Prognostic value of single-subject grey matter networks in early multiple sclerosis

The identification of prognostic markers in early multiple sclerosis (MS) is challenging and requires reliable measures that robustly predict future disease trajectories. Ideally, such measures should make inferences at the individual level to inform clinical decisions. This study investigated the prognostic value of longitudinal structural networks to predict five-year EDSS progression in patients with relapsing-remitting MS (RRMS). We hypothesized that network measures, derived from magnetic resonance imaging (MRI), outperform conventional MRI measurements at identifying patients at risk of developing disability progression. This longitudinal, multicentre study within the Magnetic Resonance Imaging in MS (MAGNIMS) network included 406 patients with RRMS (mean age = 35.7 ± 9.1 years) followed up for five years (mean follow-up = 5.0 ± 0.6 years). Expanded Disability Status Scale (EDSS) was determined to track disability accumulation. A group of 153 healthy subjects (mean age = 35.0 ± 10.1 years) with longitudinal MRI served as controls. All subjects underwent MRI at baseline and again one year after baseline. Grey matter (GM) atrophy over one year and white matter (WM) lesion load were determined. A single-subject brain network was reconstructed from T1-weighted scans based on GM atrophy measures derived from a statistical parameter mapping (SPM)-based segmentation pipeline. Key topological measures, including network degree, global efficiency and transitivity, were calculated at single-subject level to quantify network properties related to EDSS progression. Areas under receiver operator characteristic (ROC) curves were constructed for GM atrophy, WM lesion load and the network measures, and comparisons between ROC curves were conducted. The applied network analyses differentiated patients with RRMS who experience EDSS progression over five years through lower values for network degree [H(2)=30.0, p<0.001] and global efficiency [H(2)=31.3, p<0.001] from healthy controls but also from patients without progression. For transitivity, the comparisons showed no difference between the groups (H(2)= 1.5, p=0.474). Most notably, changes in network degree and global efficiency were detected independent of disease activity in the first year. The described network reorganization in patients experiencing EDSS progression was evident in the absence of GM atrophy. Network degree and global efficiency measurements demonstrated superiority of network measures in the ROC analyses over GM atrophy and WM lesion load in predicting EDSS worsening (all p-values < 0.05). Our findings provide evidence that GM network reorganization over one year discloses relevant information about subsequent clinical worsening in RRMS. Early GM restructuring towards lower network efficiency predicts disability accumulation and outperforms conventional MRI predictors

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 −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

Deep Gray Matter Iron Content in Neuromyelitis Optica and Multiple Sclerosis

Background. Neuromyelitis optica (NMO) and multiple sclerosis (MS) are often presenting with overlapping symptoms. The aim of this study was to determine whether and how NMO and MS differ regarding cerebral iron deposits in deep gray matter (DGM) and the correlation between iron deposition and clinical severity as well as to regional atrophy of the DGM. Methods. We analyzed 20 patients with NMO, 40 patients with a relapsing-remitting (RR) form of MS, and 20 healthy controls with 1.5T MRI. Quantitative susceptibility mapping (QSM) was performed to estimate iron concentration in the DGM. Results. Patients with NMO have higher magnetic susceptibility values in the substantia nigra compared to healthy controls. RRMS patients have lower magnetic susceptibility values in the thalamus compared to healthy controls and NMO patients. Atrophy of the thalamus, pulvinar, and putamen is significant both in RRMS compared to NMO patients and healthy controls. A correlation was found between the disability score (EDSS) and magnetic susceptibility in the putamen in RRMS. Conclusions. This study confirms that a disturbed cerebral iron homeostasis in patients with NMO occurs in different structures than in patients with RRMS. Increased magnetic susceptibility in substantia nigra in NMO and decreased magnetic susceptibility within the thalamus in RRMS were the only significant differences in the study sample. We could confirm that iron concentration in the thalami is decreased in RRMS compared to that in the HC group. Positive association was found between putaminal iron and EDSS in RRMS

Neurological software tool for reliable atrophy measurement (NeuroSTREAM) of the lateral ventricles on clinical-quality T2-FLAIR MRI scans in multiple sclerosis

