Elevated ATP via enhanced miRNA-30b, 30c, and 30e downregulates the expression of CD73 in CD8+ T cells of HIV-infected individuals.

CD8+ T cells play a crucial role against chronic viral infections, however, their effector functions are influenced by the expression of co-stimulatory/inhibitory receptors. For example, CD73 works with CD39 to convert highly inflammatory ATP to adenosine. However, its expression on T cells in the context of viral infections has not been well defined. Here, we analyzed the expression of CD73 on human T cells in a cohort of 102 HIV-infected individuals including those on antiretroviral therapy (ART), ART-naïve, and long-term non-progressors who were not on ART. We found that the frequency of CD73+ T cells was markedly lower among T cell subsets (e.g. naïve, effector or memory) in the peripheral blood of all HIV-infected individuals. Notably, CD73 was decreased at the cell surface, intracellular and gene levels. Functionally, CD8+CD73+ T cells exhibited decreased cytokine expression (TNF-α, IFN-γ and IL-2) upon global or antigen-specific stimulation and impaired expression of cytolytic molecules at the gene and protein levels. In contrast, CD8+CD73+ T cells expressed elevated levels of homing receptors such as CCR7, α4ß7 integrin, which suggests a migratory advantage for these cells as observed in vitro. We also observed significant migration of CD73+CD8+ T cells into the cerebrospinal fluids of multiple sclerosis (MS) patients at the time of disease relapse. Moreover, we found that elevated levels of ATP in the plasma of HIV-infected individuals upregulates the expression of miRNA30b-e in T cells in vitro. In turn, inhibition of miRNAs (30b, 30c and 30e) resulted in significant upregulation of CD73 mRNA in CD8+ T cells. Therefore, we provide a novel mechanism for the downregulation of CD73 via ATP-induced upregulation of miRNA30b, 30c and 30e in HIV infection. Finally, these observations imply that ATP-mediated downregulation of CD73 mainly occurs via its receptor, P2X1/P2RX1. Our results may in part explain why HIV-infected individuals have reduced risk of developing MS considering the role of CD73 for efficient T cell entry into the central nervous system.

MR Susceptibility Separation for Quantifying Lesion Paramagnetic and Diamagnetic Evolution in Relapsing-Remitting Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) lesion evolution may involve changes in diamagnetic myelin and paramagnetic iron. Conventional quantitative susceptibility mapping (QSM) can provide net susceptibility distribution, but not the discrete paramagnetic and diamagnetic components. PURPOSE: To apply susceptibility separation (χ separation) to follow lesion evolution in MS with comparison to R2*/R2 '/QSM. STUDY TYPE: Longitudinal, prospective. SUBJECTS: Twenty relapsing-remitting MS subjects (mean age: 42.5 ± 9.4 years, 13 females; mean years of symptoms: 4.3 ± 1.4 years). FIELD STRENGTH/SEQUENCE: Three-dimensional multiple echo gradient echo (QSM and R2* mapping), two-dimensional dual echo fast spin echo (R2 mapping), T2-weighted fluid attenuated inversion recovery, and T1-weighted magnetization prepared gradient echo sequences at 3 T. ASSESSMENT: Data were analyzed from two scans separated by a mean interval of 14.4 ± 2.0 months. White matter lesions on fluid-attenuated inversion recovery were defined by an automatic pipeline, then manually refined (by ZZ/AHW, 3/25 years' experience in MRI), and verified by a radiologist (MN, 25 years' experience in MS). Susceptibility separation yielded the paramagnetic and diamagnetic susceptibility content of each voxel. Lesions were classified into four groups based on the variation of QSM/R2* or separated into positive/negative components from χ separation. STATISTICAL TESTS: Two-sample paired t tests for assessment of longitudinal differences. Spearman correlation coefficients to assess associations between χ separation and R2*/R2 '/QSM. Significant level: P < 0.005. RESULTS: A total of 183 lesions were quantified. Categorizing lesions into groups based on χ separation demonstrated significant annual changes in QSM//R2*/R2 '. When lesions were grouped based on changes in QSM and R2*, both changing in unison yielded a significant dominant paramagnetic variation and both opposing yielded a dominant diamagnetic variation. Significant Spearman correlation coefficients were found between susceptibility-sensitive MRI indices and χ separation. DATA CONCLUSION: Susceptibility separation changes in MS lesions may distinguish and quantify paramagnetic and diamagnetic evolution, potentially providing additional insight compared to R2* and QSM alone. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults.

