Longitudinal motor system changes from acute to chronic spinal cord injury.

BACKGROUND AND PURPOSE: In acute spinal cord injury (SCI), magnetic resonance imaging (MRI) reveals tissue bridges and neurodegeneration for 2 years. This 5-year study aims to track initial lesion changes, subsequent neurodegeneration, and their impact on recovery. METHODS: This prospective longitudinal study enrolled acute SCI patients and healthy controls who were assessed clinically-and by MRI-regularly from 3 days postinjury up to 60 months. We employed histologically cross-validated quantitative MRI sequences sensitive to volume, myelin, and iron changes, thereby reflecting indirectly processes of neurodegeneration and neuroinflammation. General linear models tracked lesion and remote changes in volume, myelin- and iron-sensitive magnetic resonance indices over 5 years. Associations between lesion, degeneration, and recovery (using the Spinal Cord Independence Measure [SCIM] questionnaire and the International Standards for Neurological Classification of Spinal Cord Injury total motor score) were assessed. RESULTS: Patients' motor scores improved by an average of 12.86 (95% confidence interval [CI] = 6.70-19.00) points, and SCIM by 26.08 (95% CI = 17.00-35.20) points. Within 3-28 days post-SCI, lesion size decreased by more than two-thirds (3 days: 302.52 ± 185.80 mm2 , 28 days: 76.77 ± 88.62 mm2 ), revealing tissue bridges. Cervical cord and corticospinal tract volumes transiently increased in SCI patients by 5% and 3%, respectively, accompanied by cervical myelin decreases and iron increases. Over time, progressive atrophy was observed in both regions, which was linked to early lesion dynamics. Tissue bridges, reduced swelling, and myelin content decreases were predictive of long-term motor score recovery and improved SCIM score. CONCLUSIONS: Studying acute changes and their impact on longer follow-up provides insights into SCI trajectory, highlighting the importance of acute intervention while indicating the potential to influence outcomes in the later stages.

Coherent, time-shifted patterns of microstructural plasticity during motor-skill learning.

Motor skill learning relies on neural plasticity in the motor and limbic systems. However, the spatial and temporal characteristics of these changes-and their microstructural underpinnings-remain unclear. Eighteen healthy males received 1 h of training in a computer-based motion game, 4 times a week, for 4 consecutive weeks, while 14 untrained participants underwent scanning only. Performance improvements were observed in all trained participants. Serial myelin- and iron-sensitive multiparametric mapping at 3T during this period of intensive motor skill acquisition revealed temporally and spatially distributed, performance-related microstructural changes in the grey and white matter across a corticospinal-cerebellar-hippocampal circuit. Analysis of the trajectory of these transient changes suggested time-shifted cascades of plasticity from the dominant sensorimotor system to the contralateral hippocampus. In the cranial corticospinal tracts, changes in myelin-sensitive metrics during training in the posterior limb of the internal capsule were of greater magnitude in those who trained their upper limbs vs. lower limb trainees. Motor skill learning is associated with waves of grey and white matter plasticity, across a broad sensorimotor network.

Do the current MS clinical course descriptors need to change and if so how? A survey of the MS community.

BACKGROUND AND OBJECTIVES: The current clinical course descriptors of multiple sclerosis (MS) include a combination of clinical and magnetic resonance imaging (MRI) features. Recently there has been a growing call to base these descriptors more firmly on biological mechanisms. We investigated the implications of proposing a new mechanism-driven framework for describing MS. METHODS: In a web-based survey, multiple stakeholders rated the need to change current MS clinical course descriptors, the definitions of disease course and their value in clinical practice and related topics. RESULTS: We received 502 responses across 49 countries. In all, 77% of the survey respondents supported changing the current MS clinical course descriptors. They preferred a framework that informs treatment decisions, aids the design and conduct of clinical trials, allows patients to understand their disease, and links disease mechanisms and clinical expression of disease. Clinical validation before dissemination and ease of communication to patients were rated as the most important aspects to consider when developing any new framework for describing MS. CONCLUSION: A majority of MS stakeholders agreed that the current MS clinical course descriptors need to change. Any change process will need to engage a wide range of affected stakeholders and be guided by foundational principles.

Charting a global research strategy for progressive MS-An international progressive MS Alliance proposal.