Background: There is a need for a brain volume measure applicable to the clinical routine scans. Nearly every multiple sclerosis (MS) protocol includes low-resolution 2D T2-FLAIR imaging. Objectives: To develop and validate cross-sectional and longitudinal brain atrophy measures on clinical-quality T2-FLAIR images in MS patients. Methods: A real-world dataset from 109 MS patients from 62 MRI scanners was used to develop a lateral ventricular volume (LVV) algorithm with a longitudinal Jacobian-based extension, called NeuroSTREAM. Gold-standard LVV was calculated on high-resolution T1 1mm, while NeuroSTREAM LVV was obtained on low-resolution T2-FLAIR 3mm thick images. Scan-rescan reliability was assessed in 5 subjects. The variability of LVV measurement at different field strengths was tested in 76 healthy controls and 125 MS patients who obtained both 1.5T and 3T scans in 72hours. Clinical validation of algorithm was performed in 176 MS patients who obtained serial yearly MRI 1.5T scans for 10years. Results: Correlation between gold-standard high-resolution T1 LVV and low-resolution T2-FLAIR LVV was r=0.99, p<0.001 and the scan-rescan coefficient of variation was 0.84%. Correlation between low-resolution T2-FLAIR LVV on 1.5T and 3T was r=0.99, p<0.001 and the scan-rescan coefficient of variation was 2.69% cross-sectionally and 2.08% via Jacobian integration. NeuroSTREAM showed comparable effect size (d=0.39–0.71) in separating MS patients with and without confirmed disability progression, compared to SIENA and VIENA. Conclusions: Brain atrophy measurement on clinical quality T2-FLAIR scans is feasible, accurate, reliable, and relates to clinical outcomes. Keywords: Brain atrophy, Ventricular volume, Automated measurement, Multiple sclerosi

MRI-based brain volumetry and retinal optical coherence tomography as the biomarkers of outcome in acute methanol poisoning

Background: Basal ganglia lesions are typical findings on magnetic resonance imaging (MRI) of the brain in survivors of acute methanol poisoning. However, no data are available on the association between the magnitude of damaged brain regions, serum concentrations of markers of acute methanol toxicity, oxidative stress, neuroinflammation, and the rate of retinal nerve ganglion cell loss.Objectives: To investigate the association between MRI-based volumetry of the basal ganglia, retinal nerve fibre layer (RNFL) thickness and prognostic laboratory markers of outcomes in acute methanol poisoning.Methods: MRI-based volumetry of putamen, nucleus caudatus and globus pallidus was performed and compared with laboratory parameters of severity of poisoning and acute serum markers of oxidative damage of lipids (8-isoprostan, MDA, HHE, HNE), nucleic acids (8-OHdG, 8 - OHG, 5 - OHMU), proteins (o-Thyr, NO-Thyr, Cl-Thyr) and leukotrienes (LTC4, LTD4, LTE4, LTB4), as well as with the results of RNFL measurements by optic coherence tomography (OCT) in 16 patients with acute methanol poisoning (Group I) and in 28 survivors of poisoning two years after discharge with the same markers measured within the follow-up examination (Group II). The control group consisted of 28 healthy subjects without methanol poisoning.Results: The survivors of acute methanol poisoning had significantly lower volumes of basal ganglia than the controls. The patients with MRI signs of methanol-induced toxic brain damage had significantly lower volumes of basal ganglia than those without these signs. A positive correlation was found between the volume of putamen and arterial blood pH on admission (r = 0.45; p = 0.02 and r = 0.44; p = 0.02 for left and right putamen, correspondingly). A negative correlation was present between the volumes of putamen and acute serum lactate (r = -0.63; p < 0.001 and r = -0.59; p = 0.01), creatinine (r = -0.53; p = 0.01 and r = -0.47; p = 0.01) and glucose (r = -0.55; p < 0.001 and r = -0.50; p = 0.01) concentrations.The volume of basal ganglia positively correlated with acute concentrations of markers of lipoperoxidation (8-isoprostan: r = 0.61; p < 0.05 and r = 0.59; p < 0.05 for left and right putamen, correspondingly) and inflammation (leukotriene LTB4: r = 0.61; p < 0.05 and r = 0.61; p < 0.05 for left and right putamen, correspondingly). The higher the volume of the basal ganglia, the higher the thickness of the RNFL, with the strongest positive association between global RNFL and the volume of putamen bilaterally (all p < 0.01). In the follow-up markers of oxidative stress and inflammation, only o-Thyr concentration negatively correlated with the volume of putamen bilaterally (r = -0.39; p < 0.05 and r = -0.37; p < 0.05 for left and right putamen, correspondingly).Conclusion: In survivors of acute methanol poisoning with signs of toxic brain damage, the magnitude of affected areas correlated with acute parameters of severity of poisoning, markers of oxidative stress and neuroinflammation. There was a positive association between the basal ganglia volume and the thickness of RNFL, making OCT an important screening test and MRI-based volumetry the confirmative diagnostic method for the detection of CNS sequelae of methanol poisoning

