•PMS had more frequent impairment in combined cognitive domains compared to RRMS.•PMS had a higher prevalence of verbal memory and verbal fluency deficits.•Between-group cognitive differences were ...not significant after controlling for EDSS.•Worse cognitive performance was associated with increased physical disability.•Thalamic and T1-lesion volumes were consistent MRI predictors of cognitive disability.
Cognitive impairment (CI) is present in all stages and subtypes of multiple sclerosis (MS). However, the majority of studies examined relapsing-remitting (RRMS) patients, and did not address cognitive phenotyping. Is still not clear whether patients with progressive MS (PMS) have a distinct pattern of CI compared to RRMS. In addition, there is conflicting data regarding the correlation between clinical and cognitive disability.
To investigate the differences of CI between PMS and RRMS patients, evaluating cognitive phenotypes. We also aimed to analyze the association between physical and cognitive disability with MRI measures of grey-matter atrophy and lesion burden.
Thirty patients with PMS and twenty-four with RRMS underwent neurological, neuropsychological (BRB-N, Boston Naming, and Tower of London), and MRI assessments (3T). Brain volume evaluations were performed using FreeSurfer. Principal Components Analysis on neuropsychological yielded six principal cognitive domains. Cognitive deficits were classified according to three categories: no CI, impairment in isolated cognitive domain, or impairment in combined domains.
In the overall sample, the most frequently impaired cognitive domains were information processing speed (IPS) and visual memory. PMS patients had a higher prevalence of verbal memory and verbal fluency deficits, and more frequent impairment in combined cognitive domains compared to RRMS individuals. After multivariable regression analysis with clinical variables, EDSS was associated with most cognitive domains. Nevertheless, after including T1-lesion volume in the model, it was the most consistent predictor of cognitive performance. To further analyze the interaction between EDSS and T1-lesions, we performed GLM analysis with EDSS and T1-hypointense lesion volume as covariates, and T1-lesion volume adjusted better the model for verbal memory (p = 0.013), IPS (p = 0.021) and total number of impaired cognitive domains (p = 0.021).
RRMS and PMS patients tend to have a similar neuropsychological profile in general, but the extent of CI was greater in PMS patients. Worse cognitive performance was associated with increased physical disability, but this correlation was no longer significant after controlling for T1-lesion volume, suggesting that the underlying MS pathology might be involved in this relationship. Thalamic and T1-lesion volumes were the most consistent MRI predictors associated with cognitive disability.
Abstract Background The pathological mechanisms underlying cognitive dysfunction in multiple sclerosis (MS) are not yet fully understood and, in addition to demyelinating lesions and gray-matter ...atrophy, subclinical disease activity may play a role. Objective To evaluate the contribution of asymptomatic gadolinium-enhancing lesions to cognitive dysfunction along with gray-matter damage and callosal atrophy in relapsing-remitting MS (RRMS) patients. Methods Forty-two treated RRMS and 30 controls were evaluated. MRI (3 T) variables of interest were brain white-matter and cortical lesion load, cortical and deep gray-matter volumes, corpus callosum volume and presence of gadolinium-enhancing lesions. Outcome variables included EDSS, MS Functional Composite (MSFC) subtests and the Brief Repeatable Battery of Neuropsychological tests. Cognitive dysfunction was classified as deficits in two or more cognitive subtests. Multivariate regression analyses assessed the contribution of MRI metrics to outcomes. Results Patients with cognitive impairment (45.2%) had more cortical lesions and lower gray-matter and callosal volumes. Patients with subclinical MRI activity (15%) had worse cognitive performance. Clinical disability on MSFC was mainly associated with putaminal atrophy. The main independent predictors for cognitive deficits were high burden of cortical lesions and number of gadolinium-enhancing lesions. Conclusions Cognitive dysfunction was especially related to high burden of cortical lesions and subclinical disease activity. Cognitive studies in MS should look over subclinical disease activity as a potential contributor to cognitive impairment.
Abstract Sunlight can influence the immune system independently of vitamin D, such as through melatonin production in the pineal gland. Inflammatory disorders can suppress nocturnal melatonin ...production, but only a few studies have investigated melatonin status in multiple sclerosis (MS). We aimed to study melatonin production in association with clinical and immunological data in MS patients. Eleven treated relapsing-remitting MS (RRMS) patients and eight controls underwent neurological examination and were assessed for fatigue severity and depressive symptoms. Inflammatory cytokines were analyzed in blood samples and concentration of 6-sulfatoxymelatonin (6-SMT) was determined in 24 h urine. Patients with an abnormal proportion of overnight 6-SMT (n = 8, 72.7%) had higher disability and fatigue severity (p < 0.05). Overnight 6-SMT was inversely related with fatigue severity (p = 0.016), number of relapses in the previous 12 months (p = 0.010) and EDSS scores (p = 0.049). In conclusion, disruption of melatonin circadian rhythm production is frequent among RRMS patients and seemingly related to higher disability and fatigue scores. Future studies with larger sample size are necessary to establish melatonin status as a biomarker of disease severity in MS.