Autoimmune encephalitis is increasingly recognized as a neurologic cause of acute mental status changes with similar prevalence to infectious encephalitis. Despite rising awareness, approaches to diagnosis remain inconsistent and evidence for optimal treatment is limited. The following Canadian guidelines represent a consensus and evidence (where available) based approach to both the diagnosis and treatment of adult patients with autoimmune encephalitis. The guidelines were developed using a modified RAND process and included input from specialists in autoimmune neurology, neuropsychiatry and infectious diseases. These guidelines are targeted at front line clinicians and were created to provide a pragmatic and practical approach to managing such patients in the acute setting.

Inline dual-echo T2 quantification in brain using a fast mapping reconstruction technique.

T2 mapping from 2D proton density and T2-weighted images (PD-T2) using Bloch equation simulations can be time consuming and introduces a latency between image acquisition and T2 map production. A fast T2 mapping reconstruction method is investigated and compared with a previous modeling approach to reduce computation time and allow inline T2 maps on the MRI console. Brain PD-T2 images from five multiple sclerosis patients were used to compare T2 map reconstruction times between the new subtraction method and the Euclidean norm minimization technique. Bloch equation simulations were used to create the lookup table for decay curve matching in both cases. Agreement of the two techniques used Bland-Altman analysis for investigating individual subsets of data and all image points in the five volumes (meta-analysis). The subtraction method resulted in an average reduction of computation time for single slices from 134 s (minimization method) to 0.44 s. Comparing T2 values between the subtraction and minimization methods resulted in a confidence interval ranging from -0.06 to 0.06 ms (95% of values were within ± 0.06 ms between the techniques). Using identical reconstruction code based on the subtraction method, inline T2 maps were produced from PD-T2 images directly on the scanner console. The excellent agreement between the two methods permits the subtraction technique to be interchanged with the previous method, reducing computation time and allowing inline T2 map reconstruction based on Bloch simulations directly on the scanner.

High-resolution diffusion tensor imaging and T2 mapping detect regional changes within the hippocampus in multiple sclerosis.

Hippocampus demyelinating lesions in multiple sclerosis (MS) have been frequently observed in ex vivo histopathological studies; however, they are difficult to image and quantify in vivo. Diffusion tensor imaging (DTI) and T2 mapping could potentially detect such regional in vivo changes if acquired with sufficient spatial resolution. The goal here was to evaluate whether there are focal hippocampal abnormalities in 43 MS patients (35 relapsing-remitting, eight secondary progressive) with and without cognitive impairment (CI) versus 43 controls using high-resolution 1 mm isotropic DTI, as well as complementary methods of T2-weighted and T2 mapping at 3 T. Abnormal hippocampus regions were identified voxel-by-voxel by using mean diffusivity (MD)/T2 thresholds and avoiding voxels attributed to cerebrospinal fluid. When compared with controls, averaged left/right whole hippocampus MD was higher in both MS groups, while lower fractional anisotropy (FA) and volume, and higher T2 relaxometry and T2-weighted signal values, were only significant in CI MS. The hippocampal MD and T2 images/maps were not uniformly affected and focal regions of elevated MD/T2 were evident in MS patients. Both CI and not CI MS groups showed greater proportional areas of the hippocampus with elevated MD, whereas only the CI group showed a greater proportional area of elevated T2 relaxation times or T2-weighted signal. Higher T2 relaxometry and T2-weighted signal values of elevated regions correlated with greater disability and whole hippocampus FA negatively correlated with physical fatigue. High-resolution hippocampus DTI and T2 mapping with less partial volume effects showed whole hippocampus abnormalities with regional elevations of MD/T2 in MS, which could be interpreted as potentially from demyelination, neuron loss, and/or inflammation, and which overall were more extensive in the hippocampus of patients with larger total brain lesion volumes and CI.

