Trajectories of Symbol Digit Modalities Test performance in individuals with multiple sclerosis.

BACKGROUND: Although cognitive problems have been identified in people with multiple sclerosis (PwMS), few studies have investigated the long-term change in cognitive functioning. OBJECTIVE: To identify trajectories of change in cognitive functioning for PwMS. METHODS: Participants enrolled in the quality-of-life subgroup from the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) were eligible for our analysis. In 2006, participants in this group began to complete the Symbol Digit Modalities Test (SDMT) annually. Latent trajectory models were used to identify groups of participants with similar longitudinal change in SDMT scores. Linear and quadratic trajectory models were fit, and the models were compared. Latent trajectory models were also fit adjusting for baseline age and disease duration as well as using normalized SDMT scores. The groups identified across the approaches were compared. RESULTS: We found that classes with higher-than-average baseline values improved, classes with average baseline values remained relatively constant, and classes with lower baseline values experienced cognitive worsening. Similar results were observed in the alternative latent trajectory models accounting for other variables. CONCLUSION: Our models show that subjects with higher SDMT scores at baseline showed improvement, while subjects with lower SDMT scores at baseline showed worsening. Baseline age and disease duration were also associated with SDMT performance.

Assessment of computer adaptive testing version of the Neuro-QOL for people with multiple sclerosis.

BACKGROUND: To date, the computerized adaptive testing (CAT) version of the Neuro-quality of life (QOL) has not been assessed in a large sample of people with multiple sclerosis (MS). OBJECTIVE: The aim of this study was to assess the associations between the CAT version of Neuro-QOL and other clinical and patient-reported outcome measures. METHODS: Subjects (n = 364) enrolled in SysteMS completed the CAT version of the Neuro-QOL and the 36-Item Short Form Survey (SF-36) within 4 weeks of a clinical exam that included the Multiple Sclerosis Functional Composite-4 (MSFC-4). The correlations between the Neuro-QOL domains and the MSFC-4 subscores and the SF-36 scores were calculated. The changes over time in the Neuro-QOL and other measures were also examined. RESULTS: The lower extremity functioning score of the Neuro-QOL showed the highest correlations with MSFC-4 components including Timed 25-Foot Walk, 9-Hole Peg Test, and cognitive score. The expected domains of the Neuro-QOL showed high correlations with the SF-36 subscores, and some Neuro-QOL domains were associated with many SF-36 subscores. There was limited longitudinal change on the Neuro-QOL domains over 12 months, and the change was not associated with change on other measures. CONCLUSION: The CAT version of the Neuro-QOL shows many of the expected associations with clinical and patient-reported outcome measures.

Assessing the ecological effects of human impacts on coral reefs in Bocas del Toro, Panama.

Environmental and biological reef monitoring was conducted in Almirante Bay (Bahía Almirante) in Bocas del Toro, Panama, to assess impacts from anthropogenic developments. An integrated monitoring investigated how seasonal temperature stress, turbidity, eutrophication and physical impacts threatened reef health and biodiversity throughout the region. Environmental parameters such as total suspended solids [TSS], carbon isotopes (δ(13)C), C/N ratios, chlorophyll a, irradiance, secchi depth, size fractions of the sediments and isotope composition of dissolved inorganic carbon [DIC] of the water were measured throughout the years 2010 and 2011 and were analysed in order to identify different impact sources. Compared to data from Collin et al. (Smithsonian Contributions to the Marine Sciences 38:324-334, 2009) chlorophyll a has doubled at sites close to the city and the port Almirante (from 0.46-0.49 to 0.78-0.97 µg l(-1)) and suspension load increased, visible by a decrease in secchi depth values. Visibility decreased from 9-13 m down to 4 m at the bay inlet Boca del Drago, which is strongly exposed to river run off and dredging for the shipping traffic. Eutrophication and turbidity levels seemed to be the determining factor for the loss of hard coral diversity, most significant at chlorophyll a levels higher than 0.5 µg l(-1) and TSS levels higher than 4.7 mg l(-1). Hard coral cover within the bay has also declined, at some sites down to <10 % with extremely low diversities (7 hard coral species). The hard coral species Porites furcata dominated the reefs in highly impacted areas and showed a strong recovery after bleaching and a higher tolerance to turbidity and eutrophication compared to other hard coral species in the bay. Serious overfishing was detected in the region by a lack of adult and carnivorous fish species, such as grunts, snappers and groupers. Study sites less impacted by anthropogenic activities and/or those with local protection showed a higher hard coral cover and fish abundance; however, an overall loss of hard coral diversity was observed.

Altered adipokine levels are associated with dimethyl fumarate treatment in multiple sclerosis patients.

