Multicenter Evaluation of AI-generated DIR and PSIR for Cortical and Juxtacortical Multiple Sclerosis Lesion Detection.

Background Cortical multiple sclerosis lesions are clinically relevant but inconspicuous at conventional clinical MRI. Double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) are more sensitive but often unavailable. In the past 2 years, artificial intelligence (AI) was used to generate DIR and PSIR from standard clinical sequences (eg, T1-weighted, T2-weighted, and fluid-attenuated inversion-recovery sequences), but multicenter validation is crucial for further implementation. Purpose To evaluate cortical and juxtacortical multiple sclerosis lesion detection for diagnostic and disease monitoring purposes on AI-generated DIR and PSIR images compared with MRI-acquired DIR and PSIR images in a multicenter setting. Materials and Methods Generative adversarial networks were used to generate AI-based DIR (n = 50) and PSIR (n = 43) images. The number of detected lesions between AI-generated images and MRI-acquired (reference) images was compared by randomized blinded scoring by seven readers (all with >10 years of experience in lesion assessment). Reliability was expressed as the intraclass correlation coefficient (ICC). Differences in lesion subtype were determined using Wilcoxon signed-rank tests. Results MRI scans of 202 patients with multiple sclerosis (mean age, 46 years ± 11 [SD]; 127 women) were retrospectively collected from seven centers (February 2020 to January 2021). In total, 1154 lesions were detected on AI-generated DIR images versus 855 on MRI-acquired DIR images (mean difference per reader, 35.0% ± 22.8; P < .001). On AI-generated PSIR images, 803 lesions were detected versus 814 on MRI-acquired PSIR images (98.9% ± 19.4; P = .87). Reliability was good for both DIR (ICC, 0.81) and PSIR (ICC, 0.75) across centers. Regionally, more juxtacortical lesions were detected on AI-generated DIR images than on MRI-acquired DIR images (495 [42.9%] vs 338 [39.5%]; P < .001). On AI-generated PSIR images, fewer juxtacortical lesions were detected than on MRI-acquired PSIR images (232 [28.9%] vs 282 [34.6%]; P = .02). Conclusion Artificial intelligence-generated double inversion-recovery and phase-sensitive inversion-recovery images performed well compared with their MRI-acquired counterparts and can be considered reliable in a multicenter setting, with good between-reader and between-center interpretative agreement. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Zivadinov and Dwyer in this issue.

Diagnostic performance of computed tomography features in detecting oropharyngeal squamous cell carcinoma extranodal extension.

OBJECTIVES: Accurate pre-treatment imaging determination of extranodal extension (ENE) could facilitate the selection of appropriate initial therapy for HPV-positive oropharyngeal squamous cell carcinoma (HPV + OPSCC). Small studies have associated 7 CT features with ENE with varied results and agreement. This article seeks to determine the replicable diagnostic performance of these CT features for ENE. METHODS: Five expert academic head/neck neuroradiologists from 5 institutions evaluate a single academic cancer center cohort of 75 consecutive HPV + OPSCC patients. In a web-based virtual laboratory for imaging research and education, the experts performed training on 7 published CT features associated with ENE and then independently identified the "single most (if any) suspicious" lymph node and presence/absence of each of the features. Inter-rater agreement was assessed using percentage agreement, Gwet's AC1, and Fleiss' kappa. Sensitivity, specificity, and positive and negative predictive values were calculated for each CT feature based on histologic ENE. RESULTS: All 5 raters identified the same node in 52 cases (69%). In 15 cases (20%), at least one rater selected a node and at least one rater did not. In 8 cases (11%), all raters selected a node, but at least one rater selected a different node. Percentage agreement and Gwet's AC1 coefficients were > 0.80 for lesion identification, matted/conglomerated nodes, and central necrosis. Fleiss' kappa was always < 0.6. CT sensitivity for histologically confirmed ENE ranged 0.18-0.94, specificity 0.41-0.88, PPV 0.26-0.36, and NPV 0.78-0.96. CONCLUSIONS: Previously described CT features appear to have poor reproducibility among expert head/neck neuroradiologists and poor predictive value for histologic ENE. KEY POINTS: • Previously described CT imaging features appear to have poor reproducibility among expert head and neck subspecialized neuroradiologists as well as poor predictive value for histologic ENE. • Although it may still be appropriate to comment on the presence or absence of these CT features in imaging reports, the evidence indicates that caution is warranted when incorporating these features into clinical decision-making regarding the likelihood of ENE.

Aquaporin 4 distribution in the brain and its relevance for the radiological appearance of neuromyelitis optica spectrum disease.

