Search

Background and Objectives: Accumulating evidence points to worse clinical outcomes among adults with multiple sclerosis (MS) belonging to minority or poverty-affected groups. By contrast, little is known about the outcomes of these populations with pediatric-onset MS (POMS). Individuals with POMS represent 5% of the MS population and are more racially diverse yet have been understudied regarding socioeconomic environment or characteristics. In this study, we investigated the association between childhood social determinants of health (SDOH) and brain MRI outcomes in patients with POMS., Methods: This is a retrospective single-site cohort study of patients with POMS with brain MRI quantitatively analyzed using icobrain software to yield total white matter lesion, black hole, whole brain, white matter, and gray matter volumes. All patients with POMS evaluated at New York University Langone MS Center and who underwent high-quality volumetric MRI scans were included in this study. SDOH indicators of race, ethnicity, health insurance type, parental education, and childhood neighborhood social vulnerability index (SVI) were examined for association with MRI outcomes using linear least absolute shrinkage selection operator penalized regression modeling. Disease-modifying therapy (DMT) timing and DMT efficacy were compared for each SDOH category., Results: A total of 138 patients with POMS (70% female) were included with a mean age of 19.86 years and median disease duration of 4 years at time of scan. Public health insurance, Black race, Hispanic ethnicity, low parental education, and high SVI (greater neighborhood disadvantage) were each associated with white matter lesion and black hole volume. SVI was the strongest individual predictor of total white matter lesion (β = 4.63, p = 0.002) and black hole volume (β = 2.91, p = 0.003). In models incorporating all SDOH variables, public health insurance was the strongest predictor of total lesion (β = 2.48, p = 0.01) and black hole volume (β = 1.50, p = 0.02), attenuating the effect of SVI (β = 1.66, p = 0.33 and β = 1.00, p = 0.39). There were no differences in DMT timing or efficacy between categories of social disadvantage., Discussion: Individual-level and neighborhood-level indicators of social disadvantage are associated with worse brain MRI outcomes in POMS. Further investigation of race, ethnicity, and childhood disadvantage as risk factors of MS susceptibility and severity is needed to reduce MS health disparities.

Automated quantification of brain tissues on MR images has greatly contributed to the diagnosis and follow-up of neurological pathologies across various life stages. However, existing solutions are specifically designed for certain age ranges, limiting their applicability in monitoring brain development from infancy to late adulthood. This retrospective study aims to develop and validate a brain segmentation model across pediatric and adult populations. First, we trained a deep learning model to segment tissues and brain structures using T1-weighted MR images from 390 patients (age range: 2-81 years) across four different datasets. Subsequently, the model was validated on a cohort of 280 patients from six distinct test datasets (age range: 4-90 years). In the initial experiment, the proposed deep learning-based pipeline, icobrain-dl, demonstrated segmentation accuracy comparable to both pediatric and adult-specific models across diverse age groups. Subsequently, we evaluated intra- and inter-scanner variability in measurements of various tissues and structures in both pediatric and adult populations computed by icobrain-dl. Results demonstrated significantly higher reproducibility compared to similar brain quantification tools, including childmetrix, FastSurfer, and the medical device icobrain v5.9 (p-value< 0.01). Finally, we explored the potential clinical applications of icobrain-dl measurements in diagnosing pediatric patients with Cerebral Visual Impairment and adult patients with Alzheimer's Disease., (© 2024. The Author(s).)

Background: The connectome, constituting a unique fingerprint of a person's brain, may be influenced by its prenatal environment, potentially affecting later-life resilience and mental health., Methods: We conducted a prospective resting-state functional Magnetic Resonance Imaging study in 28-year-old offspring (N = 49) of mothers whose anxiety was monitored during pregnancy. Two offspring anxiety subgroups were defined: "High anxiety" (n = 13) group versus "low-to-medium anxiety" (n = 36) group, based on maternal self-reported state anxiety at 12-22 weeks of gestation. To predict resting-state functional connectivity of 32 by 32 ROIs, maternal state anxiety during pregnancy was included as a predictor in general linear models for both ROI-to-ROI and graph theoretical metrics. Sex, birth weight and postnatal anxiety were included as covariates., Results: Higher maternal anxiety was associated with weaker functional connectivity of medial prefrontal cortex with left inferior frontal gyrus (t = 3.45, p FDR < 0.05). Moreover, network-based statistics (NBS) confirmed our finding and revealed an additional association of weaker connectivity between left lateral prefontal cortex with left somatosensory motor gyrus in the offspring. While our results showed a general pattern of lower functional connectivity in adults prenatally exposed to maternal anxiety, we did not observe significant differences in global brain networks between groups., Conclusions: Weaker (medial) prefrontal cortex functional connectivity in the high anxiety adult offspring group suggests a long-term negative impact of prenatal exposure to high maternal anxiety, extending into adulthood. To prevent mental health problems at population level, universal primary prevention strategies should aim at lowering maternal anxiety during pregnancy., (© 2023. The Author(s).)

