Determinants and Biomarkers of Progression Independent of Relapses in Multiple Sclerosis.

Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving "chronic" worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion-independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024;96:1-20.

The contribution of tumor necrosis factor to multiple sclerosis: a possible role in progression independent of relapse?

Tumor necrosis factor (TNF) is a pleiotropic cytokine regulating many physiological and pathological immune-mediated processes. Specifically, it has been recognized as an essential pro-inflammatory cytokine implicated in multiple sclerosis (MS) pathogenesis and progression. MS is a chronic immune-mediated disease of the central nervous system, characterized by multifocal acute and chronic inflammatory demyelination in white and grey matter, along with neuroaxonal loss. A recent concept in the field of MS research is disability resulting from Progression Independent of Relapse Activity (PIRA). PIRA recognizes that disability accumulation since the early phase of the disease can occur independently of relapse activity overcoming the traditional dualistic view of MS as either a relapsing-inflammatory or a progressive-neurodegenerative disease. Several studies have demonstrated an upregulation in TNF expression in both acute and chronic active MS brain lesions. Additionally, elevated TNF levels have been observed in the serum and cerebrospinal fluid of MS patients. TNF appears to play a significant role in maintaining chronic intrathecal inflammation, promoting axonal damage neurodegeneration, and consequently contributing to disease progression and disability accumulation. In summary, this review highlights the current understanding of TNF and its receptors in MS progression, specifically focusing on the relatively unexplored PIRA condition. Further research in this area holds promise for potential therapeutic interventions targeting TNF to mitigate disability in MS patients.

The neural substrates of social cognition deficits in newly diagnosed multiple sclerosis patients.

OBJECTIVE: Cognitive and affective symptoms in multiple sclerosis (MS) can be independently impaired and have different pathways of progression. Cognitive alterations have been described since the earliest MS stages; by contrast, the social cognition (SC) domain has never been investigated in the first year from MS diagnosis. We aimed to evaluate SC and unravel its neural bases in newly diagnosed MS patients. METHODS: Seventy MS patients underwent at diagnosis a 3 T-MRI and a neuropsychological/SC assessment (median time between diagnosis and MRI/cognitive evaluation = 0 months). We tested two matched reference samples: 31 relapsing-remitting MS patients with longer course (mean ± SD disease duration = 7.0 ± 4.5 years) and 38 healthy controls (HCs). Cortical thicknesses (CTh) and volumes of brain regions were calculated. RESULTS: Newly diagnosed MS patients performed significantly lower than HCs in facial emotion recognition (global: p < 0.001; happiness: p = 0.041, anger: p = 0.007; fear: p < 0.001; disgust: p = 0.004) and theory of mind (p = 0.005), while no difference was found between newly diagnosed and longer MS patients. Compared to lower performers, higher performers in facial emotion recognition showed greater volume of amygdala (p = 0.032) and caudate (p = 0.036); higher performers in theory of mind showed greater CTh in lingual gyrus (p = 0.006), cuneus (p = 0.024), isthmus cingulate (p = 0.038), greater volumes of putamen (p = 0.016), pallidum (p = 0.029), and amygdala (p = 0.032); patients with higher empathy showed lower cuneus CTh (p = 0.042) and putamen volume (p = 0.007). INTERPRETATIONS: SC deficits are present in MS patients since the time of diagnosis and remain persistent along the disease course. Specific basal, limbic, and occipital areas play a significant role in the pathogenesis of these alterations.

Choroid plexus volume in multiple sclerosis can be estimated on structural MRI avoiding contrast injection.

We compared choroid plexus (ChP) manual segmentation on non-contrast-enhanced (non-CE) sequences and reference standard CE T1- weighted (T1w) sequences in 61 multiple sclerosis patients prospectively included. ChP was separately segmented on T1w, T2-weighted (T2w) fluid-attenuated inversion-recovery (FLAIR), and CE-T1w sequences. Inter-rater variability assessed on 10 subjects showed high reproducibility between sequences measured by intraclass correlation coefficient (T1w 0.93, FLAIR 0.93, CE-T1w 0.99). CE-T1w showed higher signal-to-noise ratio and contrast-to-noise ratio (CE-T1w 23.77 and 18.49, T1w 13.73 and 7.44, FLAIR 13.09 and 10.77, respectively). Manual segmentation of ChP resulted 3.073 ± 0.563 mL (mean ± standard deviation) on T1w, 3.787 ± 0.679 mL on FLAIR, and 2.984 ± 0.506 mL on CE-T1w images, with an error of 28.02 ± 19.02% for FLAIR and 3.52 ± 12.61% for T1w. FLAIR overestimated ChP volume compared to CE-T1w (p < 0.001). The Dice similarity coefficient of CE-T1w versus T1w and FLAIR was 0.67 ± 0.05 and 0.68 ± 0.05, respectively. Spatial error distribution per slice was calculated after nonlinear coregistration to the standard MNI152 space and showed a heterogeneous profile along the ChP especially near the fornix and the hippocampus. Quantitative analyses suggest T1w as a surrogate of CE-T1w to estimate ChP volume.Relevance statement To estimate the ChP volume, CE-T1w can be replaced by non-CE T1w sequences because the error is acceptable, while FLAIR overestimates the ChP volume. This encourages the development of automatic tools for ChP segmentation, also improving the understanding of the role of the ChP volume in multiple sclerosis, promoting longitudinal studies.Key points • CE-T1w sequences are considered the reference standard for ChP manual segmentation.• FLAIR sequences showed a higher CNR than T1w sequences but overestimated the ChP volume.• Non-CE T1w sequences can be a surrogate of CE-T1w sequences for manual segmentation of ChP.

