Networks of microstructural damage predict disability in multiple sclerosis.

BACKGROUND: Network-based measures are emerging MRI markers in multiple sclerosis (MS). We aimed to identify networks of white (WM) and grey matter (GM) damage that predict disability progression and cognitive worsening using data-driven methods. METHODS: We analysed data from 1836 participants with different MS phenotypes (843 in a discovery cohort and 842 in a replication cohort). We calculated standardised T1-weighted/T2-weighted (sT1w/T2w) ratio maps in brain GM and WM, and applied spatial independent component analysis to identify networks of covarying microstructural damage. Clinical outcomes were Expanded Disability Status Scale worsening confirmed at 24 weeks (24-week confirmed disability progression (CDP)) and time to cognitive worsening assessed by the Symbol Digit Modalities Test (SDMT). We used Cox proportional hazard models to calculate predictive value of network measures. RESULTS: We identified 8 WM and 7 GM sT1w/T2w networks (of regional covariation in sT1w/T2w measures) in both cohorts. Network loading represents the degree of covariation in regional T1/T2 ratio within a given network. The loading factor in the anterior corona radiata and temporo-parieto-frontal components were associated with higher risks of developing CDP both in the discovery (HR=0.85, p<0.05 and HR=0.83, p<0.05, respectively) and replication cohorts (HR=0.84, p<0.05 and HR=0.80, p<0.005, respectively). The decreasing or increasing loading factor in the arcuate fasciculus, corpus callosum, deep GM, cortico-cerebellar patterns and lesion load were associated with a higher risk of developing SDMT worsening both in the discovery (HR=0.82, p<0.01; HR=0.87, p<0.05; HR=0.75, p<0.001; HR=0.86, p<0.05 and HR=1.27, p<0.0001) and replication cohorts (HR=0.82, p<0.005; HR=0.73, p<0.0001; HR=0.80, p<0.005; HR=0.85, p<0.01 and HR=1.26, p<0.0001). CONCLUSIONS: GM and WM networks of microstructural changes predict disability and cognitive worsening in MS. Our approach may be used to identify patients at greater risk of disability worsening and stratify cohorts in treatment trials.

Magnetization transfer saturation reveals subclinical optic nerve injury in pediatric-onset multiple sclerosis.

BACKGROUND: The presence of subclinical optic nerve (ON) injury in youth living with pediatric-onset MS has not been fully elucidated. Magnetization transfer saturation (MTsat) is an advanced magnetic resonance imaging (MRI) parameter sensitive to myelin density and microstructural integrity, which can be applied to the study of the ON. OBJECTIVE: The objective of this study was to investigate the presence of subclinical ON abnormalities in pediatric-onset MS by means of magnetization transfer saturation and evaluate their association with other structural and functional parameters of visual pathway integrity. METHODS: Eleven youth living with pediatric-onset MS (ylPOMS) and no previous history of optic neuritis and 18 controls underwent standardized brain MRI, optical coherence tomography (OCT), Magnetoencephalography (MEG)-Visual Evoked Potentials (VEPs), and visual battery. Data were analyzed with mixed effect models. RESULTS: While ON volume, OCT parameters, occipital MEG-VEPs outcomes, and visual function did not differ significantly between ylPOMS and controls, ylPOMS had lower MTsat in the supratentorial normal appearing white matter (-0.26 nU, p = 0.0023), and in both in the ON (-0.62 nU, p < 0.001) and in the normal appearing white matter of the optic radiation (-0.56 nU, p = 0.00071), with these being positively correlated (+0.57 nU, p = 0.00037). CONCLUSIONS: Subclinical microstructural injury affects the ON of ylPOMS. This may appear as MTsat changes before being detectable by other currently available testing.

Diffusely abnormal white matter converts to T2 lesion volume in the absence of MRI-detectable acute inflammation.

