Brain volume increase after discontinuing natalizumab therapy: Evidence for reversible pseudoatrophy.

BACKGROUND: The phenomenon of pseudoatropy after initiation of anti-inflammatory therapy is believed to be reversible, but a rebound in brain volume following cessation of highly-effective therapy has not been reported. OBJECTIVES: To evaluate brain volume change in a treatment interruption study (RESTORE) in which relapsing-remitting multiple sclerosis (RRMS) patients were randomized to switch from natalizumab to placebo, from natalizumab to once-monthly intravenous methylprednisolone (IVMP), or to remain on natalizumab. METHODS: T2 lesion volume (T2LV), baseline normalized brain volumes, and follow-up percent brain volume changes (PBVC) were calculated. Approximate T2 relaxation-time (pT2) was calculated within the brain mask and the T2 lesions to estimate changes in water content. Linear mixed effects models were used to detect differences in T2LV, pT2 in whole brain, pT2 in T2-weighted lesions, and PBVC among the placebo, natalizumab, and IVMP groups. We also estimated contributions of T2LV and pT2 (in whole brain and T2 lesions) to PBVC. RESULTS: T2LV increased in the placebo group (by 0.66 ml/year, p<0.0001) and IVMP (+1.98 ml/year, p = 0.05) groups relative to the natalizumab group. The rates of PBVC were significantly different: -0.239%/year with continued natalizumab and +0.126 %/year after switch to placebo (p = 0.03), while the IVMP group showed brain volume loss (-0.74 %/ year, p = 0.08). pT2 was not statistically different between the groups (p ≥ 0.29) and did not have significant effects on PBVC (p ≥ 0.25). CONCLUSION: The increase in the brain volume in patients witching from natalizumab to placebo is consistent with reversal of so-called pseudoatrophy after starting natalizumab.

Cortical lesions uniquely predict motor disability accrual and form rarely in the absence of new white matter lesions in multiple sclerosis.

Background and objectives: Cortical lesions (CL) are common in multiple sclerosis (MS) and associate with disability and progressive disease. We asked whether CL continue to form in people with stable white matter lesions (WML) and whether the association of CL with worsening disability relates to pre-existing or new CL. Methods: A cohort of adults with MS were evaluated annually with 7 tesla (T) brain magnetic resonance imaging (MRI) and 3T brain and spine MRI for 2 years, and clinical assessments for 3 years. CL were identified on 7T images at each timepoint. WML and brain tissue segmentation were performed using 3T images at baseline and year 2. Results: 59 adults with MS had ≥1 7T follow-up visit (mean follow-up time 2±0.5 years). 9 had "active" relapsing-remitting MS (RRMS), defined as new WML in the year prior to enrollment. Of the remaining 50, 33 had "stable" RRMS, 14 secondary progressive MS (SPMS), and 3 primary progressive MS. 16 total new CL formed in the active RRMS group (median 1, range 0-10), 7 in the stable RRMS group (median 0, range 0-5), and 4 in the progressive MS group (median 0, range 0-1) (p=0.006, stable RR vs PMS p=0.88). New CL were not associated with greater change in any individual disability measure or in a composite measure of disability worsening (worsening Expanded Disability Status Scale or 9-hole peg test or 25-foot timed walk). Baseline CL volume was higher in people with worsening disability (median 1010µl, range 13-9888 vs median 267µl, range 0-3539, p=0.001, adjusted for age and sex) and in individuals with RRMS who subsequently transitioned to SPMS (median 2183µl, range 270-9888 vs median 321µl, range 0-6392 in those who remained RRMS, p=0.01, adjusted for age and sex). Baseline WML volume was not associated with worsening disability or transition from RRMS to SPMS. Discussion: CL formation is rare in people with stable WML, even in those with worsening disability. CL but not WML burden predicts future worsening of disability, suggesting that the relationship between CL and disability progression is related to long-term effects of lesions that form in the earlier stages of disease, rather than to ongoing lesion formation.

Changes in levels of the antioxidant glutathione in brain and blood across the age span of healthy adults: A systematic review.

