Cerebrovascular Reactivity in Patients With Small Vessel Disease: A Cross-Sectional Study.

BACKGROUND: Cerebrovascular reactivity (CVR) is inversely related to white matter hyperintensity severity, a marker of cerebral small vessel disease (SVD). Less is known about the relationship between CVR and other SVD imaging features or cognition. We aimed to investigate these cross-sectional relationships. METHODS: Between 2018 and 2021 in Edinburgh, we recruited patients presenting with lacunar or cortical ischemic stroke, whom we characterized for SVD features. We measured CVR in subcortical gray matter, normal-appearing white matter, and white matter hyperintensity using 3T magnetic resonance imaging. We assessed cognition using Montreal Cognitive Assessment. Statistical analyses included linear regression models with CVR as outcome, adjusted for age, sex, and vascular risk factors. We reported regression coefficients with 95% CIs. RESULTS: Of 208 patients, 182 had processable CVR data sets (median age, 68.2 years; 68% men). Although the strength of association depended on tissue type, lower CVR in normal-appearing tissues and white matter hyperintensity was associated with larger white matter hyperintensity volume (BNAWM=-0.0073 [95% CI, -0.0133 to -0.0014] %/mm Hg per 10-fold increase in percentage intracranial volume), more lacunes (BNAWM=-0.00129 [95% CI, -0.00215 to -0.00043] %/mm Hg per lacune), more microbleeds (BNAWM=-0.00083 [95% CI, -0.00130 to -0.00036] %/mm Hg per microbleed), higher deep atrophy score (BNAWM=-0.00218 [95% CI, -0.00417 to -0.00020] %/mm Hg per score point increase), higher perivascular space score (BNAWM=-0.0034 [95% CI, -0.0066 to -0.0002] %/mm Hg per score point increase in basal ganglia), and higher SVD score (BNAWM=-0.0048 [95% CI, -0.0075 to -0.0021] %/mm Hg per score point increase). Lower CVR in normal-appearing tissues was related to lower Montreal Cognitive Assessment without reaching convention statistical significance (BNAWM=0.00065 [95% CI, -0.00007 to 0.00137] %/mm Hg per score point increase). CONCLUSIONS: Lower CVR in patients with SVD was related to more severe SVD burden and worse cognition in this cross-sectional analysis. Longitudinal analysis will help determine whether lower CVR predicts worsening SVD severity or vice versa. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: ISRCTN12113543.

Quantitative T1 brain mapping in early relapsing-remitting multiple sclerosis: longitudinal changes, lesion heterogeneity and disability.

OBJECTIVES: To quantify brain microstructural changes in recently diagnosed relapsing-remitting multiple sclerosis (RRMS) using longitudinal T1 measures, and determine their associations with clinical disability. METHODS: Seventy-nine people with recently diagnosed (< 6 months) RRMS were recruited from a single-centre cohort sub-study, and underwent baseline and 1-year brain MRI, including variable flip angle T1 mapping. Median T1 was measured in white matter lesions (WML), normal-appearing white matter (NAWM), cortical/deep grey matter (GM), thalami, basal ganglia and medial temporal regions. Prolonged T1 (≥ 2.00 s) and supramedian T1 (relative to cohort WML values) WML voxel counts were also measured. Longitudinal change was assessed with paired t-tests and compared with Bland-Altman limits of agreement from healthy control test-retest data. Regression analyses determined relationships with Expanded Disability Status Scale (EDSS) score and dichotomised EDSS outcomes (worsening or stable/improving). RESULTS: Sixty-two people with RRMS (mean age 37.2 ± 10.9 [standard deviation], 48 female) and 11 healthy controls (age 44 ± 11, 7 female) contributed data. Prolonged and supramedian T1 WML components increased longitudinally (176 and 463 voxels, respectively; p < .001), and were associated with EDSS score at baseline (p < .05) and follow-up (supramedian: p < .01; prolonged: p < .05). No cohort-wide median T1 changes were found; however, increasing T1 in WML, NAWM, cortical/deep GM, basal ganglia and thalami was positively associated with EDSS worsening (p < .05). CONCLUSION: T1 is sensitive to brain microstructure changes in early RRMS. Prolonged WML T1 components and subtle changes in NAWM and GM structures are associated with disability. CLINICAL RELEVANCE STATEMENT: MRI T1 brain mapping quantifies disability-associated white matter lesion heterogeneity and subtle microstructural damage in normal-appearing brain parenchyma in recently diagnosed RRMS, and shows promise for early objective disease characterisation and stratification. KEY POINTS: • Quantitative T1 mapping detects brain microstructural damage and lesion heterogeneity in recently diagnosed relapsing-remitting multiple sclerosis. • T1 increases in lesions and normal-appearing parenchyma, indicating microstructural damage, are associated with worsening disability. • Brain T1 measures are objective markers of disability-relevant pathology in early multiple sclerosis.

