Brain MRI disease burden and sex differences in cognitive performance of patients with multiple sclerosis.

BACKGROUND: Although there is evidence that shows worse cognitive functioning in male patients with multiple sclerosis (MS), the role of brain pathology in this context is under-investigated. OBJECTIVE: To investigate sex differences in cognitive performance of MS patients, in the context of brain pathology and disease burden. METHODS: Brain MRI, neurological examination, neuropsychological assessment (Brief International Cognitive Assessment in MS-BICAMS, and Paced Auditory Verbal Learning Test-PASAT), and patient-reported outcome questionnaires were performed/administered in 1052 MS patients. RESULTS: Females had higher raw scores in the Symbol Digit Modalities Test (SDMT) (57.0 vs. 54.0; p < 0.001) and Categorical Verbal Learning Test (CVLT) (63.0 vs. 57.0; p < 0.001), but paradoxically, females evaluated their cognitive performance by MS Neuropsychological Questionnaire as being worse (16.6 vs 14.5, p = 0.004). Females had a trend for a weaker negative correlation between T2 lesion volume and SDMT ([Formula: see text] = - 0.37 in females vs. - 0.46 in men; interaction p = 0.038). On the other hand, women had a trend for a stronger correlation between Brain Parenchymal Fraction (BPF) and a visual memory test (Spearman's [Formula: see text] = 0.31 vs. 0.21; interaction p = 0.016). All these trends were not significant after correction for false discovery rate. CONCLUSIONS: Although, females consider their cognition as worse, males had at a group level slightly worse verbal memory and information processing speed. However, the sex differences in cognitive performance were smaller than the variability of scores within the same sex group. Brain MRI measures did not explain the sex differences in cognitive performance among MS patients.

Tract-wise microstructural analysis informs on current and future disability in early multiple sclerosis.

OBJECTIVES: Microstructural characterization of patients with multiple sclerosis (MS) has been shown to correlate better with disability compared to conventional radiological biomarkers. Quantitative MRI provides effective means to characterize microstructural brain tissue changes both in lesions and normal-appearing brain tissue. However, the impact of the location of microstructural alterations in terms of neuronal pathways has not been thoroughly explored so far. Here, we study the extent and the location of tissue changes probed using quantitative MRI along white matter (WM) tracts extracted from a connectivity atlas. METHODS: We quantified voxel-wise T1 tissue alterations compared to normative values in a cohort of 99 MS patients. For each WM tract, we extracted metrics reflecting tissue alterations both in lesions and normal-appearing WM and correlated these with cross-sectional disability and disability evolution after 2 years. RESULTS: In early MS patients, T1 alterations in normal-appearing WM correlated better with disability evolution compared to cross-sectional disability. Further, the presence of lesions in supratentorial tracts was more strongly associated with cross-sectional disability, while microstructural alterations in infratentorial pathways yielded higher correlations with disability evolution. In progressive patients, all major WM pathways contributed similarly to explaining disability, and correlations with disability evolution were generally poor. CONCLUSIONS: We showed that microstructural changes evaluated in specific WM pathways contribute to explaining future disability in early MS, hence highlighting the potential of tract-wise analyses in monitoring disease progression. Further, the proposed technique allows to estimate WM tract-specific microstructural characteristics in clinically compatible acquisition times, without the need for advanced diffusion imaging.

Quantitative brain morphometry identifies cerebellar, cortical, and subcortical gray and white matter atrophy in late-onset Tay-Sachs disease.

Cerebellar atrophy is a characteristic sign of late-onset Tay-Sachs disease (LOTS). Other structural neuroimaging abnormalities are inconsistently reported. Our study aimed to perform a detailed whole-brain analysis and quantitatively characterize morphometric changes in LOTS patients. Fourteen patients (8 M/6F) with LOTS from three centers were included in this retrospective study. For morphometric brain analyses, we used deformation-based morphometry, voxel-based morphometry, surface-based morphometry, and spatially unbiased cerebellar atlas template. The quantitative whole-brain morphometric analysis confirmed the finding of profound pontocerebellar atrophy with most affected cerebellar lobules V and VI in LOTS patients. Additionally, the atrophy of structures mainly involved in motor control, including bilateral ventral and lateral thalamic nuclei, primary motor and sensory cortex, supplementary motor area, and white matter regions containing corticospinal tract, was present. The atrophy of the right amygdala, hippocampus, and regions of occipital, parietal and temporal white matter was also observed in LOTS patients in contrast with controls (p < 0.05, FWE corrected). Patients with dysarthria and those initially presenting with ataxia had more severe cerebellar atrophy. Our results show predominant impairment of cerebellar regions responsible for speech and hand motor function in LOTS patients. Widespread morphological changes of motor cortical and subcortical regions and tracts in white matter indicate abnormalities in central motor circuits likely coresponsible for impaired speech and motor function.

