Lesion Load Research Articles

Choroid plexus volume is enlarged in clinically isolated syndrome patients with optic neuritis

Objectives: We investigated choroid plexus (CP) volume in patients presenting with optic neuritis (ON) as a clinically isolated syndrome (CIS), compared to a cohort with established relapsing–remitting multiple sclerosis (RRMS) and healthy controls (HCs). Methods: Three-dimensional (3D) T1, T2-FLAIR and diffusion-weighted sequences were acquired from 44 ON CIS patients at baseline, 1, 3, 6 and 12 months after the onset of ON. Fifty RRMS patients and 50 HCs were also included for comparison. Results: CP volumes was larger in both ON CIS and RRMS groups compared to HCs, but not significantly different between ON CIS and RRMS patients (analysis of covariance (ANCOVA) adjusted for multiple comparisons). Twenty-three ON CIS patients who converted to clinically definite MS (MS) demonstrated CP volume similar to RRMS patients, but significantly larger compared to HCs. In this sub-group, CP volume was not associated with the severity of optic nerve inflammation or long-term axonal loss, not with brain lesion load. A transient increase of CP volume was observed following an occurrence of new MS lesions on brain magnetic resonance imaging (MRI). Interpretation: Enlarged CP can be observed very early in a disease. It transiently reacts to acute inflammation, but not associated with the degree of tissue destruction.

Clinical significance of extended high-risk human papillomavirus genotyping and viral load in cervical cancer and precancerous lesions

Persistent infections with specific high-risk human papillomavirus (HR-HPV) strains are the leading cause of cervical cancer and precancerous lesions. HPV-16 and HPV-18 are associated with more than 70% of cervical...

White Matter Lesion Load and Location in Relation to Cognitive and Physical Dysfunctions in Relapsing Remitting Multiple Sclerosis

White Matter Lesion Load and Location in Relation to Cognitive and Physical Dysfunctions in Relapsing Remitting Multiple Sclerosis

Stroke Lesion Volume and Injury to Motor Cortex Output Determines Extent of Contralesional Motor Cortex Reorganization

Background After stroke, increases in contralesional primary motor cortex (M1CL) activity and excitability have been reported. In pre-clinical studies, M1CL reorganization is related to the extent of ipsilesional M1 (M1IL) injury, but this has yet to be tested clinically. Objectives We tested the hypothesis that the extent of damage to the ipsilesional M1 and/or its corticospinal tract (CST) determines the magnitude of M1CL reorganization and its relationship to affected hand function in humans recovering from stroke. Methods Thirty-five participants with a single subacute ischemic stroke affecting M1 or CST and hand paresis underwent MRI scans of the brain to measure lesion volume and CST lesion load. Transcranial magnetic stimulation (TMS) of M1IL was used to determine the presence of an electromyographic response (motor evoked potential (MEP+ and MEP−)). M1CL reorganization was determined by TMS applied to M1CL at increasing intensities. Hand function was quantified with the Jebsen Taylor Hand Function Test. Results The extent of M1CL reorganization was related to greater lesion volume in the MEP− group, but not in the MEP+ group. Greater M1CL reorganization was associated with more impaired hand function in MEP− but not MEP+ participants. Absence of an MEP (MEP−), larger lesion volumes and higher lesion loads in CST, particularly in CST fibers originating in M1 were associated with greater impairment of hand function. Conclusions In the subacute post-stroke period, stroke volume and M1IL output determine the extent of M1CL reorganization and its relationship to affected hand function, consistent with pre-clinical evidence. ClinicalTrials.gov Identifier: NCT02544503

Abstract 152: Relationship Between Gait Function And Damage To Descending Motor Pathways After Stroke

