Brain Atrophy In Multiple Sclerosis Research Articles

Senescence marker p16INK4a expression in patients with multiple sclerosis

ObjectivesTelomere attrition is associated with disability accumulation and brain atrophy in multiple sclerosis (MS). Downstream of telomere attrition is cellular senescence. We sought to determine differences in the cellular senescence marker p16INK4a expression between MS and healthy control participants and the association of p16INK4a expression with MS disability and treatment exposure. MethodsPatients meeting diagnostic criteria for MS and healthy controls were recruited for a cross-sectional pilot study. RNA was extracted from peripheral blood mononuclear cells (PBMCs) and p16INK4a expression levels were measured using qRT PCR. Spearman correlation coefficients and regression models were applied to compare expression levels to chronological age, assess case control differences, and determine associations with clinical outcome measures. ResultsFifty-two participants with MS (67 % female, ages 25–70) and 38 healthy controls (66 % female, ages 23–65) were included. p16INK4a levels were not linearly correlated with chronological age in MS (rhos = −0.01, p = 0.94) or control participants (rhos = 0.02, p = 0.92). Higher median p16INK4a levels were observed in the >50-year age group for MS (0.25, IQR 0.14–0.35) vs. controls (0.12, IQR 0.05–0.15) and in this age group B cell depletion therapy was associated with lower expression levels. p16INK4a expression was not associated with any of the measured MS disability outcomes. DiscussionCaution is needed with using p16INK4a expression level from PBMCs as an aging biomarker in MS participants, given lack of correlation with chronological age or large associations with clinical outcomes.

Exploring the effects of extended interval dosing of natalizumab and drug concentrations on brain atrophy in multiple sclerosis.

Extended interval dosing (EID) of natalizumab treatment is increasingly used in multiple sclerosis. Besides the clear anti-inflammatory effect, natalizumab is considered to have neuroprotective properties as well. This study aimed to study the longitudinal effects of EID compared to standard interval dosing (SID) and natalizumab drug concentrations on brain atrophy. Patients receiving EID or SID of natalizumab with a minimum radiological follow-up of 2 years were included. Changes in brain atrophy measures over time were derived from clinical routine 3D-Fluid Attenuated Inversion Recovery (FLAIR)-weighted magnetic resonance imaging (MRI) scans using SynthSeg. We found no differences between EID (n = 32) and SID (n = 50) for whole brain (-0.21% vs -0.16%, p = 0.42), ventricular (1.84% vs 1.13%, p = 0.24), and thalamic (-0.32% vs -0.32%, p = 0.97) annualized volume change over a median follow-up of 3.2 years. No associations between natalizumab drug concentration and brain atrophy rate were found. We found no clear evidence that EID compared to SID or lower natalizumab drug concentrations have a negative impact on the development of brain atrophy over time.

Systemic inflammation associates with and precedes cord atrophy in progressive multiple sclerosis.

In preclinical models of multiple sclerosis, systemic inflammation has an impact on the compartmentalized inflammatory process within the central nervous system and results in axonal loss. It remains to be shown whether this is the case in humans, specifically whether systemic inflammation contributes to spinal cord or brain atrophy in multiple sclerosis. Hence, an observational longitudinal study was conducted to delineate the relationship between systemic inflammation and atrophy using magnetic resonance imaging: the SIMS (Systemic Inflammation in Multiple Sclerosis) study. Systemic inflammation and progression were assessed in people with progressive multiple sclerosis (n = 50) over two and a half years. Eligibility criteria included: (i) primary or secondary progressive multiple sclerosis; (ii) age ≤ 70; and (iii) Expanded Disability Status Scale ≤ 6.5. First morning urine was collected weekly to quantify systemic inflammation by measuring the urinary neopterin-to-creatinine ratio using a validated ultra-performance liquid chromatography mass spectrometry technique. The urinary neopterin-to-creatinine ratio temporal profile was characterized by short-term responses overlaid on a background level of inflammation, so these two distinct processes were considered as separate variables: background inflammation and inflammatory response. Participants underwent MRI at the start and end of the study, to measure cervical spinal cord and brain atrophy. Brain and cervical cord atrophy occurred on the study, but the most striking change was seen in the cervical spinal cord, in keeping with the corticospinal tract involvement that is typical of progressive disease. Systemic inflammation predicted cervical cord atrophy. An association with brain atrophy was not observed in this cohort. A time lag between systemic inflammation and cord atrophy was evident, suggesting but not proving causation. The association of the inflammatory response with cord atrophy depended on the level of background inflammation, in keeping with experimental data in preclinical models where the effects of a systemic inflammatory challenge on tissue injury depended on prior exposure to inflammation. A higher inflammatory response was associated with accelerated cord atrophy in the presence of background systemic inflammation below the median for the study population. Higher background inflammation, while associated with cervical cord atrophy itself, subdued the association of the inflammatory response with cord atrophy. Findings were robust to sensitivity analyses adjusting for potential confounders and excluding cases with new lesion formation. In conclusion, systemic inflammation associates with, and precedes, multiple sclerosis progression. Further work is needed to prove causation since targeting systemic inflammation may offer novel treatment strategies for slowing neurodegeneration in multiple sclerosis.