BACKGROUND AND PURPOSE: To determine the precise incidence of lesions at sites of high Aquaporin-4 expression (hAQP4) and their possible association with known neuromyelitis optica spectrum disease (NMOSD) lesions patterns. MATERIALS AND METHODS: A retrospective analysis of brain and, when available, spinal cord MRI scans of 54 NMOSD patients recruited among the French NMOSD cohort was performed. Brain lesions were annotated as MS-like, non-specific, or evocative of NMOSD. The topography of hAQP4 was reassessed by human brain atlas. The incidence of lesions in hAQP4 and their association with lesions evocative of NMOSD was estimated. RESULTS: Among those included (41/54 female, mean age: 45 years) 47/54 (87%) presented brain lesions. Twenty-six/47 (55%) had lesions in hAQP4. Thirty-two/54 patients (60%) had lesions considered evocative of NMOSD. The majority of them also presented lesions in hAQP4 (65%, 21/32). Patients with lesions in hAQP4 and lesions evocative of NMOSD demonstrated more extensive myelitis compared to the other patients (7 [6-10] versus 4 [3-5] vertebral segments, P=0.009). CONCLUSION: The coexistence of lesions evocative of NMOSD and in hAQP4 is associated with significantly more extensive myelitis, and might have pathophysiological and clinical significance.

Effects of Intensive Versus Standard Ambulatory Blood Pressure Control on Cerebrovascular Outcomes in Older People (INFINITY).

BACKGROUND: Subcortical microvascular disease represented by brain white matter hyperintensity on magnetic resonance imaging is associated with functional decline in older people with hypertension. The effects of 2 levels of 24-hour average systolic blood pressure (BP) on mobility, white matter disease progression, and cognitive function over 3 years were studied. METHODS: This trial was a prospective, randomized, blinded end-points study in patients ≥75 years of age with systolic hypertension and magnetic resonance imaging evidence of white matter hyperintensity lesions. Patients were randomized to a 24-hour mean systolic BP of ≤130 mm Hg (intensive treatment) versus ≤145 mm Hg (standard treatment) with antihypertensive therapies. Primary study outcomes were changes in mobility (gait speed) and accrual of white matter hyperintensity volume after 3 years. Changes in cognitive function (executive processing) and adverse events were also evaluated. RESULTS: In 199 randomized patients, the mean age of the cohort was 80.5 years, and 54% were women; the average 24-hour systolic BP was 149 mm Hg. Goal BPs were achieved after a median treatment period of 3 to 4 months; at that time, the mean 24-hour systolic BP was 127.7 mm Hg in the intensive treatment group and 144.0 mm Hg in the standard treatment group for an average difference of 16.3 mm Hg. Changes in gait speed were not different between treatment groups (0.40±2.0 versus 0.42±2.7 s in the intensive treatment and standard treatment groups, respectively; P=0.91), whereas changes from baseline in white matter hyperintensity volumes were smaller (0.29%) in the intensive treatment group compared with the standard treatment group (0.48%; P=0.03). Cognitive outcomes also were not different between the treatment groups. Major adverse cardiovascular events were higher in the standard treatment group compared with the intensive treatment group (17 versus 4 patients; P=0.01). Falls, with or without injury, and syncope were comparable in the treatment groups. CONCLUSIONS: Intensive lowering of ambulatory BP reduction in older patients with hypertension did not result in differences in mobility outcomes but was associated with a reduction in accrual of subcortical white matter disease. Over periods >3 years, a reduction in the accumulation of white matter disease may be a factor in conserving function. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01650402.

Relationships among clinic, home, and ambulatory blood pressures with small vessel disease of the brain and functional status in older people with hypertension.

BACKGROUND: Subcortical small vessel disease, represented as white matter hyperintensity (WMH) on magnetic resonance images (MRI) is associated with functional decline in older people with hypertension. We evaluated the relationships of clinic and out-of-office blood pressures (BP) with WMH and functional status in older persons. METHODS: Using cross-sectional data from 199 older study participants enrolled in the INFINITY trial, we analyzed the clinic, 24-hour ambulatory, and home BPs and their relationships with WMH burden and mobility and cognitive outcomes. RESULTS: Volume of WMH was associated with clinic and 24-hour ambulatory systolic BP but not home systolic BP. The mobility measure, supine-to-sit time, had a significant association with 24-hour systolic BP and pulse pressure but not with diastolic BP or values obtained by home BP. Cognitive measures of processing speed (Trails Making Test Part A and the Stroop Word Test) were significantly associated with 24-hour systolic BP, but not clinic and home BPs. CONCLUSION: These data demonstrate that ambulatory BP measurements in older people are more strongly associated with WMH and certain measures of functional status compared to home BP measurements. Hence, home BP may not be a useful substitute for ambulatory BP for assessing subcortical small vessel disease and its consequences. Further longitudinal analyses comparing clinic and various types of out-of-office BP measures with small vessel brain disease are needed. Clinicaltrials.gov identifier: NCT01650402.

