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Study design:Retrospective chart review.ObjectiveTo report six patients with isolated longitudinal myelitis (LM).Setting:Outpatients at Multiple Sclerosis Center/Clinic Vanderbilt University Medical Center.Methods:1. Patients:Patients treated for LM in whom evidence for multiple sclerosis (MS), neuromyelitis optica (NMO) and systemic inflammatory disorders such as systemic lupus erythematosus (SLE) was lacking. 2. Interventions: Clinical, laboratory and imaging data, treatment and outcomes were reviewed. 3. Main Outcome Measures: LM in the absence of optic neuritis, normal or nonspecific brain magnetic resonance imaging (MRI) findings, the absence of NMO antibody.Results:All presented with monophasic myelitis with variable loss of motor, sensory and bowel/bladder functions. MRIs of the brain were normal (five cases), and in the sixth showed a single T2 hyperintense lesion, which was interpreted as an ischemic lesion due to small-vessel disease. MRIs of the spinal cord of all patients showed swelling and T2 hyperintense lesions with patchy contrast enhancement that extended from the cervicomedullary junction to the conus medullaris. Two of these patients received rituximab with clinical benefit. Another patient received one dose of rituximab, developed an allergic reaction, received further treatments with azathioprine and also made a good recovery. In one patient, approval for rituximab was obtained several months after the inflammation had subsided, and she has shown only a minimal improvement. The two patients who did not receive rituximab made no significant recovery from their maximal neurological deficits.Conclusions:Isolated LM may be a new clinical syndrome, or a variant of NMO.Spinal Cord (2009) 47, 257–261; doi:10.1038/sc.2008.99; published online 19 August 2008 [ABSTRACT FROM AUTHOR]

We report a series of four patients with Susac's syndrome, which is characterized by the triad of visual loss due to branch retinal artery occlusions, sensorineural hearing loss due to cochlear involvement, and encephalopathy due to cerebral microangiopathy. However, as we describe in this series, the clinical triad may not be apparent for years, resulting in delays in diagnosis. We also report the variable cerebrospinal fluid and brain magnetic resonance imaging findings, and treatment using a combination of steroids and intravenous immunoglobulin, followed by mycophenolate mofetil. [ABSTRACT FROM AUTHOR]

Interplay between susceptibility genes and environmental factors is considered important player in the genesis of multiple sclerosis (MS). Among environmental factors, a role for an infectious pathogen has long been considered central to the disease process. This opinion has support both from epidemiological data and the findings of immunological abnormalities in spinal fluid that reflect an immune response to an as yet undetermined antigen, possibly a pathogen, in the cerebrospinal fluid. Our review will outline the current understanding of the role of infection in the causation and progression of MS. We will review the data that point to an infectious cause of MS and consider the specific agents Chlamydophila (Chlamydia) pneumoniae, Human Herpes Virus 6, and Epstein-Barr Virus, that are implicated in either the development or progression of MS.

We describe the case of a 73-year-old woman presenting with headaches, confusion, and vision disturbances. Brain MRI showed a large T2-hyperintense lesion in the right temporo-occipital region with vasogenic edema and leptomeningeal enhancement. A leptomeningeal biopsy was performed, which led to a definitive diagnosis.

Background: Autoimmune encephalitis (AIE) encompasses a range of inflammatory disorders manifesting with some combination of encephalopathy, seizures, behavioral changes, movement disorders, dysautonomia or other neurologic symptoms. Anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is the most common AIE and is an autoantibody mediated disorder, often paraneoplastic. Untreated or undertreated AIE has a high degree of morbidity and mortality. Immunosuppressive treatment regimens including glucocorticoids, plasma exchange (PLEX), intravenous immunoglobulin (IVIG) and rituximab used alone or in combination for such patients. Patients' refractory to such treatments requires more aggressive and potentially toxic therapies. We report favorable outcomes in patients with refractory AIE who received intrathecal methotrexate (IT-MTX) as part of treatment., Methods: Cases at our institution seen between 2010 and 2020 were reviewed. We identified 5 patients in our clinical practice whose clinical presentation was compatible with NMDARE. Three patients met criteria for definite NMDARE. An additional two patients met criteria for probable NMDARE in the acute setting but were ultimately seronegative autoimmune encephalitis. All patients received at least one dose of IT-MTX after failing conventional therapies. At the time of IT-MTX administration patients were catatonic, comatose, or severely encephalopathic despite initial treatments., Results: All patients were treated with methylprednisolone; 3 received a course of IVIG, 4 underwent PLEX, and 4 received rituximab. At the time IT-MTX was given, three patients required mechanical ventilation and 1 had a pacemaker placed for autonomic failure. Two patients were under consideration for transition to palliative care. All patients improved and were at or near their premorbid baseline at last follow-up. All patients tolerated IT-MTX well., Conclusions: This retrospective review demonstrates the efficacy of intrathecal methotrexate in the treatment of severe AIE who had failed other immunosuppressive regimens., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Although often regarded as a protean illness with myriad clinical and imaging manifestations, neurosarcoidosis typically presents as recognizable syndromes that can be approached in a rational, systematic fashion. Understanding of neurosarcoidosis has progressed significantly in recent years, including updated diagnostic criteria and advances in treatment. The diagnosis of neurosarcoidosis is established by the clinical syndrome, imaging and histopathological findings, and exclusion of other causes. Mounting evidence supports the use of tumor necrosis factor inhibitors as an important addition to the therapeutic armamentarium, along with glucocorticoids and steroid-sparing cytotoxic immunosuppressants. In this narrative review, we summarize recent advances in the diagnosis and treatment of neurosarcoidosis., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose of Review: This article provides an overview and update on the neurologic manifestations of sarcoidosis., Recent Findings: The 2018 Neurosarcoidosis Consortium diagnostic criteria emphasize that biopsy is key for diagnosis and determines the level of diagnostic certainty. Thus, definite neurosarcoidosis requires nervous system biopsy and probable neurosarcoidosis requires biopsy from extraneural tissue. Without biopsy, possible neurosarcoidosis can be diagnosed if the clinical, imaging, and laboratory picture is compatible and other causes are ruled out. Recent large retrospective studies from the United States and France established that infliximab appears to be efficacious when other treatments are inadequate., Summary: Sarcoidosis is a multisystem noninfectious granulomatous disorder that is immune mediated, reflecting the response to an as-yet unidentified antigen or antigens. Neurosarcoidosis refers to neurologic involvement due to sarcoidosis that clinically manifests in 5% of cases of sarcoidosis, with asymptomatic involvement in as many as another one in five patients with sarcoidosis. Sarcoid granulomas can occur in any anatomic substrate in the nervous system, causing protean manifestations that have earned neurosarcoidosis the sobriquet the great mimic. Nevertheless, central nervous system sarcoidosis occurs in well-defined presentations that can be classified as cranial neuropathies, meningeal disease, brain parenchymal (including pituitary-hypothalamic) disease, and spinal cord disease. In addition, the peripheral nervous system is affected in the form of peripheral neuropathy and myopathy. Glucocorticoids are the cornerstone of treatment, especially in the acute stage, whereas steroid-sparing agents such as methotrexate, mycophenolate mofetil, and azathioprine are used for prolonged therapy to minimize steroid toxicity. Anti-tumor necrosis factor agents may help in refractory cases.