U-fiber diffusion kurtosis and susceptibility characteristics in relapsing-remitting multiple sclerosis may be related to cognitive deficits and neurodegeneration.

To evaluate the diffusion kurtosis and susceptibility change in the U-fiber region of patients with relapsing-remitting multiple sclerosis (pwRRMS) and their correlations with cognitive status and degeneration. Mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), kurtosis fractional anisotropy (KFA), and the mean relative quantitative susceptibility mapping (mrQSM) values in the U-fiber region were compared between 49 pwRRMS and 48 healthy controls (HCs). The U-fiber were divided into upper and deeper groups based on the location. The whole brain volume, gray and white matter volume, and cortical thickness were obtained. The correlations between the mrQSM values, DKI-derived metrics in the U-fiber region and clinical scale scores, brain morphologic parameters were further investigated. The decreased MK, AK, RK, KFA, and increased mrQSM values in U-fiber lesions (p < 0.001, FDR corrected), decreased RK, KFA, and increased mrQSM values in U-fiber non-lesions (p = 0.034, p < 0.001, p < 0.001, FDR corrected) were found in pwRRMS. There were differences in DKI-derived metrics and susceptibility values between the upper U-fiber region and the deeper one for U-fiber non-lesion areas of pwRRMS and HCs (p < 0.05), but not for U-fiber lesions in DKI-derived metrics. The DKI-derived metrics and susceptibility values were widely related with cognitive tests and brain atrophy. RRMS patients show abnormal diffusion kurtosis and susceptibility characteristics in the U-fiber region, and these underlying tissue abnormalities are correlated with cognitive deficits and degeneration. The macroscopic and microscopic tissue damages of U-fiber help to identify cognitive impairment and brain atrophy in multiple sclerosis and provide underlying pathophysiological mechanism. • Diffusion kurtosis and susceptibility changes are present in the U-fiber region of multiple sclerosis. • There are gradients in diffusion kurtosis and susceptibility characteristics in the U-fiber region. • Tissue damages in the U-fiber region are correlated with cognitive impairment and brain atrophy.

Reliability of brain atrophy measurements in multiple sclerosis using MRI: an assessment of six freely available software packages for cross-sectional analyses.

Volume measurement using MRI is important to assess brain atrophy in multiple sclerosis (MS). However, differences between scanners, acquisition protocols, and analysis software introduce unwanted variability of volumes. To quantify theses effects, we compared within-scanner repeatability and between-scanner reproducibility of three different MR scanners for six brain segmentation methods. Twenty-one people with MS underwent scanning and rescanning on three 3T MR scanners (GE MR750, Philips Ingenuity, Toshiba Vantage Titan) to obtain 3D T1-weighted images. FreeSurfer, FSL, SAMSEG, FastSurfer, CAT-12, and SynthSeg were used to quantify brain, white matterand (deep) gray matter volumes both from lesion-filled and non-lesion-filled 3D T1-weighted images. We used intra-class correlation coefficient (ICC) to quantify agreement; repeated-measures ANOVA to analyze systematic differences; and variance component analysis to quantify the standard error of measurement (SEM) and smallest detectable change (SDC). For all six software, both between-scanner agreement (ICCs ranging 0.4-1) and within-scanner agreement (ICC range: 0.6-1) were typically good, and good to excellent (ICC > 0.7) for large structures. No clear differences were found between filled and non-filled images. However, gray and white matter volumes did differ systematically between scanners for all software (p < 0.05). Variance component analysis yielded within-scanner SDC ranging from 1.02% (SAMSEG, whole-brain) to 14.55% (FreeSurfer, CSF); and between-scanner SDC ranging from 4.83% (SynthSeg, thalamus) to 29.25% (CAT12, thalamus). Volume measurements of brain, GM and WM showed high repeatability, and high reproducibility despite substantial differences between scanners. Smallest detectable change was high, especially between different scanners, which hampers the clinical implementation of atrophy measurements.

