased the ability of insulin to suppress endogenous glucose production (by 17 ± 6% and 46 ± 7%, respectively, vs placebo). Peripheral glucose uptake was not reduced by prednisolone 7.5 mg, but was decreased by prednisolone 30 mg by 34 ± 6% (p < 0.0001). Compared with placebo, prednisolone treatment tended to decrease lipolysis in the fasted state (p = 0.062), but both prednisolone 7.5 mg and prednisolone 30 mg decreased insulin-mediated suppression of lipolysis by 11 ± 5% and 34 ± 6%, respectively. Finally, prednisolone treatment increased whole-body proteolysis during hyperinsulinaemia, which tended to be driven by prednisolone 30 mg (5 ± 2%; p = 0.06). No side effects were reported by the study participants. All participants completed the study and were analysed. CONCLUSIONS/INTERPRETATION: Not only at high doses but also at low doses, glucocorticoid therapy impaired intermediary metabolism by interfering with the metabolic actions of insulin on liver and adipose tissue. These data indicate that even low-dose glucocorticoids may impair glucose tolerance when administered chronically. TRIAL REGISTRATION: ISRCTN83991850.

Clinical features and X-inactivation in females heterozygous for creatine transporter defect.

The creatine transporter defect is an X-linked cause of mental retardation. We investigated the clinical features and pattern of X-inactivation in a Dutch cohort of eight female heterozygotes. We show that symptoms of the creatine transporter defect (mental retardation, learning difficulties, and constipation) can be present in female heterozygotes. We further show that the diagnosis in females is not straightforward: (i) The creatine/creatinine ratio in urine was elevated only in three of eight females. (ii) Although as a group the females had a significantly decreased cerebral creatine concentration, individual females had creatine concentrations overlapping with normal controls. (iii) Skewed X-inactivation was found in the cultured fibroblasts, in favour of either the mutated or the wild-type allele, leading to either deficient or normal results in the creatine uptake studies in fibroblasts. Thus, screening by these tests is unreliable for the diagnosis. In addition, we found no consistent skewing of the X-inactivation in peripheral tissues indicating that there is no selection against the creatine transporter defect. We conclude that testing for creatine transporter defect should be considered in females with (mild) mental retardation. Screening by DNA analysis of the SLC6A8 gene is recommended.

Regional DTI differences in multiple sclerosis patients.

Diffusion tensor imaging (DTI) measures have shown to be sensitive to white matter (WM) damage in multiple sclerosis (MS), not only inside focal lesions but also in user-defined regions in the so-called normal-appearing white matter (NAWM). New analysis techniques for DTI measures are now available that allow for hypothesis-free localization of damage. We performed DTI measurements of 30 MS patients selected for low focal lesion loads, and of 31 age-matched healthy controls and analyzed these using tract-based spatial statistics (TBSS). Patients were found to have a lower fractional anisotropy (FA) compared to controls in a number of brain regions, including the fornices, the left corona radiata, the inferior longitudinal fasciculus in both hemispheres, both optic radiations, and parts of the corpus callosum. In the regions of reduced FA, an increase in radial diffusivity and a less pronounced increase of axial diffusivity were found. Neurocognitive assessment showed that patients had normal visuospatial memory performance, just-normal attention, and impaired processing speed; the latter was associated with abnormal FA in the corpus callosum, an area which was relatively devoid of lesions visible on proton density-weighted images in our patients. TBSS can be useful in future studies with other MS patient samples to provide an unbiased localization of damage and generate location-specific hypotheses.

Oculodentodigital Dysplasia: A Hypomyelinating Leukodystrophy with a Characteristic MRI Pattern of Brain Stem Involvement.

