Magnetic resonance imaging approaches for studying mouse models of multiple sclerosis: A mini review.

Given that multiple sclerosis (MS) is a complex disease with an unclear etiology, a single animal model is unlikely to accurately represent all aspects of pathology and clinical features of the human condition. However, the availability of three major types of murine models of MS, that is, experimental autoimmune encephalomyelitis (EAE), viral models, and toxic models, enables studies of several relevant features of this debilitating disease. Researchers have recently begun to combine magnetic resonance imaging (MRI) technologies with other experimental strategies to acquire complementary information, for example, anatomical and functional, and study the effect of experimental manipulations longitudinally in a noninvasive way. This review summarizes the latest MRI studies investigating critical aspects of MS, such as atrophy, demyelination, neuroaxonal damage, and neuroinflammation, in mouse models of MS. Advanced techniques will be briefly discussed, providing references to specialized literature for the readers. Thus, this review aims to describe different imaging protocols used to study critical aspects of MS in a research laboratory, discussing the main related findings in the most significant murine models of the disease.

Prevalence and Impact of Atrial Fibrillation on Intra-Hospital Mortality in Patients Aged ≥75 Years.

It is unclear whether the association between atrial fibrillation (AF) and intra-hospital mortality in patients aged 75 years and older is causal or not. This study aims (1) to describe the prevalence and clinical characteristics of AF in ≥75-year-old inpatients and (2) to study the association between AF and length of stay (LOS) and intra-hospital mortality. This retrospective cohort study includes consecutive patients aged ≥75 years admitted between January 2017 and December 2019 to a Belgian secondary hospital. Survival analysis was conducted on the whole dataset and a propensity score-matched dataset separately. Propensity score matching (PSM) was performed to account for the individual probability of having AF given a set of covariates. In 9,105 patients, 3,137 (34%) had a diagnosis of AF upon hospital admission. AF prevalence increased with age strata (from 29% to 38%), and Charlson Co-morbidity Index (from 28% to 57%). Intra-hospital mortality (20%) was higher in the AF group than in the AF-free group (25% vs 17%, p <0.001). The median LOS was 11 days and was shorter in those without AF (10 [4, 17] days) compared with those with AF (11 [5, 19], p <0.001). After PSM, AF was not associated with increased odds of LOS >10 days (odds ratio 1.08, confidence interval: 0.98 to 1.20, p = 0.13). The risk of intra-hospital death for patients with AF remained higher compared with those without AF (log-rank p = 0.0015 and hazard ratio 1.17; confidence interval: 1.04 to 1.32, p = 0.008). In conclusion, the prevalence of AF was high (34%) in inpatients aged ≥75 years and increased with age and co-morbidity burden. After PSM, patients with AF had a 17% higher risk of intra-hospital mortality than patients without AF.

Structural and functional brain damage in women with multiple sclerosis: A mini-review of neuroimaging sex-based studies.

Neuroimaging literature in healthy humans has shown that there are sex-related differences in healthy brain's anatomical structure, associated function and susceptibility to neurological diseases. This mini-review summarizes findings derived from the current neuroimaging studies focused on sex-related brain structural and functional damage in women with multiple sclerosis (MS). MS is a chronic, multifactorial, immune-mediated disorder of the central nervous system that affects mostly women. Even if recent neuroimaging studies have shed light on distinctive features of sex-related MS differences in brain structural and functional damage, more research is needed to better elucidate sex-related MS pathological changes and susceptibility and to implement sex-tailored treatment strategies in MS.

Predictive Accuracy of COVID-19 World Health Organization (WHO) Severity Classification and Comparison with a Bayesian-Method-Based Severity Score (EPI-SCORE).

