Cortical Lesions as an Early Hallmark of Multiple Sclerosis: Visualization by 7 T MRI.

OBJECTIVES: Compelling evidence indicates a significant involvement of cortical lesions in the progressive phase of multiple sclerosis (MS), significantly contributing to late-stage disability. Despite the promise of ultra-high-field magnetic resonance imaging (MRI) in detecting cortical lesions, current evidence falls short in providing insights into the existence of such lesions during the early stages of MS or their underlying cause. This study delineated, at the early stage of MS, (1) the prevalence and spatial distribution of cortical lesions identified by 7 T MRI, (2) their relationship with white matter lesions, and (3) their clinical implications. MATERIALS AND METHODS: Twenty individuals with early-stage relapsing-remitting MS (disease duration <1 year) underwent a 7 T MRI session involving T1-weighted MP2RAGE, T2*-weighted multiGRE, and T2-weighted FLAIR sequences for cortical and white matter segmentation. Disability assessments included the Expanded Disability Status Scale, the Multiple Sclerosis Functional Composite, and an extensive evaluation of cognitive function. RESULTS: Cortical lesions were detected in 15 of 20 patients (75%). MP2RAGE revealed a total of 190 intracortical lesions (median, 4 lesions/case [range, 0-44]) and 216 leukocortical lesions (median, 2 lesions/case [range, 0-75]). Although the number of white matter lesions correlated with the total number of leukocortical lesions (r = 0.91, P < 0.001), no correlation was observed between the number of white matter or leukocortical lesions and the number of intracortical lesions. Furthermore, the number of leukocortical lesions but not intracortical or white-matter lesions was significantly correlated with cognitive impairment (r = 0.63, P = 0.04, corrected for multiple comparisons). CONCLUSIONS: This study highlights the notable prevalence of cortical lesions at the early stage of MS identified by 7 T MRI. There may be a potential divergence in the underlying pathophysiological mechanisms driving distinct lesion types, notably between intracortical lesions and white matter/leukocortical lesions. Moreover, during the early disease phase, leukocortical lesions more effectively accounted for cognitive deficits.

Active and non-active progression independent of relapse activity within the first 20 years of relapsing multiple sclerosis.

BACKGROUND: Progression independent of relapse activity (PIRA) has been described since the early stage of relapsing multiple sclerosis (RMS). However, little is known about the relation between PIRA and inflammatory activity that is particularly important at this stage of the disease. METHOD: We included 110 patients in a prospective study within 18 months of RMS onset. MRI examinations and clinical visits were scheduled on the same day for months 0, 6, 12, 24, 36, 60, 84, 120, 180 and 240. RESULTS: The mean (SD) age of patients was 30 (6.7) years at inclusion and median (range) follow-up 15 (9-20) years. Analysis of 1118 between-visit intervals revealed 93 confirmed disability accumulation events in 68 (62%) patients: 50 (54%) events related to relapse activity worsening and 43 (46%) PIRA events, including 17 (18%) with MRI activity. The risk of PIRA between two visits (stable event as the reference category) was associated with Expanded Disability Status Scale (EDSS) score (HR: 1.41; 95% CI: 1.18 to 1.69; p<0.001), disease duration (HR: 0.75; 95% CI: 0.62 to 0.90; p<0.005) and new lesions between the visits (HR: 1.09 per lesion; 95% CI: 1.01 to 1.17; p<0.05). As compared with PIRA events with MRI activity, PIRA events without such activity occurred in patients with more disability (mean EDSS score 3, p<0.05), longer disease duration (mean 11 years, p<0.001) and greater number of T2-weighted lesions (p<0.05). CONCLUSION: This study evidenced that inflammatory activity increases the risk of PIRA in early RMS, arguing that a significant part of PIRA is accessible to treatment targeting inflammation in these patients.

Energetic dysfunction and iron overload in early Parkinson's disease: Two distinct mechanisms?

