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Objective: In multiple sclerosis (MS), cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SC GM atrophy. Using phase-sensitive inversion recovery (PSIR) magnetic resonance imaging, we determined the association of the SC GM and SC WM areas with MS disability and disease type. Methods: A total of 113 MS patients and 20 healthy controls were examined at 3T with a PSIR sequence acquired at the C2/C3 disk level. Two independent, clinically masked readers measured the cord WM and GM areas. Correlations between cord areas and Expanded Disability Status Score (EDSS) were determined. Differences in areas between groups were assessed with age and sex as covariates. Results: Relapsing MS (RMS) patients showed smaller SC GM areas than age- and sex-matched controls (p = 0.008) without significant differences in SC WM areas. Progressive MS patients showed smaller SC GM and SC WM areas compared to RMS patients (all p ≤ 0.004). SC GM, SC WM, and whole cord areas inversely correlated with EDSS (rho: -0.60, -0.32, -0.42, respectively; all p ≤ 0.001). The SC GM area was the strongest correlate of disability in multivariate models including brain GM and WM volumes, fluid-attenuated inversion recovery lesion load, T1 lesion load, SC WM area, number of SC T2 lesions, age, sex, and disease duration. Brain and spinal GM independently contributed to EDSS. Interpretation: SC GM atrophy is detectable in vivo in the absence of WM atrophy in RMS. It is more pronounced in progressive MS than RMS and contributes more to patient disability than SC WM or brain GM atrophy.

New technologies have resulted in a better understanding of blood and lymphatic vascular heterogeneity at the cellular and molecular levels. However, we still need to learn more about the heterogeneity of the cardiovascular and lymphatic systems among different species at the anatomical and functional levels. Even the deceptively simple question of the functions of fish lymphatic vessels has yet to be conclusively answered. The most common interpretation assumes a similar dual setup of the vasculature in zebrafish and mammals: a cardiovascular circulatory system, and a lymphatic vascular system (LVS), in which the unidirectional flow is derived from surplus interstitial fluid and returned into the cardiovascular system. A competing interpretation questions the identity of the lymphatic vessels in fish as at least some of them receive their flow from arteries via specialised anastomoses, neither requiring an interstitial source for the lymphatic flow nor stipulating unidirectionality. In this alternative view, the 'fish lymphatics' are a specialised subcompartment of the cardiovascular system, called the secondary vascular system (SVS). Many of the contradictions found in the literature appear to stem from the fact that the SVS develops in part or completely from an embryonic LVS by transdifferentiation. Future research needs to establish the extent of embryonic transdifferentiation of lymphatics into SVS blood vessels. Similarly, more insight is needed into the molecular regulation of vascular development in fish. Most fish possess more than the five vascular endothelial growth factor (VEGF) genes and three VEGF receptor genes that we know from mice or humans, and the relative tolerance of fish to whole-genome and gene duplications could underlie the evolutionary diversification of the vasculature. This review discusses the key elements of the fish lymphatics versus the SVS and attempts to draw a picture coherent with the existing data, including phylogenetic knowledge., (© 2024 The Author(s). Biological Reviews published by John Wiley & Sons Ltd on behalf of Cambridge Philosophical Society.)

During embryonic development, lymphatic endothelial cell (LEC) precursors are distinguished from blood endothelial cells by the expression of Prospero-related homeobox 1 (Prox1), which is essential for lymphatic vasculature formation in mouse and zebrafish. Prox1 expression initiation precedes LEC sprouting and migration, serving as the marker of specified LECs. Despite its crucial role in lymphatic development, Prox1 upstream regulation in LECs remains to be uncovered. SOX18 and COUP-TFII are thought to regulate Prox1 in mice by binding its promoter region. However, the specific regulation of Prox1 expression in LECs remains to be studied in detail. Here, we used evolutionary conservation and chromatin accessibility to identify enhancers located in the proximity of zebrafish prox1a active in developing LECs. We confirmed the functional role of the identified sequences through CRISPR/Cas9 mutagenesis of a lymphatic valve enhancer. The deletion of this region results in impaired valve morphology and function. Overall, our results reveal an intricate control of prox1a expression through a collection of enhancers. Ray-finned fish-specific distal enhancers drive pan-lymphatic expression, whereas vertebrate-conserved proximal enhancers refine expression in functionally distinct subsets of lymphatic endothelium., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background and Purpose: The human auditory system develops early in fetal life. This retrospective MR imaging study describes the in vivo prenatal anatomic development of the transverse temporal gyrus (Heschl gyrus) site of the primary auditory cortex., Materials and Methods: Two hundred seventy-two MR imaging studies of the fetal brain (19-39 weeks' gestational age) acquired from a single institution's 1.5T scanner were retrospectively examined by 2 neuroradiologists. MR imaging with pathologic findings and extreme motion artifacts was excluded. Postnatal Heschl gyrus landmarks were used as a reference on T2-weighted ssFSE sequences in the 3 orthogonal planes. The frequency of the Heschl gyrus was reported for gestational age, hemisphere, and planes. Descriptive statistics and a McNemar test were performed., Results: Two hundred thirty MR imaging studies were finally included. Fetal brains were divided by gestational age (in weeks) into 8 groups (parentheses indicate the number of observations): 19-21 (29), 22-23 (32), 24-25 (21), 26-27 (18), 28-29 (35), 30-31 (30), 32-33 (33) and >34 (32). The Heschl gyrus appeared on MR imaging between 24 and 25 weeks' gestational age (14/21 fetuses, 67%) and was visible in all fetuses after the 28th week of gestation. By its appearance (24-28 weeks' gestational age), the sagittal plane was the most sensitive in its detectability. After 28-29 weeks' gestational age, the Heschl gyrus was evident in all acquisition planes and fetuses. Results did not differ between hemispheres., Conclusions: The Heschl gyrus appears on MR imaging at 24-25 weeks' gestational age, paralleling the functional activation of the auditory system. We propose the Heschl gyrus as an early additional MR imaging marker of fetal brain development., (© 2023 by American Journal of Neuroradiology.)