Cognitive impairment (CI) is a major manifestation of multiple sclerosis (MS) and is responsible for extensively hindering patient quality of life. Cortical gray matter (cGM) damage is a significant contributor to CI, but is poorly characterized by conventional MRI let alone with quantitative MRI, such as quantitative magnetization transfer (qMT). Here we employed high-resolution qMT at 7T via the selective inversion recovery (SIR) method, which provides tissue-specific indices of tissue macromolecular content, such as the pool size ratio (PSR) and the rate of MT exchange (kmf). These indices could represent expected demyelination that occurs in the presence of gray matter damage. We utilized selective inversion recovery (SIR) qMT which provides a low SAR estimate of macromolecular-bulk water interactions using a tailored, B1 and B0 robust inversion recovery (IR) sequence acquired at multiple inversion times (TI) at 7T and fit to a two-pool model of magnetization exchange. Using this sequence, we evaluated qMT indices across relapsing-remitting multiple sclerosis patients (N = 19) and healthy volunteers (N = 37) and derived related associations with neuropsychological measures of cognitive impairment. We found a significant reduction in k mf in cGM of MS patients (15.5%, p = 0.002), unique association with EDSS (ρ = -0.922, p = 0.0001), and strong correlation with cognitive performance (ρ = -0.602, p = 0.0082). Together these findings indicate that the rate of MT exchange (k mf ) may be a significant biomarker of cGM damage relating to CI in MS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Cognitive impairment (CI) profoundly impacts quality of life for patients with multiple sclerosis (MS). Dysfunctional regulation of glutamate in gray matter (GM) has been implicated in the pathogenesis of MS by post-mortem pathological studies and in CI by in vivo magnetic resonance spectroscopy, yet GM pathology is subtle and difficult to detect using conventional T 1 - and T 2 -weighted magnetic resonance imaging (MRI). There is a need for high-resolution, clinically accessible imaging techniques that probe molecular changes in GM., Objective: To study cortical GM pathology related to CI in MS using glutamate-sensitive chemical exchange saturation transfer (GluCEST) MRI at 7.0 Tesla (7T)., Methods: A total of 20 patients with relapsing-remitting MS and 20 healthy controls underwent cognitive testing, anatomical imaging, and GluCEST imaging. Glutamate-sensitive image contrast was quantified for cortical GM, compared between cohorts, and correlated with clinical measures of CI., Results and Conclusion: Glutamate-sensitive contrast was significantly increased in the prefrontal cortex of MS patients with accumulated disability ( p  < 0.05). In addition, glutamate-sensitive contrast in the prefrontal cortex was significantly correlated with symbol digit modality test ( r S  = -0.814) and choice reaction time ( r S  = 0.772) scores in patients ( p  < 0.05), suggesting that GluCEST MRI may have utility as a marker for GM pathology and CI.

Background: Patients with biopsy-proven systemic sarcoidosis who develop a chronic CNS disorder are often presumed to have neurosarcoidosis (NS), however, the possibility of comorbid neurologic disease, such as MS, must be considered if presentation and course are not typical for NS., Methods: Retrospective chart review across 4 academic MS centers was undertaken to identify patients with diagnosis of MS (2017 McDonald criteria) and biopsy-confirmed extraneural sarcoidosis. Data were abstracted from each chart using a case report form that systematically queried for demographic, clinical, and paraclinical characteristics relevant to NS and MS., Results: Ten patients met our inclusion criteria (mean age 47.7 [±5.9] years; 80% female). Noncaseating granulomas consistent with sarcoidosis were found on biopsy in all cases (lung 7/10, mediastinum 2/10, liver 1/10, spleen 1/10, and skin 1/10). Diagnosis of MS was based on clinical history of MS-like relapses and MRI findings characteristic of demyelination and typical disease evolution during follow-up (average of 7 years). No patient developed features of NS that could be considered a "red flag" against the diagnosis of MS (such as meningeal enhancement, hydrocephalus, and pituitary involvement). All patients were treated with disease-modifying therapy for MS., Conclusions: We propose a rational diagnostic approach to patients with sarcoidosis who may have comorbid MS. When the clinical picture is equivocal, the presence of multiple "MS-typical lesions" and the absence of any "NS-typical lesions" on MRI favor diagnosis of MS. Close follow-up is required to ascertain whether clinical and radiologic disease evolution and response to MS therapies conform to the proposed diagnosis of MS.

Importance: The Neurosarcoidosis Consortium Consensus Group, an expert panel of physicians experienced in the management of patients with sarcoidosis and neurosarcoidosis, engaged in an iterative process to define neurosarcoidosis and develop a practical diagnostic approach to patients with suspected neurosarcoidosis. This panel aimed to develop a consensus clinical definition of neurosarcoidosis to enhance the clinical care of patients with suspected neurosarcoidosis and to encourage standardization of research initiatives that address this disease., Observations: The work of this collaboration included a review of the manifestations of neurosarcoidosis and the establishment of an approach to the diagnosis of this disorder. The proposed consensus diagnostic criteria, which reflect current knowledge, provide definitions for possible, probable, and definite central and peripheral nervous system sarcoidosis. The definitions emphasize the need to evaluate patients with findings suggestive of neurosarcoidosis for alternate causal factors, including infection and malignant neoplasm. Also emphasized is the need for biopsy, whenever feasible and advisable according to clinical context and affected anatomy, of nonneural tissue to document the presence of systemic sarcoidosis and support a diagnosis of probable neurosarcoidosis or of neural tissue to support a diagnosis of definite neurosarcoidosis., Conclusions and Relevance: Diverse disease presentations and lack of specificity of relevant diagnostic tests contribute to diagnostic uncertainty. This uncertainty is compounded by the absence of a pathognomonic histologic tissue examination. The diagnostic criteria we propose are designed to focus investigations on NS as accurately as possible, recognizing that multiple pathophysiologic pathways may lead to the clinical manifestations we currently term NS. Research recognizing the clinical heterogeneity of this diagnosis may open the door to identifying meaningful biologic factors that may ultimately contribute to better treatments.

