Thalamic atrophy is a highly common and disabling consequence of multiple sclerosis (MS) that occurs early in the disease process, progressively worsens over time, and negatively impacts functional and quality of life outcomes in patients. Long-term aerobic walking exercise training (ET), in particular, represents a promising approach for mitigating MS-related thalamic atrophy and its downstream consequences in persons with MS. The present early-stage trial examined the feasibility of two different doses of a 12-month remotely delivered and supported aerobic walking ET program on thalamic volume and its downstream outcomes of cognitive processing speed, walking performance, and quality of life in 25 fully-ambulatory persons with MS who were pre-screened for slowed cognitive processing speed. The 12-month trial was feasible in terms of process, resource, and management metrics, and the 12-month exercise prescriptions were both safe and associated with high adherence rates. However, the higher-dose walking ET prescription was too difficult in terms of duration and intensity. Regarding scientific feasibility, with the data pooled across conditions, 12-months of remotely delivered and supported aerobic walking ET was associated with preservation of thalamic volume (d = 1.01), along with benefits on cognitive processing speed (d = 0.41), walking endurance (d = 0.33), and aerobic fitness overall (d = 0.48). Collectively, the present feasibility data support the design and testing of a subsequent randomized controlled trial of 12-months of remotely delivered and supported aerobic walking ET on thalamic volume/atrophy and its downstream consequences in persons with MS.

This review addresses the biological mechanisms and contributions of frailty in multiple sclerosis (MS), a chronic disease of the central nervous system that causes physical and cognitive disability. The risk of frailty among persons with MS (pwMS) exceeds that of other chronic diseases, and the interactions between frailty and MS pathologies can aggravate physical disability. The hallmarks of frailty include increased vulnerability, reduced ability to respond to stressors, and elevated risk of adverse health outcomes. Although frailty is often conflated with aging, it can affect individuals with chronic conditions, such as MS, regardless of chronological age. The overlap between MS-related disability and frailty and the nexus among ambulatory impairment, fatigue, and metabolic alterations contribute to accelerated frailty risk. The utility and limitations of frailty measures such as the Fried Frailty Phenotype and the Frailty Index in MS are presented. The shared pathophysiology of MS and frailty includes metabolic dysregulation, sarcopenia, and systemic inflammation. The pathways underlying these shared pathophysiological interactions, along with their implications, are reviewed. Recognizing frailty as a distinct, intersecting condition in MS may inform care strategies, improve quality of life, and improve long-term outcomes.

BACKGROUND:GA Depot is a long-acting glatiramer acetate (GA)-based formulation designed to provide significantly extended dosing intervals compared to currently available GA formulations. OBJECTIVE:To assess GA Depot efficacy, safety, and tolerability compared to placebo in patients with relapsing multiple sclerosis (RMS). METHODS:A 52-week multi-center, double-blind, placebo-controlled phase 3 trial in RMS. Patients aged 18-55 with an Expanded Disability Status Scale (EDSS) score ⩽ 5.5 were enrolled and randomized (1:1) to intramuscular (IM) GA Depot 40 mg or matching placebo every 4 weeks. The primary endpoint was annualized relapse rate (ARR) at 52 weeks. RESULTS:A total of 1016 patients were treated with GA Depot (n = 508) or placebo (n = 508). Adjusted ARR was lower in patients treated with GA Depot compared to placebo (0.18, 95% confidence interval [CI] = 0.14 to 0.3 vs 0.26, 95% CI = 0.21 to 0.32, 30.1% relative risk reduction, p = 0.0066). GA Depot significantly reduced the number of contrast-enhancing lesions (p = 0.0083). The most common adverse events were injection site reactions (46.1% with GA Depot vs 28.7% with placebo), primarily mild and self-limited. CONCLUSION:GA Depot effectively reduced clinical and radiological activity compared to placebo in RMS patients, recapitulating the favorable profile of subcutaneous GA products with significantly less frequent injections. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT04121221 (https://clinicaltrials.gov/study/NCT04121221).