Assess the predictive accuracy of the WHO COVID-19 severity classification on COVID-19 hospitalized patients. The secondary aim was to compare its predictive power with a new prediction model, named COVID-19 EPI-SCORE, based on a Bayesian network analysis. Methods: We retrospectively analyzed a population of 295 COVID-19 RT-PCR positive patients hospitalized at Epicura Hospital Center, Belgium, admitted between March 1st and April 30th, 2020. Results: Our cohort's median age was 73 (62-83) years, and the female proportion was 43%. All patients were classified following WHO severity classification at admission. In total, 125 (42.4%) were classified as Moderate, 69 (23.4%) as Severe, and 101 (34.2%) as Critical. Death proportions through these three classes were 11.2%, 33.3%, and 67.3%, respectively, and the proportions of critically ill patients (dead or needed Invasive Mechanical Ventilation) were 11.2%, 34.8%, and 83.2%, respectively. A Bayesian network analysis was used to create a model to analyze predictive accuracy of the WHO severity classification and to create the EPI-SCORE. The six variables that have been automatically selected by our machine learning algorithm were the WHO severity classification, acute kidney injury, age, Lactate Dehydrogenase Levels (LDH), lymphocytes and activated prothrombin time (aPTT). Receiver Operation Characteristic (ROC) curve indexes hereby obtained were 83.8% and 91% for the models based on WHO classification only and our EPI-SCORE, respectively. Conclusions: Our study shows that the WHO severity classification is reliable in predicting a severe outcome among COVID-19 patients. The addition to this classification of a few clinical and laboratory variables as per our COVID-19 EPI-SCORE has demonstrated to significantly increase its accuracy.

Demographic and clinical characteristics of familial and sporadic multiple sclerosis: A single center exploratory study from Abu Dhabi.

Demographic and clinical characteristics of Familial Multiple Sclerosis (FMS) have not been fully investigated yet in Abu Dhabi. The aim of this single center exploratory study was to investigate demographic and clinical characteristics of FMS compared to sporadic MS (SMS) in Abu Dhabi. A chart review single center study was conducted in 98 patients with MS. Group comparisons were performed using Mann-Whitney and Chi-Square tests as appropriate. A p < 0.05 was considered statistically significant. 24.5% were patients with FMS and 83% were Emirates. No significant differences in demographic and clinical characteristics were found between patients with FMS and SMS in overall all MS patients and in the Emirati group analyzed alone. Patients with FMS did not differ in demographic and clinical characteristics compared to patients with SMS. Further prospective studies are needed to elucidate environmental and genetic risk factors contributing to FMS in the Emirati population.

Seropositive neuromyelitis optica spectrum disorder in Emirati patients: A case series.

OBJECTIVE: To describe clinical and radiological characteristics of seropositive neuromyelitis optica (NMO) in Emirati patients. While epidemiology of seropositive NMO in Abu Dhabi has been reported in a previous paper, its clinical and MRI profiles among Emirati patients have not been previously fully investigated. METHODS: In our case series, we describe clinical and MRI characteristics of 5 Emirati patients with NMO, consecutively admitted at Cleveland Clinic Abu Dhabi, a major tertiary hospital in Abu Dhabi, United Arab Emirates. RESULTS: Patients were all females, mean age of onset (SD) was 41 (11) years, and 67% had autoimmune comorbidities. Most patients initially presented with acute myelitis (80%) while 20% got optic neuritis. Mean (SD) number of further relapses after onset was 3 (1) and mean (SD) disease duration was 12 (11) years. At MRI, apparent longitudinal extensive transverse myelitis was present in all patients affecting mostly the central gray matter of the cervical cord but extending as well to the thoracic portion. Furthermore, seropositive NMO related brain lesions were also observed. CONCLUSIONS: Our work provides valuable information regarding seropositive NMO with the potential to increase recognition of this disorder in Abu Dhabi and confirms NMO findings described in the other populations with this disorder. Further research is needed to advance clinical and MRI characterization of seronegative NMO in the region.

Short term real-world Fingolimod efficacy and safety in Emirati patients with multiple sclerosis.