Diffusion imaging of fornix and interconnected limbic deep grey matter is linked to cognitive impairment in multiple sclerosis.

Diffusion tensor imaging (DTI) and volumetric magnetic resonance imaging (MRI) have shown white matter (WM) and deep grey matter (GM) abnormalities in the limbic system of multiple sclerosis (MS) participants. Structures like the fornix have been associated with cognitive impairment (CI) in MS, but the diffusion metrics are often biased by partial volume effects from cerebrospinal fluid (CSF) due to its small bundle size and intraventricular location. These errors in DTI parameter estimation worsen with atrophy in MS. The goal here was to evaluate DTI parameters and volumes of the fornix, as well as associated deep GM structures like the thalamus and hippocampus, with high-resolution fluid-attenuated inversion recovery (FLAIR)-DTI at 3T in 43 MS patients, with and without CI, versus 43 controls. The fornix, thalamus and hippocampus displayed atrophy and/or abnormal diffusion metrics, with the fornix showing the most extensive changes within the structures studied here, mainly in CI MS. The affected fornix volumes and diffusion metrics were associated with thalamic atrophy and atypical diffusion metrics in interconnected limbic GM, larger total lesion volume and global brain atrophy. Lower fractional anisotropy (FA) and higher mean and radial diffusivity in the fornix, lower hippocampus FA and lower thalamus volume were strongly correlated with CI in MS. Hippocampus FA and thalamus atrophy were negatively correlated with fatigue and longer time since MS symptoms onset, respectively. FLAIR-DTI and volumetric analyses provided methodologically superior evidence for microstructural abnormalities and extensive atrophy of the fornix and interconnected deep GM in MS that were associated with cognitive deficits.

The Clinical Conundrum of Managing Ischemic Stroke in Patients with Immune Thrombocytopenia.

Guidelines are lacking for management of acute ischemic stroke and stroke prevention in patients with immune thrombocytopenia (ITP). Our aim is to highlight the dilemma inherent in managing patients with both significant bleeding and thrombotic risk factors. In this review, we present two patients with history of ITP who presented with acute ischemic stroke and received tissue plasminogen activator (tPA) and endovascular thrombectomy (EVT), a rare management strategy in this patient population. In addition, we identified 27 case reports of ischemic stroke in patients with ITP; none of them received tPA or EVT. Furthermore, there are 92 patients with significant thrombocytopenia with no available data regarding the cause of thrombocytopenia, who were acutely treated with tPA or EVT. Conclusive evidence cannot be determined based on these limited number of cases. Future multicenter prospective cohort studies in patients with ITP are needed to provide better evidence-based treatment plans. At present, treatment of acute ischemic stroke in patients with ITP requires close collaboration between hematology and vascular neurology experts to find a balance between the benefit and risk of hemorrhagic complications.

Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis.

BACKGROUND: On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis. METHODS: During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T2-weighted MRI, cumulative number of new lesions enhanced on T1-weighted MRI ["enhancing lesions"], and cumulative combined number of unique lesions [new enhancing lesions on T1-weighted MRI plus new and newly enlarged lesions on T2-weighted MRI]). RESULTS: A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo. CONCLUSIONS: The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).

Human pegivirus-1 associated leukoencephalitis: Clinical and molecular features.