Rim lesions are demonstrated in early relapsing-remitting multiple sclerosis using 3 T-based susceptibility-weighted imaging in a multi-institutional setting.

PURPOSE: Rim lesions, characterised by a paramagnetic rim on susceptibility-based MRI, have been suggested to reflect chronic inflammatory demyelination in multiple sclerosis (MS) patients. Here, we assess, through susceptibility-weighted imaging (SWI), the prevalence, longitudinal volume evolution and clinical associations of rim lesions in subjects with early relapsing-remitting MS (RRMS). METHODS: Subjects (n = 44) with recently diagnosed RRMS underwent 3 T MRI at baseline (M0) and 1 year (M12) as part of a multi-centre study. SWI was acquired at M12 using a 3D segmented gradient-echo echo-planar imaging sequence. Rim lesions identified on SWI were manually segmented on FLAIR images at both time points for volumetric analysis. RESULTS: Twelve subjects (27%) had at least one rim lesion at M12. A linear mixed-effects model, with 'subject' as a random factor, revealed mixed evidence for the difference in longitudinal volume change between rim lesions and non-rim lesions (p = 0.0350 and p = 0.0556 for subjects with and without rim lesions, respectively). All 25 rim lesions identified showed T1-weighted hypointense signal. Subjects with and without rim lesions did not differ significantly with respect to age, disease duration or clinical measures of disability (p > 0.05). CONCLUSION: We demonstrate that rim lesions are detectable in early-stage RRMS on 3 T MRI across multiple centres, although their relationship to lesion enlargement is equivocal in this small cohort. Identification of SWI rims was subjective. Agreed criteria for defining rim lesions and their further validation as a biomarker of chronic inflammation are required for translation of SWI into routine MS clinical practice.

Loss of eIF4E Phosphorylation Engenders Depression-like Behaviors via Selective mRNA Translation.

The MAPK/ERK (mitogen-activated protein kinases/extracellular signal-regulated kinase) pathway is a cardinal regulator of synaptic plasticity, learning, and memory in the hippocampus. One of major endpoints of this signaling cascade is the 5' mRNA cap binding protein eIF4E (eukaryotic Initiation Factor 4E), which is phosphorylated on Ser 209 by MNK (MAPK-interacting protein kinases) and controls mRNA translation. The precise role of phospho-eIF4E in the brain is yet to be determined. Herein, we demonstrate that ablation of eIF4E phosphorylation in male mice (4Eki mice) does not impair long-term spatial or contextual fear memory, or the late phase of LTP. Using unbiased translational profiling in mouse brain, we show that phospho-eIF4E differentially regulates the translation of a subset of mRNAs linked to inflammation, the extracellular matrix, pituitary hormones, and the serotonin pathway. Consequently, 4Eki male mice display exaggerated inflammatory responses and reduced levels of serotonin, concomitant with depression and anxiety-like behaviors. Remarkably, eIF4E phosphorylation is required for the chronic antidepressant action of the selective serotonin reuptake inhibitor fluoxetine. Finally, we propose a novel phospho-eIF4E-dependent translational control mechanism in the brain, via the GAIT complex (gamma IFN activated inhibitor of translation). In summary, our work proposes a novel translational control mechanism involved in the regulation of inflammation and depression, which could be exploited to design novel therapeutics.SIGNIFICANCE STATEMENT We demonstrate that downstream of the MAPK (mitogen-activated protein kinase) pathway, eukaryotic Initiation Factor 4E (eIF4E) Ser209 phosphorylation is not required for classical forms of hippocampal LTP and memory. We reveal a novel role for eIF4E phosphorylation in inflammatory responses and depression-like behaviors. eIF4E phosphorylation is required for the chronic action of antidepressants, such as fluoxetine in mice. These phenotypes are accompanied by selective translation of extracellular matrix, pituitary hormones, and serotonin pathway genes, in eIF4E phospho-mutant mice. We also describe a previously unidentified translational control mechanism in the brain, whereby eIF4E phosphorylation is required for inhibiting the translation of gamma IFN activated inhibitor of translation element-containing mRNAs. These findings can be used to design novel therapeutics for depression.