BACKGROUND:Chronic lesion tissue expansion (CLTE) reflects slow, concentric growth of established multiple sclerosis (MS) lesions and is linked to central brain atrophy and disability progression. Whether existing MS disease-modifying therapies (DMTs) differentially influence this aspect of progressive MS biology remains unclear. OBJECTIVES:To compare the effect of current DMTs on CLTE in a multicentre, real-world MS cohort. METHODS:We conducted a retrospective, observational study using linked clinical data from MSBase and the MSBase Imaging Repository. Data from patients aged ⩾18 years with ⩾3 longitudinal MRI scans, and 7 therapies with ⩾100 stable treatment epochs were included. Therapy effects on CLTE, new T2 lesions, and brain atrophy were assessed using epoch-based covariate-adjusted generalised estimating equation models, with fingolimod as a comparator. RESULT:The cohort included 564 patients contributing 1648 stable treatment epochs. After adjustment for demographic, clinical, and imaging covariates, B-cell depleting therapy was the only DMT associated with significantly lower CLTE (β = -4.03, p = 0.017) relative to fingolimod. CLTE was independently associated with age, baseline lesion volume, and centre effects. CONCLUSIONS:B-cell depletion is associated with reduced CLTE, a promising biomarker of progressive MS biology.

CHRFAM7A is a biallelic uniquely human fusion gene present in 99.3% of humans. The direct and inverted alleles likely emerged independently in Africa and East Asia. We uncovered that the inverted allele regulates ULK4 expression through genetic epistasis. The increase in long to short ULK4 isoform ratio enhances α-tubulin acetylation leading to microtubule (MT) cytoskeleton phenotypes (cell body: microtubule rich projections; neurite: de-bundling; growth cone: fanning with MT invasion). The MT cytoskeleton gain of function enhances neuronal arborization and functional connectivity in the human brain. Considering that the previously reported direct allele leads to actin cytoskeleton gain of function, we propose that CHRFAM7A alleles represent binary human genetic background through divergent evolution of the cytoskeleton. In the human brain the two alleles represent distinct brain organization: the direct allele enhances microstructure as measured by diffusion tensor imaging while the inverted allele increases functional connectivity with increased small world propensity. The two types of brain organization likely represent different susceptibility to neuropsychiatric disease and may underlie the allelic disease associations.

Purpose:To develop a novel, fully automated marker-based method for registering PET images from a small, non-stationary, retrofitted preclinical PET detector to simultaneously acquired MRI images. Methods:We manufactured a nose cone tract with geometric markers from a material visible when imaged with a zero-echo-time MRI sequence. A one-time universal calibration determined the relation between the PET image space and the nose cone tract markers. An experiment-specific calibration was needed to determine the location of the nose cone tract markers in laboratory space, and, hence, in MRI image space. The robustness of the method was evaluated through systematic experiments. Results:Experiments demonstrated successful registration of the two imaging modalities with a spatial registration error below the PET voxel size. Conclusion:The proposed registration approach is a practical method for registering simultaneously acquired PET and MR images with sub-voxel precision when the PET device is non-stationary and the usable space inside the detector is too small for dual-modality fiducial markers.

Diffusion Tensor Image Analysis ALong the Perivascular Space (DTI-ALPS) was originally proposed to quantify glymphatic functioning. Although a direct interpretation is now questioned, cross-sectional studies show associations with disability in people with multiple sclerosis (pwMS). Regardless, serial DTI-ALPS studies are largely lacking in MS. In a longitudinal study, we investigated DTI-ALPS with respect to confirmed disability progression (CDP) and progression independent of relapse activity (PIRA) in people with relapsing-remitting MS (pwRRMS) and progressive MS (pwPMS). This study included 72 pwRRMS, 27 pwPMS, and 23 healthy controls (HC) imaged with 3T MRI and again after 5 years. The DTI-ALPS index was calculated using an automated pipeline using template-defined regions of interest (ROIs) in the superior longitudinal fasciculus and superior corona radiata. Areas corresponding to T2 hyperintensities were removed to avoid the influence of overt pathology. CDP and PIRA were assessed after 5 years and in 64 pwRRMS/17 pwPMS after 10 years. Comparisons between those with and without follow-up CDP or PIRA were assessed using analysis of covariance and repeated including normal appearing white matter (NAWM) mean diffusivity (MD) as an additional covariate. Multivariable binary logistic regression was used to explore whether DTI-ALPS offers independent value beyond general disease burden. Although significantly lower in pwMS compared with HCs (1.347 ± 0.178 versus 1.437 ± 0.132, P = 0.034, partial η 2 = 0.021), the difference was no longer so after controlling for NAWM MD (P = 0.094, partial η 2 = 0.024). DTI-ALPS decreases over 5 years were similar between HC and pwMS (P = 0.188, partial η 2 = 0.021). In pwRRMS, baseline DTI-ALPS was lower in those who developed CDP or PIRA at 5- and 10 years of follow-up (all P ≤ 0.019, partial η 2 > 0.080, except for PIRA at 5 years, P = 0.051, partial η 2 = 0.055). When controlling for NAWM MD, results were in line with original findings. Baseline T2-LV was the only retained imaging predictor of CDP and PIRA over 5 years while only baseline DTI-ALPS was selected for in 10 year models. No associations were found in the pwPMS group. Changes in DTI-ALPS over 5 years did not relate to CDP nor PIRA in neither group. In conclusion, although DTI-ALPS values were not significantly different compared with HCs after considering NAWM MD, decreased baseline DTI-ALPS is associated with disability progression in pwRRMS. The lack of associations in pwPMS suggests that DTI-ALPS may be less informative with more advanced disease.