Background and Purpose: Language reorganization has been described in brain lesions with respect to their location and timing, but little is known with respect to their etiology. We used fMRI to investigate the effects of different types of left hemisphere lesions (GL = gliomas, TLE = temporal lobe epilepsy and CA = cavernous angioma) on the topographic intra-hemispheric language plasticity, also considering their location., Methods: Forty-seven right-handed patients with 3 different left hemisphere lesions (16 GL, 15 TLE and 16 CA) and 17 healthy controls underwent BOLD fMRI with a verb-generation task. Euclidean distance was used to measure activation peak shifts among groups with respect to reference Tailarach coordinates of Inferior Frontal Gyrus, Superior Temporal Sulcus and Temporo-Parietal Junction. Mixed-model ANOVAs were used to test for differences in activation peak shifts., Results: Significant activation peak shifts were found in GL patients with respect both to HC and other groups (TLA and CA). In addition, in the same group of patients a significant effect of tumor location (anterior or posterior) was detected., Conclusions: We demonstrated that intra-hemispheric language plasticity is influenced by the type of lesion affecting the left hemisphere and that fMRI is especially valuable in the preoperative assessment of such reorganization in glioma patients., (© 2023. Italian Society of Medical Radiology.)

During development, the lymphatic vasculature forms as a second network derived chiefly from blood vessels. The transdifferentiation of embryonic venous endothelial cells (VECs) into lymphatic endothelial cells (LECs) is a key step in this process. Specification, differentiation and maintenance of LEC fate are all driven by the transcription factor Prox1, yet the downstream mechanisms remain to be elucidated. We here present a single-cell transcriptomic atlas of lymphangiogenesis in zebrafish, revealing new markers and hallmarks of LEC differentiation over four developmental stages. We further profile single-cell transcriptomic and chromatin accessibility changes in zygotic prox1a mutants that are undergoing a LEC-VEC fate shift. Using maternal and zygotic prox1a/prox1b mutants, we determine the earliest transcriptomic changes directed by Prox1 during LEC specification. This work altogether reveals new downstream targets and regulatory regions of the genome controlled by Prox1 and presents evidence that Prox1 specifies LEC fate primarily by limiting blood vascular and haematopoietic fate. This extensive single-cell resource provides new mechanistic insights into the enigmatic role of Prox1 and the control of LEC differentiation in development., (© 2023 The Authors.)

Transcriptional enhancer elements are responsible for orchestrating the temporal and spatial control over gene expression that is crucial for programming cell identity during development 1-3 . Here we describe a novel enhancer element that is important for regulating the expression of Prox1 in lymphatic endothelial cells. This evolutionarily conserved enhancer is bound by key lymphatic transcriptional regulators including GATA2, FOXC2, NFATC1 and PROX1. Genome editing of the enhancer to remove five nucleotides encompassing the GATA2-binding site resulted in perinatal death of homozygous mutant mice due to profound lymphatic vascular defects. Lymphatic endothelial cells in enhancer mutant mice exhibited reduced expression of genes characteristic of lymphatic endothelial cell identity and increased expression of genes characteristic of haemogenic endothelium, and acquired the capacity to generate haematopoietic cells. These data not only reveal a transcriptional enhancer element important for regulating Prox1 expression and lymphatic endothelial cell identity but also demonstrate that the lymphatic endothelium has haemogenic capacity, ordinarily repressed by Prox1., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Purpose: Surgical resection of cerebral cavernous malformations close to eloquent regions frequently uses fMRI and DTI for surgical planning to best preserve neurologic function. This study investigates the reliability of fMRI and DTI near cerebral cavernous malformations., Materials and Methods: Consecutive patients with cerebral cavernous malformations undergoing presurgical fMRI and DTI mapping were identified. Each cerebral cavernous malformation was hand-contoured; 2 sequential 4-mm expansion shells (S1 and S2) were created, generating 2 ROIs and 2 contralateral controls. Fractional anisotropy and regional homogeneity measurements were then extracted from each ROI and compared with the contralateral controls. Reliability, accuracy, and precision were compared as appropriate., Results: Fifty-four patients were identified and included. Errors of fractional anisotropy were significantly lower than those of regional homogeneity in S1 and S2 ( P  < .001), suggesting that fractional anisotropy is more reliable than regional homogeneity near cerebral cavernous malformations. Proximity to cerebral cavernous malformations worsened the reliability of regional homogeneity (S1 versus S2, P  < .001), but not fractional anisotropy ( P = .24). While fractional anisotropy was not significantly biased in any ROI ( P  > .05), regional homogeneity was biased toward lower signals in S1 and S2 ( P  < .05), an effect that was attenuated with distance from cerebral cavernous malformations ( P  < .05). Fractional anisotropy measurements were also more precise than regional homogeneity in S1 and S2 ( P  < .001 for both)., Conclusions: Our findings suggest that hemosiderin-rich lesions such as cerebral cavernous malformations may lead to artifactual depression of fMRI signals and that clinicians and surgeons should interpret fMRI studies near cerebral cavernous malformations with caution. While fMRI is considerably affected by cerebral cavernous malformation-related artifacts, DTI appears to be relatively unaffected and remains a reliable imaging technique near cerebral cavernous malformations., (© 2023 by American Journal of Neuroradiology.)