Feasibility of detecting atrophy relevant for disability and cognition in multiple sclerosis using 3D-FLAIR.

Disability and cognitive impairment are known to be related to brain atrophy in multiple sclerosis (MS), but 3D-T1 imaging required for brain volumetrics is often unavailable in clinical protocols, unlike 3D-FLAIR. Here our aim was to investigate whether brain volumes derived from 3D-FLAIR images result in similar associations with disability and cognition in MS as do those derived from 3D-T1 images. 3T-MRI scans of 329 MS patients and 76 healthy controls were included in this cross-sectional study. Brain volumes were derived using FreeSurfer on 3D-T1 and compared with brain volumes derived with SynthSeg and SAMSEG on 3D-FLAIR. Relative agreement was evaluated by calculating the intraclass correlation coefficient (ICC) of the 3D-T1 and 3D-FLAIR volumes. Consistency of relations with disability and average cognition was assessed using linear regression, while correcting for age and sex. The findings were corroborated in an independent validation cohort of 125 MS patients. The ICC between volume measured with FreeSurfer and those measured on 3D-FLAIR for brain, ventricle, cortex, total deep gray matter and thalamus was above 0.74 for SAMSEG and above 0.91 for SynthSeg. Worse disability and lower average cognition were similarly associated with brain (adj. R2 = 0.24-0.27, p < 0.01; adj.R2 = 0.26-0.29, p < 0.001) ventricle (adj. R2 = 0.27-0.28, p < 0.001; adj. R2 = 0.19-0.20, p < 0.001) and deep gray matter volumes (adj. R2 = 0.24-0.28, p < 0.001; adj.R2 = 0.27-0.28, p < 0.001) determined with all methods, except for cortical volumes derived from 3D-FLAIR. In this cross-sectional study, brain volumes derived from 3D-FLAIR and 3D-T1 show similar relationships to disability and cognitive dysfunction in MS, highlighting the potential of these techniques in clinical datasets.

The impact of cigarette smoking on cognitive processing speed and brain atrophy in multiple sclerosis

Background: Smoking is associated with an increased risk of multiple sclerosis (MS) and disability worsening. The relationship between smoking, cognitive processing speed, and brain atrophy remains uncertain. Objective: To quantify the impact of smoking on processing speed and brain volume in MS and to explore the longitudinal relationship between smoking and changes in processing speed. Methods: A retrospective study of MS patients who completed the processing speed test (PST) between September 2015 and March 2020. Demographics, disease characteristics, smoking history, and quantitative magnetic resonance imaging (MRI) were collected. Cross-sectional associations between smoking, PST performance, whole-brain fraction (WBF), gray matter fraction (GMF), and thalamic fraction (TF) were assessed using multivariable linear regression. The longitudinal relationship between smoking and PST performance was assessed by linear mixed modeling. Results: The analysis included 5536 subjects of whom 1314 had quantitative MRI within 90 days of PST assessment. Current smokers had lower PST scores than never smokers at baseline, and this difference persisted over time. Smoking was associated with reduced GMF but not with WBF or TF. Conclusion: Smoking has an adverse relationship with cognition and GMF. Although causality is not demonstrated, these observations support the importance of smoking cessation counseling in MS management.