Oculodentodigital dysplasia, a rare genetic disorder caused by mutations in the gene encoding gap junction protein 1, classically presents with typical facial features, dental and ocular anomalies, and syndactyly. Oligosymptomatic patients are common and difficult to recognize, in particular if syndactyly is absent. Neurologic manifestation occurs in approximately 30% of patients, and leukodystrophy or T2 hypointensity of gray matter structures or both have been noted in individual patients. To investigate MR imaging changes in oculodentodigital dysplasia, we retrospectively and systematically reviewed 12 MRIs from 6 genetically confirmed patients. Diffuse supratentorial hypomyelination, T2-hypointense Rolandic and primary visual cortex, and symmetric involvement of middle cerebellar peduncle, pyramidal tract, and medial lemniscus was present in all, T2-hypointense pallidum and dentate nucleus in 2 patients each. This consistent, characteristic pattern of diffuse supratentorial hypomyelination and brain stem involvement differs from other hypomyelinating and nonhypomyelinating leukodystrophies with brain stem involvement, and its recognition should trigger genetic testing for oculodentodigital dysplasia.

Comparing lesion segmentation methods in multiple sclerosis: Input from one manually delineated subject is sufficient for accurate lesion segmentation.

PURPOSE: Accurate lesion segmentation is important for measurements of lesion load and atrophy in subjects with multiple sclerosis (MS). International MS lesion challenges show a preference of convolutional neural networks (CNN) strategies, such as nicMSlesions. However, since the software is trained on fairly homogenous training data, we aimed to test the performance of nicMSlesions in an independent dataset with manual and other automatic lesion segmentations to determine whether this method is suitable for larger, multi-center studies. METHODS: Manual lesion segmentation was performed in fourteen subjects with MS on sagittal 3D FLAIR images from a 3T GE whole-body scanner with 8-channel head coil. We compared five different categories of automated lesion segmentation methods for their volumetric and spatial agreement with manual segmentation: (i) unsupervised, untrained (LesionTOADS); (ii) supervised, untrained (LST-LPA and nicMSlesions with default settings); (iii) supervised, untrained with threshold adjustment (LST-LPA optimized for current data); (iv) supervised, trained with leave-one-out cross-validation on fourteen subjects with MS (nicMSlesions and BIANCA); and (v) supervised, trained on a single subject with MS (nicMSlesions). Volumetric accuracy was determined by the intra-class correlation coefficient (ICC) and spatial accuracy by Dice's similarity index (SI). Volumes and SI were compared between methods using repeated measures ANOVA or Friedman tests with post-hoc pairwise comparison. RESULTS: The best volumetric and spatial agreement with manual was obtained with the supervised and trained methods nicMSlesions and BIANCA (ICC absolute agreement > 0.968 and median SI > 0.643) and the worst with the unsupervised, untrained method LesionTOADS (ICC absolute agreement = 0.140 and median SI = 0.444). Agreement with manual in the single-subject network training of nicMSlesions was poor for input with low lesion volumes (i.e. two subjects with lesion volumes ≤ 3.0 ml). For the other twelve subjects, ICC varied from 0.593 to 0.973 and median SI varied from 0.535 to 0.606. In all cases, the single-subject trained nicMSlesions segmentations outperformed LesionTOADS, and in almost all cases it also outperformed LST-LPA. CONCLUSION: Input from only one subject to re-train the deep learning CNN nicMSlesions is sufficient for adequate lesion segmentation, with on average higher volumetric and spatial agreement with manual than obtained with the untrained methods LesionTOADS and LST-LPA.

Validation of mean upper cervical cord area (MUCCA) measurement techniques in multiple sclerosis (MS): High reproducibility and robustness to lesions, but large software and scanner effects.