Aging is characterized by a gradual decline of the body's biological functions, which can lead to increased production of reactive oxygen species (ROS). Antioxidants neutralize ROS and maintain balance between oxidation and reduction. If ROS production exceeds the ability of antioxidant systems to neutralize, a damaging state of oxidative stress (OS) may exist. The reduced form of glutathione (GSH) is the most abundant antioxidant, and decline of GSH is considered a marker of OS. Our review summarizes the literature on GSH variations with age in healthy adults in brain (in vivo, ex vivo) and blood (plasma, serum), and reliability of in vivo magnetic resonance spectroscopy (MRS) measurement of GSH. A systematic PubMed search identified 35 studies. All in vivo MRS studies (N = 13) reported good to excellent reproducibility of GSH measures. In brain, 3 out of 4 MRS studies reported decreased GSH with age, measured in precuneus, cingulate, and occipital regions, while 1 study reported increased GSH with age in frontal and sensorimotor regions. In post-mortem brain, out of 3 studies, 2 reported decreased GSH with age in hippocampal and frontal regions, while 1 study reported increased GSH with age in a frontal region. Oxidized glutathione disulfide (GSSG) was reported to be increased in caudate with age in 1 study, suggesting OS. Although findings in the brain lacked a clear consensus, the majority of studies suggested a decline of GSH with age. The low number of studies (particularly ex vivo) and potential regional differences may have contributed to variability in the findings in brain. In blood, in contrast, GSH levels predominately were reported to decrease with advancing age (except in the oldest-old, who may represent a select group of particularly successful agers), while GSSG findings lacked consensus. The larger number of studies assessing age-specific GSH level changes in blood (N = 16) allowed for more robust consensus across studies than in brain. Overall, the literature suggests that aging is associated with increased OS in brain and body, but the timing and regional distribution of changes in the brain require further study. The contribution of brain OS to brain aging, and the effect of interventions to raise brain GSH levels on decline of brain function, remain understudied. Given that reliable tools to measure brain GSH exist, we hope this paper will serve as a catalyst to stimulate more work in this field.

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.

Deviation From Normative Whole Brain and Deep Gray Matter Growth in Children With MOGAD, MS, and Monophasic Seronegative Demyelination.

BACKGROUND AND OBJECTIVES: Pediatric-acquired demyelination of the CNS associated with antibodies directed against myelin oligodendrocyte glycoprotein (MOG; MOG antibody-associated disease [MOGAD]) occurs as a monophasic or relapsing disease and with variable but often extensive T2 lesions in the brain. The impact of MOGAD on brain growth during maturation is unknown. We quantified the effect of pediatric MOGAD on brain growth trajectories and compared this with the growth trajectories of age-matched and sex-matched healthy children and children with multiple sclerosis (MS, a chronic relapsing disease known to lead to failure of normal brain growth and to loss of brain volume) and monophasic seronegative demyelination. METHODS: We included children enrolled at incident attack in the prospective longitudinal Canadian Pediatric Demyelinating Disease Study who were recruited at the 3 largest enrollment sites, underwent research brain MRI scans, and were tested for serum MOG-IgG. Children seropositive for MOG-IgG were diagnosed with MOGAD. MS was diagnosed per the 2017 McDonald criteria. Monophasic seronegative demyelination was confirmed in children with no clinical or MRI evidence of recurrent demyelination and negative results for MOG-IgG and aquaporin-4-IgG. Whole and regional brain volumes were computed through symmetric nonlinear registration to templates. We computed age-normalized and sex-normalized z scores for brain volume using a normative dataset of 813 brain MRI scans obtained from typically developing children and used mixed-effect models to assess potential deviation from brain growth trajectories. RESULTS: We assessed brain volumes of 46 children with MOGAD, 26 with MS, and 51 with monophasic seronegative demyelinating syndrome. Children with MOGAD exhibited delayed (p < 0.001) age-expected and sex-expected growth of thalamus, caudate, and globus pallidus, normalized for the whole brain volume. Divergence from expected growth was particularly pronounced in the first year postonset and was detected even in children with monophasic MOGAD. Thalamic volume abnormalities were less pronounced in children with MOGAD compared with those in children with MS. DISCUSSION: The onset of MOGAD during childhood adversely affects the expected trajectory of growth of deep gray matter structures, with accelerated changes in the months after an acute attack. Further studies are required to better determine the relative impact of monophasic vs relapsing MOGAD and whether relapsing MOGAD with attacks isolated to the optic nerves or spinal cord affects brain volume over time.

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.

NigraNet: An automatic framework to assess nigral neuromelanin content in early Parkinson's disease using convolutional neural network.