Longitudinal Brain Volume Findings in an Outpatient Practice of Young People with MS (P11-3.001)

<h3>Objective:</h3> To assess in an outpatient setting the application of volumetrics with brain MRI among young people with multiple sclerosis (MS). <h3>Background:</h3> Research on brain atrophy in MS has illuminated how inflammation and neurodegenerative processes lead to cognitive and neurologic declines. However, brain volume assessment is rarely used in routine practice. Here, we examined predominantly pediatric onset MS and some younger adult-onset MS patients who underwent routine brain MRI including volumetrics. Our goal was to assess the impact of brain volume change on clinical outcomes including SDMT in this relatively young and stable MS subset. <h3>Design/Methods:</h3> 77 patients with pediatric or adult onset RRMS or CIS, 31 years of age or younger, were evaluated with at least two MRI studies. Volume data was computed on MRI images with icobrain ms software, compared to age- and sex-related norms and adjusted for differences across the various Siemens 3T scanners. Changes in volumes of whole brain (WB), white matter (WM), grey matter (GM), lateral ventricles (LV), and thalamus were calculated as an average annualized percent brain volume change per year. <h3>Results:</h3> The mean patient age was 21.6 years (range 12–31); 70% were female. The annual mean decrease of WB volume: −0.473%, WM: −0.390%, GM: −0.517%, thalamus: −0.552%, and annual LV volume increase: 1.78%. A total of 32.5% of patients had an annual decrease in GM volume &gt;0.8% (the 90% threshold for measurement error). 29.9% of patients had LV volumes increase &gt;3.5%. Whole brain volume loss and lateral ventricle increase was significantly correlated, r=−0.34 (p=0.002). Clinical and demographic features between those whose brain volume declined and those whose brain volumes remained stable will be presented. <h3>Conclusions:</h3> Quantitative MRI is a useful technique which has only begun to be incorporated into clinical practice. A proportion of young otherwise stable patients with RRMS show brain volume loss under computer-assisted analyses. <b>Disclosure:</b> Dr. O’Neill has nothing to disclose. Dr. Couvreur has received personal compensation in the range of $10,000-$49,999 for serving as a Intern Clinical application specialist at icometrix with The Prince Albert Fund. Dr. Hu has nothing to disclose. Mr. Zhang has nothing to disclose. Ms. Pehel has nothing to disclose. Ms. Sosa has nothing to disclose. Ms. Fade has nothing to disclose. Elayne Feld has nothing to disclose. Dr. Chen has received personal compensation for serving as an employee of icometrix. Dr. De Barros has received personal compensation for serving as an employee of Icometrix. Thibo Billiet has received personal compensation for serving as an employee of icometrix. Annemie Ribbens, 9599 has received personal compensation for serving as an employee of icometrix. Annemie Ribbens, 9599 has stock in icometrix. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gerson Lerhman. Dr. Krupp has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for medscape. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuroLive. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Krupp has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for Cleveland Clinic. Dr. Krupp has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for MCIC. The institution of Dr. Krupp has received research support from Biogen. The institution of Dr. Krupp has received research support from National Multiple Sclerosis Society. Dr. Krupp has received intellectual property interests from a discovery or technology relating to health care.

Third Ventricle Width is a Reliable and Clinically-Feasible Marker of Brain Atrophy in the Multiple Sclerosis Clinical Care Setting (P10-3.003)