Posterior lobules of the cerebellum and information processing speed at various stages of multiple sclerosis.

BACKGROUND: Cerebellar damage has been implicated in information processing speed (IPS) impairment associated with multiple sclerosis (MS) that might result from functional disconnection in the frontocerebellar loop. Structural alterations in individual posterior lobules, in which cognitive functioning seems preponderant, are still unknown. Our aim was to investigate the impact of grey matter (GM) volume alterations in lobules VI to VIIIb on IPS in persons with clinically isolated syndrome (PwCIS), MS (PwMS) and healthy subjects (HS). METHODS: 69 patients (37 PwCIS, 32 PwMS) and 36 HS underwent 3 T MRI including 3-dimensional T1-weighted MRIs. Cerebellum lobules were segmented using SUIT V.3.0 to estimate their normalised GM volume. Neuropsychological testing was performed to assess IPS and main cognitive functions. RESULTS: Normalised GM volumes were significantly different between PwMS and HS for the right (p<0.001) and left lobule VI (p<0.01), left crus I, right VIIb and entire cerebellum (p<0.05 for each comparison) and between PwMS and PwCIS for all lobules in subregions VI and left crus I (p<0.05). IPS, attention and working memory were impaired in PwMS compared with PwCIS. In the whole population of patients (PwMS and PwCIS), GM loss in vermis VI (R2=0.36; p<0.05 when considering age and T2 lesion volume as covariates) were associated with IPS impairment. CONCLUSIONS: GM volume decrease in posterior lobules (especially vermis VI) was associated with reduced IPS. Our results suggest a significant impact of posterior lobules pathology in corticocerebellar loop disruption resulting in automation and cognitive optimisation lack in MS. TRIAL REGISTRATION: Clinicaltrail NCT01207856, NCT01865357; Pre-results.

Neural substrates of vulnerability to postsurgical delirium as revealed by presurgical diffusion MRI.

Despite the significant impact of postoperative delirium on surgical outcomes and the long-term prognosis of older patients, its neural basis has not yet been clarified. In this study we investigated the impact of premorbid brain microstructural integrity, as measured by diffusion tensor imaging before surgery, on postoperative delirium incidence and severity, as well as the relationship among presurgical cognitive performance, diffusion tensor imaging abnormalities and postoperative delirium. Presurgical diffusion tensor imaging scans of 136 older (≥70 years), dementia-free subjects from the prospective Successful Aging after Elective Surgery study were analysed blind to the clinical data and delirium status. Primary outcomes were postoperative delirium incidence and severity during the hospital stay, as assessed by the Confusion Assessment Method. We measured cognition before surgery using general cognitive performance, a composite score based on a battery of neuropsychological tests. We investigated the association between presurgical diffusion tensor imaging parameters of brain microstructural integrity (i.e. fractional anisotropy, axial, mean and radial diffusivity) with postoperative delirium incidence and severity. Analyses were adjusted for the following potential confounders: age, gender, vascular comorbidity status, and general cognitive performance. Postoperative delirium occurred in 29 of 136 subjects (21%) during hospitalization. Presurgical diffusion tensor imaging abnormalities of the cerebellum, cingulum, corpus callosum, internal capsule, thalamus, basal forebrain, occipital, parietal and temporal lobes, including the hippocampus, were associated with delirium incidence and severity, after controlling for age, gender and vascular comorbidities. After further controlling for general cognitive performance, diffusion tensor imaging abnormalities of the cerebellum, hippocampus, thalamus and basal forebrain still remained associated with delirium incidence and severity. This study raises the intriguing possibility that structural dysconnectivity involving interhemispheric and fronto-thalamo-cerebellar networks, as well as microstructural changes of structures involved in limbic and memory functions predispose to delirium under the stress of surgery. While the diffusion tensor imaging abnormalities observed in the corpus callosum, cingulum, and temporal lobe likely constitute the neural substrate for the association between premorbid cognition, as measured by general cognitive performance, and postoperative delirium, the microstructural changes observed in the cerebellum, hippocampus, thalamus and basal forebrain seem to constitute a separate phenomenon that predisposes to postsurgical delirium independent of presurgical cognitive status.

Stroke Location Is an Independent Predictor of Cognitive Outcome.