In clinical trials, Fingolimod was an efficacious and safe treatment for multiple sclerosis (MS). Despite this, few studies have explored its real-world efficacy and safety in the Middle East. The aim of this study was to describe our clinical experience with Fingolimod at Cleveland Clinic Abu Dhabi in Emirati patients with MS. We retrospectively collected clinical and brain and spinal cord MRI activity over time in 30 Emirati MS patients [F/M = 22/8, mean (SD) disease duration at treatment initiation = 3.3 (3.6) years, age at onset = 25.9 (6.9) years] who were commenced on Fingolimod from 2015 and followed for 18 months. The proportion of MS patients clinically and radiologically silent after Fingolimod initiation over time was assessed together with annualized relapse rate (ARR) reduction and adverse events (AEs) occurrence. 70% of MS patients who started Fingolimod were naïve. The baseline ARR [mean (SD; range)] was [1.2 (0.8; 0-4)] and 23.3% of MS patients had Gadolinium enhancing lesions at baseline MRI. Overall, the ARR was reduced by 72% and, relapses and MRI activity were found in only 24% and 38% of MS patients respectively. Mild to moderate AEs were observed in 33% of MS patients. No severe AEs were recorded. In Emirati MS patients, Fingolimod is safe and efficacious as an early treatment choice.

Phase-Sensitive Inversion-Recovery MRI Improves Longitudinal Cortical Lesion Detection in Progressive MS.

Previous studies comparing phase sensitive inversion recovery (PSIR) to double inversion recovery (DIR) have demonstrated that use of PSIR improves cross-sectional in vivo detection of cortical lesions (CL) in multiple sclerosis. We studied the utility of PSIR in detection/characterization of accrual of CL over time in a 1-year longitudinal study in primary progressive multiple sclerosis (PPMS) compared to DIR. PSIR and DIR images were acquired with 3T magnetic resonance imaging (MRI) in 25 patients with PPMS and 19 healthy controls at baseline, and after 1 year in 20 patients with PPMS. CL were classified as intracortical, leucocortical or juxtacortical. Lesion counts and volumes were calculated for both time points from both sequences and compared. Correlations with measures of physical and cognitive disability were determined as well as new CL counts and volumes. Compared to DIR, PSIR led to detection of a higher number of CL involving a larger proportion of patients with PPMS both cross-sectionally (p = 0.006, 88%) and longitudinally (p = 0.007, 95%), and led to the reclassification of a third of CL seen on DIR at each time point. Interestingly, PSIR was more sensitive to new CL accumulation over time compared to DIR. PSIR is a promising technique to monitor cortical damage and disease progression in patients with PPMS over a short-term follow-up.

Corpus callosum atrophy correlates with gray matter atrophy in patients with multiple sclerosis.

OBJECTIVE: Atrophy of the corpus callosum is a recognized characteristic of multiple sclerosis (MS). We describe a new reliable method for measuring corpus callosum atrophy and correlate this with global cerebral atrophy measures. METHODS: Whole brain 3T MRI was performed in 38 relapsing-remitting MS subjects and 21 healthy controls (HC). Brain global gray and white matter volumes were segmented with SPM8. The contour of the corpus callosum was outlined on the midline of 3-D T1-weighted images by a semiautomated edge-detection technique to determine the corpus callosum area (CCA). Normalized CCA was correlated with other brain atrophy measures in MS subjects. RESULTS: CCA was disproportionately lower in MS subjects vs. HC (20.1% mean decrease; P < .001), with a large effect size (d = .62) when compared with global atrophy measures. In MS subjects, CCA correlated with brain parenchymal fraction (r = .55; P < .001) and gray matter fraction (r = .45; P = .005) but not white matter fraction (r = .18; P = .29). An inverse correlation with FLAIR hyperintense lesion volume (r = -.40; P = .01) was detected for CCA. CONCLUSION: Measurement of atrophy of the corpus callosum can have sensitivity as a useful imaging biomarker in patients with MS, even in patients with low disability levels. Both gray and white matter involvement in MS contribute to corpus callosum atrophy.

