Addition of quantitative MRI to the routine clinical care of patients with multiple sclerosis-Results from the MAGNON project.

BACKGROUND: The revised Lublin classification offers a framework for categorizing multiple sclerosis (MS) according to the clinical course and imaging results. Diagnosis of secondary progressive MS (SPMS) is often delayed by a period of uncertainty. Several quantitative magnetic resonance imaging (qMRI) markers are associated with progressive disease states, but they are not usually available in clinical practice. METHODS: The MAGNON project enrolled 629 patients (early relapsing-remitting MS (RRMS), n = 51; RRMS with suspected SPMS, n = 386; SPMS, n = 192) at 55 centers in Germany. Routine magnetic resonance imaging (MRI) scans at baseline and after 12 months were analyzed using a centralized automatic processing pipeline to quantify lesions and normalized brain and thalamic volume. Clinical measures included relapse activity, disability, and MS phenotyping. Neurologists completed questionnaires before and after receiving the qMRI reports. RESULTS: According to the physicians' reports, qMRI results changed their assessment of the patient in 31.8% (baseline scan) and 27.6% (follow-up scan). For ∼50% of patients with RRMS with suspected SPMS, reports provided additional information that the patient was transitioning to SPMS. In >25% of all patients, this information influenced the physicians' assessment of the patient's current phenotype. However, actual changes of treatment were reported only in a minority of these patients. CONCLUSIONS: The MAGNON results suggest that standardized qMRI reports may be integrated into the routine clinical care of MS patients and support the application of the Lublin classification as well as treatment decisions. The highest impact was reported in patients with suspected SPMS, indicating a potential to reduce diagnostic uncertainty.

Glial cell injury and atrophied lesion volume as measures of chronic multiple sclerosis inflammation.

BACKGROUND: Atrophied lesion volume (aLV), a proposed biomarker of disability progression in multiple sclerosis (MS) and transition into progressive MS (PMS), depicts chronic periventricular white matter (WM) pathology. Meningeal infiltrates, imaged as leptomeningeal contrast enhancement (LMCE), are linked with greater cortical pathology. OBJECTIVES: To determine the relationship between serum-derived proteomic data with the development of aLV and LMCE in a heterogeneous group of people with MS (pwMS). METHODS: Proteomic and MRI data for 202 pwMS (148 clinically isolated syndrome /relapsing-remitting MS and 54 progressive MS (PMS)) were acquired at baseline and at 5.4-year follow-up. The concentrations of 21 proteins related to multiple MS pathophysiology pathways were derived using a custom-developed Proximity Extension Assay on the Olink™ platform. The accrual of aLV was determined as the volume of baseline T2-weighted lesions that were replaced by cerebrospinal fluid over the follow-up. Regression models and age-adjusted analysis of covariance (ANCOVA) were used. RESULTS: Older age (standardized beta = 0.176, p = 0.022), higher glial fibrillary acidic protein (standardized beta = 0.312, p = 0.001), and lower myelin oligodendrocyte glycoprotein levels (standardized beta = -0.271, p = 0.002) were associated with accrual of aLV over follow-up. This relationship was driven by the pwPMS population. The presence of LMCE at the follow-up visit was not predicted by any baseline proteomic biomarker nor cross-sectionally associated with any protein concentration. CONCLUSION: Proteomic markers of glial activation are associated with chronic lesional WM pathology (measured as aLV) and may be specific to the progressive MS phenotype. LMCE presence in MS does not appear to relate to proteomic measures.

Mapping brain volume change across time in primary-progressive multiple sclerosis.