Introduction: Descending motor pathways, namely the corticospinal (CST) and corticoreticular tracts (CRT), are important for normal gait function and have been implicated in gait recovery after stroke. However, the relationship of structural injury to these tracts and gait function in the acute and chronic stage post-stroke remains unclear. Methods: Gait velocity was recorded the first week (acute) after stroke (n=127) and one year later (n= 50). CST and CRT injury were measured using weighted lesion load (wLL). The impact of CST and CRT injury on ambulation status (non-ambulatory vs. ambulatory) and gait velocity was assessed with multivariate logistic and linear regression models, respectively, acutely and chronically, controlling for wLL and lesion size. Results: Greater CRT injury resulted in a higher odds of ambulation loss acutely post-stroke (odds ratio [95% CI, p value]: CRT wLL, 1.06 [1.02-1.12, 0.007]; CST wLL 0.97 [0.95-0.99, 0.04]; lesion volume 1.00 [0.99-1.00, 0.96]). Conversely, greater CST injury had higher odds of ambulation loss at one-year (CST wLL, 1.09 [1.01-1.21, 0.04]; CRT wLL, 0.98 [0.84-1.13, 0.75]; lesion volume, 1.00 [0.99-1.00, 0.81]). For walkers (N=51 [acute] and 46 [chronic]), gait velocity was not significantly associated with CRT nor CST wLL at either time. Multicollinearity results denoted lesion measures provided independent information (maximum variance inflation factors 3.4 (acute), 4.2 (one-year)). Conclusion: Results suggest CRT injury is the dominant correlate of ambulation loss acutely, with CST the dominant correlate of persistent loss after one-year. Gait velocity is not well explained by damage to either tract. The results imply that the CRT may be the primary cortical projection for normal (pre-stroke) gait. Yet, the nervous system has sufficient redundancy to compensate for unilateral CRT injury, while CST injury may have a more enduring negative impact on gait function.

White matter lesion load determines exercise-induced dopaminergic plasticity and working memory gains in aging

Age-related dopamine reductions have been suggested to contribute to maladaptive working memory (WM) function in older ages. One promising intervention approach is to increase physical activity, as this has been associated with plasticity of the striatal dopamine system and WM improvements, however with individual differences in efficacy. The present work focused on the impact of individual differences in white-matter lesion burden upon dopamine D2-like receptor (DRD2) availability and WM changes in response to a 6 months physical activity intervention. While the intervention altered striatal DRD2 availability and WM performance in individuals with no or only mild lesions (p < 0.05), no such effects were found in individuals with moderate-to-severe lesion severity (p > 0.05). Follow-up analyses revealed a similar pattern for processing speed, but not for episodic memory performance. Linear analyses further revealed that lesion volume (ml) at baseline was associated with reduced DRD2 availability (r = −0.41, p < 0.05), and level of DRD2 change (r = 0.40, p < 0.05). Taken together, this study underlines the necessity to consider cerebrovascular health in interventions with neurocognitive targets. Future work should assess whether these findings extend beyond measures of DRD2 availability and WM.

An Interpretable Machine Learning Model to Predict Cortical Atrophy in Multiple Sclerosis

To date, the relationship between central hallmarks of multiple sclerosis (MS), such as white matter (WM)/cortical demyelinated lesions and cortical gray matter atrophy, remains unclear. We investigated the interplay between cortical atrophy and individual lesion-type patterns that have recently emerged as new radiological markers of MS disease progression. We employed a machine learning model to predict mean cortical thinning in whole-brain and single hemispheres in 150 cortical regions using demographic and lesion-related characteristics, evaluated via an ultrahigh field (7 Tesla) MRI. We found that (i) volume and rimless (i.e., without a "rim" of iron-laden immune cells) WM lesions, patient age, and volume of intracortical lesions have the most predictive power; (ii) WM lesions are more important for prediction when their load is small, while cortical lesion load becomes more important as it increases; (iii) WM lesions play a greater role in the progression of atrophy during the latest stages of the disease. Our results highlight the intricacy of MS pathology across the whole brain. In turn, this calls for multivariate statistical analyses and mechanistic modeling techniques to understand the etiopathogenesis of lesions.

Low doses of 3-phenyl-lawsone or meglumine antimoniate delivery by tattooing route are successful in reducing parasite load in cutaneous lesions of Leishmania (Viannia) braziliensis-infected hamsters.