INTRODUCTION: Identifying biomarkers reflecting cellular dysfunctions in early Parkinson's disease patients (ePD) is needed to develop targeted therapeutic strategies. We aimed to determine if cellular energetic dysfunction related to increased brain sodium concentration would be co-located to microstructural alterations and iron deposition in ePD. METHODS: We prospectively included 12 ePD (mean disease duration 20.0 ± 10.2 months) and 13 healthy controls (HC), scanned with a 7 T 1H and 23Na MRI. Complementary voxel-based and region-based assessments were performed, the latter utilizing a high-resolution multimodal template we created (combining quantitative T1 maps (qT1), transverse relaxation rate (R2*), quantitative magnetic susceptibility mapping (QSM) images) from 200 subjects. This template allowed a precise multiparametric assessment of sodium concentration, QSM, R2*, qT1, mean diffusivity, and fractional anisotropy values. A two-sided p-value<0.05 was considered statistically significant after the Bonferroni correction. RESULTS: Relative to HC, ePD showed significantly higher sodium concentration in left Substantia nigra (SN) pars reticulata (46.13 mM ± 3.52 vs 38.60 mM ± 6.10, p = 0.038), a subpart of the SN pars compacta (SNc) and ventral tegmental area, Putamen, Globus Pallidum external, accumbens nucleus and claustrum. Significantly increased QSM and R2* values, and decreased T1 values, were limited to the Nigrosomes 1 (Nig) and right SNc (all p < 0.05). QSM values in the Nig were significantly correlated to UPDRS-III scores (r = 0.91,p < 0.001). CONCLUSION: In ePD, brain sodium accumulation was broad and dissociated from iron accumulation. As with iron accumulation, a sodium-related pathophysiological approach could lead to identifying potential new therapeutic agents and deserves further investigation.

Neurofilament Light Chain Levels Interact with Neurodegenerative Patterns and Motor Neuron Dysfunction in Amyotrophic Lateral Sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving rapid motor neuron degeneration leading to brain, primarily precentral, atrophy. Neurofilament light chains are a robust prognostic biomarker highly specific to ALS, yet associations between neurofilament light chains and MR imaging outcomes are not well-understood. We investigated the role of neurofilament light chains as mediators among neuroradiologic assessments, precentral neurodegeneration, and disability in ALS. MATERIALS AND METHODS: We retrospectively analyzed a prospective cohort of 29 patients with ALS (mean age, 56 [SD, 12] years; 18 men) and 36 controls (mean age, 49 [SD, 11] years; 18 men). Patients underwent 3T (n = 19) or 7T (n = 10) MR imaging, serum (n = 23) and CSF (n = 15) neurofilament light chains, and clinical (n = 29) and electrophysiologic (n = 27) assessments. The control group had equivalent 3T (n = 25) or 7T (n = 11) MR imaging. Two trained neuroradiologists performed blinded qualitative assessments of MR imaging anomalies (n = 29 patients, n = 36 controls). Associations between precentral cortical thickness and neurofilament light chains and clinical and electrophysiologic data were analyzed. RESULTS: We observed extensive cortical thinning in patients compared with controls. MR imaging analyses showed significant associations between precentral cortical thickness and bulbar or arm impairment following distributions corresponding to the motor homunculus. Finally, uncorrected results showed positive interactions among precentral cortical thickness, serum neurofilament light chains, and electrophysiologic outcomes. Qualitative MR imaging anomalies including global atrophy (P = .003) and FLAIR corticospinal tract hypersignal anomalies (P = .033), correlated positively with serum neurofilament light chains. CONCLUSIONS: Serum neurofilament light chains may be an important mediator between clinical symptoms and neuronal loss according to cortical thickness. Furthermore, MR imaging anomalies might have underestimated prognostic value because they seem to indicate higher serum neurofilament light chain levels.

Association between brain and upper cervical spinal cord atrophy assessed by MRI and disease aggressiveness in amyotrophic lateral sclerosis.