Etiologic diagnosis is uncertain in 35% to 50% of patients with encephalitis, despite its substantial global prevalence and disease burden. We report on 2 adult female patients with fatal leukoencephalitis associated with human pegivirus-1 (HPgV-1) brain infection. Neuroimaging showed inflammatory changes in cerebral white matter. Brain-derived HPgV-1 RNA sequences clustered phylogenetically with other pegiviruses despite an 87-nucleotide deletion in the viral nonstructural (NS)2 gene. Neuropathology disclosed lymphocyte infiltration and gliosis predominantly in brain white matter. HPgV-1 NS5A antigen was detected in lymphocytes as well as in astrocytes and oligodendrocytes. HPgV-1 neuroadaptation should be considered in the differential diagnosis of progressive leukoencephalitis in humans. Ann Neurol 2018;84:789-795.

Discriminative analysis of regional evolution of iron and myelin/calcium in deep gray matter of multiple sclerosis and healthy subjects.

BACKGROUND: Combined R2* and quantitative susceptibility (QS) has been previously used in cross-sectional multiple sclerosis (MS) studies to distinguish deep gray matter (DGM) iron accumulation and demyelination. PURPOSE: We propose and apply discriminative analysis of regional evolution (DARE) to define specific changes in MS and healthy DGM. STUDY TYPE: Longitudinal (baseline and 2-year follow-up) retrospective study. SUBJECTS: Twenty-seven relapsing-remitting MS (RRMS), 17 progressive MS (PMS), and corresponding age-matched healthy subjects. FIELD STRENGTH/SEQUENCE: 4.7T 10-echo gradient-echo acquisition. ASSESSMENT: Automatically segmented caudate nucleus (CN), thalamus (TH), putamen (PU), globus pallidus, red nucleus (RN), substantia nigra, and dentate nucleus were retrospectively analyzed to quantify regional volumes, bulk mean R2*, and bulk mean QS. DARE utilized combined R2* and QS localized changes to compute spatial extent, mean intensity, and total changes of DGM iron and myelin/calcium over 2 years. STATISTICAL TESTS: We used mixed factorial analysis for bulk analysis, nonparametric tests for DARE (α = 0.05), and multiple regression analysis using backward elimination of DGM structures (α = 0.05, P = 0.1) to regress bulk and DARE measures with the follow-up Multiple Sclerosis Severity Score (MSSS). False detection rate correction was applied to all tests. RESULTS: Bulk analysis only detected significant (Q ≤ 0.05) interaction effects in RRMS CN QS (η = 0.45; Q = 0.004) and PU volume (η = 0.38; Q = 0.034). DARE demonstrated significant group differences in all RRMS structures, and in all PMS structures except the RN. The largest RRMS effect size was CN total R2* iron decrease (r = 0.74; Q = 0.00002), and TH mean QS myelin/calcium decrease for PMS (r = 0.70; Q = 0.002). DARE iron increase using total QS demonstrated the highest correlation with MSSS (r = 0.68; Q = 0.0005). DATA CONCLUSION: DARE enabled discriminative assessment of specific DGM changes over 2 years, where iron and myelin/calcium changes were the primary drivers in RRMS and PMS compared to age-matched controls, respectively. Specific DARE measures of MS DGM correlated with follow-up MSSS, and may reflect complex disease pathology. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018.

Progressive iron accumulation across multiple sclerosis phenotypes revealed by sparse classification of deep gray matter.