PURPOSE: Detection and prediction of the rate of brain volume loss with age is a significant unmet need in patients with primary progressive multiple sclerosis (PPMS). In this study we construct detailed brain volume maps for PPMS patients. These maps compare age-related changes in both cortical and sub-cortical regions with those in healthy individuals. METHODS: We conducted retrospective analyses of brain volume using T1-weighted Magnetic Resonance Imaging (MRI) scans of a large cohort of PPMS patients and healthy subjects. The volume of brain parenchyma (BP), cortex, white matter (WM), deep gray matter, thalamus, and cerebellum were measured using the robust SynthSeg segmentation tool. Age- and gender-related regression curves were constructed based on data from healthy subjects, with the 95% prediction interval adopted as the normality threshold for each brain region. RESULTS: We analyzed 495 MRI scans from 169 PPMS patients, aged 20-79 years, alongside 563 exams from healthy subjects aged 20-86. Compared to healthy subjects, a higher proportion of PPMS patients showed lower than expected brain volumes in all regions except the cerebellum. The most affected areas were BP, WM, and thalamus. Lower brain volumes correlated with longer disease duration for BP and WM, and higher disability for BP, WM, cortex, and thalamus. CONCLUSIONS: Constructing age- and gender-related brain volume maps enabled identifying PPMS patients at a higher risk of brain volume loss. Monitoring these high-risk patients may lead to better treatment decisions and improve patient outcomes.

Clinical and demographic characteristics of late-onset multiple sclerosis: LOMS-TR study.

OBJECTIVES: Multiple sclerosis (MS), which is known as a young-adult age disease, is called late-onset MS (LOMS) when it occurs at the age of 50 and older. In our study, we aimed to analyse the clinical and demographic characteristics, comorbidities, diagnostic and treatment challenges and prognosis of LOMS. METHODS: In a retrospective analysis of 136 patients diagnosed with multiple sclerosis (MS) after the age of 50, based on the 2017 McDonald criteria, and who were under observation in eight distinct MS centers across Turkey; demographic information, clinical characteristics of the disease, oligoclonal band (OCB) status, initial and current Expanded Disability Status Scale (EDSS) values, administered treatments, and the existence of spinal lesions on magnetic resonance imaging (MRI) were investigated. RESULTS: The mean age of the 136 patients was 60.96±6.42 years (51-79), the mean age at diagnosis was 54.94±4.30 years, and 89 (65.4 %) of the patients were female. Most of the cases, 61.1 % (83) had at least one comorbidity. In 97 patients who underwent lumbar puncture (LP), OCB positivity was observed in 63.6 %. In 114 patients (83.8 %), spinal lesions were detected on MRI. Eighty-seven patients had relapsing-remitting MS (RRMS) (64 %), 27 patients had secondary progressive MS (SPMS) (19.9 %), and 22 patients had primary progressive MS (PPMS) (16.2 %). The mean EDSS at the time of diagnosis was 2.44±1.46, and the mean current EDSS was 3.15±2.14. CONCLUSIONS: In LOMS patients, the rates of delay in the diagnostic process, treatment disruption and progressive disease are higher than in the general MS population. The high rates of LP applying and OCB positivity of this study may indicate the habit of looking for clear evidences in advanged age in our country. This situation and comorbidities may cause a delay in diagnosis and eliminates the window of opportunity for early diagnosis. Although the high number of spinal lesions is a known marker for progressive disease, it is an issue that needs to be discussed whether the increased frequency of progressive course at older ages is due to the nature of the disease or immune aging itself.

Time is myelin: early cortical myelin repair prevents atrophy and clinical progression in multiple sclerosis.

Cortical myelin loss and repair in multiple sclerosis (MS) have been explored in neuropathological studies, but the impact of these processes on neurodegeneration and the irreversible clinical progression of the disease remains unknown. Here, we evaluated in vivo cortical demyelination and remyelination in a large cohort of people with all clinical phenotypes of MS followed up for 5 years using magnetization transfer imaging (MTI), a technique that has been shown to be sensitive to myelin content changes in the cortex. We investigated 140 people with MS (37 clinically isolated syndrome, 71 relapsing-MS, 32 progressive-MS), who were clinically assessed at baseline and after 5 years and, along with 84 healthy controls, underwent a 3 T-MRI protocol including MTI at baseline and after 1 year. Changes in cortical volume over the radiological follow-up were computed with a Jacobian integration method. Magnetization transfer ratio was employed to calculate for each patient an index of cortical demyelination at baseline and of dynamic cortical demyelination and remyelination over the follow-up period. The three indices of cortical myelin content change were heterogeneous across patients but did not significantly differ across clinical phenotypes or treatment groups. Cortical remyelination, which tended to fail in the regions closer to CSF (-11%, P < 0.001), was extensive in half of the cohort and occurred independently of age, disease duration and clinical phenotype. Higher indices of cortical dynamic demyelination (ß = 0.23, P = 0.024) and lower indices of cortical remyelination (ß = -0.18, P = 0.03) were significantly associated with greater cortical atrophy after 1 year, independently of age and MS phenotype. While the extent of cortical demyelination predicted a higher probability of clinical progression after 5 years in the entire cohort [odds ratio (OR) = 1.2; P = 0.043], the impact of cortical remyelination in reducing the risk of accumulating clinical disability after 5 years was significant only in the subgroup of patients with shorter disease duration and limited extent of demyelination in cortical regions (OR = 0.86, P = 0.015, area under the curve = 0.93). In this subgroup, a 30% increase in cortical remyelination nearly halved the risk of clinical progression at 5 years, independently of clinical relapses. Overall, our results highlight the critical role of cortical myelin dynamics in the cascade of events leading to neurodegeneration and to the subsequent accumulation of irreversible disability in MS. Our findings suggest that early-stage myelin repair compensating for cortical myelin loss has the potential to prevent neuro-axonal loss and its long-term irreversible clinical consequences in people with MS.