Purpose: To investigate the diagnostic efficacy of MRI diagnostic algorithms with an ascending automatization, in distinguishing between high-grade glioma (HGG) and solitary brain metastases (SBM)., Methods: 36 patients with histologically proven HGG (n = 18) or SBM (n = 18), matched by size and location were enrolled from a database containing 655 patients. Four different diagnostic algorithms were performed serially to mimic the clinical setting where a radiologist would typically seek out further findings to reach a decision: pure qualitative, analytic qualitative (based on standardized evaluation of tumor features), semi-quantitative (based on perfusion and diffusion cutoffs included in the literature) and a quantitative data-driven algorithm of the perfusion and diffusion parameters. The diagnostic yields of the four algorithms were tested with ROC analysis and Kendall coefficient of concordance., Results: Qualitative algorithm yielded sensitivity of 72.2%, specificity of 78.8%, and AUC of 0.75. Analytic qualitative algorithm distinguished HGG from SBM with a sensitivity of 100%, specificity of 77.7%, and an AUC of 0.889. The semi-quantitative algorithm yielded sensitivity of 94.4%, specificity of 83.3%, and AUC = 0.889. The data-driven algorithm yielded sensitivity = 94.4%, specificity = 100%, and AUC = 0.948. The concordance analysis between the four algorithms and the histologic findings showed moderate concordance for the first algorithm, (k = 0.501, P < 0.01), good concordance for the second (k = 0.798, P < 0.01), and third (k = 0.783, P < 0.01), and excellent concordance for fourth (k = 0.901, p < 0.0001)., Conclusion: When differentiating HGG from SBM, an analytical qualitative algorithm outperformed qualitative algorithm, and obtained similar results compared to the semi-quantitative approach. However, the use of data-driven quantitative algorithm yielded an excellent differentiation., (© 2022. The Author(s).)

Lymphangiogenesis, formation of lymphatic vessels from pre-existing vessels, is a dynamic process that requires cell migration. Regardless of location, migrating lymphatic endothelial cell (LEC) progenitors probe their surroundings to form the lymphatic network. Lymphatic-development regulation requires the transcription factor MAFB in different species. Zebrafish Mafba, expressed in LEC progenitors, is essential for their migration in the trunk. However, the transcriptional mechanism that orchestrates LEC migration in different lymphatic endothelial beds remains elusive. Here, we uncover topographically different requirements of the two paralogs, Mafba and Mafbb, for LEC migration. Both mafba and mafbb are necessary for facial lymphatic development, but mafbb is dispensable for trunk lymphatic development. On the molecular level, we demonstrate a regulatory network where Vegfc-Vegfd-SoxF-Mafba-Mafbb is essential in facial lymphangiogenesis. We identify that mafba and mafbb tune the directionality of LEC migration and vessel morphogenesis that is ultimately necessary for lymphatic function., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Epigenetic regulation is integral in orchestrating the spatiotemporal regulation of gene expression which underlies tissue development. The emergence of new tools to assess genome-wide epigenetic modifications has enabled significant advances in the field of vascular biology in zebrafish. Zebrafish represents a powerful model to investigate the activity of cis -regulatory elements in vivo by combining technologies such as ATAC-seq, ChIP-seq and CUT&Tag with the generation of transgenic lines and live imaging to validate the activity of these regulatory elements. Recently, this approach led to the identification and characterization of key enhancers of important vascular genes, such as gata2a, notch1b and dll4 . In this review we will discuss how the latest technologies in epigenetics are being used in the zebrafish to determine chromatin states and assess the function of the cis -regulatory sequences that shape the zebrafish vascular network., Competing Interests: The 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 Panara, Monteiro and Koltowska.)