Diagnostic delay of multiple sclerosis: prevalence, determinants and consequences.

BACKGROUND: Early diagnosis and treatment of patients with multiple sclerosis (MS) are associated with better outcomes; however, diagnostic delays remain a major problem. OBJECTIVE: Describe the prevalence, determinants and consequences of delayed diagnoses. METHODS: This single-centre ambispective study analysed 146 adult relapsing-remitting MS patients (2016-2021) for frequency and determinants of diagnostic delays and their associations with clinical, cognitive, imaging and biochemical measures. RESULTS: Diagnostic delays were identified in 77 patients (52.7%), including 42 (28.7%) physician-dependent cases and 35 (24.0%) patient-dependent cases. Diagnosis was delayed in 22 (15.1%) patients because of misdiagnosis by a neurologist. A longer diagnostic delay was associated with trends towards greater Expanded Disability Status Scale (EDSS) scores (B = 0.03; p = 0.034) and greater z-score of the blood neurofilament light chain (B = 0.35; p = 0.031) at the time of diagnosis. Compared with patients diagnosed at their first clinical relapse, patients with a history of >1 relapse at diagnosis (n = 63; 43.2%) had a trend towards greater EDSS scores (B = 0.06; p = 0.006) and number of total (B = 0.13; p = 0.040) and periventricular (B = 0.06; p = 0.039) brain lesions. CONCLUSION: Diagnostic delays in MS are common, often determined by early misdiagnosis and associated with greater disease burden.

CSF Markers of Oxidative Stress Are Associated with Brain Atrophy and Iron Accumulation in a 2-Year Longitudinal Cohort of Early MS.

In this prospective longitudinal study, we quantified regional brain volume and susceptibility changes during the first two years after the diagnosis of multiple sclerosis (MS) and identified their association with cerebrospinal fluid (CSF) markers at baseline. Seventy patients underwent MRI (T1 and susceptibility weighted images processed to quantitative susceptibility maps, QSM) with neurological examination at the diagnosis and after two years. In CSF obtained at baseline, the levels of oxidative stress, products of lipid peroxidation, and neurofilaments light chain (NfL) were determined. Brain volumetry and QSM were compared with a group of 58 healthy controls. In MS patients, regional atrophy was identified in the striatum, thalamus, and substantia nigra. Magnetic susceptibility increased in the striatum, globus pallidus, and dentate and decreased in the thalamus. Compared to controls, MS patients developed greater atrophy of the thalamus, and a greater increase in susceptibility in the caudate, putamen, globus pallidus and a decrease in the thalamus. Of the multiple calculated correlations, only the decrease in brain parenchymal fraction, total white matter, and thalamic volume in MS patients negatively correlated with increased NfL in CSF. Additionally, negative correlation was found between QSM value in the substantia nigra and peroxiredoxin-2, and QSM value in the dentate and lipid peroxidation levels.

Brainstem lesions are associated with diffuse spinal cord involvement in early multiple sclerosis.