The glymphatic system as a potential biomarker and therapeutic target in secondary progressive multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a refractory immune-mediated inflammatory disease of the central nervous system, and some cases of the major subtype, relapsing-remitting (RR), transition to secondary progressive (SP). However, the detailed pathogenesis, biomarkers, and effective treatment strategies for secondary progressive multiple sclerosis have not been established. The glymphatic system, which is responsible for waste clearance in the brain, is an intriguing avenue for investigation and is primarily studied through diffusion tensor image analysis along the perivascular space (DTI-ALPS). This study aimed to compare DTI-ALPS indices between patients with RRMS and SPMS to uncover potential differences in their pathologies and evaluate the utility of the glymphatic system as a possible biomarker. METHODS: A cohort of 26 patients with MS (13 RRMS and 13 SPMS) who met specific criteria were enrolled in this prospective study. Magnetic resonance imaging (MRI), including diffusion MRI, 3D T1-weighted imaging, and relaxation time quantification, was conducted. The ALPS index, a measure of glymphatic function, was calculated using diffusion-weighted imaging data. Demographic variables, MRI metrics, and ALPS indices were compared between patients with RRMS and those with SPMS. RESULTS: The ALPS index was significantly lower in the SPMS group. Patients with SPMS exhibited longer disease duration and higher Expanded Disability Status Scale (EDSS) scores than those with RRMS. Despite these differences, the correlations between the EDSS score, disease duration, and ALPS index were minimal, suggesting that the impact of these clinical variables on ALPS index variations was negligible. DISCUSSION: Our study revealed the potential microstructural and functional differences between RRMS and SPMS related to glymphatic system impairment. Although disease severity and duration vary among subtypes, their influence on ALPS index differences appears to be limited. This highlights the stronger association between SP conversion and changes in the ALPS index. These findings align with those of previous research, indicating the involvement of the glymphatic system in the progression of MS. CONCLUSION: Although the causality remains uncertain, our study suggests that a reduced ALPS index, reflecting glymphatic system dysfunction, may contribute to MS progression, particularly in SPMS. This suggests the potential of the ALPS index as a diagnostic biomarker for SPMS and underscores the potential of the glymphatic system as a therapeutic target to mitigate MS progression. Future studies with larger cohorts and pathological validation are necessary to confirm these findings. This study provides new insights into the pathogenesis of SPMS and the potential for innovative therapeutic strategies.

Association of Spinal Cord Atrophy and Brain Paramagnetic Rim Lesions With Progression Independent of Relapse Activity in People With MS.

BACKGROUND AND OBJECTIVES: Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA. METHODS: From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses. RESULTS: In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; p = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; p = 0.005). Increased spinal cord atrophy (MD-APC -1.39; p = 0.0008) and PRL burden (IRR 1.95; p = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all p ≤ 0.002). DISCUSSION: Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.