BACKGROUND: Parkinson's disease (PD) demonstrates neurodegenerative changes in the substantia nigra pars compacta (SNc) using neuromelanin-sensitive (NM)-MRI. As SNc manual segmentation is prone to substantial inter-individual variability across raters, development of a robust automatic segmentation framework is necessary to facilitate nigral neuromelanin quantification. Artificial intelligence (AI) is gaining traction in the neuroimaging community for automated brain region segmentation tasks using MRI. OBJECTIVE: Developing and validating AI-based NigraNet, a fully automatic SNc segmentation framework allowing nigral neuromelanin quantification in patients with PD using NM-MRI. METHODS: We prospectively included 199 participants comprising 144 early-stage idiopathic PD patients (disease duration = 1.5 ± 1.0 years) and 55 healthy volunteers (HV) scanned using a 3 Tesla MRI including whole brain T1-weighted anatomical imaging and NM-MRI. The regions of interest (ROI) were delineated in all participants automatically using NigraNet, a modified U-net, and compared to manual segmentations performed by two experienced raters. The SNc volumes (Vol), volumes corrected by total intracranial volume (Cvol), normalized signal intensity (NSI) and contrast-to-noise ratio (CNR) were computed. One-way GLM-ANCOVA was performed while adjusting for age and sex as covariates. Diagnostic performance measurement was assessed using the receiver operating characteristic (ROC) analysis. Inter and intra-observer variability were estimated using Dice similarity coefficient (DSC). The agreements between methods were tested using intraclass correlation coefficient (ICC) based on a mean-rating, two-way, mixed-effects model estimates for absolute agreement. Cronbach's alpha and Bland-Altman plots were estimated to assess inter-method consistency. RESULTS: Using both methods, Vol, Cvol, NSI and CNR measurements differed between PD and HV with an effect of sex for Cvol and CNR. ICC values between the methods demonstrated optimal agreement for Cvol and CNR (ICC > 0.9) and high reproducibility (DSC: 0.80) was also obtained. The SNc measurements also showed good to excellent consistency values (Cronbach's alpha > 0.87). Bland-Altman plots of agreement demonstrated no association of SNc ROI measurement differences between the methods and ROI average measurements while confirming that 95 % of the data points were ranging between the limits of mean difference (d ± 1.96xSD). Percentage changes between PD and HV were -27.4 % and -17.7 % for Vol, -30.0 % and -22.2 % for Cvol, -15.8 % and -14.4 % for NSI, -17.1 % and -16.0 % for CNR for automatic and manual measurements respectively. Using automatic method, in the entire dataset, we obtained the areas under the ROC curve (AUC) of 0.83 for Vol, 0.85 for Cvol, 0.79 for NSI and 0.77 for CNR whereas in the training dataset of 0.96 for Vol, 0.95 for Cvol, 0.85 for NSI and 0.85 for CNR. Disease duration correlated negatively with NSI of the patients for both the automatic and manual measurements. CONCLUSIONS: We presented an AI-based NigraNet framework that utilizes a small MRI training dataset to fully automatize the SNc segmentation procedure with an increased precision and more reproducible results. Considering the consistency, accuracy and speed of our approach, this study could be a crucial step towards the implementation of a time-saving non-rater dependent fully automatic method for studying neuromelanin changes in clinical settings and large-scale neuroimaging studies.

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.

Patterns of white and gray structural abnormality associated with paediatric demyelinating disorders.

The impact of multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) - associated disorders (MOGAD) on brain structure in youth remains poorly understood. Reductions in cortical mantle thickness on structural MRI and abnormal diffusion-based white matter metrics (e.g., diffusion tensor parameters) have been well documented in MS but not in MOGAD. Characterizing structural abnormalities found in children with these disorders can help clarify the differences and similarities in their impact on neuroanatomy. Importantly, while MS and MOGAD affect the entire CNS, the visual pathway is of particular interest in both groups, as most patients have evidence for clinical or subclinical involvement of the anterior visual pathway. Thus, the visual pathway is of key interest in analyses of structural abnormalities in these disorders and may distinguish MOGAD from MS patients. In this study we collected MRI data on 18 MS patients, 14 MOGAD patients and 26 age- and sex-matched typically developing children (TDC). Full-brain group differences in fixel diffusion measures (fibre-bundle populations) and cortical thickness measures were tested using age and sex as covariates. Visual pathway analysis was performed by extracting mean diffusion measures within lesion free optic radiations, cortical thickness within the visual cortex, and retinal nerve fibre layer (RNFL) and ganglion cell layer thickness measures from optical coherence tomography (OCT). Fixel based analysis (FBA) revealed MS patients have widespread abnormal white matter within the corticospinal tract, inferior longitudinal fasciculus, and optic radiations, while within MOGAD patients, non-lesional impact on white matter was found primarily in the right optic radiation. Cortical thickness measures were reduced predominately in the temporal and parietal lobes in MS patients and in frontal, cingulate and visual cortices in MOGAD patients. Additionally, our findings of associations between reduced RNFLT and axonal density in MOGAD and TORT in MS patients in the optic radiations imply widespread axonal and myelin damage in the visual pathway, respectively. Overall, our approach of combining FBA, cortical thickness and OCT measures has helped evaluate similarities and differences in brain structure in MS and MOGAD patients in comparison to TDC.