Background and Purpose: An imaging biomarker of myelin integrity is an unmet need in multiple sclerosis (MS). Selective inversion recovery (SIR) quantitative magnetization transfer imaging (qMT) provides assays of myelin content in the human brain. We previously translated the SIR method to 7T and incorporated a rapid turbo field echo (TFE) readout for whole-brain imaging within clinically acceptable scan times. We herein provide histological validation and test in vivo feasibility and applicability of the SIR-TFE protocol in MS., Methods: Clinical (T 1 - and T 2 -weighted) and SIR-TFE MRI scans were performed at 7T in a postmortem MS brain and MRI data were acquired in 10 MS patients and 14 heathy volunteers in vivo. The following parameters were estimated from SIR data: the macromolecular-to-free water pool-size-ratio (PSR), the spin-lattice relaxation rate of water (R 1f ), and the MT exchange rate (k mf ). Differences in SIR parameters across tissue types, eg, white matter lesions (WM-Ls) and normal appearing WM (NAWM) in patients, and normal white matter (NWM) in heathy volunteers were evaluated. Associations between SIR parameters and disability scores were assessed., Results: For postmortem scans, correspondence was observed between WM-Ls and NAWM from histology and PSR/R 1f values. In vivo differences were detected for PSR, R 1f , and k mf between WM-Ls and NWM (P ≤ .041). Associations were seen between WM-Ls/ NAWM PSR and disability scores (r ≤ -.671, P ≤ .048)., Conclusions: SIR-qMT at 7T provides sensitive, quantitative measures of myelin integrity for clinical and research applications., (Copyright © 2018 by the American Society of Neuroimaging.)

Patients with multiple sclerosis present with focal lesions throughout the spinal cord. There is a clinical need for non-invasive measurements of spinal cord activity and functional organization in multiple sclerosis, given the cord's critical role in the disease. Recent reports of spontaneous blood oxygenation level-dependent fluctuations in the spinal cord using functional MRI suggest that, like the brain, cord activity at rest is organized into distinct, synchronized functional networks among grey matter regions, likely related to motor and sensory systems. Previous studies looking at stimulus-evoked activity in the spinal cord of patients with multiple sclerosis have demonstrated increased levels of activation as well as a more bilateral distribution of activity compared to controls. Functional connectivity studies of brain networks in multiple sclerosis have revealed widespread alterations, which may take on a dynamic trajectory over the course of the disease, with compensatory increases in connectivity followed by decreases associated with structural damage. We build upon this literature by examining functional connectivity in the spinal cord of patients with multiple sclerosis. Using ultra-high field 7 T imaging along with processing strategies for robust spinal cord functional MRI and lesion identification, the present study assessed functional connectivity within cervical cord grey matter of patients with relapsing-remitting multiple sclerosis (n = 22) compared to a large sample of healthy controls (n = 56). Patient anatomical images were rated for lesions by three independent raters, with consensus ratings revealing 19 of 22 patients presented with lesions somewhere in the imaged volume. Linear mixed models were used to assess effects of lesion location on functional connectivity. Analysis in control subjects demonstrated a robust pattern of connectivity among ventral grey matter regions as well as a distinct network among dorsal regions. A gender effect was also observed in controls whereby females demonstrated higher ventral network connectivity. Wilcoxon rank-sum tests detected no differences in average connectivity or power of low frequency fluctuations in patients compared to controls. The presence of lesions was, however, associated with local alterations in connectivity with differential effects depending on columnar location. The patient results suggest that spinal cord functional networks are generally intact in relapsing-remitting multiple sclerosis but that lesions are associated with focal abnormalities in intrinsic connectivity. These findings are discussed in light of the current literature on spinal cord functional MRI and the potential neurological underpinnings.

Background: Fingolimod is a daily oral medication used to treat relapsing multiple sclerosis (MS). Clinicians often adopt less frequent dosing for patients with profound drug-induced lymphopenia or other adverse events. Data on the effectiveness of alternate dose fingolimod are limited., Methods: We conducted a multicenter, retrospective, observational study at 14 sites and identified 170 patients with MS taking alternate doses of fingolimod for ≥1 month. Clinical and radiologic outcomes were collected and compared during daily and alternate fingolimod dosing., Results: Profound lymphopenia (77%), liver function abnormalities (9%), and infections (7%) were the most common reasons for patients to switch to alternate fingolimod dosing. The median follow-up was 12 months on daily dose and 14 months on alternate dose. Most patients (64%) took fingolimod every other day during alternate dosing. Disease activity was similar on alternate dose compared to daily dose: annualized relapse rate was 0.1 on daily dose vs 0.2 on alternate dose ( p = 0.25); proportion of patients with contrast-enhancing MRI lesions was 7.6% on daily vs 9.4% on alternate ( p = 0.55); proportion of patients with cumulative MS activity (clinical and radiologic disease) was 13.5% on daily vs 18.2% on alternate ( p = 0.337). Patients who developed contrast-enhancing lesions while on daily dose were at higher risk for breakthrough disease while on alternate dose fingolimod (odds ratio 11.4, p < 0.001)., Conclusions: These data support the clinical strategy of alternate dosing of fingolimod in patients with good disease control but profound lymphopenia or other adverse events while on daily dose., Classification of Evidence: This study provides Class IV evidence that for patients with MS on daily dose fingolimod with adverse events, alternate dose fingolimod is associated with disease activity similar to daily dose fingolimod.