Current therapeutic ways adopted for the treatment of leishmaniasis are toxic and expensive including parasite resistance is a growing problem. Given this scenario, it is urgent to explore treatment alternatives for leishmaniasis. The aim of this study was to evaluate the effect of 3-phenyl-lawsone (3-PL) naphthoquinone on Leishmania (Viannia) braziliensis infection, both in vitro and in vivo, using two local routes of administration: subcutaneous (higher dose) and tattoo (lower dose). In vitro 3-PL showed low toxicity for macrophages (CC50 >3200 µM/48h) and activity against intracellular amastigotes (IC50 = 193 ± 19 µM/48h) and promastigotes (IC50 = 116 ± 26 µM/72h), in which induced increased ROS generation. Additionally, 3-PL up-regulated the production of cytokines such as tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1), interleukin-6 (IL-6) and IL-10 in infected macrophages. However, the anti-amastigote action was independent of nitric oxide production. Treatment of hamsters infected with L. (V.) braziliensis from one week after infection with 3-PL by subcutaneous (25 µg/Kg) or tattooing (2.5 µg/Kg) route, during 3 weeks (3 times/week) or 2 weeks (2 times/week) significantly decreased the parasite load (p<0.001) in the lesion. The reduction of parasite load by 3-PL treatment was comparable to reference drug meglumine antimoniate administered by the same routes (subcutaneous 1mg/Kg and tattoo 0.1mg/Kg). In addition, treatment started from five weeks after infection with 3-PL per tattoo also decreased the parasite load. These results show the anti-leishmanial effect of 3-PL against L. (V.) braziliensis and its efficacy by subcutaneous (higher dose) and tattoo (lower dose) routes. In addition, this study shows that drug delivery by tattooing the lesion allows the use of lower doses than the conventional subcutaneous route, which may support the development of a new therapeutic strategy that can be adopted for leishmaniasis.

Early Predictors of Disability and Cognition in Multiple Sclerosis Patients: A Long-Term Retrospective Analysis.

We conducted a retrospective analysis on multiple sclerosis (MS) patients with perceived cognitive decline and long disease duration to investigate early predictors of future cognitive impairment (CI) and motor disability. Sixty-five patients complaining of cognitive decline were assessed with an extensive neuropsychological battery at the last clinical follow-up and classified as mildly impaired, severely impaired, and cognitively spared based on the results. Motor disability was assessed with EDSS, MSSS, and ARMSS. Baseline demographic, clinical, and imaging parameters were retrospectively collected and inserted in separate multivariate regression models to investigate the predictive power of future impairment. Twenty-one patients (32.3%) showed no CI, seventeen (26.2%) showed mild CI, and twenty-seven (41.5%) showed severe CI. Older and less educated patients with higher EDSS, longer disease duration, and higher white matter lesion load (WMLL) at diagnosis (particularly with cerebellar involvement) were more likely to develop CI after a mean follow-up from diagnosis of 16.5 ± 6.9 years. DMT exposure was protective. The multivariate regression analyses confirmed WMLL, disease duration, and educational levels as the parameters with significant predictive value for future CI (R2 adjusted: 0.338 p: 0.001). Older patients with progressive phenotype both at diagnosis and T1 were more likely to be not fully ambulatory at T1 (R2 adjusted: 0.796 p: 0.0001). Our results further expand knowledge on early predictors of cognitive decline and evolution over time.

Asymptomatic carotid stenosis is associated with both edge and network reconfigurations identified by single-subject cortical thickness networks.

Patients with asymptomatic carotid stenosis, even without stroke, are at high risk for cognitive impairment, and the neuroanatomical basis remains unclear. Using a novel edge-centric structural connectivity (eSC) analysis from individualized single-subject cortical thickness networks, we aimed to examine eSC and network measures in severe (> 70%) asymptomatic carotid stenosis (SACS). Twenty-four SACS patients and 24 demographically- and comorbidities-matched controls were included, and structural MRI and multidomain cognitive data were acquired. Individual eSC was estimated via the Manhattan distances of pairwise cortical thickness histograms. In the eSC analysis, SACS patients showed longer interhemispheric but shorter intrahemispheric Manhattan distances seeding from left lateral temporal regions; in network analysis the SACS patients had a decreased system segregation paralleling with white matter hyperintensity burden and recall memory. Further network-based statistic analysis identified several eSC and subgraph features centred around the Perisylvian regions that predicted silent lesion load and cognitive tests. We conclude that SACS exhibits abnormal eSC and a less-optimized trade-off between physical cost and network segregation, providing a reference and perspective for identifying high-risk individuals.