BACKGROUND: Early infratentorial and focal spinal cord lesions on magnetic resonance imaging (MRI) are associated with a higher risk of long-term disability in patients with multiple sclerosis (MS). The role of diffuse spinal cord lesions remains less understood. The purpose of this study was to evaluate focal and especially diffuse spinal cord lesions in patients with early relapsing-remitting MS and their association with intracranial lesion topography, global and regional brain volume, and spinal cord volume. METHODS: We investigated 58 MS patients with short disease duration (< 5 years) from a large academic MS center and 58 healthy controls matched for age and sex. Brain, spinal cord, and intracranial lesion volumes were compared among patients with- and without diffuse spinal cord lesions and controls. Binary logistic regression models were used to analyse the association between the volume and topology of intracranial lesions and the presence of focal and diffuse spinal cord lesions. RESULTS: We found spinal cord involvement in 75% of the patients (43/58), including diffuse changes in 41.4% (24/58). Patients with diffuse spinal cord changes exhibited higher volumes of brainstem lesion volume (p = 0.008). The presence of at least one brainstem lesion was associated with a higher probability of the presence of diffuse spinal cord lesions (odds ratio 47.1; 95% confidence interval 6.9-321.6 p < 0.001) as opposed to focal spinal cord lesions (odds ratio 0.22; p = 0.320). Patients with diffuse spinal cord lesions had a lower thalamus volume compared to patients without diffuse spinal cord lesions (p = 0.007) or healthy controls (p = 0.002). CONCLUSIONS: Diffuse spinal cord lesions are associated with the presence of brainstem lesions and with a lower volume of the thalamus. This association was not found in patients with focal spinal cord lesions. If confirmed, thalamic atrophy in patients with diffuse lesions could increase our knowledge on the worse prognosis in patients with infratentorial and SC lesions.

Oxidative Stress Markers in Cerebrospinal Fluid of Newly Diagnosed Multiple Sclerosis Patients and Their Link to Iron Deposition and Atrophy.

Oxidative stress has been implied in cellular injury even in the early phases of multiple sclerosis (MS). In this study, we quantified levels of biomarkers of oxidative stress and antioxidant capacity in cerebrospinal fluid (CSF) in newly diagnosed MS patients and their associations with brain atrophy and iron deposits in the brain tissue. Consecutive treatment-naive adult MS patients (n = 103) underwent brain MRI and CSF sampling. Healthy controls (HC, n = 99) had brain MRI. CSF controls (n = 45) consisted of patients with non-neuroinflammatory conditions. 3T MR included isotropic T1 weighted (MPRAGE) and gradient echo (GRE) images that were processed to quantitative susceptibility maps. The volume and magnetic susceptibility of deep gray matter (DGM) structures were calculated. The levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-iso prostaglandin F2α (8-isoPG), neutrophil gelatinase-associated lipocalin (NGAL), peroxiredoxin-2 (PRDX2), and malondialdehyde and hydroxyalkenals (MDA + HAE) were measured in CSF. Compared to controls, MS patients had lower volumes of thalamus, pulvinar, and putamen, higher susceptibility in caudate nucleus and globus pallidus, and higher levels of 8-OHdG, PRDX2, and MDA + HAE. In MS patients, the level of NGAL correlated negatively with volume and susceptibility in the dentate nucleus. The level of 8-OHdG correlated negatively with susceptibility in the caudate, putamen, and the red nucleus. The level of PRDX2 correlated negatively with the volume of the thalamus and both with volume and susceptibility of the dentate nucleus. From MRI parameters with significant differences between MS and HC groups, only caudate susceptibility and thalamic volume were significantly associated with CSF parameters. Our study shows that increased oxidative stress in CSF detected in newly diagnosed MS patients suggests its role in the pathogenesis of MS.

Periventricular gradient of T1 tissue alterations in multiple sclerosis.

OBJECTIVE: Pathology in multiple sclerosis is not homogenously distributed. Recently, it has been shown that structures adjacent to CSF are more severely affected. A gradient of brain tissue involvement was shown with more severe pathology in periventricular areas and in proximity to brain surfaces such as the subarachnoid spaces and ependyma, and hence termed the "surface-in" gradient. Here, we study whether (i) the surface-in gradient of periventricular tissue alteration measured by T1 relaxometry is already present in early multiple sclerosis patients, (ii) how it differs between early and progressive multiple sclerosis patients, and (iii) whether the gradient-derived metrics in normal-appearing white matter and lesions correlate better with physical disability than conventional MRI-based metrics. METHODS: Forty-seven patients with early multiple sclerosis, 52 with progressive multiple sclerosis, and 92 healthy controls were included in the study. Isotropic 3D T1 relaxometry maps were obtained using the Magnetization-Prepared 2 Rapid Acquisition Gradient Echoes sequence at 3 T. After spatially normalizing the T1 maps into a study-specific common space, T1 inter-subject variability within the healthy cohort was modelled voxel-wise, yielding a normative T1 atlas. Individual comparisons of each multiple sclerosis patient against the atlas were performed by computing z-scores. Equidistant bands of voxels were defined around the ventricles in the supratentorial white matter; the z-scores in these bands were analysed and compared between the early and progressive multiple sclerosis cohorts. Correlations between both conventional and z-score-gradient-derived MRI metrics and the Expanded Disability Status Scale were assessed. RESULTS: Patients with early and progressive multiple sclerosis demonstrated a periventricular gradient of T1 relaxation time z-scores. In progressive multiple sclerosis, z-score-derived metrics reflecting the gradient of tissue abnormality in normal-appearing white matter were more strongly correlated with disability (maximal rho = 0.374) than the conventional lesion volume and count (maximal rho = 0.189 and 0.21 respectively). In early multiple sclerosis, the gradient of normal-appearing white matter volume with z-scores > 2 at baseline correlated with clinical disability assessed at two years follow-up. CONCLUSION: Our results suggest that the surface-in white matter gradient of tissue alteration is detectable with T1 relaxometry and is already present at clinical disease onset. The periventricular gradients correlate with clinical disability. The periventricular gradient in normal-appearing white matter may thus qualify as a promising biomarker for monitoring of disease activity from an early stage in all phenotypes of multiple sclerosis.