T2*-weighted multi-echo gradient-echo magnetic resonance imaging and its reciprocal R2* are used in brain imaging due to their sensitivity to iron content. In patients with multiple sclerosis who display pathological alterations in iron and myelin contents, the use of R2* may offer a unique way to untangle mechanisms of disease. Coronal slices from 8 brains of deceased multiple sclerosis patients were imaged using a whole-body 7.0 Tesla MRI scanner. The scanning protocol included three-dimensional (3D) T2*-w multi-echo gradient-echo and 2D T2-w turbo spin echo (TSE) sequences. Histopathological analyses of myelin and iron content were done using Luxol fast blue and proteolipid myelin staining and 3,3'-diaminobenzidine tetrahydrochloride enhanced Turnbull blue staining. Quantification of R2*, myelin and iron intensity were obtained. Variations in R2* were found to be affected differently by myelin and iron content in different regions of multiple sclerosis brains. The data shall inform clinical investigators in addressing the role of T2*/R2* variations as a biomarker of tissue integrity in brains of MS patients, in vivo.

Purpose: The ability to evaluate pathological changes in the spinal cord in multiple sclerosis (MS) is limited because T 1 - and T 2 -w MRI imaging are not sensitive to biochemical changes in vivo. Amide proton transfer (APT) chemical exchange saturation transfer (CEST) can indirectly detect amide protons associated with proteins and peptides, potentially providing more pathological specificity. Here, we implement APT CEST in the cervical spinal cord of healthy and MS cohorts at 3T., Methods: APT CEST of the cervical spinal cord was obtained in a cohort of 10 controls and 10 MS patients using a novel respiratory correction methodology. APT was quantified using two methods: 1) APT w , based off the conventional magnetization transfer ratio asymmetry, and 2) ΔAPT, a spatial characterization of APT changes in MS patients relative to the controls., Results: Respiratory correction yielded highly reproducible z-spectra in white matter (intraclass correlation coefficient = 0.82). APT w signals in normal-appearing white matter (NAWM) of MS patients were significantly different from healthy controls (P = 0.04), whereas ΔAPT of MS patients highlighted large APT differences in NAWM., Conclusion: Respiration correction in the spinal cord is necessary to accurately quantify APT CEST, which can provide unique biochemical information regarding disease processes within the spinal cord. Magn Reson Med 79:806-814, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Objective: To describe clinical and imaging responses in neurosarcoidosis to infliximab, a monoclonal antibody against tumor necrosis factor-α., Methods: Investigators at 6 US centers retrospectively identified patients with CNS sarcoidosis treated with infliximab, including only patients with definite or probable neurosarcoidosis following rigorous exclusion of other causes., Results: Of 66 patients with CNS sarcoidosis (27 definite, 39 probable) treated with infliximab for a median of 1.5 years, the mean age was 47.5 years at infliximab initiation (SD 11.7, range 24-71 years); 56.1% were female; 62.1% were white, 37.0% African American, and 3% Hispanic. Sarcoidosis was isolated to the CNS in 19.7%. Using infliximab doses ranging from 3 to 7 mg/kg every 4-8 weeks, MRI evidence of a favorable treatment response was observed in 82.1% of patients with imaging follow-up (n = 56), with complete remission of active disease in 51.8% and partial MRI improvement in 30.1%; MRI worsened in 1 patient (1.8%). There was clinical improvement in 77.3% of patients, with complete neurologic recovery in 28.8%, partial improvement in 48.5%, clinical stability in 18.2%, worsening in 3%, and 1 lost to follow-up. In 16 patients in remission when infliximab was discontinued, the disease recurred in 9 (56%), typically in the same neuroanatomic location., Conclusions: Most patients with CNS sarcoidosis treated with infliximab exhibit favorable imaging and clinical treatment responses, including some previously refractory to other immunosuppressive treatments., Classification of Evidence: This study provides Class IV evidence that for patients with CNS sarcoidosis infliximab is associated with favorable imaging and clinical responses., (© 2017 American Academy of Neurology.)

Background: Optic neuritis (ON) is one of the most common presentations of multiple sclerosis (MS). Magnetic resonance imaging (MRI) of the optic nerves is challenging because of retrobulbar motion, orbital fat and susceptibility artifacts from maxillary sinuses; therefore, axonal loss is investigated with the surrogate measure of a single heuristically defined point along the nerve as opposed to volumetric investigation., Objective: The objective of this paper is to derive optic nerve volumetrics along the entire nerve length in patients with MS and healthy controls in vivo using high-resolution, clinically viable MRI., Methods: An advanced, isotropic T2-weighted turbo spin echo MRI was applied to 29 MS patients with (14 patients ON+) or without (15 patients ON-) history of ON and 42 healthy volunteers. An automated tool was used to estimate and compare whole optic nerve and surrounding cerebrospinal fluid radii along the length of the nerve., Results and Conclusion: Only ON+ MS patients had a significantly reduced optic nerve radius compared to healthy controls in the central segment of the optic nerve. Using clinically available MRI methods, we show and quantify ON volume loss for the first time in MS patients.

Spinal cord (SC) damage is linked to clinical deficits in patients with multiple sclerosis (MS), however, conventional MRI methods are not specific to the underlying macromolecular tissue changes that may precede overt lesion detection. Single-point quantitative magnetization transfer (qMT) is a method that can provide high-resolution indices sensitive to underlying macromolecular composition in a clinically feasible scan time by reducing the number of MT-weighted acquisitions and utilizing a two-pool model constrained by empirically determined constants. As the single-point qMT method relies on a priori constraints, it has not been employed extensively in patients, where these constraints may vary, and thus, the biases inherent in this model have not been evaluated in a patient cohort. We, therefore, addressed the potential biases in the single point qMT model by acquiring qMT measurements in the cervical SC in patient and control cohorts and evaluated the differences between the control and patient-derived qMT constraints (k mf , T 2f R 1f , and T 2m ) for the single point model. We determined that the macromolecular to free pool size ratio (PSR) differences between the control and patient-derived constraints are not significant (p > 0.149 in all cases). Additionally, the derived PSR for each cohort was compared, and we reported that the white matter PSR in healthy volunteers is significantly different from lesions (p < 0.005) and normal appearing white matter (p < 0.02) in all cases. The single point qMT method is thus a valuable method to quantitatively estimate white matter pathology in MS in a clinically feasible scan time.