The clinical-radiological paradox in multiple sclerosis: myth or truth?

Multiple sclerosis (MS) is an inflammatory, degenerative, demyelinating disease that ranges from benign to rapidly progressive forms. A striking characteristic of the disease is the clinical-radiological paradox. The present study was conducted to determine whether, in our cohort, the clinical-radiological paradox exists and whether lesion location is related to clinical disability in patients with MS. Retrospective data from 95 patients with MS (60 women and 35 men) treated at a single center were examined. One head-and-spine magnetic resonance imaging (MRI) examination from each patient was selected randomly, and two independent observers calculated lesion loads (LLs) on T2/fluid attenuation inversion recovery sequences manually, considering the whole brain and four separate regions (periventricular, juxtacortical, posterior fossa, and spinal cord). The LLs were compared with the degree of disability, measured by the Kurtzke Expanded Disability Status Scale (EDSS), at the time of MRI examination in the whole cohort and in patients with relapsing-remitting (RR), primarily progressive, and secondarily progressive MS. High LLs correlated with high EDSS scores in the whole cohort (r = 0.34; p < 0.01) and in the RRMS group (r = 0.27; p = 0.02). The EDSS score correlated with high regional LLs in the posterior fossa (r = 0.31; p = 0.002) and spinal cord (r = 0.35; p = 0.001). Our results indicate that the clinical-radiological paradox is a myth and support the logical connection between lesion location and neurological repercussion.

Assessment of serum interleukin 19 level in patients with warts

&lt;abstract&gt; &lt;p&gt;Background: Warts are viral cutaneous infections caused by human papilloma virus (HPV), presented by verrucous growth over the skin surface. The cell mediated immune response is considered to play a crucial role in HPV clearance. The viral load and number of lesions increase when there is an imbalance between the T-helper 1 and T-helper 2 immune responses. Interleukin (IL)-19 is a cytokine that belongs to interleukin 10 cytokines family and constitutes a sub-family with IL-20, IL-22 and IL-24. IL-19 is mainly produced by activated monocytes and to a lesser extent by B-cells, keratinocytes and fetal membranes. IL-19 was found to shift T-cell maturation away from the pro-inflammatory T-helper 1 cells toward the anti-inflammatory T-helper 2 cells. It induces IL-4 and IL-13 production in T cells and apoptosis in monocytes. Aim: This study aimed to measure serum level of IL-19 in patients with warts compared to healthy controls and to find out the correlation between this level and number, size and clinical types of warts. Methods: The study included 50 patients with warts and 50 control subjects. Serum concentration of IL-19 was measured by enzyme-linked immune sorbent assay. Results: Interleukin-19 serum level was significantly lower in patients with warts than in controls (P &amp;lt; 0.003). Moreover, there was a significant positive correlation between IL-19 serum level and the number of warts (P = 0.027). Conclusion: Serum level of IL-19 was significantly lower in patients with warts, and this low level might be crucial for an effective cell mediated immunological response to HPV.&lt;/p&gt; &lt;/abstract&gt;

Anti-leishmaniasis Effect of Staphylococcus Aureus Protein A on the Size of the Lesion and Parasitic Load.

Many studies in the past have evaluated the role of immune system boosters in the treatment of leishmania major infection. Protein A (PA) is one of the structural components in peptidoglycan cell wall of gram-negative bacteria such as staphylococcus aurous which functions as a stimulator in the cellular immune system. The present study aims to evaluate the anti-inflammatory effect of PA on the recovery of leishmania major infection. This study was conducted on 24 female Balb/c-infected mice. The experimental group received PA at a dose of 60 mg/kg for four weeks. There was no intervention for the negative control group; the third group received the solvent of PA and sterile H2O; and the positive control group received Amphotericin B at a dose of 1 mg/kg body weight. At the end of the treatment period, a real-time polymerase chain reaction (PCR) assay was performed to determine parasitic burden, and the size of the lesions was measured by caliper with an accuracy of 0.01 mm. Results showed that PA did slightly decrease the wound spread and growth but not to an extent that can be considered statistically significant. Also, differences in cycle threshold (Ct) values between the treated group and the untreated group was not impressive. Although findings showed that PA isn't such a good candidate for leishmania treatment, it may still be suitable for therapies that use multiple drugs in combination to speed up the healing of leishmaniosis, an issue that merits evaluation in future studies.