Pregnancy-induced brain magnetic resonance imaging changes in women with multiple sclerosis.

BACKGROUND AND PURPOSE: The effect of pregnancy on brain changes and radiological disease activity in women with multiple sclerosis (MS) is not well understood. This study was undertaken to describe the dynamics of lesion activity and brain volume changes during the pregnancy and postpartum periods. METHODS: This observational study of 62 women with relapsing-remitting MS included magnetic resonance imaging (221 scans) as well as clinical visits at baseline (<24 and >6 months before pregnancy), prepregnancy (<6 months before pregnancy), postpartum (<3 months after delivery), and follow-up (>12 and <24 months after delivery) periods. RESULTS: The majority of women had a mild disability and a short disease duration (median = 5.5 years). Eighteen (29.0%) women had a relapse during the year preceding pregnancy onset, nine (14.5%) during pregnancy, and 20 (32.3%) in the year following delivery. Disability status remained unchanged during follow-up. Women in the postpartum period (n = 62) had higher T2 lesion volume (median = 1.18 ml vs. 0.94 ml), greater annualized T2 lesion volume increase (0.23 ml vs. 0.0 ml), lower brain parenchymal fraction (85.6% vs. 86.4%), and greater annualized brain volume loss (-1.74% vs. -0.16%) compared with the prepregnancy period (all p < 0.001). At 12-24 months after delivery, women (n = 41) had higher T2 lesion volume (1.16 ml vs. 1.0 ml) and lower brain parenchymal fraction (86.0% vs. 86.5%) compared to the prepregnancy period (both p < 0.001). CONCLUSIONS: The postpartum period was associated with an increase in T2 lesion volume and accelerated brain volume loss in a considerable proportion of women. This should be considered in treatment decision-making and designing clinical trials.

The clinical and paraclinical correlates of employment status in multiple sclerosis.

PURPOSE: To identify the clinical and paraclinical markers of employment status in multiple sclerosis (MS). METHODS: This was a cross-sectional sub-study investigating 1226 MS patients. To minimalized confounding effect, two groups of patients, matched by sex, age, and education, were selected: 307 patients with full time employment and 153 unemployed patients receiving disability pension. We explored associations between employment status and Expanded Disability Status Scale (EDSS), 25 Foot Walk Test (25FWT), Nine Hole Peg Test (9HPT), Brief International Cognitive Assessment for MS (BICAMS), Paced Auditory Serial Addition Test (PASAT), Beck Depression Inventory (BDI), SLOAN charts (SLOAN), and brain volumetric MRI measures. RESULTS: Both groups differed significantly on all variables of interest (p < 0.001). In the univariate analyses, EDSS, SDMT (Symbol Digit Modalities Test) adjusted for BDI, 25FWT, and 9HPT best explained variability in vocational status. In multivariate analyses, the combination of EDSS, 25FWT, SDMT, BDI, and corpus callosum fraction (CCF) explained the greatest variability. As a next step, after patients were matched by EDSS, differences in SDMT, 25FWT (both p < 0.001), 9HPT, CCF, and T2 lesion volume were still present (all p < 0.005) between both groups. The best multivariate model consisted of SDMT, BDI, and T2 lesion volume. CONCLUSIONS: EDSS, walking ability, cognitive performance, and MRI volumetric parameters are independently associated with employment status.

