The impact of image contrast, resolution and reader expertise on black hole identification in Multiple Sclerosis.

OBJECTIVES: In the neuroradiological work-up of Multiple Sclerosis (MS), the detection of "black holes" (BH) represent an information of undeniable importance. Nevertheless, different sequences can be used in clinical practice to evaluate BH in MS. Aim of this study was to investigate the possible impact of different sequences, resolutions, and levels of expertise on the intra- and inter-rater reliability identification of BH in MS. METHODS: Brain MRI scans of 85 MS patients (M/F = 22/63; mean age = 36.0 ± 10.2 years) were evaluated in this prospective single-center study. The acquisition protocol included a 3 mm SE-T1w sequence, a 1 mm 3D-GrE-T1w sequence from which a resliced 3 mm sequence was also obtained. Images were evaluated independently by two readers of different expertise at baseline and after a wash-out period of 30 days. The intraclass correlation coefficient (ICC) was calculated as an index of intra and inter-reader reliability. RESULTS: For both readers, the intra-reader ICC analysis showed that the 3 mm SE-T1w and 3 mm resliced GrE-T1w images achieved an excellent performance (both with an ICC ≥ 0.95), while 1 mm 3D-GrE-T1w scans achieved a moderate one (ICC < 0.90). The inter-reader analysis showed that each of the three sequences achieved a moderate performance (all ICCs < 0.90). CONCLUSIONS: The 1 mm 3D-GrE-T1w sequence seems to be prone to a greater intra-reader variability compared to the 3 mm SE-T1w, with this effect being driven by the higher spatial resolution of the first sequence. To ensure reliability levels comparable with the standard SE-T1w in BH count, an assessment on a 3 mm resliced GrE-T1w sequence should be recommended.

Integration of the expanded disability status scale with ambulation, visual and cognitive tests.

INTRODUCTION: The Expanded Disability Status Scale (EDSS) is usually calculated through a neurological examination with self-reported performance. This may lead to incorrect assessment of Functional System scores (FSs). Aim of our study was to estimate the difference between EDSS obtained during routine visits, or after specific tests. METHODS: We enrolled 670 MS patients that underwent a regular neurology consultation, and visual evaluation using optotype tables, ambulation evaluation with a rodometer, and cognitive assessment with the Brief International Cognitive assessment for MS (BICAMS). We calculated a new integrated EDSS (iEDSS) using the refined values of the FS and compared it to the standard EDSS. RESULTS: Visual, cerebral and ambulation FSs were significantly higher compared with the self-reported counterpart [+ 1.169 (95%CI 1.077, 1.262; p < 0.001), + 0.727 (95%CI 0.653, 0.801; p < 0.001) and + 0.822 (95%CI 0.705, 0.939; p < 0.001), respectively]. Mean iEDSS was higher than EDSS (+ 0.642; p < 0.001). Visual acuity tests worsened the EDSS in 31% of cases, cognitive tests in 10%, ambulation measurement in 35%, all three measurements in 59% of cases. CONCLUSIONS: Objective measurement of FSs results in a more accurate EDSS score in almost two-thirds of cases. This could lead to a more thorough evaluation of patients in the transition or progressive phase.

Clinical correlates of R1 relaxometry and magnetic susceptibility changes in multiple sclerosis: a multi-parameter quantitative MRI study of brain iron and myelin.

OBJECTIVES: The clinical impact of brain microstructural abnormalities in multiple sclerosis (MS) remains elusive. We aimed to characterize the topography of longitudinal relaxation rate (R1) and quantitative susceptibility (χ) changes, as indices of iron and myelin, together with brain atrophy, and to clarify their contribution to cognitive and motor disability in MS. METHODS: In this cross-sectional study, voxel-based morphometry, and voxel-based quantification analyses of R1 and χ maps were conducted in gray matter (GM) and white matter (WM) of 117 MS patients and 53 healthy controls. Voxel-wise between-group differences were assessed with nonparametric permutation tests, while correlations between MRI metrics and clinical variables (global disability, cognitive and motor performance) were assessed both globally and voxel-wise within clusters emerging from the between-group comparisons. RESULTS: MS patients showed widespread R1 decrease associated with more limited modifications of χ, with atrophy mainly involving deep GM, posterior and infratentorial regions (p < 0.02). While R1 and χ showed a parallel reduction in several WM tracts (p < 0.001), reduced GM R1 values (p < 0.001) were associated with decreased thalamic χ (p < 0.001) and small clusters of increased χ in the caudate nucleus and prefrontal cortex (p < 0.02). In addition to the atrophy, χ values in the cingulum and corona radiata correlated with global disability and motor performance, while focal demyelination correlated with cognitive performance (p < 0.04). CONCLUSIONS: We confirmed the presence of widespread R1 changes, involving both GM and WM, and atrophy in MS, with less extensive modifications of tissue χ. While atrophy and χ changes are related to global and motor disability, R1 changes are meaningful correlates of cognition. KEY POINTS: • Compared to healthy controls, multiple sclerosis patients showed R1 and χ changes suggestive of iron increase within the basal ganglia and reduced iron and myelin content within (subnuclei of) the thalamus. • Thalamic volume and χ changes significantly predicted clinical disability, as well as pulvinar R1 and χ changes, independently from atrophy. • Atrophy-independent R1 and χ changes, suggestive of thalamic iron and myelin depletion, may represent a sensitive marker of subclinical inflammation.