Exploring personalized structural connectomics for moderate to severe traumatic brain injury.

Graph theoretical analysis of the structural connectome has been employed successfully to characterize brain network alterations in patients with traumatic brain injury (TBI). However, heterogeneity in neuropathology is a well-known issue in the TBI population, such that group comparisons of patients against controls are confounded by within-group variability. Recently, novel single-subject profiling approaches have been developed to capture inter-patient heterogeneity. We present a personalized connectomics approach that examines structural brain alterations in five chronic patients with moderate to severe TBI who underwent anatomical and diffusion magnetic resonance imaging. We generated individualized profiles of lesion characteristics and network measures (including personalized graph metric GraphMe plots, and nodal and edge-based brain network alterations) and compared them against healthy reference cases (N = 12) to assess brain damage qualitatively and quantitatively at the individual level. Our findings revealed alterations of brain networks with high variability between patients. With validation and comparison to stratified, normative healthy control comparison cohorts, this approach could be used by clinicians to formulate a neuroscience-guided integrative rehabilitation program for TBI patients, and for designing personalized rehabilitation protocols based on their unique lesion load and connectome.

Graph theoretical approach to brain remodeling in multiple sclerosis.

Multiple sclerosis (MS) is a neuroinflammatory disorder damaging structural connectivity. Natural remodeling processes of the nervous system can, to some extent, restore the damage caused. However, there is a lack of biomarkers to evaluate remodeling in MS. Our objective is to evaluate graph theory metrics (especially modularity) as a biomarker of remodeling and cognition in MS. We recruited 60 relapsing-remitting MS and 26 healthy controls. Structural and diffusion MRI, plus cognitive and disability evaluations, were done. We calculated modularity and global efficiency from the tractography-derived connectivity matrices. Association of graph metrics with T2 lesion load, cognition, and disability was evaluated using general linear models adjusting for age, gender, and disease duration wherever applicable. We showed that MS subjects had higher modularity and lower global efficiency compared with controls. In the MS group, modularity was inversely associated with cognitive performance but positively associated with T2 lesion load. Our results indicate that modularity increase is due to the disruption of intermodular connections in MS because of the lesions, with no improvement or preserving of cognitive functions.

Automatic localisation and per-region quantification of traumatic brain injury on head CT using atlas mapping

Rationale and objectivesTo develop a method for automatic localisation of brain lesions on head CT, suitable for both population-level analysis and lesion management in a clinical setting. Materials and methodsLesions were located by mapping a bespoke CT brain atlas to the patient’s head CT in which lesions had been previously segmented. The atlas mapping was achieved through robust intensity-based registration enabling the calculation of per-region lesion volumes. Quality control (QC) metrics were derived for automatic detection of failure cases. The CT brain template was built using 182 non-lesioned CT scans and an iterative template construction strategy. Individual brain regions in the CT template were defined via non-linear registration of an existing MRI-based brain atlas.Evaluation was performed on a multi-centre traumatic brain injury dataset (TBI) (n = 839 scans), including visual inspection by a trained expert. Two population-level analyses are presented as proof-of-concept: a spatial assessment of lesion prevalence, and an exploration of the distribution of lesion volume per brain region, stratified by clinical outcome. Results95.7% of the lesion localisation results were rated by a trained expert as suitable for approximate anatomical correspondence between lesions and brain regions, and 72.5% for more quantitatively accurate estimates of regional lesion load. The classification performance of the automatic QC showed an AUC of 0.84 when compared to binarised visual inspection scores. The localisation method has been integrated into the publicly available Brain Lesion Analysis and Segmentation Tool for CT (BLAST-CT). ConclusionAutomatic lesion localisation with reliable QC metrics is feasible and can be used for patient-level quantitative analysis of TBI, as well as for large-scale population analysis due to its computational efficiency (<2 min/scan on GPU).

Quantitative susceptibility mapping of the normal-appearing white matter as a potential new marker of disability progression in multiple sclerosis.