Natalizumab Induces Changes of Cerebrospinal Fluid Measures in Multiple Sclerosis.

BACKGROUND: There is a lack of knowledge about the evolution of cerebrospinal fluid (CSF) markers in multiple sclerosis (MS) patients undergoing natalizumab treatment. AIM: We aimed to evaluate the effect of natalizumab on basic inflammatory CSF and MRI measures. METHODS: Together, 411 patients were screened for eligibility and 93 subjects with ≥2 CSF examinations ≤6 months before and ≥12 months after natalizumab initiation were recruited. The effect of natalizumab on CSF as well as clinical and paraclinical measures was analyzed using adjusted mixed models. RESULTS: Natalizumab induced a decrease in CSF leukocytes (p < 1 × 10-15), CSF protein (p = 0.00007), the albumin quotient (p = 0.007), the IgG quotient (p = 6 × 10-15), the IgM quotient (p = 0.0002), the IgG index (p = 0.0004), the IgM index (p = 0.003) and the number of CSF-restricted oligoclonal bands (OCBs) (p = 0.0005). CSF-restricted OCBs positivity dropped from 94.6% to 86% but 26 patients (28%) had an increased number of OCBs at the follow-up. The baseline to follow-up EDSS and T2-LV were stable; a decrease in the relapse rate was consistent with a decrease in the CSF inflammatory markers and previous knowledge about the effectiveness of natalizumab. The average annualized brain volume loss during the follow-up was -0.50% (IQR = -0.96, -0.16) and was predicted by the baseline IgM index (B = -0.37; p = 0.003). CONCLUSIONS: Natalizumab is associated with a reduction of basic CSF inflammatory measures supporting its strong anti-inflammatory properties. The IgM index at the baseline predicted future brain volume loss during the course of natalizumab treatment.

Measurement of neurofilaments improves stratification of future disease activity in early multiple sclerosis.

BACKGROUND: The added value of neurofilament light chain levels in serum (sNfL) to the concept of no evidence of disease activity-3 (NEDA-3) has not yet been investigated in detail. OBJECTIVE: To assess whether combination of sNfL with NEDA-3 status improves identification of patients at higher risk of disease activity during the following year. METHODS: We analyzed 369 blood samples from 155 early relapsing-remitting MS patients on interferon beta-1a. We compared disease activity, including the rate of brain volume loss in subgroups defined by NEDA-3 status and high or low sNfL (> 90th or < 90th percentile). RESULTS: In patients with disease activity (EDA-3), those with higher sNFL had higher odds of EDA-3 in the following year than those with low sNFL (86.5% vs 57.9%; OR = 4.25, 95% CI: [2.02, 8.95]; p = 0.0001) and greater whole brain volume loss during the following year (ß = -0.36%; 95% CI = [-0.60, -0.13]; p = 0.002). Accordingly, NEDA-3 patients with high sNfL showed numerically higher disease activity (EDA-3) in the following year compared with those with low sNfL (57.1% vs 31.1%). CONCLUSION: sNfL improves the ability to identify patients at higher risk of future disease activity, beyond their NEDA-3 status. Measurement of sNfL may assist clinicians in decision-making by providing more sensitive prognostic information.

Validating atlas-based lesion disconnectomics in multiple sclerosis: A retrospective multi-centric study.

The translational potential of MR-based connectivity modelling is limited by the need for advanced diffusion imaging, which is not part of clinical protocols for many diseases. In addition, where diffusion data is available, brain connectivity analyses rely on tractography algorithms which imply two major limitations. First, tracking algorithms are known to be sensitive to the presence of white matter lesions and therefore leading to interpretation pitfalls and poor inter-subject comparability in clinical applications such as multiple sclerosis. Second, tractography quality is highly dependent on the acquisition parameters of diffusion sequences, leading to a trade-off between acquisition time and tractography precision. Here, we propose an atlas-based approach to study the interplay between structural disconnectivity and lesions without requiring individual diffusion imaging. In a multi-centric setting involving three distinct multiple sclerosis datasets (containing both 1.5 T and 3 T data), we compare our atlas-based structural disconnectome computation pipeline to disconnectomes extracted from individual tractography and explore its clinical utility for reducing the gap between radiological findings and clinical symptoms in multiple sclerosis. Results using topological graph properties showed that overall, our atlas-based disconnectomes were suitable approximations of individual disconnectomes from diffusion imaging. Small-worldness was found to decrease for larger total lesion volumes thereby suggesting a loss of efficiency in brain connectivity of MS patients. Finally, the global efficiency of the created brain graph, combined with total lesion volume, allowed to stratify patients into subgroups with different clinical scores in all three cohorts.