Brain connectivity changes underlying depression and fatigue in relapsing-remitting multiple sclerosis: A systematic review.

Multiple Sclerosis (MS) is an autoimmune disease affecting the central nervous system, characterised by neuroinflammation and neurodegeneration. Fatigue and depression are common, debilitating, and intertwined symptoms in people with relapsing-remitting MS (pwRRMS). An increased understanding of brain changes and mechanisms underlying fatigue and depression in RRMS could lead to more effective interventions and enhancement of quality of life. To elucidate the relationship between depression and fatigue and brain connectivity in pwRRMS we conducted a systematic review. Searched databases were PubMed, Web-of-Science and Scopus. Inclusion criteria were: studied participants with RRMS (n ≥ 20; ≥ 18 years old) and differentiated between MS subtypes; published between 2001-01-01 and 2023-01-18; used fatigue and depression assessments validated for MS; included brain structural, functional magnetic resonance imaging (fMRI) or diffusion MRI (dMRI). Sixty studies met the criteria: 18 dMRI (15 fatigue, 5 depression) and 22 fMRI (20 fatigue, 5 depression) studies. The literature was heterogeneous; half of studies reported no correlation between brain connectivity measures and fatigue or depression. Positive findings showed that abnormal cortico-limbic structural and functional connectivity was associated with depression. Fatigue was linked to connectivity measures in cortico-thalamic-basal-ganglial networks. Additionally, both depression and fatigue were related to altered cingulum structural connectivity, and functional connectivity involving thalamus, cerebellum, frontal lobe, ventral tegmental area, striatum, default mode and attention networks, and supramarginal, precentral, and postcentral gyri. Qualitative analysis suggests structural and functional connectivity changes, possibly due to axonal and/or myelin loss, in the cortico-thalamic-basal-ganglial and cortico-limbic network may underlie fatigue and depression in pwRRMS, respectively, but the overall results were inconclusive, possibly explained by heterogeneity and limited number of studies. This highlights the need for further studies including advanced MRI to detect more subtle brain changes in association with depression and fatigue. Future studies using optimised imaging protocols and validated depression and fatigue measures are required to clarify the substrates underlying these symptoms in pwRRMS.

Impact of long-term white matter hyperintensity changes on mobility and dexterity.