Quantification of global cerebral atrophy in multiple sclerosis from 3T MRI using SPM: the role of misclassification errors.

PURPOSE: We tested the validity of a freely available segmentation pipeline to measure compartmental brain volumes from 3T MRI in patients with multiple sclerosis (MS). Our primary focus was methodological to explore the effect of segmentation corrections on the clinical relevance of the output metrics. METHODS: Three-dimensional T1-weighted images were acquired to compare 61 MS patients to 30 age- and gender-matched normal controls (NC). We also tested the within patient MRI relationship to disability (eg, expanded disability status scale [EDSS] score) and cognition. Statistical parametric mapping v. 8 (SPM8)-derived gray matter (GMF), white matter (WMF), and total brain parenchyma fractions (BPF) were derived before and after correcting errors from T1 hypointense MS lesions and/or ineffective deep GM contouring. RESULTS: MS patients had lower GMF and BPF as compared to NC (P<.05). Cognitively impaired patients had lower BPF than cognitively preserved patients (P<.05). BPF was related to EDSS; BPF and GMF were related to disease duration (all P<.05). Errors caused bias in GMFs and WMFs but had no discernable influence on BPFs or any MRI-clinical associations. CONCLUSIONS: We report the validity of a segmentation pipeline for the detection of MS-related brain atrophy with 3T MRI. Longitudinal studies are warranted to extend these results.

An expanded composite scale of MRI-defined disease severity in multiple sclerosis: MRDSS2.

The objective of this study was to test a new version of the Magnetic Resonance Disease Severity Scale (MRDSS2), incorporating cerebral gray matter (GM) and spinal cord involvement from 3 T MRI, in modeling the relationship between MRI and physical disability or cognitive status in multiple sclerosis (MS). Fifty-five MS patients and 30 normal controls underwent high-resolution 3 T MRI. The patients had an Expanded Disability Status Scale score of 1.6±1.7 (mean±SD). The cerebral normalized GM fraction (GMF), the T2 lesion volume (T2LV), and the ratio of T1 hypointense LV to T2LV (T1/T2) were derived from brain images. Upper cervical spinal cord area (UCCA) was obtained from spinal cord images. A within-subject d-score (difference of MS from normal control) for each MRI component was calculated, equally weighted, and summed to form MRDSS2. With regard to the relationship between physical disability and MRDSS2 or its individual components, MRI-Expanded Disability Status Scale correlations were significant for MRDSS2 (r=0.33, P=0.013) and UCCA (r=-0.33, P=0.015), but not for GMF (P=0.198), T2LV (P=0.707), and T1/T2 (P=0.240). The inclusion of UCCA appeared to drive this MRI-disability relationship in MRDSS2. With regard to cognition, MRDSS2 showed a larger effect size (P=0.035) than its individual components [GMF (P=0.081), T2LV (P=0. 179), T1/T2 (P=0.043), and UCCA (P=0.818)] in comparing cognitively impaired with cognitively preserved patients (defined by the Minimal Assessment of Cognitive Function in MS). Both cerebral lesions (T1/T2) and atrophy (GMF) appeared to drive this relationship. We describe a new version of the MRDSS, which has been expanded to include cerebral GM and spinal cord involvement. MRDSS2 has concurrent validity with clinical status.

Microstructural changes in the striatum and their impact on motor and neuropsychological performance in patients with multiple sclerosis.