Age-related magnetic susceptibility changes in deep grey matter and cerebral cortex of normal young and middle-aged adults depicted by whole brain analysis.

BACKGROUND: Iron accumulates in brain tissue in healthy subjects during aging. Our goal was to conduct a detailed analysis of iron deposition patterns in the cerebral deep grey matter and cortex using region-based and whole-brain analyses of brain magnetic susceptibility. METHODS: Brain MRI was performed in 95 healthy individuals aged between 21 and 58 years on a 3T scanner. MRI protocol included T1-weighted (T1W) magnetization-prepared rapid acquisition with gradient echo images and 3D flow-compensated multi-echo gradient-echo images for quantitative susceptibility mapping (QSM). In the region-based analysis, QSM and T1W images entered an automated multi-atlas segmentation pipeline and regional mean bulk susceptibility values were calculated. The whole-brain analysis included a non-linear transformation of QSM images to the standard MNI template. For the whole-brain analysis voxel-wise maps of linear regression slopes ß and P values were calculated. Regional masks of cortical voxels with a significant association between susceptibility and age were created and further analyzed. RESULTS: In cortical regions, the highest increase of susceptibility values with age was found in areas involved in motor functions (precentral and postcentral areas, premotor cortex), in cognitive processing (prefrontal cortex, superior temporal gyrus, insula, precuneus), and visual processing (occipital gyri, cuneus, posterior cingulum, fusiform, calcarine and lingual gyrus). Thalamic susceptibility increased until the fourth decade and decreased thereafter with the exception of the pulvinar where susceptibility increase was observed throughout the adult lifespan. Deep grey matter structures with the highest increase of susceptibility values with age included the red nucleus, putamen, substantia nigra, dentate nucleus, external globus pallidus, caudate nucleus, and the subthalamic nucleus in decreasing order. CONCLUSIONS: Accumulation of iron in basal ganglia follows a linear pattern whereas in the thalamus, pulvinar, precentral cortex, and precuneus, it follows a quadratic or exponential pattern. Age-related changes of iron content are different in the pulvinar and the rest of the thalamus as well as in internal and external globus pallidus. In the cortex, areas involved in motor and cognitive functions and visual processing show the highest iron increase with aging. We suggest that the departure from normal patterns of regional brain iron trajectories during aging may be helpful in the detection of subtle neurodegenerative and neuroinflammatory processes.

Isolated Cognitive Decline in Neurologically Stable Patients with Multiple Sclerosis.

(1) Background: Cognitive deterioration is an important marker of disease activity in multiple sclerosis (MS). It is vital to detect cognitive decline as soon as possible. Cognitive deterioration can take the form of isolated cognitive decline (ICD) with no other clinical signs of disease progression present. (2) Methods: We investigated 1091 MS patients from the longitudinal GQ (Grant Quantitative) study, assessing their radiological, neurological, and neuropsychological data. Additionally, the confirmatory analysis was conducted. Clinical disease activity was defined as the presence of new relapse or disability worsening. MRI activity was defined as the presence of new or enlarged T2 lesions on brain MRI. (3) Results: Overall, 6.4% of patients experienced cognitive decline and 4.0% experienced ICD without corresponding clinical activity. The vast majority of cognitively worsening patients showed concomitant progression in other neurological and radiologic measures. There were no differences in disease severity between completely stable patients and cognitively worsening patients but with normal cognition at baseline. (4) Conclusions: Only a small proportion of MS patients experience ICD over short-term follow-up. Patients with severe MS are more prone to cognitive decline; however, patients with normal cognitive performance and mild MS might benefit from the early detection of cognitive decline the most.

Evolution of Brain Volume Loss Rates in Early Stages of Multiple Sclerosis.