Purpose: Dynamic susceptibility contrast (DSC) perfusion-weighted MR imaging (PWI) is increasingly used in clinical neuroimaging for a range of conditions. More highly concentrated GBCAs (e.g., gadobutrol) are often preferred for DSC imaging because it is thought that more Gd is present in the volume of interest during first pass for a given equivalent injection rate. However, faster injection of a less viscous GBCA (e.g., gadoteridol) might generate a more compact and narrower contrast bolus thus obviating any perceived benefit of higher Gd concentration. This preliminary study aimed to analyze and compare DSC examinations in the healthy brain hemisphere of patients with brain tumors using gadobutrol and gadoteridol administered at injection rates of 4 and 6 mL/s., Methods: Thirty-nine brain tumor patients studied with DSC-PWI were evaluated. A simplified gamma-variate model function was applied to calculate the mean peak, area under the curve (AUC), and full-width at half-maximum (FHWM) of concentration-time curves derived from ΔR2* signals at four different regions-of-interest (ROIs). Qualitative assessment of the derived CBV maps was also performed independently by 2 neuroradiologists., Results: No qualitative or quantitative differences between the two GBCAs were observed when administered at a flow rate of 4 mL/s. At a flow rate of 6 mL/s, gadoteridol showed lower FWHM values., Conclusion: Gadobutrol and gadoteridol are equivalent for clinical assessment of qualitative CBV maps and quantitative perfusion parameters (FHWM) at a flow rate of 4 mL/s. At 6 mL/s, gadoteridol produces a narrower bolus shape and potentially improves quantitative assessment of perfusion parameters., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ground-glass opacities (GGOs) are a non-specific high-resolution computed tomography (HRCT) finding tipically observed in early Coronavirus disesase 19 (COVID-19) pneumonia. However, GGOs are also seen in other acute lung diseases, thus making challenging the differential diagnosis. To this aim, we investigated the performance of a radiomics-based machine learning method to discriminate GGOs due to COVID-19 from those due to other acute lung diseases. Two sets of patients were included: a first set of 28 patients (COVID) diagnosed with COVID-19 infection confirmed by real-time polymerase chain reaction (RT-PCR) between March and April 2020 having (a) baseline HRCT at hospital admission and (b) predominant GGOs pattern on HRCT; a second set of 30 patients (nCOVID) showing (a) predominant GGOs pattern on HRCT performed between August 2019 and April 2020 and (b) availability of final diagnosis. Two readers independently segmented GGOs on HRCTs using a semi-automated approach, and radiomics features were extracted using a standard open source software (PyRadiomics). Partial least square (PLS) regression was used as the multivariate machine-learning algorithm. A leave-one-out nested cross-validation was implemented. PLS β-weights of radiomics features, including the 5% features with the largest β-weights in magnitude (top 5%), were obtained. The diagnostic performance of the radiomics model was assessed through receiver operating characteristic (ROC) analysis. The Youden's test assessed sensitivity and specificity of the classification. A null hypothesis probability threshold of 5% was chosen (p < 0.05). The predictive model delivered an AUC of 0.868 (Youden's index = 0.68, sensitivity = 93%, specificity 75%, p = 4.2 × 10 -7 ). Of the seven features included in the top 5% features, five were texture-related. A radiomics-based machine learning signature showed the potential to accurately differentiate GGOs due to COVID-19 pneumonia from those due to other acute lung diseases. Most of the discriminant radiomics features were texture-related. This approach may assist clinician to adopt the appropriate management early, while improving the triage of patients., (© 2021. The Author(s).)

Magnetic resonance imaging (MRI) plays a leading role in the non-invasive evaluation of bone marrow (BM). Normal BM pattern depends on the ratio and distribution of yellow and red marrow, which are subject to changes with age, pathologies, and treatments. Neonates show almost entirely red marrow. Over time, yellow marrow conversion takes place with a characteristic sequence leading to a red marrow persistence in proximal metaphyses of long bones. In adults, normal BM is composed of both red (40% water, 40% fat) and yellow marrow (15% water, 80% fat). Due to the higher content of fat, yellow marrow normally appears hyperintense on T1-weighted (T1w) fast spin echo (FSE) sequences and hypo-/iso-intense in short tau inversion recovery (STIR) T2-weighted (T2w); red marrow appears slightly hyperintense in T1w FSE and hyper-/iso-intense in STIR T2w. Pathologic BM has reduced fat and increased water percentages, resulting hypointense in T1w FSE and hyperintense in STIR T2w. In oncologic patients, BM MRI signal largely depends on the treatment (irradiation and/or chemotherapy) and its timing. BM fat and water amount and location in normal red/yellow and pathologic marrow are responsible for different signals in MRI sequences whose knowledge by radiologists may help to differentiate between normal and pathologic findings. Our aim was to discuss and illustrate the MRI of BM physiologic conversion and pathologic reconversion occurring in malignancies and after treatments in cancer patients.

Purpose: The head of the hippocampus (H) is classically described as having two to four digitations both in ex vivo specimens and in vivo MR coronal images. The aim of this study was to develop and evaluate a new MR-based classification of the anatomical variants of the hippocampal head in a large sample population of healthy subjects., Methods: MR images of the brain of 238 young healthy subjects (138 men and 100 women; age range 18-39) were analyzed. The head of the H was identified on coronal reformatted 3D T1 weighted MR images. The frequencies were reported for hemisphere and sex. Inter-rater reliability was assessed., Results: Eight variants of the hippocampal head were described. Class 0 (11.4%) indicated a total absence of sulci. This class was further subdivided as follows: 0A (one digitation, 10.1%) and 0B (no digitations or "null variant", 1.3%). Class 1 (25.6%) presented a single sulcus and was further subdivided into four types according to the location and the width of the sulcus [1A (8.8%), 1B (12.8%), 1C (1.3%), and 1D (2.7%)]. Class 2 (63.0%, the most frequent and the classical variant) had two symmetrical sulci and three digitations. Statistically significant differences between the two hemispheres were observed only in women and overall. Differences in prevalence between sexes were not observed., Conclusions: The large study population allowed the description of a novel morphological classification of the different anatomical variants of normal H in the coronal plane. This classification could reduce the risk of misinterpreting normal anatomical variants as pathological.