INTRODUCTION: Atrophy of the spinal cord is known to occur in multiple sclerosis (MS). The mean upper cervical cord area (MUCCA) can be used to measure this atrophy. Currently, several (semi-)automated methods for MUCCA measurement exist, but validation in clinical magnetic resonance (MR) images is lacking. METHODS: Five methods to measure MUCCA (SCT-PropSeg, SCT-DeepSeg, NeuroQLab, Xinapse JIM and ITK-SNAP) were investigated in a predefined upper cervical cord region. First, within-scanner reproducibility and between-scanner robustness were assessed using intra-class correlation coefficient (ICC) and Dice's similarity index (SI) in scan-rescan 3DT1-weighted images (brain, including cervical spine using a head coil) performed on three 3 T MR machines (GE MR750, Philips Ingenuity, Toshiba Vantage Titan) in 21 subjects with MS and 6 healthy controls (dataset A). Second, sensitivity of MUCCA measurement to lesions in the upper cervical cord was assessed with cervical 3D T1-weighted images (3 T GE HDxT using a head-neck-spine coil) in 7 subjects with MS without and 14 subjects with MS with cervical lesions (dataset B), using ICC and SI with manual reference segmentations. RESULTS: In dataset A, MUCCA differed between MR machines (p < 0.001) and methods (p < 0.001) used, but not between scan sessions. With respect to MUCCA values, Xinapse JIM showed the highest within-scanner reproducibility (ICC absolute agreement = 0.995) while Xinapse JIM and SCT-PropSeg showed the highest between-scanner robustness (ICC consistency = 0.981 and 0.976, respectively). Reproducibility of segmentations between scan sessions was highest in Xinapse JIM and SCT-PropSeg segmentations (median SI ≥ 0.921), with a significant main effect of method (p < 0.001), but not of MR machine or subject group. In dataset B, SI with manual outlines did not differ between patients with or without cervical lesions for any of the segmentation methods (p > 0.176). However, there was an effect of method for both volumetric and voxel wise agreement of the segmentations (both p < 0.001). Highest volumetric and voxel wise agreement was obtained with Xinapse JIM (ICC absolute agreement = 0.940 and median SI = 0.962). CONCLUSION: Although MUCCA is highly reproducible within a scanner for each individual measurement method, MUCCA differs between scanners and between methods. Cervical cord lesions do not affect MUCCA measurement performance.

A study of the brain's resting state based on alpha band power, heart rate and fMRI.

Considering that there are several theoretical reasons why fMRI data is correlated to variations in heart rate, these correlations are explored using experimental resting state data. In particular, the possibility is discussed that the "default network", being a brain area that deactivates during non-specific general tasks, is a hemodynamic effect caused by heart rate variations. Of fifteen healthy controls ECG, EEG and fMRI were co-registered. Slice time dependent heart rate regressors were derived from the ECG data and correlated to fMRI using a linear correlation analysis where the impulse response is estimated from the data. It was found that in most subjects substantial correlations between heart rate variations and fMRI exist, both within the brain and at the ventricles. The brain areas with high correlation to heart rate are different from the "default network" and the response functions deviate from the canonical hemodynamic response function. Furthermore, a general negative correlation was found between heart beat intervals (reverse of heart rate) and alpha power. We interpret this finding by assuming that subject's state varies between drowsiness and wakefulness. Finally, given this large correlation, we re-examined the contribution of heart rate variations to earlier reported fMRI/alpha band correlations, by adding heart rate regressors as confounders. It was found that inclusion of these confounders most often had a negligible effect. From its strong correlation to alpha power, we conclude that the heart rate variations contain important physiological information about subject's resting state. However, it does not provide a full explanation of the behaviour of the "default network". Its application as confounder in fMRI experiments is a relatively small computational effort, but may have a substantial impact in paradigms where heart rate is controlled by the stimulus.

Artifact removal in co-registered EEG/fMRI by selective average subtraction.