Grey matter (GM) damage is a clinically relevant feature of multiple sclerosis (MS) that has been previously assessed with diffusion tensor imaging (DTI). Fractional anisotropy (FA) of the basal ganglia and thalamus might be increased in MS patients, and correlates with disability scores. Despite the established role of the striatum and thalamus in motor control, mood and cognition, the impact of DTI changes within these structures on motor and neuropsychological performance has not yet been specifically addressed in MS. We investigated DTI metrics of deep GM nuclei and their potential association with mobility and neuropsychological function. DTI metrics from 3T MRI were assessed in the caudate, putamen, and thalamus of 30 MS patients and 10 controls. Sixteen of the patients underwent neuropsychological testing. FA of the caudate and putamen was higher in MS patients compared to controls. Caudate FA correlated with Expanded Disability Status Scale score, Ambulation Index, and severity of depressive symptomatology. Putamen and thalamus FA correlated with deficits in memory tests. In contrast, cerebral white matter (WM) lesion burden showed no significant correlation with any of the disability, mobility and psychometric parameters. Our findings support evidence of FA changes in the basal ganglia in MS patients, as well as deep GM involvement in disabling features of MS, including mobility and cognitive impairment. Deep GM FA appears to be a more sensitive correlate of disability than WM lesion burden.

Dietary and lifestyle guidelines for the prevention of Alzheimer's disease.

Risk of developing Alzheimer's disease is increased by older age, genetic factors, and several medical risk factors. Studies have also suggested that dietary and lifestyle factors may influence risk, raising the possibility that preventive strategies may be effective. This body of research is incomplete. However, because the most scientifically supported lifestyle factors for Alzheimer's disease are known factors for cardiovascular diseases and diabetes, it is reasonable to provide preliminary guidance to help individuals who wish to reduce their risk. At the International Conference on Nutrition and the Brain, Washington, DC, July 19-20, 2013, speakers were asked to comment on possible guidelines for Alzheimer's disease prevention, with an aim of developing a set of practical, albeit preliminary, steps to be recommended to members of the public. From this discussion, 7 guidelines emerged related to healthful diet and exercise habits.

Iron and multiple sclerosis.

Iron is essential for normal cellular functioning of the central nervous system. Abnormalities in iron metabolism may lead to neuronal death and abnormal iron deposition in the brain. Several studies have suggested a link between brain iron deposition in normal aging and chronic neurologic diseases, including multiple sclerosis (MS). In MS, it is still not clear whether iron deposition is an epiphenomenon or a mediator of disease processes. In this review, the role of iron in the pathophysiology of MS will be summarized. In addition, the importance of conventional and advanced magnetic resonance imaging techniques in the characterization of brain iron deposition in MS will be reviewed. Although there is currently not enough evidence to support clinical use of iron chelation in MS, an overview of studies of iron chelation or antioxidant therapies will be also provided.

MRI in multiple sclerosis: a review of the current literature.

PURPOSE OF REVIEW: This review summarizes the recent data pertaining to the use of magnetic resonance imaging (MRI) in assessing brain and spinal cord involvement in multiple sclerosis (MS). RECENT FINDINGS: Using MRI as a tool, investigators have made progress recently in understanding the substrate and mechanisms underlying the development and evolution of focal lesions and diffuse damage in MS. The application of refined MRI sequences has markedly improved the characterization of focal lesions, in particular cortical lesions. Promising improvements have been made to clarify the pathological specificity and sensitivity of MRI techniques by performing combined histopathologic-MRI correlation studies. The use of high-field (3 T) and ultra-high-field (UHF; >3 T) MRI has further facilitated the detection of both gray matter and white matter microstructural damage, and elucidated the topographic relationship of overt damage to venous blood vessels. The development of advanced MRI postprocessing tools has led to additional progress in detecting clinically relevant regional gray matter and white matter damage. SUMMARY: MRI continues to play a pivotal role in the investigation of MS. Ongoing advances in MRI technology should further expand the current understanding of pathologic disease mechanisms and improve diagnostic, prognostic, and monitoring ability in patients with MS.

Magnetic resonance disease severity scale (MRDSS) for patients with multiple sclerosis: a longitudinal study.