Background: One set of the developmentally important Doublesex and Male-abnormal-3 Related Transcription factors (Dmrt) is subject of intense research, because of their role in sex-determination and sexual differentiation. This likely non-monophyletic group of Dmrt genes is represented by the Drosophila melanogaster gene Doublesex ( Dsx ), the Caenorhabditis elegans Male-abnormal-3 ( Mab-3 ) gene, and vertebrate Dmrt1 genes. However, other members of the Dmrt family are much less well studied, and in arthropods, including the model organism Drosophila melanogaster , data on these genes are virtually absent with respect to their embryonic expression and function., Results: Here we investigate the complete set of Dmrt genes in members of all main groups of Arthropoda and a member of Onychophora, extending our data to Panarthropoda as a whole. We confirm the presence of at least four families of Dmrt genes (including Dsx -like genes) in Panarthropoda and study their expression profiles during embryogenesis. Our work shows that the expression patterns of Dmrt11E, Dmrt93B, and Dmrt99B orthologs are highly conserved among panarthropods. Embryonic expression of Dsx -like genes, however, is more derived, likely as a result of neo-functionalization after duplication., Conclusions: Our data suggest deep homology of most of the panarthropod Dmrt genes with respect to their function that likely dates back to their last common ancestor. The function of Dsx and Dsx -like genes which are critical for sexual differentiation in animals, however, appears to be much less conserved., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Learning a new language requires the use of extensive neural networks and can represent a powerful tool to reorganize brain neuroplasticity. In this study, we analyze how a 4 months long second language learning program (16, 2 h sessions) can lead to functional changes in the brain of healthy elderly individuals. A large number of studies point out a decline of brain-skills with age; here it is analyzed how cognition together with functional brain organization can be improved later in life. Twenty-six older adults (59-79 years old) were enrolled in the present study. A complete neuropsychological examination was administered before and after the intervention to measure global cognition levels, short- and long-term memory, attention, language access and executive functions. At the end of the program, in the intervention group, the results showed a significant improvement in global cognition together with an increased functional connectivity in the right inferior frontal gyrus (rIFG), right superior frontal gyrus (rSFG) and left superior parietal lobule (lSPL). These findings can be added to the current neurobiological breakthroughs of reshaping brain networks with a short language learning practice in healthy elderly subjects. Therefore, learning a foreign-language may represent a potentially helpful cognitive intervention for promoting healthy aging.

Purpose: To investigate modifications of Magnetic Resonance Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI) metrics in lateral white matter (WM) bundles of the cervical spinal cord in patients with previous stroke in the vascular territory of the middle cerebral artery (MCA)., Methods: Twenty consecutive patients with a previous ischemic stroke of the MCA territory and a varying degree of upper motor impairment were enrolled. DKI was centered at the C3C4 and C5C6 intervertebral level., Results: The fractional anisotropy (FA) values in C3C4 and C5C6 were found to be significantly lower in the lateral WM bundles contralateral to the ischemic lesion and thus, in the WM bundle including the affected corticospinal tract (CST) (p = 0.005 and p = 0.008, respectively), as well as mean kurtosis (MK) and axonal water fraction (AWF) values (p = 0.004 and p = 0.04. respectively). FA values correlated significantly with the Global Motor Index (GMI) both for C3C4 (ρ = 0.61, p = 0.004) and C5C6 (ρ = 0.69, p = 0.002). At C3C4, AWF correlated significantly with GMI (ρ = 0.54, p = 0.03). No correlations were found between lateral WM bundle volumes and GMI., Conclusion: A reduction of anisotropy and microstructural complexity in the affected lateral WM bundle of the cervical spinal cord was observed in patients with previous ischemic stroke involving the CST. The correlations between these metrics and motor performance were statistically significant.

Background: Sox (Sry-related high-mobility-group box) genes represent important factors in animal development. Relatively little, however, is known about the embryonic expression patterns and thus possible function(s) of Sox genes during ontogenesis in panarthropods (Arthropoda+Tardigrada+Onychophora). To date, studies have been restricted exclusively to higher insects, including the model system Drosophila melanogaster, with no comprehensive data available for any other arthropod group, or any tardigrade or onychophoran., Results: This study provides a phylogenetic analysis of panarthropod Sox genes and presents the first comprehensive analysis of embryonic expression patterns in the flour beetle Tribolium castaneum (Hexapoda), the pill millipede Glomeris marginata (Myriapoda), and the velvet worm, Euperipatoides kanangrensis (Onychophora). 24 Sox genes were identified and investigated: 7 in Euperipatoides, 8 in Glomeris, and 9 in Tribolium. Each species possesses at least one ortholog of each of the five expected Sox gene families, B, C, D, E, and F, many of which are differentially expressed during ontogenesis., Conclusion: Sox gene expression (and potentially function) is highly conserved in arthropods and their closest relatives, the onychophorans. Sox B, C and D class genes appear to be crucial for nervous system development, while the Sox B genes Dichaete (D) and Sox21b likely play an additional conserved role in panarthropod segmentation. The Sox B gene Sox21a likely has a conserved function in foregut and Malpighian tubule development, at least in Hexapoda. The data further suggest that Sox D and E genes are involved in mesoderm differentiation, and that Sox E genes are involved in gonadal development. The new data expand our knowledge about the expression and implied function of Sox genes to Mandibulata (Myriapoda+Pancrustacea) and Panarthropoda (Arthropoda+Onychophora).