Purpose: To empirically characterize and quantify the impact of gradient weighting schemes on the appearance and fidelity of diffusion tensor imaging of the human spinal cord in vivo in clinically relevant scan time equivalents (STE)., Materials and Methods: In five healthy controls at 3T, we evaluated test-retest reproducibility and performed voxelwise analysis of diffusion tensor imaging (DTI)-derived indices (fractional anisotropy [FA], mean [MD], axial [AD], and radial [RD] diffusivity) in the cervical spinal cord to assess spatial dependencies of measurement error and differences across three different sampling schemes (6, 15, and 32 directions) at STE of 4.5, 9, and 18 minutes. A subjective assessment was also performed., Results: With six directions, column-specific errors are highest (effect size = 2.9%, 4.4%, 7.2% for FA in dorsal column, lateral column, and gray matter) and different than the 15-direction scheme (P < 0.05). STE sequences with 15 and 32 directions exhibited small differences in error (P > 0.05). For FA and AD, measurement errors are prevalent in gray matter, while partial volume effects with cerebrospinal fluid heavily influence RD. Measurement errors decreased with increasing scan time (P < 0.01), albeit with diminishing returns at scan times longer than 9 minutes (P < 0.05)., Conclusion: A 15-direction scheme of 9 minutes yields measurements of the cervical spinal cord with low error. J. Magn. Reson. Imaging 2016;44:1608-1618., (© 2016 International Society for Magnetic Resonance in Medicine.)

High-magnetic-field (7 T) chemical exchange saturation transfer (CEST) MRI provides information on the tissue biochemical environment. Multiple sclerosis (MS) affects the entire central nervous system, including the spinal cord. Optimal CEST saturation parameters found via simulation were implemented for CEST MRI in 10 healthy controls and 10 patients with MS, and the results were examined using traditional asymmetry analysis and a Lorentzian fitting method. In addition, T1 - and T2 *-weighted images were acquired for lesion localization and the transmitted B1 (+) field was evaluated to guide imaging parameters. Distinct spectral features for all tissue types studied were found both up- and downfield from the water resonance. The z spectra in healthy subjects had the expected z spectral shape with CEST effects apparent from 2.0 to 4.5 ppm. The z spectra from patients with MS demonstrated deviations from this expected normal shape, indicating this method's sensitivity to known pathology as well as to tissues appearing normal on conventional MRI. Examination of the calculated CESTasym revealed increased asymmetry around the amide proton resonance (Δω = 3.5 ppm), but it was apparent that this measure is complicated by detail in the CEST spectrum upfield from water, which is expected to result from the nuclear Overhauser effect. The z spectra upfield (negative ppm range) were also distinct between healthy and diseased tissue, and could not be ignored, particularly when considering the conventional asymmetry analysis used to quantify the CEST effect. For all frequencies greater than +1 ppm, the Lorentzian differences (and z spectra) for lesions and normal-appearing white matter were distinct from those for healthy white matter. The increased frequency separation and signal-to-noise ratio, in concert with prolonged T1 at 7 T, resulted in signal enhancements necessary to detect subtle tissue changes not possible at lower field strengths. This study presents CEST imaging metrics that may be sensitive to the extensive and temporally varying biochemical neuropathology of MS in the spinal cord. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: The clinical course of multiple sclerosis (MS) is mainly attributable to cervical and upper thoracic spinal cord dysfunction. High-resolution, 7T anatomical imaging of the cervical spinal cord is presented. Image contrast between gray/white matter and lesions surpasses conventional, clinical T1- and T2-weighted sequences at lower field strengths., Objective: To study the spinal cord of healthy controls and patients with MS using magnetic resonance imaging at 7T., Methods: Axial (C2-C5) T1- and T2*-weighted and sagittal T2*-/spin-density-weighted images were acquired at 7T in 13 healthy volunteers (age 22-40 years), and 15 clinically diagnosed MS patients (age 19-53 years, Extended Disability Status Scale, (EDSS) 0-3) in addition to clinical 3T scans. In healthy volunteers, a high-resolution multi-echo gradient echo scan was obtained over the same geometry at 3T. Evaluation included signal and contrast to noise ratios and lesion counts for healthy and patient volunteers, respectively., Results/conclusion: High-resolution images at 7T exceeded resolutions reported at lower field strengths. Gray and white matter were sharply demarcated and MS lesions were more readily visualized at 7T compared to clinical acquisitions, with lesions apparent at both fields. Nerve roots were clearly visualized. White matter lesion counts averaged 4.7 vs 3.1 (52% increase) per patient at 7T vs 3T, respectively (p=0.05)., (© The Author(s), 2015.)

Purpose: Our goal is to develop an accurate, automated tool to characterize the optic nerve (ON) and cerebrospinal fluid (CSF) to better understand ON changes in disease., Methods: Multi-atlas segmentation is used to localize the ON and sheath on T2-weighted MRI (0.6 mm(3) resolution). A sum of Gaussian distributions is fit to coronal slice-wise intensities to extract six descriptive parameters, and a regression forest is used to map the model space to radii. The model is validated for consistency using tenfold cross-validation and for accuracy using a high resolution (0.4 mm(2) reconstructed to 0.15 mm(2)) in vivo sequence. We evaluated this model on 6 controls and 6 patients with multiple sclerosis (MS) and a history of optic neuritis., Results: In simulation, the model was found to have an explanatory R-squared for both ON and sheath radii greater than 0.95. The accuracy of the method was within the measurement error on the highest possible in vivo resolution. Comparing healthy controls and patients with MS, significant structural differences were found near the ON head and the chiasm, and structural trends agreed with the literature., Conclusion: This is a first demonstration that the ON can be exclusively, quantitatively measured and separated from the surrounding CSF using MRI., (© 2015 Wiley Periodicals, Inc.)

Purpose: A diffusion-weighted multishot echo-planar imaging approach combined with SENSE and a two-dimensional (2D) navigated motion correction was investigated as an alternative to conventional single-shot counterpart to obtain optic nerve images at higher spatial resolution with reduced artifacts., Methods: Fifteen healthy subjects were enrolled in the study. Six of these subjects underwent a repeated acquisition at least 2 weeks after the initial scan session to address reproducibility. Both single-shot and multishot diffusion tensor imaging studies of the human optic nerve were performed with matched scan time. Effect of subject motions were corrected using 2D phase navigator during multishot image reconstruction. Tensor-derived indices from proposed multishot were compared against conventional single-shot approach. Image resolution difference, right-left optic nerve asymmetry, and test-retest reproducibility were also assessed., Results: In vivo results of acquired multishot images and quantitative maps of diffusion properties of the optic nerve showed significantly reduced image artifacts (e.g., distortions and blurring), and the derived diffusion indices were comparable to those from other studies. Single-shot scans presented larger variability between right and left optic nerves than multishot scans. Multishot scans also presented smaller variations across scans at different time points when compared with single-shot counterparts., Conclusion: The multishot technique has considerable potential for providing improved information on optic nerve pathology and may also be translated to higher fields., (© 2014 Wiley Periodicals, Inc.)