Post-contrast FLAIR MRI can demonstrate meningeal signal enhancement in people with multiple sclerosis (pwMS), including enhancement along the leptomeninges and dura mater. Although these enhancement patterns have been variably interpreted as reflecting inflammatory processes, their biological specificity and relationship to cortical lesion pathology remain uncertain. To evaluate the association between cortical lesion burden and distinct patterns of meningeal enhancement (ME), including dura mater enhancement (DME), leptomeningeal enhancement (LME), and meningeal perivascular enhancement (MPVE) on MRI in pwMS. 214 pwMS (173 relapsing–remitting, 41 progressive) underwent 3T MRI including 3D FLAIR pre- and post-contrast, and subtraction imaging. ME (LME + DME) and MPVE were visually classified. Cortical lesions were quantified using a validated multi-modal approach incorporating MMCLE, FLAIR-squared, AI-DIR, and T1/T2 ratio maps, with expert verification. Analyses were adjusted for age, sex, disease duration, disease subtype, and disease-modifying treatment, and corrected for multiple comparisons. 142 (66.4

BACKGROUND:Perivascular space (PVS) alterations may be associated with acute and chronic inflammatory activity in people with multiple sclerosis (pwMS). PURPOSE:Investigate whether diffusion tensor image analysis along the PVS (DTI-ALPS) or PVS number/volume are associated with lesion evolution in pwMS over 5-years. METHODS:182 patients (142 relapsing-remitting MS [pwRRMS] and 40 progressive MS [pwPMS]) underwent clinical and MRI examinations at baseline and 5-year follow-up. All pwMS were assessed for contrast enhancing lesions (CELs), T2 lesions, T1 lesions and cortical lesions (CLs). A subset of 86 pwMS were analyzed for presence of paramagnetic rim lesions (PRL). Associations between DTI-ALPS, PVS number/volume and lesion types were evaluated using regression and ANCOVA models, adjusting for age, sex, disease duration and normal-appearing white matter mean diffusivity, with false discovery rate correction for multiple comparisons, resulting in q values. RESULTS:In pwRRMS, baseline DTI-ALPS was associated with baseline CEL number (q < 0.001), T1 lesion number (q = 0.013), T2 lesion volume (q = 0.037) and T1 lesion volume (q < 0.002). It was associated with accumulation of new/enlarging CL (q = 0.013) and T1 lesions (q = 0.007), absolute change in T1 lesion volume (q = 0.025) and trended with newly appearing PRLs (q = 0.066). Absolute 5-year change in PVS volume was related to PRL presence at baseline (q = 0.018). CONCLUSION:PVS alterations are associated with lesion evolution in pwRRMS.

