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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 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) may be a significant biomarker of cGM damage relating to CI in MS.
Copyright © 2019 Elsevier Inc. All rights reserved.
OBJECTS - The diffusion-based spherical mean technique (SMT) provides a novel model to relate multi-b-value diffusion magnetic resonance imaging (MRI) data to features of tissue microstructure. We propose the first clinical application of SMT to image the brain of patients with multiple sclerosis (MS) and investigate clinical feasibility and translation.
METHODS - Eighteen MS patients and nine age- and sex-matched healthy controls (HCs) underwent a 3.0 Tesla scan inclusive of clinical sequences and SMT images (isotropic resolution of 2 mm). Axial diffusivity (AD), apparent axonal volume fraction (V ), and effective neural diffusivity (D ) parametric maps were fitted. Differences in AD, V , and D between anatomically matched regions reflecting different tissues types were estimated using generalized linear mixed models for binary outcomes.
RESULTS - Differences were seen in all SMT-derived parameters between chronic black holes (cBHs) and T2-lesions (P ≤ 0.0016), in V and AD between T2-lesions and normal appearing white matter (NAWM) (P < 0.0001), but not between the NAWM and normal WM in HCs. Inverse correlations were seen between V and AD in cBHs (r = -0.750, P = 0.02); in T2-lesions D values were associated with V (r = 0.824, P < 0.0001) and AD (r = 0.570, P = 0.014).
INTERPRETATIONS - SMT-derived metrics are sensitive to pathological changes and hold potential for clinical application in MS patients.
© 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) in which the immune system damages the protective insulation surrounding the nerve fibers that project from neurons. A hallmark of MS and its animal model, experimental autoimmune encephalomyelitis (EAE), is autoimmunity against proteins of the myelin sheath. Most studies in this field have focused on the roles of CD4 T lymphocytes, which form part of the adaptive immune system as both mediators and regulators in disease pathogenesis. Consequently, the treatments for MS often target the inflammatory CD4 T-cell responses. However, many other lymphocyte subsets contribute to the pathophysiology of MS and EAE, and these subsets include CD8 T cells and B cells of the adaptive immune system, lymphocytes of the innate immune system such as natural killer cells, and subsets of innate-like T and B lymphocytes such as γδ T cells, natural killer T cells, and mucosal-associated invariant T cells. Several of these lymphocyte subsets can act as mediators of CNS inflammation, whereas others exhibit immunoregulatory functions in disease. Importantly, the efficacy of some MS treatments might be mediated in part by effects on lymphocytes other than CD4 T cells. Here we review the contributions of distinct subsets of lymphocytes on the pathogenesis of MS and EAE, with an emphasis on lymphocytes other than CD4 T cells. A better understanding of the distinct lymphocyte subsets that contribute to the pathophysiology of MS and its experimental models will inform the development of novel therapeutic approaches.
Various sensors that detect double-stranded RNA, presumably of viral origin, exist in eukaryotic cells and induce IFN-responses. Ongoing IFN-responses have also been documented in a variety of human autoimmune diseases including relapsing-remitting multiple sclerosis (RRMS) but their origins remain obscure. We find increased IFN-responses in leukocytes in relapsing-remitting multiple sclerosis at distinct stages of disease. Moreover, endogenous RNAs isolated from blood cells of these same patients recapitulate this IFN-response if transfected into naïve cells. These endogenous RNAs are double-stranded RNAs, contain Alu and Line elements and are transcribed from leukocyte transcriptional enhancers. Thus, transcribed endogenous retrotransposon elements can co-opt pattern recognition sensors to induce IFN-responses in RRMS.
Copyright © 2019. Published by Elsevier Ltd.
Spinal cord lesions detected on MRI hold important diagnostic and prognostic value for multiple sclerosis. Previous attempts to correlate lesion burden with clinical status have had limited success, however, suggesting that lesion location may be a contributor. Our aim was to explore the spatial distribution of multiple sclerosis lesions in the cervical spinal cord, with respect to clinical status. We included 642 suspected or confirmed multiple sclerosis patients (31 clinically isolated syndrome, and 416 relapsing-remitting, 84 secondary progressive, and 73 primary progressive multiple sclerosis) from 13 clinical sites. Cervical spine lesions were manually delineated on T2- and T2*-weighted axial and sagittal MRI scans acquired at 3 or 7 T. With an automatic publicly-available analysis pipeline we produced voxelwise lesion frequency maps to identify predilection sites in various patient groups characterized by clinical subtype, Expanded Disability Status Scale score and disease duration. We also measured absolute and normalized lesion volumes in several regions of interest using an atlas-based approach, and evaluated differences within and between groups. The lateral funiculi were more frequently affected by lesions in progressive subtypes than in relapsing in voxelwise analysis (P < 0.001), which was further confirmed by absolute and normalized lesion volumes (P < 0.01). The central cord area was more often affected by lesions in primary progressive than relapse-remitting patients (P < 0.001). Between white and grey matter, the absolute lesion volume in the white matter was greater than in the grey matter in all phenotypes (P < 0.001); however when normalizing by each region, normalized lesion volumes were comparable between white and grey matter in primary progressive patients. Lesions appearing in the lateral funiculi and central cord area were significantly correlated with Expanded Disability Status Scale score (P < 0.001). High lesion frequencies were observed in patients with a more aggressive disease course, rather than long disease duration. Lesions located in the lateral funiculi and central cord area of the cervical spine may influence clinical status in multiple sclerosis. This work shows the added value of cervical spine lesions, and provides an avenue for evaluating the distribution of spinal cord lesions in various patient groups.
© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: firstname.lastname@example.org.
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- and T-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 ( < 0.05). In addition, glutamate-sensitive contrast in the prefrontal cortex was significantly correlated with symbol digit modality test ( = -0.814) and choice reaction time ( = 0.772) scores in patients ( < 0.05), suggesting that GluCEST MRI may have utility as a marker for GM pathology and CI.
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 - and T -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 ), and the MT exchange rate (k ). 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 values. In vivo differences were detected for PSR, R , and k 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.
The purpose of this work was to evaluate the feasibility and reproducibility of the spherical mean technique (SMT), a multi-compartmental diffusion model, in the spinal cord of healthy controls, and to assess its ability to improve spinal cord characterization in multiple sclerosis (MS) patients at 3 T. SMT was applied in the cervical spinal cord of eight controls and six relapsing-remitting MS patients. SMT provides an elegant framework to model the apparent axonal volume fraction v , intrinsic diffusivity D , and extra-axonal transverse diffusivity D (which is estimated as a function of v and D ) without confounds related to complex fiber orientation distribution that reside in diffusion MRI modeling. SMT's reproducibility was assessed with two different scans within a month, and SMT-derived indices in healthy and MS cohorts were compared. The influence of acquisition scheme on SMT was also evaluated. SMT's v , D , and D measurements all showed high reproducibility. A decrease in v was observed at the site of lesions and normal appearing white matter (p < 0.05), and trends towards a decreased D and increased D were seen. Importantly, a twofold reduction in acquisition yielded similarly high accuracy with SMT. SMT provides a fast, reproducible, and accurate method to improve characterization of the cervical spinal cord, and may have clinical potential for MS patients.
Copyright © 2018 John Wiley & Sons, Ltd.
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, TR, and T) 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.