OBJECTIVE: To describe the dynamics of brain volume loss (BVL) at different stages of relapsing-remitting multiple sclerosis (RRMS), to describe the association between BVL and clinical measures, and to investigate an effect of treatment escalation on the rate of BVL. METHODS: Together, 1903 patients predominantly with RRMS from the Avonex-Steroids-Azathioprine cohort (N = 166), the study of early IFN-ß1a treatment cohort (N = 180), and the quantitative MRI cohort (N = 1,557) with ≥2 MRI scans and ≥1-year of follow-up were included. Brain MRI scans (N = 7,203) were performed using a single 1.5-T machine. Relationships between age or disease duration and global and tissue-specific BVL rates were analyzed using mixed models. RESULTS: Age was not associated with the rate of BVL (ß = -0.003; Cohen f2 = 0.0005; adjusted p = 0.39). Although disease duration was associated with the rate of BVL, its effect on the BVL rate was minimal (ß = -0.012; Cohen f2 = 0.004; adjusted p = 4 × 10-5). Analysis of association between tissue-specific brain volume changes and age (ß = -0.019 to -0.011; adjusted p = 0.028-1.00) or disease duration (ß = -0.028 to -0.008; adjusted p = 0.16-0.96) confirmed these results. Although increase in the relapse rate (ß = 0.10; adjusted p = 9 × 10-9), Expanded Disability Status Scale (EDSS; ß = 0.17; adjusted p = 8 × 10-5), and EDSS change (ß = 0.15; adjusted p = 2 × 10-5) were associated with accelerated rate of BVL, their effect on the rate of BVL was minimal (all Cohen f2 ≤ 0.007). In 94 patients who escalated therapy, the rate of BVL decreased following treatment escalation by 0.29% (ß = -0.29; Cohen f2 = 0.133; p = 5.5 × 10-8). CONCLUSIONS: The rate of BVL is relatively stable throughout the course of RRMS. The accelerated BVL is weakly associated with concurrent higher disease activity, and timely escalation to high-efficacy immunotherapy helps decrease the rate of BVL.

Serum neurofilament light chain reflects inflammation-driven neurodegeneration and predicts delayed brain volume loss in early stage of multiple sclerosis.

BACKGROUND: Serum neurofilament light chain (sNfL) is a marker of neuroaxonal injury. There is a lack of studies investigating the dynamics of relationships between sNfL levels and radiological disease activity over long-term follow-up in multiple sclerosis (MS). OBJECTIVES: To investigate the relationship among repeated measures of sNfL, lesion burden accumulation, brain volume loss and clinical measures. METHODS: We investigated 172 patients in the early stages of MS (McDonald 2017 criteria). Clinical exams were performed every 3 months and brain magnetic resonance imaging (MRI) scans were collected annually over 48 months. sNfL levels were measured in serum by Simoa assay at the time of treatment initiation and then annually over 36 months. RESULTS: In repeated-measures analysis, considering all time points, we found a strong relationship between percentage changes of sNfL and lesion burden accumulation assessed by T1 lesion volume (p < 0.001) and T2 lesion number (p < 0.001). There was no relationship between percentage changes of sNfL and brain volume loss over 36 months (p > 0.1). Early sNfL levels were associated with delayed brain volume loss after 48 months (p < 0.001). Patients with No Evidence of Disease Activity (NEDA-3) status showed lower sNfL levels compared with active MS patients. CONCLUSIONS: sNfL is associated with ongoing neuroinflammation and predictive of future neurodegeneration in early MS.

Neurofilament levels are associated with blood-brain barrier integrity, lymphocyte extravasation, and risk factors following the first demyelinating event in multiple sclerosis.