Concomitant diagnosis of multiple sclerosis and human immunodeficiency virus (HIV) infection: case report and the review of literature.

BACKGROUND: To date, few cases of multiple sclerosis (MS) patients with concomitant Human Immunodeficiency Virus (HIV) infection have been described. However, none of the previously described cases has been treated with Natalizumab, probably due to the increasing risk of progressive multifocal leukoencephalopathy (PML). CASE: We report the case of a patient concomitantly diagnosed for HIV infection and MS treated with combined antiretroviral therapy (cART) and Natalizumab for 19 months, without clinical or radiological MS activity. CONCLUSIONS: Our case might suggest considering Natalizumab in patients with concomitant HIV infection, especially for those with significant disease activity requiring a high efficacy disease modifying treatment.

Impact of COVID-19 and system recovery in delivering healthcare to people with multiple sclerosis: a population-based Study.

BACKGROUND: COVID-19 pandemic has affected the management of multiple sclerosis (MS). OBJECTIVE: To explore the impact of COVID-19 on healthcare delivery to people with MS and the subsequent recovery of the system. METHODS: In this population-based study in the Campania Region (Italy), we included people with MS across pre-COVID-19, lockdown, pre-vaccination, and vaccination periods. Differences in continuous outcomes between periods were explored using linear mixed models (annualized hospitalization rate (AHR) and adherence measured as medication possession ratio (MPR)). Differences in disease-modifying treatment (DMT) prescription rates (first DMT prescription, any DMT switch, switch from platform to highly effective DMT, and combination of first DMT prescription and any DMT switch) were assessed using an interrupted time series design. RESULTS: Compared with pre-COVID-19, AHR decreased during the lockdown (Coeff = 0.64;95%CI = -0.69, -0.59; p < 0.01), and remained lower during pre-vaccination and vaccination periods. Adherence decreased during pre-vaccination (Coeff = -0.04;95%CI = -0.05, -0.03; p < 0.01) and vaccination periods (Coeff = -0.07;95%CI = -0.08, -0.07; p < 0.01). After the lockdown, there was an increase in any DMT switch (IRR 2.05 95%CI 1.38,3.05; p < 0.01), in switch from platform to highly effective DMTs (IRR 4.45;95%CI 2.48,8.26; p < 0.01) and in first DMT prescriptions (IRR 2.48;95%CI 1.64,3.74; p < 0.01). CONCLUSIONS: DMT prescriptions quickly returned to pre-pandemic levels, reflecting good health system recovery. However, adherence has remained lower than the past, as from suboptimal care. Assessing long-term COVID-19 impact on MS healthcare is warranted.

Stratification of multiple sclerosis patients using unsupervised machine learning: a single-visit MRI-driven approach.