White matter hyperintensities (WMH), a common feature of cerebral small vessel disease, are related to worse clinical outcomes after stroke. We assessed the impact of white matter hyperintensity changes over 1 year after minor stroke on change in mobility and dexterity, including differences between the dominant and non-dominant hands and objective in-person assessment versus patient-reported experience. We recruited participants with lacunar or minor cortical ischaemic stroke, performed medical and cognitive assessments and brain MRI at presentation and at 1 year. At both time points, we used the timed-up and go test and the 9-hole peg test to assess mobility and dexterity. At 1 year, participants completed the Stroke Impact Scale. We ran two linear mixed models to assess change in timed-up and go and 9-hole peg test, adjusted for age, sex, stroke severity (National Institutes of Health Stroke Scale), dependency (modified Rankin Score), vascular risk factor score, white matter hyperintensity volume (as % intracranial volume) and additionally for 9-hole peg test: Montreal cognitive assessment, hand (dominant/non-dominant), National Adult Reading Test (premorbid IQ), index lesion side. We performed ordinal logistic regression, corrected for age and sex, to assess relations between timed-up and go and Stroke Impact Scale mobility, and 9-hole peg test and Stroke Impact Scale hand function. We included 229 participants, mean age 65.9 (standard deviation = 11.13); 66% male. 215/229 attended 1-year follow-up. Over 1 year, timed-up and go time increased with aging (standardized ß [standardized 95% Confidence Interval]: 0.124[0.011, 0.238]), increasing National Institutes of Health Stroke Scale (0.106[0.032, 0.180]), increasing modified Rankin Score (0.152[0.073, 0.231]) and increasing white matter hyperintensity volume (0.176[0.061, 0.291]). Men were faster than women (-0.306[0.011, 0.238]). Over 1 year, slower 9-hole peg test was related to use of non-dominant hand (0.290[0.155, 0.424]), aging (0.102[0.012, 0.192]), male sex (0.182[0.008, 0.356]), increasing National Institutes of Health Stroke Scale (0.160 [0.094, 0.226]), increasing modified Rankin Score (0.100[0.032, 0.169]), decreasing Montreal cognitive assessment score (-0.090[-0.167, -0.014]) and increasing white matter hyperintensity volume (0.104[0.015, 0.193]). One year post-stroke, Stroke Impact Scale mobility worsened per second increase on timed-up and go, odds ratio 0.67 [95% confidence interval 0.60, 0.75]. Stroke Impact Scale hand function worsened per second increase on the 9-hole peg test for the dominant hand (odds ratio 0.79 [0.71, 0.86]) and for the non-dominant hand (odds ratio 0.88 [0.83, 0.93]). Decline in mobility and dexterity is associated with white matter hyperintensity volume increase, independently of stroke severity. Mobility and dexterity declined more gradually for stable and regressing white matter hyperintensity volume. Dominant and non-dominant hands might be affected differently. In-person measures of dexterity and mobility are associated with self-reported experience 1-year post-stroke.

Magnetic Resonance Imaging Tissue Signatures Associated With White Matter Changes Due to Sporadic Cerebral Small Vessel Disease Indicate That White Matter Hyperintensities Can Regress.

BACKGROUND: White matter hyperintensities (WMHs) might regress and progress contemporaneously, but we know little about underlying mechanisms. We examined WMH change and underlying quantitative magnetic resonance imaging tissue measures over 1 year in patients with minor ischemic stroke with sporadic cerebral small vessel disease. METHODS AND RESULTS: We defined areas of stable normal-appearing white matter, stable WMHs, progressing and regressing WMHs based on baseline and 1-year brain magnetic resonance imaging. In these areas we assessed tissue characteristics with quantitative T1, fractional anisotropy (FA), mean diffusivity (MD), and neurite orientation dispersion and density imaging (baseline only). We compared tissue signatures cross-sectionally between areas, and longitudinally within each area. WMH change masks were available for N=197. Participants' mean age was 65.61 years (SD, 11.10), 59% had a lacunar infarct, and 68% were men. FA and MD were available for N=195, quantitative T1 for N=182, and neurite orientation dispersion and density imaging for N=174. Cross-sectionally, all 4 tissue classes differed for FA, MD, T1, and Neurite Density Index. Longitudinally, in regressing WMHs, FA increased with little change in MD and T1 (difference estimate, 0.011 [95% CI, 0.006-0.017]; -0.002 [95% CI, -0.008 to 0.003] and -0.003 [95% CI, -0.009 to 0.004]); in progressing and stable WMHs, FA decreased (-0.022 [95% CI, -0.027 to -0.017] and -0.009 [95% CI, -0.011 to -0.006]), whereas MD and T1 increased (progressing WMHs, 0.057 [95% CI, 0.050-0.063], 0.058 [95% CI, 0.050 -0.066]; stable WMHs, 0.054 [95% CI, 0.045-0.063], 0.049 [95% CI, 0.039-0.058]); and in stable normal-appearing white matter, MD increased (0.004 [95% CI, 0.003-0.005]), whereas FA and T1 slightly decreased and increased (-0.002 [95% CI, -0.004 to -0.000] and 0.005 [95% CI, 0.001-0.009]). CONCLUSIONS: Quantitative magnetic resonance imaging shows that WMHs that regress have less abnormal microstructure at baseline than stable WMHs and follow trajectories indicating tissue improvement compared with stable and progressing WMHs.