PURPOSE: To create an automated framework for localized analysis of deep gray matter (DGM) iron accumulation and demyelination using sparse classification by combining quantitative susceptibility (QS) and transverse relaxation rate (R2*) maps, for evaluation of DGM in multiple sclerosis (MS) phenotypes relative to healthy controls. MATERIALS AND METHODS: R2*/QS maps were computed using a 4.7T 10-echo gradient echo acquisition from 16 clinically isolated syndrome (CIS), 41 relapsing-remitting (RR), 40 secondary-progressive (SP), 13 primary-progressive (PP) MS patients, and 75 controls. Sparse classification for R2*/QS maps of segmented caudate nucleus (CN), putamen (PU), thalamus (TH), and globus pallidus (GP) structures produced localized maps of iron/myelin in MS patients relative to controls. Paired t-tests, with age as a covariate, were used to test for statistical significance (P ≤ 0.05). RESULTS: In addition to DGM structures found significantly different in patients compared to controls using whole region analysis, singular sparse analysis found significant results in RRMS PU R2* (P = 0.03), TH R2* (P = 0.04), CN QS (P = 0.04); in SPMS CN R2* (P = 0.04), GP R2* (P = 0.05); and in PPMS CN R2* (P = 0.04), TH QS (P = 0.04). All sparse regions were found to conform to an iron accumulation pattern of changes in R2*/QS, while none conformed to demyelination. Intersection of sparse R2*/QS regions also resulted in RRMS CN R2* becoming significant, while RRMS R2* TH and PPMS QS TH becoming insignificant. Common iron-associated volumes in MS patients and their effect size progressively increased with advanced phenotypes. CONCLUSION: A localized technique for identifying sparse regions indicative of iron or myelin in the DGM was developed. Progressive iron accumulation with advanced MS phenotypes was demonstrated, as indicated by iron-associated sparsity and effect size. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1464-1473.

Spin echo transverse relaxation and atrophy in multiple sclerosis deep gray matter: A two-year longitudinal study.

BACKGROUND: Deep gray matter (DGM) is affected in relapsing-remitting multiple sclerosis (RRMS) and may be studied using short-term longitudinal MRI. OBJECTIVE: To investigate two-year changes in spin-echo transverse relaxation rate (R2) and atrophy in DGM, and its relationship with disease severity in RRMS patients. METHODS: Twenty six RRMS patients and 26 matched controls were imaged at 4.7 T. Multiecho spin-echo R2 maps and atrophy measurements were obtained in DGM at baseline and two-year follow-up. Differences between MRI measures and correlations to disease severity were examined. RESULTS: After two years, mean R2 values in the globus pallidus and pulvinar increased by ~4% (p<0.001) in patients and <1.7% in controls. Two-year changes in R2 showed significant correlation to disease severity in the globus pallidus, pulvinar, substantia nigra, and thalamus. Multiple regression of the two-year R2 difference using these four DGM structures as variables, yielded high correlation with disease severity (r=0.83, p<0.001). Two-year changes in volume and R2 showed significant correlation only for the globus pallidus in multiple sclerosis (MS) (p<0.05). CONCLUSIONS: Two-year difference R2 measurements in DGM correlate to disease severity in MS. R2 mapping and atrophy measurements over two years can be used to identify changes in DGM in MS.

Medical Tourism for CCSVI Procedures in People with Multiple Sclerosis: An Observational Study.

BACKGROUND: Many Canadians with multiple sclerosis (MS) have recently travelled internationally to have procedures for a putative condition called chronic cerebrospinal venous insufficiency (CCSVI). Here, we describe where and when they went and describe the baseline characteristics of persons with MS who participated in this non-evidence-based medical tourism for CCSVI procedures. METHODS: We conducted a longitudinal observational study that used online questionnaires to collect patient-reported information about the safety, experiences, and outcomes following procedures for CCSVI. A convenience sample of all Albertans with MS was recruited between July 2011 and March 2013. RESULTS: In total, 868 individuals enrolled; 704 were included in this cross-sectional, baseline analysis. Of these, 128 (18.2%) participants retrospectively reported having procedures for CCSVI between April 2010 and September 2012. The proportion of participants reporting CCSVI procedures declined from 80 (62.5%) in 2010, to 40 (31.1%) in 2011, and 8 (6.3%) in 2012. In multivariable logistic regression analysis, CCSVI procedures were independently associated with longer disease duration, secondary progressive clinical course, and greater disability status. CONCLUSIONS: Although all types of people with MS pursued procedures for CCSVI, a major driver of participation was greater disability. This highlights that those with the greatest disability are the most vulnerable to unproven experimental procedures. Participation in CCSVI procedures waned over time possibly reflecting unmet expectations of treated patients, decreased media attention, or that individuals who wanted procedures had them soon after the CCSVI hypothesis was widely publicized.

Validation of quantitative susceptibility mapping with Perls' iron staining for subcortical gray matter.

