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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 (T1 - and T2 -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 (R1f ), and the MT exchange rate (kmf ). 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/R1f values. In vivo differences were detected for PSR, R1f , and kmf 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. [ABSTRACT FROM AUTHOR]

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. Magn Reson Med 74:953-963, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objective We examined the expression of IL-33 as an indicator of an innate immune response in relapsing remitting MS (RRMS) and controls. We proposed a link between the expression of IL-33 and IL-33 regulated genes to histone deacetylase (HDAC) activity and in particular HDAC3, an enzyme that plays a role in the epigenetic regulation of a number genes including those which regulate inflammation. Methods Using TaqMan low density arrays, flow cytometry and ELIZA, expression of IL-33, and family of innate immune response genes which regulate cytokine gene expression was examined in RRMS patients and controls. Results Intracellular expression of IL-33 and IL-33 regulated genes are increased in patients with RRMS. In addition, following in vitro culture with TLR agonist lipopolysaccharide (LPS), there is increased induction of both IL-33 and HDAC3 in RRMS patients over that seen in controls. Also, culture of PBMC with IL-33 led to the expression of genes which overlapped with that seen in RRMS patients suggesting that the gene expression signature seen in RRMS is likely to be driven by IL-33 mediated innate immune pathways. Expression of levels of IL-33 but not IL-1 (another gene regulated by TLR agonists) is completely inhibited by Trichostatin A (TSA) establishing a closer regulation of IL-33 but not IL-1 with HDAC. Interpretation These results demonstrate the over expression of innate immune genes in RRMS and offer a causal link between the epigenetic regulation by HDAC and the induction of IL-33. [ABSTRACT FROM AUTHOR]

ABSTRACT 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. J Neuroimaging 2012;22:137-144. [ABSTRACT FROM AUTHOR]

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 (7T) 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 7T 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. Magn Reson Med, 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

To describe five patients with ictal aphasia and one patient with ictal amnesia, who had focal positron emission tomography (PET) hypermetabolism but no clear ictal activity on electroencephalography (EEG). 18F-Fluorodeoxyglucose (FDG)–PET scans with concomitant EEG were obtained in five patients with suspected ictal aphasia or ictal amnesia without ictal activity on EEG. We reviewed medical history, EEG, imaging data, and treatment outcome. Brain magnetic resonance imaging (MRI) showed no structural abnormalities in any of the patients. EEG showed left temporal irregular delta activity in three patients, with aphasia and nonspecific abnormalities in two other patients, all without clear ictal pattern. All patients demonstrated focal hypermetabolism on PET scan. The hypermetabolism was in the left frontotemporal region in patients with ictal aphasia and in the bilateral hippocampal region in the patient with amnesia. Three patients who received intravenous benzodiazepines during their episodes had transient clinical improvement. With antiepileptic drug (AED) treatment, symptoms gradually resolved in all patients. Concomitant resolution of PET hypermetabolism was documented in three patients who had follow up scans. One patient with ictal aphasia later developed recurrent episodes, each with recurrent PET hypermetabolism. This patient and one other patient required immune-modulating therapy in addition to AEDs. FDG-PET imaging should be considered as a diagnostic tool in patients with suspected ictal aphasia or amnesia, who fail to show clear evidence of ictal activity on EEG. [ABSTRACT FROM AUTHOR]

The relationship between the p53 signal pathway and the response of human peripheral blood mononuclear cells (PBMC) to interferon (IFN)-β has hitherto not been examined. Using an oligonucleotide microarray, we found differential expression of at least 70 genes involved in the p53 signal pathway, including p53, which regulate cell proliferation and cell death following stimulation with IFN-β. We verified our observations on a limited set of p53-regulated genes at the transcriptional and translational levels. We also examined the consequences of the activation of the p53 signal pathway by IFN-β in PBMC. When cultured in the presence of T-cell mitogens, IFN-β restricted the entry of lymphocytes from the G0/G1 phase to the S phase and reduced the number of cells in the G2 phase. The addition of IFN-β alone did not increase apoptosis. However, in the presence of actinomycin D, a DNA-damaging agent, addition of IFN-β enhanced the susceptibility of PBMC to apoptosis. These observations suggest that, in spite of the activation of a number of mutually overlapping pathways mediating cell death, cell cycle arrest was the most evident consequence of IFN-β signalling in PBMC. [ABSTRACT FROM AUTHOR]