Background: We evaluated imaging features suggestive of neurodegeneration within the brainstem and upper cervical spinal cord (UCSC) in non-progressive multiple sclerosis (MS)., Methods: Standardized 3-Tesla three-dimensional brain magnetic resonance imaging (MRI) studies were prospectively acquired. Rates of change in volume, surface texture, curvature were quantified at the pons and medulla-UCSC. Whole and regional brain volumes and T2-weighted lesion volumes were also quantified. Independent regression models were constructed to evaluate differences between those of Black or African ancestry (B/AA) and European ancestry (EA) with non-progressive MS., Results: 209 people with MS (pwMS) having at least two MRI studies, 29% possessing 3-6 timepoints, resulted in 487 scans for analysis. Median follow-up time between MRI timepoints was 1.33 (25th-75th percentile: 0.51-1.98) years. Of 183 non-progressive pwMS, 88 and 95 self-reported being B/AA and EA, respectively. Non-progressive pwMS demonstrated greater rates of decline in pontine volume ( p  < 0.0001) in B/AA and in medulla-UCSC volume ( p  < 0.0001) for EA pwMS. Longitudinal surface texture and curvature changes suggesting reduced tissue integrity were observed at the ventral medulla-UCSC ( p  < 0.001), dorsal pons ( p  < 0.0001) and dorsal medulla ( p  < 0.0001) but not the ventral pons ( p  = 0.92) between groups., Conclusions: Selectively vulnerable regions within the brainstem-UCSC may allow for more personalized approaches to disease surveillance and management.

Background: Relatively little is known about how global and regional brain volumes changes in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) compare with Multiple Sclerosis (MS), Neuromyelitis optica spectrum disorder (NMOSD), and healthy controls (HC)., Objective: To compare global and regional brain volumes in MOGAD, MS, NMOSD, and HC cross-sectionally as well as longitudinally in a subset of patients., Methods: We retrospectively reviewed all adult MOGAD and NMOSD patients with brain MRI performed in stable remission and compared them with MS patients and HC. Volumetric parameters were assessed using the FDA-approved icobrain software. adjusted for age and sex., Results: Twenty-four MOGAD, 47 NMOSD, 40 MS patients, and 37 HC were included in the cross-sectional analyses. Relative to HC, the age-adjusted whole brain (WB) volume was significantly lower in patients with MOGAD (p=0.0002), NMOSD (p=0.042), and MS (p=0.01). Longitudinal analysis of a subset of 8 MOGAD, 22 NMOSD, and 34 MS patients showed a reduction in the WB and cortical gray matter (CGM) volumes over time in all three disease groups, without statistically significant differences between groups. The MOGAD group had a greater loss of thalamic volume compared to MS (p=0.028) and NMOSD (p=0.023) and a greater loss of hippocampal volumes compared to MS (p=0.007)., Conclusions: Age-adjusted WB volume loss was evident in all neuroinflammatory conditions relative to HC in cross-sectional comparisons. In longitudinal analyses, MOGAD patients had a higher thalamic atrophy rate relative to MS and NMOSD, and a higher hippocampal atrophy rate relative to MS. Larger studies are needed to validate these findings and to investigate their clinical implications., Competing Interests: Declaration of Competing Interest Itay Lotan – no conflict of interest related to the study. Thibo Billiet- an employee of icometrix. Annemie Ribbens- an employee of icometrix. Win Van Hecke- founder of icometrix. Benny Huang- no conflict of interest related to the study. Ilya Kister- Ilya Kister reports he served on advisory boards for Biogen, Genentech, and Horizon and received research support for investigator-initiated grants from Genentech, Sanofi Genzyme, Biogen, EMD Serono, National MS Society, and Guthy Jackson Charitable Foundation. He received royalties from Walters-Kluwer for 'Top 100 Diagnosis in Neurology'. Eyal Lotan- no conflict of interest related to the study., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Purpose: Diffusion tensor imaging (DTI) can detect microstructural changes of white matter in multiple sclerosis (MS) and might clarify mechanisms responsible for disability. Thus, we aimed to compare DTI metrics in relapsing-remitting MS patients (RRMS) with healthy controls (HCs), and explore the correlations between DTI metrics, total brain white matter (TBWM) and white matter lesion (WML) with clinical parameters compared to volumetric measures., Material and Methods: 37 RRMS patients and 19 age/sex-matched HCs were included. All participants had clinical assessments, structural and diffusion scans on a 3T MRI. Volumetric and white matter DTI metrics; fractional anisotropy (FA), mean, radial and axial diffusivities (MD, RD and AD) were estimated and correlated with clinical parameters. The mean group differences were calculated using t-tests, and univariate correlations with Pearson correlation coefficients., Results: Compared to HCs, statistically significant increases in MD (+3.6%), RD (+4.8%), AD (+2.7%) and a decrease in FA (-4.3%) for TBWM in RRMS was observed ( p < .01). MD and RD in TBWM and AD in WML correlated moderately with disability status. Volumetric segmentation indicated a decrease in the total brain volume, GM and WM(-5%) with a reciprocal increase in CSF(+26%) in RRMS( p < .01). Importantly, DTI parameters showed a medium correlation with cognitive domains in contrast to white matter-related volumetric measurements in RRMS(Pearson correlation, p < .05)., Conclusions: Our study shows a correlation of DTI metrics with clinical symptoms of MS, in particular cognition. More generally, these findings indicated that DTI is a useful and unique technique for evaluating the clinical features of white matter disease and warrants further investigation into its clinical role.