Serum macrophage migration inhibitory factor levels predict brain atrophy in people with primary progressive multiple sclerosis.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a cytokine linked to multiple sclerosis (MS) progression that is thought to be inhibited by ibudilast. SPRINT-MS was a phase 2 placebo-controlled trial of ibudilast in progressive multiple sclerosis (PMS). OBJECTIVE: To determine whether baseline MIF levels predict imaging outcomes and assess the effects of ibudilast on serum and cerebrospinal fluid (CSF) MIF levels in people with PMS treated with ibudilast. METHODS: Participants in the SPRINT-MS trial were treated with either ibudilast or placebo and underwent brain magnetic resonance imaging (MRI) every 24 weeks over a duration of 96 weeks. MIF was measured in serum and CSF. RESULTS: MIF levels were compared with imaging outcomes in 223 participants from the SPRINT-MS study. In the primary progressive multiple sclerosis (PPMS) cohort, males had higher serum (p < 0.001) and CSF (p = 0.01) MIF levels, as compared with females. Higher baseline serum MIF levels in PPMS were associated with faster brain atrophy (beta = -0.113%, 95% confidence interval (CI): -0.204% to -0.021%; p = 0.016). These findings were not observed in secondary progressive multiple sclerosis (SPMS). Ibudilast did not affect either serum or CSF MIF levels. CONCLUSIONS: Serum MIF levels were associated with male sex and predicted brain atrophy in PPMS, but not SPMS. Ibudilast did not demonstrate an effect on MIF levels, as compared with placebo, although we cannot exclude a functional effect.

The effect of ibudilast on thalamic volume in progressive multiple sclerosis.

BACKGROUND: Thalamic volume loss is known to be associated with clinical and cognitive disability in progressive multiple sclerosis (PMS). OBJECTIVE: To investigate the treatment effect of ibudilast on thalamic atrophy more than 96 weeks in the phase 2 trial in progressive(MS Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS]). METHODS: A total of 231 participants were randomized to either ibudilast (n = 114) or placebo (n = 117). Thalamic volume change was computed using Bayesian Sequence Adaptive Multimodal Segmentation tool (SAMseg) incorporating T1, fluid-attenuated inversion recovery (FLAIR), and fractional anisotropy maps and analyzed with a mixed-effects repeated-measures model. RESULTS: There was no significant difference in thalamic volumes between treatment groups. On exploratory analysis, participants with primary progressive multiple sclerosis (PPMS) on placebo had a 0.004% greater rate of thalamic atrophy than PPMS participants on ibudilast (p = 0.058, 95% confidence interval (CI) = -0.008 to <0.001). Greater reductions in thalamic volumes at more than 96 weeks were associated with worsening multiple sclerosis functional composite (MSFC-4) scores (p = 0.002) and worsening performance on the symbol digit modality test (SDMT) (p < 0.001). CONCLUSION: In a phase 2 trial evaluating ibudilast in PMS, no treatment effect was demonstrated in preventing thalamic atrophy. Participants with PPMS exhibited a treatment effect that trended toward significance. Longitudinal changes in thalamic volume were related to worsening of physical and cognitive disability, highlighting this outcome's clinical importance.

Association of MRI leptomeningeal enhancement with disability worsening in progressive multiple sclerosis: A clinical and post-mortem study.

BACKGROUND: Leptomeningeal enhancement (LME) has been described as a biomarker of meningeal inflammation in multiple sclerosis (MS). OBJECTIVE: The aim of this study was to (1) assess if LME is predictive of disability worsening in progressive MS (pMS) patients and (2) investigate the pathological substrates of LME in an independent post-mortem MS series. METHODS: In total, 115 pMS patients were imaged yearly with 1.5T MRI, using post-contrast CUBE 3D FLAIR for LME detection. Endpoint: to identify the baseline variables predictive of confirmed disability worsening (CDW) at 24 months follow-up. Post-mortem, inflammation, and structural changes of the leptomeninges were assessed in 12 MS/8 control brains. RESULTS: LME (27% of patients at baseline) was associated with higher EDSS and lower brain volume (nBV). LME was unchanged in most patients over follow-up. LME at baseline MRI was independently associated with higher risk of 24 months CDW (HR 3.05, 95% CI 1.36-6.84, p = 0.007) in a Cox regression, including age, nBV, T2 lesion volume, high-efficacy treatments, and MRI disease activity. Post-mortem, focal structural changes (fibrosis) of the leptomeninges were observed in MS, usually associated with inflammation (Kendall's Tau 0.315, p < 0.0001). CONCLUSIONS: LME is frequently detected in pMS patients using 1.5T MRI and is independently predictive of disability progression. LME could result from both focal leptomeningeal post-inflammatory fibrosis and inflammation.