PURPOSE: To study the relative contributions of brain and upper cervical spinal cord compartmental atrophy to disease aggressiveness in amyotrophic lateral sclerosis (ALS). METHODS: Twenty-nine ALS patients and 24 age- and gender-matched healthy controls (HC) were recruited. Disease duration and the Revised-ALS Functional Rating Scale (ALSFRS-R) at baseline, 3- and 6-months follow-up were assessed. Patients were clinically differentiated into fast (n=13) and slow (n=16) progressors according to their ALSFRS-R progression rate. Brain grey (GM) and white matter, brainstem sub-structures volumes and spinal cord cross-sectional area (SC-CSA) at C1-C2 vertebral levels were measured from a 3D-T1-weighted MRI. RESULTS: Fast progressors showed significant GM, medulla oblongata and SC atrophy compared to HC (p<0.001, p=0.013 and p=0.008) and significant GM atrophy compared to slow progressors (p=0.008). GM volume correlated with the ALSFRS-R progression rate (Rho/p=-0.487/0.007), the ALSFRS-R at 3-months (Rho/p=0.622/0.002), and ALSFRS-R at 6-months (Rho/p=0.407/0.039). Medulla oblongata volume and SC-CSA correlated with the ALSFRS-R at 3-months (Rho/p=0.510/0.015 and Rho/p=0.479/0.024). MRI measures showed high performance to discriminate between fast and slow progressors. CONCLUSION: Our study suggests an association between compartmental atrophy and disease aggressiveness. This result is consistent with the combination of upper and lower motor neuron degeneration as the main driver of disease worsening and severity in ALS. Our study highlights the potential of brain and spinal cord atrophy measured by MRI as biomarker of disease aggressiveness signature.

Variability by region and method in human brain sodium concentrations estimated by 23Na magnetic resonance imaging: a meta-analysis.

Sodium imaging (23Na-MRI) is of interest in neurological conditions given potential sensitivity to the physiological and metabolic status of tissues. Benchmarks have so far been restricted to parenchyma or grey/white matter (GM/WM). We investigate (1) the availability of evidence, (2) regional pooled estimates and (3) variability attributable to region/methodology. MEDLINE literature search for tissue sodium concentration (TSC) measured in specified 'healthy' brain regions returned 127 reports, plus 278 retrieved from bibliographies. 28 studies met inclusion criteria, including 400 individuals. Reporting variability led to nested data structure, so we used multilevel meta-analysis and a random effects model to pool effect sizes. The pooled mean from 141 TSC estimates was 40.51 mM (95% CI 37.59-43.44; p < 0.001, I2Total=99.4%). Tissue as a moderator was significant (F214 = 65.34, p-val < .01). Six sub-regional pooled means with requisite statistical power were derived. We were unable to consider most methodological and demographic factors sought because of non-reporting, but each factor included beyond tissue improved model fit. Significant residual heterogeneity remained. The current estimates provide an empirical point of departure for better understanding in 23Na-MRI. Improving on current estimates supports: (1) larger, more representative data collection/sharing, including (2) regional data, and (3) agreement on full reporting standards.

Combining sodium MRI, proton MR spectroscopic imaging, and intracerebral EEG in epilepsy.

Whole brain ionic and metabolic imaging has potential as a powerful tool for the characterization of brain diseases. We combined sodium MRI (23 Na MRI) and 1 H-MR Spectroscopic Imaging (1 H-MRSI), assessing changes within epileptogenic networks in comparison with electrophysiologically normal networks as defined by stereotactic EEG (SEEG) recordings analysis. We applied a multi-echo density adapted 3D projection reconstruction pulse sequence at 7 T (23 Na-MRI) and a 3D echo-planar spectroscopic imaging sequence at 3 T (1 H-MRSI) in 19 patients suffering from drug-resistant focal epilepsy who underwent presurgical SEEG. We investigated 23 Na MRI parameters including total sodium concentration (TSC) and the sodium signal fraction associated with the short component of T2 * decay (f), alongside the level of metabolites N-acetyl aspartate (NAA), choline compounds (Cho), and total creatine (tCr). All measures were extracted from spherical regions of interest (ROIs) centered between two adjacent SEEG electrode contacts and z-scored against the same ROI in controls. Group comparison showed a significant increase in f only in the epileptogenic zone (EZ) compared to controls and compared to patients' propagation zone (PZ) and non-involved zone (NIZ). TSC was significantly increased in all patients' regions compared to controls. Conversely, NAA levels were significantly lower in patients compared to controls, and lower in the EZ compared to PZ and NIZ. Multiple regression analyzing the relationship between sodium and metabolites levels revealed significant relations in PZ and in NIZ but not in EZ. Our results are in agreement with the energetic failure hypothesis in epileptic regions associated with widespread tissue reorganization.

Grey-matter sodium concentration as an individual marker of multiple sclerosis severity.