BACKGROUND:Multiple sclerosis (MS) is a chronic neurological disease affecting both white and gray matter of the central nervous system. Despite the well-established involvement of cortical lesions in MS, feasibility limitations in their visualization on typical magnetic resonance imaging (MRI) protocols prevent their evaluation in nearly all clinical trials. Recently, several post-processing methods, including synthetic contrasts and artificial intelligence (AI)-based approaches, have shown potential for enhancing cortical lesion detection on conventional MRI data. These methods have the potential to reanalyze existing clinical-trial data to answer key mechanistic questions about both MS development and about treatment effects. METHODS:We sought to evaluate the feasibility of combining and extending existing methods into a unified framework for analysis using the data from the large, multicenter, phase 3 ORATORIO trial (full n = 732, age=44.6 ± 8.0; development subset n = 80, age=46.6 ± 7.1). We specifically evaluated three of the most promising of them - fluid-attenuated inversion recovery squared (FLAIR2), T1/T2 ratio, and artificial intelligence-derived double inversion recovery (AI-DIR) - and introduced a new combined contrast called multi-modal cortical lesion enhanced (MMCLE). We also harnessed transformer-based semantic segmentation to improve automated detection and delineation of these lesions. RESULTS:At baseline, we detected 14.8 + /-20.72 lesions per participant, with 86.0% true positive rate and 8.4% false positive rate across subjects for blinded MMCLE, using simultaneous review of all contrasts as the reference. High reproducibility was observed across field strengths and acquisition types (ICC 88.8-92.5%). CONCLUSIONS:We confirmed that cortical lesions can be clearly visualized and quantified with these methods. Using deep learning, we also confirmed that the simultaneous use of multiple contrasts improves quantification.

Severe multiple sclerosis (MS) presents challenges for clinical research due to patient mobility constraints and specialized care needs. Traditional MRI studies often exclude this population but portable, ultra-low-field (ULF) MRI at 0.064 T enables bedside imaging. To (i) compare ULF MRI volumetry with standard 3 T, (ii) assess the capability of portable ULF MRI in characterizing severe MS. This prospective study enrolled two cohorts. Cohort 1 included healthy controls (HC) and people with MS (pwMS). Cohort 2 enrolled individuals with progressive MS, with either severe or less severe MS. Both cohorts underwent ULF MRI while those in Cohort 1 were also scanned on 3 T MRI. Clinical assessments included disability and cognition. MRI data was processed using both conventional (e.g., SIENAX) and AI-driven (e.g., WMH-SynthSeg) techniques. Group comparisons and MRI-clinical associations were assessed. Cohort 1 included 14 HCs (39 ± 13 years, 11 females) and 33 pwMS (32 ± 10 years, 24 females). Cohort 2 included 24 severe MS individuals (62 ± 10, 15 females) and 16 less severe MS individuals (61 years ± 11, 8 females). MRI passed quality control except for scans from 2 individuals in Cohort 2. In Cohort 1, 3 T and ULF MRI showed robust disease differences, with strongest effect sizes for ULF MRI-derived whole brain (partial η2 = 0.264), cortical gray matter (GM) (partial η2 = 0.234), and thalamic volumes (partial η2 = 0.266) from WMH-SynthSeg. In terms of severe versus less severe disease in Cohort 2, the largest effect sizes were obtained with SIENAX-derived cortical GM volume (partial η2 = 0.349) and whole brain volume (partial η2 = 0.290), while WMH-SynthSeg yielded the highest effect size for WM volume (partial η2 = 0.209). For clinical outcomes, associations were dependent on processing method, although SIENAX yielded the most consistent correlations in Cohort 2. Portable, ULF MRI is feasible in pwMS and provides insights into late-stage neurodegeneration in severe MS.

Predicting disease progression at the individual level is essential for personalized medicine. We previously developed machine-learning tools to estimate 5-year progression risk in people with multiple sclerosis (PwMS). Such models should account for disease-modifying therapy (DMT) and objective outcome definitions. In a retrospective multicenter case–control study, we evaluated adults with relapsing–remitting multiple sclerosis (RRMS) at baseline. Using machine-learning, we developed two complementary tools for individualized 5-year risk estimation: DAAE-M, optimized for transparency, software-neutral use, and mitigation of indication bias, and ELIE, optimized for dynamic landmark-based modeling, complex treatment histories, and mitigation of immortal-time bias. Disease progression was defined using both a clinical outcome (RRMS-to-progressive MS) and an objective outcome (late-stage confirmed progression independent of relapse activity). Among 34,510 people with RRMS (72.6