BACKGROUND: Progressive forms of multiple sclerosis (MS) affect more than 1 million individuals globally. Recent approvals of ocrelizumab for primary progressive MS and siponimod for active secondary progressive MS have opened the therapeutic door, though results from early trials of neuroprotective agents have been mixed. The recent introduction of the term 'active' secondary progressive MS into the therapeutic lexicon has introduced potential confusion to disease description and thereby clinical management. OBJECTIVE: This paper reviews recent progress, highlights continued knowledge and proposes, on behalf of the International Progressive MS Alliance, a global research strategy for progressive MS. METHODS: Literature searches of PubMed between 2015 and May, 2021 were conducted using the search terms "progressive multiple sclerosis", "primary progressive multiple sclerosis", "secondary progressive MS". Proposed strategies were developed through a series of in-person and virtual meetings of the International Progressive MS Alliance Scientific Steering Committee. RESULTS: Sustaining and accelerating progress will require greater understanding of underlying mechanisms, identification of potential therapeutic targets, biomarker discovery and validation, and conduct of clinical trials with improved trial design. Encouraging developments in symptomatic and rehabilitative interventions are starting to address ongoing challenges experienced by people with progressive MS. CONCLUSION: We need to manage these challenges and realise the opportunities in the context of a global research strategy, which will improve quality of life for people with progressive MS.

Cortical involvement determines impairment 30 years after a clinically isolated syndrome.

Many studies report an overlap of MRI and clinical findings between patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), which in part is reflective of inclusion of subjects with variable disease duration and short periods of follow-up. To overcome these limitations, we examined the differences between RRMS and SPMS and the relationship between MRI measures and clinical outcomes 30 years after first presentation with clinically isolated syndrome suggestive of multiple sclerosis. Sixty-three patients were studied 30 years after their initial presentation with a clinically isolated syndrome; only 14% received a disease modifying treatment at any time point. Twenty-seven patients developed RRMS, 15 SPMS and 21 experienced no further neurological events; these groups were comparable in terms of age and disease duration. Clinical assessment included the Expanded Disability Status Scale, 9-Hole Peg Test and Timed 25-Foot Walk and the Brief International Cognitive Assessment For Multiple Sclerosis. All subjects underwent a comprehensive MRI protocol at 3 T measuring brain white and grey matter (lesions, volumes and magnetization transfer ratio) and cervical cord involvement. Linear regression models were used to estimate age- and gender-adjusted group differences between clinical phenotypes after 30 years, and stepwise selection to determine associations between a large sets of MRI predictor variables and physical and cognitive outcome measures. At the 30-year follow-up, the greatest differences in MRI measures between SPMS and RRMS were the number of cortical lesions, which were higher in SPMS (the presence of cortical lesions had 100% sensitivity and 88% specificity), and grey matter volume, which was lower in SPMS. Across all subjects, cortical lesions, grey matter volume and cervical cord volume explained 60% of the variance of the Expanded Disability Status Scale; cortical lesions alone explained 43%. Grey matter volume, cortical lesions and gender explained 43% of the variance of Timed 25-Foot Walk. Reduced cortical magnetization transfer ratios emerged as the only significant explanatory variable for the symbol digit modality test and explained 52% of its variance. Cortical involvement, both in terms of lesions and atrophy, appears to be the main correlate of progressive disease and disability in a cohort of individuals with very long follow-up and homogeneous disease duration, indicating that this should be the target of therapeutic interventions.

Applying causal models to explore the mechanism of action of simvastatin in progressive multiple sclerosis.

Understanding the mode of action of drugs is a challenge with conventional methods in clinical trials. Here, we aimed to explore whether simvastatin effects on brain atrophy and disability in secondary progressive multiple sclerosis (SPMS) are mediated by reducing cholesterol or are independent of cholesterol. We applied structural equation models to the MS-STAT trial in which 140 patients with SPMS were randomized to receive placebo or simvastatin. At baseline, after 1 and 2 years, patients underwent brain magnetic resonance imaging; their cognitive and physical disability were assessed on the block design test and Expanded Disability Status Scale (EDSS), and serum total cholesterol levels were measured. We calculated the percentage brain volume change (brain atrophy). We compared two models to select the most likely one: a cholesterol-dependent model with a cholesterol-independent model. The cholesterol-independent model was the most likely option. When we deconstructed the total treatment effect into indirect effects, which were mediated by brain atrophy, and direct effects, simvastatin had a direct effect (independent of serum cholesterol) on both the EDSS, which explained 69% of the overall treatment effect on EDSS, and brain atrophy, which, in turn, was responsible for 31% of the total treatment effect on EDSS [ß = -0.037; 95% credible interval (CI) = -0.075, -0.010]. This suggests that simvastatin's beneficial effects in MS are independent of its effect on lowering peripheral cholesterol levels, implicating a role for upstream intermediate metabolites of the cholesterol synthesis pathway. Importantly, it demonstrates that computational models can elucidate the causal architecture underlying treatment effects in clinical trials of progressive MS.

