Italian adaptation of the Edinburgh Social Cognition Test (ESCoT):A new tool for the assessment of theory of mind and social norm understanding

The relevance of social cognition assessment has been formally described in the Diagnostic and Statistical Manual of Mental Disorders-5. However, social cognition tools evaluating different socio-cognitive components for Italian-speaking populations are lacking. The Edinburgh Social Cognition Test (ESCoT) is a new social cognition measure that uses animations of everyday social interactions to assess (i) cognitive theory of mind, (ii) affective theory of mind, (iii) interpersonal social norm understanding, and (iv) intrapersonal social norm understanding. Previous studies have shown that the ESCoT is a sensitive measure of social cognition in healthy and clinical populations in the United Kingdom. This work aimed to adapt and validate the ESCoT in an Italian population of healthy adults. A translation-back-translation procedure was followed to create and refine the Italian version. Then, 94 healthy adults (47 females, mean age  35 ± 15.9) completed the ESCoT, a battery of conventional social cognition tests (Yoni; Reading the Mind in the Eyes Strange Stories, and Social Norm Questionnaire, SNQ) and measures of intelligence and executive functions. Reliability, convergent validity, and predictors of performance on the ESCoT were examined. Results demonstrated good reliability of the ESCoT and an association between the ESCoT scores and some traditional social cognition tests (Yoni cognitive subscale, SNQ). Hierarchical regression results showed that the ESCoT total score was associated with age. Also, the ESCoT subscore (intrapersonal social norm understanding) was associated with education. These findings support the ESCoT as a valid tool testing social norm understanding, a reliable measure of social cognition for an adult Italian population, and provides further evidence that the ESCoT is sensitive to age- and education-related changes in social cognition, and it is a task not affected by general cognitive functioning

Age-related brain atrophy may be mitigated by internal jugular vein enlargement in male individuals without neurologic disease.

Objectives To assess the relationship between cross-sectional area of internal jugular veins and brain volumes in healthy individuals without neurologic disease. Methods A total of 193 healthy individuals without neurologic disease (63 male and 130 female; age > 20 to < 70 years) received magnetic resonance venography and structural brain magnetic resonance imaging at 3T. The internal jugular vein cross-sectional area was assessed at C2–C3, C4, C5–C6, and C7–T1. Normalized whole brain volume was assessed. Partial correlation analyses were used to determine associations. Results There was an inverse relationship between normalized whole brain volume and total internal jugular vein cross-sectional area (C7–T1: males r = −0.346, p = 0.029; females r = −0.301, p = 0.002). After age adjustment, association of normalized whole brain volume and normalized gray matter volume with internal jugular vein cross-sectional area became positive in males (normalized whole brain volume and right internal jugular vein cross-sectional area (C2–C3) changed from r = −0.163 to r = 0.384, p = 0.002), but not in the females. Conclusion Sex differences exist in the relationship between brain volume and internal jugular vein cross-sectional area in healthy individuals without neurologic disease

CSF neurofilament light chain predicts 10-year clinical and radiologic worsening in multiple sclerosis

Background Neurofilament light chain (NfL) is an attractive biomarker of disease activity and progression in MS, but there is a lack in long-term prognostic data. Objective To test the long-term clinical and radiological prognostic value of cerebrospinal fluid (CSF)-NfL among newly diagnosed patients with MS. Methods Newly diagnosed MS patients where followed prospectively with baseline CSF-NfL and repeated MRI and clinical assessments for up to 10 years. Associations between baseline CSF-NfL and longitudinal MRI and clinical assessments were found by Generalized Estimating Equations analysis. Results Forty-two participants were included. CSF-NfL at baseline was significantly associated with the rate of atrophy in globus pallidus (p = 0.009) and hippocampus (p = 0.001) as evaluated by MRI. Baseline volumes of thalamus (β −0.33; 95% CI −0.57 to −0.10, p = 0.006), T1 (β 0.28; 95% CI 0.11 to 0.44, p = 0.001) and T2 (β 0.16; 95% CI 0.04 to 0.27, p = 0.008) lesions and baseline levels of CSF-NfL (β 0.9; 95% CI 0.3 to 1.5, p = 0.002) significantly predicted EDSS worsening over 10 years. Baseline CSF-NfL gave a comparable prediction to the best MRI volumetric predictors. Conclusion CSF-NfL predicted the clinical and radiological course of newly diagnosed patients with MS over a 10-year period, underlining its prognostic role.publishedVersio