Competing Interests: Michiel Bronswijk has received grants from Prion Medical, Taewoong, and Takeda, and has consultancy agreements with Prion Medical and Taewoong. Diederik Persyn, Thomas Billiet, and Ruben Spitaels declare no conflicts of interest. Hannah van Malenstein has consultancy agreements with Boston Scientific. Schalk Van der Merwe holds the Cook and Boston-Scientific chair in interventional endoscopy and holds consultancy agreements with Cook, Pentax, and Olympus.

The free water elimination (FWE) model and its kurtosis variant (DKI-FWE) can separate tissue and free water signal contributions, thus providing tissue-specific diffusional information. However, a downside of these models is that the associated parameter estimation problem is ill-conditioned, necessitating the use of advanced estimation techniques that can potentially bias the parameter estimates. In this work, we propose the T 2 -DKI-FWE model that exploits the T 2 relaxation properties of both compartments, thereby better conditioning the parameter estimation problem and providing, at the same time, an additional potential biomarker (the T 2 of tissue). In our approach, the T 2 of tissue is estimated as an unknown parameter, whereas the T 2 of free water is assumed known a priori and fixed to a literature value (1573 ms). First, the error propagation of an erroneous assumption on the T 2 of free water is studied. Next, the improved conditioning of T 2 -DKI-FWE compared to DKI-FWE is illustrated using the Cramér-Rao lower bound matrix. Finally, the performance of the T 2 -DKI-FWE model is compared to that of the DKI-FWE and T 2 -DKI models on both simulated and real datasets. The error due to a biased approximation of the T 2 of free water was found to be relatively small in various diffusion metrics and for a broad range of erroneous assumptions on its underlying ground truth value. Compared to DKI-FWE, using the T 2 -DKI-FWE model is beneficial for the identifiability of the model parameters. Our results suggest that the T 2 -DKI-FWE model can achieve precise and accurate diffusion parameter estimates, through effective reduction of free water partial volume effects and by using a standard nonlinear least squares approach. In conclusion, incorporating T 2 relaxation properties into the DKI-FWE model improves the conditioning of the model fitting, while only requiring an acquisition scheme with at least two different echo times., Competing Interests: Declaration of Competing Interest VA has a collaboration agreement with icometrix. JV is co-inventor of a patent on the denoising methodology that was used in this study (US10698065B2). TB is employee of icometrix. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Diffusion-weighted imaging studies have repeatedly shown that white matter correlates with reading throughout development. However, the neurobiological interpretation of this relationship is constrained by the limited microstructural specificity of diffusion imaging. A critical component of white matter microstructure is myelin, which can be investigated noninvasively using MRI. Here, we examined the link between myelin water fraction (MWF) and reading ability in 10-year-old children (n = 69). To better understand this relationship, we additionally investigated how these two variables relate to fractional anisotropy (FA; a common index of diffusion-weighted imaging). Our analysis revealed that lower MWF coheres with better reading scores in left-hemispheric tracts relevant for reading. While we replicated previous reports on a positive relationship between FA and MWF, we did not find any evidence for an association between reading and FA. Together, these findings contrast previous research suggesting that poor reading abilities might be rooted in lower myelination and emphasize the need for further longitudinal research to understand how this relationship evolves throughout reading development. Altogether, this study contributes important insights into the role of myelin-related processes in the relationship between reading and white matter structure., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: The authors declare that they have no conflict of interest.

Diffusion tensor imaging (DTI) provides information about tissue microstructure and its degree of organization by quantifying water diffusion. We aimed to monitor longitudinal changes in DTI parameters (fractional isotropy, FA; mean diffusivity, MD; axial diffusivity, AD; radial diffusivity, RD) of the anterior cruciate ligament (ACL) following primary repair with internal bracing (IBLA). Fourteen patients undergoing IBLA were enrolled prospectively and scheduled for clinical follow-up, including instrumented laxity testing, and DTI at 3, 6, 12, and 24 months postoperatively. DTI was also performed in seven healthy subjects. Fiber tractography was used for 3D segmentation of the whole ACL volume, from which median DTI parameters were calculated. The posterior cruciate ligament (PCL) served as a control. Longitudinal DTI changes were assessed using a linear mixed model, and repeated measures correlations were calculated between DTI parameters and clinical laxity tests. At follow-up, thirteen patients had a stable knee and one patient sustained an ACL rerupture after 12 months postoperatively. The ACL repair showed a significant decrease of FA within the first 12 months after surgery, followed by stable FA values thereafter, while ACL diffusivities decreased over time returning towards normal values at 24 months postoperatively. For PCL there were no significant DTI changes over time. There was a significant correlation between ACL FA and laxity tests (r = -0.42, P = .017). This study has shown the potential of DTI to longitudinally monitor diffusion changes in the ACL following IBLA. The DTI findings suggest that healing of the ACL repair is incomplete at 24 months postoperatively., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