Pathologically altered iron levels, detected using iron-sensitive MRI techniques such as quantitative susceptibility mapping (QSM), are observed in neurological disorders such as multiple sclerosis (MS) and may play a crucial role in disease pathophysiology. However, brain iron changes occur slowly, even in neurological diseases, and can be influenced by physiological factors such as diet. Therefore, novel analysis methods are needed to improve sensitivity to disease-related iron changes as compared to conventional region-based analysis methods. This study introduces IRONMAP, Iron Network Mapping and Analysis Protocol, which is a novel network-based analysis method to evaluate over-time changes in magnetic susceptibility. With this novel methodology, we analyzed short-term (<1 year) longitudinal QSM data from a cohort of individuals with MS (pwMS) and healthy controls (HCs) and assessed disease-related network patterns, comparing the new approach to a conventional per-region rate-of-change method. IRONMAP analysis was able to detect over-time, MS-related brain iron abnormalities that were undetectable using the rate-of-change approach. IRONMAP was applicable on the per-subject level, improving binary classification of pwMS vs HCs compared to rate-of-change data alone (areas under the curve: 0.773 vs 0.636, p = 0.024). Further analysis revealed that the observed IRONMAP-derived HC network structure closely aligned with simulated networks based on healthy aging-related susceptibility data, suggesting that disruptions in normal aging-related iron changes may contribute to the network differences seen in pwMS. IRONMAP is generalizable to any neurological disease, including Alzheimer's disease and Parkinson's disease, and may allow for study of brain iron abnormalities over shorter timeframes than previously possible.

Background:The 30-day Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) has been used to risk-stratify patients undergoing transcatheter aortic valve replacement (TAVR). Whether surgical mortality risk predicts stroke and neurocognitive outcomes following TAVR is unknown. We evaluated the association between STS-PROM and clinical outcomes, including stroke, acute brain injury on diffusion-weighted magnetic resonance imaging (DW-MRI), and cognitive decline in patients undergoing TAVR. Methods:Patient-level data were pooled from 4 prospective trials: (1) DEFLECT III (N = 87), (2) NeuroTAVR (N = 44), (3) REFLECT I (N = 214), and (4) REFLECT II (N = 258). All studies included patients undergoing TAVR with a protocol-mandated predischarge DW-MRI and serial cognitive and neurologic assessments. All patients were evaluated by a board-certified neurologist at baseline, postprocedure, and 30 days. Clinical outcomes, including stroke, cognitive decline (Montreal Cognitive Assessment score), death, myocardial infarction, vascular, and bleeding complications were adjudicated by the same clinical events committee. Imaging analysis was performed by a single core laboratory using identical methods. The DW-MRI measures included total lesion number, individual lesion volume, and total lesion volume. Outcomes were compared between low (STS <4), intermediate (STS 4-8), and high (STS >8) risk groups. Results:In total, 537 of 603 patients with DW-MRI and complete STS assessment undergoing transfemoral TAVR were included in this pooled analysis, of which 253 (47%) were low risk, 198 (37%) intermediate risk, and 86 (16%) high risk patients. At 30 days, high risk patients had higher rates of all-cause and cardiovascular mortality, myocardial infarction, acute kidney injury, bleeding, and vascular complications. Rates of stroke, disabling stroke, DW-MRI measures of brain injury, and cognitive decline were similar across risk categories. Conclusions:This pooled analysis demonstrates that the STS score does not predict stroke, cognitive decline, or acute brain injury after TAVR.

BACKGROUND:The personality traits Neuroticism and/or Conscientiousness are associated with depression, brain atrophy, cognitive impairment and job loss in multiple sclerosis (MS). OBJECTIVES:We aimed to assess whether Neuroticism and Conscientiousness predict per-year risk for MS disease worsening defined by transition to secondary progressive MS (SPMS) or disability progression on the Expanded Disability Status Scale (EDSS). METHODS:In a retrospective, longitudinal analysis of 375 persons with relapsing remitting MS (PwRRMS), we evaluated Neuroticism and Conscientiousness using the NEO Five Factor Inventory. In the first analysis, PwRRMS were grouped on whether their disease course changed to SPMS. In the second analysis subjects were grouped into those with EDSS increases vs stable. Cox regression modeling was employed to account for varying length of follow-up. RESULTS:High Conscientiousness was significantly associated with a decreased hazard of course change (HR = 0.97 per T score point of Conscientiousness, 95 % CI [0.95 to 1.00], p = .049). A trend for Conscientiousness predicting EDSS increases (HR = 0.98 per T score point of Conscientiousness, 95 % CI [0.97 to 1.00], p = .051) was observed. Neuroticism was non-significant across survival analyses. CONCLUSION:Conscientiousness can serve as a protective factor against MS disease worsening.