Diffusely abnormal white matter, characterised by biochemical changes of myelin in the absence of frank demyelination, has been associated with clinical progression in secondary progressive multiple sclerosis. However, little is known about changes of diffusely abnormal white matter over time and their relation to focal white matter lesions. The objectives of this work were: (i) to characterize the longitudinal evolution of focal white matter lesions, diffusely abnormal white matter and diffusely abnormal white matter that transforms into focal white matter lesions; and (ii) to determine whether gadolinium enhancement, known to be associated with the development of new focal white matter lesions, is also related to diffusely abnormal white matter voxels that transform into focal white matter lesions. Our data included 4220 MRI scans of 689 secondary progressive multiple sclerosis participants, followed for 156 weeks, and 2677 scans of 686 relapsing-remitting multiple sclerosis participants, followed for 96 weeks. Focal white matter lesions and diffusely abnormal white matter were segmented using a previously validated, automatic thresholding technique based on normalized T2 intensity values. Using longitudinally registered images, diffusely abnormal white matter voxels at each visit that transformed into focal white matter lesions on the last MRI scan as well as their overlap with gadolinium-enhancing lesion masks were identified. Our results showed that the average yearly rate of conversion of diffusely abnormal white matter to focal white matter lesions was 1.27 cm3 for secondary progressive multiple sclerosis and 0.80 cm3 for relapsing-remitting multiple sclerosis. Focal white matter lesions in secondary progressive multiple sclerosis participants significantly increased (t = 3.9; P = 0.0001) while diffusely abnormal white matter significantly decreased (t = -4.3 P < 0.0001) and the ratio of focal white matter lesions to diffusely abnormal white matter increased (t = 12.7; P < 0.00001). Relapsing-remitting multiple sclerosis participants also showed an increase in the focal white matter lesions to diffusely abnormal white matter ratio (t = 6.9; P < 0.00001) but without a significant change of the individual volumes. Gadolinium enhancement was associated with 7.3% and 18.7% of focal new T2 lesion formation in the infrequent scans of the relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis cohorts, respectively. In comparison, only 0.1% and 0.0% of diffusely abnormal white matter to focal white matter lesions voxels overlapped with gadolinium enhancement. We conclude that diffusely abnormal white matter transforms into focal white matter lesions over time in both relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis. Diffusely abnormal white matter appears to represent a form of pre-lesional pathology that contributes to T2 lesion volume increase over time, independent of new focal inflammation and gadolinium enhancement.

Permanent tissue damage in multiple sclerosis lesions is associated with reduced pre-lesion myelin and axon volume fractions.

BACKGROUND: The use of advanced magnetic resonance imaging (MRI) techniques in MS research has led to new insights in lesion evolution and disease outcomes. It has not yet been determined if, or how, pre-lesional abnormalities in normal-appearing white matter (NAWM) relate to the long-term evolution of new lesions. OBJECTIVE: To investigate the relationship between abnormalities in MRI measures of axonal and myelin volume fractions (AVF and MVF) in NAWM preceding development of black-hole (BH) and non-BH lesions in people with MS. METHODS: We obtained magnetization transfer and diffusion MRI at 6-month intervals in patients with MS to estimate MVF and AVF during lesion evolution. Lesions were classified as either BH or non-BH on the final imaging visit using T1 maps. RESULTS: Longitudinal data from 97 new T2 lesions from 9 participants were analyzed; 25 lesions in 8 participants were classified as BH 6-12 months after initial appearance. Pre-lesion MVF, AVF, and MVF/AVF were significantly lower, and T1 was significantly higher, in the lesions that later became BHs (p < 0.001) compared to those that did not. No significant pre-lesion abnormalities were found in non-BH lesions (p > 0.05). CONCLUSION: The present work demonstrated that pre-lesion abnormalities are associated with worse long-term lesion-level outcome.

Cortical lesion hotspots and association of subpial lesions with disability in multiple sclerosis.

BACKGROUND: Dramatic improvements in visualization of cortical (especially subpial) multiple sclerosis (MS) lesions allow assessment of impact on clinical course. OBJECTIVE: Characterize cortical lesions by 7 tesla (T) T2*-/T1-weighted magnetic resonance imaging (MRI); determine relationship with other MS pathology and contribution to disability. METHODS: Sixty-four adults with MS (45 relapsing-remitting/19 progressive) underwent 3 T brain/spine MRI, 7 T brain MRI, and clinical testing. RESULTS: Cortical lesions were found in 94% (progressive: median 56/range 2-203; relapsing-remitting: 15/0-168; p = 0.004). Lesion distribution across 50 cortical regions was nonuniform (p = 0.006), with highest lesion burden in supplementary motor cortex and highest prevalence in superior frontal gyrus. Leukocortical and white matter lesion volumes were strongly correlated (r = 0.58, p < 0.0001), while subpial and white matter lesion volumes were moderately correlated (r = 0.30, p = 0.002). Leukocortical (p = 0.02) but not subpial lesions (p = 0.40) were correlated with paramagnetic rim lesions; both were correlated with spinal cord lesions (p = 0.01). Cortical lesion volumes (total and subtypes) were correlated with expanded disability status scale, 25-foot timed walk, nine-hole peg test, and symbol digit modality test scores. CONCLUSION: Cortical lesions are highly prevalent and are associated with disability and progressive disease. Subpial lesion burden is not strongly correlated with white matter lesions, suggesting differences in inflammation and repair mechanisms.