Brain atrophy and clinical characteristics predicting SDMT performance in multiple sclerosis: A 10-year follow-up study

Objectives To identify Magnetic Resonance Imaging (MRI), clinical and demographic biomarkers predictive of worsening information processing speed (IPS) as measured by Symbol Digit Modalities Test (SDMT). Methods Demographic, clinical data and 1.5 T MRI scans were collected in 76 patients at time of inclusion, and after 5 and 10 years. Global and tissue-specific volumes were calculated at each time point. For the primary outcome of analysis, SDMT was used. Results Worsening SDMT at 5-year follow-up was predicted by baseline age, Expanded Disability Status Scale (EDSS), SDMT, whole brain volume (WBV) and T2 lesion volume (LV), explaining 30.2% of the variance of SDMT. At 10-year follow-up, age, EDSS, grey matter volume (GMV) and T1 LV explained 39.4% of the variance of SDMT change. Conclusion This longitudinal study shows that baseline MRI-markers, demographic and clinical data can help predict worsening IPS. Identification of patients at risk of IPS decline is of importance as follow-up, treatment and rehabilitation can be optimized.publishedVersio

Retinal blood vessel analysis using optical coherence tomography in multiple sclerosis

Background: Both greater retinal neurodegenerative pathology and greater cardiovascular burden have been seen in persons with multiple sclerosis (pwMS).1,2 Moreover, studies have described multiple extracranial and intracranial vasculature changes in pwMS.3 However, only a few studies have examined the retinal vasculature in multiple sclerosis (MS). Objectives: To determine if there are differences in retinal vasculature between pwMS and healthy controls (HCs) and their relationship to peripapillary retinal nerve fiber layer (pRNFL) thickness. Materials and methods: A total of 167 pwMS (113 relapsing-remitting MS (RRMS) and 54 progressive MS (PMS)) and 48 HCs were scanned using optical coherence tomography (OCT). Earlier OCT scans were available in a smaller sample size of 101 pwMS and 35 HCs for additional longitudinal 5-year follow-up analysis. The semiautomated segmentation of the retinal vasculature was performed in a blinded manner on peripapillary scans using the optical coherence tomography segmentation and evaluation GUI (OCTSEG) in MatLab. (Figure 1). Automated segmentation of the pRNFL was performed in the native Heidelberg OCT software. The sum of bilateral measures of total retinal vessel diameter, the total number of retinal vessels and average vessel diameter were calculated. Independent sample t-test and paired t-test were used for cross-sectional and longitudinal analyses, respectively and non-parametric Spearman's test for determining correlations. Results: PwMS had a significantly smaller total vessel diameter (2.5 cm vs 2.7 cm, age-adjusted p=0.017) and numerically fewer number of retinal vessels when compared to HCs (35.1 vs 36.8, age-adjusted p=0.167). No significant differences between the pwRRMS and pwPMS were found. Over the follow-up, pwMS had significant decrease in number of retinal vessels (36.7 vs. 33.0, p<0.001) and significant increase in the average vessel diameter (0.072cm vs. 0.081cm, p<0.001). No longitudinal changes in the HCs were noted. Only in pwMS, lower pRNFL was associated with fewer retinal vessels and total vessel diameter (r=0.191, p=0.018 and r=0.216, p=0.007). Conclusions: PwMS have retinal vasculature that results in smaller and fewer retinal vessels when compared to HCs that were related to reduced pRNFL. Over time, a reduction of retinal vasculature occurred. Future investigations should determine the relevance of retinal vasculature in regards to MS disease outcomes, presence of cardiovascular abnormalities and cerebral/retinal perfusion

Associations between changes in ferritin levels and susceptibility-weighted imaging filtered phase in patients with relapsing–remitting multiple sclerosis over 24weeks of therapy with subcutaneous interferon beta-1a three times weekly

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Hypoperfusion of brain parenchyma is associated with the severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis: a cross-sectional preliminary report