BACKGROUND: We previously described a composite MRI scale combining T1-lesions, T2-lesions and whole brain atrophy in multiple sclerosis (MS): the magnetic resonance disease severity scale (MRDSS). OBJECTIVE: Test strength of the MRDSS vs. individual MRI measures for sensitivity to longitudinal change. METHODS: We studied 84 MS patients over a 3.2±0.3 year follow-up. Baseline and follow-up T2-lesion volume (T2LV), T1-hypointense lesion volume (T1LV), and brain parenchymal fraction (BPF) were measured. MRDSS was the combination of standardized T2LV, T1/T2 ratio and BPF. RESULTS: Patients had higher MRDSS at follow-up vs. baseline (p<0.001). BPF decreased (p<0.001), T1/T2 increased (p<0.001), and T2LV was unchanged (p>0.5). Change in MRDSS was larger than the change in MRI subcomponents. While MRDSS showed significant change in relapsing-remitting (RR) (p<0.001) and secondary progressive (SP) phenotypes (p<0.05), BPF and T1/T2 ratio changed only in RRMS (p<0.001). Longitudinal change in MRDSS was significantly different between RRMS and SPMS (p=0.0027); however, change in the individual MRI components did not differ. Evaluation with respect to predicting on-study clinical worsening as measured by EDSS revealed a significant association only for T2LV (p=0.038). CONCLUSION: Results suggest improved sensitivity of MRDSS to longitudinal change vs. individual MRI measures. MRDSS has particularly high sensitivity in RRMS.

Atlas-based versus individual-based fiber tracking of the corpus callosum in patients with multiple sclerosis: reliability and clinical correlations.

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), the presence of lesions and normal-appearing white matter damage may affect the reliability of diffusion tensor (DT) magnetic resonance imaging (MRI)-based tractography. We compared the performance of an individual-based method for corpus callosum (CC) fiber tracking in MS with those of two atlas-based methods. METHODS: Brain DT MRI scans were acquired from 35 patients with MS and 18 age-matched healthy volunteers (HV). DT-derived metrics from the CC-the mean diffusivity (MD) and fractional anisotropy (FA)-were calculated using an individual-based and two atlas-based methods with different types of subject registration (linear and nonlinear) to a CC atlas. Customized termination criteria were applied to stop the tracking algorithm when using the individual-based method. RESULTS: All the methods were able to distinguish between MS patients and HV. Using the individual-based method, stronger relationships were found between CC DT-derived metrics and the subjects' clinical condition. CONCLUSION: CC DT tractography using an individual-based method is more sensitive than the atlas-based ones to tract-specific alterations related to MS disability. An atlas-based method with nonlinear registration can be a valid alternative when an automated postprocessing is warranted, such as in the case of high volumes of data.

Approaches to normalization of spinal cord volume: application to multiple sclerosis.

BACKGROUND AND PURPOSE: To determine the proper method for the normalization of spinal cord volume. MATERIALS AND METHODS: A group of 34 multiple sclerosis (MS) patients (28 relapsing and 6 progressive) and 15 healthy controls had whole spinal cord 3-mm thick T2-weighted axial fast spin-echo magnetic resonance imaging (MRI) images obtained at 3T. For each participant, four volumes were measured (C2-3 volume, cervical cord volume, thoracic cord volume, and whole cord volume). The volumes were normalized by the number of slices and three potential measures of body size (intracranial volume [ICV], body mass index, and body surface area) using the proportional method. RESULTS: All raw volumes and volumes normalized by number of slices or ICV were significantly lower in progressive MS patients compared to relapsing MS patients/healthy controls (P < .05). In addition, C2-3 volume and cervical cord volume were significantly correlated with Expanded Disability Status Scale score (P < .05). All regional volumes showed high intercorrelation, and normalization by the number of slices significantly increased some correlations. Regarding reliability, whole cord volume regardless of normalization technique had lower coefficient of variation than C2-3 volume. CONCLUSIONS: Since normalization factor had limited impact on reliability and the ability to detect differences, normalization by the number of slices is recommended.