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.

[Formula: see text] Disrupted cognitive development following pediatric acquired demyelinating syndromes: a longitudinal study.

Long-term cognitive deficits have been observed in some children who experience an acquired demyelinating syndrome (ADS). We examined changes in cognitive functioning over the first two years following incident ADS andtested whether normalized brain and thalamic volume accounted for decline over time. Twenty-five youth (mean age 12.8 years) with ADS, 9 of whom were diagnosed with multiple sclerosis (MS) and 16 of whom experienced monophasic ADS (monoADS), underwent two neuropsychological evaluationsand MRI scans at approximately6- and 24-months post ADS-onset. We examined changes in cognitive outcomes over time and between patient groups. Generalized linear mixed-effect regression models were used to examine the association of normalized brain and thalamic volumesbetween the two timepointswith cognitive z-scores. Cognitive performance was within the age-expected range for both groups and remained stable over time on 15 measures. In the combined sample of monoADS and MS patients, declines (p < .05) were noted on the Symbol Digit Modalities Test (SDMT), the Auditory Working Memory (AWM), and the WJ-III Visual Matching (VisMat)tests, but did not survive FDR correction. Clinically significant declines, as measured by the Reliable Change Index, were observed on the SDMT,AWM, and VisMattests by 19, 42, and 32%, respectively. Lower normalized brain volume at 6-months predicted a negative change in SDMT (B = 0.45, 95%CI: 0.07,0.83) and AWM (B = 0.30, 95%CI: 0.13, 0.47). Chronicity of demyelination is not required for cognitive decline nor for reduced brain volume, suggesting that even a single demyelinating event may negatively impact cognitive potential in children.

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.

Assessing the differential sensitivities of wave-CAIPI ViSTa myelin water fraction and magnetization transfer saturation for efficiently quantifying tissue damage in MS.

BACKGROUND: Wave-CAIPI Visualization of Short Transverse relaxation time component (ViSTa) is a recently developed, short-T1-sensitized MRI method for fast quantification of myelin water fraction (MWF) in the human brain. It represents a promising technique for the evaluation of subtle, early signals of demyelination in the cerebral white matter of multiple sclerosis (MS) patients. Currently however, few studies exist that robustly assess the utility of ViSTa MWF measures of myelin compared to more conventional MRI measures of myelin in the brain of MS patients. Moreover, there are no previous studies evaluating the sensitivity of ViSTa MWF for the non-invasive detection of subtle tissue damage in both normal-appearing white matter (NAWM) and white matter lesions of MS patients. As a result, a central purpose of this study was to systematically evaluate the relationship between myelin sensitivity of T1-based ViSTa MWF mapping and a more generally recognized metric, Magnetization Transfer Saturation (MTsat), in healthy control and MS brain white matter. METHODS: ViSTa MWF and MTsat values were evaluated in automatically-classified normal appearing white matter (NAWM), white matter (WM) lesion tissue, cortical gray matter, and deep gray matter of 29 MS patients and 10 healthy controls using 3T MRI. MWF and MT sat were also assessed in a tract-specific manner using the Johns Hopkins University WM atlas. MRI-derived measures of cerebral myelin content were uniquely compared by employing non-normal distribution-specific measures of median, interquartile range and skewness. Separate analyses of variance were applied to test tissue-specific differences in MTsat and ViSTa MWF distribution metrics. Non-parametric tests were utilized when appropriate. All tests were corrected for multiple comparisons using the False Discovery Rate method at the level, α=0.05. RESULTS: Differences in whole NAWM MS tissue damage were detected with a higher effect size when using ViSTa MWF (q = 0.0008; ƞ2 = 0.34) compared to MTsat (q = 0.02; ƞ2= 0.24). We also observed that, as a possible measure of WM pathology, ViSTa-derived NAWM MWF voxel distributions of MS subjects were consistently skewed towards lower MWF values, while MTsat voxel distributions showed reduced skewness values. We further identified tract-specific reductions in mean ViSTa MWF of MS patients compared to controls that were not observed with MTsat. However, MTsat (q = 1.4 × 10-21; ƞ2 = 0.88) displayed higher effect sizes when differentiating NAWM and MS lesion tissue. Using regression analysis at the group level, we identified a linear relationship between MTsat and ViSTa MWF in NAWM (R2 = 0.46; p = 7.8 × 10-4) lesions (R2 = 0.30; p = 0.004), and with all tissue types combined (R2 = 0.71; p = 8.4 × 10-45). The linear relationship was also observed in most of the WM tracts we investigated. ViSTa MWF in NAWM of MS patients correlated with both disease duration (p = 0.02; R2 = 0.27) and WM lesion volume (p = 0.002; R2 = 0.34). CONCLUSION: Because ViSTa MWF and MTsat metrics exhibit differential sensitivities to tissue damage in MS white matter, they can be collected in combination to provide an efficient, comprehensive measure of myelin water and macromolecular pool proton signals. These complementary measures may offer a more sensitive, non-invasive biopsy of early precursor signals in NAWM that occur prior to lesion formation. They may also aid in monitoring the efficacy of remyelination therapies.