Deep grey matter injury in multiple sclerosis: a NAIMS consensus statement.

Although multiple sclerosis has traditionally been considered a white matter disease, extensive research documents the presence and importance of grey matter injury including cortical and deep regions. The deep grey matter exhibits a broad range of pathology and is uniquely suited to study the mechanisms and clinical relevance of tissue injury in multiple sclerosis using magnetic resonance techniques. Deep grey matter injury has been associated with clinical and cognitive disability. Recently, MRI characterization of deep grey matter properties, such as thalamic volume, have been tested as potential clinical trial end points associated with neurodegenerative aspects of multiple sclerosis. Given this emerging area of interest and its potential clinical trial relevance, the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative held a workshop and reached consensus on imaging topics related to deep grey matter. Herein, we review current knowledge regarding deep grey matter injury in multiple sclerosis from an imaging perspective, including insights from histopathology, image acquisition and post-processing for deep grey matter. We discuss the clinical relevance of deep grey matter injury and specific regions of interest within the deep grey matter. We highlight unanswered questions and propose future directions, with the aim of focusing research priorities towards better methods, analysis, and interpretation of results.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.

BACKGROUND: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis. METHODS: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. RESULTS: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. CONCLUSIONS: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Predicting disability progression and cognitive worsening in multiple sclerosis using patterns of grey matter volumes.

OBJECTIVE: In multiple sclerosis (MS), MRI measures at the whole brain or regional level are only modestly associated with disability, while network-based measures are emerging as promising prognostic markers. We sought to demonstrate whether data-driven patterns of covarying regional grey matter (GM) volumes predict future disability in secondary progressive MS (SPMS). METHODS: We used cross-sectional structural MRI, and baseline and longitudinal data of Expanded Disability Status Scale, Nine-Hole Peg Test (9HPT) and Symbol Digit Modalities Test (SDMT), from a clinical trial in 988 people with SPMS. We processed T1-weighted scans to obtain GM probability maps and applied spatial independent component analysis (ICA). We repeated ICA on 400 healthy controls. We used survival models to determine whether baseline patterns of covarying GM volume measures predict cognitive and motor worsening. RESULTS: We identified 15 patterns of regionally covarying GM features. Compared with whole brain GM, deep GM and lesion volumes, some ICA components correlated more closely with clinical outcomes. A mainly basal ganglia component had the highest correlations at baseline with the SDMT and was associated with cognitive worsening (HR=1.29, 95% CI 1.09 to 1.52, p<0.005). Two ICA components were associated with 9HPT worsening (HR=1.30, 95% CI 1.06 to 1.60, p<0.01 and HR=1.21, 95% CI 1.01 to 1.45, p<0.05). ICA measures could better predict SDMT and 9HPT worsening (C-index=0.69-0.71) compared with models including only whole and regional MRI measures (C-index=0.65-0.69, p value for all comparison <0.05). CONCLUSIONS: The disability progression was better predicted by some of the covarying GM regions patterns, than by single regional or whole-brain measures. ICA, which may represent structural brain networks, can be applied to clinical trials and may play a role in stratifying participants who have the most potential to show a treatment effect.

Conversion of diffusely abnormal white matter to focal lesions is linked to progression in secondary progressive multiple sclerosis.

BACKGROUND: Diffusely abnormal white matter (DAWM) regions are observed in magnetic resonance images of secondary progressive multiple sclerosis (SPMS) patients. However, their role in clinical progression is still not established. OBJECTIVES: To characterize the longitudinal volumetric and intensity evolution of DAWM and focal white matter lesions (FWML) and assess their associations with clinical outcomes and progression in SPMS. METHODS: Data include 589 SPMS participants followed up for 3 years (3951 time points). FWML and DAWM were automatically segmented. Screening DAWM volumes that transformed into FWML at the last visit (DAWM-to-FWML) and normalized T1-weighted intensities (indicating severity of damage) in those voxels were calculated. RESULTS: FWML volume increased and DAWM volume decreased with an increase in disease duration (p < 0.001). The Expanded Disability Status Scale (EDSS) was positively associated with FWML volumes (p = 0.002), but not with DAWM. DAWM-to-FWML volume was higher in patients who progressed (2.75 cm3 vs. 1.70 cm3; p < 0.0001). Normalized T1-weighted intensity of DAWM-to-FWML was negatively associated with progression (p < 0.00001). CONCLUSION: DAWM transformed into FWML over time, and this transformation was associated with clinical progression. DAWM-to-FWML voxels had greater normalized T1-weighted intensity decrease over time, in keeping with relatively greater tissue damage. Evaluation of DAWM in progressive multiple sclerosis provides a useful measure for therapies aiming to protect this at-risk tissue with the potential to slow progression.