OBJECTIVE: Quantification of brain injury in patients with variable disability despite similar disease duration may be relevant to identify the mechanisms underlying disability in multiple sclerosis (MS). We aimed to compare grey-matter sodium abnormalities (GMSAs), a parameter reflecting neuronal and astrocyte dysfunction, in MS patients with benign multiple sclerosis (BMS) and non-benign multiple sclerosis (NBMS). METHODS: We identified never-treated BMS patients in our local MS database of 1352 patients. A group with NBMS was identified with same disease duration. All participants underwent 23Na magnetic resonance imaging (MRI). The existence of GMSA was detected by statistical analysis. RESULTS: In total, 102 individuals were included (21 BMS, 25 NBMS and 56 controls). GMSA was detected in 10 BMS and 19 NBMS (11/16 relapsing-remitting multiple sclerosis (RRMS) and 8/9 secondary progressive multiple sclerosis (SPMS) patients) (p = 0.05). On logistic regression including the presence or absence of GMSA, thalamic volume, cortical grey-matter volume and T2-weighted lesion load, thalamic volume was independently associated with BMS status (odds ratio (OR) = 0.64 for each unit). Nonetheless, the absence of GMSA was independently associated when excluding patients with significant cognitive alteration (n = 7) from the BMS group (OR = 4.6). CONCLUSION: Detection of GMSA in individuals and thalamic volume are promising to differentiate BMS from NBMS as compared with cortical or whole grey-matter atrophy and T2-weighted lesions.

Increased Sodium Concentration in Substantia Nigra in Early Parkinson's Disease: A Preliminary Study With Ultra-High Field (7T) MRI.

Pathophysiology of idiopathic Parkinson's disease (iPD) is complex and still misunderstood. At a time when treatments with disease-modifying potential are being developed, identification of early markers of neurodegeneration is essential. Intracerebral sodium accumulation could be one of them. Indeed, it may be in relation to the mitochondrial dysfunction that early exists in iPD. For the first time, we used brain sodium (23Na) MRI to explore sodium concentration changes that have already been reported to be related to neurodegeneration in other diseases. We prospectively included 10 iPD patients (mean age 52.2 ± 5.9 years-old) with motor symptoms that started <36 months before inclusion and 12 healthy subjects (mean age 53 ± 6.4 years-old). Patients were scanned in OFF medication state by using proton (1H) and 23Na MRI at 7T. We then extracted quantitative Total Sodium Concentration (TSC) from five regions of interest known to be early impaired in iPD [substantia nigra (SN), putamen, caudate nucleus, pallidum, thalamus] and in one region supposed to be relatively spared in the first stages of the disease [cortical gray matter (neocortex)]. Potential atrophy in these structures was also investigated with 1H MRI. Relative to healthy subjects, iPD patients showed higher TSC in the SN (43.73 ± 4.64 vs. 37.72 ± 5.62, p = 0.006 after Bonferroni correction). A trend of increase in sodium concentrations was found within the pallidum (45.80 ± 4.19 vs. 41.07 ± 4.94, p = 0.017), putamen (48.65 ± 4.58 vs. 43.66 ± 5.04, p = 0.041) and the cortical gray matter (56.34 ± 3.92 vs. 50.81 ± 5.50, p = 0.021). No significant brain atrophy was found in patients compared to controls. Thus, alteration of sodium homeostasis in the SN in the absence of atrophy could be considered as a potential early marker of cellular dysfunction in iPD.

Cognitive performance shows domain specific associations with regional cortical thickness in multiple sclerosis.

Multiple Sclerosis (MS) patients often suffer from significant cognitive impairment. Earlier research has shown relationships between regional cortical atrophy and cognitive deterioration. However, due to a large number of neuropsychological assessments and a heterogenous pattern of cognitive deficits in MS patients, reported associations patterns are also heterogenous. Using an extensive neuropsychological battery of 23 different tasks, we explored domain (attention/information processing, memory, spatial processing, executive functioning) and task-specific associations with regional cortical thickness in a representative sample of MS patients (N = 97). Cortical regions associated with multiple cognitive tasks in the left hemisphere were predominantly located in the inferior insula (attention p < 0.001, memory p = 0.047, spatial processing p = 0.004, executive functioning p = 0.037), the gyrus frontalis superior (attention p = 0.015, memory p = 0.037, spatial processing p = 0.033, executive functioning p = 0.017) and temporal medial (attention p < 0.001, memory two clusters p = 0.016 and p < 0.001, executive functioning p = 0.016). In the right hemisphere, we detected the strongest association in the sulcus interparietalis with five cluster (attention SDMT p = 0.003 and TAP_DA p < 0.001; memory Rey recall p = 0.013 and VLMT verbal learning p = 0.016; spatial processing Rey copy p < 0.001). We replicated parts of our results in an independent sample of 30 mildly disabled MS patients. Moreover, comparisons to 29 healthy controls showed that the regional associations seemed to represent rather pathophysiological dependency than a physiological one. We believe that our results may prove useful in diagnosis and rehabilitation of cognitive impairments and may serve as guidance in future magnetic resonance imaging (MRI) studies.

