Identification of direct connections between the dura and the brain.

The arachnoid barrier delineates the border between the central nervous system and dura mater. Although the arachnoid barrier creates a partition, communication between the central nervous system and the dura mater is crucial for waste clearance and immune surveillance1,2. How the arachnoid barrier balances separation and communication is poorly understood. Here, using transcriptomic data, we developed transgenic mice to examine specific anatomical structures that function as routes across the arachnoid barrier. Bridging veins create discontinuities where they cross the arachnoid barrier, forming structures that we termed arachnoid cuff exit (ACE) points. The openings that ACE points create allow the exchange of fluids and molecules between the subarachnoid space and the dura, enabling the drainage of cerebrospinal fluid and limited entry of molecules from the dura to the subarachnoid space. In healthy human volunteers, magnetic resonance imaging tracers transit along bridging veins in a similar manner to access the subarachnoid space. Notably, in neuroinflammatory conditions such as experimental autoimmune encephalomyelitis, ACE points also enable cellular trafficking, representing a route for immune cells to directly enter the subarachnoid space from the dura mater. Collectively, our results indicate that ACE points are a critical part of the anatomy of neuroimmune communication in both mice and humans that link the central nervous system with the dura and its immunological diversity and waste clearance systems.

The frequency and characteristics of multiple sclerosis misdiagnosis in Latin America: A referral center study in Buenos Aires, Argentina.

OBJECTIVE: Most contemporary data concerning the frequency and causes of multiple sclerosis (MS) misdiagnosis are from North America and Europe with different healthcare system structure and resources than countries in Latin America. We sought to determine the frequency, and potential contributors to MS misdiagnosis in patients evaluated at an MS referral center in Argentina. METHODS: The study was a retrospective medical record review. We included patients evaluated at the MS Clinic at Fleni between April 2013 and March 2021. Diagnoses prior to consultation, final diagnoses after consultation, demographic, clinical and paraclinical data, and treatment were extracted and classified. RESULTS: Seven hundred thirty-six patients were identified. Five hundred seventy-two presented with an established diagnosis of MS and after evaluation, misdiagnosis was identified in 89 (16%). Women were at 83% greater risk of misdiagnosis (p = 0.034). The most frequent alternative diagnoses were cerebrovascular disease, radiological isolated syndrome (RIS), and headache. Seventy-four (83%) of misdiagnosed patients presented with a syndrome atypical for demyelination, 62 (70%) had an atypical brain magnetic resonance imaging (MRI), and 54 (61%) were prescribed disease-modifying therapy. CONCLUSION: Sixteen percent of patients with established MS were subsequently found to have been misdiagnosed. Women were at higher risk for misdiagnosis. Expert application of the McDonald criteria may prevent misdiagnosis and its associated morbidity and healthcare system cost.

Multiple sclerosis and neuromyelitis optica spectrum disorders in Argentina: comparing baseline data from the Argentinean MS Registry (RelevarEM).

The objective of this study was to describe and compare the baseline epidemiological data of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) patients included in RelevarEM (Clinical Trials registry number NCT03375177). METHODS: RelevarEM is a longitudinal, strictly observational MS and NMOSD registry in Argentina. Epidemiological and comorbidity data from MS and NMOSD patients were described and compared. For comorbidities, the Charlson comorbidity index (CCI) was used to calculate the burden at entry. CCI was stratified in 0 and ≥ 1 and described for the entire cohort. RESULTS: A total of 1588 and 75 MS and NMOSD patients (respectively) were included. For MS patients, the mean age was 42 ± 7 years, female sex 65.3%, mean EDSS 2, and mean disease duration 8 ± 6 years. In NMOSD, the mean age was 40 ± 7 years, female sex 78.7%, mean disease duration 5 ± 3.5 years, and mean EDSS 2.5. The most frequent MS phenotype was RRMS in 82.4%. In MS, the CCI was 0 in 85.8.2% while ≥ 1 was in 14.2% of patients. Regarding phenotype stratification, CCI ≥ 1 was 3.9% in CIS, 13.5% in RRMS, 28.7% in SPMS, and 17.4% in PPMS (p < 0.001 between groups). In NMOSD, the CCI was 0 in 64% while ≥ 1 was in 36%. The MS/NMOSD ratio found was 21/1. CONCLUSIONS: This is the first analysis of the longitudinal Argentinean registry of MS and NMOSD describing and comparing conditions that contributes to provide reliable real-world data in the country.