Patterns of brain atrophy in recently-diagnosed relapsing-remitting multiple sclerosis.

Recurrent neuroinflammation in relapsing-remitting MS (RRMS) is thought to lead to neurodegeneration, resulting in progressive disability. Repeated magnetic resonance imaging (MRI) of the brain provides non-invasive measures of atrophy over time, a key marker of neurodegeneration. This study investigates regional neurodegeneration of the brain in recently-diagnosed RRMS using volumetry and voxel-based morphometry (VBM). RRMS patients (N = 354) underwent 3T structural MRI <6 months after diagnosis and 1-year follow-up, as part of the Scottish multicentre 'FutureMS' study. MRI data were processed using FreeSurfer to derive volumetrics, and FSL for VBM (grey matter (GM) only), to establish regional patterns of change in GM and normal-appearing white matter (NAWM) over time throughout the brain. Volumetric analyses showed a decrease over time (q<0.05) in bilateral cortical GM and NAWM, cerebellar GM, brainstem, amygdala, basal ganglia, hippocampus, accumbens, thalamus and ventral diencephalon. Additionally, NAWM and GM volume decreased respectively in the following cortical regions, frontal: 14 out of 26 regions and 16/26; temporal: 18/18 and 15/18; parietal: 14/14 and 11/14; occipital: 7/8 and 8/8. Left GM and NAWM asymmetry was observed in the frontal lobe. GM VBM analysis showed three major clusters of decrease over time: 1) temporal and subcortical areas, 2) cerebellum, 3) anterior cingulum and supplementary motor cortex; and four smaller clusters within the occipital lobe. Widespread GM and NAWM atrophy was observed in this large recently-diagnosed RRMS cohort, particularly in the brainstem, cerebellar GM, and subcortical and occipital-temporal regions; indicative of neurodegeneration across tissue types, and in accord with limited previous studies in early disease. Volumetric and VBM results emphasise different features of longitudinal lobar and loco-regional change, however identify consistent atrophy patterns across individuals. Atrophy measures targeted to specific brain regions may provide improved markers of neurodegeneration, and potential future imaging stratifiers and endpoints for clinical decision making and therapeutic trials.

Network analysis characterizes key associations between subjective fatigue and specific depressive symptoms in early relapsing-remitting multiple sclerosis.

BACKGROUND: Fatigue is common and disabling in multiple sclerosis (MS), yet its mechanisms are poorly understood. In particular, overlap in measures of fatigue and depression complicates interpretation. We applied a multivariate network approach to quantify relationships between fatigue and other variables in early MS. METHODS: Data were collected from patients with newly diagnosed immunotherapy-naïve relapsing-remitting MS at baseline and month 12 follow-up in FutureMS, a Scottish nationally representative cohort. Subjective fatigue was assessed by Fatigue Severity Scale. Detailed phenotyping included measures assessing each of physical disability, affective disorders, cognitive performance, sleep quality, and structural brain imaging. Network analysis was conducted to estimate partial correlations between variables. Baseline networks were compared between those with persistent and remitted fatigue at one-year follow up. RESULTS: Data from 322 participants at baseline, and 323 at month 12, were included. At baseline, 154 patients (47.8%) reported clinically significant fatigue. In the network analysis, fatigue severity showed strongest connections with depression, followed by Expanded Disability Status Scale. Conversely, fatigue severity was not linked to objective cognitive performance or brain imaging variables. Even after controlling for measurement of "tiredness" in our measure of depression, four specific depressive symptoms remained linked to fatigue. Results were consistent at baseline and month 12. Overall network strength was not significantly different between groups with persistent and remitted fatigue (4.89 vs 2.90, p = 0.11). CONCLUSIONS: Our findings support robust links between subjective fatigue and depression in early relapsing-remitting MS. Shared mechanisms between specific depressive symptoms and fatigue could be key targets of treatment and research in MS-related fatigue.