This retrospective correlation study investigated the putative link between methylene tetrahydrofolate reductase (MTHFR) A1298C mutations and chemotherapy-related brain function changes in adult childhood-leukemia survivors. To this end, we determined the relationship between the particular MTHFR1298 genotype (AA, AC or CC) of 31 adult childhood-leukemia survivors, and (1) their CSF Tau and phosphorylated Tau (pTau) levels at the time of treatment, (2) their adult performance intelligence quotient (PIQ), and (3) their regional brain connectivity using diffusion magnetic resonance imaging (dMRI) and resting-state functional MRI (rsfMRI). We confirmed that neuropathology markers Tau and pTau significantly increased in CSF of children after intrathecal methotrexate administration. Highest concentrations of these toxicity markers were found during the induction phase of the therapy. Moreover, CSF concentrations of Tau and pTau during treatment were influenced by the children's particular MTHFR1298 genotype. CSF Tau (but not pTau) levels significantly dropped after folinic acid supplementation. At adult age (on average 13.1 years since the end of their treatment), their particular MTHFR1298 genotype (AA, AC or CC) influenced the changes in PIQ and cortical connectivity that we found to be related to their childhood exposure to chemotherapeutics. In summary, we suggest that homozygous MTHFR1298CC individuals are more vulnerable to the adult sequelae of antifolate chemotherapy., Competing Interests: The authors have read the journal’s policy and have the following competing interests: TB is an employee of Icometrix. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Objective: To longitudinally monitor remodeling of human autograft following anterior cruciate ligament (ACL) reconstruction with DTI., Methods: Twenty-eight patients underwent DTI follow-up at 3, 8, and 14 months after clinically successful ACL reconstruction with tendon autograft. Among these, 18 patients had a concomitant lateral extra-articular procedure (LET). DTI data from 7 healthy volunteers was also obtained. Diffusion parameters (fractional anisotropy, FA; mean diffusivity, MD; axial diffusivity, AD; and radial diffusivity, RD) were evaluated within the fiber tractography volumes of the ACL graft and posterior cruciate ligament (PCL) in all patients. Data were analyzed using a linear mixed-effects model with post hoc testing using Bonferroni-Holm correction for multiple testing. The effect of additional LET was studied., Results: The ACL graft showed a significant decrease of FA over time (F = 4.00, p = 0.025), while the diffusivities did not significantly change over time. For PCL there were no significant DTI changes over time. A different evolution over time between patients with and without LET was noted for all diffusivity values of the ACL graft with reduced AD values in patients with LET at 8 months postoperatively (p = 0.048; adjusted p = 0.387). DTI metrics of the ACL graft differed largely from both native ACL and tendon at 14 months postoperatively., Conclusion: Our study has shown the potential of DTI to longitudinally monitor the remodeling process in human ACL reconstruction. DTI analysis indicates that graft remodeling is incomplete at 14 months postoperatively., Key Points: • DTI can be used to longitudinally monitor the remodeling process in human ACL reconstruction. • DTI analysis indicates that autograft remodeling is incomplete at 14 months postoperatively. • DTI may be helpful for evaluating new ACL treatments.

Background: Magnetic resonance imaging (MRI) data from multiple sclerosis (MS) patients treated in real-world settings are important for understanding disease-modifying therapy effects, including no evidence of disease activity (NEDA) assessment. This longitudinal, retrospective, single-cohort analysis assessed MRI and clinical disease outcomes in patients with relapsing-remitting MS treated with natalizumab for up to 5 years in Prague, the Czech Republic., Methods: The primary study endpoint was the proportion of patients free of new or enlarging fluid-attenuated inversion recovery (FLAIR) lesions after at least 2 years of natalizumab treatment. Secondary endpoints included percentage brain volume change over time, the number of new T1-hypointense lesions that persisted for ≥6 months, FLAIR and T1-hypointense lesion volume change over time, and the proportion of patients with NEDA-3 (defined as no relapses, no confirmed disability worsening, and no new or enlarging FLAIR lesions)., Results: A total of 193 patients were included in the study. During year 1 of natalizumab treatment, 78.9% of patients had no new or enlarging FLAIR lesions and 79.5% had no new T1 lesions. These proportions increased in years 2-5, with ≥98.0% of patients free of new or enlarging FLAIR lesions and ≥98.8% free of new T1 lesions. During year 1 on natalizumab, 52.2% of patients achieved NEDA-3; this proportion increased to ≥69.2% in years 2-5., Conclusion: This study provides additional evidence that long-term MS disease activity, as measured by both MRI activity and NEDA-3, is well-controlled in patients treated with natalizumab in real-world settings., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