<h3>Objective:</h3> Examine reliability and clinical utility of third ventricle width (TVW) on standard-of-care MRIs as a marker of cerebral atrophy in real-world multiple sclerosis (MS) clinical care settings. <h3>Background:</h3> Cerebral atrophy is emerging as an important marker of MS disease progression, but clinically-feasible volumetric measurements remain elusive in clinical care settings. Research supports TVW as a reliable, valid, fast, and easy manual two-dimensional MRI estimate of cerebral atrophy that correlates with clinical disability and tracks with volumetric changes. Importantly, most TVW research has utilized standardized research MRIs; it is unclear how findings translate to standard-of-care (SoC) MRIs (i.e., variable field strengths and sequence parameters). We evaluated real-world clinical utility by examining reliability and clinical relevance of TVW measured from SoC (i.e., clinical) MRIs. <h3>Design/Methods:</h3> We measured TVW from SoC brain MRIs in 563 consecutive patients aged 18–65 years. Three trained raters blind to other patient data measured TVW in millimeters from midpoints of left and right boundaries of the third ventricle in axial T1-weighted images. TVWs were adjusted for demographic characteristics. Disability was assessed with the gold-standard MS Functional Composite (MSFC) evaluating cognition (SDMT), upper extremity coordination (NHPT), and gait (T25FW). GLM assessed TVW differences across level of level of impairment (number of MSFC components &lt;5^th percentile). <h3>Results:</h3> Interrater reliability of TVW measurement indicated excellent absolute-agreement (two-way mixed effects ICCs: single-rating 0.982; 95%CI: 0.958, 0.994; mean-rating <i>k</i>=3, 0.994; 0.986, 0.998). Medium-to-large difference in TVW across MSFC impairment (<i>p</i> for trend &lt;0.001; η_p²=0.089): TVW (mean [95%CI]) increased across patients impaired on no (n=245; 3.34 [3.14, 3.54]), one (n=155; 3.74 [3.45, 3.99]), two (n=106; 4.30 [4.00, 4.60]), and three (n=57; 4.81 [4.40, 5.22]) MSFC tasks. <h3>Conclusions:</h3> Measurement of TVW from standard-of-care MRIs is a highly-reliable and clinically-relevant marker of brain atrophy in MS that can be easily implemented into routine clinical care. <b>Disclosure:</b> Dr. Levy has nothing to disclose. Dr. Patel has nothing to disclose. Mr. Sumowski has nothing to disclose.

Percentage brain volume change in multiple sclerosis mainly reflects white matter and cortical volume.

Brain atrophy in multiple sclerosis (MS), as measured by percentage brain volume change (PBVC) from brain magnetic resonance imaging (MRI), has been established as an outcome parameter in clinical trials. It is unknown to what extent volume changes within different brain tissue compartments contribute to PBVC. We analyzed pairs of MRI scans (at least 6 months apart) in 600 patients with relapsing-remitting MS. Multiple regression revealed that PBVC mainly reflects volume loss of white and cortical gray matter, while deep gray matter and white matter lesions were less represented. Our findings aid the interpretation of PBVC changes in MS.

Confounder-adjusted MRI-based predictors of multiple sclerosis disability.

Both aging and multiple sclerosis (MS) cause central nervous system (CNS) atrophy. Excess brain atrophy in MS has been interpreted as "accelerated aging." Current paper tests an alternative hypothesis: MS causes CNS atrophy by mechanism(s) different from physiological aging. Thus, subtracting effects of physiological confounders on CNS structures would isolate MS-specific effects. Standardized brain MRI and neurological examination were acquired prospectively in 646 participants enrolled in ClinicalTrials.gov Identifier: NCT00794352 protocol. CNS volumes were measured retrospectively, by automated Lesion-TOADS algorithm and by Spinal Cord Toolbox, in a blinded fashion. Physiological confounders identified in 80 healthy volunteers were regressed out by stepwise multiple linear regression. MS specificity of confounder-adjusted MRI features was assessed in non-MS cohort (n = 158). MS patients were randomly split into training (n = 277) and validation (n = 131) cohorts. Gradient boosting machine (GBM) models were generated in MS training cohort from unadjusted and confounder-adjusted CNS volumes against four disability scales. Confounder adjustment highlighted MS-specific progressive loss of CNS white matter. GBM model performance decreased substantially from training to cross-validation, to independent validation cohorts, but all models predicted cognitive and physical disability with low p-values and effect sizes that outperform published literature based on recent meta-analysis. Models built from confounder-adjusted MRI predictors outperformed models from unadjusted predictors in the validation cohort. GBM models from confounder-adjusted volumetric MRI features reflect MS-specific CNS injury, and due to stronger correlation with clinical outcomes compared to brain atrophy these models should be explored in future MS clinical trials.