Progressive multiple sclerosis: from pathogenic mechanisms to treatment.

During the past decades, better understanding of relapsing-remitting multiple sclerosis disease mechanisms have led to the development of several disease-modifying therapies, reducing relapse rates and severity, through immune system modulation or suppression. In contrast, current therapeutic options for progressive multiple sclerosis remain comparatively disappointing and challenging. One possible explanation is a lack of understanding of pathogenic mechanisms driving progressive multiple sclerosis. Furthermore, diagnosis is usually retrospective, based on history of gradual neurological worsening with or without occasional relapses, minor remissions or plateaus. In addition, imaging methods as well as biomarkers are not well established. Magnetic resonance imaging studies in progressive multiple sclerosis show decreased blood-brain barrier permeability, probably reflecting compartmentalization of inflammation behind a relatively intact blood-brain barrier. Interestingly, a spectrum of inflammatory cell types infiltrates the leptomeninges during subpial cortical demyelination. Indeed, recent magnetic resonance imaging studies show leptomeningeal contrast enhancement in subjects with progressive multiple sclerosis, possibly representing an in vivo marker of inflammation associated to subpial demyelination. Treatments for progressive disease depend on underlying mechanisms causing central nervous system damage. Immunity sheltered behind an intact blood-brain barrier, energy failure, and membrane channel dysfunction may be key processes in progressive disease. Interfering with these mechanisms may provide neuroprotection and prevent disability progression, while potentially restoring activity and conduction along damaged axons by repairing myelin. Although most previous clinical trials in progressive multiple sclerosis have yielded disappointing results, important lessons have been learnt, improving the design of novel ones. This review discusses mechanisms involved in progressive multiple sclerosis, correlations between histopathology and magnetic resonance imaging studies, along with possible new therapeutic approaches.

Optimal detection of infratentorial lesions with a combined dual-echo MRI sequence: "PT2".

BACKGROUND: The infratentorial compartment is cardinal for multiple sclerosis (MS) diagnosis. T2-weighted (T2) and proton density-weighted (PD) magnetic resonance imaging (MRI) can visualize infratentorial lesions, but only suboptimally. OBJECTIVE: To combine PD and T2 for better lesion assessment. METHODS: T2 and PD from 35 cases were averaged to form "PT2" images. Two raters counted infratentorial lesions and qualitatively assessed their conspicuity. RESULTS: PT2 showed 244 infratentorial lesions, of which 94% and 74% were seen in PD and T2. PT2 received higher grades for image quality and lesion conspicuity (p < 0.001 for all comparisons). CONCLUSION: PT2 could improve our ability to diagnose and monitor MS.

Novel marmoset (Callithrix jacchus) model of human Herpesvirus 6A and 6B infections: immunologic, virologic and radiologic characterization.

Human Herpesvirus 6 (HHV-6) is a ubiquitous virus with an estimated seroprevalence of 95% in the adult population. HHV-6 is associated with several neurologic disorders, including multiple sclerosis, an inflammatory demyelinating disease affecting the CNS. Animal models of HHV-6 infection would help clarify its role in human disease but have been slow to develop because rodents lack CD46, the receptor for cellular entry. Therefore, we investigated the effects of HHV-6 infections in a non-human primate, the common marmoset Callithrix jacchus. We inoculated a total of 12 marmosets with HHV-6A and HHV-6B intravenously and HHV-6A intranasally. Animals were monitored for 25 weeks post-inoculation clinically, immunologically and by MRI. Marmosets inoculated with HHV-6A intravenously exhibited neurologic symptoms and generated virus-specific antibody responses, while those inoculated intravenously with HHV-6B were asymptomatic and generated comparatively lower antibody responses. Viral DNA was detected at a low frequency in paraffin-embedded CNS tissue of a subset of marmosets inoculated with HHV-6A and HHV-6B intravenously. When different routes of HHV-6A inoculation were compared, intravenous inoculation resulted in virus-specific antibody responses and infrequent detection of viral DNA in the periphery, while intranasal inoculation resulted in negligible virus-specific antibody responses and frequent detection of viral DNA in the periphery. Moreover, marmosets inoculated with HHV-6A intravenously exhibited neurologic symptoms, while marmosets inoculated with HHV-6A intranasally were asymptomatic. We demonstrate that a marmoset model of HHV-6 infection can serve to further define the contribution of this ubiquitous virus to human neurologic disorders.