Backgrounds: Irradiation of the hippocampus plays a role in neurocognitive toxicity. Its delineation is complex and in practice different head position can vary hippocampus morphology on axial images; so atlas in a single standard position can result ineffective to describe different hippocampal morphologies in different head set-up. The purpose of our study was to develop a guide based on magnetic resonance imaging for hippocampus delineation in three different head set-ups., Materials and Methods: Three patients were selected to elaborate our guide. Patients were submitted to a planning computed tomography of the brain district in different head positions: 1° patient in neutral, 2° patient in over-extended and 3° patient in head hypo-extended position; axial images of 2-mm thickness were obtained. Computed tomography images were fused with diagnostic brain magnetic resonance images; then hippocampus was delineated according to RTOG atlas. Contours were revised by two neuro-radiologists with >5-year expertise in neuroimaging., Results: A guide was developed for each of three head positions considered. RTOG atlas provided an easy and reliable guide for hippocampus delineation in neutral position of the head. Discrepancies were observed in cranial and caudal limit in case of head over/hypo-extension, as well as in hippocampal morphology near the encephalic trunk where hippocampus takes an oblong shape in over-extended set-up, and short and stocky in hypo-extension., Conclusion: Our guide can represent a useful tool for hippocampal delineation in clinical practice and for different anatomic variations due to different head positions. Certainly, it should be validated in practice.

Purpose: Abnormal brain perfusion is a critical mechanism in neonatal brain injury. The aim of the present study was to compare Cerebral Blood Flow (CBF) evaluated with ASL MRI in three groups of neonates: preterms without brain lesions on MRI (PN), preterms with periventricular white matter lesions (PNp) and term neonates with normal MRI (TN). The correlation between CBF and clinical outcome was explored., Materials and Methods: The institutional review board approved this prospective study and waived informed consent. The perfusion ASL data from 49 consecutive preterm neonates (PN) studied at term-equivalent age and 15 TN were evaluated. Statistically significant differences in gray matter CBF were evaluated by using a linear mixed-model analysis and Mann-Whitney U test. Logistic regression analysis was used to assess the relation between CBF and neuromotor outcome at 12 months., Results: Comparison of means indicated that the CBF of the whole brain were significantly higher in PN compared to TN ( P  = 0.011). This difference remained significant when considering the frontal ( P  = 0.038), parietal ( P  = 0.002), temporal ( P  = 0.030), occipital ( P  = 0.041) and cerebellar ( P  = 0.010) gray matter. In the PN group, lower CBF in basal ganglia was associated with a worse neuromotor outcome ( P  = 0.012)., Conclusions: ASL MRI demonstrated differences in brain perfusion of the basal ganglia between PN and TN. In PN, a positive correlation between CBF and neuromotor outcome was demonstrated in this area.

Objective: To characterize the accrual of long-term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (MRI) data used in clinical trials have long-term prognostic value., Methods: This is a prospective study of 517 actively managed MS patients enrolled at a single center., Results: More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit. At this last assessment, neurologic disability as measured by the Expanded Disability Status Scale (EDSS) was stable or improved compared to baseline in 41% of patients. Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first 2 years had long-term outcomes that were no different from those of the cohort as a whole. 25-OH vitamin D serum levels were inversely associated with short-term MS disease activity; however, these levels had no association with long-term disability. At a median time of 16.8 years after disease onset, 10.7% (95% confidence interval [CI] = 7.2-14%) of patients reached an EDSS ≥ 6, and 18.1% (95% CI = 13.5-22.5%) evolved from relapsing MS to secondary progressive MS (SPMS)., Interpretation: Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies. Notably, the NEDA 2-year endpoint was not a predictor of long-term stability. Finally, the data call into question the utility of annual MRI assessments as a treat-to-target approach for MS care. Ann Neurol 2016;80:499-510., Competing Interests: Potential Conflicts of Interest Companies that make MS DMTs described in this manuscript include: Bayer, Biogen, EMD Serono, Pfizer, and Teva. The following authors disclosed financial relationships with these companies. SB: consultancy- EMD Serono, Teva; BACC: consultancy- Biogen, EMD Serono, Teva; GRC: consultancy- Biogen, Teva, EMD Serono, Pfizer; DSG: speaking fees- EMD Serono, Teva; EC-H: consultancy- Biogen, Teva; DTO: consultancy and speaking fees- Teva; DP: consultancy- Biogen; SSZ: speaking fees- Biogen., (© 2016 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)