Inner Retinal Layer Changes Reflect Changes in Ambulation Score in Patients with Primary Progressive Multiple Sclerosis.

The establishment of surrogate markers to detect disability progression in persons with multiple sclerosis (PwMS) is important to improve monitoring of clinical deterioration. Optical coherence tomography (OCT) could be such a tool. However, sufficient longitudinal data of retinal neuroaxonal degeneration as a marker of disease progression exist only for PwMS with a relapsing-remitting course (RRMS) so far. In contrast, longitudinal data of retinal layers in patients with primary-progressive MS (PPMS) are inconsistent, and the association of OCT parameters with ambulatory performance in PwMS has rarely been investigated. We aimed to investigate the relative annual rates of change in retinal layers in PwMS (RRMS and PPMS) compared with healthy controls (HC) using OCT and to evaluate their association with ambulatoryfunctionalscore (AS) worsening in PPMS. A retrospective analysis of a longitudinal OCT dataset of the retinal layers of PwMS and HC from two MS centers in Germany was performed. Walking ability was measured over a standardized distance of 500 m, and changes during the observation period were categorized using the AS and the expanded disability status scale (EDSS). 61 HC with 121 eyes and 119 PwMS (PPMS: 57 patients with 108 eyes; RRMS: 62 patients with 114 eyes) were included. The median follow-up time for PwMS was 3 years. The relative annual change of pRNFL (peripapillary retinal nerve fiber layer) and INL (inner nuclear layer) was significantly different in PwMS compared with HC. RRMS and PPMS subgroups did not differ in the annual atrophy rates. In patients with PPMS, worsening of the AS was significantly associated with increased thinning of the TMV (total macular volume), GCIP (ganglion cell and inner plexiform layer), and ONPL (outer nuclear and outer plexiform layer) (all p-value < 0.05, r > 0.30). For every -0.1% decrease in the TMV, GCIP, and ONPL, the risk of a deterioration in the AS increased by 31% (hazard ratio (HR): 1.309), 11% (HR: 1.112), and 16% (HR: 1.161), respectively. In addition, worsening EDSS in PPMS was significantly associated with the relative annual atrophy rates of pRNFL, TMV, and GCIP (all p-value < 0.05). Disability progression in PPMS can be measured using OCT, and increasing annual atrophy rates of the inner retinal layers are associated with worsening ambulation. OCT is a robust and side-effect-free imaging tool, making it suitable for routine monitoring of PwMS.

Effect of ibudilast on thalamic magnetization transfer ratio and volume in progressive multiple sclerosis.

BACKGROUND: Thalamic volume (TV) is a sensitive biomarker of disease burden of injury in multiple sclerosis (MS) and appears to reflect overall lesion loads. Ibudilast showed significant treatment effect on brain atrophy and magnetization transfer ratio (MTR) of normal-appearing brain tissue but not in new/enlarging T2 lesion in the SPRINT-MS randomized clinical trial. OBJECTIVE: To evaluate the effect of ibudilast on thalamic tissue integrity and volume in the SPRINT-MS. METHODS: A total of 255 participants with progressive MS were randomized to oral ibudilast or placebo, and thalamic MTR and normalized TV over 96 weeks were quantified. Mixed-effect modeling assessed treatment effects on the thalamic MTR and TV, separately. Similarly, the measures were compared between the participants with confirmed disability progression (CDP). RESULTS: Ibudilast's treatment effect was observed compared to placebo for thalamic MTR (p = 0.03) but not for TV (p = 0.68) while TV correlated with T2 lesion volume (p < 0.001). CDP associated with thalamic MTR (p = 0.04) but not with TV (p = 0.7). CONCLUSION: Ibudilast showed an effect on thalamic MTR, which was associated with CDP, suggesting a clinically relevant effect on thalamic tissue integrity. However, the treatment effect was not observed in TV, suggesting that thalamic atrophy is more closely associated with global inflammatory activity than local tissue integrity. CLINICALTRIALS.GOV: NCT01982942.