BACKGROUND AND PURPOSE: On top of functional outcome, accurate prediction of cognitive outcome for stroke patients is an unmet need with major implications for clinical management. We investigated whether stroke location may contribute independent prognostic value to multifactorial predictive models of functional and cognitive outcomes. METHODS: Four hundred twenty-eight consecutive patients with ischemic stroke were prospectively assessed with magnetic resonance imaging at 24 to 72 hours and at 3 months for functional outcome using the modified Rankin Scale and cognitive outcome using the Montreal Cognitive Assessment (MoCA). Statistical maps of functional and cognitive eloquent regions were derived from the first 215 patients (development sample) using voxel-based lesion-symptom mapping. We used multivariate logistic regression models to study the influence of stroke location (number of eloquent voxels from voxel-based lesion-symptom mapping maps), age, initial National Institutes of Health Stroke Scale and stroke volume on modified Rankin Scale and MoCA. The second part of our cohort was used as an independent replication sample. RESULTS: In univariate analyses, stroke location, age, initial National Institutes of Health Stroke Scale, and stroke volume were all predictive of poor modified Rankin Scale and MoCA. In multivariable analyses, stroke location remained the strongest independent predictor of MoCA and significantly improved the prediction compared with using only age, initial National Institutes of Health Stroke Scale, and stroke volume (area under the curve increased from 0.697-0.771; difference=0.073; 95% confidence interval, 0.008-0.155). In contrast, stroke location did not persist as independent predictor of modified Rankin Scale that was mainly driven by initial National Institutes of Health Stroke Scale (area under the curve going from 0.840 to 0.835). Similar results were obtained in the replication sample. CONCLUSIONS: Stroke location is an independent predictor of cognitive outcome (MoCA) at 3 months post stroke.

Early Fiber Number Ratio Is a Surrogate of Corticospinal Tract Integrity and Predicts Motor Recovery After Stroke.

BACKGROUND AND PURPOSE: The contribution of imaging metrics to predict poststroke motor recovery needs to be clarified. We tested the added value of early diffusion tensor imaging (DTI) of the corticospinal tract toward predicting long-term motor recovery. METHODS: One hundred seventeen patients were prospectively assessed at 24 to 72 hours and 1 year after ischemic stroke with diffusion tensor imaging and motor scores (Fugl-Meyer). The initial fiber number ratio (iFNr) and final fiber number ratio were computed as the number of streamlines along the affected corticospinal tract normalized to the unaffected side and were compared with each other. The prediction of motor recovery (ΔFugl-Meyer) was first modeled using initial Fugl-Meyer and iFNr. Multivariate ordinal logistic regression models were also used to study the association of iFNr, initial Fugl-Meyer, age, and stroke volume with Fugl-Meyer at 1 year. RESULTS: The iFNr correlated with the final fiber number ratio at 1 year (r=0.70; P<0.0001). The initial Fugl-Meyer strongly predicted motor recovery (≈73% of initial impairment) for all patients except those with initial severe stroke (Fugl-Meyer<50). For these severe patients (n=26), initial Fugl-Meyer was not correlated with motor recovery (R(2)=0.13; p=ns), whereas iFNr showed strong correlation (R(2)=0.56; P<0.0001). In multivariate analysis, the iFNr was an independent predictor of motor outcome (ß=2.601; 95% confidence interval=0.304-5.110; P=0.031), improving prediction compared with using only initial Fugl-Meyer, age, and stroke volume (P=0.026). CONCLUSIONS: Early measurement of FNr at 24 to 72 hours poststroke is a surrogate marker of corticospinal tract integrity and provides independent prediction of motor outcome at 1 year especially for patients with severe initial impairment.

Head circumference as a useful surrogate for intracranial volume in older adults.

BACKGROUND: Intracranial volume (ICV) has been proposed as a measure of maximum lifetime brain size. Accurate ICV measures require neuroimaging which is not always feasible for epidemiologic investigations. We examined head circumference as a useful surrogate for ICV in older adults. METHODS: 99 older adults underwent Magnetic Resonance Imaging (MRI). ICV was measured by Statistical Parametric Mapping 8 (SPM8) software or Functional MRI of the Brain Software Library (FSL) extraction with manual editing, typically considered the gold standard. Head circumferences were determined using standardized tape measurement. We examined estimated correlation coefficients between head circumference and the two MRI-based ICV measurements. RESULTS: Head circumference and ICV by SPM8 were moderately correlated (overall r = 0.73, men r = 0.67, women r = 0.63). Head circumference and ICV by FSL were also moderately correlated (overall r = 0.69, men r = 0.63, women r = 0.49). CONCLUSIONS: Head circumference measurement was strongly correlated with MRI-derived ICV. Our study presents a simple method to approximate ICV among older patients, which may prove useful as a surrogate for cognitive reserve in large scale epidemiologic studies of cognitive outcomes. This study also suggests the stability of head circumference correlation with ICV throughout the lifespan.