Mechanisms of central brain atrophy in multiple sclerosis

Background: Change in ventricular volume has been suggested as surrogate measure of central brain atrophy (CBA) applicable to the everyday management of multiple sclerosis (MS) patients. Objectives: We investigated the contribution of inflammatory activity (including the severity of lesional tissue damage) to CBA. Methods: Fifty patients with relapsing–remitting multiple sclerosis (RRMS) were enrolled. Lesional activity during 4 years of follow-up was analysed using custom-build software, which segmented expanding part of the chronic lesions, new confluent lesions and new free-standing lesions. The degree of lesional tissue damage was assessed by change in mean diffusivity (MD). Volumetric change of lateral ventricles was used to measure CBA. Results: During follow-up, ventricles expanded on average by 12.6% ± 13.7% (mean ± SD). There was a significant increase of total lesion volume, 69.3% of which was due to expansion of chronic lesions. Correlation between volume of combined lesional activity and CBA (r2 = 0.67) increased when lesion volume was adjusted by the degree of tissue damage severity (r2 = 0.81). Regression analysis explained 90% of CBA variability, revealing that chronic lesion expansion was by far the largest contributor to ventricular enlargement. Discussion: CBA is almost entirely explained by the combination of the volume and severity of lesional activity. The expansion of chronic lesions plays a central role in this process.

Mediterranean Diet Score is Associated with Disability and Brain Atrophy in Multiple Sclerosis (S14.002)

Mediterranean Diet Score is Associated with Disability and Brain Atrophy in Multiple Sclerosis (S14.002)

Choroid Plexus Volume Predicts Expansion of Chronic Lesions and Associated Brain Atrophy in Multiple Sclerosis

Choroid Plexus Volume Predicts Expansion of Chronic Lesions and Associated Brain Atrophy in Multiple Sclerosis

Brain atrophy in multiple sclerosis

Brain atrophy in multiple sclerosis

Magnetic resonance imaging measures of brain atrophy in multiple sclerosis

Magnetic resonance imaging measures of brain atrophy in multiple sclerosis

Serum amyloid A level correlates with T2 lesion volume and cortical volume in patients with multiple sclerosis

It is unclear whether brain atrophy in multiple sclerosis (MS) is associated with not only neuroinflammation but also systemic inflammation. Here we found that systemic inflammatory marker serum amyloid A (SAA) was moderately correlated with cortical volume in the patients with clinically isolated syndrome (CIS) and MS (r = −0.41, p = 0.019). SAA was also significantly correlated with T2 lesion volume (T2LV) even after adjusting for age, disease duration, and disease modifying therapy (p = 0.0050). Thus, systemic inflammation may be associated with cortical atrophy, possibly via an increase in the T2LV in patients with CIS/MS.

Relationships Among Circulating Levels of Hemostasis Inhibitors, Chemokines, Adhesion Molecules, and MRI Characteristics in Multiple Sclerosis.

Background: Several studies suggested cross talk among components of hemostasis, inflammation, and immunity pathways in the pathogenesis, neurodegeneration, and occurrence of cerebral microbleeds (CMBs) in multiple sclerosis (MS).Objectives: This study aimed to evaluate the combined contribution of the hemostasis inhibitor protein C (PC) and chemokine C-C motif ligand 18 (CCL18) levels to brain atrophy in MS and to identify disease-relevant correlations among circulating levels of hemostasis inhibitors, chemokines, and adhesion molecules, particularly in CMB occurrence in MS.Methods: Plasma levels of hemostasis inhibitors (ADAMTS13, PC, and PAI1), CCL18, and soluble adhesion molecules (sNCAM, sICAM1, sVCAM1, and sVAP1) were evaluated by multiplex in 138 MS patients [85 relapsing-remitting (RR-MS) and 53 progressive (P-MS)] and 42 healthy individuals (HI) who underwent 3-T MRI exams. Association of protein levels with MRI outcomes was performed by regression analysis. Correlations among protein levels were assessed by partial correlation and Pearson's correlation.Results: In all patients, regression analysis showed that higher PC levels were associated with lower brain volumes, including the brain parenchyma (p = 0.002), gray matter (p < 0.001), cortex (p = 0.001), deep gray matter (p = 0.001), and thalamus (p = 0.001). These associations were detectable in RR-MS but not in P-MS patients. Higher CCL18 levels were associated with higher T2-lesion volumes in all MS patients (p = 0.03) and in the P-MS (p = 0.003). In the P-MS, higher CCL18 levels were also associated with lower volumes of the gray matter (p = 0.024), cortex (p = 0.043), deep gray matter (p = 0.029), and thalamus (p = 0.022). PC-CCL18 and CCL18-PAI1 levels were positively correlated in both MS and HI, PC–sVAP1 and PAI1–sVCAM1 only in MS, and PC–sICAM1 and PC–sNCAM only in HI. In MS patients with CMBs (n = 12), CCL18–PAI1 and PAI1–sVCAM1 levels were better correlated than those in MS patients without CMBs, and a novel ADAMTS13–sVAP1 level correlation (r = 0.78, p = 0.003) was observed.Conclusions: Differences between clinical phenotype groups in association of PC and CCL18 circulating levels with MRI outcomes might be related to different aspects of neurodegeneration. Disease-related pathway dysregulation is supported by several protein level correlation differences between MS patients and HI. The integrated analysis of plasma proteins and MRI measures provide evidence for new relationships among hemostasis, inflammation, and immunity pathways, relevant for MS and for the occurrence of CMBs.