Thalamic asymmetry in Multiple Sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a chronic neuroinflammatory disease that affects the central nervous system. Asymmetry is one of the finding in brain MRI of these patients, which is related to the debilitating symptoms of the disease. This study aimed to investigate and compare the thalamic asymmetry in MS patients and its relationship with other MRI and clinical findings of these patients. METHODS: This cross-sectional study conducted on 83 patients with relapse-remitting MS (RRMS), 43 patients with secondary progressive MS (SPMS), and 89 healthy controls. The volumes of total intracranial, total gray matter, total white matter, lesions, thalamus, and also the thalamic asymmetry indices were calculated. The 9-hole peg test (9-HPT) and Expanded Disability Status Scale (EDSS) were assessed as clinical findings. RESULTS: We showed that the normalized whole thalamic volume in healthy subjects was higher than MS patients (both RRMS and SPMS). Thalamic asymmetry index (TAI) was significantly different between RRMS patients and SPMS patients (p = 0.011). The absolute value of TAI was significantly lower in healthy subjects than in RRMS (p < 0.001) and SPMS patients (p < 0.001), and SPMS patients had a higher absolute TAI compared to RRMS patients (p = 0.037). CONCLUSIONS: In this cross-sectional study we showed a relationship between normalized whole thalamic volume and MS subtype. Also, we showed that the asymmetric indices of the thalamus can be related to the progression of the disease. Eventually, we showed that thalamic asymmetry can be related to the disease progression and subtype changes in MS.

Visual function resists early neurodegeneration in the visual system in primary progressive multiple sclerosis.

BACKGROUND: Neurodegeneration in multiple sclerosis (MS) affects the visual system but dynamics and pathomechanisms over several years especially in primary progressive MS (PPMS) are not fully understood. METHODS: We assessed longitudinal changes in visual function, retinal neurodegeneration using optical coherence tomography, MRI and serum NfL (sNfL) levels in a prospective PPMS cohort and matched healthy controls. We investigated the changes over time, correlations between outcomes and with loss of visual function. RESULTS: We followed 81 patients with PPMS (mean disease duration 5.9 years) over 2.7 years on average. Retinal nerve fibre layer thickness (RNFL) was reduced in comparison with controls (90.1 vs 97.8 µm; p<0.001). Visual function quantified by the area under the log contrast sensitivity function (AULCSF) remained stable over a continuous loss of RNFL (0.46 µm/year, 95% CI 0.10 to 0.82; p=0.015) up until a mean turning point of 91 µm from which the AULCSF deteriorated. Intereye RNFL asymmetry above 6 µm, suggestive of subclinical optic neuritis, occurred in 15 patients and was related to lower AULCSF but occurred also in 5 out of 44 controls. Patients with an AULCSF progression had a faster increase in Expanded Disability Status Scale (beta=0.17/year, p=0.043). sNfL levels were elevated in patients (12.2 pg/mL vs 8.0 pg/mL, p<0.001), but remained stable during follow-up (beta=-0.14 pg/mL/year, p=0.291) and were not associated with other outcomes. CONCLUSION: Whereas neurodegeneration in the anterior visual system is already present at onset, visual function is not impaired until a certain turning point. sNfL is not correlated with structural or functional impairment in the visual system.

Assessing the utility of magnetic resonance imaging-based "SuStaIn" disease subtyping for precision medicine in relapsing-remitting and secondary progressive multiple sclerosis.