Metabotropic glutamate type 5 receptor binding availability during dextroamphetamine sensitization in mice and humans.

Background: Glutamate transmission is implicated in drug-induced behavioural sensitization and the associated long-lasting increases in mesolimbic output. Metabotropic glutamate type 5 (mGlu5) receptors might be particularly important, but most details are poorly understood. Methods: We first assessed in mice (n = 51, all male) the effects of repeated dextroamphetamine administration (2.0 mg/kg, i.p.) on locomotor activity and binding of the mGlu5 ligand [3H]ABP688. In a parallel study, in 19 stimulant-drug-naïve healthy human volunteers (14 female) we administered 3 doses of dextroamphetamine (0.3 mg/kg, p.o.) or placebo, followed by a fourth dose 2 weeks later. We measured [11C]ABP688 binding using positron emission tomography before and after the induction phase. We assessed psychomotor and behavioural sensitization using speech rate, eye blink rate and self-report. We measured the localization of mGlu5 relative to synaptic markers in mouse striatum using immunofluorescence. Results: We observed amphetamine-induced psychomotor sensitization in mice and humans. We did not see group differences in mGlu5 availability following 3 pre-challenge amphetamine doses, but group differences did develop in mice administered 5 doses. In mice and humans, individual differences in mGlu5 binding after repeated amphetamine administration were negatively correlated with the extent of behavioural sensitization. In drug-naïve mice, mGlu5 was expressed at 67% of excitatory synapses on dendrites of striatal medium spiny neur. Limitations: Correlational results should be interpreted as suggestive because of the limited sample size. We did not assess sex differences. Conclusion: Together, these results suggest that changes in mGlu5 availability are not part of the earliest neural adaptations in stimulant-induced behavioural sensitization, but low mGlu5 binding might identify a higher propensity for sensitization.

Automated separation of diffusely abnormal white matter from focal white matter lesions on MRI in multiple sclerosis.

BACKGROUND: Previous histopathology and MRI studies have addressed the differences between focal white matter lesions (FWML) and diffusely abnormal white matter (DAWM) in multiple sclerosis (MS). These two categories of white matter T2-weighted (T2w) hyperintensity show different degrees of demyelination, axonal loss and immune cell density on histopathology, potentially offering distinct correlations with symptoms. OBJECTIVES: 1) To automate the separation of FWML and DAWM using T2w MRI intensity thresholds and to investigate their differences in magnetization transfer ratios (MTR), which are sensitive to myelin content; 2) to correlate MTR values in FWML and DAWM with normalized signal intensity values on fluid attenuated inversion recovery (FLAIR), T2w, and T1-weighted (T1w) contrasts, as well as with the ratio of T2w/T1w normalized values, in order to determine whether these normalized intensities can be used when MTR is not available. METHODS: We used three MRI datasets: datasets 1 and 2 had 20 MS participants each, scanned with similar 3T MRI protocols in 2 centers, including: 3D T1w (MP2RAGE), 3D FLAIR, 2D T2w, and 3D magnetization-transfer (MT) contrasts. Dataset 3 consisted of 67 scans of participants enrolled in a multisite study and had T1w and T2w contrasts. We used the first dataset to develop an automated technique to separate FWML from DAWM and the second and third to validate the automation of the technique. We applied the automatic thresholds to all datasets to assess the overlap of the manual and the automated masks using Dice kappa. We also assessed differences in mean MTR values between NAWM, DAWM and FWML, using manually and automatically derived masks in datasets 1 and 2. Finally, we used the mean intensity of manually-traced areas of NAWM on T2w images as the normalization factor for each MRI contrast, and compared these with the normalized-intensity values obtained using automated NAWM (A-NAWM) masks as the normalization factor. ANOVA assessed the MTR differences across tissue types. Paired t-test or Wilcoxon signed-ranked test assessed FWML and DAWM differences between manual and automatically derived volumes. Pearson correlations assessed the relationship between MTR and normalized intensity values in the manual and automatically derived masks. RESULTS: The mean Dice-kappa values for dataset 1 were: 0.79 for DAWM masks and 0.90 for FWML masks. In dataset 2, mean Dice-kappa values were: 0.78 for DAWM and 0.87 for FWML. In dataset 3, mean Dice-kappa values were 0.72 for DAWM, and 0.87 for FWML. Manual and automated DAWM and FWML volumes were not significantly different in all datasets. MTR values were significantly lower in manually and automatically derived FWML compared with DAWM in both datasets (dataset 1 manual: F â€‹= â€‹111,08, p â€‹< â€‹0.0001; automated: F â€‹= â€‹153.90, p â€‹< â€‹0.0001; dataset 2 manual: F â€‹= â€‹31.25, p â€‹< â€‹0.0001; automated: F â€‹= â€‹74.04, p â€‹< â€‹0.0001). In both datasets, manually derived FWML and DAWM MTR values showed significant correlations with normalized T1w (r â€‹= â€‹0.77 to 0.94) intensities. CONCLUSIONS: The separation of FWML and DAWM on MRI scans of MS patients using automated intensity thresholds on T2w images is feasible. MTR values are significantly lower in FWML than DAWM, and DAWM values are significantly lower than NAWM, reflecting potentially greater demyelination within focal lesions. T1w normalized intensity values exhibit a significant correlation with MTR values in both tissues of interest and could be used as a proxy to assess demyelination when MTR or other myelin-sensitive images are not available.