The formation of inflammatory demyelinated lesions in cerebral white matter.

OBJECTIVE: Vascular permeability and inflammatory demyelination are intimately linked in the brain, but what is their temporal relationship? We aimed to determine the radiological correlates of the earliest tissue changes accompanying demyelination in a primate model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in the common marmoset. METHODS: By 7T magnetic resonance imaging (MRI), T1 maps, proton density, and T2-weighted images were acquired before and after EAE induction in 5 marmosets (every other week before lesions appeared, weekly thereafter). From scans before and after intravenous injection of contrast material, we measured the evolution of lesional blood-brain barrier (BBB) permeability, comparing in vivo MRI to postmortem tissue examination. RESULTS: On average, BBB permeability increased 3.5-fold (p < 0.0001) over the 4 weeks prior to lesion appearance. Permeability gradually decreased after lesion appearance, with attendant changes in the distribution of inflammatory cells (predominantly macrophages and microglia) and demyelination. On tissue analysis, we also identified small perivascular foci of microglia and T cells without blood-derived macrophages or demyelination. These foci had no visible MRI correlates, although permeability within the foci, but not outside, increased in the weeks before the animals died (p < 0.0001). INTERPRETATION: This study provides compelling evidence that in marmoset EAE, which forms lesions strongly resembling those of MS, early changes in vascular permeability are associated with perivascular inflammatory cuffing and parenchymal microglial activation but precede the arrival of blood-derived monocytes that accompany demyelination. Prospective detection of transient permeability changes could afford an opportunity for early intervention to forestall tissue damage in newly forming lesions.

Sodium intake is associated with increased disease activity in multiple sclerosis.

BACKGROUND: Recently, salt has been shown to modulate the differentiation of human and mouse Th17 cells and mice that were fed a high-sodium diet were described to develop more aggressive courses of experimental autoimmune encephalomyelitis. However, the role of sodium intake in multiple sclerosis (MS) has not been addressed. We aimed to investigate the relationship between salt consumption and clinical and radiological disease activity in MS. METHODS: We conducted an observational study in which sodium intake was estimated from sodium excretion in urine samples from a cohort of 70 relapsing-remitting patients with MS who were followed for 2 years. The effect of sodium intake in MS disease activity was estimated using regression analysis. We then replicated our findings in a separate group of 52 patients with MS. RESULTS: We found a positive correlation between exacerbation rates and sodium intake in a multivariate model adjusted for age, gender, disease duration, smoking status, vitamin D levels, body mass index and treatment. We found an exacerbation rate that was 2.75-fold (95% CI 1.3 to 5.8) or 3.95-fold (95% CI 1.4 to 11.2) higher in patients with medium or high sodium intakes compared with the low-intake group. Additionally, individuals with high-sodium intake had a 3.4-fold greater chance of developing a new lesion on the MRI and on average had eight more T2 lesions on MRI. A similar relationship was found in the independent replication group. CONCLUSIONS: Our results suggest that a higher sodium intake is associated with increased clinical and radiological disease activity in patients with MS.

Seven-tesla phase imaging of acute multiple sclerosis lesions: a new window into the inflammatory process.

OBJECTIVE: In multiple sclerosis (MS), accurate, in vivo characterization of dynamic inflammatory pathological changes occurring in newly forming lesions could have major implications for understanding disease pathogenesis and mechanisms of tissue destruction. Here, we investigated the potential of ultrahigh-field magnetic resonance imaging (MRI; 7T), particularly phase imaging combined with dynamic contrast enhancement, to provide new insights in acute MS lesions. METHODS: Sixteen active MS patients were studied at 7T. Noncontrast, high-resolution T2* magnitude and phase scans, T1 scans before/after gadolinium contrast injection, and dynamic contrast-enhanced (DCE) T1 scans were acquired. T2*/phase features and DCE pattern were determined for acute and chronic lesions. When possible, 1-year follow-up 7T MRI was performed. RESULTS: Of 49 contrast-enhancing lesions, 44 could be analyzed. Centrifugal DCE lesions appeared isointense or hypointense on phase images, whereas centripetal DCE lesions showed thin, hypointense phase rims that clearly colocalized with the initial site of contrast enhancement. This pattern generally disappeared once enhancement resolved. Conversely, in 43 chronic lesions also selected for the presence of hypointense phase rims, the findings were stable over time, and the rims were typically thicker and darker. These considerations suggest different underlying pathological processes in the 2 lesion types. INTERPRETATION: Ultrahigh-field MRI and, especially, phase contrast, are highly sensitive to tissue changes in acute MS lesions, which differ from the patterns seen in chronic lesions. In acute lesions, the hypointense phase rim reflects the expanding inflammatory edge and may directly correspond to inflammatory byproducts and sequelae of blood-brain barrier opening.

