Lesion-level correspondence and longitudinal properties of paramagnetic rim and slowly expanding lesions in multiple sclerosis.

BACKGROUND: Paramagnetic rim lesions (PRLs) and slowly expanding lesions (SELs) have been posited as markers of chronic active lesions (CALs). OBJECTIVE: To assess the lesion-level concordance of PRLs and SELs in MS and to characterize changes in brain tissue integrity in CALs over time. METHODS: MRIs were analyzed from a substudy of AFFINITY [NCT03222973], a phase 2 trial of opicinumab in relapsing MS. Assessments included (1) identification of SELs based on longitudinal MRIs over 72 weeks, and identification of PRLs on susceptibility-weighted imaging (SWI) filtered phase images at week 72; (2) evaluation of subject-level correlation of SEL and PRL counts, volumes, and degree of lesion-level overlap between SELs and PRLs; and (3) characterization of tissue integrity over time in overlapping and non-overlapping SELs and PRLs. RESULTS: In 41 subjects, 119 chronic PRLs and 267 SELs were detected. Of 119 (39.5%) chronic PRLs, 47 co-localized with a SEL; 46/267 (17.2%) SELs co-localized with a PRL. PRLs co-localized with SELs showed expansion and worsening microstructural damage over time. SELs with and without co-localization with PRLs showed ongoing tissue damage. CONCLUSIONS: Chronic MS lesions identified as both PRL and SEL were associated with the most severe accumulation of tissue damage. TRIAL REGISTRATION: AFFINITY [NCT03222973].

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.

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 learning segmentation of orbital fat to calibrate conventional MRI for longitudinal studies.

In conventional non-quantitative magnetic resonance imaging, image contrast is consistent within images, but absolute intensity can vary arbitrarily between scans. For quantitative analysis of intensity data, images are typically normalized to a consistent reference. The most convenient reference is a tissue that is always present in the image, and is unlikely to be affected by pathological processes. In multiple sclerosis neuroimaging, both the white and gray matter are affected, so normalization techniques that depend on brain tissue may introduce bias or remove biological changes of interest. We introduce a complementary procedure, image "calibration," the goal of which is to remove technical intensity artifacts while preserving biological differences. We demonstrate a deep learning approach to segmenting fat from within the orbit of the eyes on T1-weighted images at 1.5 and 3 â€‹T to use as a reference tissue, and use it to calibrate 1018 scans from 256 participants in a study of pediatric-onset multiple sclerosis. The machine segmentations agreed with the adjudicating expert (DF) segmentations better than did those of other expert humans, and calibration resulted in better agreement with semi-quantitative magnetization transfer ratio imaging than did normalization with the WhiteStripe1 algorithm. We suggest that our method addresses two key priorities in the field: (1) it provides a robust option for serial calibration of conventional scans, allowing comparison of disease change in persons imaged at multiple time points in their disease; and (ii) the technique is fast, as the deep learning segmentation takes only 0.5 â€‹s/scan, which is feasible for both large and small datasets.

Physical activity and dentate gyrus volume in pediatric acquired demyelinating syndromes.

OBJECTIVE: To assess the association between daily moderate-to-vigorous physical activity (MVPA) and dentate gyrus volume (DGv) in pediatric patients with acquired demyelinating syndromes (ADSs) of the CNS. METHODS: Cross-sectional analysis of accelerometry (7 days) and research protocol MRI data from 12 pediatric MS and 18 children with monophasic ADS (monoADS). Total brain and DGv were quantified using standardized methods. The association of daily minutes of MVPA with normalized DGv (nDGv) was assessed using multivariable generalized linear models. RESULTS: Median (interquartile range) MVPA was lower in MS patients [9.5 (14)] and exhibited less variation than in monoADS patients [24.5 (47)]. nDGv did not differ significantly between groups [mean nDGv (SD) [cm3]: MS 0.34 (0.1); monoADS 0.4 (0.1); p = 0.100]. In the monoADS group, every 1-minute increase in MVPA was associated with a 2.4-mm3 increase in nDGv (p = 0.0017), an association that was independent of age at incident demyelination, time from incident demyelination, sex, and brain white matter T2 lesion volume. No significant association was found between MVPA and nDGv (-2.6 mm3/min, p = 0.16) in the MS group. CONCLUSIONS: Higher MVPA associates with greater nDGv in children who have recovered from monophasic demyelination. Larger studies are required to determine whether MVPA can promote regional brain development, or limit tissue damage, in youth with MS.

Lower physical activity is associated with higher disease burden in pediatric multiple sclerosis.