Microperimetry as a diagnostic tool for the detection of early, subclinical retinal damage and visual impairment in multiple sclerosis

BackgroundA majority of multiple sclerosis patients experience visual impairment, often as the initial presenting symptom of the disease. While structural changes in the retinal nerve fiber layer and optic nerve have demonstrated correlations with brain atrophy in multiple sclerosis using magnetic resonance imaging, a non-invasive, cost-effective, and clinically efficacious modality to identify early damage and facilitate prompt therapeutic intervention to slow the progression of multiple sclerosis and its ocular manifestations, is still urgently needed. In this study, we sought to determine the role of macular sensitivity measured by microperimetry in the detection of subclinical multiple sclerosis-related retinal damage and visual dysfunction.MethodsThis cross-sectional observational case-control study involved population-based samples of multiple sclerosis patients and age-, race-, and gender-matched healthy control subjects. Among the key criteria for the multiple sclerosis patients were diagnosis by the McDonald criteria, visual acuity greater than 20/25, and no history of optic neuritis. Macular sensitivity and average macular thickness were measured in all subjects using microperimetry and spectral-domain optical coherence tomography, respectively. Pearson correlation coefficients were measured using bivariate correlations. Sample means, mean differences, and 95% confidence intervals were calculated using independent sample t-tests.ResultsTwenty-eight eyes from 14 MS patients and 18 eyes from 9 control subjects were included. Mean macular sensitivity of control subjects and multiple sclerosis patients in decibels was 18.2 ± 0.4 and 16.5 ± 0.4, respectively, corresponding to a mean difference of 1.7 (95% CI, 1.1–2.4; P < 0.001). Macular sensitivity was positively correlated with macular thickness in multiple sclerosis patients (r = 0.49, P = 0.01) but not control subjects (r = 0.15, P = 0.55).ConclusionsMacular sensitivity as measured by microperimetry was decreased in multiple sclerosis patients with normal visual acuity and no history of optic neuritis. Furthermore, macular sensitivity demonstrated a positive correlation with macular thickness as measured by optical coherence tomography. As such, microperimetry may represent a non-invasive and efficient method to identify signs of subclinical visual dysfunction that correspond with early macular architectural changes characteristic of multiple sclerosis.

Sex differences in brain atrophy in multiple sclerosis

BackgroundWomen are more susceptible to multiple sclerosis (MS) than men by a ratio of approximately 3:1. However, being male is a risk factor for worse disability progression. Inflammatory genes have been linked to susceptibility, while neurodegeneration underlies disability progression. Thus, there appears to be a differential effect of sex on inflammation versus neurodegeneration. Further, gray matter (GM) atrophy is not uniform across the brain in MS, but instead shows regional variation. Here, we study sex differences in neurodegeneration by comparing regional GM atrophy in a cohort of men and women with MS versus their respective age- and sex-matched healthy controls.MethodsVoxel-based morphometry (VBM), deep GM substructure volumetry, and cortical thinning were used to examine regional GM atrophy.ResultsVBM analysis showed deep GM atrophy in the thalamic area in both men and women with MS, whereas men had additional atrophy in the putamen as well as in localized cortical regions. Volumetry confirmed deep GM loss, while localized cortical thinning confirmed GM loss in the cerebral cortex. Further, MS males exhibited worse performance on the 9-hole peg test (9HPT) than MS females. We observed a strong correlation between thalamic volume and 9HPT performance in MS males, but not in MS females.ConclusionMore regional GM atrophy was observed in men with MS than women with MS, consistent with previous observations that male sex is a risk factor for worse disease progression.