Perivenular brain lesions in a primate multiple sclerosis model at 7-tesla magnetic resonance imaging.

BACKGROUND Magnetic resonance imaging (MRI) can provide in vivo assessment of tissue damage, allowing evaluation of multiple sclerosis (MS) lesion evolution over time--a perspective not obtainable with postmortem histopathology. Relapsing-remitting experimental autoimmune encephalomyelitis (EAE) is an experimental model of MS that can be induced in the common marmoset, a small new world primate, and that causes perivenular white matter (WM) lesions similar to those observed in MS. METHODS Brain lesion development and evolution were studied in vivo and postmortem in four marmosets with EAE through serial T2- and T2*-weighted scans at 7-tesla. Supratentorial WM lesions were identified and characterized. RESULTS Of 97 lesions observed, 86 (88%) were clearly perivenular, and 62 (72%) developed around veins that were visible even prior to EAE induction. The perivenular configuration was confirmed by postmortem histopathology. Most affected veins, and their related perivascular Virchow-Robin spaces, passed into the subarachnoid space rather than the ventricles. CONCLUSION As in human MS, the intimate association between small veins and EAE lesions in the marmoset can be studied with serial in vivo MRI. This further strengthens the usefulness of this model for understanding the process of perivenular lesion development and accompanying tissue destruction in MS.

New Imaging Markers in Multiple Sclerosis and Related Disorders: Smoldering Inflammation and the Central Vein Sign.

Concepts of multiple sclerosis (MS) biology continue to evolve, with observations such as "progression independent of disease activity" challenging traditional phenotypic categorization. Iron-sensitive, susceptibility-based imaging techniques are emerging as highly translatable MR imaging sequences that allow for visualization of at least 2 clinically useful biomarkers: the central vein sign and the paramagnetic rim lesion (PRL). Both biomarkers demonstrate high specificity in the discrimination of MS from other mimics and can be seen at 1.5 T and 3 T field strengths. Additionally, PRLs represent a subset of chronic active lesions engaged in "smoldering" compartmentalized inflammation behind an intact blood-brain barrier.

Super resolution using sparse sampling at portable ultra-low field MR.

Ultra-low field (ULF) magnetic resonance imaging (MRI) holds the potential to make MRI more accessible, given its cost-effectiveness, reduced power requirements, and portability. However, signal-to-noise ratio (SNR) drops with field strength, necessitating imaging with lower resolution and longer scan times. This study introduces a novel Fourier-based Super Resolution (FouSR) approach, designed to enhance the resolution of ULF MRI images with minimal increase in total scan time. FouSR combines spatial frequencies from two orthogonal ULF images of anisotropic resolution to create an isotropic T2-weighted fluid-attenuated inversion recovery (FLAIR) image. We hypothesized that FouSR could effectively recover information from under-sampled slice directions, thereby improving the delineation of multiple sclerosis (MS) lesions and other significant anatomical features. Importantly, the FouSR algorithm can be implemented on the scanner with changes to the k-space trajectory. Paired ULF (Hyperfine SWOOP, 0.064 tesla) and high field (Siemens, Skyra, 3 Tesla) FLAIR scans were collected on the same day from a phantom and a cohort of 10 participants with MS or suspected MS (6 female; mean ± SD age: 44.1 ± 4.1). ULF scans were acquired along both coronal and axial planes, featuring an in-plane resolution of 1.7 mm × 1.7 mm with a slice thickness of 5 mm. FouSR was evaluated against registered ULF coronal and axial scans, their average (ULF average) and a gold standard SR (ANTs SR). FouSR exhibited higher SNR (47.96 ± 12.6) compared to ULF coronal (36.7 ± 12.2) and higher lesion conspicuity (0.12 ± 0.06) compared to ULF axial (0.13 ± 0.07) but did not exhibit any significant differences contrast-to-noise-ratio (CNR) compared to other methods in patient scans. However, FouSR demonstrated superior image sharpness (0.025 ± 0.0040) compared to all other techniques (ULF coronal 0.021 ± 0.0037, q = 5.9, p-adj. = 0.011; ULF axial 0.018 ± 0.0026, q = 11.1, p-adj. = 0.0001; ULF average 0.019 ± 0.0034, q = 24.2, p-adj. < 0.0001) and higher lesion sharpness (-0.97 ± 0.31) when compared to the ULF average (-1.02 ± 0.37, t(543) = -10.174, p = <0.0001). Average blinded qualitative assessment by three experienced MS neurologists showed no significant difference in WML and sulci or gyri visualization between FouSR and other methods. FouSR can, in principle, be implemented on the scanner to produce clinically useful FLAIR images at higher resolution on the fly, providing a valuable tool for visualizing lesions and other anatomical structures in MS.