Structural Connectivity Alterations in Amyotrophic Lateral Sclerosis: A Graph Theory Based Imaging Study.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder. Diffusion magnetic resonance imagining (MRI) studies have consistently showed widespread alterations in both motor and non-motor brain regions. However, connectomics and graph theory based approaches have shown inconsistent results. Hub-centered lesion patterns and their impact on local and large-scale brain networks remain to be established. The objective of this work is to characterize topological properties of structural brain connectivity in ALS using an array of local, global and hub-based network metrics. MATERIALS AND METHODS: Magnetic resonance imagining data were acquired from 25 patients with ALS and 26 age-matched healthy controls. Structural network graphs were constructed from diffusion tensor MRI. Network-based statistics (NBS) and graph theory metrics were used to compare structural networks without a priori regions of interest. RESULTS: Patients with ALS exhibited global network alterations with decreased global efficiency (Eglob) (p = 0.03) and a trend of reduced whole brain mean degree (p = 0.05) compared to controls. Six nodes showed significantly decreased mean degree in ALS: left postcentral gyrus, left interparietal and transverse parietal sulcus, left calcarine sulcus, left occipital temporal medial and lingual sulcus, right precentral gyrus and right frontal inferior sulcus (p < 0.01). Hub distribution was comparable between the two groups. There was no selective hub vulnerability or topological reorganization centered on these regions as the hub disruption index (κ) was not significant for the relevant metrics (degree, local efficiency and betweenness centrality). Using NBS, we identified an impaired motor subnetwork of 11 nodes and 10 edges centered on the precentral and the paracentral nodes (p < 0.01). Significant clinical correlations were identified between degree in the frontal area and the disease progression rate of ALS patients (p < 0.01). CONCLUSION: Our study provides evidence that alterations of structural connectivity in ALS are primarily driven by node degree and white matter tract degeneration within an extended network around the precentral and the paracentral areas without hub-centered reorganization.

Quantitative Brain Sodium MRI Depicts Corticospinal Impairment in Amyotrophic Lateral Sclerosis.

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that mainly affects the upper and lower motor neurons. Recent sodium (23Na) MRI studies have shown that abnormal sodium concentration is related to neuronal suffering in neurodegenerative conditions. Purpose To use 23Na MRI to investigate abnormal sodium concentrations and map their distribution in the brains of study participants with ALS as compared with healthy control subjects. Materials and Methods Twenty-seven participants with ALS (mean age, 54 years ± 10 [standard deviation], eight women) and 30 healthy control subjects (mean age, 50 years ± 10; 16 women) were prospectively recruited between September 2015 and October 2017 and were examined by using conventional proton MRI and sodium MRI at 3 T. Voxel-based statistical mapping was used to compare quantitative whole-brain total sodium concentration (TSC) maps in participants with ALS with those in control subjects and to localize regions of abnormal elevated TSC. Potential overlap of abnormal elevated TSC with regions of atrophy as detected with 1H MRI also was investigated. Results Voxel-based statistical mapping analyses revealed higher sodium concentration in motor regions (bilateral precentral gyri, corticospinal tracts, and the corpus callosum) of participants with ALS (two-sample t test, P < .005; age and sex as covariates). In these regions, mean TSC was higher in participants with ALS (mean, 45.6 mmol/L wet tissue ± 3.2) than in control subjects (mean, 41.8 mmol/L wet tissue ± 2.7; P < .001; Cohen d = 1.28). Brain regions showing higher TSC represented a volume of 15.4 cm3 that did not overlap with gray matter atrophy occupying a volume of 16.9 cm3. Elevated TSC correlated moderately with corticospinal conduction failure assessed with transcranial magnetic stimulation in the right upper limb (Spearman ρ = -0.57; 95% confidence interval: -0.78, -0.16; P = .005; n = 23). Conclusion Quantitative 23Na MRI is sensitive to alterations of brain sodium homeostasis within disease-relevant regions in patients with amyotrophic lateral sclerosis (ALS). This supports further investigation of abnormal sodium concentration as a potential marker of neurodegenerative processes in patients with ALS that could be used as a secondary endpoint in clinical trials. © RSNA, 2019 Online supplemental material is available for this article.