Brain volume loss in individuals over time: Source of variance and limits of detectability.

BACKGROUND: Brain volume loss measured from magnetic resonance imaging (MRI) is a marker of neurodegeneration and predictor of disability progression in MS, and is commonly used to assess drug efficacy at the group level in clinical trials. Whether measures of brain volume loss could be useful to help guide management of individual patients depends on the relative magnitude of the changes over a given interval to physiological and technical sources of variability. GOAL: To understand the relative contributions of neurodegeneration vs. physiological and technical sources of variability to measurements of brain volume loss in individuals. MATERIAL AND METHODS: Multiple T1-weighted 3D MPRAGE images were acquired from a healthy volunteer and MS patient over varying time intervals: 7 times on the first day (before breakfast at 7:30AM and then every 2 â€‹h for 12 â€‹h), each day for the next 6 working days, and 6 times over the remainder of the year, on 2 â€‹Siemens MRI scanners: 1.5T Sonata (S1) and 3.0T TIM Trio (S2). Scan-reposition-rescan data were acquired on S2 for daily, monthly and 1-year visits. Percent brain volume change (PBVC) was measured from baseline to each follow-up scan using FSL/SIENA. We estimated the effect of physiologic fluctuations on brain volume using linear regression of the PBVC values over hourly and daily intervals. The magnitude of the physiological effect was estimated by comparing the root-mean-square error (RMSE) of the regression of all the data points relative to the regression line, for the hourly scans vs the daily scans. Variance due to technical sources was assessed as the RMSE of the regression over time using the intracranial volume as a reference. RESULTS: The RMSE of PBVC over 12 â€‹h, for both scanners combined, ("Hours", 0.15%), was similar to the day-to-day variation over 1 week ("Days", 0.14%), and both were smaller than the RMS error over the year (0.21%). All of these variations, however, were smaller than the scan-reposition-rescan RMSE (0.32%). The variability of PBVC for the individual scanners followed the same trend. The standard error of the mean (SEM) for PBVC was 0.26 for S1, and 0.22 for S2. From these values, we computed the minimum detectable change (MDC) to be 0.7% on S1 and 0.6% on S2. The location of the brain along the z-axis of the magnet inversely correlated with brain volume change for hourly and daily brain volume fluctuations (p â€‹< â€‹0.01). CONCLUSION: Consistent diurnal brain volume fluctuations attributable to physiological shifts were not detectable in this small study. Technical sources of variation dominate measured changes in brain volume in individuals until the volume loss exceeds around 0.6-0.7%. Reliable interpretation of measured brain volume changes as pathological (greater than normal aging) in individuals over 1 year requires changes in excess of about 1.1% (depending on the scanner). Reliable brain atrophy detection in an individual may be feasible if the rate of brain volume loss is large, or if the measurement interval is sufficiently long.

Spatial distribution of multiple sclerosis lesions in the cervical spinal cord.