BACKGROUND: Patient stratification and individualized treatment decisions based on multiple sclerosis (MS) clinical phenotypes are arbitrary. Subtype and Staging Inference (SuStaIn), a published machine learning algorithm, was developed to identify data-driven disease subtypes with distinct temporal progression patterns using brain magnetic resonance imaging; its clinical utility has not been assessed. The objective of this study was to explore the prognostic capability of SuStaIn subtyping and whether it is a useful personalized predictor of treatment effects of natalizumab and dimethyl fumarate. METHODS: Subtypes were available from the trained SuStaIn model for 3 phase 3 clinical trials in relapsing-remitting and secondary progressive MS. Regression models were used to determine whether baseline SuStaIn subtypes could predict on-study clinical and radiological disease activity and progression. Differences in treatment responses relative to placebo between subtypes were determined using interaction terms between treatment and subtype. RESULTS: Natalizumab and dimethyl fumarate reduced inflammatory disease activity in all SuStaIn subtypes (all p < 0.001). SuStaIn MS subtyping alone did not discriminate responder heterogeneity based on new lesion formation and disease progression (p > 0.05 across subtypes). CONCLUSION: SuStaIn subtypes correlated with disease severity and functional impairment at baseline but were not predictive of disability progression and could not discriminate treatment response heterogeneity.

Multimodal diagnostics in multiple sclerosis: predicting disability and conversion from relapsing-remitting to secondary progressive disease course - protocol for systematic review and meta-analysis.

BACKGROUND: The number of patients diagnosed with multiple sclerosis (MS) has increased significantly over the last decade. The challenge is to identify the transition from relapsing-remitting to secondary progressive MS. Since available methods to examine patients with MS are limited, both the diagnostics and prognostication of disease progression would benefit from the multimodal approach. The latter combines the evidence obtained from disparate radiologic modalities, neurophysiological evaluation, cognitive assessment and molecular diagnostics. In this systematic review we will analyse the advantages of multimodal studies in predicting the risk of conversion to secondary progressive MS. METHODS AND ANALYSIS: We will use peer-reviewed publications available in Web of Science, Medline/PubMed, Scopus, Embase and CINAHL databases. In vivo studies reporting the predictive value of diagnostic methods will be considered. Selected publications will be processed through Covidence software for automatic deduplication and blind screening. Two reviewers will use a predefined template to extract the data from eligible studies. We will analyse the performance metrics (1) for the classification models reflecting the risk of secondary progression: sensitivity, specificity, accuracy, area under the receiver operating characteristic curve, positive and negative predictive values; (2) for the regression models forecasting disability scores: the ratio of mean absolute error to the range of values. Then, we will create ranking charts representing performance of the algorithms for calculating disability level and MS progression. Finally, we will compare the predictive power of radiological and radiomical correlates of clinical disability and cognitive impairment in patients with MS. ETHICS AND DISSEMINATION: The study does not require ethical approval because we will analyse publicly available literature. The project results will be published in a peer-review journal and presented at scientific conferences. PROSPERO REGISTRATION NUMBER: CRD42022354179.

Effects of Ibudilast on Retinal Atrophy in Progressive Multiple Sclerosis Subtypes: Post Hoc Analyses of the SPRINT-MS Trial.

BACKGROUND AND OBJECTIVES: Ganglion cell + inner plexiform layer (GCIPL) thinning, measured by optical coherence tomography (OCT), reflects global neurodegeneration in multiple sclerosis (MS). Atrophy of the inner (INL) and outer nuclear layer (ONL) may also be prominent in progressive MS (PMS). The phase 2, SPRINT-MS trial found reduced brain atrophy with ibudilast therapy in PMS. In this post hoc analysis of the SPRINT-MS trial, we investigate (1) retinal atrophy (2) differences in response by subtype and (3) associations between OCT and MRI measures of neurodegeneration. METHODS: In the multicenter, double-blind SPRINT-MS trial, participants with secondary progressive MS (SPMS) or primary progressive MS (PPMS) were randomized to ibudilast or placebo. OCT and MRI data were collected every 24 weeks for 96 weeks. Extensive OCT quality control and algorithmic segmentation produced consistent results across Cirrus HD-OCT and Spectralis devices. Primary endpoints were GCIPL, INL, and ONL atrophy, assessed by linear mixed-effects regression. Secondary endpoints were associations of OCT measures, brain parenchymal fraction, and cortical thickness, assessed by partial Pearson correlations. RESULTS: One hundred thirty-four PPMS and 121 SPMS participants were included. GCIPL atrophy was 79% slower in the ibudilast (-0.07 ± 0.23 µm/y) vs placebo group (-0.32 ± 0.20 µm/y, p = 0.003). This effect predominated in the PPMS cohort (ibudilast: -0.08 ± 0.29 µm/y vs placebo: -0.60 ± 0.29 µm/y, a decrease of 87%, p < 0.001) and was not detected in the SPMS cohort (ibudilast: -0.21 ± 0.28 µm/y vs placebo: -0.14 ± 0.27 µm/y, p = 0.55). GCIPL, INL, and ONL atrophy rates correlated with whole brain atrophy rates across the cohort (r = 0.27, r = 0.26, and r = 0.20, respectively; p < 0.001). Power calculations from these data show future trials of similar size and design have ≥80% power to detect GCIPL atrophy effect sizes of approximately 40%. DISCUSSION: Ibudilast treatment decreased GCIPL atrophy in PMS, driven by the PPMS cohort, with no effect seen in SPMS. Modulated atrophy of retinal layers may be detectable in sample sizes smaller than the SPRINT-MS trial and correlate with whole brain atrophy in PMS, further highlighting their utility as outcomes in PMS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that ibudilast reduces composite ganglion cell + inner plexiform layer atrophy, without reduction of inner or outer nuclear layer atrophy, in patients with primary progressive MS but not those with secondary progressive MS.