Metabolic counterparts of sodium accumulation in multiple sclerosis: A whole brain 23Na-MRI and fast 1H-MRSI study.

BACKGROUND: Increase of brain total sodium concentrations (TSC) is present in multiple sclerosis (MS), but its pathological involvement has not been assessed yet. OBJECTIVE: To determine in vivo the metabolic counterpart of brain sodium accumulation. MATERIALS/METHODS: Whole brain 23Na-MR imaging and 3D-1H-EPSI data were collected in 21 relapsing-remitting multiple sclerosis (RRMS) patients and 20 volunteers. Metabolites and sodium levels were extracted from several regions of grey matter (GM), normal-appearing white matter (NAWM) and white matter (WM) T2 lesions. Metabolic and ionic levels expressed as Z-scores have been averaged over the different compartments and used to explain sodium accumulations through stepwise regression models. RESULTS: MS patients showed significant 23Na accumulations with lower choline and glutamate-glutamine (Glx) levels in GM; 23Na accumulations with lower N-acetyl aspartate (NAA), Glx levels and higher Myo-Inositol (m-Ins) in NAWM; and higher 23Na, m-Ins levels with lower NAA in WM T2 lesions. Regression models showed associations of TSC increase with reduced NAA in GM, NAWM and T2 lesions, as well as higher total-creatine, and smaller decrease of m-Ins in T2 lesions. GM Glx levels were associated with clinical scores. CONCLUSION: Increase of TSC in RRMS is mainly related to neuronal mitochondrial dysfunction while dysfunction of neuro-glial interactions within GM is linked to clinical scores.

Dynamic 23Na MRI - A non-invasive window on neuroglial-vascular mechanisms underlying brain function.

A novel magnetic resonance imaging (MRI) acquisition and reconstruction method for obtaining a series of dynamic sodium 23Na-MRI acquisitions was designed to non-invasively assess the signal variations of brain sodium during a hand motor task in 14 healthy human volunteers on an ultra high field (7T) MR scanner. Regions undergoing activation and deactivation were identified with reference to conventional task-related BOLD functional MRI (fMRI). Activation observed in the left central regions, the supplementary motor areas and the left cerebellum induced an increase in the sodium signal observed at ultra short echo time and a decrease in the 23Na signal observed at long echo time. Based on a simple model of two distinct sodium pools (namely, restricted and mobile sodium), the ultra short echo time measures the totality of sodium whereas the long echo time is mainly sensitive to mobile sodium. This activation pattern is consistent with previously described processes related to an influx of Na+ into the intracellular compartments and a moderate increase in the cerebral blood volume (CBV). In contrast, deactivation observed in the right central regions ipsilateral to the movement, the precuneus and the left cerebellum induced a slight decrease in sodium signal at ultra short echo time and an increase of sodium signal at longer echo times. This inhibitory pattern is compatible with a slight decrease in CBV and an efflux of intracellular Na+ to the extracellular compartments that may reflect neural dendritic spine and astrocytic shrinkage, and an increase of sodium in the extracellular fraction. In conclusion, cerebral dynamic 23Na MRI experiments can provide access to the ionic transients following a functional task occurring within the neuro-glial-vascular ensemble. This has the potential to open up a novel non-invasive window on the mechanisms underlying brain function.

An MRI evaluation of grey matter damage in African Americans with MS.