OBJECTIVE: Co-registration of EEG (electroencephalogram) and fMRI (functional magnetic resonance imaging) remains a challenge due to the large artifacts induced on the EEG by the MR (magnetic resonance) sequence magnetic fields. Thus, we present an algorithm, based on the average-subtraction method, which is able to correct EEG data for gradient and pulse artifacts. METHODS: MR sequence timing parameters are estimated from the EEG data and both slice and volume artifact templates are subtracted from the data. A clustering algorithm is proposed to account for the variability of the pulse artifact. RESULTS: The algorithm is able to keep the spontaneous EEG as well as visual evoked potentials (VEPs), while removing gradient and pulse artifacts with only a subtraction of selectively averaged data. In the frequency domain, the artifact frequencies are strongly attenuated. Estimated MR sequence time parameters showed that the correction is extremely sensitive to the slice time value. Pulse artifact clustering showed that most of the variability is due to the time jitter of the pulse artifact markers. CONCLUSIONS: Selective subtraction of averages in combination with proper time alignment is enough to remove most of the MR-induced artifacts. SIGNIFICANCE: Clean EEG can be obtained from raw signals that are corrupted by MR-induced artifacts during simultaneous EEG-fMRI scanning without using dedicated hardware to synchronize EEG and fMRI clocks.

Has the degree of contrast enhancement with MR imaging in laryngeal carcinoma added value to anatomic parameters regarding prediction of response to radiation therapy?

BACKGROUND AND PURPOSE: Our aim was to retrospectively investigate the prognostic significance of the degree of contrast enhancement in tumors and its additional value in previously considered MR imaging parameters with regard to local control of laryngeal cancer treated with radiation therapy (RT) alone. MATERIALS AND METHODS: Pretreatment MR images of 64 consecutive patients (54 men and 10 women, 43-80 years of age) with supraglottic and glottic cancer were retrospectively reviewed on clinical and previously considered MR imaging parameters such as tumor involvement of specific laryngeal anatomic subsites, including laryngeal cartilages, tumor volume, extralaryngeal tumor spread, and, in addition, the degree of contrast enhancement. Clinical and MR imaging parameters were associated with regard to local control at 2 years by using the Cox regression model. "Local control" was defined as absence of primary tumor recurrence. RESULTS: When using a threshold of the mean average contrast enhancement of 77%, the 2-year local control rate in the groups of patients with a degree of enhancement below and above this threshold was 57% and 70%, respectively (P=.3). Enhancement of tumor tissue in pre-epiglottic space (PES) was low, most probably due to its adipose tissue and poor vascular content, whereas tumor tissue involving paraglottic space (PGS) did enhance. Results of multivariate analysis indicated that the degree of contrast enhancement yielded the prognostic information (P=.07) with 2 independent prognostic factors: primary tumor volume (P=.007) and subglottic extension (P=.002) with regard to local control. Using these previously mentioned 3 MR imaging parameters as potential risk factors, we defined 4 categories, resulting in the following local control rates respectively: 90% for the group without risk factors, 73% for the group with 1, 60% for the group with 2, and finally 0% for the group with 3 risk factors, which was significantly lower than the rates in previous risk groups (P < .001). CONCLUSION: PES has a lower degree of contrast enhancement than the PGS and may correlate with the worse outcome. Including a low degree of contrast enhancement as a parameter to primary tumor volume and subglottic extension may increase the predictive value of MR imaging for local outcome and may be helpful to identify a subset of patients whose tumors all recurred locally within 2 years after primary RT.

Diagnostic Accuracy of Neuroimaging to Delineate Diffuse Gliomas within the Brain: A Meta-Analysis.