A 30-Year Clinical and Magnetic Resonance Imaging Observational Study of Multiple Sclerosis and Clinically Isolated Syndromes.

OBJECTIVE: Clinical outcomes in multiple sclerosis (MS) are highly variable. We aim to determine the long-term clinical outcomes in MS, and to identify early prognostic features of these outcomes. METHODS: One hundred thirty-two people presenting with a clinically isolated syndrome were prospectively recruited between 1984 and 1987, and followed up clinically and radiologically 1, 5, 10, 14, 20, and now 30 years later. All available notes and magnetic resonance imaging scans were reviewed, and MS was defined according to the 2010 McDonald criteria. RESULTS: Clinical outcome data were obtained in 120 participants at 30 years. Eighty were known to have developed MS by 30 years. Expanded Disability Status Scale (EDSS) scores were available in 107 participants, of whom 77 had MS; 32 (42%) remained fully ambulatory (EDSS scores ≤3.5), all of whom had relapsing-remitting MS (RRMS), 3 (4%) had RRMS and EDSS scores >3.5, 26 (34%) had secondary progressive MS (all had EDSS scores >3.5), and MS contributed to death in 16 (20%). Of those with MS, 11 received disease-modifying therapy. The strongest early predictors (within 5 years of presentation) of secondary progressive MS at 30 years were presence of baseline infratentorial lesions and deep white matter lesions at 1 year. INTERPRETATION: Thirty years after onset, in a largely untreated cohort, there was a divergence of MS outcomes; some people accrued substantial disability early on, whereas others ran a more favorable long-term course. These outcomes could, in part, be predicted by radiological findings from within 1 year of first presentation. ANN NEUROL 2020;87:63-74.

Longitudinal changes of spinal cord grey and white matter following spinal cord injury.

OBJECTIVES: Traumatic and non-traumatic spinal cord injury produce neurodegeneration across the entire neuraxis. However, the spatiotemporal dynamics of spinal cord grey and white matter neurodegeneration above and below the injury is understudied. METHODS: We acquired longitudinal data from 13 traumatic and 3 non-traumatic spinal cord injury patients (8-8 cervical and thoracic cord injuries) within 1.5 years after injury and 10 healthy controls over the same period. The protocol encompassed structural and diffusion-weighted MRI rostral (C2/C3) and caudal (lumbar enlargement) to the injury level to track tissue-specific neurodegeneration. Regression models assessed group differences in the temporal evolution of tissue-specific changes and associations with clinical outcomes. RESULTS: At 2 months post-injury, white matter area was decreased by 8.5% and grey matter by 15.9% in the lumbar enlargement, while at C2/C3 only white matter was decreased (-9.7%). Patients had decreased cervical fractional anisotropy (FA: -11.3%) and increased radial diffusivity (+20.5%) in the dorsal column, while FA was lower in the lateral (-10.3%) and ventral columns (-9.7%) of the lumbar enlargement. White matter decreased by 0.34% and 0.35% per month at C2/C3 and lumbar enlargement, respectively, and grey matter decreased at C2/C3 by 0.70% per month. CONCLUSIONS: This study describes the spatiotemporal dynamics of tissue-specific spinal cord neurodegeneration above and below a spinal cord injury. While above the injury, grey matter atrophy lagged initially behind white matter neurodegeneration, in the lumbar enlargement these processes progressed in parallel. Tracking trajectories of tissue-specific neurodegeneration provides valuable assessment tools for monitoring recovery and treatment effects.

Primary progressive multiple sclerosis presenting under the age of 18 years: Fact or fiction?