To investigate the normal-appearing white matter (NAWM) susceptibility in a cohort of newly diagnosed multiple sclerosis (MS) patients and to evaluate possible correlations between NAWM susceptibility and disability progression. Fifty-nine patients with a diagnosis of MS (n = 53) or clinically isolated syndrome (CIS) (n = 6) were recruited and followed up. All participants underwent neurological examination, blood sampling for serum neurofilament light chain (sNfL) level assessment, lumbar puncture for the quantification of cerebrospinal fluid (CSF) β-amyloid1-42 (Aβ) levels, and brain MRI. T2-weighted scans were used to quantify white matter (WM) lesion loads. For each scan, we derived the NAWM volume fraction and the WM lesion volume fraction. Quantitative susceptibility mapping (QSM) of the NAWM was calculated using the susceptibility tensor imaging (STI) suite. Susceptibility maps were computed with the STAR algorithm. Primary progressive patients (n = 9) showed a higher mean susceptibility value in the NAWM than relapsing-remitting (n = 44) and CIS (n = 6) (p = 0.01 and p = 0.02). Patients with a higher susceptibility in the NAWM showed increased sNfL concentration (ρ = 0.38, p = 0.004) and lower CSF Aβ levels (ρ = -0.34, p = 0.009). Mean NAWM susceptibility turned out to be a predictor of the expanded disability status scale (EDSS) worsening at follow-up (β = 0.41, t = 2.66, p = 0.01) and of the MS severity scale (MSSS) (β = 0.38, t = 2.43, p = 0.019). QSM in the NAWM seems to predict the EDSS increment over time. This finding might provide evidence on the role of QSM in identifying patients with an increased risk of early disability progression. • NAWM-QSM is higher in PPMS patients than in RRMS. • NAWM-QSM seems to be a predictor of EDSS worsening over time. • Patients with higher NAWM-QSM show increased sNfL concentration and lower CSF Aβ levels.

Is There Reduced Hemodynamic Brain Activation in Multiple Sclerosis Even with Undisturbed Cognition?

Cognitive impairments related to changes in deep gray matter and other brain regions occur in up to 70% of people with multiple sclerosis. But do such brain changes also occur in patients without significant cognitive impairment? Eighteen participants with relapsing-remitting multiple sclerosis (RRMS) and fifteen healthy controls participated in this study. Cognitive status, depression, and fatigue were assessed using the Multiple Sclerosis Inventory of Cognition (MUSIC), Beck's Depression Inventory (BDI-II), and the Fatigue Severity Scale (FSS). fMRI was recorded while a participant performed the modified attention network test (ANT). The effects of ANT executive attention network on hemodynamic activation of a priori defined regions of interest, including the hippocampus, anterior cingulate cortex (ACC), thalamus, caudate nucleus, pallidum, and putamen were studied. The individual lesion load was estimated. For fMRI data analysis a general linear model with randomization statistics including threshold-free cluster enhancement as implemented in the FSL software was used. Participants with RRMS showed reduced activation of the executive attention network in the hippocampus, pallidum, and ACC. The thalamus was involved in both group activations but did not differ between groups. In summary, functional changes in the brain can also be demonstrated in RRMS patients without cognitive deficits. The affected brain regions can best be assigned to the attention network for executive control. This association could likely serve as a biological indicator of susceptibility to imminent cognitive impairment in MS.

A novel eye-movement impairment in multiple sclerosis indicating widespread cortical damage.