BACKGROUND: Brain imaging in diffuse glioma is used for diagnosis, treatment planning, and follow-up. PURPOSE: In this meta-analysis, we address the diagnostic accuracy of imaging to delineate diffuse glioma. DATA SOURCES: We systematically searched studies of adults with diffuse gliomas and correlation of imaging with histopathology. STUDY SELECTION: Study inclusion was based on quality criteria. Individual patient data were used, if available. DATA ANALYSIS: A hierarchic summary receiver operating characteristic method was applied. Low- and high-grade gliomas were analyzed in subgroups. DATA SYNTHESIS: Sixty-one studies described 3532 samples in 1309 patients. The mean Standard for Reporting of Diagnostic Accuracy score (13/25) indicated suboptimal reporting quality. For diffuse gliomas as a whole, the diagnostic accuracy was best with T2-weighted imaging, measured as area under the curve, false-positive rate, true-positive rate, and diagnostic odds ratio of 95.6%, 3.3%, 82%, and 152. For low-grade gliomas, the diagnostic accuracy of T2-weighted imaging as a reference was 89.0%, 0.4%, 44.7%, and 205; and for high-grade gliomas, with T1-weighted gadolinium-enhanced MR imaging as a reference, it was 80.7%, 16.8%, 73.3%, and 14.8. In high-grade gliomas, MR spectroscopy (85.7%, 35.0%, 85.7%, and 12.4) and 11C methionine-PET (85.1%, 38.7%, 93.7%, and 26.6) performed better than the reference imaging. LIMITATIONS: True-negative samples were underrepresented in these data, so false-positive rates are probably less reliable than true-positive rates. Multimodality imaging data were unavailable. CONCLUSIONS: The diagnostic accuracy of commonly used imaging is better for delineation of low-grade gliomas than high-grade gliomas on the basis of limited evidence. Improvement is indicated from advanced techniques, such as MR spectroscopy and PET.

Voxel-based analysis of quantitative T1 maps demonstrates that multiple sclerosis acts throughout the normal-appearing white matter.

BACKGROUND AND PURPOSE: Disease activity in normal-appearing white matter (NAWM) in multiple sclerosis (MS) has been demonstrated in vivo with T1 relaxation time measurements. We aimed to investigate the spatial distribution of T1 increases in MS NAWM without a priori selection of specific regions. METHODS: Whole-brain quantitative T1 maps were measured in 67 patients with one of the 3 main clinical types of MS (13 primary progressive [PP], 36 relapsing-remitting [RR], and 18 secondary progressive [SP]) and in 23 healthy control subjects. After registration to standard space and segmentation of NAWM, the maps were analyzed by using voxel-based analyses with a cluster-based corrected P threshold of .05. RESULTS: Group mean T1 relaxation times throughout NAWM increased when going from control subjects to PP to RR to SP MS. In the RR and SP MS groups, the T1 increases compared with control subjects were significant throughout the NAWM, without apparent preference for specific brain regions. In RR MS, 16% of NAWM voxels displayed a significant increase in T1 compared with control subjects, and in SP, this fraction was 49%. The comparison between RR MS and the subsequent phase SP MS revealed that, in these patients, disease progression occurs throughout the NAWM. In patients with PP MS, the spatial extent of significant T1 increases is limited. There were no correlations with clinical disability scales or brain volume in a substantial fraction of voxels. CONCLUSION: This study demonstrates that in patients with RR MS and SP MS, NAWM disease processes have no regional preferences but can occur throughout the brain.

Normal-appearing white matter changes vary with distance to lesions in multiple sclerosis.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) disease processes in normal-appearing white matter (NAWM) may be different close to MR-visible lesions than farther from these lesions. We aimed to investigate the relationship of NAWM changes to the distance to the lesions. METHODS: We measured B(1)-corrected T1 and magnetization transfer ratio (MTR) maps in 63 patients with MS (11 primary progressive, 34 relapsing-remitting, 18 secondary progressive). We used histogram analyses to assess the global properties of lesions, of 4 consecutive 1-mm pixel layers of NAWM around the lesions, and of distant NAWM located at least 4-mm from lesions in all directions. In 22 healthy controls, we measured white matter MTR and T1 histograms. Histogram parameters were statistically analyzed by using a linear mixed model. RESULTS: The first and second NAWM pixel layers around the lesions had a significantly lower MTR histogram peak position than distant NAWM, whereas T1 histogram peak position was similar between all types of NAWM. Furthermore, MTR histograms of distant NAWM were statistically indistinguishable from those of control white matter, whereas T1 histograms of distant NAWM had significantly decreased peak height for relapsing-remitting MS and secondary progressive MS and significantly increased peak position for secondary progressive MS. CONCLUSION: Our results may suggest that axonal damage and demyelination in NAWM mainly arise as a secondary result of visible lesions, with the largest effect close to these lesions. NAWM disease farther from the lesions may be mainly characterized by subtle blood-brain barrier damage, with leakage of fibrinogen into the parenchyma and microplaque formation, processes that are detected with T1 but not with MTR.

