Cortical gray matter (GM) damage is now widely recognized in multiple sclerosis (MS). The standard MRI does not reliably detect cortical GM lesions, although cortical volume loss can be measured. In this study, we demonstrate that the gradient echo MRI can reliably and quantitatively assess cortical GM damage in MS patients using standard clinical scanners. High resolution multi-gradient echo MRI was used for regional mapping of tissue-specific MRI signal transverse relaxation rate values (R2*) in 10 each relapsing–remitting, primary-progressive and secondary-progressive MS subjects. A voxel spread function method was used to correct artifacts induced by background field gradients. R2* values from healthy controls (HCs) of varying ages were obtained to establish baseline data and calculate ΔR2* values – age-adjusted differences between MS patients and HC. Thickness of cortical regions was also measured in all subjects. In cortical regions, ΔR2* values of MS patients were also adjusted for changes in cortical thickness. Symbol digit modalities (SDMT) and paced auditory serial addition (PASAT) neurocognitive tests, as well as Expanded Disability Status Score, 25-foot timed walk and nine-hole peg test results were also obtained on all MS subjects. We found that ΔR2* values were lower in multiple cortical GM and normal appearing white matter (NAWM) regions in MS compared with HC. ΔR2* values of global cortical GM and several specific cortical regions showed significant (p < 0.05) correlations with SDMT and PASAT scores, and showed better correlations than volumetric measures of the same regions. Neurological tests not focused on cognition (Expanded Disability Status Score, 25-foot timed walk and nine-hole peg tests) showed no correlation with cortical GM ΔR2* values. The technique presented here is robust and reproducible. It requires less than 10 min and can be implemented on any MRI scanner. Our results show that quantitative tissue-specific R2* values can serve as biomarkers of tissue injury due to MS in the brain, including the cerebral cortex, an area that has been difficult to evaluate using standard MRI.
Fatigue is associated with reduced quality of life and social participation, and poor employment outcomes. However, most studies examining fatigue are limited by small sample sizes or short follow-up periods.To characterize the natural history of fatigue.The North American Research Committee on Multiple Sclerosis Registry participants with ≥7 years of longitudinal data between 2004 and 2019 and a relapsing disease course were included. A subset of participants enrolled within 5 years of diagnosis was identified. The Fatigue Performance Scale assessed fatigue and ≥1-point increase in Fatigue Performance Scale sustained at the next survey defined fatigue worsening.Of 3057 participants with longitudinal data, 944 were within 5 years of multiple sclerosis diagnosis. Most participants (52%) reported fatigue worsening during follow-up. Median time to fatigue worsening ranged from 3.5 to 5 years at lower levels of index fatigue. Fatigue worsening was associated with lower annual income, increasing disability, lower initial fatigue level, taking injectable disease-modifying therapies and increasing depression levels in the relapsing multiple sclerosis participants.Most multiple sclerosis participants early in their disease suffer from fatigue and at least half reported fatigue worsening over time. Understanding factors associated with fatigue may help to identify populations most at risk of fatigue worsening will be informative for the overall management of patients with multiple sclerosis.
Abstract In many cancers including glioblastoma, males have higher incidence and mortality. Although the mechanisms underlying this phenomenon have yet to be elucidated, there are inherent sex differences in metabolism. Males not only have higher glucose metabolism relative to females, but males also have higher amounts of abdominal visceral fat, a well-known metabolic biomarker for poor cardiovascular and cancer outcomes that could contribute to enhanced tumorigenesis. Previously, we identified that in renal cell carcinoma, females with male-pattern visceral fat did significantly poorly compared to all other patients (PMID 29558292) and that in lower grade gliomas, tumor glycolysis specifically stratified males (PMID: 28768910). We hypothesized that in glioblastoma, visceral fat would selectively stratify females and serum glucose would selectively stratify males. We retrospectively analyzed abdominal/pelvic computed tomographic (CT) datasets for the normalized relative visceral fat area (rVFA) and random glucose measurements at diagnosis from 159 males and 105 females with glioblastoma. Females with rVFA > 30.5% had significantly reduced median overall survival (OS) (11.6 months, n=63) vs females with rVFA < 30.5% (20.9 months, n=42, p=0.006), that was close to the median rVFA of 32.7%. For males, the optimized rVFA threshold was higher than the median (43.6%); males with rVFA > 58.9% had significantly reduced median OS (10.7 months, n=14) compared to males with rVFA < 58.9% (20.5 months, n=145, p=0.02). However, after adjusting rVFA for age and tumor size, it was an independent predictor in females, but not in males. Conversely, there was a male-specific survival effect of glucose: males with prediabetic random serum glucose greater than 179.5 mg/dL had shorter OS (9.9 months vs 20.9 months; p=0.007), where no glucose level could stratify females. These data support the use of metabolism to predict sex-specific cancer outcomes and suggest that interventions that target metabolism can improve sex-specific outcomes in glioblastoma.