Using multiple imputation to efficiently correct cerebral MRI whole brain lesion and atrophy data in patients with multiple sclerosis.

Automated segmentation of brain MRI scans into tissue classes is commonly used for the assessment of multiple sclerosis (MS). However, manual correction of the resulting brain tissue label maps by an expert reader remains necessary in many cases. Since automated segmentation data awaiting manual correction are "missing", we proposed to use multiple imputation (MI) to fill-in the missing manually-corrected MRI data for measures of normalized whole brain volume (brain parenchymal fraction-BPF) and T2 hyperintense lesion volume (T2LV). Automated and manually corrected MRI measures from 1300 patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB) were identified. Simulation studies were conducted to assess the performance of MI with missing data both missing completely at random and missing at random. An imputation model including the concurrent automated data as well as clinical and demographic variables explained a high proportion of the variance in the manually corrected BPF (R(2)=0.97) and T2LV (R(2)=0.89), demonstrating the potential to accurately impute the missing data. Further, our results demonstrate that MI allows for the accurate estimation of group differences with little to no bias and with similar precision compared to an analysis with no missing data. We believe that our findings provide important insights for efficient correction of automated MRI measures to obviate the need to perform manual correction on all cases.

Treatment satisfaction, adherence and behavioral assessment in patients de-escalating from natalizumab to interferon ß.

BACKGROUND: De-escalating natalizumab (NTZ) to interferon beta 1b (IFN B 1B) is a possible treatment option in multiple sclerosis (MS) patients interrupting NTZ because of increased risk of progressive multifocal leukoencephalopathy (PML). The aim of this study was to evaluate satisfaction and adherence to treatment, behavioral and fatigue changes in patients switched to IFN B 1B compared to continued NTZ treatment. METHODS: A 1 year, prospective, randomized, rater-blinded, parallel-group study. Nineteen relapsing remitting (RR) MS patients, randomly assigned to undergo either NTZ (n = 10) or IFN B 1B (n = 9) treatment, who had previously received NTZ for at least 12 months with disease stability and fearing or at risk for PML were included. Patients underwent behavioral and treatment assessments at baseline, after 24-week and 1 year follow-up. Behavioral assessment included measures of cognition, fatigue and quality of life. Treatment assessment included measures of satisfaction, persistence and adherence to treatment. Clinical-radiological disease activity and safety were also assessed. RESULTS: Baseline characteristics of patients were similar between groups except for Euro Quality Visual Analogue Scale, being higher in the NTZ group (p = 0.04). Within-group comparisons at the three time points, as well as interaction analysis of treatment effect over time did not show any statistically significant differences in behavioral or treatment assessments, but a coherent trend favoring NTZ over IFN B 1B. CONCLUSIONS: De-escalating NTZ to IFN B 1B is feasible and associated with overall good patient related outcome and persistently stable behavioral measures.

INtensive versus standard ambulatory blood pressure lowering to prevent functional DeclINe in the ElderlY (INFINITY).

Reductions in mobility and cognitive function linked to accrual of brain microvascular disease related white matter hyperintensities (WMHs) on magnetic resonance imaging can occur in older hypertensive patients in as little as 2 years. We have designed a trial evaluating 2 levels of ambulatory blood pressure (ABP) control in individuals with normal or mildly impaired mobility and cognition who have detectable cerebrovascular disease (>0.5% WMH fraction of intracranial volume) on functional outcomes. The study is a prospective randomized, open-label trial with blinded end points, in patients ages ≥75 years with elevated 24-hour systolic blood pressure (BP) (145 mm Hg in the untreated state) who do not have unstable cardiovascular disease, heart failure, or stroke. The primary and key secondary outcomes in the trial are change from baseline in mobility and cognitive function and damage to brain white matter as demonstrated by accrual of WMH volume and changes in diffusion tensor imaging. Approximately 300 patients will be enrolled, and 200 randomized to 1 of 2 levels of ABP control (intensive to achieve a goal 24-hour systolic BP of ≤130 mm Hg or standard to achieve a goal 24-hour systolic BP of ≤145 mm Hg) for a total of 36 months using similar antihypertensive regimens. The analytical approach provides 85% power to show a clinically meaningful effect in differences in mobility accompanied by quantitative differences in WMH between treatment groups. The INFINITY trial is the first to guide antihypertensive therapy using ABP monitoring rather than clinic BP to reduce cerebrovascular disease.