OBJECT Diffusion MRI has uniquely enabled in vivo delineation of white matter tracts, which has been applied to the segmentation of eloquent pathways for intraoperative mapping. The last decade has also seen the development from earlier diffusion tensor models to higher-order models, which take advantage of high angular resolution diffusion-weighted imaging (HARDI) techniques. However, these advanced methods have not been widely implemented for routine preoperative and intraoperative mapping. The authors report on the application of residual bootstrap q-ball fiber tracking for routine mapping of potentially functional language pathways, the development of a system for rating tract injury to evaluate the impact on clinically assessed language function, and initial results predicting long-term language deficits following glioma resection. METHODS The authors have developed methods for the segmentation of 8 putative language pathways including dorsal phonological pathways and ventral semantic streams using residual bootstrap q-ball fiber tracking. Furthermore, they have implemented clinically feasible preoperative acquisition and processing of HARDI data to delineate these pathways for neurosurgical application. They have also developed a rating scale based on the altered fiber tract density to estimate the degree of pathway injury, applying these ratings to a subset of 35 patients with pre- and postoperative fiber tracking. The relationships between specific pathways and clinical language deficits were assessed to determine which pathways are predictive of long-term language deficits following surgery. RESULTS This tracking methodology has been routinely implemented for preoperative mapping in patients with brain gliomas who have undergone awake brain tumor resection at the University of California, San Francisco (more than 300 patients to date). In this particular study the authors investigated the white matter structure status and language correlation in a subcohort of 35 subjects both pre- and postsurgery. The rating scales developed for fiber pathway damage were found to be highly reproducible and provided significant correlations with language performance. Preservation of the left arcuate fasciculus (AF) and the temporoparietal component of the superior longitudinal fasciculus (SLF-tp) was consistent in all patients without language deficits (p < 0.001) at the long-term follow-up. Furthermore, in patients with short-term language deficits, the AF and/or SLF-tp were affected, and damage to these 2 pathways was predictive of a long-term language deficit (p = 0.005). CONCLUSIONS The authors demonstrated the successful application of q-ball tracking in presurgical planning for language pathways in brain tumor patients and in assessing white matter tract integrity postoperatively to predict long-term language dysfunction. These initial results predicting long-term language deficits following tumor resection indicate that postoperative injury to dorsal language pathways may be prognostic for long-term clinical language deficits. Study results suggest the importance of dorsal stream tract preservation to reduce language deficits in patients undergoing glioma resection, as well as the potential prognostic value of assessing postoperative injury to dorsal language pathways to predict long-term clinical language deficits.

Purpose: To present and assess a procedure for measurement of spinal cord total cross-sectional areas (TCA) and gray matter (GM) areas based on phase-sensitive inversion recovery imaging (PSIR). In vivo assessment of spinal cord GM and white matter (WM) could become pivotal to study various neurological diseases, but it is challenging because of insufficient GM/WM contrast provided by conventional magnetic resonance imaging (MRI)., Materials and Methods: We acquired 2D PSIR images at 3T at each disc level of the spinal axis in 10 healthy subjects and measured TCA, cord diameters, WM and GM areas, and GM area/TCA ratios. Second, we investigated 32 healthy subjects at four selected levels (C2-C3, C3-C4, T8-T9, T9-T10, total acquisition time <8 min) and generated normative reference values of TCA and GM areas. We assessed test-retest, intra- and interoperator reliability of the acquisition strategy, and measurement steps., Results: The measurement procedure based on 2D PSIR imaging allowed TCA and GM area assessments along the entire spinal cord axis. The tests we performed revealed high test-retest/intraoperator reliability (mean coefficient of variation [COV] at C2-C3: TCA = 0.41%, GM area = 2.75%) and interoperator reliability of the measurements (mean COV on the 4 levels: TCA = 0.44%, GM area = 4.20%; mean intraclass correlation coefficient: TCA = 0.998, GM area = 0.906)., Conclusion: 2D PSIR allows reliable in vivo assessment of spinal cord TCA, GM, and WM areas in clinically feasible acquisition times. The area measurements presented here are in agreement with previous MRI and postmortem studies., (© 2014 Wiley Periodicals, Inc.)

Importance: In multiple sclerosis (MS), upper cervical cord gray matter (GM) atrophy correlates more strongly with disability than does brain or cord white matter (WM) atrophy. The corresponding relationships in the thoracic cord are unknown owing to technical difficulties in assessing GM and WM compartments by conventional magnetic resonance imaging techniques., Objectives: To investigate the associations between MS disability and disease type with lower thoracic cord GM and WM areas using phase-sensitive inversion recovery magnetic resonance imaging at 3 T, as well as to compare these relationships with those obtained at upper cervical levels., Design, Setting, and Participants: Between July 2013 and March 2014, a total of 142 patients with MS (aged 25-75 years; 86 women) and 20 healthy control individuals were included in this cross-sectional observational study conducted at an academic university hospital., Main Outcomes and Measures: Total cord areas (TCAs), GM areas, and WM areas at the disc levels C2/C3, C3/C4, T8/9, and T9/10. Area differences between groups were assessed, with age and sex as covariates., Results: Patients with relapsing MS (RMS) had smaller thoracic cord GM areas than did age- and sex-matched control individuals (mean differences [coefficient of variation (COV)]: 0.98 mm2 [9.2%]; P = .003 at T8/T9 and 0.93 mm2 [8.0%]; P = .01 at T9/T10); however, there were no significant differences in either the WM area or TCA. Patients with progressive MS showed smaller GM areas (mean differences [COV]: 1.02 mm2 [10.6%]; P < .001 at T8/T9 and 1.37 mm2 [13.2%]; P < .001 at T9/T10) and TCAs (mean differences [COV]: 3.66 mm2 [9.0%]; P < .001 at T8/T9 and 3.04 mm2 [7.2%]; P = .004 at T9/T10) compared with patients with RMS. All measurements (GM, WM, and TCA) were inversely correlated with Expanded Disability Status Scale score. Thoracic cord GM areas were correlated with lower limb function. In multivariable models (which also included cord WM areas and T2 lesion number, brain WM volumes, brain T1 and fluid-attenuated inversion recovery lesion loads, age, sex, and disease duration), cervical cord GM areas had the strongest correlation with Expanded Disability Status Scale score followed by thoracic cord GM area and brain GM volume., Conclusions and Relevance: Thoracic cord GM atrophy can be detected in vivo in the absence of WM atrophy in RMS. This atrophy is more pronounced in progressive MS than RMS and correlates with disability and lower limb function. Our results indicate that remarkable cord GM atrophy is present at multiple cervical and lower thoracic levels and, therefore, may reflect widespread cord GM degeneration.