Highly Sensitive 3-Tesla Real Inversion Recovery MRI Detects Leptomeningeal Contrast Enhancement in Chronic Active Multiple Sclerosis.

BACKGROUND: Leptomeningeal contrast enhancement (LME) on T2-weighted Fluid-Attenuated Inversion Recovery (T2-FLAIR) MRI is a reported marker of leptomeningeal inflammation, which is known to be associated with progression of multiple sclerosis (MS). However, this MRI approach, as typically implemented on clinical 3-tesla (T) systems, detects only a few enhancing foci in ~25% of patients and has thus been criticized as poorly sensitive. PURPOSE: To compare an optimized 3D real-reconstruction inversion recovery (Real-IR) MRI sequence on a clinical 3 T scanner to T2-FLAIR for prevalence, characteristics, and clinical/radiological correlations of LME. MATERIALS AND METHODS: We obtained 3D T2-FLAIR and Real-IR scans before and after administration of standard-dose gadobutrol in 177 scans of 154 participants (98 women, 64%; mean ± SD age: 49 ± 12 years), including 124 with an MS-spectrum diagnosis, 21 with other neurological and/or inflammatory disorders, and 9 without neurological history. We calculated contrast-to-noise ratios (CNR) in 20 representative LME foci and determined association of LME with cortical lesions identified at 7 T (n = 19), paramagnetic rim lesions (PRL) at 3 T (n = 105), and clinical/demographic data. RESULTS: We observed focal LME in 73% of participants on Real-IR (70% in established MS, 33% in healthy volunteers, P < 0.0001), compared to 33% on T2-FLAIR (34% vs. 11%, P = 0.0002). Real-IR showed 3.7-fold more LME foci than T2-FLAIR ( P = 0.001), including all T2-FLAIR foci. LME CNR was 2.5-fold higher by Real-IR ( P < 0.0001). The major determinant of LME status was age. Although LME was not associated with cortical lesions, the number of PRL was associated with the number of LME foci on both T2-FLAIR ( P = 0.003) and Real-IR ( P = 0.0003) after adjusting for age, sex, and white matter lesion volume. CONCLUSIONS: Real-IR a promising tool to detect, characterize, and understand the significance of LME in MS. The association between PRL and LME highlights a possible role of the leptomeninges in sustaining chronic inflammation.

Initial investigation of the blood-brain barrier in MS lesions at 7 tesla.

BACKGROUND: We previously described two dynamics of contrast enhancement in scans of active multiple sclerosis lesions: Medium-sized, early lesions enhance centrifugally, whereas larger, slightly older lesions enhance centripetally. Due to technical limitations, our previous study did not characterize lesions < 5 mm in diameter, cortical enhancement, and anatomical structures within lesions. OBJECTIVE: The objective of this paper is to obtain initial observations of these important aspects of lesion development on a 7 tesla scanner at high spatial resolution. METHODS: We scanned eight patients, acquiring precontrast T2*-weighted scans, T1-weighted scans before and after contrast, and high-resolution dynamic contrast-enhanced scans during and up to 30 min after contrast. RESULTS: We detected 15 enhancing lesions, obtaining dynamic data in 10: Five lesions < 4 mm enhanced centrifugally (initial central enhancement expanded outward), and five lesions > 4 mm enhanced centripetally (initial peripheral enhancement gradually filled the lesion). A leukocortical lesion initially showed enhancement in its white matter portion, which gradually spread into the cortex. Seventy-three percent of lesions were clearly perivenular. CONCLUSION: Most active lesions are perivenular, and the smallest lesions enhance centrifugally. This supports the idea that lesions grow outward from a central vein.