MRI diffusion data suffers from significant inter- and intra-site variability, which hinders multi-site and/or longitudinal diffusion studies. This variability may arise from a range of factors, such as hardware, reconstruction algorithms and acquisition settings. To allow a reliable comparison and joint analysis of diffusion data across sites and over time, there is a clear need for robust data harmonization methods. This review article provides a comprehensive overview of diffusion data harmonization concepts and methods, and their limitations. Overall, the methods for the harmonization of multi-site diffusion images can be categorized in two main groups: diffusion parametric map harmonization (DPMH) and diffusion weighted image harmonization (DWIH). Whereas DPMH harmonizes the diffusion parametric maps (e.g., FA, MD, and MK), DWIH harmonizes the diffusion-weighted images. Defining a gold standard harmonization technique for dMRI data is still an ongoing challenge. Nevertheless, in this paper we provide two classification tools, namely a feature table and a flowchart, which aim to guide the readers in selecting an appropriate harmonization method for their study., (Copyright © 2020 Pinto, Paolella, Billiet, Van Dyck, Guns, Jeurissen, Ribbens, den Dekker and Sijbers.)

Objective: In a previous pilot monocentric study, we investigated the relation between human leukocyte antigen (HLA) genotype and multiple sclerosis (MS) disease progression over 2 years. HLA-A*02 allele was correlated with better outcomes, whereas HLA-B*07 and HLA-B*44 were correlated with worse outcomes. The objective of this extension study was to further investigate the possible association of HLA genotype with disease status and progression in MS as measured by sensitive and complex clinical and imaging parameters., Methods: Hundred and forty-six MS patients underwent HLA typing. Over a 4-year period of follow-up, we performed three clinical and magnetic resonance imaging (MRI) assessments per patient, which respectively included Expanded Disability Status Scale, Multiple Sclerosis Severity Scale, Timed-25-Foot-Walk, 9-Hole Peg Test, Symbol Digit Modalities Test, Brief Visual Memory Test, California Verbal Learning Test-II, and whole-brain atrophy, fluid-attenuated inversion recovery (FLAIR) lesion volume change and number of new FLAIR lesions using icobrain. We then compared the clinical and MRI outcomes between predefined HLA patient groups., Results: Results of this larger study with a longer follow-up are in line with what we have previously shown. HLA-A*02 allele is associated with potentially better MS outcomes, whereas HLA-B*07, HLA-B*44, HLA-B*08, and HLA-DQB1*06 with a potential negative effect. Results for HLA-DRB1*15 are inconclusive., Conclusion: In the era of MS treatment abundance, HLA genotype might serve as an early biomarker for MS outcomes to inform individualized treatment decisions.

Competing Interests: None

Introduction: Based on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS. However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile. Hence, the unmet need for safer and more selective treatments remains. Specifically restoring immune tolerance towards myelin antigens may provide an attractive alternative. In this respect, antigen-specific tolerisation with autologous tolerogenic dendritic cells (tolDC) is a promising approach., Methods and Analysis: Here, we will evaluate the clinical use of tolDC in a well-defined population of MS patients in two phase I clinical trials. In doing so, we aim to compare two ways of tolDC administration, namely intradermal and intranodal. The cells will be injected at consecutive intervals in three cohorts receiving incremental doses of tolDC, according to a best-of-five design. The primary objective is to assess the safety and feasibility of tolDC administration. For safety, the number of adverse events including MRI and clinical outcomes will be assessed. For feasibility, successful production of tolDC will be determined. Secondary endpoints include clinical and MRI outcome measures. The patients' immune profile will be assessed to find presumptive evidence for a tolerogenic effect in vivo., Ethics and Dissemination: Ethics approval was obtained for the two phase I clinical trials. The results of the trials will be disseminated in a peer-reviewed journal, at scientific conferences and to patient associations., Trial Registration Numbers: NCT02618902 and NCT02903537; EudraCT numbers: 2015-002975-16 and 2015-003541-26., Competing Interests: Competing interests: CCG received speaker honoraria and travel expenses for attending meeting from Genzyme, Novartis Pharma GmbH, and Bayer Health Care. Her work is funded by the German Ministry for Education and Research (BMBF; 01GI1603A) and the German Research Foundation (DFG; GR3946/3-1 and SFB128 A09). HW receives honoraria for acting as a member of Scientific Advisory Boards and as consultant for Biogen, Evgen, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche Ltd., Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, TEVA, and WebMD Global. Prof. Wiendl is acting as a paid consultant for Abbvie, Actelion, Biogen, IGES, Novartis, Roche, Sanofi-Genzyme, and the Swiss Multiple Sclerosis Society. His research is funded by the German Ministry for Education and Research (BMBF; 01FI1601E, 01GI1603A, and O1GI1603D), Deutsche Forschungsgesellschaft (DFG; SFB128 A09, A10, Z02, V and SFB1009 A03), Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children’s Foundation, Biogen GmbH, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi-Genzyme. The institution of BW receives honoraria for acting as a member of Scientific Advisory Boards for Biogen, Merck Serono, Roche, Sanofi-Genzyme, Novartis and speaker honoraria and travel support from Biogen, Merck Serono, Roche, Sanofi-Genzyme, Novartis, TEVA. CRT receives honoraria for acting as a member of Scientific Advisory Boards for Biogen, and Merck Serono, and speaker honoraria or travel support from Biogen, Merck Serono, Roche, Sanofi-Genzyme and Novartis. SPR receives speaker honoraria or travel support from Biogen, Merck Serono, Roche, Sanofi-Genzyme and Novartis. PP is a medical advisory board member of Icometrix NV. The other authors report no conflict of interest., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: This study aimed to assess functional and structural brain connectivity in adult childhood leukemia survivors and the link with cognitive functioning and previously identified risk factors such as intrathecal methotrexate dose and age at start of therapy., Methods: Thirty-one nonirradiated adult childhood leukemia survivors and 35 controls underwent cognitive testing and multimodal magnetic resonance imaging (resting state functional MRI, T1-weighted, diffusion-weighted, and myelin water imaging [MWI]). Analyses included dual regression, voxel-based morphometry, advanced diffusion, and MWI modeling techniques besides stepwise discriminant function analysis to identify the most affected executive cognitive domain. Correlations with discrete intrathecal MTX doses and (semi)continuous variables were calculated using Spearman's rank and Pearson's correlation, respectively. All correlation tests were two-sided. Positive and negative T-contrasts in functional and structural MRI analysis were one-sided., Results: Survivors demonstrated lower functional connectivity between the default mode network (DMN) and inferior temporal gyrus (ITG; P < .008). Additionally, we observed higher fractional anisotropy (FA; P = .04) and lower orientation dispersion index (ODI; P = .008) at the left centrum semiovale, which could-given that several fiber bundles cross this region-suggest selective reduced integrity of the respective white matter tracts. Set shifting reaction time, a measure of cognitive flexibility, was mostly impaired and correlated with lower FA (r = -0.53, P = .003) and higher ODI (r = 0.40, P = .04) in survivors but not with DMN-ITG connectivity. There were no statistically significant differences between survivors and controls in WM or GM volume, nor was there a statistically significant correlation between imaging measurements and age at start of therapy or intrathecal methotrexate dose., Conclusions: Adult, nonirradiated childhood leukemia survivors show altered brain connectivity, which is linked with cognitive flexibility.