No sex-specific difference in disease trajectory in multiple sclerosis patients before and after age 50.

BACKGROUND: The disease course in multiple sclerosis (MS) is influenced by many factors, including age, sex, and sex hormones. Little is known about sex-specific changes in disease course around age 50, which may represent a key biological transition period for reproductive aging. METHODS: Male and female subjects with no prior chemotherapy exposure were selected from a prospective MS cohort to form groups representing the years before (38-46 years, N=351) and after (54-62 years, N=200)age 50. Primary analysis assessed for interaction between effects of sex and age on clinical (Expanded Disability Status Scale, EDSS; relapse rate) and radiologic (T2 lesion volume, T2LV; brain parenchymal fraction, BPF) outcomes. Secondarily, we explored patient-reported outcomes (PROs). RESULTS: As expected, there were age- and sex- related changes with male and older cohorts showing worse disease severity (EDSS), brain atrophy (BPF), and more progressive course.There was no interaction between age and sex on cross-sectional adjusted clinical (EDSS, relapse rate) or radiologic (BPF, T2LV) measures, or on 2-year trajectories of decline.There was a significant interaction between age and sex for a physical functioning PRO (SF-36): the older female cohort reported lower physical functioning than men (p=0.002). There were no differences in depression (Center for Epidemiological Study - Depression, CES-D) or fatigue (Modified Fatigue Impact Scale, MFIS) scores. CONCLUSIONS: There was no interaction between age and sex suggestive of an effect of reproductive aging on clinical or radiologic progression. Prospective analyses across the menopausal transition are needed.

Interferon beta 1b following natalizumab discontinuation: one year, randomized, prospective, pilot trial.

BACKGROUND: Natalizumab (NTZ) discontinuation leads to multiple sclerosis reactivation.The objective of this study is to compare disease activity in MS patients who continued on NTZ treatment to those who were switched to subcutaneous interferon 1b (IFNB) treatment. METHODS: 1-year randomized, rater-blinded, parallel-group, pilot study (ClinicalTrial.gov ID: NCT01144052). Relapsing remitting MS patients on NTZ for ≥12 months who had been free of disease activity on this therapy (no relapses and disability progression for ≥6 months, no gadolinium-enhancing lesions on baseline MRI) were randomized to NTZ or IFNB. Primary endpoint was time to first on-study relapse. Additional clinical, MRI and safety parameters were assessed. Analysis was based on intention to treat. RESULTS: 19 patients (NTZ n=10; IFNB n=9) with similar baseline characteristics were included. 78% of IFNB treated patients remained relapse free (NTZ group: 100%), and 25% remained free of new T2 lesions (NTZ group: 62.5%). While time to first on-study relapse was not significantly different between groups (p=0.125), many secondary clinical and radiological endpoints (number of relapses, proportion of relapse free patients, number of new T2 lesions) showed a trend, or were significant (new T2 lesions at month 6) in favoring NTZ. CONCLUSIONS: De-escalation therapy from NTZ to IFNB over 1 year was associated with some clinical and radiological disease recurrence. Overall no major safety concerns were observed.

Quantitative MRI analysis in children with multiple sclerosis: a multicenter feasibility pilot study.

BACKGROUND: Pediatric multiple sclerosis (MS) is a rare disorder with significant consequences. Quantitative MRI measurements may provide significant insights, however multicenter collaborative studies are needed given the small numbers of subjects. The goal of this study is to demonstrate feasibility and evaluate lesion volume (LV) characteristics in a multicenter cohort of children with MS. METHODS: A common MRI-scanning guideline was implemented at six member sites of the U.S. Network of Pediatric MS Centers of Excellence. We included in this study the first ten scans performed at each site on patients meeting the following inclusion criteria: pediatric RRMS within 3 years of disease onset, examination within 1 month of MRI and no steroids 1 month prior to MRI. We quantified T2 number, T2-LV and individual lesion size in a total of 53 MRIs passing quality control procedures and assessed gadolinium-enhancing lesion number and LV in 55 scans. We studied MRI measures according to demographic features including age, race, ethnicity and disability scores, controlling for disease duration and treatment duration using negative binomial regression and linear regression. RESULTS: The mean number of T2 lesions was 24.30 ± 19.68 (range:1-113) and mean gadolinium-enhancing lesion count was 1.85 ± 5.84, (range:0-32). Individual lesion size ranged from 14.31 to 55750.60 mm3. Non-white subjects had higher T2-LV (unadjusted pT2-LV = 0.028; adjusted pT2-LV = 0.044), and maximal individual T2-LV (unadjusted pMax = 0.007; adjusted pMax = 0.011) than white patients. We also found a trend toward larger mean lesion size in males than females (p = 0.07). CONCLUSION: Assessment of MRI lesion LV characteristics is feasible in a multicenter cohort of children with MS.