Glial fibrillary acidic protein and multiple sclerosis progression independent of acute inflammation.

BACKGROUND: The clinical relevance of serum glial fibrillary acidic protein (sGFAP) concentration as a biomarker of MS disability progression independent of acute inflammation has yet to be quantified. OBJECTIVE: To test whether baseline values and longitudinal changes in sGFAP concentration are associated with disability progression without detectable relapse of magnetic resonance imaging (MRI) inflammatory activity in participants with secondary-progressive multiple sclerosis (SPMS). METHODS: We retrospectively analyzed longitudinal sGFAP concentration and clinical outcome data from the Phase 3 ASCEND trial of participants with SPMS, with no detectable relapse or MRI signs of inflammatory activity at baseline nor during the study (n = 264). Serum neurofilament (sNfL), sGFAP, T2 lesion volume, Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), and composite confirmed disability progression (CDP) were measured. Linear and logistic regressions and generalized estimating equations were used in the prognostic and dynamic analyses. RESULTS: We found a significant cross-sectional association between baseline sGFAP and sNfL concentrations and T2 lesion volume. No or weak correlations between sGFAP concentration and changes in EDSS, T25FW, and 9HPT, or CDP were observed. CONCLUSION: Without inflammatory activity, changes in sGFAP concentration in participants with SPMS were neither associated with current nor predictive of future disability progression.

Cardiovascular risk factors in secondary progressive multiple sclerosis: A cross-sectional analysis from the MS-STAT2 randomized controlled trial.

BACKGROUND AND PURPOSE: There is increasing evidence that cardiovascular risk (CVR) contributes to disability progression in multiple sclerosis (MS). CVR is particularly prevalent in secondary progressive MS (SPMS) and can be quantified through validated composite CVR scores. The aim was to examine the cross-sectional relationships between excess modifiable CVR, whole and regional brain atrophy on magnetic resonance imaging, and disability in patients with SPMS. METHODS: Participants had SPMS, and data were collected at enrolment into the MS-STAT2 trial. Composite CVR scores were calculated using the QRISK3 software. Prematurely achieved CVR due to modifiable risk factors was expressed as QRISK3 premature CVR, derived through reference to the normative QRISK3 dataset and expressed in years. Associations were determined with multiple linear regressions. RESULTS: For the 218 participants, mean age was 54 years and median Expanded Disability Status Scale was 6.0. Each additional year of prematurely achieved CVR was associated with a 2.7 mL (beta coefficient; 95% confidence interval 0.8-4.7; p = 0.006) smaller normalized whole brain volume. The strongest relationship was seen for the cortical grey matter (beta coefficient 1.6 mL per year; 95% confidence interval 0.5-2.7; p = 0.003), and associations were also found with poorer verbal working memory performance. Body mass index demonstrated the strongest relationships with normalized brain volumes, whilst serum lipid ratios demonstrated strong relationships with verbal and visuospatial working memory performance. CONCLUSIONS: Prematurely achieved CVR is associated with lower normalized brain volumes in SPMS. Future longitudinal analyses of this clinical trial dataset will be important to determine whether CVR predicts future disease worsening.