<p>Abstract</p> <p>Background</p> <p>Several studies have reported hypoperfusion of the brain parenchyma in multiple sclerosis (MS) patients. We hypothesized a possible relationship between abnormal perfusion in MS and hampered venous outflow at the extracranial level, a condition possibly associated with MS and known as chronic cerebrospinal venous insufficiency (CCSVI).</p> <p>Methods</p> <p>We investigated the relationship between CCSVI and cerebral perfusion in 16 CCSVI MS patients and 8 age- and sex-matched healthy controls. Subjects were scanned in a 3-T scanner using dynamic susceptibility, contrast-enhanced, perfusion-weighted imaging. Cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were measured in the gray matter (GM), white matter (WM) and the subcortical GM (SGM). The severity of CCSVI was assessed according to the venous hemodynamic insufficiency severity score (VHISS) on the basis of the number of venous segments exhibiting flow abnormalities.</p> <p>Results</p> <p>There was a significant association between increased VHISS and decreased CBF in the majority of examined regions of the brain parenchyma in MS patients. The most robust correlations were observed for GM and WM (<it>r </it>= -0.70 to -0.71, <it>P </it>< 0.002 and <it>P </it>corrected = 0.022), and for the putamen, thalamus, pulvinar nucleus of thalamus, globus pallidus and hippocampus (<it>r </it>= -0.59 to -0.71, <it>P </it>< 0.01 and <it>P </it>corrected < 0.05). No results for correlation between VHISS and CBV or MTT survived multiple comparison correction.</p> <p>Conclusions</p> <p>This pilot study is the first to report a significant relationship between the severity of CCSVI and hypoperfusion in the brain parenchyma. These preliminary findings should be confirmed in a larger cohort of MS patients to ensure that they generalize to the MS population as a whole. Reduced perfusion could contribute to the known mechanisms of virtual hypoxia in degenerated axons.</p

Plasma 24-hydroxycholesterol is associated with narrower common carotid artery and greater flow velocities in relapsing multiple sclerosis

Background: Multiple sclerosis (MS) studies suggest greater cardiovascular disease burden and disturbances in the cholesterol pathways1,2 The potential impact of oxidized cholesterol molecules (oxysterols) on MS is emerging (Figure 1).3 Objective: To determine the relationship between multiple oxysterol molecules and atherosclerosis burden in MS patients. Materials and methods: A total of 99 MS patients (61 relapsing-remitting MS (RRMS) and 38 progressive MS (PMS)) patients and 38 healthy controls (HCs) underwent magnetic resonance angiography (MRA) and the cross-sectional area (CSA) of the common carotid artery (CCA) was determined at three different levels before the bifurcation (C7, C6 and C5). Additionally, an echo-color Doppler ultrasound was performed and measures of blood flow velocities were derived. Blood samples acquired at the time of the imaging examinations were analyzed and 24-, 25-, 27-hydroxycholesterol (24HC, 25HC, 27HC) and 7-ketocholesterol (7KC) were quantified in ng/mL. Results: In the MS patients, higher levels of 24HC were significantly associated with smaller CCA CSA measured at all three cervical levels (r=-0.201, p=0.046; r=-0.228, p=0.023, and r=-0.215, p=0.032, for C7, C6 and C5, respectively). These associations were driven by the RRMS group only (r=-0.407, p=0.002 for C7; r=-0.414, p=0.002, for C6; and r=-0.368, p=0.006 for C5). No associations were seen in the HCs. Despite adjusting for the significant age effect (B=0.445, p=0.004), higher 24HC levels were independently associated with smaller CCA CSA (B=-0.20, p=0.045). 24HC was additionally associated with greater time-averaged and peak diastolic CCA velocities. RRMS patients treated with potent anti-inflammatory therapies had lower oxysterol levels (p=0.019). RRMS patients in the lower 24HC quartiles had significantly higher expanded disability status scale (EDSS) scores when compared to RRMS patients in the higher two 24HC quartiles (2.5 (IQR 1.9-3.1) vs 2.0 (1.5-2.5), p=0.038). Conclusions: Greater 24HC levels are associated with smaller CSA CCA and greater flow velocities in RRMS patients. The higher inflammatory activity in RRMS patients may contribute to the production of highly reactive oxysterols and worsen the atherosclerotic burden in the MS population. Potent anti-inflammatory medications can significantly decrease oxysterol levels