Radial diffusivity in the cerebellar peduncles correlates with clinical severity in Friedreich ataxia.

Friedreich ataxia (FRDA) is a common inherited ataxia, caused by an expanded GAA repeat sequence in the Frataxin (FXN) gene. The proprioceptive system, which enters the cerebellum through the cerebellar peduncles, is a primary focus of pathology. In this study, we investigate the relationship of clinical and genetic data with diffusion-tensor imaging (DTI) indices reflecting white matter integrity of the cerebellar peduncles. Nine FRDA patients underwent DTI. After between-subject registration using tract-based spatial statistics, a white matter atlas was used for computing average values of DTI indices in the regions of interest. These were the inferior, middle and superior cerebellar peduncles (ICP, MCP, SCP). For Bonferroni correction, significance threshold was set to p < 0.0056. We found that radial diffusivity (D(⊥)) within the ICP significantly correlated with scores on the Friedreich Ataxia Rating Scale (FARS, Spearman's ρ = 0.883, p = 0.0016, all two-sided) and, at trend level, with number of trinucleotide repeats (ρ = 0.812, p = 0.008). D(⊥) in the SCP correlated with scores on the Scale for the Assessment and Rating of Ataxia (SARA, ρ = 0.867, p = 0.0025). These findings support the role of DTI, and especially D(⊥), as an informative biomarker in FRDA.

Fronto-striatal damage may contribute to resistance to fatigue-lowering medications in multiple sclerosis.

BACKGROUND AND PURPOSE: Commonly used fatigue-lowering medications have not been proven effective in treating multiple sclerosis (MS)-related fatigue. A neuroanatomical basis for treatment-resistant fatigue in MS has not been explored. The aim of this study was to investigate the association between brain diffusion abnormality patterns and resistance to fatigue-lowering treatment. METHODS: Retrospective patient stratification: 1. treatment-resistant (n = 22) received anti-fatigue and/or anti-depressant and/or anxiolytic medication and the latest two Modified Fatigue Impact Scale (MFIS) score≥38; 2. responder (n = 16): received anti-fatigue and/or antidepressant and/or anxiolytic medication while the latest MFIS was <38, and minimum one previous MFIS was ≥38; 3. non-treated never-fatigued (n = 26): received none of the above-mentioned medications and MFIS was always<38 (over minimum four years assessed with MFIS every 1-2 years). 3T brain MRI was used to perform a cross-sectional voxel-wise comparison of fractional anisotropy (FA) between the groups. RESULTS: Treatment-resistant versus responder patients showed more extensive brain damage (ie, lower FA) favoring the fronto-striatal pathways. Both groups showed more widespread brain damage than non-treated never-fatigued patients. A mean fronto-striatal FA value of 0.26 could perfectly predict response to modafinil/armodafinil. CONCLUSION: Fronto-striatal damage may play a role in the development of resistance to fatigue-lowering treatment. Fronto-striatal FA may serve as a biomarker to predict response to fatigue-lowering medications in MS.

Serum GFAP and NfL Levels Differentiate Subsequent Progression and Disease Activity in Patients With Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Neurodegeneration and astrocytic activation are pathologic hallmarks of progressive multiple sclerosis (MS) and can be quantified by serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP). We investigated sNfL and sGFAP as tools for stratifying patients with progressive MS based on progression and disease activity status. METHODS: We leveraged our Comprehensive Longitudinal Investigation of MS at the Brigham and Women's Hospital (CLIMB) natural history study, which includes clinical, MRI data and serum samples collected over more than 20 years. We included patients with MS with a confirmed Expanded Disability Status Scale (EDSS) score ≥3 that corresponds with our classifier for patients at high risk of underlying progressive pathology. We analyzed sNfL and sGFAP within 6 months from the confirmed EDSS score ≥3 corresponding with our baseline visit. Patients who further developed 6-month confirmed disability progression (6mCDP) were classified as progressors. We further stratified our patients into active/nonactive based on new brain/spinal cord lesions or relapses in the 2 years before baseline or during follow-up. Statistical analysis on log-transformed sGFAP/sNfL assessed the baseline association with demographic, clinical, and MRI features and associations with future disability. RESULTS: We included 257 patients with MS who had an average EDSS score of 4.0 and a median follow-up after baseline of 7.6 years. sNfL was higher in patients with disease activity in the 2 years before baseline (adjusted ß = 1.21; 95% CI 1.04-1.42; p = 0.016), during the first 2 years of follow-up (adjusted ß = 1.17; 95% CI = 1.01-1.36; p = 0.042). sGFAP was not increased in the presence of disease activity. Higher sGFAP levels, but not sNfL levels, were associated with higher risk of 6mCDP (adjusted hazard ratio [HR] = 1.71; 95% CI = 1.19-2.45; p = 0.004). The association was stronger in patients with low sNfL (adjusted HR = 2.44; 95% CI 1.32-4.52; p = 0.005) and patients who were nonactive in the 2 years prior or after the sample. DISCUSSION: Higher levels of sGFAP correlated with subsequent progression, particularly in nonactive patients, whereas sNfL reflected acute disease activity in patients with MS at high risk of underlying progressive pathology. Thus, sGFAP and sNfL levels may be used to stratify patients with progressive MS for clinical research studies and clinical trials and may inform clinical care.