ABSTRACT Background Calorie restriction (CR) ameliorates preclinical models of multiple sclerosis (MS) through reduction of inflammation. The aim of this trial was to study the effects of 12-week iCR on metabolic, immunological and clinical outcomes in people with MS (pwMS). Methods Participants with relapsing-remitting MS were randomly assigned to intermittent CR (iCR) or a control group for 12 weeks. Primary outcome was change in leptin levels; secondary outcomes included changes in anthropometric and body composition measures, peripheral blood metabolic and immunologic profiling, and clinical measures. Mixed effects linear regression models were used to evaluate differences. Results Forty-two pwMS were randomized, 34 completed the study (17 iCR and 17 control). Leptin levels decreased in the iCR group and were significantly lower in the iCR than the control group at 6 (mean difference 11.49 mg/dL, 95% CI 32.54, 9.54; P =0.01) and 12 weeks (6.97 mg/dL, 95% CI 28.02, 14.06; P =0.03). We observed a significant reduction of weight, body mass index and body adiposity measures over the 6 and 12-weeks in the iCR group. Immune profiling showed a significant increase in CD45RO + regulatory T cell numbers after 6 weeks of iCR. Lysophosphatidylcholine, lysophophatidylethanolamine and phosphatidylinositol lipid species were significantly increased after 12 weeks in the iCR group compared to baseline, and all three were higher at 12 weeks compared to controls. Exploratory cognitive testing demonstrated improvement in the symbol digit modality test score in the iCR group. Conclusions Short term iCR is safe, feasible and can benefit metabolic and immunologic profiles in pwMS. ClinicalTrial.gov number: NCT03539094 (first patient screened on 11/14/17; first patient recruited on 1/29/2018; last patient recruited on 11/24/2021).
This study assessed the tissue integrity of major cervical cord tracts by using diffusion tensor imaging (DTI) to determine the relationship with specific clinical functions carried by those tracts.
Methods:
This was a cross-sectional study of 37 patients with multiple sclerosis or neuromyelitis optica with remote cervical cord disease. Finger vibratory thresholds, 25-foot timed walk (25FTW), 9-hole peg test (9HPT), and Expanded Disability Status Scale were determined. DTI covered cervical regions C1 through C6 with 17 5-mm slices (0.9 × 0.9 mm in-plane resolution). Regions of interest included posterior columns (PCs) and lateral corticospinal tracts (CSTs). Hierarchical linear mixed-effect modeling included covariates of disease subtype (multiple sclerosis vs neuromyelitis optica), disease duration, and sex.
Results:
Vibration thresholds were associated with radial diffusivity (RD) and fractional anisotropy (FA) in the PCs (both p < 0.01), but not CSTs (RD, p = 0.29; FA, p = 0.14). RD and FA in PCs, and RD in CSTs were related to 9HPT (each p < 0.0001). 25FTW was associated with RD and FA in PCs (p < 0.0001) and RD in CSTs (p = 0.008). Expanded Disability Status Scale was related to RD and FA in PCs and CSTs (p < 0.0001). Moderate/severe impairments in 9HPT (p = 0.006) and 25FTW (p = 0.017) were more likely to show combined moderate/severe tissue injury within both PCs and CSTs by DTI.
Conclusions:
DTI can serve as an imaging biomarker of spinal cord tissue injury at the tract level. RD and FA demonstrate strong and consistent relationships with clinical outcomes, specific to the clinical modality.
Comorbidity is common in multiple sclerosis (MS) with the most prevalent conditions being depression, anxiety, hypertension, and hyperlipidemia. Limited information regarding the representation of comorbidity status is available from phase III clinical trials in MS leading to concern about the potential underrepresentation of individuals with comorbidity in clinical trials. The objective was to estimate the prevalence of comorbidities in MS clinical trial populations.