BACKGROUND: Increased blood brain barrier (BBB) permeability, CNS inflammation and neuroaxonal damage are pathological hallmarks in early multiple sclerosis (MS). OBJECTIVE: To investigate the associations of neurofilament light chain (NfL) levels with measures of BBB integrity and central nervous system (CNS) inflammation in MS during the first demyelinating event. METHODS: Blood and cerebrospinal fluid (CSF) were obtained from 142 MS (McDonald 2017) treatment-naive patients from the SET study (63% female; age: 29.7 ± 7.9 years) following the disease onset. NfL, albumin, immunoglobulin G (IgG), and immunoglobulin M (IgM) levels were measured in CSF and blood samples. Albumin quotient was computed as a marker of BBB integrity. Immune cell subset counts in CSF were measured using flow cytometry. MS risk factors, such as Human leukocyte antigen DRB1 locus gene (HLA DRB1)*1501, anti-Epstein-Barr virus (EBV) antibodies, and 25-hydroxy vitamin D3, were also measured. RESULTS: Higher serum NfL (sNfL) levels were associated with higher albumin quotient (p < 0.001), CSF CD80+ (p = 0.012), and CD80+ CD19+ (p = 0.015) cell frequency. sNfL levels were also associated with contrast-enhancing and T2 lesions on brain magnetic resonance imaging (MRI; all p ⩽ 0.001). Albumin quotient was not associated with any of the MS risk factors assessed. sNfL levels were associated with anti-EBV viral capsid antigen (VCA) IgG levels (p = 0.0026). CONCLUSION: sNfL levels during the first demyelinating event of MS are associated with greater impairment of BBB integrity, immune cell extravasation, and brain lesion activity on MRI.

Interpretation of Brain Volume Increase in Multiple Sclerosis.

BACKGROUND AND PURPOSE: A high variability of brain MRI volume change measurement renders challenging its interpretation in multiple sclerosis (MS). Occurrence and clinical relevance of observed apparent brain volume increase (BVI) in MS patients have not been investigated yet. The objective was to quantify the prevalence and factors associated with BVI. METHODS: We examined 366 MS patients (2,317 scans) and 44 controls (132 scans). Volumetric analysis of brain volume changes was performed by SIENA and ScanView. BVI was defined as brain volume change >0%. We compared characteristics of patients with and without BVI. RESULTS: BVI was found in 26.3% (from 1,951) longitudinal scans (SIENA). If BVI occurred, a probability that BVI will be repeated consecutively more than or equal to two times was 15.9%. The repeated BVI was associated with clinical disease activity in 50% of cases. BVI was associated with shorter time and lower T2 lesion volume increase between two MRI scans, and higher normalized brain volume (all P < .0001). A proportion of scans with BVI was higher when analyzed by ScanView (35.3%) and in controls (36.4% by SIENA). CONCLUSIONS: BVI occurs in a great proportion of MR scans over short-term follow-up and is not associated with disease stabilization. Although BVI can be caused by several factors, the results indicate that measurement error may contribute to BVI in the majority of cases. Clinicians should be aware of the frequent occurrence of apparent BVI, interpret brain volume changes in MS patients with great caution, and use methods with precise quantification of brain volume changes.

Long-term effectiveness of natalizumab on MRI outcomes and no evidence of disease activity in relapsing-remitting multiple sclerosis patients treated in a Czech Republic real-world setting: A longitudinal, retrospective study.

BACKGROUND: Magnetic resonance imaging (MRI) data from multiple sclerosis (MS) patients treated in real-world settings are important for understanding disease-modifying therapy effects, including no evidence of disease activity (NEDA) assessment. This longitudinal, retrospective, single-cohort analysis assessed MRI and clinical disease outcomes in patients with relapsing-remitting MS treated with natalizumab for up to 5 years in Prague, the Czech Republic. METHODS: The primary study endpoint was the proportion of patients free of new or enlarging fluid-attenuated inversion recovery (FLAIR) lesions after at least 2 years of natalizumab treatment. Secondary endpoints included percentage brain volume change over time, the number of new T1-hypointense lesions that persisted for ≥6 months, FLAIR and T1-hypointense lesion volume change over time, and the proportion of patients with NEDA-3 (defined as no relapses, no confirmed disability worsening, and no new or enlarging FLAIR lesions). RESULTS: A total of 193 patients were included in the study. During year 1 of natalizumab treatment, 78.9% of patients had no new or enlarging FLAIR lesions and 79.5% had no new T1 lesions. These proportions increased in years 2-5, with ≥98.0% of patients free of new or enlarging FLAIR lesions and ≥98.8% free of new T1 lesions. During year 1 on natalizumab, 52.2% of patients achieved NEDA-3; this proportion increased to ≥69.2% in years 2-5. CONCLUSION: This study provides additional evidence that long-term MS disease activity, as measured by both MRI activity and NEDA-3, is well-controlled in patients treated with natalizumab in real-world settings.