Effect of blood pressure-lowering agents on microvascular function in people with small vessel diseases (TREAT-SVDs): a multicentre, open-label, randomised, crossover trial.

BACKGROUND: Hypertension is the leading risk factor for cerebral small vessel disease. We aimed to determine whether antihypertensive drug classes differentially affect microvascular function in people with small vessel disease. METHODS: We did a multicentre, open-label, randomised crossover trial with blinded endpoint assessment at five specialist centres in Europe. We included participants aged 18 years or older with symptomatic sporadic small vessel disease or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and an indication for antihypertensive treatment. Participants were randomly assigned (1:1:1) to one of three sequences of antihypertensive treatment using a computer-generated multiblock randomisation, stratified by study site and patient group. A 2-week washout period was followed by three 4-week periods of oral monotherapy with amlodipine, losartan, or atenolol at approved doses. The primary endpoint was change in cerebrovascular reactivity (CVR) determined by blood oxygen level-dependent MRI response to hypercapnic challenge in normal-appearing white matter from the end of washout to the end of each treatment period. Efficacy analyses were done by intention-to-treat principles in all randomly assigned participants who had at least one valid assessment for the primary endpoint, and analyses were done separately for participants with sporadic small vessel disease and CADASIL. This trial is registered at ClinicalTrials.gov, NCT03082014, and EudraCT, 2016-002920-10, and is terminated. FINDINGS: Between Feb 22, 2018, and April 28, 2022, 75 participants with sporadic small vessel disease (mean age 64·9 years [SD 9·9]) and 26 with CADASIL (53·1 years [7·0]) were enrolled and randomly assigned to treatment. 79 participants (62 with sporadic small vessel disease and 17 with CADASIL) entered the primary efficacy analysis. Change in CVR did not differ between study drugs in participants with sporadic small vessel disease (mean change in CVR 1·8 × 10-4%/mm Hg [SE 20·1; 95% CI -37·6 to 41·2] for amlodipine; 16·7 × 10-4%/mm Hg [20·0; -22·3 to 55·8] for losartan; -7·1 × 10-4%/mm Hg [19·6; -45·5 to 31·1] for atenolol; poverall=0·39) but did differ in patients with CADASIL (15·7 × 10-4%/mm Hg [SE 27·5; 95% CI -38·3 to 69·7] for amlodipine; 19·4 × 10-4%/mm Hg [27·9; -35·3 to 74·2] for losartan; -23·9 × 10-4%/mm Hg [27·5; -77·7 to 30·0] for atenolol; poverall=0·019). In patients with CADASIL, pairwise comparisons showed that CVR improved with amlodipine compared with atenolol (-39·6 × 10-4%/mm Hg [95% CI -72·5 to -6·6; p=0·019) and with losartan compared with atenolol (-43·3 × 10-4%/mm Hg [-74·3 to -12·3]; p=0·0061). No deaths occurred. Two serious adverse events were recorded, one while taking amlodipine (diarrhoea with dehydration) and one while taking atenolol (fall with fracture), neither of which was related to study drug intake. INTERPRETATION: 4 weeks of treatment with amlodipine, losartan, or atenolol did not differ in their effects on cerebrovascular reactivity in people with sporadic small vessel disease but did result in differential treatment effects in patients with CADASIL. Whether antihypertensive drug classes differentially affect clinical outcomes in people with small vessel diseases requires further research. FUNDING: EU Horizon 2020 programme.

Longitudinal microstructural MRI markers of demyelination and neurodegeneration in early relapsing-remitting multiple sclerosis: Magnetisation transfer, water diffusion and g-ratio.