BACKGROUND: Obesity is linked to increased risk of multiple sclerosis (MS) and worsening disease severity. Recent experimental and clinical data indicates that adipokines are involved in regulating immune response and serve as cross talk between immune and neural system. Dimethyl fumarate (DMF) is an oral MS medication with unknown mechanism of action. It upregulates the nuclear factor E2-related factor 2 (Nrf2) pathway, a pathway for adipocyte differentiation. To determine a possible relationship between treatment with dimethyl fumarate, serum adipokine profiles and treatment response in patients with MS, we conducted an observational cohort study and measured serum adipokine and Vitamin D levels before and after treatment with DMF and examined their association with treatment response. METHODS: We identified patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) study who were treated with dimethyl fumarate and had available serum samples. Longitudinal pre-treatment and on-treatment samples were available in 23 patients. Cross-sectional on-treatment samples were available in 91 patients, who were classified into DMF responders and non-responders based on radiologic and clinical relapse activity or disability progression. We measured serum leptin, adiponectin, resistin, ghrelin, fatty acid binding protein-4 (FABP-4) and-5 (FABP-5), vitamins D2 and D3. Statistical analysis was performed with paired t-tests, Wilcoxon signed-rank and Mann-Whitney U tests. RESULTS: After treatment with DMF, serum adiponectin levels significantly increased, whereas FABP-4 levels significantly decreased compared to baseline levels, without a statistically significant change in the patients' BMI. Ghrelin levels were insignificantly lower post-treatment. FABP-4 levels were significantly higher in DMF responders compared to non-responders. This effect was sex-specific, with higher FABP4 levels associated with treatment response in males, but not females. CONCLUSION: DMF treatment is associated with significant changes in serum adipokine levels, primarily adiponectin and FABP-4. Sex may affect the association between FABP-4 and treatment response.

Obesity is associated with the Optic Neuritis severity in Male patients with Multiple Sclerosis.

BACKGROUND: Obesity is an important modifiable risk factor of MS; a deeper biological understanding of this association is needed. OBJECTIVE: To evaluate the determinants of acute optic neuritis (AON) severity and recovery in multiple sclerosis (MS). METHODS: We included 61 patients with MS with recorded AON severity and recovery according to visual acuity outcomes before, at, and, after the relapse. We measured body mass index (BMI) and the serum concentration of estrogen, leptin, testosterone, sex hormone-binding globulin, and vitamin D. We tested the association between BMI and serum hormones and AON severity and recovery with logistic regressions. RESULTS: In males, moderate/severe AON was associated with higher BMI (31.26 kg/m2 vs 25.73 kg/m2, logistic regression, p= 0.03), higher serum estrogen levels (32.24 nmol/L vs 23.06 nmol/L, logistic regression, p=0.04), and higher serum leptin levels (12.29 ng/mL vs mild AON: 4.1 ng/mL, logistic regression, p=0.06) than mild AON. These observations were not seen in female patients. We did not find an association with BMI or hormone levels and AON recovery. CONCLUSION: BMI, serum leptin, and serum estrogen were associated with AON severity in male patients but not in female patients. No association of these factors and AON recovery was observed.

Comparison of health-related quality of life across treatment groups in individuals with multiple sclerosis.

BACKGROUND: Outcome measures typically used to evaluate disease modifying therapies (DMTs) provide important information regarding their effects on disease activity, but they do not capture the full impact of living with multiple sclerosis (MS). Patient reported outcome measures (PROs) are increasingly being used to capture an individual's subjective experience of disease. We compared DMTs across a wide range of PRO outcomes in individuals with MS. METHODS: Subjects enrolled in SysteMS completed the computer adaptive testing version of the Neuro-QoL within four weeks of a clinical neurological exam. Neuro-QoL measures included the following 11 health-related quality of life (HRQOL) domains: Ability to participate in Social Roles and Activities, Anxiety, Cognitive Function, Depression, Emotional and Behavioral Dyscontrol, Fatigue, Lower Extremity Function (mobility), Positive Affect and Wellbeing, Satisfaction with Social Roles and Activities, Stigma, and Upper Extremity Function (fine motor). Treatments were grouped based on the three main modes of delivery: injectable, oral and infusion. The three treatment groups were compared using linear regression adjusting for two sets of covariates (set 1: age, sex, disease duration and EDSS; set 2: age, sex, disease duration, EDSS and treatment duration). We also compared the individual treatments using linear regression. RESULTS: After adjusting for the first set of clinical and demographic features of MS, there was a difference between treatment groups for Upper Extremity Function and Stigma. Subjects using injectable treatments reported better functioning in terms of Upper Extremity Function and Stigma than subjects using infusion treatments. In addition, subjects using injectable treatments reported better Upper Extremity Function than subjects treated with oral DMTs. When all individual treatments were compared, interferon-treated subjects reported significantly better functioning in terms of Stigma than natalizumab treated subjects. When further adjusting for time on treatment, the group differences were attenuated and no longer statistically significant. CONCLUSION: We examined differences between MS treatment groups across a wide range of HRQOL outcomes. The results suggest that overall there are few differences between treatments on the physical, cognitive and emotional dimensions of well-being.