With the increase of survival rates of pediatric cancer patients, the number of children facing potential cognitive sequelae has grown. Previous adult studies suggest that white matter (WM) microstructural changes may contribute to cognitive impairment. This study aims to investigate WM microstructure in childhood bone and soft tissue sarcoma. Differences in (micro-)structure can be investigated using diffusion MRI (dMRI). The typically used diffusion tensor model (DTI) assumes Gaussian diffusion, and lacks information about fiber populations. In this study, we compare WM structure of childhood bone and soft tissue sarcoma survivors (n = 34) and matched controls (n = 34), combining typical and advanced voxel-based models (DTI and NODDI model, respectively), as well as recently developed fixel-based models (for estimations of intra-voxel differences, apparent fiber density [AFD] and fiber cross-section [FC]). Parameters with significant findings were compared between treatments, and correlated with subscales of the WAIS-IV intelligence test, age at diagnosis, age at assessment and time since diagnosis. We encountered extensive regions showing lower fractional anisotropy, overlapping with both significant NODDI parameters and fixel-based parameters. In contrast to these diffuse differences, the fixel-based measure of AFD was reduced in the cingulum and corpus callosum only. Furthermore, AFD of the corpus callosum was significantly predicted by chemotherapy treatment and correlated positively with time since diagnosis, visual puzzles and similarities task scores. This study suggests altered WM structure of childhood bone and soft tissue sarcoma survivors. We conclude global chemotherapy-related changes, with particular vulnerability of centrally located WM bundles. Finally, such differences could potentially recover after treatment., (© 2018 Wiley Periodicals, Inc.)

Background and Purpose: Crohn's disease (CD) is marked by transmural inflammation of the bowel wall leading to stricturing and/or penetrating complications in the majority of patients. The natural history and operative risk after the diagnosis of an ileal penetrating complication is understudied. The aim was to study the disease course and need for surgery in patients diagnosed with a penetrating ileal CD complication and to assess the risk factors associated with worse postoperative outcome., Patients and Methods: In this cohort study, all cross-sectional imaging exams (computed tomography and/or magnetic resonance imaging) performed between 2006 and 2014 in patients with CD in a tertiary referral centre were reviewed for the presence of ileal penetrating complications (defined as abscesses, phlegmones and/or fistula). Demographic, clinical, biochemical, radiological and endoscopic factors were assessed retrospectively in these patients as well as the need for surgery (intestinal resection and/or strictureplasties) and postoperative complications., Results: In total, 1803 cross-sectional imaging exams in 957 CD patients were performed during the study period. In 113 patients, penetrating ileal CD complications were identified. The majority of these patients were referred for surgery (86%) (median time to surgery 1 month, interquartile range: 1-4.9 months). In multivariate analysis, only the presence of abscesses was associated with subsequent surgery (P=0.034; hazard ratio=1.65; 95% confidence interval: 1.04-2.61). Severe postoperative complications (Dindo-Clavien>II) were present in 13% of the patients. Albumin less than 32 g/l was associated with a five-fold increase in severe complications (P=0.039; hazard ratio=4.9; 95% confidence interval: 1-22). Up to 35% of the patients needed no further medical treatment during the first 5 years postoperatively., Conclusion: In this cohort, the majority of patients with penetrating ileal CD underwent surgery. The presence of an abscess showed a significant association with the need for surgery. There was an acceptable postoperative complication rate. Patients with low albumin had an unfavourable postoperative course. The long-term outcome after surgery was favourable.