The source of inter-subject variability and the influence of age and gender on morphometric characteristics of the spinal cord, such as the total cross-sectional area (TCA), the gray matter (GM) and white matter (WM) areas, currently remain under investigation. Understanding the effect of covariates such as age, gender, brain volumes, and skull- and vertebra-derived metrics on cervical and thoracic spinal cord TCA and GM areas in healthy subjects would be fundamental for exploring compartment specific changes in neurological diseases affecting the spinal cord. Using Magnetic Resonance Imaging at 3T we investigated 32 healthy subjects using a 2D phase sensitive inversion recovery sequence and we measured TCA, GM and WM areas at 4 cervical and thoracic levels of the spinal cord. We assessed age and gender relationships of cord measures and explored associations between cord measures and a) brain volumes and b) skull- and vertebra-derived metrics. Age and gender had a significant effect on TCA, WM and GM areas (with women and elderly having smaller values than men and younger people respectively), but not on the GM area/TCA ratio. The total intracranial volume and C3 vertebra dimensions showed the highest correlations with cord measures. When used in multi-regression models, they reduced cord areas group variability by approximately a third. Age and gender influences on cord measures and normalization strategies here presented might be of use in the study of compartment specific changes in various neurological diseases affecting the spinal cord.

Background and Purpose: The loss of contrast on T1-weighted MR images at 3T may affect the detection of hyperintense punctate lesions indicative of periventricular leukomalacia in preterm neonates. The aim of the present study was to determine which 3T T1-weighted sequence identified the highest number of hyperintense punctate lesions and to explore the relationship between the number of hyperintense punctate lesions and clinical outcome., Materials and Methods: The presence of hyperintense punctate lesions was retrospectively evaluated in 200 consecutive preterm neonates on 4 axial T1-weighted sequences: 3-mm inversion recovery and spin-echo and 1- and 3-mm reformatted 3D-fast-field echo. Statistically significant differences in the number of hyperintense punctate lesions were evaluated by using a linear mixed-model analysis. Logistic regression analysis was used to assess the relation between the number of hyperintense punctate lesions and neuromotor outcome at 3 months., Results: Thirty-one neonates had at least 1 hyperintense punctate lesion indicative of periventricular leukomalacia in at least 1 of the 4 sequences. The 1-mm axial reformatted 3D-fast-field echo sequence identified the greatest number of hyperintense punctate lesions (P < .001). No statistically significant differences were found among the 3-mm T1-weighted sequences. The greater number of hyperintense punctate lesions detected by the 1-mm reformatted T1 3D-fast-field echo sequence in the central region of the brain was associated with a worse clinical outcome., Conclusions: At 3T, the 1-mm axial reformatted T1 3D-fast-field echo sequence identified the greatest number of hyperintense punctate lesions in the central region of preterm neonate brains, and this number was associated with neuromotor outcome., (© 2015 by American Journal of Neuroradiology.)

Purpose: To grade brain gliomas by using a data-driven analysis of multiparametric magnetic resonance (MR) imaging, taking into account the heterogeneity of the lesions at MR imaging, and to compare these results with the most widespread current radiologic reporting methods., Materials and Methods: One hundred eighteen patients with histologically confirmed brain gliomas were evaluated retrospectively. Conventional and advanced MR sequences (perfusion-weighted imaging, MR spectroscopy, and diffusion-tensor imaging) were performed. Three evaluations were conducted: semiquantitative (based on conventional and advanced sequences with reported cutoffs), qualitative (exclusively based on conventional MR imaging), and quantitative. For quantitative analysis, four volumes of interest were placed: regions with contrast material enhancement, regions with highest and lowest signal intensity on T2-weighted images, and regions of most restricted diffusivity. Statistical analysis included t test, receiver operating characteristic (ROC) analysis, discriminant function analysis (DFA), leave-one-out cross-validation, and Kendall coefficient of concordance., Results: Significant differences were noted in age, relative cerebral blood volume (rCBV) in contrast-enhanced regions (cutoff > 2.59; sensitivity, 80%; specificity, 91%; area under the ROC curve [AUC] = 0.937; P = .0001), areas of lowest signal intensity on T2-weighted images (>2.45, 57%, 97%, 0.852, and P = .0001, respectively), restricted diffusivity regions (>2.61, 54%, 97%, 0.808, and P = .0001, respectively), and choline/creatine ratio in regions with the lowest signal intensity on T2-weighted images (>2.07, 49%, 88%, 0.685, and P = .0007, respectively). DFA that included age; rCBV in contrast-enhanced regions, areas of lowest signal intensity on T2-weighted images, and areas of restricted diffusivity; and choline/creatine ratio in areas with lowest signal intensity on T2-weighted images was used to classify 95% of patients correctly. Quantitative analysis showed a higher concordance with histologic findings than qualitative and semiquantitative methods (P < .0001)., Conclusion: A quantitative multiparametric MR imaging evaluation that incorporated heterogeneity at MR imaging significantly improved discrimination between low- and high-grade brain gliomas with a very high AUC (ie, 0.95), thus reducing the risk of inappropriate or delayed surgery, respectively.