White Matter Diffusion Changes during the First Year of Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND PURPOSE: Natalizumab treatment strongly affects relapsing-remitting multiple sclerosis, possibly by restraining white matter damage. This study investigated changes in white matter diffusivity in patients with relapsing-remitting multiple sclerosis during their first year of natalizumab treatment by using diffusion tensor imaging. MATERIALS AND METHODS: The study included patients with relapsing-remitting multiple sclerosis initiating natalizumab at baseline (n = 22), patients with relapsing-remitting multiple sclerosis continuing interferon-ß or glatiramer acetate (n = 17), and healthy controls (n = 12). Diffusion tensor imaging parameters were analyzed at baseline and month 12. We measured the extent and severity of white matter damage with diffusion tensor imaging parameters such as fractional anisotropy, comparing the patient groups with healthy controls at both time points. RESULTS: The extent and severity of white matter damage were reduced significantly in the natalizumab group with time (fractional anisotropy-based extent, 56.8% to 47.2%; severity, z = -0.67 to -0.59; P = .02); this reduction was not observed in the interferon-ß/glatiramer acetate group (extent, 41.4% to 39.1%, and severity, z = -0.64 to -0.67; P = .94). Cognitive performance did not change with time in the patient groups but did correlate with the severity of damage (r = 0.53, P = < .001). CONCLUSIONS: In patients with relapsing-remitting multiple sclerosis starting natalizumab treatment, the extent and severity of white matter damage were reduced significantly in the first year of treatment. These findings may aid in explaining the large observed clinical effect of natalizumab in relapsing-remitting multiple sclerosis.

Diffusion-weighted imaging of the head and neck in healthy subjects: reproducibility of ADC values in different MRI systems and repeat sessions.

BACKGROUND AND PURPOSE: DWI is typically performed with EPI sequences in single-center studies. The purpose of this study was to determine the reproducibility of ADC values in the head and neck region in healthy subjects. In addition, the reproducibility of ADC values in different tissues was assessed to identify the most suitable reference tissue. MATERIALS AND METHODS: We prospectively studied 7 healthy subjects, with EPI and TSE sequences, on 5 MR imaging systems at 3 time points in 2 institutions. ADC maps of EPI (with 2 b-values and 6 b-values) and TSE sequences were compared. Mean ADC values for different tissues (submandibular gland, sternocleidomastoid muscle, spinal cord, subdigastric lymph node, and tonsil) were used to evaluate intra- and intersubject, intersystem, and intersequence variability by using a linear mixed model. RESULTS: On 97% of images, a region of interest could be placed on the spinal cord, compared with 87% in the tonsil. ADC values derived from EPI-DWI with 2 b-values and calculated EPI-DWI with 2 b-values extracted from EPI-DWI with 6 b-values did not differ significantly. The standard error of ADC measurement was the smallest for the tonsil and spinal cord (standard error of measurement = 151.2 × 10(-6) mm/s(2) and 190.1 × 10(-6) mm/s(2), respectively). The intersystem difference for mean ADC values and the influence of the MR imaging system on ADC values among the subjects were statistically significant (P < .001). The mean difference among examinations was negligible (ie, <10 × 10(-6) mm/s(2)). CONCLUSIONS: In this study, the spinal cord was the most appropriate reference tissue and EPI-DWI with 6 b-values was the most reproducible sequence. ADC values were more precise if subjects were measured on the same MR imaging system and with the same sequence. ADC values differed significantly between MR imaging systems and sequences.