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&prime;-deoxyguanosine (8-OHdG), 8-iso prostaglandin F2&alpha; (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

MRI correlates of disability progression in patients with CIS over 48 months

Background: Gray matter (GM) and white matter (WM) pathology has an important role in disease progression of multiple sclerosis (MS). Objectives: To investigate the association between the development of GM and WM pathology and clinical disease progression in patients with clinically isolated syndrome (CIS). Methods: This prospective, observational, 48-month follow-up study examined 210 CIS patients treated with 30 µg of intramuscular interferon beta-1a once a week. MRI and clinical assessments were performed at baseline, 6, 12, 24, 36 and 48 months. Associations between clinical worsening [24-weeks sustained disability progression (SDP) and occurrence of a second clinical attack] and longitudinal changes in lesion accumulation and brain atrophy progression were investigated by a mixed-effect model analysis after correction for multiple comparisons. Results: SDP was observed in 32 (15.2%) CIS patients, while 146 (69.5%) were stable and 32 (15.2%) showed sustained disability improvement. 112 CIS patients (53.3%) developed clinically definite MS (CDMS). CIS patients who developed SDP showed increased lateral ventricle volume (p < .001), and decreased GM (p = .011) and cortical (p = .001) volumes compared to patients who remained stable or improved in disability. Converters to CDMS showed an increased rate of accumulation of number of new/enlarging T2 lesions (p < .001), decreased whole brain (p = .007) and increased lateral ventricle (p = .025) volumes. Conclusions: Development of GM pathology and LVV enlargement are associated with SDP. Conversion to CDMS in patients with CIS over 48 months is dependent on the accumulation of new lesions, LVV enlargement and whole brain atrophy progression

Volumetric MRI Markers and Predictors of Disease Activity in Early Multiple Sclerosis: A Longitudinal Cohort Study

<div><h3>Objectives</h3><p>To compare clinical and MRI parameters between patients with clinically isolated syndrome and those converting to clinically definite multiple sclerosis within 2 years, to identify volumetric MRI predictors of this conversion and to assess effect of early relapses.</p> <h3>Methods</h3><p>The SET study comprised 220 patients with clinically isolated syndrome treated with interferon beta (mean age, 29 years; Expanded Disability Status Scale, 1.5). Three patients with missing data were excluded from the analysis. Physical disability, time to clinically definite multiple sclerosis and volumetric MRI data were recorded for 2 years.</p> <h3>Results</h3><p>Patients reaching clinically definite multiple sclerosis showed impaired recovery of neurological function, faster decrease in corpus callosum cross-sectional area, higher T2 lesion volume and more contrast-enhancing lesions. Six-month decrease in corpus callosum cross-sectional area (≥1%) and baseline T2 lesion volume (≥5 cm³) predicted clinically definite multiple sclerosis within 2 years (hazard ratios 2.5 and 1.8, respectively). Of 22 patients fulfilling both predictive criteria, 83% reached clinically definite multiple sclerosis (hazard ratio 6.5). More relapses were associated with poorer recovery of neurological function and accelerated brain atrophy.</p> <h3>Conclusions</h3><p>Neurological impairment is more permanent, brain atrophy is accelerated and focal inflammatory activity is greater in patients converting to clinically definite multiple sclerosis. Six-month corpus callosum atrophy and baseline T2 lesion volume jointly help predict individual risk of clinically definite multiple sclerosis. Early relapses contribute to permanent damage of the central nervous system.</p> </div