Spinal cord lesions detected on MRI hold important diagnostic and prognostic value for multiple sclerosis. Previous attempts to correlate lesion burden with clinical status have had limited success, however, suggesting that lesion location may be a contributor. Our aim was to explore the spatial distribution of multiple sclerosis lesions in the cervical spinal cord, with respect to clinical status. We included 642 suspected or confirmed multiple sclerosis patients (31 clinically isolated syndrome, and 416 relapsing-remitting, 84 secondary progressive, and 73 primary progressive multiple sclerosis) from 13 clinical sites. Cervical spine lesions were manually delineated on T2- and T2*-weighted axial and sagittal MRI scans acquired at 3 or 7 T. With an automatic publicly-available analysis pipeline we produced voxelwise lesion frequency maps to identify predilection sites in various patient groups characterized by clinical subtype, Expanded Disability Status Scale score and disease duration. We also measured absolute and normalized lesion volumes in several regions of interest using an atlas-based approach, and evaluated differences within and between groups. The lateral funiculi were more frequently affected by lesions in progressive subtypes than in relapsing in voxelwise analysis (P < 0.001), which was further confirmed by absolute and normalized lesion volumes (P < 0.01). The central cord area was more often affected by lesions in primary progressive than relapse-remitting patients (P < 0.001). Between white and grey matter, the absolute lesion volume in the white matter was greater than in the grey matter in all phenotypes (P < 0.001); however when normalizing by each region, normalized lesion volumes were comparable between white and grey matter in primary progressive patients. Lesions appearing in the lateral funiculi and central cord area were significantly correlated with Expanded Disability Status Scale score (P < 0.001). High lesion frequencies were observed in patients with a more aggressive disease course, rather than long disease duration. Lesions located in the lateral funiculi and central cord area of the cervical spine may influence clinical status in multiple sclerosis. This work shows the added value of cervical spine lesions, and provides an avenue for evaluating the distribution of spinal cord lesions in various patient groups.

White matter plasticity and maturation in human cognition.

White matter plasticity likely plays a critical role in supporting cognitive development. However, few studies have used the imaging methods specific to white matter tissue structure or experimental designs sensitive to change in white matter necessary to elucidate these relations. Here we briefly review novel imaging approaches that provide more specific information regarding white matter microstructure. Furthermore, we highlight recent studies that provide greater clarity regarding the relations between changes in white matter and cognition maturation in both healthy children and adolescents and those with white matter insult. Finally, we examine the hypothesis that white matter is linked to cognitive function via its impact on neural synchronization. We test this hypothesis in a population of children and adolescents with recurrent demyelinating syndromes. Specifically, we evaluate group differences in white matter microstructure within the optic radiation; and neural phase synchrony in visual cortex during a visual task between 25 patients and 28 typically developing age-matched controls. Children and adolescents with demyelinating syndromes show evidence of myelin and axonal compromise and this compromise predicts reduced phase synchrony during a visual task compared to typically developing controls. We investigate one plausible mechanism at play in this relationship using a computational model of gamma generation in early visual cortical areas. Overall, our findings show a fundamental connection between white matter microstructure and neural synchronization that may be critical for cognitive processing. In the future, longitudinal or interventional studies can build upon our knowledge of these exciting relations between white matter, neural communication, and cognition.

Estimating and accounting for the effect of MRI scanner changes on longitudinal whole-brain volume change measurements.

OBJECTIVE: Longitudinal MRI studies are often subjected to mid-study scanner changes, which may alter image characteristics such as contrast, signal-to-noise ratio, contrast-to-noise ratio, intensity non-uniformity and geometric distortion. Measuring brain volume loss under these conditions can render the results potentially unreliable across the timepoint of the change. Estimating and accounting for this effect may improve the reliability of estimates of brain atrophy rates. METHODS: We analyzed 237 subjects who were scanned at 1.5 T for the Alzheimer's Disease Neuroimaging Initiative (ADNI) study and were subject to intra-vendor or inter-vendor scanner changes during follow-up (up to 8 years). Sixty-three subjects scanned on GE Signa HDx and HDxt platforms were also subject to a T1-weighted sequence change from Magnetization Prepared Rapid Gradient Echo (MP-RAGE) to Fast Spoiled Gradient Echo with IR Preparation (IR-FSPGR), as part of the transition from ADNI-1 to ADNI-2/GO. Two-timepoint percentage brain volume changes (PBVCs) between the baseline "screening" and the follow-up scans were calculated using SIENA. A linear mixed-effects model with subject-specific random slopes and intercepts was applied to estimate the fixed effects of scanner hardware changes on the PBVC measures. The same model also included a term to estimate the fixed effects of the T1-weighted sequence change. RESULTS: Different hardware upgrade or change combinations led to different offsets in the PBVC (SE; p): Philips Intera to Siemens Avanto, -1.81% (0.30; p < 0.0001); GE Genesis Signa to Philips Intera, 0.99% (0.47, p = 0.042); GE Signa Excite to Signa HDx, 0.33% (0.095, p = 0.0005); GE Signa Excite to Signa HDxt, -0.023% (0.23, p = 0.92); GE Signa Excite to Signa HDx to Signa HDxt, 0.25% (0.095, p = 0.010) and 0.27% (0.16, p = 0.098), respectively; GE Signa HDx to Signa HDxt, -0.24% (0.25, p = 0.34); Siemens Symphony to Symphony TIM, -0.39% (0.16; p = 0.019). The sequence change from MP-RAGE to IR-SPGR was associated with an average -1.63% (0.12; p < 0.0001) change. CONCLUSION: Inter-vendor scanner changes generally led to greater effects on PBVC measurements than did intra-vendor scanner upgrades. The effect of T1-weighted sequence change was comparable to that of the inter-vendor scanner changes. Inclusion of the corrective fixed-effects terms for the scanner hardware and T1-weighted sequence changes yielded better model goodness-of-fits, and thus, potentially more reliable estimates of whole-brain atrophy rates.