Early neurofilament light and glial fibrillary acidic protein levels improve predictive models of multiple sclerosis outcomes.

BACKGROUND: Early risk-stratification in multiple sclerosis (MS) may impact treatment decisions. Current predictive models have identified that clinical and imaging characteristics of aggressive disease are associated with worse long-term outcomes. Serum biomarkers, neurofilament (sNfL) and glial fibrillary acidic protein (sGFAP), reflect subclinical disease activity through separate pathological processes and may contribute to predictive models of clinical and MRI outcomes. METHODS: We conducted a retrospective analysis of the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB study), where patients with multiple sclerosis are seen every 6 months and undergo Expanded Disability Status Scale (EDSS) assessment, have annual brain MRI scans where volumetric analysis is conducted to calculate T2-lesion volume (T2LV) and brain parenchymal fraction (BPF), and donate a yearly blood sample for subsequent analysis. We included patients with newly diagnosed relapsing-remitting MS and serum samples obtained at baseline visit and 1-year follow-up (both within 3 years of onset), and were assessed at 10-year follow-up. We measured sNfL and sGFAP by single molecule array at baseline visit and at 1-year follow-up. A predictive clinical model was developed using age, sex, Expanded Disability Status Scale (EDSS), pyramidal signs, relapse rate, and spinal cord lesions at first visit. The main outcome was odds of developing of secondary progressive (SP)MS at year 10. Secondary outcomes included 10-year EDSS, brain T2LV and BPF. We compared the goodness-of-fit of the predictive clinical model with and without sNfL and sGFAP at baseline and 1-year follow-up, for each outcome by area under the receiver operating characteristic curve (AUC) or R-squared. RESULTS: A total 144 patients with median MS onset at age 37.4 years (interquartile range: 29.4-45.4), 64% female, were included. SPMS developed in 25 (17.4%) patients. The AUC for the predictive clinical model without biomarker data was 0.73, which improved to 0.77 when both sNfL and sGFAP were included in the model (P = 0.021). In this model, higher baseline sGFAP associated with developing SPMS (OR=3.3 [95%CI:1.1,10.6], P = 0.04). Adding 1-year follow-up biomarker levels further improved the model fit (AUC = 0.79) but this change was not statistically significant (P = 0.15). Adding baseline biomarker data also improved the R-squared of clinical models for 10-year EDSS from 0.24 to 0.28 (P = 0.032), while additional 1-year follow-up levels did not. Baseline sGFAP was associated with 10-year EDSS (ß=0.58 [95%CI:0.00,1.16], P = 0.05). For MRI outcomes, baseline biomarker levels improved R-squared for T2LV from 0.12 to 0.27 (P<0.001), and BPF from 0.15 to 0.20 (P = 0.042). Adding 1-year follow-up biomarker data further improved T2LV to 0.33 (P = 0.0065) and BPF to 0.23 (P = 0.048). Baseline sNfL was associated with T2LV (ß=0.34 [95%CI:0.21,0.48], P<0.001) and 1-year follow-up sNfL with BPF (ß=-2.53% [95%CI:-4.18,-0.89], P = 0.003). CONCLUSIONS: Early biomarker levels modestly improve predictive models containing clinical and MRI variables. Worse clinical outcomes, SPMS and EDSS, are associated with higher sGFAP levels and worse MRI outcomes, T2LV and BPF, are associated with higher sNfL levels. Prospective study implementing these predictive models into clinical practice are needed to determine if early biomarker levels meaningfully impact clinical practice.