OBJECTIVES: To stratify patients with multiple sclerosis (pwMS) based on brain MRI-derived volumetric features using unsupervised machine learning. METHODS: The 3-T brain MRIs of relapsing-remitting pwMS including 3D-T1w and FLAIR-T2w sequences were retrospectively collected, along with Expanded Disability Status Scale (EDSS) scores and long-term (10 ± 2 years) clinical outcomes (EDSS, cognition, and progressive course). From the MRIs, volumes of demyelinating lesions and 116 atlas-defined gray matter regions were automatically segmented and expressed as z-scores referenced to external populations. Following feature selection, baseline MRI-derived biomarkers entered the Subtype and Stage Inference (SuStaIn) algorithm, which estimates subgroups characterized by distinct patterns of biomarker evolution and stages within subgroups. The trained model was then applied to longitudinal MRIs. Stability of subtypes and stage change over time were assessed via Krippendorf's α and multilevel linear regression models, respectively. The prognostic relevance of SuStaIn classification was assessed with ordinal/logistic regression analyses. RESULTS: We selected 425 pwMS (35.9 ± 9.9 years; F/M: 301/124), corresponding to 1129 MRI scans, along with healthy controls (N = 148; 35.9 ± 13.0 years; F/M: 77/71) and external pwMS (N = 80; 40.4 ± 11.9 years; F/M: 56/24) as reference populations. Based on 11 biomarkers surviving feature selection, two subtypes were identified, designated as "deep gray matter (DGM)-first" subtype (N = 238) and "cortex-first" subtype (N = 187) according to the atrophy pattern. Subtypes were consistent over time (α = 0.806), with significant annual stage increase (b = 0.20; p < 0.001). EDSS was associated with stage and DGM-first subtype (p ≤ 0.02). Baseline stage predicted long-term disability, transition to progressive course, and cognitive impairment (p ≤ 0.03), with the latter also associated with DGM-first subtype (p = 0.005). CONCLUSIONS: Unsupervised learning modelling of brain MRI-derived volumetric features provides a biologically reliable and prognostically meaningful stratification of pwMS. KEY POINTS: • The unsupervised modelling of brain MRI-derived volumetric features can provide a single-visit stratification of multiple sclerosis patients. • The so-obtained classification tends to be consistent over time and captures disease-related brain damage progression, supporting the biological reliability of the model. • Baseline stratification predicts long-term clinical disability, cognition, and transition to secondary progressive course.

Radial peripapillary vessel density as early biomarker in preperimetric glaucoma and amnestic mild cognitive impairment.

PURPOSE: To investigate the vessel density (VD) of the radial peripapillary capillary (RPC) plexus in patients affected by preperimetric glaucoma (PPG), amnestic mild cognitive impairment (aMCI) and in a healthy control group using optical coherence tomography angiography (OCTA) in order to clarify the pathogenetic mechanisms of these neurodegenerative diseases. METHODS: In this prospective study, we studied 54 eyes of 54 patients with PPG, 54 eyes of 54 patients with aMCI and 54 healthy controls. All subjects underwent structural spectral domain optical coherence tomography (SD)-OCT to assess the ganglion cell complex (GCC) and the retinal nerve fibre layer (RNFL). OCTA was used to evaluate the VD of the RPC in different regions (whole image, inside disc and peripapillary). RESULTS: The PPG and aMCI groups showed a statistically significant reduction in SD-OCT and parameters with respect to controls (p < 0.001). No statistically significant difference was found in GCC and RNFL parameters between the two study groups (p > 0.05). At OCTA examination, PPG and aMCI patients exhibited a statistically significant reduction in the VD of the RPC in whole image, inside and peripapillary regions compared to healthy controls (p < 0.001). When comparing the two study groups, the OCTA parameters were significantly impaired in PPG with respect to aMCI patients. Significant correlations were found between structural OCT and OCTA parameters in PPG and aMCI groups (p < 0.05). CONCLUSIONS: RPC vessel density could represent a helpful and sensible biomarker to identify early retinal microvascular changes in PPG and MCI in order to better understand the vascular pathophysiological mechanisms involved in these neurodegenerative diseases.

Correlation between the optic nerve pial diameter and radial peripapillary vascular changes in primary open-angle glaucoma.

PURPOSE: To assess the optic nerve pial diameter (ONPD) in patients with primary open-angle glaucoma (POAG) using standardized A-scan ultrasound and to evaluate the correlation between the ONPD and structural, vascular optic nerve head features and visual field parameters in glaucomatous eyes. METHODS: In this prospective study, we enrolled 126 eyes of 63 POAG patients and 124 eyes of 62 healthy controls. In all subjects, the ONPD was evaluated by means of A-scan ultrasound. Spectral domain (SD)-OCT was used to assess ganglion cell complex (GCC), retinal nerve fiber layer (RNFL), thicknesses, and the optic nerve head (ONH) morphology. OCTA measured the vessel density (VD) of radial peripapillary capillary (RPC) plexus. RESULTS: The ONPD showed a statistically significant reduction in POAG group with respect to controls (p < 0.001). SD-OCT and OCTA parameters showed a significant impairment in patient group with respect to controls (p < 0.001). The ONH analysis revealed significantly lower values in rim area (p = 0.009) and an increased cup-to-disc area ratio (p = 0.013) and cup volume (p < 0.001) in patients with respect to controls. Significant correlations were shown in POAG group between ONPD and RPC plexus (p = 0.006). Moreover, significant correlation was also found between ONPD and structural SD-OCT parameters (p = 0.001) and between ONPD and visual field parameters (p = 0.001). CONCLUSIONS: The standardized A-scan ultrasound measurements of the ONPD showed a significant correlation with structural and vascular glaucomatous changes measured by means of SD-OCT and OCTA. These results confirm the diagnostic reliability of the ultrasound evaluation in glaucoma optic neuropathy.