Quantitative susceptibility mapping (QSM) measures bulk susceptibilities in the brain, which can arise from many sources. In iron-rich subcortical gray matter (GM), non-heme iron is a dominant susceptibility source. We evaluated the use of QSM for iron mapping in subcortical GM by direct comparison to tissue iron staining. We performed in situ or in vivo QSM at 4.7 T combined with Perls' ferric iron staining on the corresponding extracted subcortical GM regions. This histochemical process enabled examination of ferric iron in complete slices that could be related to susceptibility measurements. Correlation analyses were performed on an individual-by-individual basis and high linear correlations between susceptibility and Perls' iron stain were found for the three multiple sclerosis (MS) subjects studied (R(2) = 0.75, 0.62, 0.86). In addition, high linear correlations between susceptibility and transverse relaxation rate (R2*) were found (R(2) = 0.88, 0.88, 0.87) which matched in vivo healthy subjects (R(2) = 0.87). This work validates the accuracy of QSM for brain iron mapping and also confirms ferric iron as the dominant susceptibility source in subcortical GM, by demonstrating high linear correlation of QSM to Perls' ferric iron staining.

Subcortical gray matter segmentation and voxel-based analysis using transverse relaxation and quantitative susceptibility mapping with application to multiple sclerosis.

PURPOSE: To investigate subcortical gray matter segmentation using transverse relaxation rate (R2 *) and quantitative susceptibility mapping (QSM) and apply it to voxel-based analysis in multiple sclerosis (MS). MATERIALS AND METHODS: Voxel-based variation in R2 * and QSM within deep gray matter was examined and compared to standard whole-structure analysis using 37 MS subjects and 37 matched controls. Deep gray matter nuclei (caudate, putamen, globus pallidus, and thalamus) were automatically segmented and morphed onto a custom atlas based on QSM and standard T1 -weighted images. Segmentation accuracy and scan-rescan reliability were tested. RESULTS: When considering only significant regions as returned by the multivariate voxel-based analysis, increased R2 * and QSM was found in MS subjects compared to controls in portions of all four nuclei studied (P < 0.002). For R2 *, regional analysis yielded at least 66-fold improved P-value significance in all nuclei over standard whole-structure analysis, while for QSM only thalamus benefited, with 5-fold improvement in significance. Improved segmentation over standard methods, particularly for globus pallidus (2.8 times higher Dice score), was achieved by incorporating high-contrast QSM into the atlas. Voxel-based reliability was highest for QSM (<1% variation). CONCLUSION: Automatic segmentation of iron-rich deep gray matter can be improved by incorporating QSM. Voxel-based evaluation yielded increased R2 * and QSM in MS subjects in all four nuclei studied with R2 *, benefiting the most from localized analysis over whole-structure measures.

Decision-making under explicit risk is impaired in multiple sclerosis: relationships with ventricular width and disease disability.

BACKGROUND: Decision-making is an essential function of everyday life. Decision-making under explicit risk requires developing advantageous decision strategies based on fixed outcomes (e.g., probabilities of winning or losing a bet). Decision-making and its neural substrates have been rarely studied in MS. We expected performance in decision-making under risk to be lowered in MS patients, and negatively correlated with disease-related disability, cognition, and ventricular width. METHODS: Three groups were included: 32 MS patients and 20 healthy controls were examined with conventional neuropsychological tests and the Game-of-Dice Task (GDT) assessing decision-making under explicit risk. Linear 2-D ventricular width was assessed on MS patients' clinical MRIs and compared to a third group, 20 non-MS neurological control patients. RESULTS: Compared to healthy controls, MS patients showed impaired GDT and neuropsychological performance, depending on the MS-subtype (relapsing-remitting (RR), n = 22; secondary progressive, n = 10) and disability severity among RR-MS patients. In MS patients, GDT performance correlated with processing speed, intercaudate ratio, and third ventricle ratio (p's < 0.05). Mediation analysis showed that the link between GDT performance and processing speed was fully explained by ventricular size. CONCLUSION: Decision-making under explicit risk was reduced in MS patients, but only those with more pronounced disability. Independent of processing speed, decision-making under explicit risk correlates inversely with central atrophy in MS.