OBJECTIVE: Multiple sclerosis (MS) is less prevalent in African Americans (AAs) than Caucasians (CAs) but in the former the disease course tends to be more severe. In order to clarify the MRI correlates of disease severity in AAs, we performed a multimodal brain MRI study to comprehensively assess the extent of grey matter (GM) damage and the degree of functional adaptation to structural damage in AAs with MS. METHODS: In this cross-sectional study, we characterized GM damage in terms of focal lesions and volume loss and functional adaptation during the execution of a simple motor task on a sample of 20 AAs and 20 CAs with MS and 20 healthy controls (CTRLs). RESULTS: In AAs, we observed a wider range of EDSS scores than CAs, with multisystem involvement being more likely in AAs (p < 0.01). While no significant differences were detected in lesion loads and global brain volumes, AAs showed regional atrophy in the posterior lobules of cerebellum, temporo-occipital and frontal regions in comparison with CAs (p < 0.01), with cerebellar atrophy being the best metric in differentiating AAs from CAs (p = 0.007, AUC = 0.96 and p = 0.005, AUC = 0.96, respectively for right and left cerebellar clusters). In AAs, the functional analysis of cortical activations showed an increase in task-related activation of areas involved in high level processing and a decreased activation in the medial prefrontal cortex compared to CAs. INTERPRETATION: In our study, the direct comparison of AAs and CAs points to cerebellar atrophy as the main difference between subgroups.

Distribution of brain sodium long and short relaxation times and concentrations: a multi-echo ultra-high field 23Na MRI study.

Sodium (23Na) MRI proffers the possibility of novel information for neurological research but also particular challenges. Uncertainty can arise in in vivo 23Na estimates from signal losses given the rapidity of T2* decay due to biexponential relaxation with both short (T2*short) and long (T2*long) components. We build on previous work by characterising the decay curve directly via multi-echo imaging at 7 T in 13 controls with the requisite number, distribution and range to assess the distribution of both in vivo T2*short and T2*long and in variation between grey and white matter, and subregions. By modelling the relationship between signal and reference concentration and applying it to in vivo 23Na-MRI signal, 23Na concentrations and apparent transverse relaxation times of different brain regions were measured for the first time. Relaxation components and concentrations differed substantially between regions of differing tissue composition, suggesting sensitivity of multi-echo 23Na-MRI toward features of tissue composition. As such, these results raise the prospect of multi-echo 23Na-MRI as an adjunct source of information on biochemical mechanisms in both physiological and pathophysiological states.

Brain sodium MRI in human epilepsy: Disturbances of ionic homeostasis reflect the organization of pathological regions.

In light of technical advancements supporting exploration of MR signals other than 1H, sodium (23Na) has received attention as a marker of ionic homeostasis and cell viability. Here, we evaluate for the first time the possibility that 23Na-MRI is sensitive to pathological processes occurring in human epilepsy. A normative sample of 27 controls was used to normalize regions of interest (ROIs) from 1424 unique brain locales on quantitative 23Na-MRI and high-resolution 1H-MPRAGE images. ROIs were based on intracerebral electrodes in ten patients undergoing epileptic network mapping. The stereo-EEG gold standard was used to define regions as belonging to primarily epileptogenic, secondarily irritative and to non-involved regions. Estimates of total sodium concentration (TSC) on 23Na-MRI and cerebrospinal fluid (CSF) on 1H imaging were extracted for each patient ROI, and normalized against the same region in controls. ROIs with disproportionate CSF contributions (ZCSF≥1.96) were excluded. TSC levels were found to be elevated in patients relative to controls except in one patient, who suffered non-convulsive seizures during the scan, in whom we found reduced TSC levels. In the remaining patients, an ANOVA (F1100= 12.37, p<0.0001) revealed a highly significant effect of clinically-defined zones (F1100= 11.13, p<0.0001), with higher normalized TSC in the epileptogenic zone relative to both secondarily irritative (F1100= 11, p=0.0009) and non-involved regions (F1100= 17.8, p<0.0001). We provide the first non-invasive, in vivo evidence of a chronic TSC elevation alongside ZCSF levels within the normative range, associated with the epileptogenic region even during the interictal period in human epilepsy, and the possibility of reduced TSC levels due to seizure. In line with modified homeostatic mechanisms in epilepsy - including altered mechanisms underlying ionic gating, clearance and exchange - we provide the first indication of 23Na-MRI as an assay of altered sodium concentrations occurring in epilepsy associated with the organization of clinically relevant divisions of pathological cortex.

Increased total sodium concentration in gray matter better explains cognition than atrophy in MS.