In a previous longitudinal diffusion tensor imaging (DTI) study, we observed cerebral white matter (WM) alterations (reduced fractional anisotropy (FA)) related to decreased cognitive performance 3-5 months after chemotherapy-treatment (t2) when compared to baseline (t1) (Deprez et al. in Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 30(3), 274-281. doi:10.1200/JCO.2011.36.8571, 2012). The current study investigates the evolution and the nature of these previously observed microstructural changes. Twenty-five young women with early-stage breast cancer who received chemotherapy treatment (C+), 14 who did not receive chemotherapy (C-) and 15 healthy controls (HC) previously studied, underwent reassessment 3-4 years after treatment (t3). We assessed (1) longitudinal changes of cognitive performance and FA and (2) cross-sectional group differences in myelin-water-imaging and multishell diffusion MRI metrics at t3. MRI metrics were assessed on a voxel-by-voxel basis and in regions-of-interest (ROI) in which previous WM injury was detected. Longitudinal results: Mixed-effects modeling revealed significant group-time interactions for verbal memory and processing speed (p < 0.05) reflecting regained performance in the C+ group at t3. Furthermore, in chemotherapy-treated patients, FA returned to baseline levels at t3 in all ROIs (p < 0.002), whereas no FA changes were seen in controls. Additionally, FA increase from t2 to t3 correlated with time since treatment in two of the four regions (r = 0.40, p < 0.05). Cross-sectional results: Advanced diffusion MRI and myelin-water imaging metrics in the ROIs did not differ between groups. Similarly, no whole-brain voxelwise differences were detected. Initial WM alterations and reduced cognitive performance following chemotherapy-treatment were found to recover in a group of young breast cancer survivors three to four years after treatment.

Background and Aim: Transmural inflammation in Crohn's disease [CD] leads to stricturing or penetrating complications. Factors impacting on the need and timing of surgery in ileal stricturing CD [IS-CD] are understudied. Our aim was to identify risk factors in IS-CD associated with the need for surgery over time., Methods: All cross-sectional imaging [XSI] performed for CD between 2006 and 2015 in a tertiary referral centre was analysed. The electronic charts of patients with IS-CD were reviewed for demographic, clinical, biochemical, imaging, genetic, and endoscopic factors. An independent cohort was used for validation., Results: A total of 1803 XSI were performed in 957 patients with CD. IS-CD was diagnosed in 235 patients, and 161 of these [69%] needed surgery. Prestenotic dilation (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.22-3.45, p = 0.007], C-reactive protein at diagnosis of IS-CD > 11 mg/L [HR 1.53, 95% CI 1.05-2.24, p = 0.026], Montreal B3 phenotype [HR 1.58, 95% CI 1.06-2.36, p = 0.023], previous/current anti-tumour necrosis factor [TNF] exposure [HR 1.44, 95% CI 1.00-2.06, p = 0.048], and presence of at least one NOD2 rs2066844 risk allele [HR 1.51, 95% CI 1.02-2.23, p = 0.038] significantly impacted on the need for surgery in multivariate analysis. The risk stratification model [BACARDI] yielded a surgery-free survival after 5 years of 77%, 38%,19%, and 0% for the low, medium, high, and all risk groups, respectively. Based on an independent cohort of 27 patients, the results were validated and demonstrated adequate performance., Conclusions: This risk model can facilitate therapeutic decisions in IS-CD and suggest the correct time for surgery in daily clinical practice., (Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Background: Differences in corpus callosum (CC) morphology and microstructure have been implicated in late-life depression and may distinguish between late and early-onset forms of the illness. However, a multimodal approach using complementary imaging techniques is required to disentangle microstructural alterations from macrostructural partial volume effects., Methods: 107 older adults were assessed: 55 currently-depressed patients without dementia and 52 controls without cognitive impairment. We investigated group differences and clinical associations in 7 sub-regions of the mid-sagittal corpus callosum using T1 anatomical data, white matter hyperintensity (WMH) quantification and two different diffusion MRI (dMRI) models (multi-tissue constrained spherical deconvolution, yielding apparent fibre density, AFD; and diffusion tensor imaging, yielding fractional anisotropy, FA and radial diffusivity, RD)., Results: Callosal AFD was lower in patients compared to controls. There were no group differences in CC thickness, surface area, FA, RD, nor whole brain or WMH volume. Late-onset of depression was associated with lower FA, higher RD and lower AFD. There were no associations between any imaging measures and psychotic features or depression severity as assessed by the geriatric depression scale. WMH volume was associated with lower FA and AFD, and higher RD in patients., Limitations: Patients were predominantly treatment-resistant. Measurements were limited to the mid-sagittal CC. dMRI analysis was performed on a smaller cohort, n=77. AFD was derived from low b-value data., Conclusions: Callosal structure is largely preserved in LLD. WMH burden may impact on CC microstructure in late-onset depression suggesting vascular pathology has additional deleterious effects in these patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Primary non-response to infliximab in Crohn's disease is still incompletely understood. Our aim was to further characterize the role of inflammatory burden during infliximab induction therapy., Materials and Methods: We studied a well-characterized cohort of 201 anti-TNF naive Crohn's disease patients treated with infliximab 5mg/kg at week 0, 2, 6 and 14 who had serum samples drawn just before every infusion. All serum samples were analyzed for CRP, albumin, TNF, IFN-γ, IL-6, IL-8, IL-10, infliximab trough concentrations (in-house-developed ELISA) and antibodies to infliximab (HMSA, Prometheus Laboratories Inc., San Diego, CA). Primary non-response was defined as the absence of clinical improvement at week 14., Results: The incidence of primary non-response to infliximab was 8% (n = 16). IL-8 concentrations at baseline were higher (p = .01) and albumin at week 6 was lower in primary non-responders (p = .01) compared to responders. During induction, IFN-γ and IL-6 concentrations decreased significantly at week 2 and week 6 in responders compared to primary non-responders (p < .05). Serum TNF increased significantly after each infliximab infusion and this increase from week 0 to week 14 was more pronounced in responders (p = .03). Multiple logistic regression identified TNF/CRP ratio at baseline as predictive for primary non-response to infliximab at week 14 (OR 2.8 (95% CI 1.4-5.5; p = .003))., Conclusions: In this intensively sampled cohort of Crohn's disease patients, we demonstrate that inflammatory burden is more determining for primary non-response than drug exposure or immunogenicity. Our findings furthermore suggest that the contribution of TNF in inflammation might be higher in primary non-response, contradicting the non-TNF-driven concept.