Possible progressive multifocal leukoencephalopathy and active multiple sclerosis under dimethyl fumarate: the central role of MRI in informing therapeutic decisions.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) can rarely occur in Multiple Sclerosis (MS) patients undergoing dimethyl fumarate (DMF) treatment. Our case stresses the limits of current diagnostic and stratification risk criteria, highlighting the potential role of Magnetic Resonance Imaging (MRI) in advising clinical choices. CASE PRESENTATION: A 54 years old MS male patient treated with DMF, after 3 years of clinical stability developed a subacute clinical worsening. He had no severe lymphopenia but MRI signs suggestive of a coexistence of PML and MS activity. Although his viral title was negative, DMF was discontinued, with clinical and radiological improvement. CONCLUSIONS: This case highlights the challenges behind PML diagnosis, especially in patients not fulfilling the risk stratification criteria and that might present with concurrent disease activity, stressing the potential role of MRI in informing therapeutic decisions.

Peripapillary vascular density in resolved non-arteritic anterior ischemic optic neuropathy: colocalization between structural and vascular parameters.

INTRODUCTION/AIMS: Non-arteritic anterior ischemic optic neuropathy (NAION) is an acute infarction of the prelaminar anterior optic disc, resulting from the occlusion of posterior ciliary arteries. Here, we evaluated the correlation between structural and vascular features in a case of resolved NAION. METHODS: Observational case report. RESULTS: A 50-year-old male patient was referred at an Eye clinic due to an altitudinal visual field defect in the left eye, occurred 9 months before. Fundus examination was unremarkable, while structural SD-OCT reveals retinal nerve fiber layer (RNFL), ganglion cell complex (GCC) thinning associated with reduction of peripapillary vascular density at OCT Angiography. DISCUSSION: We found a precise spatial correlation among RNFL and GCC thinning, peripapillary vascular reduction and visual field defects. This case demonstrates that OCTA represents a new, valid and non-invasive imaging technique in the diagnosis and follow-up of NAION, even after the resolution of the acute phase, in the absence of clinical signs at fundus examination.

Natalizumab is associated with early improvement of working ability in relapsing-remitting multiple sclerosis patients: WANT observational study results.

BACKGROUND: The Work Ability in Natalizumab-Treated MS Patients (WANT) study assessed work ability, quality of life, and cognitive processing speed during natalizumab treatment. METHODS: WANT was a 1-year, prospective, multicenter observational study conducted in Italy. Inclusion criteria included relapsing-remitting multiple sclerosis (MS), natalizumab treatment, full-time worker status, and loss of working hours due to MS as measured by the Work Productivity and Activity Impairment Questionnaire for MS (WPAI:MS). The primary endpoint was change in WPAI:MS domain scores after 1 year on natalizumab. Secondary endpoints included change in annualized relapse rate (ARR), Multiple Sclerosis Impact Scale (MSIS-29) score, and Symbol Digit Modalities Test (SDMT) score. RESULTS: At enrollment, the 91 patients had a mean age of 38.3 (standard deviation [SD], 9.0) years and a mean ARR of 1.5 (SD, 0.8). After 1 year, improvements were observed in all WPAI:MS domains, with significant reductions in Absenteeism (-4.2 [SD, 26.0], p = 0.0190) and Work Productivity Loss (-7.2 [SD, 28.6]; p = 0.0456). These changes were accompanied by a low ARR (0.1), and 87.9% of patients were relapse free. Significant improvement was observed in MSIS-29 physical and psychological domains (reductions of 2.8 [SD, 11.6; p = 0.0295] and 6.3 [SD, 15.6; p = 0.0007], respectively) and SDMT score (increase of 2.4 [SD, 7.9; p = 0.0006]). Adverse events were reported in 32 of 104 patients (30.8%). CONCLUSIONS: The reductions in Absenteeism and Work Productivity Loss and the improved physical and psychological functioning reported after 1 year of natalizumab treatment in real-world settings extend our understanding of natalizumab's effects on patient-centric and health economics outcomes.