Longitudinal MR imaging of iron in multiple sclerosis: an imaging marker of disease.

PURPOSE: To investigate the relationship between magnetic resonance (MR) imaging markers of iron content and disease severity in patients with multiple sclerosis (MS) over a 2-year period. MATERIALS AND METHODS: This prospective study was approved by the local ethics committee, and written informed consent was obtained from all participants. Seventeen patients with MS and 17 control subjects were examined twice, 2 years apart, by using phase imaging and transverse relaxation (R2*) mapping at 4.7 T. Quantitative differences in iron content in deep gray matter between patients and control subjects were evaluated with repeated-measures multivariate analysis of variance separately for R2* mapping and phase imaging. Multiple regression analysis was used to evaluate correlations of MR imaging measures, both 2-year-difference and single-time measurements, to baseline disease severity. RESULTS: R2* mapping using 2-year-difference measurements had the highest correlation to disease severity (r = 0.905, P < .001) compared with R2* mapping using single-time measurements (r = 0.560, P = .019) and phase imaging by using either single-time (r = 0.539, P = .026) or 2-year-difference (r = 0.644, P = .005) measurements. Significant increases in R2* occur during 2 years in the substantia nigra (P < .001) and globus pallidus (P = .035), which are both predictors of disease in regression analysis, in patients compared with control subjects. There were group differences in the substantia nigra, globus pallidus, pulvinar thalamus, thalamus, and caudate nucleus, compared with control subjects with R2* mapping (P < .05), and group differences in the caudate nucleus and pulvinar thalamus, compared with control subjects with phase imaging (P < .05). CONCLUSION: There are significant changes in deep gray matter iron content in MS during 2 years measured with MR imaging, changes that are strongly related to physical disability. Longitudinal measurements may produce a higher correlation to disease severity compared with single-time measurements because baseline iron content of deep gray matter is variable among subjects.

Multiple sclerosis: validation of MR imaging for quantification and detection of iron.

PURPOSE: To investigate the relationship between iron staining and magnetic resonance (MR) imaging measurements in postmortem subjects with multiple sclerosis (MS). MATERIALS AND METHODS: Institutional ethical approval was obtained, and informed consent was obtained from the subjects and/or their families. Four MR imaging methods based on transverse relaxation (T2 weighting, R2 mapping, and R2* mapping) and phase imaging were performed by using a 4.7-T system in three in situ postmortem patients with MS less than 28 hours after death and in one in vivo patient 1 year before death. Iron staining with the Perls iron reaction was performed after brain extraction. Region-of-interest measurements from six subcortical gray matter structures were obtained from MR imaging and then correlated with corresponding locations on photographs of iron-stained pathologic slices by using a separate linear least-squares regression in each subject. Iron status of white matter lesions, as determined by staining, was compared with appearance on MR images. RESULTS: R2* mapping had the highest intrasubject correlations with iron in subcortical gray matter (R(2) = 0.857, 0.628, and 0.685; all P < .001), while R2 mapping (R(2) = 0.807, 0.615, 0.628, and 0.489; P < .001 and P = .001, .034, and .001, respectively), phase imaging (R(2) = 0.672, 0.441, 0.596, 0.548; all P ≤ .001), and T2-weighted imaging (R(2) = 0.463, 0.582, 0.650, and 0.551; all P < .001) had lower but still strong correlations. Within lesions, hypointense areas on phase images did not always represent iron. A hyperintense rim surrounding lesions on R2* maps was only present with iron staining, yet not all iron-staining lesions had R2* rim hyperintensity. CONCLUSION: All four MR imaging methods had significant linear correlations with iron and could potentially be used to determine iron status of subcortical gray matter structures in MS, with R2* mapping being preferred. A reliable method of determining iron status within MS lesions was not established.