Abstract Background Daily practice is still faced with uncertainty in predicting the long-term disability of multiple sclerosis (MS). Most information comes from northern hemisphere cohorts, but in ...South America this information is scarce, and race, genetic and environmental factors could play an important role in the heterogeneity observed in disease outcomes. Methods We evaluated 197 patients attending our MS Center gathering clinical and demographic information. Outcome measures analyzed were time from first clinical symptom to EDSS of 6, 7 and 8. For survival analysis we employed Cox regression models and the Kaplan–Meier method. Results Time to EDSS 6 was 25.83 years (95% CI 15.36–36.31), and 36.25 years (95% CI 20.72–51.78) for EDSS 7. Male sex was associated with a 4.63 and 4.69 fold increased risk to EDSS 6 and 7, respectively (p < 0.001 and p = 0.006). Motor and brainstem symptoms at onset were also associated with an 8.1 and 13.1 fold increased risk to EDSS 6, respectively (p = 0.04 and p = 0.01). The number of relapses in five and ten years of disease onset was associated with a slightly increased risk to EDSS 8 (1.28 and 1.19, respectively; p = 0.032 and p = 0.015). Conclusions Male patients presenting with frequent relapses, especially those with motor and brainstem involvement, deserve close observation and should be cautiously monitored to early signs of treatment failure.
•Rigorous outcomes were difficult to sustain and did not prevent cognitive decline.•Absence of cognitive decline was linked to better subsequent MS evolution.•Early MS inflammatory activity was ...associated with future clinical disability.•Joint clinical/cognitive measures were better linked to later overall disability.•The evaluation of more than one cognitive domain is preferable.
The demand for better outcome measures in multiple sclerosis (MS) management has been increasingly recognized. Nevertheless, the prognostic impacts of available outcome measures for long-term clinical and especially cognitive disability have not been thoroughly investigated. We, therefore, aimed to explore the sustainability and long-term predictive value of outcome measures in MS.
We studied a cohort of 42 relapsing-remitting MS patients and 30 healthy subjects. Evaluations were performed at baseline and after two (Y2) and six years (Y6), and included neurological and neuropsychological evaluation (BRBN), MRI (3T), and quality of life assessment. Combined clinical and cognitive measures were evaluated, such as minimal and no evidence of disease activity (MEDA and NEDA, respectively). We performed logistic regression with bootstrapping and calculated the diagnostic properties to identify patients who reached six-year clinical and/or cognitive worsening.
NEDA status was observed in up to 30.8% of patients at Y2, but only in 5% at Y6, and did not preclude cognitive decline (SDMT and BRBN). The absence of MRI activity and MEDA status at Y2 were associated with less EDSS worsening in the following years but without impact on cognition. The absence of deterioration on combined clinical/cognitive measures at Y2 (e.g., T25W+ 9HPT + BRBN) was associated with better outcomes in the following years (clinical and cognitive), with moderate to large effect sizes. For the identification of clinical worsening at Y6, best accuracies were found for MEDA (70.6%), and clinical worsening (71.4%), but only MEDA remained in the final model after multivariable logistic regression analysis (OR = 6.81, p = 0.017). For combined clinical and cognitive worsening at Y6, only T25W+ 9HPT + BRBN remained in the final model (OR = 8.5, p = 0.017).
Early MS inflammatory disease activity is associated with future clinical disability. Nevertheless, NEDA was difficult to sustain in the long-term and did not preclude cognitive deterioration. Clinical and cognitive measures combined predicted outcomes better than each one isolated. Our data suggest that the evaluation of more than one cognitive domain yields a better predictive outcome measure.
Demyelinating and inflammatory myelopathies represent a group of diseases with characteristic patterns in neuroimaging and several differential diagnoses. The main imaging patterns of demyelinating ...myelopathies (multiple sclerosis, neuromyelitis optica spectrum disorder, acute disseminated encephalomyelitis, and myelin oligodendrocyte glycoprotein antibody-related disorder) and inflammatory myelopathies (systemic lupus erythematosus-myelitis, sarcoidosis-myelitis, Sjögren-myelitis, and Behçet's-myelitis) will be discussed in this article, highlighting key points to the differential diagnosis.
Abstract The present study evaluated the effects of cyclic variations of hydrostatic pressure (HP) on neurotransmitters in the whole brain of flounder. The concentrations of the biogenic amines ...L-3,4-dihydroxyphenylalanine (L-DOPA), dopamine (DA), norepinephrine (NE), epinephrine (E), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyramine (3-MT), 5-hydroxytryptamine (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) were measured. Fish were subjected to HP cyclic variations which mimic naturally occurring conditions for a period of 14 days. DA, NE and 5-HT concentrations were significantly smaller by 21, 24 and 36%, respectively, compared to control fish. The concentrations of monoamine metabolites HVA, 3-MT and 5-HIAA were also smaller than those in control fish. These results suggest that central monoaminergic systems were influenced during long exposure to cyclic HP. The decreases of central neurotransmitters content might be involved in the physiological and behavioral responses to intermittent HP in fish.
Abstract Higher MS relapse frequency is observed during warmer months in different regions, but evidence for an underlying immunological variation is lacking. Therefore, we investigated seasonal ...variations of cytokine production in relapsing-remitting MS patients. Twenty-one patients and eight controls had blood samples drawn in each season, evaluating for IL-10, IL-6, TNF-α and IFN-γ. The lowest levels of cytokine production were observed in spring samples, with a significant increase from spring to summer for most cytokines, and especially IFN-γ and TNF-α. This phenomenon may underlie the higher prevalence of clinical and subclinical MS activity observed in warmer months.