Background: The high value of the specific absorption rate (SAR) of radio-frequency (RF) energy arising from the series of RF refocusing pulses in T2-weighted (T2-w) turbo spin echo (TSE) MRI hampers its clinical application at 7.0 Tesla (7T). T2-w gradient and spin echo (GRASE) uses the speed from gradient refocusing in combination with the chemical-shift/static magnetic field (B0) inhomogeneity insensitivity from spin-echo refocusing to acquire T2-w images with a limited number of refocusing RF pulses, thus reducing SAR., Objectives: To investigate whether low SAR T2-w GRASE could replace T2-w TSE in detecting white matter (WM) disease in MS patients imaged at 7T., Methods: The .7 mm3 isotropic T2-w TSE and T2-w GRASE images with variable echo times (TEs) and echo planar imaging (EPI) factors were obtained on a 7T scanner from postmortem samples of MS brains. These samples were derived from brains of 3 female MS patients. WM lesions (WM-Ls) and normal-appearing WM (NAWM) signal intensity, WM-Ls/NAWM contrast-to-noise ratio (CNR) and MRI/myelin staining sections comparisons were obtained., Results: GRASE sequences with EPI factor/TE = 3/50 and 3/75 ms were comparable to the SE technique for measures of CNR in WM-Ls and NAWM and for detection of WM-Ls. In all sequences, however, identification of areas with remyelination, Wallerian degeneration, and gray matter demyelination, as depicted by myelin staining, was not possible., Conclusions: T2-w GRASE images may replace T2-w TSE for clinical use. However, even at 7T, both sequences fail in detecting and characterizing MS disease beyond visible WM-Ls., (Copyright © 2015 by the American Society of Neuroimaging.)

Background: Multiple sclerosis (MS) is the most common cause of nontraumatic neurological disability in young adults. There is great need for developing effective treatments to arrest the disease. As of today, there is no cure for MS but several agents mitigating its effects are available. The era of disease-modifying therapy began with the use of interferon beta and glatiramer acetate in the 1990s. Given the injectable nature and the limited efficacy of these agents, efforts are ongoing to develop new treatments., Summary of Review: We provide an overview of the ongoing developments in MS therapy. After considering the clinical features and measures of drug efficacy in MS clinical trials, we report the phase-III clinical trials results of: (1) 3 oral agents approved within the last 5 years, fingolimod (Gilenya), dimethylfumarate (Tecfidera), and teriflunomide (Aubagio); (2) the oral agent laquinimod; and (3) the monoclonal antibodies daclizumab, ocrelizumab, and alemtuzumab. We will then briefly mention remyelinating and neuroprotective agents that are in very early studies. We will end with a possible approach to different clinical scenarios to guide the choice of disease-modifying therapy in patients., Conclusions: The newer agents offer the convenience of oral administration (for the oral agents) and potentially higher efficacy, but their long-term safety profile remains unknown. All available agents attack only 1 aspect of MS, that is, inflammatory demyelination. Arresting or reversing the progression of disability will be feasible only with agents affecting remyelination and neuroprotection, still in relatively early research.

Objective: Neurosarcoidosis is a rare granulomatous disease that can result in cranial neuropathy, chronic meningitis, and intracranial granuloma formation. Meningeal involvement may cause focal nodular enhancement that can simulate common cranial base tumors. The objective of the current study is to further define the clinical features of neurosarcoidosis in a large cohort of patients, focusing on characteristics relevant to the skull base surgeon., Study Design: Retrospective series., Setting: Two tertiary academic referral centers., Patients: Consecutive patients diagnosed with neurosarcoidosis., Intervention(s): Review of clinical presentation, physical examination, radiologic findings, biopsy results, and laboratory testing., Main Outcome Measures: Prevalence and distribution of cranial neuropathy, radiologic features of meningeal enhancement, and patterns of simulated tumors., Results: A total of 305 patients met study criteria. The mean age at diagnosis was 47 years and 53% were female. The optic nerve was the most commonly involved cranial nerve, followed by the trigeminal and the facial nerve. Meningeal enhancement was present in 67% of cases with 17% demonstrating focal or multicentric nodular enhancement simulating tumor. The most common locations of inflammatory tumor development included the cavernous sinus, petrous temporal bone, and sphenoid wing; six patients had bilateral internal auditory canal lesions, several mimicking neurofibromatosis type II., Conclusion: Establishing the diagnosis of neurosarcoidosis remains challenging. Meningeal involvement and cranial neuropathy often mimic other more common conditions. Careful review of patient history and clinical imaging can reveal important clues toward the diagnosis of neurosarcoidosis. The clinician must maintain a high index of suspicion in patients with atypical presentation to avoid misdiagnosis and facilitate early medical treatment.

Background: The enthusiasm for natalizumab, a highly efficacious agent in the treatment of multiple sclerosis (MS), has been tempered by the risks of progressive multifocal leukoencephalopathy associated with its use, and strategies to minimize those risks are of great interest. Extended interval dosing (EID) has been proposed as a way to maintain the efficacy of natalizumab while reducing exposure to it. We reviewed a cohort of patients who received natalizumab at 6-8-week intervals instead of the typical infusions every 4 weeks with the goal to assess if patients on EID had an increase in clinical relapses., Methods: This is a retrospective review of all patients with MS treated with natalizumab at two MS centers where patients were offered the opportunity to switch to an EID every 6 or 8 weeks., Results: A total of 361 patients received natalizumab for 22 ± 13 months (minimum duration 6 months). Of these, 96 patients received EID natalizumab at some point for 20 ± 11 months (minimum duration 6 months). Over the study period, there was no significant difference between the relapse rate in the monthly dosing (13%) and the EID (13%) groups of patients., Conclusion: Natalizumab is effective in controlling MS as very few clinical relapses were observed in our dataset. We found that EID did not compromise the treatment effect as measured by relapse rate and no significant breakthrough disease activity was observed. EID is an optional regimen for maintenance natalizumab therapy, but prospective studies are warranted to determine its efficacy.