Detection and clinical correlation of leukocortical lesions in pediatric-onset multiple sclerosis on multi-contrast MRI.

OBJECTIVE: To determine the frequency of cortical lesions (CLs) in patients with pediatric-onset multiple sclerosis (POMS) using multi-contrast magnetic resonance imaging (MRI), and the relationship between frontal CL load and upper limb dexterity assessed with the Nine-Hole Peg Test (9-HPT). METHODS: Participants completed the 9-HPT and were imaged on a 3T MRI scanner to collect T1-weighted three-dimensional (3D) magnetization prepared rapid gradient echo (MPRAGE), proton density-weighted, T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. CLs were manually segmented using all MRI contrasts. RESULTS: We enrolled 24 participants with POMS (mean (standard deviation) age at first symptom: 13.3 (±2.7) years; mean age at scan: 18.8 (±3) years; mean disease duration of 5 (±3.2) years). A total of 391 CLs (mean, 16.3 ± 27.2; median, 7) were identified in 19 of 24 POMS patients (79%). The total number of CLs was positively associated with white matter lesion volume ( p = 0.04) but not with thalamic volume, age at the time of the scan, or disease duration. The number of frontal CLs was associated with slower performance on the 9-HPT ( p = 0.05). CONCLUSION: Multi-contrast 3T MRI led to a high rate of CL detection, demonstrating that cortical pathology occurs even in pediatric-onset disease. Frontal lobe CL count was associated with reduced manual dexterity, indicating that these CLs are clinically relevant.

Enhanced Recruitment During Executive Control Processing in Cognitively Preserved Patients With Pediatric-Onset MS.

OBJECTIVES: Youth and young adults with pediatric-onset multiple sclerosis (MS) are vulnerable to executive dysfunction; however, some patients do not demonstrate functional deficits despite showing abnormalities on structural magnetic resonance imaging (MRI). Cognitively intact adults with MS have shown enhanced activation patterns relative to healthy controls on working memory tasks. We aim to evaluate whether cognitively preserved pediatric-onset MS patients engage compensatory recruitment strategies to facilitate age-normative performance on a task of working memory. METHODS: Twenty cognitively preserved patients (mean age=18.7±2.7 years; 15 female) and 20 age- and sex-matched controls (mean age=18.5±2.9 years; 15 female) underwent neuropsychological testing and 3.0 Tesla MRI, including structural and functional acquisitions. Patterns of activation during the Alphaspan task, a working memory paradigm with two levels of executive control demand, were examined via whole-brain and region of interest (ROI) analyses. RESULTS: Across all participants, lower accuracy and greater activation of regions implicated in working memory were observed during the high demand condition. MS patients demonstrated 0.21 s longer response time than controls. ROI analyses revealed enhanced activation for pediatric-onset MS patients relative to controls in the right middle frontal, left paracingulate, right supramarginal, and left superior parietal gyri during the low executive demand condition, over and above differences in response time. MS patients also demonstrated heightened activation in the right supramarginal gyrus in the high executive demand condition. CONCLUSIONS: Our findings suggest that pediatric-onset MS patients may engage compensatory recruitment strategies during working memory processing. (JINS, 2019, 25, 432-442).

Histological Underpinnings of Grey Matter Changes in Fibromyalgia Investigated Using Multimodal Brain Imaging.