OBJECTIVE: To evaluate the association between physical activity (PA) and multiple sclerosis (MS) disease activity, depression, and fatigue in a cohort of children with MS and monophasic acquired demyelinating syndrome (mono-ADS). METHODS: In this cross-sectional study of consecutive patients attending a specialized pediatric MS clinic, we administered the PedsQL Multidimensional Fatigue Scale, Center for Epidemiological Studies Depression Scale, and Godin Leisure-Time Exercise Questionnaire. Quantitative MRI analysis was performed to obtain whole brain and T2 lesion volume in a subset of participants (n = 60). RESULTS: A total of 110 patients (79 mono-ADS; 31 MS; 5-18 years; M:F 1:1.2) were included. Patients with MS reported less strenuous (33.21 ± 31.88 metabolic equivalents [METs] vs 15.97 ± 22.73 METs, p = 0.002) and total (44.48 ± 39.35 METs vs 67.28 ± 59.65 METs; p = 0.0291) PA than those with mono-ADS. Patients with MS who reported greater amounts of moderate PA METs had fewer sleep/rest fatigue symptoms (r = -0.4). Participation in strenuous PA was associated with smaller T2 lesion volumes (r = -0.66) and lower annualized relapse rate (r = -0.66). No associations were found between total brain volume and participation in PA. CONCLUSIONS: Children with MS are less physically active than children with mono-ADS. Reasons for this are unclear, but may be related to ongoing disease activity, perceived limitations, or symptoms such as depression or fatigue. Children with MS reporting higher levels of strenuous PA had lower T2 lesion volumes and lower relapse rates, suggesting a potential protective effect of strenuous PA in this population. Further longitudinal studies are needed to establish the relationship of PA to MS symptoms and disease activity in this population.

Onset of multiple sclerosis before adulthood leads to failure of age-expected brain growth.

OBJECTIVE: To determine the impact of pediatric-onset multiple sclerosis (MS) on age-expected brain growth. METHODS: Whole brain and regional volumes of 36 patients with relapsing-remitting MS onset prior to 18 years of age were segmented in 185 longitudinal MRI scans (2-11 scans per participant, 3-month to 2-year scan intervals). MRI scans of 25 age- and sex-matched healthy normal controls (NC) were also acquired at baseline and 2 years later on the same scanner as the MS group. A total of 874 scans from 339 participants from the NIH-funded MRI study of normal brain development acquired at 2-year intervals were used as an age-expected healthy growth reference. All data were analyzed with an automatic image processing pipeline to estimate the volume of brain and brain substructures. Mixed-effect models were built using age, sex, and group as fixed effects. RESULTS: Significant group and age interactions were found with the adjusted models fitting brain volumes and normalized thalamus volumes (p < 10(-4)). These findings indicate a failure of age-normative brain growth for the MS group, and an even greater failure of thalamic growth. In patients with MS, T2 lesion volume correlated with a greater reduction in age-expected thalamic volume. To exclude any scanner-related influence on our data, we confirmed no significant interaction of group in the adjusted models between the NC and NIH MRI Study of Normal Brain Development groups. CONCLUSIONS: Our results provide evidence that the onset of MS during childhood and adolescence limits age-expected primary brain growth and leads to subsequent brain atrophy, implicating an early onset of the neurodegenerative aspect of MS.

Epitope spreading as an early pathogenic event in pediatric multiple sclerosis.

OBJECTIVES: For most adults with initial clinical presentation of multiple sclerosis (MS), biological disease was likely initiated many years prior. Pediatric-onset MS provides an opportunity to study early disease processes. METHODS: Using antigen microarrays, including CNS-related proteins, lipids, and other autoantigens, we studied early immunologic events involved in clinical onset of pediatric MS. Serum samples were collected at the time of incident acquired CNS demyelinating syndromes (ADS) in children who, in subsequent prospective follow-up, were ascertained to have either pediatric MS (ADS-MS) or a monophasic illness (ADS-mono). Samples were obtained both at the time of ADS presentation and 3 months into follow-up. We used an initial training set of samples to implicate antibody signatures associated with each group, and then a test set. An additional set of follow-up samples (stability set) was used as a form of internal validation. RESULTS: Children with ADS-MS tended to have distinguishable serum antibody patterns both at the time of ADS presentation and 3 months into follow-up. At the time of ADS, serum samples from patients with ADS-MS or ADS-mono reacted against similar numbers of CNS antigens, although CNS antigens implicated in adult MS were more often targeted in children with ADS-MS. The follow-up ADS-MS samples reacted against a broader panel of CNS antigens, while corresponding ADS-mono samples exhibited a contraction of the initial antibody response. CONCLUSIONS: Our findings in this prospective cohort of pediatric-onset CNS demyelinating diseases point to an active process of epitope spreading during early stages of MS, not seen in monophasic CNS inflammatory conditions.