In vivo MRI is sensitive to remyelination in a nonhuman primate model of multiple sclerosis.

Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is challenging. Using experimental autoimmune encephalomyelitis (EAE) in common marmosets, a model of MS that recapitulates focal cerebral inflammatory demyelinating lesions, we investigated whether MRI is sensitive to, and can characterize, remyelination. In six animals followed with multisequence 7 T MRI, 31 focal lesions, predicted to be demyelinated or remyelinated based on signal intensity on proton density-weighted images, were subsequently assessed with histopathology. Remyelination occurred in four of six marmosets and 45% of lesions. Radiological-pathological comparison showed that MRI had high statistical sensitivity (100%) and specificity (90%) for detecting remyelination. This study demonstrates the prevalence of spontaneous remyelination in marmoset EAE and the ability of in vivo MRI to detect it, with implications for preclinical testing of pro-remyelinating agents.

Disease activity after discontinuation of disease-modifying therapies in patients with multiple sclerosis in Argentina: data from the nationwide registry RelevarEM.

INTRODUCTION: The discontinuation of disease-modifying therapies (DMTs) in multiple sclerosis (MS) is commonly seen in real-world settings due to several factors. AREA COVER: The aim of this study is to describe the frequency of disease activity after discontinuation of DMTs in MS patients included in the Argentinean MS and NMOSD registry. DISCUSION: Patients with relapsing remitting MS (RRMS) and active secondary progressive MS (SPMS) were included based on the following criteria: they discontinued treatment for more than 6 months, they had been treated with a DMT for ≥2 years, and they had at least 6 months of follow-up in the registry after discontinuation. Demographic and clinical data were collected. Disease activity during follow-up was defined as the presence of a clinical relapse or a new magnetic resonance (MRI) lesion (either new lesions on T2-weighted sequence and/or contrast enhancement). Bivariate analysis was applied to identify clinical and demographic factors related to disease activity. CONCLUSION: We included 377 patients (75.5% RRMS, 22.5% SPMS) who had discontinued DMTs. The mean (SD) follow-up after discontinuation was 15.7 (7.9) months. After discontinuation, the presence of relapse was detected in 18.8% and 3.5% in RRMS and SPMS, respectively; and new MRI activity in 22% and 3.5%, respectively. We found that higher risk of relapse and MRI activity was associated with younger age (p < 0.001), shorter disease duration (p < 0.001), and RRMS phenotype (p = 0.006). Males showed higher MRI activity (p 0.011). This study provides real-world data that can guide physicians when considering discontinuation of DMTs.

In vivo quantification of T2 anisotropy in white matter fibers in marmoset monkeys.

T2-weighted MRI at high field is a promising approach for studying noninvasively the tissue structure and composition of the brain. However, the biophysical origin of T2 contrast, especially in white matter, remains poorly understood. Recent work has shown that R2 (=1/T2) may depend on the tissue's orientation relative to the static magnetic field (B(0)) and suggested that this dependence could be attributed to local anisotropy in the magnetic properties of brain tissue. In the present work, we analyzed high-resolution, multi-gradient-echo images of in vivo marmoset brains at 7T, and compared them with ex vivo diffusion tensor images, to show that R2 relaxation in white matter is highly sensitive to the fiber orientation relative to the main field. We directly demonstrate this orientation dependence by performing in vivo multi-gradient-echo experiments in two orthogonal brain positions, uncovering a nearly 50% change in the R2 relaxation rate constant of the optic radiations. We attribute this substantial R2 anisotropy to local subvoxel susceptibility effects arising from the highly ordered and anisotropic structure of the myelin sheath.

FLAIR*: a combined MR contrast technique for visualizing white matter lesions and parenchymal veins.