Effectiveness of fingolimod in real-world relapsing-remitting multiple sclerosis Italian patients: the GENIUS study.

BACKGROUND: Fingolimod is the first oral agent approved for treatment of relapsing-remitting multiple sclerosis (RRMS). We aimed to evaluate fingolimod effectiveness in a real-world sample of RRMS patients. METHODS: A retrospective, multicentre study in patients treated with fingolimod, whom clinical and radiological data were collected in the 2 years preceding and following the initiation of fingolimod. RESULTS: Out of 414 patients, 56.8% received prior first-line injectable disease-modifying therapies, 25.4% were previously treated with natalizumab, 1.2% with immunosuppressant agents, and 16.7% were treatment naive. The annualized relapse rate decreased by 65% in the first year and by 70% after two years of treatment. Age ≤ 40 years, ≥ 1 relapse in the 24 months before fingolimod initiation and previous treatment with natalizumab were risk factors for relapses. Overall, 67.9% patients had no evidence of disease activity (NEDA-3) after 1 year and 54.6% after 2 years of treatment. A higher proportion of naïve (81.2% in 1 year and 66.7% after 2 years) or first-line injected patients (70.2% and 56.6%) achieved NEDA-3 than those previously treated with natalizumab (54.3% and 42.9%). CONCLUSIONS: Fingolimod appeared to be effective in naive patients and after first-line treatment failure in reducing risk of relapse and disease activity throughout the 2-year follow-up.

Correction to: Cognitive assessment in multiple sclerosis-an Italian consensus.

In the original article, Maria Pia Amato's second affiliation was not included. The second affiliation is IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy. The correct affiliation is presented here.

Cognitive assessment in multiple sclerosis-an Italian consensus.

The aim of this consensus paper was to define the state of the art on cognitive assessment of persons with multiple sclerosis (PwMS), with the purpose of providing recommendations for the Italian centers involved in MS management. While there are no formal guidelines published regarding the assessment of cognitive function in MS, on the basis of an expert opinion meeting, held in Milan (Italy) on July 4, 2016, we report the recommendations of a panel of Italian experts including MS neurologists and neuropsychologists for the assessment and follow-up of cognitive function in adult MS subjects.

Cerebellar lobule atrophy and disability in progressive MS.

OBJECTIVE: To investigate global and lobular cerebellar volumetries in patients with progressive multiple sclerosis (MS), testing the contribution of cerebellar lobular atrophy to both motor and cognitive performances. METHODS: Eighty-two patients with progressive MS and 46 healthy controls (HC) were enrolled in this cross-sectional study. Clinical evaluation included motor and cognitive testing: Expanded Disability Status Scale, cerebellar Functional System score, Timed 25-Foot Walk Test, 9-Hole Peg Test (9-HPT), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT) and California Verbal Learning Test II (CVLT). Cerebellar volumes were automatically obtained using the Spatially Unbiased Infratentorial Toolbox. A hierarchical multiple linear regression analysis was performed to assess the relationship between MRI variables of supratentorial and cerebellar damage (grey matter fraction, T2 lesion volume, metrics of cerebellar atrophy and cerebellar lesion volume) and motor/cognitive scores. RESULTS: Patients with MS exhibited lower cerebellar volumes compared with HC. Regression analysis showed that cerebellar metrics accounted for extra variance in both motor and cognitive performances, with cerebellar lesion volume, cerebellar Lobules VI, Crus I and VIIIa atrophy being independent predictors of 9-HPT, SDMT, BVMT and CVLT performances. CONCLUSIONS: Atrophy of specific cerebellar lobules explains different aspects of motor and cognitive disability in patients with progressive MS. Investigation of cerebellar involvement provides further insight into the pathophysiological basis of clinical disability in progressive MS.

Affective disorders and Health-Related Quality of Life (HRQoL) in adolescents and young adults with Multiple Sclerosis (MS): the moderating role of resilience.