Previous cohort studies on paediatric multiple sclerosis (MS) have reported very low frequencies for a primary progressive MS (PPMS) course ranging from 0% to 7%. We identified six patients presenting prior to the age of 18 years and fulfilling the 2017 McDonald Criteria for PPMS. Presentation with progressive neurological symptoms and signs in young people should prompt evaluation for genetic causes such as leukodystrophies, hereditary spastic paraparesis and mitochondrial diseases given the rarity of primary progressive course in paediatric MS. In the absence of an alternative diagnosis, with new therapeutic options becoming available for PPMS, this diagnosis should then be considered.

Ongoing microstructural changes in the cervical cord underpin disability progression in early primary progressive multiple sclerosis.

BACKGROUND: Pathology in the spinal cord of patients with primary progressive multiple sclerosis (PPMS) contributes to disability progression. We previously reported abnormal Q-space imaging (QSI)-derived indices in the spinal cord at baseline in patients with early PPMS, suggesting early neurodegeneration. OBJECTIVE: The aim was to investigate whether changes in spinal cord QSI over 3 years in the same cohort are associated with disability progression and if baseline QSI metrics predict clinical outcome. METHODS: Twenty-three PPMS patients and 23 healthy controls recruited at baseline were invited for follow-up cervical cord 3T magnetic resonance imaging (MRI) and clinical assessment after 1 year and 3 years. Cord cross-sectional area (CSA) and QSI measures were obtained, together with standard brain MRI measures. Mixed-effect models assessed MRI changes over time and their association with clinical changes. Linear regression identified baseline MRI indices associated with disability at 3 years. RESULTS: Over time, patients deteriorated clinically and showed an increase in cord QSI indices of perpendicular diffusivity that was associated with disability worsening, independently of the decrease in CSA. Higher perpendicular diffusivity and lower CSA at baseline predicted worse disability at 3 years. CONCLUSION: Increasing spinal cord perpendicular diffusivity may indicate ongoing neurodegeneration, which underpins disability progression in PPMS, independently of the development of spinal cord atrophy.

H2 Production in the 10B(n,α)7Li Reaction in Water.

We demonstrate a method for measuring the H2 produced in water from the 10B(n,α)7Li fission reaction. Low energy neutrons from the NIST Center for Neutron Research interact with borate-containing water in a temperature-controlled high pressure cell made from titanium. After exposure for one to several hours, the water is extracted and sparged with argon. H2 entrained in the sparging gas is sampled with a small mass spectrometer. To determine the neutron exposure, a small amount of sodium is included in the borate solution. The water is collected and 24Na activation is measured in a counting apparatus on the following day. The G-value for H2 at room temperature is found to be (1.18 ± 0.10) molecules H2/100eV, in good agreement with previous estimates and recent modeling calculations.

Improved performance of the 2017 McDonald criteria for diagnosis of multiple sclerosis in children in a real-life cohort.

OBJECTIVE: To compare the performance of the 2017 McDonald criteria with that of the 2010 criteria for the diagnosis of multiple sclerosis (MS) in children in the clinical setting. METHODS: In this retrospective, multi-centre study, we identified children who presented with symptoms suggestive of a clinically isolated syndrome (CIS) and were followed up for at least 2 years or until their second attack. RESULTS: Of 156 children with CIS followed up for a median of 4.17 years, 94 (60.3%) were diagnosed with MS. In all, 83 (88.3%) of these fulfilled the 2010 dissemination in space (DIS) criteria at onset. Three additional children fulfilled the 2017 DIS criteria because of the inclusion of symptomatic lesions. Of the 59 children with MS who underwent post-gadolinium magnetic resonance imaging (MRI), 44 (74.6%) fulfilled the 2010 dissemination in time (DIT) criteria at baseline. When the presence of oligoclonal bands (OCBs) was used to substitute DIT, an additional 35 children (79/94, 84.0%) were diagnosed with MS according to the 2017 criteria. The 2017 criteria had higher accuracy (87.2% vs 66.7%), higher sensitivity (84.0% vs 46.8%), but reduced specificity (91.9% vs 96.8%) when compared to the 2010 criteria. CONCLUSION: The improved performance of the 2017 criteria when compared to the 2010 criteria was predominantly due to the inclusion of intrathecal OCBs.

Clinical relevance of cortical network dynamics in early primary progressive MS.