Objective: To share our experience on clinical presentation and management of patients diagnosed with Hashimoto's Encephalopathy (HE) at Vanderbilt Medical Center between 1999 and 2012., Background: HE is a rare disorder characterized by encephalopathy and central nervous system (CNS) dysfunction, elevated antithyroid antibodies, the absence of infection or structural abnormalities in the CNS, and a response to treatment with steroids. The relationship between thyroid antibodies and encephalopathy has remained unresolved., Design/methods: Retrospective chart review., Results: We identified 13 patients who met the criteria for the diagnosis of HE. The median age was 49 years (range, 2-66) and all except one were women. Encephalopathy in the form of altered mental status, stroke-like symptoms or seizures, with prompt resolution of symptoms upon receiving steroids, was the commonest presentation, seen in 7 patients. The second commonest presentation was subacute progressive decrease in cognitive function, which reversed within days to weeks after steroid therapy, seen in 4 patients. Electroencephalogram (EEG) was available in 12 patients and was abnormal in 8, showing nonspecific cerebral dysfunction in all 8 and epileptiform activity in 3. Treatment consisted of steroids in the acute phase for 12 of 13 patients with rapid improvement in symptoms. Maintenance therapy was rituximab in 7 patients, intravenous immunoglobulin (IVIg) in 7, azathioprine in 4, mycophenolate mofetil in 3, and methotrexate in 1 (some patients received sequential therapy with different agents). There was complete or near complete resolution of symptoms in 12 of the 13 patients., Conclusions: We present a cohort of patients in whom CNS dysfunction was associated with elevated antithyroid antibodies and reversal of disease followed immunomodulatory therapies., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The objective of this work is to report on a series of five patients with adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia (ALSP). ALSP is a rare adult-onset leukodystrophy, which encompasses hereditary diffuse leukoencephalopathy with axonal spheroids and pigmentary orthochromatic leukodystrophy. This was a retrospective chart review and literature review. Five previously healthy women presented with a rapidly progressive neurological disorder at ages 39, 37, 40, 30, and 47, respectively. All five individuals were initially diagnosed as suffering from multiple sclerosis. The clinical courses of the five patients were dominated by progressive spastic quadriparesis (patient 5, newly diagnosed, has paraparesis at this time) and dementia. Brain magnetic resonance imaging (MRI) showed diffuse cerebral atrophy, corpus callosal atrophy, and diffuse T2 hyperintensities in the subcortical and periventricular white matter with no gadolinium enhancing lesions. Three patients showed involvement of pyramidal tracts from motor cortex to the brainstem. Cerebrospinal fluid was normal in all cases. Diagnosis of ALSP was established by biopsy (two cases) and autopsy (two cases). Histopathology showed the presence of neuroaxonal spheroids in all four cases and pigmented glia in three. In the fifth case, diagnosis was established by genetic analysis alone that showed a disease-causing mutation in the colony-stimulating factor 1 receptor (CSF1R) gene. Genetic analysis was done in three patients with available DNA, and identified the disease-causing mutation in all three, including a novel mutation F828S. ALSP may be suspected in adults with rapid to subacute progression of neurological disease when (1) MRI shows corpus callosal atrophy on a background of generalized brain atrophy and diffuse white matter disease without postcontrast enhancement, (2) CSF studies are normal, and (3) studies for systemic inflammatory diseases and specific leukodystrophies are normal. Diagnosis may be made without histopathological evidence when a disease-causing mutation is demonstrated in the CSF1R gene.

Objective: To investigate differences in T2 intensity of deep gray matter (dGM) structures by magnetic resonance imaging (MRI) in multiple sclerosis (MS) patients undergoing various immunomodulatory therapies., Background: In MS, dGM T2 hypointensities by MRI are hypothesized to represent iron deposition and are known to be associated with worse disease stage as assessed by brain atrophy, cognitive and physical disability. The relation between immunotherapies and T2 intensity, however, has been not been investigated in detail., Methods: A total of 255 MS patients were stratified into those on no treatment (NON, n= 45), and those on immunomodulatory treatments for ≥6 months (ie, interferon beta [IFNβ]n= 118, glatiramer acetate [GA]n= 41, natalizumab [NAT]n= 39, and mycophenolate mofetil [MMF]n= 12). T2 intensities of dentate nucleus (DN), substantia nigra (SN), red nucleus (RN), and globus pallidus (GP) were measured. Group differences in T2 intensities were assessed using a linear regression model with T2 intensities as outcome variable, treatment group as main independent variable, and clinical measures such as Expanded Disability Status Scale (EDSS) score, years of MS, and 25-feet walk time (T25-FW) as covariates. To compare T2 intensities before and after treatment in a subset of NAT-treated patients, we used the Wilcoxon signed-rank test., Results: When adjusted for EDSS, duration of disease and T25-FW, across all deep nuclei, NAT-treated patients had significantly higher T2 intensities than untreated patients (DN p= 1.65 × 10(-5) ; SN p= 2.37 × 10(-5) ; RN p= 3.90 × 10(-6) ; GP p= 1.05 × 10(-6) ), IFNβ-treated patients (DN p= 1.65 × 10(-5) ; SN p= 2.37 × 10(-5) ; RN p= 3.90 × 10(-6) ; GP p= 1.05 × 10(-6) ), and GA-treated patients (DN p= 1.65 × 10(-5) ; SN p= 2.37 × 10(-5) ; RN p= 3.90 × 10(-6) ; GP p= 1.05 × 10(-6) ). In a subset of MS patients receiving NAT, there was a significant increase in T2 intensities in all the dGM nuclei after 24 months of treatment (DN p= 0.00021; SN p= <0.0001; RN p= 0.00015; GP p= 0.00011)., Conclusion: Our preliminary observations suggest that long-term NAT therapy in MS patients may affect T2 intensity levels of dGM brain nuclei, hence suggesting a potential effect of NAT beyond anti-inflammatory effect. Prospective studies are warranted to provide more insights into our preliminary observations. , (Copyright © 2011 by the American Society of Neuroimaging.)