Chronic pain patients present with cortical gray matter alterations, observed with anatomical magnetic resonance (MR) imaging. Reduced regional gray matter volumes are often interpreted to reflect neurodegeneration, but studies investigating the cellular origin of gray matter changes are lacking. We used multimodal imaging to compare 26 postmenopausal women with fibromyalgia with 25 healthy controls (age range: 50-75 years) to test whether regional gray matter volume decreases in chronic pain are associated with compromised neuronal integrity. Regional gray matter decreases were largely explained by T1 relaxation times in gray matter, a surrogate measure of water content, and not to any substantial degree by GABAA receptor concentration, an indirect marker of neuronal integrity measured with [18F] flumazenil PET. In addition, the MR spectroscopy marker of neuronal viability, N-acetylaspartate, did not differ between patients and controls. These findings suggest that decreased gray matter volumes are not explained by compromised neuronal integrity. Alternatively, a decrease in neuronal matter could be compensated for by an upregulation of GABAA receptors. The relation between regional gray matter and T1 relaxation times suggests decreased tissue water content underlying regional gray matter decreases. In contrast, regional gray matter increases were explained by GABAA receptor concentration in addition to T1 relaxation times, indicating perhaps increased neuronal matter or GABAA receptor upregulation and inflammatory edema. By providing information on the histological origins of cerebral gray matter alterations in fibromyalgia, this study advances the understanding of the neurobiology of chronic widespread pain. SIGNIFICANCE STATEMENT: Regional gray matter alterations in chronic pain, as detected with voxel-based morphometry of anatomical magnetic resonance images, are commonly interpreted to reflect neurodegeneration, but this assumption has not been tested. We found decreased gray matter in fibromyalgia to be associated with T1 relaxation times, a surrogate marker of water content, but not with GABAA receptor concentration, a surrogate of neuronal integrity. In contrast, regional gray matter increases were partly explained by GABAA receptor concentration, indicating some form of neuronal plasticity. The study emphasizes that voxel-based morphometry is an exploratory measure, demonstrating the need to investigate the histological origin of gray matter alterations for every distinct clinical entity, and advances the understanding of the neurobiology of chronic (widespread) pain.

Promise and pitfalls of g-ratio estimation with MRI.

The fiber g-ratio is the ratio of the inner to the outer diameter of the myelin sheath of a myelinated axon. It has a limited dynamic range in healthy white matter, as it is optimized for speed of signal conduction, cellular energetics, and spatial constraints. In vivo imaging of the g-ratio in health and disease would greatly increase our knowledge of the nervous system and our ability to diagnose, monitor, and treat disease. MRI based g-ratio imaging was first conceived in 2011, and expanded to be feasible in full brain white matter with preliminary results in 2013. This manuscript reviews the growing g-ratio imaging literature and speculates on future applications. It details the methodology for imaging the g-ratio with MRI, and describes the known pitfalls and challenges in doing so.

Impact of immunoablation and autologous hematopoietic stem cell transplantation on gray and white matter atrophy in multiple sclerosis.

BACKGROUND: Immunoablation and autologous hematopoietic stem cell transplantation (IA/aHSCT) halts relapses, white matter (WM) lesion formation, and pathological whole-brain (WB) atrophy in multiple sclerosis (MS) patients. Whether the latter was due to effects on gray matter (GM) or WM warranted further exploration. OBJECTIVE: To model GM and WM volume changes after IA/aHSCT to further understand the effects seen on WB atrophy. METHODS: GM and WM volume changes were calculated from serial baseline and follow-up magnetic resonance imaging (MRI) ranging from 1.5 to 10.5 years in 19 MS patients treated with IA/aHSCT. A mixed-effects model with two predictors (total busulfan dose and baseline T1-weighted WM lesion volume "T1LV") characterized the time-courses after IA/aHSCT. RESULTS: Accelerated short-term atrophy of 2.1% and 3.2% occurred in GM and WM, respectively, on average. Both busulfan dose and T1LV were significant predictors of WM atrophy, whereas only busulfan was a significant predictor of GM atrophy. Compared to baseline, a significant reduction in GM atrophy, not WM atrophy, was found. The average rates of long-term GM and WM atrophy were -0.18%/year (standard error (SE): 0.083) and -0.07%/year (SE: 0.14), respectively. CONCLUSION: Chemotherapy-related toxicity affected both GM and WM. WM was further affected by focal T1-weighted lesion-related pathologies. Long-term rates of GM and WM atrophy were comparable to those of normal-aging.