BACKGROUND: Structural cortical networks (SCNs) reflect the covariance between the cortical thickness of different brain regions, which may share common functions and a common developmental evolution. SCNs appear abnormal in neurodegenerative conditions such as Alzheimer's and Parkinson's diseases, but have never been assessed in primary progressive multiple sclerosis (PPMS). OBJECTIVE: The aim of this study was to test whether SCNs are abnormal in early PPMS and change over 5 years, and correlate with disability worsening. METHODS: A total of 29 PPMS patients and 13 healthy controls underwent clinical and brain magnetic resonance imaging (MRI) assessments for 5 years. Baseline and 5-year follow-up cortical thickness values were obtained and used to build correlation matrices, considered as weighted graphs to obtain network metrics. Bootstrap-based statistics assessed SCN differences between patients and controls and between patients with fast and slow progression. RESULTS: At baseline, patients showed features of lower connectivity (p = 0.02) and efficiency (p < 0.001) than controls. Over 5 years, patients, especially those with fastest clinical progression, showed significant changes suggesting an increase in network connectivity (p < 0.001) and efficiency (p < 0.02), not observed in controls. CONCLUSION: SCNs are abnormal in early PPMS. Longitudinal SCN changes demonstrated a switch from low- to high-efficiency networks especially among fast progressors, indicating their clinical relevance.

Reduced neurite density in the brain and cervical spinal cord in relapsing-remitting multiple sclerosis: A NODDI study.

BACKGROUND: Multiple sclerosis (MS) affects both brain and spinal cord. However, studies of the neuraxis with advanced magnetic resonance imaging (MRI) are rare because of long acquisition times. We investigated neurodegeneration in MS brain and cervical spinal cord using neurite orientation dispersion and density imaging (NODDI). OBJECTIVE: The aim of this study was to investigate possible alterations, and their clinical relevance, in neurite morphology along the brain and cervical spinal cord of relapsing-remitting MS (RRMS) patients. METHODS: In total, 28 RRMS patients and 20 healthy controls (HCs) underwent brain and spinal cord NODDI at 3T. Physical and cognitive disability was assessed. Individual maps of orientation dispersion index (ODI) and neurite density index (NDI) in brain and spinal cord were obtained. We examined differences in NODDI measures between groups and the relationships between NODDI metrics and clinical scores using linear regression models adjusted for age, sex and brain tissue volumes or cord cross-sectional area (CSA). RESULTS: Patients showed lower NDI in the brain normal-appearing white matter (WM) and spinal cord WM than HCs. In patients, a lower NDI in the spinal cord WM was associated with higher disability. CONCLUSION: Reduced neurite density occurs in the neuraxis but, especially when affecting the spinal cord, it may represent a mechanism of disability in MS.

Extreme ultraviolet photon conversion efficiency of tetraphenyl butadiene.

Extreme ultraviolet (EUV) radiation can be converted to visible light using tetraphenyl butadiene (TPB) as a phosphor. 1 µm films of TPB were prepared using thermal vapor deposition of the pure material and by spin coating suspensions of TPB in high-molecular-weight polystyrene/toluene solutions. Calibrated sources and detectors were used to determine the effective photon conversion efficiency of the films for incident EUV radiation in the wavelength range of $125\;{\rm nm}\le\lambda\le 200\;{\rm nm}$125nm≤λ≤200nm. After exposure to atmosphere, the efficiency of the vapor-deposited films decreased significantly, while the efficiency of the spin-coated films remained unchanged. The production of TPB films by spin coating offers the advantages of simplicity and long-term stability.

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.

Multiple sclerosis.

Multiple sclerosis continues to be a challenging and disabling condition but there is now greater understanding of the underlying genetic and environmental factors that drive the condition, including low vitamin D levels, cigarette smoking, and obesity. Early and accurate diagnosis is crucial and is supported by diagnostic criteria, incorporating imaging and spinal fluid abnormalities for those presenting with a clinically isolated syndrome. Importantly, there is an extensive therapeutic armamentarium, both oral and by infusion, for those with the relapsing remitting form of the disease. Careful consideration is required when choosing the correct treatment, balancing the side-effect profile with efficacy and escalating as clinically appropriate. This move towards more personalised medicine is supported by a clinical guideline published in 2018. Finally, a comprehensive management programme is strongly recommended for all patients with multiple sclerosis, enhancing health-related quality of life through advocating wellness, addressing aggravating factors, and managing comorbidities. The greatest remaining challenge for multiple sclerosis is the development of treatments incorporating neuroprotection and remyelination to treat and ultimately prevent the disabling, progressive forms of the condition.