Ocrelizumab reduces cortical and deep grey matter loss compared to the S1P-receptor modulator in multiple sclerosis.

INTRODUCTION: Ocrelizumab (OCR) and Fingolimod (FGL) are two high-efficacy treatments in multiple sclerosis which, besides their strong anti-inflammatory activity, may limit neurodegeneration. AIM: To compare the effect of OCR and FGL on clinical and MRI endpoints. METHODS: 95 relapsing-remitting patients (57 OCR, 38 FGL) clinically followed for 36 months underwent a 3-Tesla MRI at baseline and after 24 months. The annualized relapse rate, EDSS, new cortical/white matter lesions and regional cortical and deep grey matter volume loss were evaluated. RESULTS: OCR reduced the relapse rate from 0.48 to 0.04, FGL from 0.32 to 0.05 (both p < 0.001). Compared to FGL, OCR-group experienced fewer new white matter lesions (12% vs 32%, p = 0.005), no differences in new cortical lesions, lower deep grey matter volume loss (- 0.12% vs - 0.66%; p = 0.002, Cohen's d = 0.54), lower global cortical thickness change (- 0.45% vs - 0.70%; p = 0.036; d = 0.42) and reduced cortical thinning/volume loss in several regions of interests, including those of parietal gyrus (d-range = 0.65-0.71), frontal gyrus (d-range = 0.47-0.60), cingulate (d-range = 0.41-0.72), insula (d = 0.36), cerebellum (cortex d = 0.72, white matter d = 0.44), putamen (d = 0.35) and thalamus (d = 0.31). The effect on some regional thickness changes was confirmed in patients without focal lesions. CONCLUSIONS: When compared with FGL, patients receiving OCR showed greater suppression of focal MRI lesions accumulation and lower cortical and deep grey matter volume loss.

CSF levels of Chitinase3like1 correlate with early response to cladribine in multiple sclerosis.

Background: Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed. Aim: To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine. Methods: Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs. Results: Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91). Conclusions: CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation.

Association of Levels of CSF Osteopontin With Cortical Atrophy and Disability in Early Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: To evaluate CSF inflammatory markers with accumulation of cortical damage as well as disease activity in patients with early relapsing-remitting MS (RRMS). METHODS: CSF levels of osteopontin (OPN) and 66 inflammatory markers were assessed using an immune-assay multiplex technique in 107 patients with RRMS (82 F/25 M, mean age 35.7 ± 11.8 years). All patients underwent regular clinical assessment and yearly 3T MRI scans for 2 years while 39 patients had a 4-year follow-up. White matter lesion number and volume, cortical lesions (CLs) and volume, and global cortical thickness (CTh) were evaluated together with the 'no evidence of disease activity' (NEDA-3) status, defined by no relapses, no disability worsening, and no MRI activity, including CLs. RESULTS: The random forest algorithm selected OPN, CXCL13, TWEAK, TNF, IL19, sCD30, sTNFR1, IL35, IL16, and sCD163 as significantly associated with changes in global CTh. OPN and CXCL13 were most related to accumulation of atrophy after 2 and 4 years. In a multivariate linear regression model on CSF markers, OPN (p < 0.001), CXCL13 (p = 0.001), and sTNFR1 (p = 0.024) were increased in those patients with accumulating atrophy (adjusted R-squared 0.615). The 10 markers were added in a model that included all clinical, demographic, and MRI variables: OPN (p = 0.002) and IL19 (p = 0.022) levels were confirmed to be significantly increased in patients developing more CTh change over the follow-up (adjusted R-squared 0.619). CXCL13 and OPN also revealed the best association with NEDA-3 after 2 years, with OPN significantly linked to disability accumulation (OR 2.468 [1.46-5.034], p = 0.004) at the multivariate logistic regression model. DISCUSSION: These data confirm and expand our knowledge on the prognostic role of the CSF inflammatory profile in predicting changes in cortical pathology and disease activity in early MS. The data emphasize a crucial role of OPN.