Brain volume change after high-dose immunosuppression and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis.

BACKGROUND: Brain volume loss (BVL) is commonly observed after high-dose immunosuppression and autologous hematopoietic cell transplantation (HDIT/HCT) for treatment of multiple sclerosis (MS). To better understand the mechanisms of underlying BVL associated with this treatment, we characterized the time courses of whole-brain (WB), grey-matter (GM) and white-matter (WM) volume loss in relapsing-remitting MS (RRMS) patients who received BEAM-based HDIT/HCT. METHODS: We used Jacobian integration to measure MRI-based WB, GM and WM volume changes up to 5 years after transplant in twenty-four RRMS participants who underwent BEAM-based HDIT/HCT. Using a two-piecewise mixed-effects model, we estimated the short-term (baseline to 1 year) and long-term (beyond 1 year) rates of BVL after HDIT/HCT. We also compared the rates based on the presence of gadolinium-enhancing lesions at baseline, and the maintenance of event-free survival during follow-up. RESULTS: On average, accelerated short-term BVL of -1.37% (SE: 0.21), -0.86% (SE: 0.28) and -2.18% (SE: 0.26) occurred in WB, GM and WM, respectively. Baseline T1-weighted MRI WM lesion volume was a significant predictor in the WB (short-term) and the WM (short-term and long-term). The average rates of BVL after the initial acceleration were -0.22%/y (SE: 0.10), -0.13%/y (SE: 0.11) and -0.36%/y (SE: 0.11) in the WB, GM and WM, respectively. Participants with gadolinium-enhancing lesions at baseline had significantly higher short-term rates of GM (-1.56% vs. -0.27%, p = 0.01) and WB volume loss (-1.94% vs. -0.81%, p = 0.006) at 1 year follow-up as compared to those without gadolinium-enhancing lesions. WM volume loss was not significantly different (-2.59% vs. -1.66%, p = 0.16). Participants who maintained event-free survival had similar rates of BVL compared to those who did not. CONCLUSIONS: BVL may accelerate for months after HDIT/HCT. However, over the long-term, adequate HDIT/HCT may reduce BVL rates to those similar to normal aging at the WB level.

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.

Identifying multiple sclerosis subtypes using unsupervised machine learning and MRI data.

Multiple sclerosis (MS) can be divided into four phenotypes based on clinical evolution. The pathophysiological boundaries of these phenotypes are unclear, limiting treatment stratification. Machine learning can identify groups with similar features using multidimensional data. Here, to classify MS subtypes based on pathological features, we apply unsupervised machine learning to brain MRI scans acquired in previously published studies. We use a training dataset from 6322 MS patients to define MRI-based subtypes and an independent cohort of 3068 patients for validation. Based on the earliest abnormalities, we define MS subtypes as cortex-led, normal-appearing white matter-led, and lesion-led. People with the lesion-led subtype have the highest risk of confirmed disability progression (CDP) and the highest relapse rate. People with the lesion-led MS subtype show positive treatment response in selected clinical trials. Our findings suggest that MRI-based subtypes predict MS disability progression and response to treatment and may be used to define groups of patients in interventional trials.

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.

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.