In multiple sclerosis, remyelination trials have yet to deliver success like that achieved for relapse rates with disease course modifying treatment trials. The challenge is to have a clinical, functional outcome measure. Currently, there are none that have been validated, other than visual evoked potentials in optic neuritis. Like vision, quick eye movements (saccades) are heavily dependent on myelination. We proposed that it is possible to extrapolate from demyelination of the medial longitudinal fasciculus in the brainstem to quantitative assessment of cortical networks governing saccadic eye movements in multiple sclerosis. We have developed and validated a double-step saccadic test, which consists of a pair of eye movements towards two stimuli presented in quick succession (the demonstrate eye movement networks with saccades protocol). In this single-centre, cross-sectional cohort study we interrogated the structural and functional relationships of double-step saccades in multiple sclerosis. Data were collected for double-step saccades, cognitive function (extended Rao's Brief Repeatable Battery), disability (Expanded Disability Status Scale) and visual functioning in daily life (National Eye Institute Visual Function Questionnaire). MRI was used to quantify grey matter atrophy and multiple sclerosis lesion load. Multivariable linear regression models were used for analysis of the relationships between double-step saccades and clinical and MRI metrics. We included 209 individuals with multiple sclerosis (mean age 54.3 ± 10.5 years, 58% female, 63% relapsing-remitting multiple sclerosis) and 60 healthy control subjects (mean age 52.1 ± 9.2 years, 53% female). The proportion of correct double-step saccades was significantly reduced in multiple sclerosis (mean 0.29 ± 0.22) compared to controls (0.45 ± 0.22, P < 0.001). Consistent with this, there was a significantly larger double-step dysmetric saccadic error in multiple sclerosis (mean vertical error -1.18 ± 1.20°) compared to controls (-0.54 ± 0.86°, P < 0.001). Impaired double-step saccadic metrics were consistently associated with more severe global and local grey matter atrophy (correct responses-cortical grey matter: β = 0.42, P < 0.001), lesion load (vertical error: β = -0.28, P < 0.001), progressive phenotypes, more severe physical and cognitive impairment (correct responses-information processing: β = 0.46, P < 0.001) and visual functioning. In conclusion, double-step saccades represent a robust metric that revealed a novel eye-movement impairment in individuals with multiple sclerosis. Double-step saccades outperformed other saccadic tasks in their statistical relationship with clinical, cognitive and visual functioning, as well as global and local grey matter atrophy. Double-step saccades should be evaluated longitudinally and tested as a potential novel outcome measure for remyelination trials in multiple sclerosis.

Age-related blood transcriptional regulators affect disease progression in pediatric multiple sclerosis

BackgroundPediatric onset multiple sclerosis patients (POMS) are defined as multiple sclerosis with an onset before the age of 18 years. Compared to adult onset multiple sclerosis (AOMS), POMS has more severe disease activity at onset, but better recovery. Little is known about the molecular mechanism responsible for the differences in the clinical presentations. MethodsPeripheral Blood Mononuclear Cells samples were taken from 22 POMS patients (mean age 14.1 ± 2.4 years, 15 females, 7 male), and 16 AOMS patients, (mean age 30.8 ± 6.1 years,10 females, 6 males), and gene-expression were analyzed using Affymetrix Inc. HU-133-A2 microarrays. Differentially Expressed Genes (DEGs) that significantly distinguished between POMS and AOMS with pvalue <0.05 after false discovery rate correction were evaluated using Partek software. Twenty-one matched age and gender control was applied to clarify age-related changes. Clinical assessment was performed by analysis of expanded disability status scale (EDSS) and brain MRI lesion loads. Gene functional analysis was performed by Ingenuity Pathway Analysis software. ResultsCompared to AOMS, POMS had higher EDSS (3.0 IQR 2.0–3.0 and 2.0 IQR 2.0–3.0, p = 0.005), volume of T1 (2.72 mm3, IQR 0.44–8.39 mm3 and 0.5 mm3 IQR 0–1.29 mm3 respectively, p = 0.04) and T2 (3.70 mm3, IQR 1.3–9.6 and 0.96 mm3, IQR 0.24–4.63 respectively, p = 0.02) brain MRI lesions. The POMS transcriptional profile was characterized by 551 DEGs, enriched by cell cycling, B lymphocyte signaling and senescent pathways (p < 0.02). Of these, 183 DEGs significantly correlated with T2 lesions volume. The POMS MRI correlated DEGs (n = 183) and their upstream regulators (n = 718) has overlapped with age related DEGs obtained from healthy subjects (n = 497). This evaluated common DEGs (n = 29) defined as POMS age-related regulators, suggesting to promote effect on disease severity. ConclusionOur finding of higher transcriptional levels of genes involved in cell cycle, cell migration and B cell proliferation that promoted by transcriptional level of age-associated genes and transcription factors allows better understanding of the more aggressive clinical course that defines the POMS.