PURPOSE: To investigate the moderating role of resilience in the relationship between affective disorders and Health-Related Quality of Life (HRQoL) for adolescents and young adults with multiple sclerosis (MS). METHODS: A quantitative methodology was adopted. Fifty-three adolescents and young adults were interviewed to assess resilience as a personality trait (Ego-Resiliency Scale) and resilience as an interactive competence (CYRM-28), Health-Related Quality of Life (PedsQL 4.0), depression and anxiety (BDI-II and STAI-Y). RESULTS: Affective disorders, both depression (ß = -.38, p < .001) and anxiety (State ß = -.35, p < .001; Trait ß = -.41, p < .001), were negatively associated with HRQoL. Data also showed that the resilience competencies using Individual (ß = .22, p < .001) and relational resources (ß = .12, p < .05) are significantly associated HRQoL. According to the regression analyses, we tested the moderating role of resilience competence using individual resources on the relationship between the Depression Cognitive Factor and Emotional Functioning. Data show that in step 2 of the regression analysis, we obtained a variation of ß = -.45 (p < .001) to ß = -.30 (p < .001) in the dimension for the Depression Cognitive Factor. The Sobel test showed that the moderating effect of resilience was significant regarding the increase in R2 (p < .01). CONCLUSIONS: Resilience competence using individual resources moderates the relationship between the Depression Cognitive Factor and Emotional Functioning in adolescents with MS. Our study suggests that to improve well-being for adolescents with MS resilience could play a key role.

In vivo dentate nucleus MRI relaxometry correlates with previous administration of Gadolinium-based contrast agents.

OBJECTIVES: To evaluate changes in T1 and T2* relaxometry of dentate nuclei (DN) with respect to the number of previous administrations of Gadolinium-based contrast agents (GBCA). METHODS: In 74 relapsing-remitting multiple sclerosis (RR-MS) patients with variable disease duration (9.8±6.8 years) and severity (Expanded Disability Status Scale scores:3.1±0.9), the DN R1 (1/T1) and R2* (1/T2*) relaxation rates were measured using two unenhanced 3D Dual-Echo spoiled Gradient-Echo sequences with different flip angles. Correlations of the number of previous GBCA administrations with DN R1 and R2* relaxation rates were tested, including gender and age effect, in a multivariate regression analysis. RESULTS: The DN R1 (normalized by brainstem) significantly correlated with the number of GBCA administrations (p<0.001), maintaining the same significance even when including MS-related factors. Instead, the DN R2* values correlated only with age (p=0.003), and not with GBCA administrations (p=0.67). In a subgroup of 35 patients for whom the administered GBCA subtype was known, the effect of GBCA on DN R1 appeared mainly related to linear GBCA. CONCLUSIONS: In RR-MS patients, the number of previous GBCA administrations correlates with R1 relaxation rates of DN, while R2* values remain unaffected, suggesting that T1-shortening in these patients is related to the amount of Gadolinium given. KEY POINTS: • In multiple sclerosis, previous Gadolinium administrations correlate with dentate nuclei T1 relaxometry. • Such correlation is linked to linear Gadolinium chelates and unrelated to disease duration or severity. • Dentate nuclei T2* relaxometry is age-related and independent of previous Gadolinium administrations. • Changes in dentate nuclei T1 relaxometry are not determined by iron accumulation. • MR relaxometry can quantitatively assess Gadolinium accumulation in dentate nuclei.

Uric acid: a potential biomarker of multiple sclerosis and of its disability.

BACKGROUND: Uric acid (UA) is a strong natural scavenger of reactive oxygen and nitrogen species, with evidence of possible use in the treatment of animal models of multiple sclerosis (MS). Consequently, serum UA has gained much attention as a possible biomarker of MS. We aim to investigate differences in serum UA levels between MS subjects and controls and evaluate possible relationships of UA with MS clinical features. METHODS: We recruited relapsing-remitting and secondary progressive MS subjects and healthy controls and measured their serum UA levels. We excluded subjects presenting concomitant conditions affecting UA levels. RESULTS: MS subjects (n=362) and controls (n=181) were recruited by propensity score matching (PSM). Statistical analyses were corrected for age, gender, and renal function. MS subjects presented significantly lower serum UA levels than controls (analysis of variance, p=0.014, adjusted r2=0.3036). Linear regression analysis showed a relationship between UA levels and disease duration (p<0.001, adjusted r2=0.3158, coefficient -0.00039), time from diagnosis (p<0.001, adjusted r2=0.3100, coefficient -0.0012), and Expanded Disability Status Scale (EDSS) (p<0.001, adjusted r2=0.3230, coefficient -0.1). CONCLUSIONS: Our findings support the importance of serum UA as a biomarker of MS disability and progression. Further studies with longitudinal design should be specifically designed to evaluate the importance of UA in the different stages of MS and in relation to distinct therapeutic strategies.