Objective: The identification of a biomarker with prognostic value is an unmet need in multiple sclerosis (MS). The objective of this study was to investigate a possible association of HLA genotype with disease status and progression in MS, based on comprehensive and sensitive clinical and magnetic resonance imaging (MRI) parameters to measure disease effects., Method: A total of 118 MS patients (79 females, 39 males) underwent HLA typing. Patient MS status was assessed at two time points in a 2-year interval, based on clinical scores (including EDSS, MSSS, T25FW, 9-HPT, SDMT, BVMT, CVLT-II) and MRI evaluations. Quantitative brain MRI values were obtained for whole brain atrophy, FLAIR lesion volume change and number of new lesions using MSmetrix. Predefined HLA patient groups were compared as of disease status and progression. Global assessment was achieved by an overall t-statistic and assessment per measurement by a Welch test and/or Mann Whitney U test. The effects of multiple covariates, including age, gender and disease duration as well as scan parameters, were also evaluated using a regression analysis., Results: The HLA-A*02 allele was associated with better outcomes in terms of MSSS, EDSS and new lesion count (Welch test p-value<0.05). The HLA-B*07 and HLA-B*44 alleles showed a global negative effect on disease status, although none of the measurements reached significance (p-value<0.05). Results for the HLA-DRB1*15, HLA-DQB1*06 and HLA-B*08 alleles were inconclusive. The influence of the confounding variables on the statistical analysis was limited., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Hippocampal volume is commonly decreased in late-life depression. According to the depression-as-late-life-neuropsychiatric-disorder model, lower hippocampal volume in late-life depression is associated with neurodegenerative changes. The purpose of this prospective study was to examine whether lower hippocampal volume in late-life depression is associated with Alzheimer's disease pathology., Method: Of 108 subjects who participated, complete, good-quality data sets were available for 100: 48 currently depressed older adults and 52 age- and gender-matched healthy comparison subjects who underwent structural MRI, [ 18 F]flutemetamol amyloid positron emission tomography imaging, apolipoprotein E genotyping, and neuropsychological assessment. Hippocampal volumes were defined manually and normalized for total intracranial volume. Amyloid binding was quantified using the standardized uptake value ratio in one cortical composite volume of interest. The authors investigated group differences in hippocampal volume (both including and excluding amyloid-positive participants), group differences in amyloid uptake and in the proportion of positive amyloid scans, and the association between hippocampal volume and cortical amyloid uptake., Results: A significant difference was observed in mean normalized total hippocampal volume between patients and comparison subjects, but there were no group differences in cortical amyloid uptake or proportion of amyloid-positive subjects. The difference in hippocampal volume remained significant after the amyloid-positive subjects were excluded. There was no association between hippocampal volume and amyloid uptake in either patients or comparison subjects., Conclusions: Lower hippocampal volume was not related to amyloid pathology in this sample of patients with late-life depression. These data counter the common belief that changes in hippocampal volume in late-life depression are due to prodromal Alzheimer's disease.