Lower cerebral arterial blood flow is associated with greater serum neurofilament light chain levels in multiple sclerosis patients

Background: Hypoperfusion, vascular pathology, and cardiovascular risk factors are associated with disease severity in multiple sclerosis (MS).1,2 In particular, the total cerebral arterial blood flow (CABF), measured as a sum of all arterial flow in the neck, was associated with the cognitive performance of MS patients.3 Objective: To assess relationships between CABF and serum neurofilament light chain (sNfL), as neuronal damage biomarker with good prognostic value and treatment responsiveness.4 If the cerebrovascular changes are an independent pathophysiological factor in MS, a relationship should remain significant after controlling for common MS-based disease measures (i.e., T2 lesion volume and brain volume). Materials and methods: Total CABF was measured in 137 patients (86 clinically isolated syndrome (CIS)/relapsing-remitting (RR) and 51 progressive MS (PMS)) and 48 healthy controls (HCs) using Doppler ultrasound. sNfL was quantitated using a single molecule assay (Simoa). Three point zero T magnetic resonance imaging (MRI) examination allowed quantification of T2 lesion and whole-brain volume (WBV). Multiple linear regression models determined the sNfL associated with CABF after correction for demographic and MRI-derived variables. Results: After adjustment for age, sex and body mass index (BMI), total CABF remained statistically significant and model comparisons showed that CABF explained additional 2.6% of the sNfL variance (β=-0.167, p=0.044). (Table 1) CABF also remained significant in a step-wise regression model (β=0.18, p=0.034) upon the inclusion of T2 lesion burden and WBV effects. The explained sNfL variance improved from 17.4%, 22.7% with the presence of at least 2 CVD variable and 25.8% with both CVD and CABF predictors. Lastly, the disease-modifying therapy was not kept in the final model as an independent predictor of sNfL. Patients in the lowest CABF quartile (CABF≤761 mL/min) had significantly higher sNfL (34.6 pg/mL versus 23.9 pg/mL, adjusted-p=0.042) when compared to the highest quartile (CABF≥1130 mL/min). Conclusions: Lower CABF is associated with increased sNfL in MS patients, highlighting direct and independent relationship between cerebral hypoperfusion and axonal pathology. This relationship remained significant in the CIS/RRMS after adjusting for age, sex, and BMI effects

Muscle quantitative MRI as a novel biomarker in hereditary transthyretin amyloidosis with polyneuropathy: a cross-sectional study

BACKGROUND: The development of reproducible and sensitive outcome measures has been challenging in hereditary transthyretin (ATTRv) amyloidosis. Recently, quantification of intramuscular fat by magnetic resonance imaging (MRI) has proven as a sensitive marker in patients with other genetic neuropathies. The aim of this study was to investigate the role of muscle quantitative MRI (qMRI) as an outcome measure in ATTRv. METHODS: Calf- and thigh-centered multi-echo T2-weighted spin-echo and gradient-echo sequences were obtained in patients with ATTRv amyloidosis with polyneuropathy (n = 24) and healthy controls (n = 12). Water T2 (wT2) and fat fraction (FF) were calculated. Neurological assessment was performed in all ATTRv subjects. Quantitative MRI parameters were correlated with clinical and neurophysiological measures of disease severity. RESULTS: Quantitative imaging revealed significantly higher FF in lower limb muscles in patients with ATTRv amyloidosis compared to controls. In addition, wT2 was significantly higher in ATTRv patients. There was prominent involvement of the posterior compartment of the thighs. Noticeably, FF and wT2 did not exhibit a length-dependent pattern in ATTRv patients. MRI biomarkers correlated with previously validated clinical outcome measures, Polyneuropathy Disability scoring system, Neuropathy Impairment Score (NIS) and NIS-lower limb, and neurophysiological parameters of axonal damage regardless of age, sex, treatment and TTR mutation. CONCLUSIONS: Muscle qMRI revealed significant difference between ATTRv and healthy controls. MRI biomarkers showed high correlation with clinical and neurophysiological measures of disease severity making qMRI as a promising tool to be further investigated in longitudinal studies to assess its role at monitoring onset, progression, and therapy efficacy for future clinical trials on this treatable condition