PURPOSE: To evaluate a magnetic resonance (MR) imaging contrast technique, called FLAIR*, that combines the advantages of T2-weighted fluid-attenuated inversion recovery (FLAIR) contrast and T2*-weighted contrast on a single image for assessment of white matter (WM) diseases such as multiple sclerosis (MS). MATERIALS AND METHODS: This prospective pilot study was HIPAA compliant and institutional review board approved. Ten patients with clinically definite MS (eight men, two women; mean age, 41 years) provided informed consent and underwent 3.0-T MR imaging. Images from a T2-weighted FLAIR sequence were combined with images from a T2*-weighted segmented echo-planar imaging sequence performed during contrast material injection, yielding high-isotropic-resolution (0.55 × 0.55 × 0.55 mm(3)) FLAIR* images. Qualitative assessment was performed for image quality, lesion conspicuity, and vein conspicuity. Contrast-to-noise ratio (CNR) was calculated to compare normal-appearing WM (NAWM) with cerebrospinal fluid, lesions, and veins. To evaluate the differences in CNR among imaging modalities, a bootstrap procedure clustered on subjects was used, together with paired t tests. RESULTS: High-quality FLAIR* images of the brain were produced at 3.0 T, yielding conspicuous lesions and veins. Lesion-to-NAWM and NAWM-to-vein CNR values were significantly higher for FLAIR* images than for T2-weighted FLAIR images (P < .0001). Findings on FLAIR* images included intralesional veins for lesions located throughout the brain and a hypointense rim around some WM lesions. CONCLUSION: High-isotropic-resolution FLAIR* images obtained at 3.0 T yield high contrast for WM lesions and parenchymal veins, making it well suited to investigate the relationship between WM abnormalities and veins in a clinical setting.

Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions.

OBJECTIVE: Multiple sclerosis (MS) lesions develop around small, inflamed veins. New lesions enhance with gadolinium on magnetic resonance imaging (MRI), reflecting disruption of the blood-brain barrier (BBB). Single time point results from pathology and standard MRI cannot capture the spatiotemporal expansion of lesions. We investigated the development and expansion of new MS lesions, focusing on the dynamics of BBB permeability. METHODS: We performed dynamic contrast-enhanced (DCE) MRI in relapsing-remitting MS. We obtained data over 65 minutes, during and after gadolinium injection. We labeled spatiotemporal enhancement dynamics as centrifugal when initially central enhancement expanded outward and centripetal when initially peripheral enhancement gradually filled the center. RESULTS: We detected 34 enhancing lesions in 200 DCE-MRI scans. In 65%, enhancement first appeared as a closed ring; in 18%, as a nodule; and in 18%, as an open ring. Lesions with initially nodular enhancement were smaller than those initially enhancing as rings (p < 0.0001). All initially nodular lesions enhanced centrifugally, whereas initially ringlike lesions enhanced centripetally, becoming nodular if small (82%) or nearly nodular if larger (18%). Open-ring lesions were periventricular or juxtacortical and enhanced centripetally. Centrifugally enhancing lesions evolved into centripetally enhancing lesions over several days. INTERPRETATION: The rapid change of enhancement dynamics from centrifugal to centripetal reflects the outward growth of MS lesions around their central vein and suggests that factors mediating lesion growth and tissue repair derive from different locations at different times. We propose a model of new lesion growth that unites our imaging observations with existing pathology data.

Gender differences in 1,25 dihydroxyvitamin D3 immunomodulatory effects in multiple sclerosis patients and healthy subjects.

Vitamin D(3) is best known as a calcium homeostasis modulator; however, it also has immune-modulating potential. In this study, we demonstrated that immunomodulatory effects of vitamin D(3) are significantly stronger in females than in males in multiple sclerosis patients, as well as in healthy subjects. Inhibition of self-reactive T cell proliferation and reduction in IFN-γ- and IL-17-secreting cell numbers were considerably greater in females. Furthermore, the increase in IL-10-secreting and CD4(+)CD25(+)FoxP3(+) regulatory T cell numbers were also greater in females. In parallel with these findings, female subjects had fewer CYP24A1 transcripts encoding the 1,25-dihydroxyvitamin D(3)-inactivating enzyme, as well as greater binding and internalization of vitamin D(3)-binding protein, a transporter for vitamin D(3) and its metabolites. These gender-based disparities lead to the accumulation of vitamin D(3) and its metabolites in target cells from female subjects and result in a more potent anti-inflammatory effect. Interestingly, 17-ß estradiol reproduced these effects on self-reactive T cells and macrophages from male subjects, suggesting a functional synergy between 1,25-dihydroxyvitamin D(3) and 17-ß estradiol, mediated through estrogen receptor α. Collectively, these results demonstrate estrogen-promoted differences in vitamin D(3) metabolism, suggesting a greater protective effect of vitamin D(3)-based therapeutic strategies in women.