Dynamic regulation of serum aryl hydrocarbon receptor agonists in MS

Objective: Several factors influence the clinical course of autoimmune inflammatory diseases such as MS and inflammatory bowel disease. Only recently, the complex interaction between the gut microbiome, dietary factors, and metabolism has started to be appreciated with regard to its potential to modulate acute and chronic inflammation. One of the molecular sensors that mediates the effects of these environmental signals on the immune response is the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor with key functions in immune cells. Methods: In this study, we analyzed the levels of AHR agonists in serum samples from patients with MS and healthy controls in a case-control study. Results: We detected a global decrease of circulating AHR agonists in relapsing-remitting MS patients as compared to controls. However, during acute CNS inflammation in clinically isolated syndrome or active MS, we measured increased AHR agonistic activity. Moreover, AHR ligand levels in patients with benign MS with relatively mild clinical impairment despite longstanding disease were unaltered as compared to healthy controls. Conclusions: Collectively, these data suggest that AHR agonists in serum are dynamically modulated during the course of MS. These findings may guide the development of biomarkers to monitor disease activity as well as the design of novel therapeutic interventions for MSInstituto de Salud Carlos III, Unión Europea PT13/0010/004

A Preference for Contralateral Stimuli in Human Object- and Face-Selective Cortex

Visual input from the left and right visual fields is processed predominantly in the contralateral hemisphere. Here we investigated whether this preference for contralateral over ipsilateral stimuli is also found in high-level visual areas that are important for the recognition of objects and faces. Human subjects were scanned with functional magnetic resonance imaging (fMRI) while they viewed and attended faces, objects, scenes, and scrambled images in the left or right visual field. With our stimulation protocol, primary visual cortex responded only to contralateral stimuli. The contralateral preference was smaller in object- and face-selective regions, and it was smallest in the fusiform gyrus. Nevertheless, each region showed a significant preference for contralateral stimuli. These results indicate that sensitivity to stimulus position is present even in high-level ventral visual cortex

Cervical spondylosis is a risk factor for localized spinal cord lesions in multiple sclerosis

OBJECTIVES: To answer the question whether cervical spondylosis would increase the incidence of cord lesions in MS patients, we investigated the statistical association between the two pathologies. METHODS: We extracted demographics, basic disease characteristics and MRI data of a cohort of 304 consecutive MS patients. For a subset of 176 patients, a detailed analysis independently assessed for each cervical level the co-existence of spinal canal narrowing from spondylosis and corresponding cord signal abnormalities. RESULTS: The cohort had typical demographics and in over 80 % of cases there was at least one cord lesion. EDSS correlated with age, disease duration, cerebral lesion burden and spinal cord lesions. After adjusting for either age, disease duration, central lesion burden, or EDSS, the presence of spinal spondylosis was not significantly associated with spinal cord lesions (p \u3e 0.05). In the subset of 176 subjects with the level-by-level spine data, we found a highly statistically significant association (Pearson\u27s chi(2) = 23.7, p \u3c 0.001) between canal narrowing and cord lesion at the level directly above or below. This association remained highly significant in both univariable and multivariable logistic regression models adjusting for age, disease duration, MS treatment, cerebral lesion burden and disability scores (p \u3c 0.001). CONCLUSIONS: The data from our cohort of MS patients suggest an indirect contribution of cervical spondylosis to disability by increasing the risk of developing localized cord lesions. While further studies are needed to confirm the findings and clarify disease mechanisms, closer attention should be paid to worsening spondylosis in patients with MS

A paradox of social distancing for SARS-CoV-2: loneliness and heightened immunological risk

The World Health Organization declared the SARS-CoV-2 virus a global pandemic in March of 2020. In an effort to reduce the harms and rate of exponential spread, regional and national governments across the world instituted a variety of measures. These have included orders for citizens to practice social distancing, which in the US has affected over 300 million people. In their most extreme, these social distancing measures are isolation orders to “shelter in place”, at one point affecting ~17 million Americans. Data regarding the effects of these policies are emerging, but two outcomes include greater social isolation and likely increased loneliness. An important distinction arises between these two concepts. Social isolation is the objective lack of, or reduction in, social contact. Loneliness is the subjective discrepancy between the desired and actual levels of social connection. Objective social isolation and subjective loneliness are only weakly correlated (r ~ 0.2), but both have independent real-world health consequences and are associated with long-term increases in mortality (29% and 26%, respectively). The magnitude of these effects rival that of smoking and obesity on long-term health risks. Emerging evidence for the social repercussions of the pandemic is worrisome; a recent longitudinal study following more than 35,000 people reported that while overall loneliness has not changed during the COVID pandemic, individuals who described high levels of baseline social isolation are now experiencing significantly worse pandemic-related loneliness. Now more than ever the most socially vulnerable would likely benefit from clinical assessment and support. Our own unpublished survey data (N = 155) indicate that 60% of respondents from an online campaign in the USA, Israel, and UK report a greater sense of loneliness since the pandemic began

Paramagnetic Rim Lesions in Multiple Sclerosis: Comparison of Visualization at 1.5-T and 3-T MRI