Chemical exchange saturation transfer (CEST) MRI is a molecular imaging method that has previously been successful at reporting variations in tissue protein and glycogen contents and pH. We have implemented amide proton transfer (APT), a specific form of chemical exchange saturation transfer imaging, at high field (7 T) and used it to study healthy human subjects and patients with multiple sclerosis. The effects of static field inhomogeneities were mitigated using a water saturation shift referencing method to center each z-spectrum on a voxel-by-voxel basis. Contrary to results obtained at lower fields, APT imaging at 7 T revealed significant contrast between white and gray matters, with a higher APT signal apparent within the white matter. Preliminary studies of multiple sclerosis showed that the APT asymmetry varied with the type of lesion examined. An increase in APT asymmetry relative to healthy tissue was found in some lesions. These results indicate the potential utility of APT at high field as a noninvasive biomarker of white matter pathology, providing complementary information to other MRI methods in current clinical use., (Copyright © 2011 Wiley-Liss, Inc.)

The mitogen-activated protein kinases (MAPKs) play a central role in mediating the activation and transcriptional responses of diverse cells, including glia. c-Jun N-terminal kinase (JNK), a member of the MAPK family, is activated by a variety of stress and proinflammatory signals and in turn phosphorylates its downstream substrates including nuclear factors, leading to transcriptional activation of target genes. There are at least three subtypes of JNK (i.e., JNKs 1-3) that may play isoform-specific roles. This study examined the role of JNK isoforms in the induction of inducible nitric oxide synthase (iNOS) in astrocytes in response to lipopolysachharide (LPS) and interferon (IFN)-gamma. While an inhibitor of the JNK pathway (SP600125) inhibited iNOS expression, ectopic expression of a constitutively active form of MEKK1 (MAPK/ERK kinase kinase- 1), an upstream activator of JNK, led to an induction of co-transfected iNOS promoter activity and, in the presence of LPS, to an enhanced expression of iNOS. RNA knockdown studies with JNK subtype-specific short-interfering RNA (siRNA), indicated that JNK1- but not JNK2- nor JNK3-specific siRNA, interfered with LPS/IFNgamma induction of iNOS. It is concluded that, of the three JNK forms, JNK1 is the major mediator of iNOS induction and perhaps, inflammatory signaling in general, in glial cells.

Astrocytes and microglia, the two immune-regulatory cells of the central nervous system (CNS), are activated by a variety of pathogens and cytokines to elicit rapid transcriptional responses. This program of activation is initiated by a set of intracellular signaling cascades that includes mitogen-activated protein kinase (MAPK), nuclear factor (NF) kappaB, and Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathways. This study defines the critical role that NADPH oxidase(Phox)-derived reactive oxygen species (ROS) play in lipopolysaccharide (LPS)- and interferon (IFN)gamma-induced signaling cascades leading to gene expression in glial cells. Treatment of rat microglia and astrocytes with LPS and IFNgamma resulted in a rapid activation of Phox and the release of ROS followed by an induction of inducible nitric oxide synthase (iNOS) expression. iNOS induction was blocked by inhibitors of Phox, i.e., diphenylene iodonium chloride (DPI) and 4-(2-aminoethyl) benzenesulfonylfluoride (AEBSF), suggesting an involvement of ROS signaling in iNOS gene expression. Exogenous catalase but not superoxide dismutase suppressed the basal activity and completely blocked induced levels of NO/iNOS, suggesting that hydrogen peroxide is the ROS involved. Phox inhibitors and catalase also suppressed LPS/IFNgamma-induced expression of cytokines, i.e., interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)alpha and blocked LPS activation of MAP kinases (i.e., p38 MAPK, c-Jun N-terminal kinase and extracellular signal-regulated kinase), NFkappaB, and IFNgamma-induced STAT1 phosphorylation. A microglial cell line stably transfected with a mutant form of Phox subunit, i.e., p47(phox) W(193)R, and primary astrocytes derived from Phox-deficient mice showed attenuated ROS production and induction of iNOS in response to LPS/IFNgamma, further strengthening the notion that Phox-derived ROS are crucial for proinflammatory gene expression in glial cells., (Copyright 2004 Wiley-Liss, Inc.)

Thromboxane A2 (TxA2) receptors belong to the class of G-protein-coupled receptors. Knowledge of the relationship of structure to function for TxA2 receptors is limited because of their low levels of expression, lengthy purification procedures and poor recoveries. A C-terminal hexahistidine-tag (C-His) was ligated to the alpha-isoform of TxA2 receptors and expressed in COS-7 and Chinese hamster ovary cells. The C-His-TxA2 receptors bound the radioligands 125I-7-[(1R,2S,3S,5R)-6, 6-dimethyl-3-(4-benzenesulfonylamino)bicyclo[3.1. 1]hept-2-yl]-5(Z)-heptenoic acid, an antagonist, and 125I-[1S-1alpha, 2beta(5Z),3alpha(1E,3S*), 4alpha]-7-[3[(3-hydroxy-4-(4'-phenoxy)-1butenyl)-7-oxabicycl o-[2.2. 1]heptan-2-yl]-5-heptanoic acid, an agonist, with affinities not significantly different from those of the wild type (wt)-TxA2 receptors. LipofectAMINE transfection of the cDNAs resulted in high levels of expression (Bmax = 95 +/- 6 pmol/mg) of the C-His-TxA2 receptors. In competition binding studies the IC50 values of five different ligands were not significantly different between C-His-TxA2 and wt-TxA2 receptors. Agonist-induced stimulation of cAMP and total inositol phosphate formation were not significantly different between the two receptors. Purification on a Ni2+-NTA column resulted in a rapid (within 4 h) purification with a 36 +/- 2% recovery and a 30 +/- 6-fold purification (n = 5). The partially purified receptors were resolved on SDS-polyacrylamide gel electrophoresis, transferred to a nitrocellulose membrane, dissolved in acetone/trifluoroacetic acid/hexafluoroisopropanol/sinapinic acid, and successfully subjected to matrix-assisted laser desorption ionization-time of flight mass spectrometry analysis. The results suggest that the combination of a high level of expression of C-His-TxA2 receptors and a rapid purification procedure followed by SDS- polyacrylamide gel electrophoresis may provide a useful approach for mass-spectrometry based structure-function and other studies of TxA2 receptors.