OBJECTIVE: To investigate whether brain total sodium accumulation assessed by 23Na MRI is associated with cognitive deficit in relapsing-remitting multiple sclerosis (RRMS). METHODS: Eighty-nine participants were enrolled in the study (58 patients with RRMS with a disease duration ≤10 years and 31 matched healthy controls). Patients were classified as cognitively impaired if they failed at least 2 tasks on the Brief Repeatable Battery. MRI was performed at 3T using 23Na MRI to obtain total sodium concentration (TSC) in the different brain compartments (lesions, normal-appearing white matter [NAWM], gray matter [GM]) and 1H- magnetization-prepared rapid gradient echo to assess GM atrophy (GM fraction). RESULTS: The mean disease duration was 3.1 years and the median Expanded Disability Status Scale score was 1 (range 0-4.5). Thirty-seven patients were classified as cognitively preserved and 21 as cognitively impaired. TSC was increased in GM and NAWM in cognitively impaired patients compared to cognitively preserved patients and healthy controls. Voxel-wise analysis demonstrated that sodium accumulation was mainly located in the neocortex in cognitively impaired patients. Regression analysis evidenced than the 2 best independent predictors of cognitive impairment were GM TSC and age. Receiver operating characteristic analyses demonstrated that sensitivity and specificity of the GM TSC to classify patients according to their cognitive status were 76% and 71%, respectively. CONCLUSIONS: This study provides 2 main findings. (1) In RRMS, total sodium accumulation in the GM is better associated with cognitive impairment than GM atrophy; and (2) total sodium accumulation in patients with cognitive impairment is mainly located in the neocortex.

Hypoperfusion of the thalamus is associated with disability in relapsing remitting multiple sclerosis.

BACKGROUND: While gray matter (GM) perfusion abnormalities have been evidenced in multiple sclerosis (MS) patients, the relationships with disability still remain unclear. Considering that atrophy is known to impact on perfusion, we aimed to assess perfusion abnormalities in GM of MS patients, outside atrophic regions and investigate relationships with disability. METHODS: Brain perfusion of 23 relapsing remitting MS patients and 16 matched healthy subjects were assessed at 3T using the pseudo-continuous arterial spin labeling magnetic resonance imaging technique. In order to locate potential GM perfusion abnormalities in regions spared by atrophy, we combined voxelwise comparisons of GM cerebral blood flow (CBF) maps (cortex and deep GM) (P<0.005, FWE-corrected) and voxel-based-morphometry analysis (P<0.005, FDR-corrected) to exclude atrophic regions. Disability was assessed using the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite score (MSFC). RESULTS: In patients, significant GM hypoperfusion outside atrophic regions was depicted only in bilateral thalami. No other cluster was found to be hypoperfused compared to controls. Perfusion of thalami was correlated to MSFC (P=0.011, rho=0.523). A trend of correlation was found between perfusion of thalami and EDSS (P=0.061, rho=-0.396). CONCLUSION: In relapsing remitting MS, perfusion abnormalities in thalamic regions contribute to disability. These findings suggest that functional impairments of thalami, representing a major brain hub, may disturb various cerebral functions even before structural damage.

Improvement of spasticity following intermittent theta burst stimulation in multiple sclerosis is associated with modulation of resting-state functional connectivity of the primary motor cortices.

BACKGROUND: Intermittent theta burst stimulation (iTBS) of the primary motor cortex improves transiently lower limbs spasticity in multiple sclerosis (MS). However, the cerebral mechanisms underlying this effect have never been investigated. OBJECTIVE: To assess whether modulation of spasticity induced by iTBS is underlined by functional reorganization of the primary motor cortices. METHODS: A total of 17 patients with MS suffering from lower limbs spasticity were randomized to receive real iTBS or sham iTBS during the first half of a 5-week indoor rehabilitation programme. Spasticity was assessed using the Modified Ashworth Scale and the Visual Analogue Scale at baseline, after the stimulation session and at the end of the rehabilitation programme. Resting-state functional magnetic resonance imaging (fMRI) was performed at the three time points, and brain functional networks topology was analysed using graph-theoretical approach. RESULTS: At the end of stimulation, improvement of spasticity was greater in real iTBS group than in sham iTBS group ( p = 0.026). iTBS had a significant effect on the balance of the connectivity degree between the stimulated and the homologous primary motor cortex ( p = 0.005). Changes in inter-hemispheric balance were correlated with improvement of spasticity (rho = 0.56, p = 0.015). CONCLUSION: This longitudinal resting-state fMRI study evidences that functional reorganization of the primary motor cortices may underlie the effect of iTBS on spasticity in MS.