Deep gray matter volume loss drives disability worsening in multiple sclerosis.

OBJECTIVE: Gray matter (GM) atrophy occurs in all multiple sclerosis (MS) phenotypes. We investigated whether there is a spatiotemporal pattern of GM atrophy that is associated with faster disability accumulation in MS. METHODS: We analyzed 3,604 brain high-resolution T1-weighted magnetic resonance imaging scans from 1,417 participants: 1,214 MS patients (253 clinically isolated syndrome [CIS], 708 relapsing-remitting [RRMS], 128 secondary-progressive [SPMS], and 125 primary-progressive [PPMS]), over an average follow-up of 2.41 years (standard deviation [SD] = 1.97), and 203 healthy controls (HCs; average follow-up = 1.83 year; SD = 1.77), attending seven European centers. Disability was assessed with the Expanded Disability Status Scale (EDSS). We obtained volumes of the deep GM (DGM), temporal, frontal, parietal, occipital and cerebellar GM, brainstem, and cerebral white matter. Hierarchical mixed models assessed annual percentage rate of regional tissue loss and identified regional volumes associated with time-to-EDSS progression. RESULTS: SPMS showed the lowest baseline volumes of cortical GM and DGM. Of all baseline regional volumes, only that of the DGM predicted time-to-EDSS progression (hazard ratio = 0.73; 95% confidence interval, 0.65, 0.82; p < 0.001): for every standard deviation decrease in baseline DGM volume, the risk of presenting a shorter time to EDSS worsening during follow-up increased by 27%. Of all longitudinal measures, DGM showed the fastest annual rate of atrophy, which was faster in SPMS (-1.45%), PPMS (-1.66%), and RRMS (-1.34%) than CIS (-0.88%) and HCs (-0.94%; p < 0.01). The rate of temporal GM atrophy in SPMS (-1.21%) was significantly faster than RRMS (-0.76%), CIS (-0.75%), and HCs (-0.51%). Similarly, the rate of parietal GM atrophy in SPMS (-1.24-%) was faster than CIS (-0.63%) and HCs (-0.23%; all p values <0.05). Only the atrophy rate in DGM in patients was significantly associated with disability accumulation (beta = 0.04; p < 0.001). INTERPRETATION: This large, multicenter and longitudinal study shows that DGM volume loss drives disability accumulation in MS, and that temporal cortical GM shows accelerated atrophy in SPMS than RRMS. The difference in regional GM atrophy development between phenotypes needs to be taken into account when evaluating treatment effect of therapeutic interventions. Ann Neurol 2018;83:210-222.

Structural network disruption markers explain disability in multiple sclerosis.

OBJECTIVE: To evaluate whether structural brain network metrics correlate better with clinical impairment and information processing speed in multiple sclerosis (MS) beyond atrophy measures and white matter lesions. METHODS: This cross-sectional study included 51 healthy controls and 122 patients comprising 58 relapsing-remitting, 28 primary progressive and 36 secondary progressive. Structural brain networks were reconstructed from diffusion-weighted MRIs and standard metrics reflecting network density, efficiency and clustering coefficient were derived and compared between subjects' groups. Stepwise linear regression analyses were used to investigate the contribution of network measures that explain clinical disability (Expanded Disability Status Scale (EDSS)) and information processing speed (Symbol Digit Modalities Test (SDMT)) compared with conventional MRI metrics alone and to determine the best statistical model that explains better EDSS and SDMT. RESULTS: Compared with controls, network efficiency and clustering coefficient were reduced in MS while these measures were also reduced in secondary progressive relative to relapsing-remitting patients. Structural network metrics increase the variance explained by the statistical models for clinical and information processing dysfunction. The best model for EDSS showed that reduced network density and global efficiency and increased age were associated with increased clinical disability. The best model for SDMT showed that lower deep grey matter volume, reduced efficiency and male gender were associated with worse information processing speed. CONCLUSIONS: Structural topological changes exist between subjects' groups. Network density and global efficiency explained disability above non-network measures, highlighting that network metrics can provide clinically relevant information about MS pathology.