Enhanced axonal metabolism during early natalizumab treatment in relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: The considerable clinical effect of natalizumab in patients with relapsing-remitting multiple sclerosis might be explained by its possible beneficial effect on axonal functioning. In this longitudinal study, the effect of natalizumab on absolute concentrations of total N-acetylaspartate, a marker for neuronal integrity, and other brain metabolites is investigated in patients with relapsing-remitting multiple sclerosis by using MR spectroscopic imaging. MATERIALS AND METHODS: In this explorative observational study, 25 patients with relapsing-remitting multiple sclerosis initiating natalizumab treatment were included and scanned every 6 months for 18 months. Additionally 18 matched patients with relapsing-remitting multiple sclerosis continuing treatment with interferon-ß or glatiramer acetate were included along with 12 healthy controls. Imaging included short TE 2D-MR spectroscopic imaging with absolute metabolite quantification of total N-acetylaspartate, creatine and phosphocreatine, choline-containing compounds, myo-inositol, and glutamate. Concentrations were determined for lesional white matter, normal-appearing white matter, and gray matter. RESULTS: At baseline in both patient groups, lower concentrations of total N-acetylaspartate and creatine and phosphocreatine were found in lesional white matter compared with normal-appearing white matter and additionally lower glutamate in lesional white matter of patients receiving natalizumab. In those patients, a significant yearly metabolite increase was found for lesional white matter total N-acetylaspartate (7%, P < .001), creatine and phosphocreatine (6%, P = .042), and glutamate (10%, P = .028), while lesion volumes did not change. In patients receiving interferon-ß/glatiramer acetate, no significant change was measured in lesional white matter for any metabolite, while whole-brain normalized lesion volumes increased. CONCLUSIONS: Patients treated with natalizumab showed an increase in total N-acetylaspartate, creatine and phosphocreatine, and glutamate in lesional white matter. These increasing metabolite concentrations might be a sign of enhanced axonal metabolism.

Multicontrast MR imaging at 7T in multiple sclerosis: highest lesion detection in cortical gray matter with 3D-FLAIR.

BACKGROUND AND PURPOSE: 7T MR imaging has led to improved detection and classification of cortical MS lesions, mainly based on T2*-weighted gradient-echo sequences. Depiction of cortical GM by using the recommended MS imaging protocol has not yet been investigated at 7T. We aimed to investigate prospectively which recommended sequence for clinical use has the highest value at 7T, in terms of GM and WM lesion detection. MATERIALS AND METHODS: Thirty-seven patients with MS (mean age, 43.8 years; 25 women) and 7 healthy controls (mean age, 40.4 years; 5 women) underwent multicontrast 7T MR imaging including the recommended clinical 2D-T2WI, 3D-T1WI, 3D-FLAIR, and GM-specific 3D-DIR. Lesions were scored and categorized anatomically by 3 raters, in consensus. The value of sequences was evaluated lesion-wise and patient-wise (Wilcoxon signed-rank test). RESULTS: At 7T, 3D-FLAIR detected the highest number of total cortical GM lesions (217), 89% more than 3D-DIR and 87% and 224% more than 2D-T2WI and 3D-T1WI. Patient-wise analysis showed that this difference between 3D-FLAIR and 3D-DIR was statistically significant (P<.04), and most pronounced for the number of mixed lesions (P<.03). 3D-FLAIR also detected the highest number of total WM lesions (2605), but the difference with 3D-DIR and 3D-T1WI was not significant. CONCLUSIONS: When using recommended clinical sequences at 7T, the best way to detect cortical GM lesions is with 3D-FLAIR and not by GM-specific 3D-DIR or by conventional 2D-T2WI and 3D-T1WI sequences.