Background: Multiple sclerosis (MS) is characterized by both acute and chronic intrathecal inflammation. A subset of MS lesions show paramagnetic rims on susceptibility-weighted MRI sequences, reflecting iron accumulation in microglia. These paramagnetic rim lesions (PRLs) have been proposed as a marker of compartmentalized smoldering disease. PRLs have been demonstrated at 7 T and, more recently, at 3 T. As susceptibility effects are weaker at lower field strength, it remains unclear if PRLs are visible at 1.5 T. Objective: To compare the visualization of PRLs using susceptibility-weighted imaging at 1.5-T and 3-T MRI in patients with MS. Methods: This retrospective study included 9 patients (5 women, 4 men; mean age, 46.8 years) with MS who underwent both 1.5-T and 3-T MRI using a comparable susceptibility-weighted sequence from the same manufacturer (GE SWAN). Lesions measuring \u3e3 mm were annotated. Two reviewers independently assessed images at each field strength in separate sessions, classifying the annotated lesions based on susceptibility-weighted images as isointense, diffusely paramagnetic, or PRL. Discrepancies were discussed at consensus sessions including a third reviewer. Agreement was assessed using kappa coefficients. Results: Of 140 annotated lesions, based on the 3-T consensus readings, 115 (82%) were isointense, 16 (11%) were diffusely paramagnetic, and 9 (6%) were PRLs; based on the 1.5-T consensus readings, 115 (82%) were isointense, 14 (10%) were diffusely paramagnetic, and 11 (8%) were PRLs. Mean lesion diameter was 11.9 mm for PRLs, versus 6.4 mm for diffusely paramagnetic lesions (p=.006) and 7.8 mm for isointense lesions (p=.003). Interrater agreement for lesion classification as PRL was substantial at 1.5 T (kappa=0.65) and 3 T (kappa=0.70). Agreement for PRL was also substantial between the consensus readings at the two field strengths (kappa=0.79). Conclusion: We show comparable identification of PRLs at 1.5-T and 3-T MRI, with substantial interrater agreement at both field strengths and substantial consensus agreement between the field strengths. Clinical Impact: PRL may be an emerging marker of chronic neuroinflammation in MS. Their visibility at 1.5 T supports the translational potential of PRL identification to more widespread clinical settings, where 1.5-T scanners are prevalent

The neutrophil-to-lymphocyte and monocyte-to-lymphocyte ratios are independently associated with neurological disability and brain atrophy in multiple sclerosis

Abstract Background Serum hematological indices such as the neutrophil-lymphocyte ratio (NLR) or monocyte-lymphocyte ratio (MLR) have been used as biomarkers of pathogenic inflammation and prognostication in multiple areas of medicine; recent evidence shows correlation with psychological parameters as well. Objectives/Aims: To characterize clinical, neuroimaging, and psycho-neuro-immunological associations with NLR and MLR in persons with multiple sclerosis (MS). Methods We identified a large cohort of clinically well-defined patients from our longitudinal database that included MS-related outcomes, disease-modifying therapy, patient-reported outcome (PRO) measures, and quantified cerebral MRI at 1.5 T. We queried hospital records for complete blood counts within 2 months of each clinic visit and excluded those obtained during clinical relapses. Four hundred eighty-three patients, with a mean of 3 longitudinal observations each, were identified who met these criteria. Initial analyses assessed the association between NLR and MLR as the outcomes, and psychological and demographic predictors in univariable and multivariable models controlling for age, gender and treatment. The second set of analyses assessed the association between clinical and MRI outcomes including whole brain atrophy and T2-hyperintense lesion volume, with NLR and MLR as predictors in univariable and multivariable models. All analyses used a mixed effects linear or logistic regression model with repeated measures. Results Unadjusted analyses demonstrated significant associations between higher (log-transformed) NLR (but not MLR) and PRO measures including increasing depression (p = 0.01), fatigue (p  0.05) even after controlling for all clinical and demographic covariates. Sensitivity analyses using a subset of untreated patients (N = 146) corroborated these results. Conclusions Elevated NLR and MLR may represent hematopoetic bias toward increased production and pro-inflammatory priming of the myeloid innate immune system (numerator) in conjunction with dysregulated adaptive immune processes (denominator), and consequently reflect a complementary and independent marker for severity of MS-related neurological disability and MRI outcomes

Illustration of the experimental conditions and the anatomical position of the regions of interest (ROIs).

<p>(A), Illustration of the position of the four stimulus categories (faces, objects, scenes, and scrambled images) left and right of the fixation spot. (B) Illustration of the 5 ROIs for one subject onto a flattened brain. Indicated sulci: CS: calcarine sulcus; ITS: inferior temporal sulcus. Indicated anatomical directions: D: dorsal; V: ventral; P: posterior; A: anterior.</p

Responses to contralateral and ipsilateral stimuli in the regions of interest.

<p>(A) The response (percent signal change relative to the fixation condition) in each ROI is shown for each stimulus condition (F: faces, O: objects, Se: scenes, Sa: scrambled images). (B) Preference index in each ROI averaged across all stimulus conditions. (C) Preference index in each ROI for the stimulus condition that elicited the strongest responses. Error bars represent the standard error of the mean across subjects.</p

Dynamic regulation of serum aryl hydrocarbon receptor agonists in MS

Objective: Several factors influence the clinical course of autoimmune inflammatory diseases such as MS and inflammatory bowel disease. Only recently, the complex interaction between the gut microbiome, dietary factors, and metabolism has started to be appreciated with regard to its potential to modulate acute and chronic inflammation. One of the molecular sensors that mediates the effects of these environmental signals on the immune response is the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor with key functions in immune cells. Methods: In this study, we analyzed the levels of AHR agonists in serum samples from patients with MS and healthy controls in a case-control study. Results: We detected a global decrease of circulating AHR agonists in relapsing-remitting MS patients as compared to controls. However, during acute CNS inflammation in clinically isolated syndrome or active MS, we measured increased AHR agonistic activity. Moreover, AHR ligand levels in patients with benign MS with relatively mild clinical impairment despite longstanding disease were unaltered as compared to healthy controls. Conclusions: Collectively, these data suggest that AHR agonists in serum are dynamically modulated during the course of MS. These findings may guide the development of biomarkers to monitor disease activity as well as the design of novel therapeutic interventions for MS