INTRODUCTION: Quantitative microstructural MRI, such as myelin-sensitive magnetisation transfer ratio (MTR) or saturation (MTsat), axon-sensitive water diffusion Neurite Orientation Dispersion and Density Imaging (NODDI), and the aggregate g-ratio, may provide more specific markers of white matter integrity than conventional MRI for early patient stratification in relapsing-remitting multiple sclerosis (RRMS). The aim of this study was to determine the sensitivity of such markers to longitudinal pathological change within cerebral white matter lesions (WML) and normal-appearing white matter (NAWM) in recently diagnosed RRMS. METHODS: Seventy-nine people with recently diagnosed RRMS, from the FutureMS longitudinal cohort, were recruited to an extended MRI protocol at baseline and one year later. Twelve healthy volunteers received the same MRI protocol, repeated within two weeks. Ethics approval and written informed consent were obtained. 3T MRI included magnetisation transfer, and multi-shell diffusion-weighted imaging. NAWM and whole brain were segmented from 3D T1-weighted MPRAGE, and WML from T2-weighted FLAIR. MTR, MTsat, NODDI isotropic (ISOVF) and intracellular (ICVF) volume fractions, and g-ratio (calculated from MTsat and NODDI data) were measured within WML and NAWM. Brain parenchymal fraction (BPF) was also calculated. Longitudinal change in BPF and microstructural metrics was assessed with paired t-tests (α = 0.05) and linear mixed models, adjusted for confounding factors with False Discovery Rate (FDR) correction for multiple comparisons. Longitudinal changes were compared with test-retest Bland-Altman limits of agreement from healthy control white matter. The influence of longitudinal change on g-ratio was explored through post-hoc analysis in silico by computing g-ratio with realistic simulated MTsat and NODDI values. RESULTS: In NAWM, g-ratio and ICVF increased, and MTsat decreased over one year (adjusted mean difference = 0.007, 0.005, and -0.057 respectively, all FDR-corrected p < 0.05). There was no significant change in MTR, ISOVF, or BPF. In WML, MTsat, NODDI ICVF and ISOVF increased over time (adjusted mean difference = 0.083, 0.024 and 0.016, respectively, all FDR-corrected p < 0.05). Group-level longitudinal changes exceeded test-retest limits of agreement for NODDI ISOVF and ICVF in WML only. In silico analysis showed g-ratio may increase due to a decrease in MTsat or ISOVF, or an increase in ICVF. DISCUSSION: G-ratio and MTsat changes in NAWM over one year may indicate subtle myelin loss in early RRMS, which were not apparent with BPF or NAWM MTR. Increases in NAWM and WML NODDI ICVF were not anticipated, and raise the possibility of axonal swelling or morphological change. Increases in WML MTsat may reflect myelin repair. Changes in NODDI ISOVF are more likely to reflect alterations in water content. Competing MTsat and ICVF changes may account for the absence of g-ratio change in WML. Longitudinal changes in microstructural measures are significant at a group level, however detection in individual patients in early RRMS is limited by technique reproducibility. CONCLUSION: MTsat and g-ratio are more sensitive than MTR to early pathological changes in RRMS, but complex dependence of g-ratio on NODDI parameters limit the interpretation of aggregate measures in isolation. Improvements in technique reproducibility and validation of MRI biophysical models across a range of pathological tissue states are needed.

Rationale and design of the brain magnetic resonance imaging protocol for FutureMS: a longitudinal multi-centre study of newly diagnosed patients with relapsing-remitting multiple sclerosis in Scotland.