Temporal association of sNfL and gad-enhancing lesions in multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is an autoimmune demyelinating disorder, which is characterized by relapses and remissions. Serum neurofilament light chain (sNfL) is an emerging biomarker of disease activity but its clinical use is still limited. In this study, we aim to characterize the temporal association between sNfL and new clinical relapses and new gadolinium-enhancing (Gd+) lesions. METHODS: Annual sNfL levels were measured with a single-molecule array (SIMOA) assay in 94 patients with MS enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) study. We used a multivariable linear mixed-effects model to test the temporal association of sNfL with clinical relapses and/or new Gd+ lesions. We adjusted this model for age, disease duration, sex, and disease-modifying therapies (DMTs) use. RESULTS: In the 3 months after a Gd+ lesion, we observed an average 35% elevation in sNfL (P < 0.0001) compared to remission samples. We also observed an average 32.3% elevation in sNfL at the time of or prior to a Gd+ lesion (P = 0.002) compared to remission. We observed a significant elevation in sNfL after a clinical relapse only when associated with a Gd+ lesion. INTERPRETATION: Our findings support sNfL as a marker of clinical relapses and Gd+ lesions. sNfL peaks in a 3-month window around Gd+ lesions. sNfL shows promise as a biomarker of neurological inflammation and possibly of simultaneous Gd+ lesions during a clinical relapse.

Cross-sectional study of smoking exposure: no differential effect on OCT metrics in a cohort of MS patients.

BACKGROUND: Optical coherence tomography (OCT) provides quantitative measures of retinal layer thickness. Cigarette smoking is a risk factor for multiple sclerosis (MS) onset and disease severity: its effects on OCT metrics have not been assessed. OBJECTIVE: The objective of this study was to assess the effect of smoking history on retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform (GCIP) of MS patients by OCT. METHODS: 112 MS patients were recruited from the Brigham and Women's Hospital. Spectralis OCT scans were acquired to measure GCIP, peripapillary RNFL, and total macular volume. Multivariable linear mixed effects regression model assessed RNFL and GCIP change with fixed effects for smoking history while adjusting for optic neuritis eye status, age, disease duration, sex, baseline EDSS, and disease modifying therapies (DMTs). RESULTS: Smoking histories were available for 102 patients: 46 (45.10%) had a history of smoking cigarettes and 56 (54.90%) never smoked. No statistically significant differences were found between ever-smokers and never-smokers with respect to GCIP, RNFL, and macular volume. CONCLUSION: Our study shows no significant difference in retinal thickness between ever-smokers and never-smokers. If confirmed, this result suggests mechanistic differences between the retina and other central nervous system (CNS) compartments in response to smoking and should be noted when considering OCT as a surrogate measure of CNS activity.

Soluble Fms-Like Tyrosine Kinase-1 Alters Cellular Metabolism and Mitochondrial Bioenergetics in Preeclampsia.

Preeclampsia is a maternal hypertensive disorder that affects up to 1 out of 12 pregnancies worldwide. It is characterized by proteinuria, endothelial dysfunction, and elevated levels of the soluble form of the vascular endothelial growth factor receptor-1 (VEGFR-1, known as sFlt-1). sFlt-1 effects are mediated in part by decreasing VEGF signaling. The direct effects of sFlt-1 on cellular metabolism and bioenergetics in preeclampsia, have not been established. The goal of this study was to evaluate whether sFlt-1 causes mitochondrial dysfunction leading to disruption of normal functioning in endothelial and placental cells in preeclampsia. Endothelial cells (ECs) and first-trimester trophoblast (HTR-8/SVneo) were treated with serum from preeclamptic women rich in sFlt-1 or with the recombinant protein. sFlt-1, dose-dependently inhibited ECs respiration and acidification rates indicating a metabolic phenotype switch enhancing glycolytic flux. HTR-8/SVneo displayed a strong basal glycolytic metabolism, remaining less sensitive to sFlt-1-induced mitochondrial impairment. Moreover, results obtained in ECs exposed to serum from preeclamptic subjects demonstrated that increased sFlt-1 leads to metabolic perturbations accountable for mitochondrial dysfunction observed in preeclampsia. sFlt-1 exacerbated mitochondrial reactive oxygen species (ROS) formation and mitochondrial membrane potential dissipation in ECs and trophoblasts exposed to serum from preeclamptic women. Forcing oxidative metabolism by culturing cells in galactose media, further sensitized cells to sFlt-1. This approach let us establish that sFlt-1 targets mitochondrial function in ECs. Effects of sFlt-1 on HTR-8/SVneo cells metabolism were amplified in galactose, demonstrating that sFlt-1 only target cells that rely mainly on oxidative metabolism. Together, our results establish the early metabolic perturbations induced by sFlt-1 and the resulting endothelial and mitochondrial dysfunction in preeclampsia.