Introduction: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease. MS prevalence varies geographically and is notably high in Scotland. Disease trajectory varies significantly between individuals and the causes for this are largely unclear. Biomarkers predictive of disease course are urgently needed to allow improved stratification for current disease modifying therapies and future targeted treatments aimed at neuroprotection and remyelination. Magnetic resonance imaging (MRI) can detect disease activity and underlying damage non-invasively in vivo at the micro and macrostructural level. FutureMS is a prospective Scottish longitudinal multi-centre cohort study, which focuses on deeply phenotyping patients with recently diagnosed relapsing-remitting MS (RRMS). Neuroimaging is a central component of the study and provides two main primary endpoints for disease activity and neurodegeneration. This paper provides an overview of MRI data acquisition, management and processing in FutureMS. FutureMS is registered with the Integrated Research Application System (IRAS, UK) under reference number 169955. Methods and analysis: MRI is performed at baseline (N=431) and 1-year follow-up, in Dundee, Glasgow and Edinburgh (3T Siemens) and in Aberdeen (3T Philips), and managed and processed in Edinburgh. The core structural MRI protocol comprises T1-weighted, T2-weighted, FLAIR and proton density images. Primary imaging outcome measures are new/enlarging white matter lesions (WML) and reduction in brain volume over one year. Secondary imaging outcome measures comprise WML volume as an additional quantitative structural MRI measure, rim lesions on susceptibility-weighted imaging, and microstructural MRI measures, including diffusion tensor imaging and neurite orientation dispersion and density imaging metrics, relaxometry, magnetisation transfer (MT) ratio, MT saturation and derived g-ratio measures. Conclusions: FutureMS aims to reduce uncertainty around disease course and allow for targeted treatment in RRMS by exploring the role of conventional and advanced MRI measures as biomarkers of disease severity and progression in a large population of RRMS patients in Scotland.

The prevalence of paramagnetic rim lesions in multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Recent findings from several studies have shown that paramagnetic rim lesions identified using susceptibility-based MRI could represent potential diagnostic and prognostic biomarkers in multiple sclerosis (MS). Here, we perform a systematic review and meta-analysis of the existing literature to assess their pooled prevalence at lesion-level and patient-level. METHODS: Both database searching (PubMed and Embase) and handsearching were conducted to identify studies allowing the lesion-level and/or patient-level prevalence of rim lesions or chronic active lesions to be calculated. Pooled prevalence was estimated using the DerSimonian-Laird random-effects model. Subgroup analysis and meta-regression were performed to explore possible sources of heterogeneity. PROSPERO registration: CRD42020192282. RESULTS: 29 studies comprising 1230 patients were eligible for analysis. Meta-analysis estimated pooled prevalences of 9.8% (95% CI: 6.6-14.2) and 40.6% (95% CI: 26.2-56.8) for rim lesions at lesion-level and patient-level, respectively. Pooled lesion-level and patient-level prevalences for chronic active lesions were 12.0% (95% CI: 9.0-15.8) and 64.8% (95% CI: 54.3-74.0), respectively. Considerable heterogeneity was observed across studies (I2>75%). Subgroup analysis revealed a significant difference in patient-level prevalence between studies conducted at 3T and 7T (p = 0.0312). Meta-regression analyses also showed significant differences in lesion-level prevalence with respect to age (p = 0.0018, R2 = 0.20) and disease duration (p = 0.0018, R2 = 0.48). Other moderator analyses demonstrated no significant differences according to MRI sequence, gender and expanded disability status scale (EDSS). CONCLUSION: In this study, we show that paramagnetic rim lesions may be present in an important proportion of MS patients, notwithstanding significant variation in their assessment across studies. In view of their possible clinical relevance, we believe that clear guidelines should be introduced to standardise their assessment across research centres to in turn facilitate future analyses.

Raptor-Mediated Proteasomal Degradation of Deamidated 4E-BP2 Regulates Postnatal Neuronal Translation and NF-κB Activity.

The translation initiation repressor 4E-BP2 is deamidated in the brain on asparagines N99/N102 during early postnatal brain development. This post-translational modification enhances 4E-BP2 association with Raptor, a central component of mTORC1 and alters the kinetics of excitatory synaptic transmission. We show that 4E-BP2 deamidation is neuron specific, occurs in the human brain, and changes 4E-BP2 subcellular localization, but not its disordered structure state. We demonstrate that deamidated 4E-BP2 is ubiquitinated more and degrades faster than the unmodified protein. We find that enhanced deamidated 4E-BP2 degradation is dependent on Raptor binding, concomitant with increased association with a Raptor-CUL4B E3 ubiquitin ligase complex. Deamidated 4E-BP2 stability is promoted by inhibiting mTORC1 or glutamate receptors. We further demonstrate that deamidated 4E-BP2 regulates the translation of a distinct pool of mRNAs linked to cerebral development, mitochondria, and NF-κB activity, and thus may be crucial for postnatal brain development in neurodevelopmental disorders, such as ASD.